CD4-targeted il-15 molecules and methods of use

Abstract

Provided are CD4-targeted IL- 15 variant molecules and methods for use.

Description

CD4-TARGETED IL-15 MOLECULES AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 710,400, filed on October 22, 2024, and U.S. Provisional Application No.63 / 802,281, filed on May 8, 2025, which are hereby incorporated herein by reference in their entireties for all purposes.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on October 18, 2024, is named 1553-US-PSP_SL.xml and is 1,312,829 bytes in size.BACKGROUND

[0003] Human immunodeficiency virus (HIV) is the causative agent of the lifethreatening illness, autoimmune deficiency syndrome (AIDS). Antiretroviral therapy (ART) can suppress viral replication and extend life, but it is unable to eliminate the HIV reservoir that persists within latently infected cells. This reservoir can exist in a quiescent state that makes it refractory to clearance by natural immunity. Latent HIV can persist for decades despite treatment, rapidly reseeding infection if treatment is interrupted. Lifelong therapy is associated with multiple comorbidities such as cardiovascular disease, diabetes and cancer. It is also associated with challenges related to tolerability, drug-drug interactions, resistance and adherence.

[0004] Many drugs that have been developed to treat other diseases have been tested as strategies for activating HIV expression. While many of these are effective in vitro, the doses that can be achieved in vivo are significantly limited by poor tolerability of these molecules (Siliciano etal., J Infect Dis (2021) 223(12 Suppl 2): 13-21). Several common gamma chain (IL-2RY; IL2RG; CD132; NCBI Gene ID: 3561) cytokines, including IL-2 and IL-15, have been shown to activate HIV expression, but dosing of these has also been limited by poor tolerability (Chun et al., Nat Med (1999) 5:651-655; Miller et al., Nat Med (2022) 28:392-400). Mouse models indicate that the production of IFN-y by NK cells mediates the immunotoxicity induced by IL-15-based therapeutics (Guo et al., J Immunol (2015) 195:2353-2364). This tolerabilitycould potentially be improved by targeting IL-15 specifically to cells infected with HIV.However, early attempts at targeting cytokines to specific cellular markers showed limited effectiveness because the cytokines themselves have high affinity for their receptors (Tzeng et al., Proc Natl Acad Sci (2015)112:3320-3325). The potential of IL-15 as a strategy for activating HIV expression is limited by the preferential activity seen with native IL-15 on CD4+ T cells. Although the HIV reservoir exists in both naive and memory CD4+ T cells, IL- 15 primarily activates memory CD4+ T cells (Kanegane et al., Blood (1996) 88:230-235).SUMMARY

[0005] Provided is an interleukin- 15 variant (IL-15v) comprising the amino acid sequence of any one of SEQ IDNOs: 743, 750-752, 754-756, 758, 768-771, 774, 777, 779, 783-788, 790-798, 801-808, 810-813 and 1125. In some embodiments, the IL- 15v binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM. In some embodiments, the IL-15v binds to IL-2RPy with a binding equilibrium dissociation constant (KD) of at least 1 nM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM.

[0006] Also provided is a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain and (ii) an IL-15 variant (IL-15v), the fusion protein comprising the amino acid sequence of any one of SEQ IDNOs: 817, 824-826, 828-830, 832, 842-845, 848, 851, 853, 857-862, 864-872, 875-882, 884-887 and 1127. In some embodiments, the fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 1136, 1143-1145, 1147-1149, 1151, 1162-1165, 1168, 1171, 1173-1174, 1178-1183, 1185-1193 and 1196-1203 and 1205-1208. In some embodiments, the IL-15v binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM. In some embodiments, the IL-15v binds to IL-2RPy with a binding equilibrium dissociation constant (KD) of at least 1 nM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM. In some embodiments, the IL-15v induces CD4+ T cell proliferation with an EC50 of less than 5 nM, e.g., less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, e.g., wherein CD4+ T cell proliferation potency is measured bymarker of proliferation Ki-67 activation (MKI67; NCBI Gene ID: 4288). In some embodiments, the IL-15v induces CD8+ T cells and / or natural killer (NK) cell proliferation with an EC50 of greater than 100 nM, e.g., wherein CD8+ T cell and / or NK cell proliferation potency is measured by Ki-67 activation.

[0007] With respect to further embodiments of the IL-15v or the IL-15RA SUSHI-IL-15v fusion protein, some embodiments, the IL-15v is PEGylated. In some embodiments, the IL-15v or the fusion protein is fused to an immunoglobulin crystallizable fragment (Fc). In some embodiments, the IL-15v or the fusion protein comprises a transmembrane domain.

[0008] Further provided is a chimeric antigen receptor (CAR) comprising the IL-15v or the IL-15RA SUSHI-IL-15v fusion protein, as described above and herein. Also provided is a CAR-T cell transfected with a polynucleotide that encodes the IL-15v or the IL-15RA SUSHI-IL-15v fusion protein, as described above and herein. Further provided is a host cell transfected with a polynucleotide that encodes the IL-15v or the IL-15RA SUSHI-IL-15v fusion protein, as described above and herein.

[0009] Further provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 1, 2, 3, 4, 5 and 6 (1); SEQ ID NOs: 1, 7, 3, 4, 8 and 9 (2); SEQ ID NOs: 1, 10, 3, 11, 5 and 6 (3); SEQ ID NOs: 1, 10, 3, 11, 12 and 6 (4); SEQ ID NOs: 1, 10, 3, 11, 8 and 9 (5); SEQ ID NOs: 1, 13, 3, 11, 8 and 9 (6); SEQ ID NOs: 1, 14, 3, 11, 8 and 9 (7); SEQ ID NOs: 1, 15, 3, 11, 8 and 9 (8); SEQ ID NOs: 1, 16, 3, 11, 8 and 9 (9); SEQ ID NOs: 1, 15, 3, 11, 12 and 17 (10); SEQ ID NOs: 1, 16, 3, 11, 12 and 18 (11); SEQ ID NOs: 1, 1078, 3, 11, 8 and 9 (12); SEQ ID NOs: 1, 1079, 3, 11, 8 and 9 (13, 14, 17, 18 and 19); SEQ ID NOs: 1, 1080, 3, 11, 8 and 9 (15); SEQ ID NOs: 1, 1081, 3, 11, 8 and 9 (16); SEQ ID NOs: 19, 20, 21, 22, 23 and 24 (1.17); SEQ ID NOs: 25, 26, 27, 28, 29 and 30 (1.25); SEQ ID NOs: 31, 32, 33, 34, 29 and 35 (1.26); SEQ ID NOs: 25, 36, 37, 28, 29 and 38 (1.27); SEQ ID NOs: 25, 1082, 39, 28, 29 and 38 (1.28); SEQ ID NOs: 40, 41, 42, 28, 29 and 35 (1.29); SEQ ID NOs: 25, 43, 39, 28, 29 and 38 (1.30); SEQ ID NOs: 25, 44, 45, 28, 29 and 35 (1.31); SEQ ID NOs: 25, 46, 47, 28, 29 and 35 (1.32); SEQ ID NOs: 25, 48, 49, 28, 29 and 35 (1.33); SEQ ID NOs: 25, 48, 50, 28, 29 and 35 (1.34); SEQ ID NOs: 51, 52, 53, 54, 55 and 56 (1.45) or SEQ ID NOs: 51, 57, 53, 58, 55 and 56 (1.46, 1.47, 1.48). In some embodiments, the VH and VL comprise,respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 625 and 626 (1); SEQ ID NOs: 627 and 628 (2); SEQ ID NOs: 629 and 630 (3); SEQ ID NOs: 629 and 631 (4); SEQ ID NOs: 629 and 632 (5); SEQ ID NOs: 633 and 632 (6); SEQ ID NOs: 634 and 632 (7); SEQ ID NOs: 635 and 632 (8); SEQ ID NOs: 636 and 632 (9); SEQ ID NOs: 635 and 637 (10); SEQ ID NOs: 636 and 638 (11); SEQ ID NOs: 639 and 632 (12); SEQ ID NOs: 640 and 632 (13); SEQ ID NOs: 641 and 632 (14); SEQ ID NOs: 642 and 632 (15); SEQ ID NOs: 643 and 632 (16); SEQ ID NOs: 640 and 644 (17); SEQ ID NOs: 640 and 645 (18); SEQ ID NOs: 640 and 646 (19); SEQ ID NOs: 647 and 648 (1.17); SEQ ID NOs: 649 and 650 (1.25); SEQ ID NOs: 651 and 652 (1.26); SEQ ID NOs: 653 and 654 (1.27); SEQ ID NOs: 655 and 656 (1.28); SEQ ID NOs: 657 and 658 (1.29); SEQ ID NOs: 659 and 660 (1.30); SEQ ID NOs: 661 and 662 (1.31); SEQ ID NOs: 663 and 664 (1.32); SEQ ID NOs: 665 and 666 (1.33); SEQ ID NOs: 667 and 666 (1.34); SEQ ID NOs: 668 and 669 (1.45); SEQ ID NOs: 670 and 671 (1.46); SEQ ID NOs: 672 and 673 (1.47) or SEQ ID NOs: 672 and 671 (1.48).

[0010] Further provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 25, 83, 84, 85, 86 and 87 (1.1); SEQ ID NOs: 88, 89, 90, 91, 92 and 93 (1.4); SEQ ID NOs: 94, 95, 96, 97, 98 and 99 (1.5); SEQ ID NOs: 88, 100, 101, 102, 103 and 104 (2.9); SEQ ID NOs: 88, 105, 106, 107, 108 and 93 (2.10); SEQ ID NOs: 88, 109, 110, 111, 108 and 112 (2.11); SEQ ID NOs: 88, 109, 110, 111, 113 and 112 (2.11 VL N50G); SEQ ID NOs: 88, 114, 106, 107, 108 and 115 (2.12); SEQ ID NOs: 88, 114, 106, 107, 113 and 115 (2.12 VLN50G); SEQ ID NOs: 88, 116, 117, 118, 108 and 119 (2.13); SEQ ID NOs: 120, 121, 122, 102, 113 and 123 (2.14) or SEQ ID NOs: 88, 124, 122, 125, 113 and 104 (2.15). In some embodiments, the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 682 and 683 (1.1); SEQ ID NOs: 684 and 685 (1.4); SEQ ID NOs: 686 and 687 (1.5); SEQ ID NOs: 688 and 689 (2.9); SEQ ID NOs: 690 and 691 (2.10); SEQ ID NOs: 692 and 693 (2.11); SEQ ID NOs: 692 and 694 (2.11 VL N50G); SEQ ID NOs: 695 and 696 (2.12); SEQ ID NOs: 695 and 697 (2.12 VL N50G); SEQ ID NOs: 698 and 699 (2.13); SEQ ID NOs:700 and 701 (2.14) or SEQ ID NOs: 702 and 703 (2.15). In some embodiments, the antibody or antigen-binding fragment thereof is insensitive to ( / .< ., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant ID rsl 1064416 (F123L). Further provided is a means for binding to CD4 D2 that is insensitive to amino acid substitution resulting from polymorphism variant ID rsl 1064416 (F123L).

[0011] Further provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 126, 127, 128, 129, 130 and 99 (1.6); SEQ ID NOs: 126, 131, 132, 129, 133 and 99 (1.7); SEQ ID NOs: 126, 134, 135, 136, 133 and 99 (1.8); SEQ ID NOs: 126, 137, 128, 129, 138 and 99 (1.9); SEQ ID NOs: 126, 139, 128, 140, 141 and 99 (1.10); SEQ ID NOs: 142, 143, 128, 145, 141 and 99 (1.19); SEQ ID NOs: 126, 146, 147, 140, 141 and 99 (2.2) or SEQ ID NOs: 148, 149, 150, 129, 151 and 99 (2.3). In some embodiments, the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 704 and 705 (1.6); SEQ ID NOs: 706 and 707 (1.7); SEQ ID NOs: 708 and 709 (1.8); SEQ ID NOs: 710 and 711 (1.9); SEQ ID NOs: 712 and 713 (1.10); SEQ ID NOs: 714 and 715 (1.19); SEQ ID NOs: 716 and 717 (2.2) or SEQ ID NOs: 718 and 719 (2.3). In some embodiments, the antibody or antigen-binding fragment thereof is insensitive to (i.e., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L). Further provided is a means for binding to one or both of CD4 D2 and D3 that is insensitive to amino acid substitution resulting from polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

[0012] Further provided is antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 158, 159, 160, 145, 161 and 162 (1.20); SEQ ID NOs: 163, 164, 160, 165, 166 and 162 (1.21); SEQ ID NOs: 163, 164, 160, 165, 161 and 162 (1.22); SEQ ID NOs: 158, 167, 168, 145, 98 and 169 (1.23); SEQ ID NOs: 170, 171, 172, 173, 141 and 99 (2.1) orSEQ ID NOs: 25, 174, 175, 176, 29 and 177 (2.8). In some embodiments, the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 722 and 723 (1.20); SEQ ID NOs: 724 and 725 (1.21); SEQ ID NOs: 724 and 726 (1.22); SEQ ID NOs: 727 and 728 (1.23); SEQ ID NOs: 727 and 729 (1.23 VL C36Y); SEQ ID NOs: 730 and 731 (2.1) or SEQ ID NOs: 732 and 733 (2.8). In some embodiments, the antibody or antigen-binding fragment thereof is insensitive to (i.e., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C). In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope within CD4 D3 comprising amino acid residues at positions 218, 220, 260, 271, 274-277, 279, 283 and 285, wherein the residue positions are with reference to SEQ ID NO: 1120. Further provided is a means for binding to CD4 D3 that is insensitive to amino acid substitution resulting from polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C). In some embodiments, the means binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

[0013] With respect to further embodiments of the CD4-binding antibody or antigenbinding fragment thereof (DI, D2, D2 / D3 or D3), in some embodiments, the antibody or antigen-binding fragment thereof binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

[0014] Further provided is a CD4-targeted interleukin- 15 (IL-15) molecule comprising: (a) a first polypeptide comprising an immunoglobulin heavy chain comprising a first immunoglobulin fragment crystallizable domain (Fc domain); (b) a second polypeptide comprising an immunoglobulin light chain (VL-CL), wherein the first polypeptide and the second polypeptide form an antigen binding domain that specifically binds to CD4; and (c) a third polypeptide comprising a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL-15 or variant thereof (IL-15v), and (iii) a second Fc domain, wherein the first Fc domain and the second Fc domain heterodimerize to form a bispecific molecule that binds to CD4 and an IL-2PY complex (CD122 and CD132). In some embodiments, the antigen binding domain that specifically binds to CD4 competes with orcomprises a heavy chain variable region (VH) and a light chain variable region (VL) from an antibody selected from the group consisting of ibalizumab, tregalizumab, keliximab, zanolimumab, clenoliximab, priliximab, UB-421, RPA-T4, SK3, MEM241 and OKT-4.

[0015] In some embodiments of the CD4-targeted IL-15 molecule, the antigen binding domain that specifically binds to CD4 specifically binds to the CD4 DI domain. In some embodiments, the antigen binding domain specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 1, 2, 3, 4, 5 and 6 (1); SEQ ID NOs: 1, 7, 3, 4, 8 and 9 (2); SEQ ID NOs: 1, 10, 3, 11, 5 and 6 (3); SEQ ID NOs: 1, 10, 3, 11, 12 and 6 (4); SEQ ID NOs: 1, 10, 3, 11, 8 and 9 (5); SEQ ID NOs: 1, 13, 3, 11, 8 and 9 (6); SEQ ID NOs: 1, 14, 3, 11, 8 and 9 (7); SEQ ID NOs: 1, 15, 3, 11, 8 and 9 (8); SEQ ID NOs: 1, 16, 3, 11, 8 and 9 (9); SEQ ID NOs: 1, 15. 3, 11, 12 and 17 (10); SEQ ID NOs: 1, 16, 3, 11, 12 and 18 (11); SEQ ID NOs: 1, 1078, 3, 11, 8 and 9 (12); SEQ ID NOs: 1, 1079, 3, 11, 8 and 9 (13, 14, 17, 18 and 19); SEQ ID NOs: 1, 1080. 3, 11, 8 and 9 (15); SEQ ID NOs: 1, 1081, 3, 11, 8 and 9 (16); SEQ ID NOs: 19, 20, 21, 22, 23 and 24 (1.17); SEQ ID NOs: 25, 26, 27, 28, 29 and 30 (1.25); SEQ ID NOs: 31, 32, 33, 34, 29 and 35 (1.26); SEQ ID NOs: 25, 36, 37, 28, 29 and 38 (1.27); SEQ ID NOs: 25, 1082, 39, 28, 29 and 38 (1.28); SEQ ID NOs: 40, 41, 42, 28, 29 and 35 (1.29); SEQ ID NOs: 25, 43, 39, 28, 29 and 38 (1.30); SEQ ID NOs: 25, 44, 45, 28, 29 and 35 (1.31); SEQ ID NOs: 25, 46, 47, 28, 29 and 35 (1.32); SEQ ID NOs: 25, 48, 49, 28, 29 and 35 (1.33); SEQ ID NOs: 25, 48, 50, 28, 29 and 35 (1.34); SEQ ID NOs: 51, 52, 53, 54, 55 and 56 (1.45); SEQ ID NOs: 51, 57, 53, 58, 55 and 56 (1.46, 1.47, 1.48); SEQ ID NOs: 59, 60, 61, 62, 63 and 64 (keliximab) or SEQ ID NOs: 65, 66, 67, 68, 69 and 70 (UB-421). In some embodiments, the antigen binding domain specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of: SEQ ID NOs: 178, 179, 180, 181, 182 and 6 (1); SEQ ID NOs: 178, 183, 180, 181, 182 and 9 (2); SEQ ID NOs: 178, 184, 180, 181, 182 and 6 (4); SEQ ID NOs: 178, 184, 180, 181, 182 and 9 (3, 5); SEQ ID NOs: 178, 185, 180, 181, 182 and 9 (6, 7, 12); SEQ ID NOs: 178, 186, 180, 181, 182 and 9 (8); SEQ ID NOs: 178, 187, 180, 181, 182 and 9 (9); SEQ ID NOs: 178, 186, 180, 181, 182 and 17 (10); SEQ ID NOs: 178, 187, 180, 181, 182 and 18 (11); SEQ ID NOs: 178, 188, 180, 181, 182 and 9 (13, 14, 17, 18, 19); SEQ ID NOs: 178, 189, 180, 181, 182 and 9 (15); SEQ ID NOs: 178, 190, 180, 181, 182 and 9 (16); SEQ ID NOs: 191, 192, 193, 194, 195 and 24 (1.17); SEQ ID NOs:196, 197, 198, 199, 200 and 30 (1.25); SEQ IDNOs: 201, 202, 203, 199, 200 and 35 (1.26); SEQ ID NOs: 204, 205, 206, 199, 200 and 38 (1.27); SEQ ID NOs: 196, 207, 208, 199, 200 and 38 (1.28); SEQ ID NOs: 209, 210, 211, 199, 200 and 35 (1.29); SEQ ID NOs: 196, 212, 208, 199, 200 and 38 (1.30); SEQ IDNOs: 196, 213, 214, 199, 200 and 35 (1.31); SEQ ID NOs: 196, 213, 215, 199, 200 and 35 (1.32); SEQ IDNOs: 196, 216, 217, 199, 200 and 35 (1.33); SEQ ID NOs: 196, 216, 218, 199, 200 and 35 (1.34); SEQ ID NOs: 219, 220, 221, 222, 223 and 56 (1.45); SEQ ID NOs: 219, 224, 221, 225, 223 and 56 (1.46, 1.47, 1.48); SEQ ID NOs: 226, 227, 228, 229, 230 and 64 (keliximab) or SEQ ID NOs: 231, 232, 233, 234, 235 and 70 (UB-421). In some embodiments, the antigen binding domain that specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of: SEQ ID NOs: 323, 324, 325, 326, 182 and 327 (1); SEQ ID NOs: 323, 328, 325, 326, 182 and 329 (2); SEQ ID NOs: 323, 330, 325, 326, 182 and 327 (4); SEQ ID NOs: 323, 330, 325, 326, 182 and 329 (5); SEQ IDNOs: 323, 331, 325, 326, 182 and 329 (6, 7, 12); SEQ ID NOs: 323, 332, 325, 326, 182 and 329 (8); SEQ ID NOs: 323, 333, 325, 326, 182 and 329 (9); SEQ ID NOs: 323, 332, 325, 326, 182 and 334 (10); SEQ ID NOs: 323, 333, 325, 326, 182 and 335 (11); SEQ ID NOs: 323, 336, 325, 326, 182 and 329 (13, 14, 17, 18 and 19); SEQ ID NOs: 323, 337, 325, 326, 182 and 329 (15); SEQ ID NOs: 323, 338, 325, 326, 182 and 329 (16); SEQ ID NOs: 339, 340, 341, 342, 195 and 1131 (1.17); SEQ ID NOs: 344, 345, 346, 347, 200 and 348 (1.25); SEQ ID NOs: 349, 350, 351, 347, 200 and 352 (1.26); SEQ ID NOs: 353, 354, 355, 347, 200 and 356 (1.27); SEQ ID NOs: 344, 350, 357, 347, 200 and 356 (1.28); SEQ ID NOs: 358, 350, 359, 347, 200 and 352 (1.29); SEQ ID NOs: 343, 354, 357, 347, 200 and 356 (1.30); SEQ ID NOs: 343, 360, 361, 347, 200 and 352 (1.31); SEQ ID NOs: 343, 360, 362, 347, 200 and 352 (1.32); SEQ ID NOs: 343, 363, 364, 347, 200 and 352 (1.33); SEQ ID NOs: 343, 363, 365, 347, 200 and 352 (1.34); SEQ ID NOs: 366, 367, 368, 1084, 223 and 369 (1.45); SEQ ID NOs: 366, 367, 368, 370, 223 and 369 (1.46, 1.47, 1.48); SEQ ID NOs: 371, 372, 373, 374, 230 and 375 (keliximab) or SEQ ID NOs: 376, 377, 378, 379, 235 and 380 (UB-421). In some embodiments, the antigen binding domain that specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of: SEQ ID NOs: 463, 464, 465, 466, 467 and 327 (1); SEQ ID NOs: 463, 468, 465, 466, 469 and 329 (2); SEQ ID NOs: 463, 470, 465, 466, 467 and 327 (3); SEQ ID NOs: 463, 470, 465, 466, 469 and 327 (4); SEQ ID NOs: 463, 470, 465, 466, 469 and 329 (5);SEQ ID NOs: 463, 1132, 465, 466, 469 and 329 (6); SEQ ID NOs: 463, 471, 465, 466, 469 and 329 (7); SEQ ID NOs: 463, 472, 465, 466, 469 and 329 (8); SEQ ID NOs: 463, 473, 465, 466, 469 and 329 (9); SEQ ID NOs: 463, 472, 465, 466, 474 and 334 (10); SEQ ID NOs: 463, 473, 465, 466, 474 and 335 (11); SEQ ID NOs: 463, 475, 465, 466, 469 and 329 (12); SEQ ID NOs: 463, 478, 465, 466, 469 and 329 (13, 14, 17, 18 and 19); SEQ ID NOs: 463, 476, 465, 466, 469 and 329 (15); SEQ ID NOs: 463, 477, 465, 466, 469 and 329 (16); SEQ ID NOs: 479, 480, 481, 482, 483 and 1131 (1.17); SEQ ID NOs: 484, 485, 486, 487, 488 and 348 (1.25); SEQ ID NOs: 489, 490, 491, 487, 492 and 352 (1.26); SEQ ID NOs: 493, 494, 495, 487, 492 and 356 (1.27); SEQ ID NOs: 484, 496, 497, 487, 492 and 356 (1.28); SEQ ID NOs: 498, 499, 500, 487, 492 and 352 (1.29); SEQ ID NOs: 484, 501, 497, 487, 492 and 356 (1.30); SEQ ID NOs: 484, 502, 503, 487, 492 and 352 (1.31); SEQ ID NOs: 484, 504, 505, 487, 506 and 352 (1.32); SEQ ID NOs: 484, 507, 508, 487, 492 and 352 (1.33); SEQ ID NOs: 484, 507, 509, 487, 492 and 352 (1.34); SEQ ID NOs: 510, 511, 512, 513, 514 and 369 (1.45); SEQ ID NOs: 510, 515, 512, 516, 514 and 369 (1.46, 1.47, 1.48); SEQ ID NOs: 517, 518, 519, 374, 520 and 375 (keliximab) or SEQ ID NOs: 521, 522, 523, 524, 525 and 380 (UB-421). In some embodiments, the antigen binding domain that specifically binds to CD4 DI and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 625 and 626 (1); SEQ ID NOs: 627 and 628 (2); SEQ ID NOs: 629 and 630 (3); SEQ ID NOs: 629 and 631 (4); SEQ ID NOs: 629 and 632 (5); SEQ ID NOs: 633 and 632 (6); SEQ ID NOs: 634 and 632 (7); SEQ ID NOs: 635 and 632 (8); SEQ ID NOs: 636 and 632 (9); SEQ ID NOs: 635 and 637 (10); SEQ ID NOs: 636 and 638 (11); SEQ ID NOs: 639 and 632 (12); SEQ ID NOs: 640 and 632 (13); SEQ ID NOs: 641 and 632 (14); SEQ ID NOs: 642 and 632 (15); SEQ ID NOs: 643 and 632 (16); SEQ ID NOs: 640 and 644 (17); SEQ ID NOs: 640 and 645 (18); SEQ ID NOs: 640 and 646 (19); SEQ ID NOs: 647 and 648 (1.17); SEQ ID NOs: 649 and 650 (1.25); SEQ ID NOs: 651 and 652 (1.26); SEQ ID NOs: 653 and 654 (1.27); SEQ ID NOs: 655 and 656 (1.28); SEQ ID NOs: 657 and 658 (1.29); SEQ ID NOs: 659 and 660 (1.30); SEQ ID NOs: 661 and 662 (1.31); SEQ ID NOs: 663 and 664 (1.32); SEQ ID NOs: 665 and 666 (1.33); SEQ ID NOs: 667 and 666 (1.34); SEQ ID NOs: 668 and 669 (1.45); SEQ ID NOs: 670 and 671 (1.46); SEQ ID NOs: 672 and 673 (1.47); SEQ ID NOs: 672 and 671 (1.48); SEQ ID NOs: 674 and 675 (keliximab) or SEQ ID NOs: 676 and 677 (UB-421).

[0016] In some embodiments of the CD4-targeted IL- 15 molecule, the antigen binding domain that specifically binds to CD4 specifically binds to the CD4 D2 domain. In some embodiments, the antigen binding domain specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 71, 72, 73, 74, 75 and 76 (ibalizumab); SEQ ID NOs: 77, 78, 79, 80, 81 and 82 (tregalizumab); SEQ ID NOs: 25, 83, 84, 85, 86 and 87 (1.1); SEQ ID NOs: 88, 89, 90, 91, 92 and 93 (1.4); SEQ ID NOs: 94, 95, 96, 97, 98 and 99 (1.5); SEQ ID NOs: 88, 100, 101, 102, 103 and 104 (2.9); SEQ ID NOs: 88, 105, 106, 107, 108 and 93 (2.10); SEQ ID NOs: 88, 109, 110, 111, 108 and 112 (2.11); SEQ ID NOs: 88, 109, 110, 111, 113 and 112 (2.11 VL N50G); SEQ ID NOs: 88, 114, 106, 107, 108 and 115 (2.12); SEQ ID NOs: 88, 114, 106, 107, 113 and 115 (2.12 VLN50G); SEQ ID NOs: 88, 116, 117, 118, 108 and 119 (2.13); SEQ ID NOs: 120, 121, 122, 102, 113 and 123 (2.14) or SEQ ID NOs: 88, 124, 122, 125, 113 and 104 (2.15). In some embodiments, the antigen binding domain specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of: SEQ ID NOs: 236, 237, 238, 239, 240 and 76 (ibalizumab); SEQ ID NOs: 241, 242, 243, 244, 245 and 82 (tregalizumab); SEQ ID NOs: 246, 247, 248, 249, 250 and 87 (1.1); SEQ ID NOs: 251, 252, 253, 254, 255 and 93 (1.4); SEQ ID NOs: 256, 257, 258, 259, 255 and 99 (1.5); SEQ ID NOs: 251, 260, 261, 262, 263 and 104 (2.9); SEQ ID NOs: 251, 264, 265, 266, 267 and 93 (2.10); SEQ ID NOs: 251, 268, 269, 270, 267 and 112 (2.11); SEQ ID NOs: 251, 268, 269, 270, 263 and 112 (2.11 VLN50G); SEQ ID NOs: 251, 271, 265, 266, 267 and 115 (2.12); SEQ ID NOs: 251, 271, 265, 266, 263 and 115 (2.12 VL N50G); SEQ ID NOs: 251, 272, 273, 274, 267 and 119 (2.13); SEQ ID NOs: 275, 276, 277, 262, 263 and 123 (2.14) or SEQ ID NOs: 251, 278, 277, 279, 263 and 104 (2.15). In some embodiments, the antigen binding domain that specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of: SEQ ID NOs: 366, 381, 382, 383, 240 and 384 (ibalizumab); SEQ ID NOs: 385, 386, 387, 388, 245 and 389 (tregalizumab); SEQ ID NOs: 390, 391, 392, 393, 250 and 394 (1.1); SEQ ID NOs: 395, 396, 397, 398, 255 and 399 (1.4); SEQ ID NOs: 400, 401, 402, 403, 255 and 404 (1.5); SEQ ID NOs: 395, 405, 406, 407, 263 and 408 (2.9); SEQ ID NOs: 395, 409, 410, 411, 267 and 399 (2.10); SEQ ID NOs: 395, 412, 413, 414, 267 and 399 (2.11); SEQ ID NOs: 395, 412, 413, 414,263 and 399 (2.11 VLN50G); SEQ IDNOs: 395, 415, 410, 411, 267 and 408 (2.12); SEQ ID NOs: 395, 415, 410, 411, 263 and 408 (2.12 VL N50G); SEQ ID NOs: 395, 416, 417, 418, 267 and 419 (2.13); SEQ ID NOs: 420, 421, 422, 407, 263 and 408 (2.14) or SEQ ID NOs: 395, 423, 422, 424, 263 and 408 (2.15). In some embodiments, the antigen binding domain that specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of: SEQ ID NOs: 526, 527, 528, 529, 530 and 384 (ibalizumab); SEQ ID NOs: 531, 532, 533, 534, 535 and 389 (tregalizumab); SEQ ID NOs: 536, 537, 538, 539, 540 and 394 (1.1); SEQ ID NOs: 541, 542, 543, 544, 545 and 399 (1.4); SEQ ID NOs: 546, 547, 548, 549, 550 and 404 (1.5); SEQ ID NOs: 541, 551, 552, 553, 554 and 408 (2.9); SEQ IDNOs: 541, 555, 556, 557, 558 and 399 (2.10); SEQ ID NOs: 541, 559, 560, 561, 562 and 399 (2.11); SEQ IDNOs: 541, 559, 560, 561, 563 and 399 (2.11 VLN50G); SEQ ID NOs: 541, 564, 556, 557, 558 and 408 (2.12); SEQ IDNOs: 541, 564, 556, 557, 565 and 408 (2.12 VL N50G); SEQ ID NOs: 541, 566, 567, 568, 569 and 419 (2.13); SEQ IDNOs: 570, 571, 572, 553, 565 and 408 (2.14) or SEQ IDNOs: 541, 573, 572, 574, 575 and 408 (2.15). In some embodiments, the antigen binding domain that specifically binds to CD4 D2 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 678 and 679 (ibalizumab); SEQ ID NOs: 680 and 681 (tregalizumab); SEQ ID NOs: 682 and 683 (1.1); SEQ ID NOs: 684 and 685 (1.4); SEQ ID NOs: 686 and 687 (1.5); SEQ ID NOs: 688 and 689 (2.9); SEQ ID NOs: 690 and 691 (2.10); SEQ ID NOs: 692 and 693 (2.11); SEQ ID NOs: 692 and 694 (2.11 VL N50G); SEQ ID NOs: 695 and 696 (2.12); SEQ ID NOs: 695 and 697 (2.12 VLN50G); SEQ IDNOs: 698 and 699 (2.13); SEQ ID NOs: 700 and 701 (2.14) or SEQ ID NOs: 702 and 703 (2.15). In some embodiments, the antibody or antigen-binding fragment thereof is insensitive to (i.e., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant ID rsl 1064416 (F123L).

[0017] In some embodiments of the CD4-targeted IL- 15 molecule, the antigen binding domain that specifically binds to CD4 specifically binds to one or both of the CD4 D2 domain and the CD4 D3 domain. In some embodiments, the antigen binding domain specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 126, 127, 128, 129, 130 and 99 (1.6); SEQ ID NOs: 126, 131, 132, 129, 133 and 99 (1.7); SEQ ID NOs: 126, 134, 135, 136, 133 and 99 (1.8); SEQ ID NOs: 126, 137, 128, 129, 138 and 99 (1.9); SEQ ID NOs: 126, 139, 128, 140, 141 and 99 (1.10); SEQ ID NOs: 142, 143, 128, 145, 141 and 99 (1.19); SEQ ID NOs: 126, 146, 147, 140, 141 and 99 (2.2) or SEQ ID NOs: 148, 149, 150, 129, 151 and 99 (2.3). In some embodiments, the antigen binding domain specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of: SEQ ID NOs: 280, 281, 282, 283, 284 and 99 (1.6); SEQ ID NOs: 280, 285, 286, 283, 284 and 99 (1.7); SEQ ID NOs: 280, 287, 288, 283, 284 and 99 (1.8); SEQ ID NOs: 289, 290, 282, 283, 284 and 99 (1.9); SEQ ID NOs: 289, 291, 292, 293, 255 and 99 (1.10); SEQ ID NOs: 294, 295, 296, 297, 255 and 99 (1.19); SEQ ID NOs: 289, 298, 299, 293, 255 and 99 (2.2) or SEQ ID NOs: 289, 300, 301, 283, 284 and 99 (2.3). In some embodiments, the antigen binding domain that specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of: SEQ ID NOs: 425, 426, 427, 428, 284 and 404 (1.6); SEQ ID NOs: 425, 426, 429, 428, 284 and 404 (1.7); SEQ ID NOs: 425, 426, 430, 428, 284 and 404 (1.8); SEQ ID NOs: 431, 432, 427, 428, 284 and 404 (1.9); SEQ ID NOs: 431, 433, 427, 434, 255 and 404 (1.10); SEQ ID NOs: 431, 435, 436, 437, 255 and 404 (1.19); SEQ ID NOs: 431, 438, 439, 434, 255 and 404 (2.2) or SEQ ID NOs: 431, 438, 440, 428, 284 and 404 (2.3). In some embodiments, the antigen binding domain that specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of: SEQ ID NOs: 576, 577, 578, 579, 580 and 404 (1.6); SEQ ID NOs: 576, 581, 582, 579, 583 and 404 (1.7); SEQ ID NOs: 576, 584, 585, 586, 583 and 404 (1.8); SEQ ID NOs: 587, 588, 578, 579, 589 and 404 (1.9); SEQ ID NOs: 587, 590, 578, 591, 592 and 404 (1.10); SEQ ID NOs: 593, 594, 595, 596, 597 and 404 (1.19); SEQ ID NOs: 587, 598, 599, 591, 597 and 404 (2.2) or SEQ ID NOs: 587, 600, 601, 579, 602 and 404 (2.3). In some embodiments, the antigen binding domain that specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 704 and 705 (1.6); SEQ ID NOs: 706 and 707 (1.7); SEQ ID NOs: 708 and 709 (1.8); SEQ ID NOs: 710 and 711 (1.9); SEQ ID NOs: 712 and 713 (1.10); SEQ ID NOs: 714 and 715 (1.19); SEQ ID NOs: 716 and 717 (2.2) or SEQ ID NOs: 718 and 719 (2.3). In some embodiments, the antibody or antigen-binding fragment thereof is insensitive to (i.e., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

[0018] In some embodiments of the CD4-targeted IL- 15 molecule, the antigen binding domain that specifically binds to CD4 specifically binds to the CD4 D3 domain. In some embodiments, the antigen binding domain specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of: SEQ ID NOs: 152, 153, 154, 155, 156 and 157 (OKT4); SEQ ID NOs: 158, 159, 160, 145, 161 and 162 (1.20); SEQ ID NOs: 163, 164, 160, 165, 166 and 162 (1.21); SEQ ID NOs: 163, 164, 160, 165, 161 and 162 (1.22); SEQ ID NOs: 158, 167, 168, 145, 98 and 169 (1.23); SEQ ID NOs: 170, 171, 172, 173, 141 and 99 (2.1) or SEQ ID NOs: 25, 174, 175, 176, 29 and 177 (2.8). In some embodiments, the antigen binding domain specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of: SEQ ID NOs: 302, 303, 304, 305, 245 and 157 (OKT4); SEQ ID NOs: 306, 307, 1083, 297, 308 and 162 (1.20); SEQ ID NOs: 309, 310, 311, 312, 313 and 162 (1.21); SEQ ID NOs: 309, 310, 311, 312, 308 and 162 (1.22); SEQ ID NOs: 314, 315, 316, 297, 255 and 169 (1.23); SEQ ID NOs: 317, 318, 319, 320, 255 and 99 (2.1) or SEQ ID NOs: 196, 321, 322, 199, 200 and 177 (2.8). In some embodiments, the antigen binding domain that specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of: SEQ ID NOs: 441, 442, 443, 444, 245 and 445 (OKT4); SEQ ID NOs: 446, 447, 448, 437, 308 and 449 (1.20); SEQ ID NOs: 450, 451, 448, 452, 313 and 449 (1.21); SEQ ID NOs: 450, 451, 448, 452, 308 and 449 (1.22); SEQ ID NOs: 453, 454, 455, 437, 255 and 456 (1.23); SEQ ID NOs: 457, 458, 459, 460, 255 and 404 (2.1) or SEQ ID NOs: 343, 350, 461, 347, 200 and 462 (2.8). In some embodiments, the antigen binding domain that specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of: SEQ ID NOs: 603, 604, 605, 606, 607 and 445 (OKT4); SEQ ID NOs: 608, 609, 610, 596, 611 and 449 (1.20); SEQ ID NOs: 612, 613, 610, 614, 615 and 449 (1.21); SEQ ID NOs: 612, 613, 610, 614, 611 and 449 (1.22); SEQ ID NOs: 616, 617, 618, 596, 550 and 456 (1.23); SEQ ID NOs: 619, 620, 621, 622, 597 and 404 (2.1) or SEQ ID NOs: 484, 623, 624, 487, 492 and 462 (2.8). In some embodiments, the antigen binding domain that specifically binds to CD4 D3 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below: SEQ ID NOs: 720 and 721 (OKT4); SEQ ID NOs: 722 and 723 (1.20); SEQ ID NOs: 724 and 725 (1.21); SEQ ID NOs: 724 and 726 (1.22); SEQ ID NOs: 727 and 728 (1.23); SEQ ID NOs: 727 and 729 (1.23 VL C36Y); SEQ ID NOs: 730 and 731 (2.1) or SEQ ID NOs: 732 and 733 (2.8). In some embodiments, the antibody or antigen-binding fragment thereof is insensitive to (i.e., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C). In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope within CD4 D3 comprising amino acid residues at positions 218, 220, 260, 271, 274-277, 279, 283 and 285, wherein the residue positions are with reference to SEQ ID NO: 1120.

[0019] With respect to further embodiments of the CD4-targeted IL- 15 molecule, in some embodiments, the antigen binding domain that specifically binds to CD4 binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

[0020] Further provided is a means for targeting IL- 15 to CD4 D2 that is insensitive to (i.e., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant ID rsl 1064416 (F123L). Further provided is a means for targeting IL-15 to one or both of CD4 D2 and D3 that is insensitive to (i.e., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L). Further provided is a means for targeting IL-15 to CD4 D3 that is insensitive to (i.e., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C). In some embodiments, the means specifically binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

[0021] In some embodiments of the CD4-targeted IL-15 molecule, the fusion protein comprises an IL- 15 receptor alpha subunit (IL15RA) SUSHI domain that binds to IL- 15, is no longer than 65 amino acids, and comprises the amino acid sequence of SEQ ID NO: 734, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 734. In some embodiments, the IL15RA SUSHI domain comprises the amino acid sequence of SEQ ID NO: 735, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 735. In some embodiments, the IL15RA SUSHI domain comprises the amino acid sequence of any one of SEQ ID NOs: 736-739.

[0022] In some embodiments of the CD4-targeted IL-15v molecule, the fusion protein comprises an IL-15 variant comprising one or more of the following amino acid substitutions: N1D, N4D, S7G, D8N, D30N, D61N, E64Q, N65A, N65D, I68A, N71L, N71E, N72D, N77L, N79G, N79P, Q108E, N112A, N112G, N112D, N112S or N112K; or one of the following combinations of amino acid substitutions: N1D, N4D and D8N; N1D and D61N; N1D and E64Q; N1D and N65D; N4D and D61N; N4D and E64Q; N4D and N65D; S7G and N65D; D8G and D61N; D8G and E64Q; D8G and N65D; D8N and D61N; D8N and E64Q D8N and N65D; D30N and N65D; D61N and E64Q; D61N and N65D; E64Q and N65D; E64Q and Q108E; N65A and I68A; N65D and I68A; N71L and N79P; N71L and N112D; N79P and N112D; S7G, N65A and I68A; S7G, N65D and I68A; D30N, E64Q and N65D; D61N, E64Q and N65D; D61N, N65D and I68A; N71Q, N79Q and N112Q; N71 A, N79A and N112A;N71G, N79G and N112G; N71S, N79L and N112E; N71E, N79P and N112K; N71L, N79P and N112K; N71L, N79P and N112D; N71K, N79P and N112D; N71E, N79P and N112S; N71E, N79P and N112D; N1D, D61N, E64Q and Q108E; N4D, D61N, E64Q and Q108E; N71Q, N77L, N79Q and N112Q; N71 A, N77L, N79A and N112A; N71G, N77L, N79G and N112G; N71S, N77L, N79L and N112E; N71E, N77L, N79P and N112K; N71L, N77L, N79P and N112K; N71E, N77L, N79P and N112S; N71E, N77L, N79P and N112D; S7G, N65D, N71L, N79P and N112D; S7G, N65D, N71E, N77L, N79P and N112D; S7G, N65D, N71E, N77L, N79P and N112S; S7G, N65D, N71L, N77L, N79P and N112K; or S7G, N65D, N71E, N77L, N79P and N112K; wherein the position numbers are with respect to SEQ ID NO: 740 (wild-typeIL-15). In some embodiments, the fusion protein comprises an IL-15 variant comprising one or more of the following amino acid substitutions: S7G and N65D; N65D and I68A; S7G, N65D and I68A; S7G, N65D, N71L, N79P and N112D; S7G, N65D, N71E, N77L, N79P and N112D; S7G, N65D, N71E, N77L, N79P and N112S; S7G, N65D, N71L, N77L, N79P and N112K; or S7G, N65D, N71E, N77L, N79P, N112K; wherein the position numbers are with respect to SEQ ID NO: 740. In some embodiments, the CD4-targeted IL-15v molecule comprises an IL-15 or IL-15v of any one of SEQ ID NOs: 740-813, 1124 and 1125. In some embodiments, the CD4-targeted IL-15v molecule comprises an IL-15 or IL-15v of any one of SEQ ID NOs: 743, 750-752, 754-756, 758, 768-771, 774, 777, 779, 783-788, 790-798, 801-808, 810-813 and 1125.

[0023] In some embodiments of the CD4-targeted IL-15v molecule, the fusion protein comprises in sequential order from N-terminus to C-terminus, (i) the IL15RA SUSHI domain, (ii) the IL-15 or variant thereof, and (iii) Fc domain. In some embodiments, the fusion protein comprises a flexible linker between the IL15RA SUSHI domain and the IL-15 or variant thereof. In some embodiments the linker has a length of from about 4 to about 50 amino acids, e.g., from about 5 amino acids to about 25 amino acids, e.g., from about 15 amino acids to about 25 amino acids. In some embodiments, the linker comprises from 1 to 10 units, e.g., 1 to 5 units, e.g., 3 to 5 units, of a poly-glycine serine linker selected from GGGS, GGGGS and combinations thereof. In some embodiments, the linker comprises 5 units of GGGGS (GGGGSGGGGSGGGGSGGGGSGGGGS; SEQ ID NO: 1085).

[0024] Structurally, in some embodiments of the CD4-targeted IL-15 molecule, the fusion protein comprises: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL-15 or variant thereof (IL-15v) of any one of SEQ ID NOs: 814-887, 1126 and 1127. In some embodiments, the fusion protein comprises: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL- 15 or variant thereof (IL-15v) of any one of SEQ ID NOs: 817, 824-826, 828-830, 832, 842-845, 848, 851, 853, 857-862, 864-872, 875-882, 884-887 and 1127. Functionally, in some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM. In some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RPY with a KD of at least 1 pM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM. In some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusionprotein binds to IL-2RPy with a KD that is at least 1000-fold to the KD of the antigen binding domain specifically binding to CD4. In some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RPy with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM, and the antigen binding domain that specifically binds to CD4 binds to CD4 with a KD of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM. In some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein induces CD4+ T cell proliferation with an EC50 of less than 5 nM, e.g., less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, e.g., wherein CD4+ T cell proliferation potency is measured by marker of proliferation Ki-67 activation (MKI67; NCBI Gene ID: 4288). In some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein activates both naive CD4+ T cells and memory CD4+ T cells. In some embodiments, the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein induces CD8+ T cells and / or natural killer (NK) cell proliferation with an EC50 of greater than 100 nM, e.g., wherein CD8+ T cell and / or NK cell proliferation potency is measured by Ki-67 activation.

[0025] In some embodiments of the CD4-targeted IL- 15 molecule, the first Fc domain and the second Fc domain are human IgGl . In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L234A, L234V, L234F, L235A, L235E, G237A, P331S, and any combination thereof, wherein the numbering of the residues is according to Eu numbering. In some embodiments, the first Fc domain and the second Fc domain are human IgG4. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, G237A, S228P, and any combination thereof, wherein the numbering of the residues is according to Eu numbering. In some embodiments, the first and second Fc domain comprise amino acid substitutions to facilitate heterodimerization. In some embodiments, the first Fc domain and the second Fc domain comprise the following amino acid substitutions (Eu numbering), respectively: T366W and T366S / L368A / Y407V; T366S / L368A / Y407V and T366W;T366W / S354C and T366S / L368A / Y407V / Y349C; T366S / L368A / Y407V / Y349C and T366W / S354C; S364H / F405A and Y349T / T394; Y349T / T394 and S364H / F405A;T350V / L351Y / F405A / Y407V and T350V / T366L / K392L / T394W;T350V / T366L / K392L / T394W and T350V / L351 Y / F405A / Y407V; K360D / D399M / Y407A and E345R / Q347R / T366V / K409V; E345R / Q347R / T366V / K409V and K360D / D399M / Y407A; K409D / K392D and D399K / E356K; D399K / E356K and K409D / K392D; K360E / K409W and Q347R / D399V / F405T; Q347R / D399V / F405T and K360E / K409W; K360E / K409W / Y349C and Q347R / D399V / F405T / S354C; Q347R / D399V / F405T / S354C and K360E / K409W / Y349C;K370E / K409W and E357N / D399V / F405T; or E357N / D399V / F405T and K370E / K409W. In some embodiments, neither of the first nor second Fc domain comprise amino acid substitutions to extend serum half-life. In some embodiments, one or both of the first and second Fc domain comprise amino acid substitutions to extend serum half-life. In some embodiments, one or both of the first Fc domain and the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering): tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (252Y, 254T and 256E); leucine at position 428 (428L); glutamine at position 250 and leucine at position 428 (250Q and 428L); leucine at position 428 and serine at position 434 (428L and 434S); leucine at position 428 and alanine at position 434 (428L and 434A); arginine at position 311 and leucine at position 428 (311R and 428L); glycine at position 309 and leucine at position 428 (309G and 428L); glutamine at position 307, valine at position 311 and valine at position 378 (307Q, 311V and 378V); or aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311 and valine at position 378 (256D, 286D, 307R, 311V and 378V). In some embodiments, one of the first or the second Fc domain comprise amino acid substitutions to facilitate purification. In some embodiments, one of the first Fc domain or the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering): one or both of an arginine at position 435 (H435R) and a phenylalanine or an alanine at position 436 (Y436F or Y436A).

[0026] In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to CD4 DI and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 921, 922 and 923 (100); SEQ ID NOs: 924, 922 and 925 (101); SEQ ID NOs: 926, 922 and 925 (102); SEQ ID NOs: 926, 922 and 1074 (103); SEQ ID NOs: 926, 922 and 1075 (104); SEQ ID NOs: 926, 922 and 1076 (105); SEQ ID NOs: 926, 922 and 974 (106); SEQ ID NOs: 926, 929 and 1076 (107); SEQ ID NOs: 927, 928 and 925 (108); SEQ ID NOs: 926, 929 and 925 (109); SEQID NOs: 926, 922 and 985 (110); SEQ ID NOs: 930, 922 and 923 (111); SEQ ID NOs: 931, 922 and 925 (112); SEQ ID NOs: 932, 922 and 933 (113); SEQ ID NOs: 934, 922 and 935 (114); SEQ ID NOs: 936, 937 and 923 (115); SEQ ID NOs: 938, 939 and 923 (116); SEQ ID NOs: 940, 941 and 923 (117); SEQ ID NOs: 942, 943 and 923 (118); SEQ ID NOs: 944, 945 and 923 (119); SEQ ID NOs: 946, 947 and 923 (120); SEQ ID NOs: 948, 949 and 923 (121); SEQ ID NOs: 950, 951 and 923 (122); SEQ ID NOs: 952, 953 and 923 (123); SEQ ID NOs: 954, 955 and 923 (124); SEQ ID NOs: 956, 955 and 923 (125); SEQ ID NOs: 957, 958 and 923 (126); SEQ ID NOs: 959, 960 and 923 (127); SEQ ID NOs: 961, 962 and 923 (128); SEQ ID NOs: 961, 960 and 923 (129); SEQ ID NOs: 926, 922 and 1091 (249); SEQ ID NOs: 926, 922 and 1092 (251); SEQ ID NOs: 926, 922 and 1093 (252); SEQ ID NOs: 926, 922 and 1094 (253); SEQ ID NOs: 926, 922 and 1095 (254); SEQ ID NOs: 926, 922 and 1096 (255); SEQ ID NOs: 926, 922 and 1097 (259); SEQ ID NOs: 926, 922 and 1098 (260); SEQ ID NOs: 926, 922 and 1099 (261) or SEQ ID NOs: 926, 922 and 1100 (262).

[0027] In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D2 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 1086, 1087 and 1088 (245); SEQ ID NOs: 963, 964 and 923 (130); SEQ ID NOs: 965, 966 and 923 (131); SEQ ID NOs: 967, 968 and 923 (132); SEQ ID NOs: 969, 970 and 923 (133); SEQ ID NOs: 969, 970 and 971 (134); SEQ ID NOs: 969, 970 and 972 (135); SEQ ID NOs: 973, 970 and 974 (136); SEQ ID NOs: 975, 976 and 923 (137); SEQ ID NOs: 977, 978 and 923 (138); SEQ ID NOs: 977, 978 and 971 (139); SEQ ID NOs: 977, 978 and 972 (140); SEQ ID NOs: 977, 979 and 972 (141); SEQ ID NOs: 980, 979 and 974 (142); SEQ ID NOs: 981, 982 and 923 (143); SEQ ID NOs: 981, 982 and 971 (144); SEQ ID NOs: 981, 982 and 972 (145); SEQ ID NOs: 981, 983 and 972 (146); SEQ ID NOs: 984, 983 and 974 (147); SEQ ID NOs: 984, 983 and 985 (148); SEQ ID NOs: 986, 987 and 923 (149); SEQ ID NOs: 988, 989 and 923 (150); SEQ ID NOs: 988, 989 and 971 (151); SEQ ID NOs: 988, 989 and 972 (152); SEQ ID NOs: 990, 991 and 923 (153); SEQ ID NOs: 990, 991 and 971 (154); SEQ ID NOs: 990, 991 and 972 (155) or SEQ ID NOs: 992, 991 and 974 (156).

[0028] In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to one or both of CD4 D2 and CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acidsequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 993, 994 and 923 (157); SEQ ID NOs: 995, 996 and 923 (158); SEQ ID NOs: 997, 998 and 923 (159); SEQ ID NOs: 999, 1000 and 923 (160); SEQ ID NOs: 1001, 1002 and 923 (161); SEQ ID NOs: 1003, 1004 and 923 (162); SEQ ID NOs: 1005, 1006 and 923 (163) or SEQ ID NOs: 1007, 1008 and 923 (164).

[0029] In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 1089, 1090 and 1088 (246); SEQ ID NOs: 1009, 1010 and 923 (165); SEQ ID NOs: 1009, 1010 and 971 (166); SEQ ID NOs: 1009, 1010 and 972 (167); SEQ ID NOs: 1011, 1012 and 923 (168); SEQ ID NOs: 1011, 1012 and 971 (169); SEQ ID NOs: 1011, 1012 and 972 (170); SEQ ID NOs: 1013, 1012 and 974 (171); SEQ ID NOs: 1011, 1014 and 923 (172); SEQ ID NOs: 1011, 1014 and 971 (173); SEQ ID NOs: 1011, 1014 and 972 (174); SEQ ID NOs: 1013, 1014 and 974 (175); SEQ ID NOs: 1015, 1016 and 923 (176); SEQ ID NOs: 1015, 1016 and 971 (177); SEQ ID NOs: 1015, 1017 and 971 (178); SEQ ID NOs: 1015, 1016 and 972 (179); SEQ ID NOs: 1015, 1017 and 972 (180); SEQ ID NOs: 1018, 1017 and 974 (181); SEQ ID NOs: 1018, 1017 and 985 (182); SEQ ID NOs: 1019, 1020 and 923 (183); SEQ ID NOs: 1019, 1020 and 971 (184); SEQ ID NOs: 1019, 1020 and 972 (185); SEQ ID NOs: 1021, 1020 and 974 (186); SEQ ID NOs: 1022, 1023 and 923 (187); SEQ ID NOs: 1024, 1025 and 923 (188); SEQ ID NOs: 1011, 1014 and 1026 (189); SEQ ID NOs: 1027, 1014 and 1028 (190); SEQ ID NOs: 1027, 1014 and 1029 (191); SEQ ID NOs: 1011, 1014 and 1030 (192); SEQ ID NOs: 1011, 1014 and 1031 (193); SEQ ID NOs: 1011, 1014 and 1032 (194); SEQ ID NOs: 1011, 1014 and 1077 (220); SEQ ID NOs: 1011, 1014 and 1033 (195); SEQ ID NOs: 1011, 1014 and 1034 (196); SEQ ID NOs: 1011, 1014 and 1035 (197); SEQ ID NOs: 1011, 1014 and 1036 (198); SEQ ID NOs: 1011, 1014 and 1037 (199); SEQ ID NOs: 1011, 1014 and 1038 (200); SEQ ID NOs: 1011, 1014 and 1039 (201); SEQ ID NOs: 1011, 1014 and 1040 (202); SEQ ID NOs: 1011, 1014 and 1041 (203); SEQ ID NOs: 1011, 1014 and 1042 (204); SEQ ID NOs: 1011, 1014 and 1043 (205); SEQ ID NOs: 1011, 1014 and 1044 (206); SEQ ID NOs: 1011, 1014 and 1045 (207); SEQ ID NOs: 1011, 1014 and 1046 (208); SEQ ID NOs: 1011, 1014 and 1047 (209); SEQ ID NOs: 1011, 1014 and 1048 (210); SEQ ID NOs: 1011, 1014 and 1049 (211); SEQ IDNOs: 1011, 1014 and 1050 (212); SEQ IDNOs: 1011, 1014 and 1051 (213); SEQ IDNOs: 1011, 1014 and 1052 (214); SEQ IDNOs: 1011, 1014 and 1053 (215); SEQ IDNOs: 1011, 1014 and 1054 (216); SEQ ID NOs: 1011, 1014 and 1055 (217) or SEQ ID NOs: 1011, 1014 and 1056 (218).

[0030] In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 1011, 1014 and 1057 (219). In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 1011, 1014 and 923 (172); SEQ ID NOs: 1011, 1014 and 971 (173); SEQ IDNOs: 1011, 1014 and 972 (174); SEQ IDNOs: 1011, 1014 and 1026 (189); SEQ ID NOs: 1011, 1014 and 1030 (192); SEQ ID NOs: 1011, 1014 and 1031 (193); SEQ ID NOs: 1011, 1014 and 1032 (194); SEQ ID NOs: 1011, 1014 and 1077 (220); SEQ ID NOs: 1011, 1014 and 1033 (195); SEQ ID NOs: 1011, 1014 and 1034 (196); SEQ IDNOs: 1011, 1014 and 1035 (197); SEQ IDNOs: 1011, 1014 and 1036 (198); SEQ ID NOs: 1011, 1014 and 1037 (199); SEQ ID NOs: 1011, 1014 and 1038 (200); SEQ ID NOs: 1011, 1014 and 1039 (201); SEQ ID NOs: 1011, 1014 and 1040 (202); SEQ ID NOs: 1011, 1014 and 1041 (203); SEQ ID NOs: 1011, 1014 and 1042 (204); SEQ ID NOs: 1011, 1014 and 1043 (205); SEQ ID NOs: 1011, 1014 and 1044 (206); SEQ ID NOs: 1011, 1014 and 1045 (207); SEQ ID NOs: 1011, 1014 and 1046 (208); SEQ ID NOs: 1011, 1014 and 1047 (209); SEQ IDNOs: 1011, 1014 and 1048 (210); SEQ IDNOs: 1011, 1014 and 1049 (211); SEQ ID NOs: 1011, 1014 and 1050 (212); SEQ ID NOs: 1011, 1014 and 1051 (213); SEQ ID NOs: 1011, 1014 and 1052 (214); SEQ ID NOs: 1011, 1014 and 1053 (215); SEQ IDNOs: 1011, 1014 and 1054 (216); SEQ ID NOs: 1011, 1014 and 1055 (217) or SEQ ID NOs: 1011, 1014 and 1056 (218) (antibody SCT 1.22).

[0031] In some embodiments, the CD4-targeted IL-15v molecule comprises a heavy chain (HC1) and a light chain (LC1) that bind to Rhesus CD4 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identicalto, respectively, the full length of the amino acid sequences set forth in: SEQ ID NOs: 1101, 1102 and 1103 (247), SEQ ID NOs: 1058, 1059 and 1060 (221) or SEQ ID NOs: 1221, 1222 and 1223 (277).

[0032] With respect to further embodiments of the CD4-targeted IL-15v molecules, in some embodiments, the CD4-targeted IL-15v has a serum half-life in a human or a non-human primate of less than 24 hours, e.g., less than 20 hours, less than 18 hours, less than 16 hours.

[0033] Provided is a polynucleotide or multiple polynucleotides encoding the IL-15v, the fusion protein, the CAR, the antibody or antigen-binding fragment, or the CD4-targeted IL-15v molecule as described above and herein. In some embodiments, the polynucleotide or polynucleotides encode the heavy chain comprising the antigen binding domain that specifically binds to CD4 and comprise a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1104, 1107, 1109, 1112, 1115, 1118 and 1228, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1104, 1107, 1109, 1112, 1115, 1118 and 1228. In some embodiments, the polynucleotide or polynucleotides encode the light chain comprising the antigen binding domain that specifically binds to CD4 and comprise a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1105, 1110, 1113, 1116 and 1229, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1105, 1110, 1113, 1116 and 1229. In some embodiments, the polynucleotide or polynucleotides encode the IL15RASushi-IL15v-Fc fusion protein and comprise a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1106, 1108, 1111, 1114, 1117, 1119 and 1230, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1106, 1108, 1111, 1114, 1117, 1119 and 1230. In some embodiments, the polynucleotide or polynucleotides encode the heavy chain comprising the antigen binding domain that specifically binds to CD4, the light chain comprising the antigen binding domain that specifically binds to CD4 and the IL15RASushi-IL15v-Fc fusion protein of a CD4-targeted IL-15v, as described herein, and comprise the following polynucleotide sequences, or polynucleotide sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the polynucleotide sequences set forth, respectively, in: SEQ ID NOs: 1104, 1105 and 1106; SEQ ID NOs: 1107, 1105 and 1108; SEQ ID NOs: 1109, 1110 and 1111;SEQ ID NOs: 1112, 1113 and 1114; SEQ ID NOs: 1115, 1116 and 1117; SEQ ID NOs: 1118, 1113 and 1119; or SEQ ID NOs: 1228, 1229 and 1230. In some embodiments, the polynucleotide or polynucleotides are DNA, cDNA, RNA or mRNA. Further provided is an expression cassette or multiple expression cassettes comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides as described above and herein. Further provided is a vector comprising the polynucleotide or polynucleotides or the expression cassette as described herein. In some embodiments, the vector is a plasmid vector or a viral vector. In some embodiments, the viral vector comprises a DNA virus or an RNA virus. In some embodiments, the viral vector is from a viral family selected from the group consisting of: Adenoviridae (e.g., Adenovirus), Arenaviridae (e.g., lymphocytic choriomeningitis mammarenavirus, Cali mammarenavirus (a.k.a., Pichinde mammarenavirus), Poxviridae (e.g., Vaccinia virus), Herpesviridae (e.g., Herpesvirus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus Hl), Reoviridae (e.g., Reovirus), Retroviridae (e.g., Lentivirus), Picomaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., Measles virus, Newcastle disease virus (NDV)), Rhabdoviridae (e.g., Vesicular stomatitis virus (VSV)), Togaviridae (e.g., Alphavirus, Sindbis virus) and Enteroviridae (e.g., Echovirus). Further provided is a lipoplex, e.g., lipid nanoparticle (LNP), comprising the polynucleotide or polynucleotides, the expression cassette, or the vector as described herein. In some embodiments of the lipoplex, e.g., lipid nanoparticle (LNP), the polynucleotide or polynucleotides are mRNA.

[0034] Further provided is a cell or population of cells comprising the polynucleotide or polynucleotides, the expression cassette, or the vector, as described herein, wherein the cell or population of cells expresses the IL-15v, the IL-15RA SUSHI domain-IL-15v fusion protein or the CD4-targeted IL-15 molecule, as described herein. In some embodiments, the cell or population of cells is a eukaryotic cell. In some embodiments, the cell or population of cells comprises a mammalian cell, an insect cell, a plant cell or a yeast cell. In some embodiments, the mammalian cell is a Chinese Hamster Ovary (CHO) cell. In some embodiments, the mammalian cell is a human cell. In some embodiments, the cell is a human embryonic kidney cell. In some embodiments, the population of cells produces at least 4 g / L, e.g., at least 5 g / L, at least 6 g / L, at least 7 g / L, at least 8 g / L, at least 9 g / L, or more, CD4-targeted IL- 15 molecule.

[0035] Further provided is a method of producing a CD4-targeted IL-15 molecule. In some embodiments, the method comprises: (a) culturing a cell or population of cells, described above and herein, transformed with the polynucleotide or polynucleotides, or the expression cassette or multiple expression cassettes, or the vector, described above and herein, in a cell culture under conditions sufficient to express the CD4-targeted IL-15 molecules; and (b) isolating or purifying the CD4-targeted IL- 15 molecules from the cell culture. In some embodiments, the polypeptide comprising the antigen binding domain that specifically binds to CD4 and the polypeptide comprising the IL15RASushi-IL15v-Fc fusion protein are expressed and assembled in the same cell. In some embodiments, the isolating or purifying step comprises Protein A chromatography. In some embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, of the CD4-targeted IL- 15 molecules are isolated or purified. In some embodiments, the cell or population of cells are cultured in a culture volume of at least 2L, e.g., at least 5L, 10L, 50L, 100L, 150L, 200L, 250L, 500L, WOOL, 2000L, or more. In some embodiments, the population of cells produces at least 4 g / L, e.g., at least 5 g / L, at least 6 g / L, at least 7 g / L, at least 8 g / L, at least 9 g / L, or more, of the CD4-targeted IL-15 molecule. In some embodiments, the method further comprises formulating the CD4-targeted IL-15 molecules into a sterile pharmaceutical composition suitable for administration to a human subject.

[0036] Further provided is a pharmaceutical composition comprising the CD4-targeted IL-15 molecule, the polynucleotide or polynucleotides, the expression cassette or multiple expression cassettes, the vector, or the lipoplex (e.g, LNP), described above and herein, and a pharmaceutically acceptable carrier. In some embodiments, the composition comprises an aqueous formulation. In some embodiments, the composition is lyophilized. In some embodiments, the pharmaceutical composition is formulated for intravenous, subcutaneous, intramuscular, intradermal, or mucosal (e.g. buccal, intranasal, intrarectal, intravaginal) administration. In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the pharmaceutical composition further comprises a second additional therapeutic agent. In some embodiments, the pharmaceutical composition further comprises second and third therapeutic agents. In some embodiments, the pharmaceutical composition further comprises a latency reversal agent (LRA). In some embodiments, the pharmaceutical composition further comprises a toll-like receptor (TLR) agonist. In some embodiments, the pharmaceutical composition further comprises a TLR agonist selected from a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or aTLR9 agonist. In some embodiments, the TLR3 agonist is selected from the group consisting of rintatolimod and Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose (poly ICLC (HILTONOL®)). In some embodiments, the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, resiquimod and NKTR-262. In some embodiments, the TLR8 agonist is selected from the group consisting of selgantolimod, motolimod, resiquimod and NKTR-262. In some embodiments, the TLR9 agonist is selected from the group consisting of cavrotolimod, cobitolimod, agatolimod, leftolimod, litenimod and tilsotolimod. In some embodiments, the pharmaceutical composition further comprises a multispecific T-cell engager, e.g., abispecific T-cell engager. In some embodiments, the pharmaceutical composition further comprises a CD4-Fc fusion protein. In some embodiments, the pharmaceutical composition further comprises GS 8588. In some embodiments, the pharmaceutical composition further comprises a lipid nanoparticle (LNP) comprising a human immunodeficiency virus (HIV) tat mRNA. In some embodiments, the pharmaceutical composition further comprises a non-nucleoside reverse transcriptase inhibitor (NNRTI) as targeted activator of cell kill (TACK). In some embodiments, the TACK is selected from efavirenz (EFV), rilpivirine (RPV), pyrimidone pyrOl, and pyrimidone pyr02. In some embodiments, the pharmaceutical composition further comprises a Second Mitochondria-derived Activator of Caspase (SMAC) mimetic or an inhibitor of cellular inhibitor of apoptosis proteins (cIAP). In some embodiments, the SMAC mimetic or cIAP inhibitor is selected from xevinapant, dasminapant, birinapant, tolinapant lactate, ciapavir and AZD5582. In some embodiments, the pharmaceutical composition further comprises an inhibitor of phosphatase and tensin homolog (PTEN inhibitor. In some embodiments, the pharmaceutical composition further comprises an inhibitor of one or both of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2). In some embodiments, the inhibitor of one or both of PTPN1 and PTPN2 is selected from 3 -Hydroxy- 1,2,3 -benzotriazin-4(3H)-one (HODHBt), avarol, osunprotafib, trodusquemine, S nitrosoglutathione, S-nitroso-N-acetylpenicillamine, talaramide Q, aurothiomalate disodium, daiokanzoto, berberine chloride, and alpha-tocopherolquinone. In some embodiments, the pharmaceutical composition further comprises one or more anti-HIV vaccines. In some embodiments, the anti-HIV vaccine is a viral vector vaccine. In some embodiments, the viral vector is selected from an arenavirus vector, a modified vaccinia virus Ankara (MV A)) vector, and a simian (e.g., chimpanzee, gorilla, rhesus) adenovirus vector. In some embodiments, the pharmaceutical composition further comprises one or more anti-HIV broadly neutralizing antibodies, e.g., that bind todifferent epitopes or regions of gpl20 selected from the group consisting of: (i) third variable loop (V3) (e.g., high mannose patch) comprising aN332 oligomannose glycan; (ii) second variable loop (V2) (e.g., Env trimer apex); (iii) CD4 binding site (CD4bs); (iv) gpl20 / gp41 interface; or (v) silent face of gpl20. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that binds to the third variable loop (V3) (e.g., high mannose patch) comprising a N332 oligomannose glycan and the second antigen binding molecule binds to the CD4 binding site (CD4bs). In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), 10-1074, 10-1074-J, elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-128 and PGT-134. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS 9723, 3BNC117, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04); CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS 9723, 3BNC117, VRC07 and VRC07-523. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 second variable loop (V2) (e.g., Env trimer apex). In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 / gp41 interface. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01. In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to an epitope or region of gp41 in the membrane proximal region (MPER). In some embodiments, the pharmaceutical composition further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-lOOcF, 4E10, DH511.11P, 2F5, A32, 7b2, andLNOl.

[0037] Further provided is a method of inducing, stimulating or promoting the proliferation of CD4+ T cells. In some embodiments, the method comprises contacting the CD4+ T cells with an effective amount of the CD4-targeted IL-15 molecule, the means for targeting IL-15v to CD4, or the pharmaceutical composition, as described above and herein. In some embodiments, the CD4+ T cells are in vivo. In some embodiments, the CD4+ T cells are in vitro. In some embodiments, the CD4+ T cell proliferation is induced, stimulated or promoted with a potency that is at least 100-fold, e.g., at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 600-fold, or more, in comparison to the potency for inducing, stimulating or promoting CD8+ T cell or NK cell proliferation. In some embodiments, the cell proliferation potency is measured by Ki -67 activation.

[0038] Further provided is a method or use of activating a latent viral reservoir in a subject infected with human immunodeficiency virus (HIV). Further provided is a method or use of treating or preventing human immunodeficiency virus (HIV) in a subject in need thereof. In some embodiments, the method or use comprises administering to a subject a therapeutically effective amount of the CD4-targeted IL- 15 molecule, the means for targeting IL-15v to CD4, the polynucleotide or polynucleotides, the expression cassette, the vector, the lipoplex (e.g, LNP), or the pharmaceutical composition, as described above and herein. In some embodiments, the method or use further comprises administering to the subject one or more additional therapeutic agents. In some embodiments, the method or use further comprisesadministering an HIV latency reversing agent (LRA). In some embodiments, the method or use further comprises administering a toll-like receptor (TLR) agonist. In some embodiments, the method or use further comprises administering a TLR agonist selected from a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist. In some embodiments, the TLR3 agonist is selected from the group consisting of rintatolimod and Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose (poly ICLC (HILTONOL®)). In some embodiments, the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, resiquimod and NKTR-262. In some embodiments, the TLR8 agonist is selected from the group consisting of selgantolimod, motolimod resiquimod and NKTR-262. In some embodiments, the TLR9 agonist is selected from the group consisting of cavrotolimod, cobitolimod, agatolimod, leftolimod, litenimod and tilsotolimod. In some embodiments, the method further comprises administering a multispecific T-cell engager, e.g., a bispecific T-cell engager. In some embodiments, the method further comprises administering a CD4-Fc fusion protein. In some embodiments, the method further comprises administering GS 8588. In some embodiments, the method further comprises administering a lipid nanoparticle (LNP) comprising an HIV tat mRNA. In some embodiments, the method further comprises administering a non-nucleoside reverse transcriptase inhibitor (NNRTI) as targeted activator of cell kill (TACK). In some embodiments, the TACK is selected from efavirenz (EFV), rilpivirine (RPV), pyrimidone pyrOl, and pyrimidone pyr02. In some embodiments, the method further comprises administering a Second Mitochondria-derived Activator of Caspase (SMAC) mimetic or an inhibitor of cellular inhibitor of apoptosis proteins (cIAP). In some embodiments, the SMAC mimetic or cIAP inhibitor is selected from xevinapant, dasminapant, birinapant, tolinapant lactate, ciapavir and AZD5582. In some embodiments, the method further comprises administering an inhibitor of one or both of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2). In some embodiments, the inhibitor of one or both of PTPN1 and PTPN2 is selected from 3 -Hydroxy- 1,2,3 -benzotriazin-4(3H)-one (HODHBt), avarol, osunprotafib, trodusquemine, S nitrosoglutathione, S-nitroso-N-acetylpenicillamine, talaramide Q, aurothiomalate disodium, daiokanzoto, berberine chloride, and alpha-tocopherolquinone. In some embodiments, the method further comprises administering one or more anti-HIV vaccines. In some embodiments, the anti-HIV vaccine is a viral vector vaccine. In some embodiments, the viral vector is selected from an arenavirus vector, modified vaccinia virus Ankara (MV A)) vector, and a simian (e.g., chimpanzee, gorilla, rhesus) adenovirus vector. In some embodiments, the method further comprises administeringan HIV vaccine in a prime-boost regimen, e.g., comprising: (a) Priming at a first time point by co-administering a first viral vector with the CD4-targeted IL- 15 molecule; and (b) Boosting at a second time point by co-administering a second viral vector with the CD4-targeted IL-15 molecule. In some embodiments, the first viral vector and the second viral vector are the same or are different. In some embodiments, the method further comprises administering to the subject one or more anti -HIV broadly neutralizing antibodies. In some embodiments, the one or more anti -HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 selected from the group consisting of (i) third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan; (ii) second variable loop (V2) and / or Env trimer apex; (iii) CD4 binding site (CD4bs); (iv) gpl20 / gp41 interface; or (v) silent face of gpl20. In some embodiments, the method further comprises administering to the subject the one or more antiHIV broadly neutralizing antibodies that bind to an epitope or region of gpl20 in the third variable loop (V3) and / or high mannose patch comprising aN332 oligomannose glycan and competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab, GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. In some embodiments, the method further comprises administering to the subject one or more anti -HIV broadly neutralizing antibodies that bind to an epitope or region of gpl20 in the second variable loop (V2) and / or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01. In some embodiments, the method further comprises administering to the subject one or more anti -HIV broadly neutralizing antibodies that bind to an epitope or region of gpl20 in the CD4 binding site (CD4bs) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), 3BNC117, GS-9723, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25. In some embodiments, the method further comprises administering to the subject one or more anti -HIV broadly neutralizing antibodies that bind to an epitope or region ofgpl20 in the gpl20 / gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01. In some embodiments, the method further comprises administering to the subject one or more anti -HIV broadly neutralizing antibodies that bind to an epitope or region of gpl20 silent face and competes with or comprises VH and VL regions from an antibody selected from VRC-PG05 and SF12. In some embodiments, the method further comprises administering to the subject one or more anti -HIV broadly neutralizing antibodies that bind to an epitope or region of gp41 in the membrane proximal region (MPER). In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, A32, 7b2, and LN01. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202. In some embodiments, the subject is not receiving antiretroviral therapy (ART) or ART is discontinued prior to administration of the CD4-targeted IL-15, the polynucleotide or polynucleotides, the expression cassette, the vector, the LNP or the pharmaceutical composition. In some embodiments, ART is discontinued after one or more administrations of the CD4-targeted IL-15, the polynucleotide or polynucleotides, the expression cassette, the vector, the LNP or the pharmaceutical composition. In some embodiments, the method further comprises administering one or more antiretroviral therapy (ART) agents to the subject. In some embodiments, the method further comprises administering one or more innate immune activators. In some embodiments, the one or more innate immune activators comprises an agonist of a receptor selected from the group consisting of firns related tyrosine kinase 3 (FLT3), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotide binding oligomerization domain containing 2 (N0D2). In some embodiments, the method further comprises administering one or both of GS-3583 and inarigivir soproxil (GS-9992). In some embodiments, the method further comprises co-administering one or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor. In some embodiments, the method further comprises the one or more immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2),transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6);HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI 6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domainsand long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the method further comprises co-administering one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the method further comprises co-administering one or more agonists or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the method further comprises co-administering one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the NK-cell inhibitoryimmune checkpoint proteins or receptors are selected from the group consisting of killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD 161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94), killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the method further comprises co-administering one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the NK-cell stimulatory immune checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from the group consisting of zimberelimab (AB 122), pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, ASC22, durvalumab, BMS-936559, CK-301, envafolimab (ASC-22, KN-035), PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-l / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFP-EC domain), CA-170 (PD-Ll / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the one or more immune checkpoint inhibitors comprises a small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002. In some embodiments, the subject is chronically infected with HIV. In some embodiments, the subject is heavily treatment experienced (HTE). In some embodiments the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition are administered systemically or locally. In some embodiments, the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition is administered via a route selected from intravenous, subcutaneous, intramuscular, intradermal, and mucosal e.g. buccal, intranasal, intrarectal, intravaginal). In some embodiments, the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by the same routes of administration. In some embodiments, the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by different routes of administration. In some embodiments, the CD4-targeted IL- 15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are co-administered according to the same schedule (e.g., co-administered at the same time intervals). In some embodiments, the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are co-administered according to different schedules e.g., co-administered at different time intervals). In some embodiments, the method comprises multiple administrations of the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition, optionally with one or more additional therapeutic agents, at predetermined intervals. In some embodiments, the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v have a serum half-life in a human of less than 3 days, less than 2 days or less than 1 day. In some embodiments, the subject or the mammal is a human. In someembodiments, the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v have a serum half-life in a human of less than 24 hours, e.g., less than 20 hours, less than 18 hours, less than 16 hours. In some embodiments, the subject or the mammal is a human.

[0039] Further provided is a kit comprising one or more unitary doses of an IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v, polynucleotide or polynucleotides encoding the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v, an expression cassette of claim, a vector, a lipoplex (e.g„ LNP) or a pharmaceutical composition comprising an IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v, as described above and herein. In some embodiments, the one or more unitary doses are in a single container. In some embodiments, the one or more unitary doses are in two or more separate containers. In some embodiments, the kit comprises one or more containers selected from the group consisting of vials, ampoules and pre-loaded syringes. In some embodiments, the one or more containers comprising the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v, in an aqueous solution. In some embodiments, the one or more unitary doses are the same. In some embodiments, the kit comprises two or more unitary doses, wherein the unitary doses are the same. In some embodiments, the one or more unitary doses are different. In some embodiments, the kit comprises two or more unitary doses, wherein the unitary doses are different. In some embodiments, the kit further comprises one or more unitary doses of one or more additional therapeutic agents. In some embodiments, the kit further comprises at least one latency reversal agent (LRA). In some embodiments, the kit further comprises at least one toll-like receptor (TLR) agonist. In some embodiments, the TLR agonist is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist. In some embodiments, the TLR3 agonist is selected from the group consisting of rintatolimod and Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose (poly ICLC (HILTONOL®)). In some embodiments, the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, resiquimod and NKTR-262. In some embodiments, the TLR8 agonist is selected from the group consisting of selgantolimod, motolimod resiquimod and NKTR-262. In some embodiments, the TLR9 agonist is selected from the group consisting of cavrotolimod, cobitolimod, agatolimod, leftolimod, litenimod and tilsotolimod. In some embodiments, the kit further comprises a multispecific T-cell engager, e.g., a bispecific T-cell engager. In some embodiments, the kit further comprises a CD4-Fc fusion protein. In some embodiments, the kit further comprises one or more unitary doses of GS 8588. In some embodiments, the kit furthercomprises a lipid nanoparticle (LNP) comprising an HIV tat mRNA. In some embodiments, the kit further comprises a non-nucleoside reverse transcriptase inhibitor (NNRTI) as targeted activator of cell kill (TACK). In some embodiments, the TACK is selected from efavirenz (EFV), rilpivirine (RPV), pyrimidone pyrOl, and pyrimidone pyr02. In some embodiments, the kit further comprises a Second Mitochondria-derived Activator of Caspase (SMAC) mimetic or an inhibitor of cellular inhibitor of apoptosis proteins (cIAP). In some embodiments, the SMAC mimetic or cIAP inhibitor is selected from xevinapant, dasminapant, birinapant, tolinapant lactate, ciapavir and AZD5582. In some embodiments, the kit further comprises an inhibitor of one or both of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2). In some embodiments, the inhibitor of one or both of PTPN1 and PTPN2 is selected from 3-Hydroxy-l,2,3-benzotriazin-4(3H)-one (HODHBt), avarol, osunprotafib, trodusquemine, S nitrosoglutathione, S-nitroso-N-acetylpenicillamine, talaramide Q, aurothiomalate disodium, daiokanzoto, berberine chloride, and alphatocopherolquinone. In some embodiments, the kit further comprises one or more anti-HIV vaccines. In some embodiments, the anti-HIV vaccine is a viral vector vaccine. In some embodiments, the viral vector is selected from an arenavirus vector, modified vaccinia virus Ankara (MV A)) vector, and a simian (e.g., chimpanzee, gorilla, rhesus) adenovirus vector. In some embodiments, the kit further comprises one or more anti-HIV broadly neutralizing antibodies that bind to different epitopes or regions of gpl20 selected from the group consisting of: (i) third variable loop (V3) (e.g, high mannose patch) comprising a N332 oligomannose glycan; (ii) second variable loop (V2) (e.g, Env trimer apex); (iii) CD4 binding site (CD4bs); (iv) gpl20 / gp41 interface; or (v) silent face of gpl20. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that binds to the third variable loop (V3) (e.g., high mannose patch) comprising a N332 oligomannose glycan and the second antigen binding molecule binds to the CD4 binding site (CD4bs). In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprisesVH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), 10-1074, 10-1074- J, elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-128 and PGT-134. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS-9723, 3BNC117, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04); CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS-9723, 3BNC117, VRC07 and VRC07-523. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 second variable loop (V2) (e.g., Env trimer apex). In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 / gp41 interface. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01. In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to an epitope or region of gp41 in the membrane proximal region (MPER). In some embodiments, the kit further comprises an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-lOOcF, 4E10, DH511.11P, 2F5, A32, 7b2, andLNOl. In some embodiments, the kit further comprises one or more innate immune activators. In some embodiments, the kit further comprises an agonist of a receptor selected from the group consisting of firns related tyrosine kinase 3 (FLT3), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotidebinding oligomerization domain containing 2 (NOD2). In some embodiments, the kit further comprises one or both of GS-3583 and inarigivir soproxil (GS-9992). In some embodiments, the kit further comprises one or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD 150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI 6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor,three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the kit further comprises one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the kit further comprises one or more agonists or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. In some embodiments the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40);TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the kit further comprises one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the kit further comprises one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the NK-cell stimulatory immune checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, the kit further comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from the group consisting of zimberelimab (AB 122), pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, ASC22, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN2034 (balstilimab), JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT- 1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-l / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFP-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the kit further comprises a small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figures 1A-1F illustrate the design of (A) IL-15-Fc / IL-15Ra-Fc fusion molecules, (B) N-terminal IL-15-Fc fusion CD4-targeted molecules, (C and D) N-terminal IL-15Ra-IL-15-Fc fusion CD4-targeted molecules, (E) C-terminal Fc-IL-15-IL-15Ra CD4-targeted molecules and (F) C-terminal Fc-IL-15Ra-IL-15 CD4-targeted IL- 15 molecules.

[0041] Figures 2A-2D illustrate in vitro potency of Fc-IL-15 variant fusion proteins on CD4+ T cell, CD8+ T cell and NK cell proliferation.

[0042] Figure 3 illustrates cryoelectron microscopy (Cryo-EM) structure of human anti-CD4 Fab 1.22 bound to human CD4 at 2.7A. The determined atomic structure confirms that the CD4 targeting arm binds to domain 3 of human CD4 and that the SNP positions Phe227 and Arg265 do not participate in the binding.

[0043] Figure 4 illustrates epitope of human CD4 recognized by the CD4 targeting antigen binding domain 1.22. The atomic structure of the complex between human CD4 and the anti-CD4 Fab 1.22 shows that the recognized residues are exclusively in domain 3 (D3) of CD4. The CD4 epitope is formed by residues 218, 220, 260, 271, 274-277, 279, 283 and 285. A CD4 residue was considered to be in contact with the Fab if the van-der-Waals radius of any of its atoms was within 0.4 A of an atom in the Fab as implemented in the analysis and visualization software program Chimera (rbvi.ucsf.edu / chimera / ).

[0044] Figure 5 illustrates binding to human CD4 (Arg265, dark grey bars) or human CD4 with a common polymorphism (hCD4.Trp265, light grey bars), as determined by ELISA. X-axis refers to anti-CD4 antibody clones; summarized in Tables A1-A4 and B. Y axis refers to optical density (OD) at 450 nm.

[0045] Figures 6A-6H illustrate graphics showing the IL- 15 receptor quaternary complex (Figure 6A), IL-15 interface with contact amino acid residues selected for substitution, e.g., S7, D61, E65, N65, 168 and QI 08 (Figure 6B) and interaction of these contact residues with surrounding residues from fL-2RPy (complex of CD122 (NCBI Gene ID: 3560) and CD132 (NCBI Gene ID: 3561)) (Figures 6C-6H). MLY refers to methylated lysine 71.

[0046] Figure 7 illustrates predicted stability of possible variants designed to mitigate glycan and deamidation liabilities.

[0047] Figure 8 illustrates the IL- 15 receptor quaternary complex in stick representation with IL-15 N-linked glycosylation and deamidation sites labeled.

[0048] Figures 9A-9B illustrate HIV virion RNA production after treatment with DMSO (vehicle control), 1 nM recombinant human IL-15, 1 nM CD4-targeted IL-15 (Molecule 101), or PMA and ionomycin in peripheral blood mononuclear cells (PBMCs) from anti-retroviral therapy (ART)-suppressed people with HIV (PWH) (Panel 9A; N = 17). Each symbol represents the geometric mean of six replicates from a single donor. Panel 9B shows paired comparison of IL-15 and CD4-targeted IL-15 (Molecule 101). Lines connect symbols representing results from the same donor. Significance was assessed by Wilcoxon matched pairs signed rank test.

[0049] Figure 10 illustrates HIV virion RNA production after treatment withCD4-targeted IL-15 in PBMCs from ART-suppressed PWH and activation of Ki67 expression. HIV viral reactivation ex vivo is plotted using the left axis and shown with dashed line and closed symbols. Ki67 expression is plotted on the right axis and shown with solid line and open symbols.

[0050] Figure 11 illustrates HIV virion RNA production after treatment with multiple CD4-targeted IL-15 molecules in PBMCs from ART-suppressed PWH. Each symbol represents the geometric mean of six replicates from a single donor.

[0051] Figure 12 illustrates HIV virion RNA production after treatment with pattern recognition receptor agonists in PBMCs from ART-suppressed PWH. Each symbol representsthe geometric mean of twelve replicates from a single donor. Conditions significantly different from the vehicle control were determined by Wilcoxon matched pairs signed rank test.

[0052] Figures 13A-13B. Figure 13A illustrates HIV virion RNA production after treatment with TLR7, TLR8, N0D2, TLR3, TLR2 agonists with or without recombinant human IL- 15 in PBMCs from ART-suppressed PWH (N = 7). “P / I” indicates the positive control condition, treatment with PMA and ionomycin. Each symbol represents the geometric mean of 12 replicates from a single donor. Significance was assessed by Wilcoxon matched pairs signed rank test. Figure 13B illustrates combined effects (e.g., synergy) calculated using Bliss independence model for TLR7, TLR8, N0D2, TLR3, TLR2 agonists with combination with recombinant human IL-15.

[0053] Figures 14A-14F. Figures 14A-14C illustrate HIV virion RNA production after treatment with TLR8 (14A), TLR2 (14B) or N0D2 (14C) agonists with or without recombinant human IL-15 in PBMCs from ART-suppressed PWH (N = 16). “PMA + lono” indicates the positive control condition, treatment with PMA and ionomycin. Each symbol represents the geometric mean of 12 replicates from a single donor. Significance was assessed by Wilcoxon matched pairs signed rank test. Figures 14D-14F demonstrate synergy for HIV virion RNA production after treatment of recombinant human IL-15 combined with TLR8 (14D), TLR2 (14E) or N0D2 (14F) agonists. Combined effects (e.g., synergy) were calculated using Bliss independence model and significance was assessed by paired two tailed t-test.

[0054] Figures 15A-15C. Figure 15A illustrates HIV virion RNA production after treatment with TLR8 or NOD2 agonists with or without CD4-targeted IL-15v (Molecule 277; Table 20) in PBMCs from ART-suppressed PWH (N = 16). Each symbol represents the geometric mean of 12 replicates from a single donor. Significance was assessed by Wilcoxon matched pairs signed rank test. Figure 15B and 15C demonstrate synergy observed after treatment of TLR8 (15B) and NOD2 (15C) with CD4-targeted IL-15v. Combined effects (e.g., synergy) were calculated using Bliss independence model and significance was assessed by paired two tailed t-test.

[0055] Figures 16A-16D. Figures 16A-B provide structures of illustrative HIV protease activators (a.k.a., non-nucleoside reverse transcriptase inhibitors (NNRTIs) as targeted activators of cell kill (TACK)) used in combination assays. Figure 16A provides structure of HIV protease activator used in combination with Molecule 101. Figure 16B provides structure of HIV protease activator used in combination with Molecule 173. Figures 16C-D illustratevirion production after treatment of PBMCs from ART-suppressed PWH with CD4-targeted IL- 15 with (Fig. 16C) bNAbs (N = 8 for Molecule 101; N =7 for Molecule 173) or (Fig. 16D) HIV protease activator (N = 17 for Molecule 101 and Molecule 173). Each symbol represents the geometric mean of eight replicates from a single donor. Lines connect samples from the same donor. Geometric means for each condition are shown at the top of the graph. Significance was assessed by Wilcoxon matched pairs signed rank test.

[0056] Figures 17A-17B. Figure 17A illustrates killing of HIV-infected CEM-NKr-CCR5-LucR+ cells by a dose titration of amtabafusp alfa (GS-8588) with a high concentration of each indicated CD4-targeted IL-15v molecule. Figure 17B illustrates the percent inhibition of amtabafusp alfa (GS-8588)-mediated killing of HIV-infected CEM-NKr-CCR5-LucR+ cells when pre-incubated with a dose titration of each indicated CD4-targeted IL-15v.

[0057] Figures 18A-18I illustrate single dose pharmacokinetic curves for (Fig. 18 A) Molecule 263 in rhesus macaques, (Fig. 18B) Molecule 264 in rhesus macaques, (Fig. 18C) Molecule 247 in rhesus macaques, (Fig. 18D) Molecule 247 in cynomolgus macaques, (Fig. 18E) Molecule 100 in cynomolgus macaques, (Fig. 18F) Molecule 101 in cynomolgus macaques, (Fig. 18G) Molecule 109 in cynomolgus macaques, (Fig. 18H) Molecule 173 in cynomolgus macaques, and (Fig. 181) Molecule 175 in cynomolgus macaques.

[0058] Figures 19A-19I illustrate the effect of single dose administration on CD4+ T cells, CD8+ T cells and NK cells after dosing with (Fig. 19A) Molecule 263 in rhesus macaques, (Fig. 19B) Molecule 264 in rhesus macaques, (Fig. 19C) Molecule 247 in rhesus macaques, (Fig. 19D) Molecule 247 in cynomolgus macaques, (Fig. 19E) Molecule 100 in cynomolgus macaques, (Fig. 19F) Molecule 101 in cynomolgus macaques, (Fig. 19G) Molecule 109 in cynomolgus macaques, (Fig. 19H) Molecule 173 in cynomolgus macaques, and (Fig. 191) Molecule 175 in cynomolgus macaques.

[0059] Figure 20 illustrates a study design with a rhesus CD4-targeted IL-15 tool molecule, Molecule 247, in SIVmac251 -infected, ART-suppressed rhesus macaques. Rhesus macaques were infected for over a year and then treated with daily with subcutaneous antiretroviral therapy (ART: 2.5 mg / ml dolutegravir (DTG), 40 mg / ml emtricitabine (FTC), 5.1 mg / ml tenofovir disoproxil fumarate (TDF)) for a year prior to therapeutic intervention.Animals were administered either Molecule 247 or vehicle control (placebo) intravenously (IV), biweekly for a total of six doses in the presence of ART as shown.

[0060] Figure 21 illustrates SIV viral reactivation activity by Molecule 247 in chronically infected, ART suppressed rhesus macaques. Plasma SIV viral RNA was assessed by SIV Gag RNA-specific quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) during dosing and up to 6 months after the last dose. PCR assays with 8 and 15 copy / ml lower limits of quantification (LLOQs) were utilized: 15 copy / ml assay was used from day 47 to 51 and day 85 to 238 and the 8 copy / ml assay was used for all other timepoints. Viral loads for individual animals in the vehicle (intact lines) and CD4-targeted IL15v (broken lines) groups are shown.

[0061] Figure 22 illustrates CD4+ T cell counts measured after the first, fourth and sixth dose of Molecule 247 or the vehicle control from the study shown in Figure 20.

[0062] Figures 23A-23B illustrate the activation of Ki67 in naive and memory CD4+ T cells after the first, fourth and sixth doses of Molecule 247 (Fig. 23 A) or the vehicle control (Fig. 23B) from the study shown in Figure 20.

[0063] Figure 24 illustrates the study design for Molecule 247 dosed in combination with bNAb, PGT-121, in chronically infected, ART suppressed rhesus macaques. SHIV-SF162P3 infected and ART (DTG+FTC+TDF) suppressed rhesus macaques were treated as shown. Upon completion of dosing and PGT-121 washout, animals were released from ART and followed for up to 9 months to study viral rebound kinetics in plasma.

[0064] Figure 25 illustrates viral rebound kinetics following ART treatment interruption in the 3 groups shown in Figure 24.

[0065] Figure 26 illustrates a study design for a combination study of CD4-targeted IL-15 (Molecule 247) with AZD5582 in ART-suppressed SIV-infected rhesus macaques.

[0066] Figures 27A-27C illustrate SIV viral reactivation in the study shown in Figure 26. Plasma viral RNA was assessed by SIV Gag RNA-specific quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) during dosing. PCR assay with 3 copy / ml lower limits of quantification (LLOQs) were utilized. Viral loads for individual animals from all three experimental groups were shown.

[0067] Figures 28A-28C illustrate IL-15v-mediated enhancement of tumor cell killing in vitro. NK cell proliferation (Fig. 28 A), CD107a-mediated NK cell degranulation (Fig. 28B) and cytotoxicity (Fig. 28C) of Raji cells upon treatment with recombinant human IL-15 (rhIL-15) or IL-15 mutein with high affinity (N65D; IL-15m (Hi)) or medium affinity (S7G N65D; IL-15m(Med)) or low affinity (N65D I68A; IL-15m (Low)) or isotype control. Cells were incubated 150 nM of indicated reagent and 1 nM of CD20-targeted NKG2D NK cell engager.Cytotoxicity data in (Fig. 28C) is normalized to Raji cell in control conditions.DETAILED DESCRIPTION1. Introduction

[0068] Provided are multi-specific orbispecific molecules, targeting CD4 and IL-15 receptor (CD 122 / CD 132), designed for high selectivity, improved tolerability, drug-like properties, and manufacturing efficiency. The herein described CD4-targeted IL-15v molecules include three components: (1) a CD4 binding domain, (2) a fusion protein comprising an IL-15 receptor alpha (IL-15Ra) Sushi domain and an IL-15 variant, and (3) a Fc domain.

[0069] The CD4 binding arm ( / .< ., antigen binding domain) is derived from a human sequence antibody sequence and selected for high affinity to CD4, low polyspecificity, high thermodynamic stability, low sequence liabilities for manufacturing and low immunogenicity. In some embodiments, the CD4 binding domain is specific for CD4 domain 3 (D3), avoiding competition with the natural CD4 ligand, MHC II, or with HIV Env, both of which bind CD4 domain 1 (DI). In some embodiments, a CD4 binding domain binds to CD4 in the presence or absence of commonly known polymorphisms, e.g., CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

[0070] The fusion protein has an IL-15Ra Sushi domain, a flexible linker and a variant of human IL-15. This IL-15Ra Sushi domain-IL-15v fusion design mimics the natural interaction between IL-15 and IL-15Ra, which typically binds IL-15 as the cytokine is synthesized and facilitates trans presentation to IL- 15 receptor beta / gamma (IL-15RPy;CD122 / CD132). Because IL-15Ra facilitates production and secretion of IL-15 under physiological conditions, acting as a chaperone that improves IL- 15 production, the IL-15Ra Sushi domain-IL-15v fusion protein improves production of the IL-15v-based molecule. See, e.g., Bergamaschi, etal., J Immunol (2009) 183(5):3064-72. In some embodiments, amino acid substitutions have been introduced into the human IL-15 that decrease its affinity for the IL-15RPY (CD 122 / CD 132). By reducing the affinity of the IL-15Ra Sushi domain-IL-15v fusion protein for its receptor, these amino acid substitutions significantly increase the pharmacokinetic properties of the molecule, mitigating the target mediated drug disposition that typically limits the stability of IL-15 molecules (Lu et al., Eur J Pharm Sci (2023) 186:106450).In certain embodiments, the CD4-targeted IL-15v molecules are designed to have a binding affinity for CD4 that is at least about 1000-fold stronger than a binding affinity for IL-15RPy. The attenuation of ZL-15RPy binding reduces the activation of cells that do not express the CD4 receptor, including NK and CD8+ T cells, which are typically strongly activated by wild-type IL-15. The herein described CD4-targeted IL-15v molecules are designed to achieve attenuation with a minimal combination of amino acids substitutions to the wild-type IL-15 sufficient to reduce binding affinity to the IL-15RPy or IL-2RPy complex (CD122 / CD132) and to reduce or minimize the potential for immunogenicity (e.g., anti-drug antibodies). The present disclosure demonstrates that the herein described CD4-targeted IL-15 molecules achieve higher levels of in vivo CD4+ T cell stimulation than have previously been reported with untargeted IL- 15 molecules and that this activation surprisingly includes both naive and memory CD4+ T cells. See, e.g, Example 14 and Figure 22, which shows 10-fold expansion of CD4+ T cells.Additionally, the herein described CD4-targeted IL- 15 molecules unexpectedly induce higher levels of HIV activation in comparison to wild-type IL-15, even when both molecules are used at saturating concentrations. Further, the monovalent IL-15Ra Sushi domain-IL-15v fusion protein in the format design decreases the likelihood of avidity-driven binding to IL- 15 receptors.

[0071] The Fc domain of the herein described CD4-targeted IL-15 molecules is designed to facilitate desired heterodimerization of the two heavy chains. As used herein, a “heavy chain” refers to a full-length polypeptide and may or may not contain immunoglobulin domains.Manufacturability is enhanced by substitutions in the Fc domain that reduce Protein A binding on one Fc domain polypeptide, allowing the use of Protein A-based affinity chromatography to efficiently enrich for heterodimers over the corresponding homodimer contaminants. Additional substitutions were introduced to the Fc region to abrogate binding to Fc gamma receptor (FcyR) and reduce or eliminate the potential for antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC). Furthermore, in the CD4-targeted IL- 15 molecules described herein, it is possible that the C-terminal lysine of the heavy and light chains might be clipped. Accordingly, in various embodiments of the CD4-targeted IL-15 molecules described herein, the C-terminal lysine of the heavy and light chains is present or absent.

[0072] The herein described CD4-targeted IL-15v provide a therapeutic modality that reduces the latent reservoir and enhances HIV control in the absence of daily or regular antiretroviral therapy (Dybul etal., Lancet HIV (2021) 8:e51-58). Activation of HIV expressionin latently infected cells increases the expression of HIV proteins and improves the efficacy of reservoir targeting modalities. The herein described CD4-targeted IL-15v improve cytokine targeting and tolerability to facilitate robust HIV activation and enhanced clearance of viral reservoirs, an important part of a strategy to induce HIV control in the absence of therapy.2. CD4 Binding Domains

[0073] Provided are antibodies and antigen-binding fragments thereof that specifically bind to CD4, e.g., human CD4 (NCBI Gene ID: 920; Uniprot P01730). The extracellular (EC) portion of CD4 comprises four immunoglobulin-like domains (D1-D4), comprised of residues 1-369 (Wu, et al., Nature (1997) 387(6632):527-30). In various embodiments, the CD4 binding domains specifically bind to one or more of domain 1 (DI), domain 2, (D2) or domain 3 (D3) of CD4, e.g., human CD4. The structure of human CD4 is described, e.g., in Wang, etal., Nature (1990) 348:411-418; Ryu, etal., Nature (1990) 348(6300):419-26; Leahy, FASEB J(1995) 9(1): 17-25; Barclay, et al., Philos Trans R Soc Lond B Biol Sci (1993) 342(1299):7-12; Garrett, et al., J Mol Biol (1993) 234(3):763-78; Sakihama, et al., Immunology Today (1995)16(12): 581 -87; and Wu, et al., Nature (1997) 387(6632):527-30. According to Ryu, et al., the first domain (DI) of CD4 comprises residues 1-98 and the second domain (D2) of CD4 contains residues 99-173. According to Wu, et al., residues 179-181 connect D1D2 to D3D4 and D3D4 is within residues 182-361, residues 362-363 being a carboxy-terminal extension, and residues 364-369 may provide a flexible linkage to the transmembrane segment. Freeman, et al., Structure (2010) 18(12): 1632-41 describes the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2A° resolution. Matthias, et al., Nat Immunol (2002) 3(8):727-32 reports that the CD4 DI, D2 and D4 domains each contain a disulfide bod and that the D2 disulfide bond is redox-active. As used herein, the signal peptide of human CD4 corresponds to amino acid residues 1-25, CD4 EC DI corresponds to amino acid residues 26-125, CD4 EC D2 corresponds to amino acid residues 126-203, CD4 EC D3 corresponds to amino acid residues 204-317, and CD4 EC DI corresponds to amino acid residues 318-374, wherein the amino acid residue positions are with respect to SEQ ID NO: 1120 (see, e.g., uniprot.org / uniprotkb / P01730 / entry).MNRGVPFRHLLLVLQLALLPAATQGKKWLGKKGDTVELTCTASQKKS IQFHWKNSNQIKILGN QGSFLTKGPSKLNDRADSRRSLWDQGNFPLI IKNLKIEDSDTYICEVEDQKEEVQLLVFGLTAN SDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQKK VEFKIDIWLAFQKASSIVYKKEGEQVEFSFPLAFTVEKLTGSGELWWQAERASSSKSWITFDLKNKEVSVKRVTQDPKLQMGKKLPLHLTLPQALPQYAGSGNLTLALEAKTGKLHQEVNLWMRAT QLQKNLTCEVWGPTSPKLMLSLKLENKEAKVSKREKAVWVLNPEAGMWQCLLSDSGQVLLESNI KVLPTWSTPVQPMALIVLGGVAGLLLFIGLGI FFCVRCRHRRRQAERMSQIKRLLSEKKTCQCP HRFQKTCSPI (human CD4 ; Uniprot P01730; SEQ ID NO: 1120) .

[0074] As used herein, numbering of a given amino acid polymer or nucleic acid polymer “corresponds to”, is “corresponding to” or is “relative to” the numbering of a selected or reference amino acid polymer or nucleic acid polymer when the position of any given polymer component (e.g., amino acid, nucleotide, also referred to generically as a “residue”) is designated by reference to the same or to an equivalent position (e.g., based on an optimal alignment or a consensus sequence) in the selected amino acid or nucleic acid polymer, rather than by the actual numerical position of the component in the given polymer.

[0075] With regard to the binding of an antibody or antigen-binding fragment thereof to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a nontarget molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. An antibody or antigen-binding fragment thereof that “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. Affinities of antibodies can be readily determined using conventional techniques, for example, those described by Scatchard et al. (Ann. N. Y. Acad. Sci. USA 51: 660 (1949), ELISA assays, biolayer interferometry (BLI) assays, and surface plasmon resonance (SPR) assays). Binding properties of an antibody to antigens, cells or tissues thereof may generally be determined and assessed using immunodetection methods including, for example, immunofluorescence-based assays, such as immuno-histochemistry (IHC) and / or fluorescence- activated cell sorting (FACS).

[0076] “Antigen-binding antibody fragments” comprise a portion of an intact antibody, for example, the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include without limitation scFv, sc(Fv)2, Fab, F(ab)2, Fab’, F(ab’)2, Facb, and Fv fragments; diabodies; linear F(ab')2 fragments (e.g., Zapata et al., Protein Eng. (1995) 8(10): 1057-1062); single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen combining sites and is still capable of cross-linking antigen. Antigen-binding antibody fragments of use are reviewed in, e.g., Kitten, et al., Med Sci (Paris). (2019) 35(12): 1092-1097 and Chiu, et al., Antibodies (Basel). (2019) 8(4):55.Domains That Bind to CD4 D1

[0077] Provided are antibodies or antigen-binding fragments thereof that specifically bind to CD4D1.

[0078] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 1, 2, 3, 4, 5 and 6; (1)2) SEQ ID NOs: 1, 7, 3, 4, 8 and 9; (2)3) SEQ ID NOs: 1, 10, 3, 11, 5 and 6; (3)4) SEQ ID NOs: 1, 10, 3, 11, 12 and 6; (4)5) SEQ ID NOs: 1, 10, 3, 11, 8 and 9; (5)6) SEQ ID NOs: 1, 13, 3, 11, 8 and 9; (6)7) SEQ ID NOs: 1, 14, 3, 11, 8 and 9; (7)8) SEQ ID NOs: 1, 15, 3, 11, 8 and 9; (8)9) SEQ ID NOs: 1, 16, 3, 11, 8 and 9; (9)10) SEQ ID NOs: 1, 15, 3, 11, 12 and 17; (10)11) SEQ ID NOs: 1, 16, 3, 11, 12 and 18; (11)12) SEQ ID NOs: 1, 1078, 3, 11, 8 and 9; (12)13) SEQ ID NOs: 1, 1079, 3, 11, 8 and 9; (13, 14, 17, 18 and 19)14) SEQ ID NOs: 1, 1080, 3, 11, 8 and 9; (15)15) SEQ ID NOs: 1, 1081, 3, 11, 8 and 9; (16)16) SEQ ID NOs: 19, 20, 21, 22, 23 and 24; (1.17)17) SEQ ID NOs: 25, 26, 27, 28, 29 and 30; (1.25)18) SEQ ID NOs: 31, 32, 33, 34, 29 and 35; (1.26)19) SEQ ID NOs: 25, 36, 37, 28, 29 and 38; (1.27)20) SEQ ID NOs: 25, 1082, 39, 28, 29 and 38; (1.28)21) SEQ ID NOs: 40, 41, 42, 28, 29 and 35; (1.29)22) SEQ ID NOs: 25, 43, 39, 28, 29 and 38; (1.30)23) SEQ ID NOs: 25, 44, 45, 28, 29 and 35; (1.31)24) SEQ ID NOs: 25, 46, 47, 28, 29 and 35; (1.32)25) SEQ ID NOs: 25, 48, 49, 28, 29 and 35; (1.33)26) SEQ ID NOs: 25, 48, 50, 28, 29 and 35; (1.34)27) SEQ ID NOs: 51, 52, 53, 54, 55 and 56; (1.45) or28) SEQ ID NOs: 51, 57, 53, 58, 55 and 56; (1.46, 1.47, 1.48).

[0079] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 178, 179, 180, 181, 182 and 6; (1)2) SEQ ID NOs: 178, 183, 180, 181, 182 and 9; (2)3) SEQ ID NOs: 178, 184, 180, 181, 182 and 6; (4)4) SEQ ID NOs: 178, 184, 180, 181, 182 and 9; (3, 5)5) SEQ ID NOs: 178, 185, 180, 181, 182 and 9; (6, 7, 12)6) SEQ ID NOs: 178, 186, 180, 181, 182 and 9; (8)7) SEQ ID NOs: 178, 187, 180, 181, 182 and 9; (9)8) SEQ ID NOs: 178, 186, 180, 181, 182 and 17; (10)9) SEQ ID NOs: 178, 187, 180, 181, 182 and 18; (11)10) SEQ ID NOs: 178, 188, 180, 181, 182 and 9; (13, 14, 17, 18, 19)11) SEQ ID NOs: 178, 189, 180, 181, 182 and 9; (15)12) SEQ ID NOs: 178, 190, 180, 181, 182 and 9; (16)13) SEQ ID NOs: 191, 192, 193, 194, 195 and 24; (1.17)14) SEQ ID NOs: 196, 197, 198, 199, 200 and 30; (1.25)15) SEQ ID NOs: 201, 202, 203, 199, 200 and 35; (1.26)16) SEQ ID NOs: 204, 205, 206, 199, 200 and 38; (1.27)17) SEQ ID NOs: 196, 207, 208, 199, 200 and 38; (1.28)18) SEQ ID NOs: 209, 210, 211, 199, 200 and 35; (1.29)19) SEQ ID NOs: 196, 212, 208, 199, 200 and 38; (1.30)20) SEQ ID NOs: 196, 213, 214, 199, 200 and 35; (1.31)21) SEQ ID NOs: 196, 213, 215, 199, 200 and 35; (1.32)22) SEQ ID NOs: 196, 216, 217, 199, 200 and 35; (1.33)23) SEQ ID NOs: 196, 216, 218, 199, 200 and 35; (1.34)24) SEQ ID NOs: 219, 220, 221, 222, 223 and 56; (1.45) or25) SEQ ID NOs: 219, 224, 221, 225, 223 and 56; (1.46, 1.47, 1.48).

[0080] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 323, 324, 325, 326, 182 and 327; (1)2) SEQ ID NOs: 323, 328, 325, 326, 182 and 329; (2)3) SEQ ID NOs: 323, 330, 325, 326, 182 and 327; (4)4) SEQ ID NOs: 323, 330, 325, 326, 182 and 329; (5)5) SEQ ID NOs: 323, 331, 325, 326, 182 and 329; (6, 7, 12)6) SEQ ID NOs: 323, 332, 325, 326, 182 and 329; (8)7) SEQ ID NOs: 323, 333, 325, 326, 182 and 329; (9)8) SEQ ID NOs: 323, 332, 325, 326, 182 and 334; (10)9) SEQ ID NOs: 323, 333, 325, 326, 182 and 335; (11)10) SEQ ID NOs: 323, 336, 325, 326, 182 and 329; (13, 14, 17, 18 and 19)11) SEQ ID NOs: 323, 337, 325, 326, 182 and 329; (15)12) SEQ ID NOs: 323, 338, 325, 326, 182 and 329; (16)13) SEQ ID NOs: 339, 340, 341, 342, 195 and 1131; (1.17)14) SEQ ID NOs: 344, 345, 346, 347, 200 and 348; (1.25)15) SEQ ID NOs: 349, 350, 351, 347, 200 and 352; (1.26)16) SEQ ID NOs: 353, 354, 355, 347, 200 and 356; (1.27)17) SEQ ID NOs: 344, 350, 357, 347, 200 and 356; (1.28)18) SEQ ID NOs: 358, 350, 359, 347, 200 and 352; (1.29)19) SEQ ID NOs: 343, 354, 357, 347, 200 and 356; (1.30)20) SEQ ID NOs: 343, 360, 361, 347, 200 and 352; (1.31)21) SEQ ID NOs: 343, 360, 362, 347, 200 and 352; (1.32)22) SEQ ID NOs: 343, 363, 364, 347, 200 and 352; (1.33)23) SEQ ID NOs: 343, 363, 365, 347, 200 and 352; (1.34)24) SEQ ID NOs: 366, 367, 368, 1084, 223 and 369; (1.45) or25) SEQ ID NOs: 366, 367, 368, 370, 223 and 369; (1.46, 1.47, 1.48).

[0081] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 463, 464, 465, 466, 467 and 327; (1)2) SEQ ID NOs: 463, 468, 465, 466, 469 and 329; (2)3) SEQ ID NOs: 463, 470, 465, 466, 467 and 327; (3)4) SEQ ID NOs: 463, 470, 465, 466, 469 and 327; (4)5) SEQ ID NOs: 463, 470, 465, 466, 469 and 329; (5)6) SEQ ID NOs: 463, 1132, 465, 466, 469 and 329; (6)7) SEQ ID NOs: 463, 471, 465, 466, 469 and 329; (7)8) SEQ ID NOs: 463, 472, 465, 466, 469 and 329; (8)9) SEQ ID NOs: 463, 473, 465, 466, 469 and 329; (9)10) SEQ ID NOs: 463, 472, 465, 466, 474 and 334; (10)11) SEQ ID NOs: 463, 473, 465, 466, 474 and 335; (11)12) SEQ ID NOs: 463, 475, 465, 466, 469 and 329; (12)13) SEQ ID NOs: 463, 478, 465, 466, 469 and 329; (13, 14, 17, 18 and 19) 14) SEQ ID NOs: 463, 476, 465, 466, 469 and 329; (15)15) SEQ ID NOs: 463, 477, 465, 466, 469 and 329; (16)16) SEQ ID NOs: 479, 480, 481, 482, 483 and 1131; (1.17) 17) SEQ ID NOs: 484, 485, 486, 487, 488 and 348; (1.25)18) SEQ ID NOs: 489, 490, 491, 487, 492 and 352; (1.26)19) SEQ ID NOs: 493, 494, 495, 487, 492 and 356; (1.27)20) SEQ ID NOs: 484, 496, 497, 487, 492 and 356; (1.28)21) SEQ ID NOs: 498, 499, 500, 487, 492 and 352; (1.29)22) SEQ ID NOs: 484, 501, 497, 487, 492 and 356; (1.30)23) SEQ ID NOs: 484, 502, 503, 487, 492 and 352; (1.31)24) SEQ ID NOs: 484, 504, 505, 487, 506 and 352; (1.32)25) SEQ ID NOs: 484, 507, 508, 487, 492 and 352; (1.33)26) SEQ ID NOs: 484, 507, 509, 487, 492 and 352; (1.34)27) SEQ ID NOs: 510, 511, 512, 513, 514 and 369; (1.45) or 28) SEQ ID NOs: 510, 515, 512, 516, 514 and 369; (1.46, 1.47, 1.48).

[0082] In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 625 and 626; (1)2) SEQ ID NOs: 627 and 628; (2)3) SEQ ID NOs: 629 and 630; (3)4) SEQ ID NOs: 629 and 631 ; (4)5) SEQ ID NOs: 629 and 632; (5)6) SEQ ID NOs: 633 and 632; (6)7) SEQ ID NOs: 634 and 632; (7)8) SEQ ID NOs: 635 and 632; (8)9) SEQ ID NOs: 636 and 632; (9)10) SEQ ID NOs: 635 and 637; (10)11) SEQ ID NOs: 636 and 638; (11)12) SEQ ID NOs: 639 and 632; (12)13) SEQ ID NOs: 640 and 632; (13)14) SEQ ID NOs: 641 and 632; (14)15) SEQ ID NOs: 642 and 632; (15)16) SEQ ID NOs: 643 and 632; (16)17) SEQ ID NOs: 640 and 644; (17)18) SEQ ID NOs: 640 and 645; (18)19) SEQ ID NOs: 640 and 646; (19)20) SEQ ID NOs: 647 and 648; (1.17)21) SEQ ID NOs: 649 and 650; (1.25)22) SEQ ID NOs: 651 and 652; (1.26)23) SEQ ID NOs: 653 and 654; (1.27)24) SEQ ID NOs: 655 and 656; (1.28)25) SEQ ID NOs: 657 and 658; (1.29)26) SEQ ID NOs: 659 and 660; (1.30)27) SEQ ID NOs: 661 and 662; (1.31)28) SEQ ID NOs: 663 and 664; (1.32)29) SEQ ID NOs: 665 and 666; (1.33)30) SEQ ID NOs: 667 and 666; (1.34)31) SEQ ID NOs: 668 and 669; (1.45)32) SEQ ID NOs: 670 and 671; (1.46)33) SEQ ID NOs: 672 and 673; (1.47) or34) SEQ ID NOs: 672 and 671; (1.48).

[0083] “Homology” or “identity” or “similarity” as used herein in the context of nucleic acids and polypeptides refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the amino acid sequences or nucleic acid sequences, respectively. Homology and identity can each be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When an equivalent position in the compared sequences is occupied by the same base or amino acid, then the molecules are identical at that position; when the equivalent site occupied by the same or a similar amino acid residue (e.g., similar in steric and / or electronic nature), then the molecules can be referred to as homologous (similar) at that position. Expression as a percentage of homology / similarity or identity refers to a function of the number of identical or similar amino acids at positions shared by the compared sequences. In comparing two sequences, the absence of residues (amino acids or nucleic acids) or presence of extra residues also decreases the identity and homology / similarity.

[0084] As used herein, “identity” means the percentage of identical nucleotide or amino acid residues at corresponding positions in two or more sequences when the sequences are aligned to maximize sequence matching, / .< ., taking into account gaps and insertions. Sequences are generally aligned for maximum correspondence over a designated region, e.g., a region at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or more amino acids or nucleotides in length, and can be up to the full length of the reference polypeptide or polynucleotide sequence. For sequencecomparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer program, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Otherwise, standard parameters can be used. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0085] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least 20 contiguous positions, usually 30 to 75, 40 to 50, or the full length of a sequence, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0086] Optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (e.g., GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.

[0087] One example of algorithms that are suitable for determining percent sequence identity are the Basic Local Alignment Search Tool (BLAST), BLAST 2.0 and PSLBLAST algorithms, which are described in Altschul, et al., J. Mol. Biol. (1990) 215: 403-410, Altschul, et al., Nucleic Acids Res. (1977) 25: 3389-3402, and Altschul, et al., Nucleic Acids Res. (1997) 25(17):3389-402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (blast.ncbi.nlm.nih.gov / Blast.cgi).

[0088] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to theaccumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTP program (for polypeptide sequences) or the BLASTN program (for polynucleotide sequences) uses as defaults a word length (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands.

[0089] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLASTP algorithm parameters W, T and X determine the sensitivity and speed of the alignment.

[0090] In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions ( / .< ., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence ( / .< ., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0091] Residue positions which are not identical can differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine (Gly, G), alanine (Ala, A), valine (Vai, V), leucine (Leu, L), and isoleucine (He, I); a group of amino acids having aliphatic-hydroxyl side chains is serine (Ser, S) and threonine (Thr, T); a group of amino acids having amide-containing side chains is asparagine (Asn, N) and glutamine (Gin, Q); a group of amino acids having aromatic side chains is phenylalanine (Phe, F), tyrosine (Tyr, Y), and tryptophan (Trp, W); a group of amino acids having basic side chains is lysine (Lys, K), arginine (Arg, R), and histidine (His, H); and a group of amino acids havingsulfur-containing side chains is cysteine (Cys, C) and methionine (Met, M). Further, glutamic acid (Glu, E) and aspartic acid (Asp, D) are conservative amino acid substitutions.

[0092] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 2, 3, 4, 5 and 6 (according to Kabat);2) SEQ ID NOs: 178, 179, 180, 181, 182 and 6 (according to IMGT);3) SEQ ID NOs: 323, 324, 325, 326, 182 and 327 (according to Chothia); or4) SEQ ID NOs: 463, 464, 465, 466, 467 and 327 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 625 and 626 (antibody 1).

[0093] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 7, 3, 4, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 183, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 328, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 468, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 627 and 628 (antibody 2).

[0094] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 10, 3, 11, 5 and 6 (according to Kabat);2) SEQ ID NOs: 178, 184, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 330, 325, 326, 182 and 327 (according to Chothia); or4) SEQ ID NOs: 463, 470, 465, 466, 467 and 327 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 629 and 630 (antibody 3).

[0095] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 10, 3, 11, 12 and 6 (according to Kabat);2) SEQ ID NOs: 178, 184, 180, 181, 182 and 6 (according to IMGT);3) SEQ ID NOs: 323, 330, 325, 326, 182 and 327 (according to Chothia); or4) SEQ ID NOs: 463, 470, 465, 466, 469 and 327 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 629 and 631 (antibody 4).

[0096] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 10, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 184, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 330, 325, 326, 182 and 329 (according to Chothia); or 4) SEQ ID NOs: 463, 470, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 629 and 632 (antibody 5).

[0097] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 13, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 185, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 331, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 1132, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 633 and 632 (antibody 6).

[0098] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 14, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 185, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 331, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 471, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 634 and 632 (antibody 7).

[0099] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 15, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 186, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 332, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 472, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 635 and 632 (antibody 8).

[0100] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 16, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 187, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 333, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 473, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 636 and 632 (antibody 9).

[0101] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 15, 3, 11, 12 and 17 (according to Kabat);2) SEQ ID NOs: 178, 186, 180, 181, 182 and 17 (according to IMGT);3) SEQ ID NOs: 323, 332, 325, 326, 182 and 334 (according to Chothia); or4) SEQ ID NOs: 463, 472, 465, 466, 474 and 334 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 635 and 637 (antibody 10).

[0102] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 16, 3, 11, 12 and 18 (according to Kabat);2) SEQ ID NOs: 178, 187, 180, 181, 182 and 18 (according to IMGT);3) SEQ ID NOs: 323, 333, 325, 326, 182 and 335 (according to Chothia); or4) SEQ ID NOs: 463, 473, 465, 466, 474 and 335 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 636 and 638 (antibody 11).

[0103] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 1078, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 185, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 331, 325, 326, 182 and 329 (according to Chothia); or 4) SEQ ID NOs: 463, 475, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 639 and 632 (antibody 12).

[0104] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 1079, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 188, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 336, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 475, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 640 and 632 (antibody 13). In some embodiments, provided is an antibody or antigenbinding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 641 and 632 (antibody 14). In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 640 and 644 (antibody 17). In some embodiments, provided is an antibody or antigenbinding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length ofthe amino acid sequences set forth in SEQ ID NOs: 640 and 645 (antibody 18). In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 640 and 646 (antibody 19).

[0105] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 1080, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 189, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 337, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 476, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 642 and 632 (antibody 15).

[0106] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 1, 1080, 3, 11, 8 and 9 (according to Kabat);2) SEQ ID NOs: 178, 190, 180, 181, 182 and 9 (according to IMGT);3) SEQ ID NOs: 323, 338, 325, 326, 182 and 329 (according to Chothia); or4) SEQ ID NOs: 463, 477, 465, 466, 469 and 329 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 643 and 632 (antibody 16).

[0107] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 19, 20, 21, 22, 23 and 24 (according to Kabat);2) SEQ ID NOs: 191, 192, 193, 194, 195 and 24 (according to IMGT);3) SEQ ID NOs: 339, 340, 341, 342, 195 and 1131 (according to Chothia); or4) SEQ ID NOs: 479, 480, 481, 482, 483 and 1131 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 647 and 648 (antibody 1.17).

[0108] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 26, 27, 28, 29 and 30 (according to Kabat);2) SEQ ID NOs: 196, 197, 198, 199, 200 and 30 (according to IMGT);3) SEQ ID NOs: 344, 345, 346, 347, 200 and 348 (according to Chothia); or4) SEQ ID NOs: 484, 485, 486, 487, 488 and 348 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 649 and 650 (antibody 1.25).

[0109] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 31, 32, 33, 34, 29 and 35 (according to Kabat);2) SEQ ID NOs: 201, 202, 203, 199, 200 and 35 (according to IMGT);3) SEQ ID NOs: 349, 350, 351, 347, 200 and 352 (according to Chothia); or4) SEQ ID NOs: 489, 490, 491, 487, 492 and 352 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 651 and 652 (antibody 1.26).

[0110] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 36, 37, 28, 29 and 38 (according to Kabat);2) SEQ ID NOs: 204, 205, 206, 199, 200 and 38 (according to IMGT);3) SEQ ID NOs: 353, 354, 355, 347, 200 and 356 (according to Chothia); or4) SEQ ID NOs: 493, 494, 495, 487, 492 and 356 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 653 and 654 (antibody 1.27).[OHl] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 1082, 39, 28, 29 and 38 (according to Kabat);2) SEQ ID NOs: 196, 207, 208, 199, 200 and 38 (according to IMGT);3) SEQ ID NOs: 344, 350, 357, 347, 200 and 356 (according to Chothia); or 4) SEQ ID NOs: 484, 496, 497, 487, 492 and 356 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 655 and 656 (antibody 1.28).

[0112] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 40, 41, 42, 28, 29 and 35 (according to Kabat);2) SEQ ID NOs: 209, 210, 211, 199, 200 and 35 (according to IMGT);3) SEQ ID NOs: 358, 350, 359, 347, 200 and 352 (according to Chothia); or 4) SEQ ID NOs: 498, 499, 500, 487, 492 and 352 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 657 and 658 (antibody 1.29).

[0113] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 43, 39, 28, 29 and 38 (according to Kabat);2) SEQ ID NOs: 196, 212, 208, 199, 200 and 38 (according to IMGT);3) SEQ ID NOs: 343, 354, 357, 347, 200 and 356 (according to Chothia); or4) SEQ ID NOs: 484, 501, 497, 487, 492 and 356 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 659 and 660 (antibody 1.30).

[0114] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 44, 45, 28, 29 and 35 (according to Kabat);2) SEQ ID NOs: 196, 213, 214, 199, 200 and 35 (according to IMGT);3) SEQ ID NOs: 343, 360, 361, 347, 200 and 352 (according to Chothia); or4) SEQ ID NOs: 484, 502, 503, 487, 492 and 352 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 661 and 662 (antibody 1.31).

[0115] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 46, 47, 28, 29 and 35 (according to Kabat);2) SEQ ID NOs: 196, 213, 215, 199, 200 and 35 (according to IMGT);3) SEQ ID NOs: 343, 360, 362, 347, 200 and 352 (according to Chothia); or4) SEQ ID NOs: 484, 504, 505, 487, 506 and 352 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 663 and 664 (antibody 1.32).

[0116] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 48, 49, 28, 29 and 35 (according to Kabat);2) SEQ ID NOs: 196, 216, 217, 199, 200 and 35 (according to IMGT);3) SEQ ID NOs: 343, 363, 364, 347, 200 and 352 (according to Chothia); or4) SEQ ID NOs: 484, 507, 508, 487, 492 and 352 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 665 and 666 (antibody 1.33).

[0117] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 48, 50, 28, 29 and 35 (according to Kabat);2) SEQ ID NOs: 196, 216, 218, 199, 200 and 35 (according to IMGT);3) SEQ ID NOs: 343, 363, 365, 347, 200 and 352 (according to Chothia); or4) SEQ ID NOs: 484, 507, 509, 487, 492 and 352 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 667 and 666 (antibody 1.34).

[0118] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 51, 52, 53, 54, 55 and 56 (according to Kabat);2) SEQ ID NOs: 219, 220, 221, 222, 223 and 56 (according to IMGT);3) SEQ ID NOs: 366, 367, 368, 1084, 223 and 369 (according to Chothia); or 4) SEQ ID NOs: 510, 511, 512, 513, 514 and 369 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 668 and 669 (antibody 1.45).

[0119] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 51, 57, 53, 58, 55 and 56 (according to Kabat);2) SEQ ID NOs: 219, 224, 221, 225, 223 and 56 (according to IMGT);3) SEQ ID NOs: 366, 367, 368, 370, 223 and 369 (according to Chothia); or4) SEQ ID NOs: 510, 515, 512, 516, 514 and 369 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 DI, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 670 and 671, 672 and 673, or 672 and 671 (antibody 1.46, 1.47 or 1.48).Antigen Binding Domains That Specifically Bind to CD4 D2

[0120] Provided are antibodies or antigen-binding fragments thereof that specifically bind to CD4 D2. Antibodies or antigen-binding fragments thereof that specifically bind to CD4 D2 are useful in combination therapies with molecules that comprise a CD4 DI extracellular domain, e.g, a CD4 Dl-Fc fusion protein, e.g, a molecule comprising CD4 DI.22, described in Chen, et al., J. Virol. (2014) 88(2): 1125-1139. For example, antibodies or antigen-binding fragments thereof that specifically bind to CD4 D2 are useful in combination therapies with molecules comprising CD4 DI, e.g, molecules comprising a CD4-Fc fusion protein described, e.g, in certain embodiments, the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v, as described herein, is combined or co-administered with. In some embodiments, the antibodies or antigen-binding fragments thereof that specifically bind to CD4D2, described herein, are insensitive to ( / .< ., bind to CD4 in the presence and absence of the polymorphism) the amino acid substitutions resulting from CD4 polymorphism variant ID rsl 1064416 (F123L), wherein the amino acid positions are with reference to SEQ ID NO: 1120.

[0121] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 25, 83, 84, 85, 86 and 87; (1.1)2) SEQ ID NOs: 88, 89, 90, 91, 92 and 93; (1.4)3) SEQ ID NOs: 94, 95, 96, 97, 98 and 99; (1.5)4) SEQ ID NOs: 88, 100, 101, 102, 103 and 104; (2.9)5) SEQ ID NOs: 88, 105, 106, 107, 108 and 93; (2.10)6) SEQ ID NOs: 88, 109, 110, 111, 108 and 112; (2.11)7) SEQ ID NOs: 88, 109, 110, 111, 113 and 112; (2.11 VL N50G)8) SEQ ID NOs: 88, 114, 106, 107, 108 and 115; (2.12)9) SEQ ID NOs: 88, 114, 106, 107, 113 and 115; (2.12 VLN50G)10) SEQ ID NOs: 88, 116, 117, 118, 108 and 119; (2.13)11) SEQ ID NOs: 120, 121, 122, 102, 113 and 123; (2.14) or12) SEQ ID NOs: 88, 124, 122, 125, 113 and 104; (2.15).

[0122] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 246, 247, 248, 249, 250 and 87; (1.1)2) SEQ ID NOs: 251, 252, 253, 254, 255 and 93; (1.4)3) SEQ ID NOs: 256, 257, 258, 259, 255 and 99; (1.5)4) SEQ ID NOs: 251, 260, 261, 262, 263 and 104; (2.9)5) SEQ ID NOs: 251, 264, 265, 266, 267 and 93; (2.10)6) SEQ ID NOs: 251, 268, 269, 270, 267 and 112; (2.11)7) SEQ ID NOs: 251, 268, 269, 270, 263 and 112; (2.11 VLN50G)8) SEQ ID NOs: 251, 271, 265, 266, 267 and 115; (2.12)9) SEQ ID NOs: 251, 271, 265, 266, 263 and 115; (2.12 VLN50G) 10) SEQ ID NOs: 251, 272, 273, 274, 267 and 119; (2.13)11) SEQ ID NOs: 275, 276, 277, 262, 263 and 123; (2.14) or12) SEQ ID NOs: 251, 278, 277, 279, 263 and 104; (2.15).

[0123] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 390, 391, 392, 393, 250 and 394; (1.1)2) SEQ ID NOs: 395, 396, 397, 398, 255 and 399; (1.4)3) SEQ ID NOs: 400, 401, 402, 403, 255 and 404; (1.5)4) SEQ ID NOs: 395, 405, 406, 407, 263 and 408; (2.9)5) SEQ ID NOs: 395, 409, 410, 411, 267 and 399; (2.10)6) SEQ ID NOs: 395, 412, 413, 414, 267 and 399; (2.11)7) SEQ ID NOs: 395, 412, 413, 414, 263 and 399; (2.11 VLN50G)8) SEQ ID NOs: 395, 415, 410, 411, 267 and 408; (2.12)9) SEQ ID NOs: 395, 415, 410, 411, 263 and 408; (2.12 VLN50G)10) SEQ ID NOs: 395, 416, 417, 418, 267 and 419; (2.13)11) SEQ ID NOs: 420, 421, 422, 407, 263 and 408; (2.14) or12) SEQ ID NOs: 395, 423, 422, 424, 263 and 408; (2.15).

[0124] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 536, 537, 538, 539, 540 and 394; (1.1)2) SEQ ID NOs: 541, 542, 543, 544, 545 and 399; (1.4)3) SEQ ID NOs: 546, 547, 548, 549, 550 and 404; (1.5)4) SEQ ID NOs: 541, 551, 552, 553, 554 and 408; (2.9)5) SEQ ID NOs: 541, 555, 556, 557, 558 and 399; (2.10)6) SEQ ID NOs: 541, 559, 560, 561, 562 and 399; (2.11)7) SEQ ID NOs: 541, 559, 560, 561, 563 and 399; (2.11 VLN50G)8) SEQ ID NOs: 541, 564, 556, 557, 558 and 408; (2.12)9) SEQ ID NOs: 541, 564, 556, 557, 565 and 408; (2.12 VL N50G)10) SEQ ID NOs: 541, 566, 567, 568, 569 and 419; (2.13)11) SEQ ID NOs: 570, 571, 572, 553, 565 and 408; (2.14) or12) SEQ ID NOs: 541, 573, 572, 574, 575 and 408; (2.15).

[0125] In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 682 and 683; (1.1)2) SEQ ID NOs: 684 and 685; (1.4)3) SEQ ID NOs: 686 and 687; (1.5)4) SEQ ID NOs: 688 and 689; (2.9)5) SEQ ID NOs: 690 and 691; (2.10)6) SEQ ID NOs: 692 and 693; (2.11)7) SEQ ID NOs: 692 and 694; (2.11 VL N50G)8) SEQ ID NOs: 695 and 696; (2.12)9) SEQ ID NOs: 695 and 697; (2.12 VL N50G)10) SEQ ID NOs: 698 and 699; (2.13)11) SEQ ID NOs: 700 and 701; (2.14) or12) SEQ ID NOs: 702 and 703; (2.15).

[0126] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 83, 84, 85, 86 and 87 (according to Kabat);2) SEQ ID NOs: 246, 247, 248, 249, 250 and 87 (according to IMGT);3) SEQ ID NOs: 390, 391, 392, 393, 250 and 394 (according to Chothia); or4) SEQ ID NOs: 536, 537, 538, 539, 540 and 394 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences setforth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 682 and 683 (antibody SCT1.1).

[0127] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 89, 90, 91, 92 and 93 (according to Kabat);2) SEQ ID NOs: 251, 252, 253, 254, 255 and 93 (according to IMGT);3) SEQ ID NOs: 395, 396, 397, 398, 255 and 399 (according to Chothia); or4) SEQ ID NOs: 541, 542, 543, 544, 545 and 399 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 684 and 685 (antibody SCT1.4).

[0128] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 94, 95, 96, 97, 98 and 99 (according to Kabat);2) SEQ ID NOs: 256, 257, 258, 259, 255 and 99 (according to IMGT);3) SEQ ID NOs: 400, 401, 402, 403, 255 and 404 (according to Chothia); or4) SEQ ID NOs: 546, 547, 548, 549, 550 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 686 and 687 (antibody SCT1.5).

[0129] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 100, 101, 102, 103 and 104 (according to Kabat);2) SEQ ID NOs: 251, 260, 261, 262, 263 and 104 (according to IMGT);3) SEQ ID NOs: 395, 405, 406, 407, 263 and 408 (according to Chothia); or4) SEQ ID NOs: 541, 551, 552, 553, 554 and 408 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 688 and 689 (antibody SCT2.9).

[0130] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 105, 106, 107, 108 and 93 (according to Kabat);2) SEQ ID NOs: 251, 264, 265, 266, 267 and 93 (according to IMGT);3) SEQ ID NOs: 395, 409, 410, 411, 267 and 399 (according to Chothia); or4) SEQ ID NOs: 541, 555, 556, 557, 558 and 399 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 690 and 691 (antibody SCT2.10).

[0131] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 109, 110, 111, 108 and 112 (according to Kabat);2) SEQ ID NOs: 251, 268, 269, 270, 267 and 112 (according to IMGT);3) SEQ ID NOs: 395, 412, 413, 414, 267 and 399 (according to Chothia); or4) SEQ ID NOs: 541, 559, 560, 561, 562 and 399 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 692 and 693 (antibody SCT2.11).

[0132] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 109, 110, 111, 113 and 112 (according to Kabat);2) SEQ ID NOs: 251, 268, 269, 270, 263 and 112 (according to IMGT);3) SEQ ID NOs: 395, 412, 413, 414, 263 and 399 (according to Chothia); or4) SEQ ID NOs: 541, 559, 560, 561, 563 and 399 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 692 and 694 (antibody SCT2.11 VL N50G).

[0133] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 114, 106, 107, 108 and 115 (according to Kabat);2) SEQ ID NOs: 251, 271, 265, 266, 267 and 115 (according to IMGT);3) SEQ ID NOs: 395, 415, 410, 411, 267 and 408 (according to Chothia); or4) SEQ ID NOs: 541, 564, 556, 557, 558 and 408 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 695 and 696 (antibody SCT2.12).

[0134] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 114, 106, 107, 113 and 115 (according to Kabat);2) SEQ ID NOs: 251, 271, 265, 266, 263 and 115 (according to IMGT);3) SEQ ID NOs: 395, 415, 410, 411, 263 and 408 (according to Chothia); or4) SEQ ID NOs: 541, 564, 556, 557, 565 and 408 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 695 and 697 (antibody SCT2.12 VL N50G).

[0135] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 88, 116, 117, 118, 108 and 119 (according to Kabat);2) SEQ ID NOs: 251, 272, 273, 274, 267 and 119 (according to IMGT);3) SEQ ID NOs: 395, 416, 417, 418, 267 and 419 (according to Chothia); or4) SEQ ID NOs: 541, 566, 567, 568, 569 and 419 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 698 and 699 (antibody SCT2.13).

[0136] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 120, 121, 122, 102, 113 and 123 (according to Kab at);2) SEQ ID NOs: 275, 276, 277, 262, 263 and 123 (according to IMGT);3) SEQ ID NOs: 420, 421, 422, 407, 263 and 408 (according to Chothia); or4) SEQ ID NOs: 570, 571, 572, 553, 565 and 408 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 700 and 701 (antibody SCT2.14).

[0137] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:5) SEQ ID NOs: 88, 124, 122, 125, 113 and 104 (according to Kabat);6) SEQ ID NOs: 251, 278, 277, 279, 263 and 104 (according to IMGT);7) SEQ ID NOs: 395, 423, 422, 424, 263 and 408 (according to Chothia); or8) SEQ ID NOs: 541, 573, 572, 574, 575 and 408 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D2, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 702 and 703 (antibody SCT2.15).Domains That Bind to One or Both of CD4 D2 and CD4 D3

[0138] Provided are antibodies or antigen-binding fragments thereof that specifically bind to one or both of CD4 D2 and CD4 D3. Antibodies or antigen-binding fragments thereof that specifically bind to one or both of CD4 D2 and CD4 D3 are useful in combination therapies with molecules that comprise a CD4 DI extracellular domain, e.g., a CD4 Dl-Fc fusion protein, e.g., a molecule comprising CD4 DI.22, described in Chen, etal., J. Virol. (2014) 88(2): 1125-1139. For example, antibodies or antigen-binding fragments thereof that specifically bind to one or both of CD4 D2 and CD4 D3 are useful in combination therapies with molecules comprising CD4 DI, e.g., molecules comprising a CD4-Fc fusion protein described, e.g., in WO 2011 / 146891, WO 2019 / 183387, WO 2022 / 046644 (e.g., amtabafusp alfa (GS-8588)) and WO 2024 / 094690. In some embodiments, the antibodies or antigen-binding fragments thereof that specifically bind to one or both of CD4 D2 and CD4 D3, described herein, are insensitive to the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L), wherein the amino acid positions are with reference to SEQ ID NO: 1120.

[0139] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 126, 127, 128, 129, 130 and 99; (1.6)2) SEQ ID NOs: 126, 131, 132, 129, 133 and 99; (1.7)3) SEQ ID NOs: 126, 134, 135, 136, 133 and 99; (1.8)4) SEQ ID NOs: 126, 137, 128, 129, 138 and 99; (1.9)5) SEQ ID NOs: 126, 139, 128, 140, 141 and 99; (1.10)6) SEQ ID NOs: 142, 143, 128, 145, 141 and 99; (1.19)7) SEQ ID NOs: 126, 146, 147, 140, 141 and 99; (2.2) or8) SEQ ID NOs: 148, 149, 150, 129, 151 and 99; (2.3).

[0140] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 280, 281, 282, 283, 284 and 99; (1.6)2) SEQ ID NOs: 280, 285, 286, 283, 284 and 99; (1.7)3) SEQ ID NOs: 280, 287, 288, 283, 284 and 99; (1.8)4) SEQ ID NOs: 289, 290, 282, 283, 284 and 99; (1.9)5) SEQ ID NOs: 289, 291, 292, 293, 255 and 99; (1.10)6) SEQ ID NOs: 294, 295, 296, 297, 255 and 99; (1.19)7) SEQ ID NOs: 289, 298, 299, 293, 255 and 99; (2.2) or8) SEQ ID NOs: 289, 300, 301, 283, 284 and 99; (2.3).

[0141] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 425, 426, 427, 428, 284 and 404; (1.6)2) SEQ ID NOs: 425, 426, 429, 428, 284 and 404; (1.7)3) SEQ ID NOs: 425, 426, 430, 428, 284 and 404; (1.8)4) SEQ ID NOs: 431, 432, 427, 428, 284 and 404; (1.9)5) SEQ ID NOs: 431, 433, 427, 434, 255 and 404; (1.10)6) SEQ ID NOs: 431, 435, 436, 437, 255 and 404; (1.19)7) SEQ ID NOs: 431, 438, 439, 434, 255 and 404; (2.2) or8) SEQ ID NOs: 431, 438, 440, 428, 284 and 404; (2.3).

[0142] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 576, 577, 578, 579, 580 and 404; (1.6)2) SEQ ID NOs: 576, 581, 582, 579, 583 and 404; (1.7)3) SEQ ID NOs: 576, 584, 585, 586, 583 and 404; (1.8)4) SEQ ID NOs: 587, 588, 578, 579, 589 and 404; (1.9)5) SEQ ID NOs: 587, 590, 578, 591, 592 and 404; (1.10)6) SEQ ID NOs: 593, 594, 595, 596, 597 and 404; (1.19)7) SEQ ID NOs: 587, 598, 599, 591, 597 and 404; (2.2) or8) SEQ ID NOs: 587, 600, 601, 579, 602 and 404; (2.3).

[0143] In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 704 and 705; (1.6)2) SEQ ID NOs: 706 and 707; (1.7)3) SEQ ID NOs: 708 and 709; (1.8)4) SEQ ID NOs: 710 and 711; (1.9)5) SEQ ID NOs: 712 and 713; (1.10)6) SEQ ID NOs: 714 and 715; (1.19)7) SEQ ID NOs: 716 and 717; (2.2) or8) SEQ ID NOs: 718 and 719; (2.3).

[0144] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 126, 127, 128, 129, 130 and 99 (according to Kabat);2) SEQ ID NOs: 280, 281, 282, 283, 284 and 99 (according to IMGT);3) SEQ ID NOs: 425, 426, 427, 428, 284 and 404 (according to Chothia); or4) SEQ ID NOs: 576, 577, 578, 579, 580 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 704 and 705 (antibody SCT1.6).

[0145] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 126, 131, 132, 129, 133 and 99 (according to Kabat);2) SEQ ID NOs: 280, 285, 286, 283, 284 and 99 (according to IMGT);3) SEQ ID NOs: 425, 426, 429, 428, 284 and 404 (according to Chothia); or4) SEQ ID NOs: 576, 581, 582, 579, 583 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 706 and 707 (antibody SCT1.7).

[0146] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 126, 134, 135, 136, 133 and 99 (according to Kabat);2) SEQ ID NOs: 280, 287, 288, 283, 284 and 99 (according to IMGT);3) SEQ ID NOs: 425, 426, 429, 428, 284 and 404 (according to Chothia); or4) SEQ ID NOs: 576, 584, 585, 586, 583 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 708 and 709 (antibody SCT1.8).

[0147] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 126, 137, 128, 129, 138 and 99 (according to Kabat);2) SEQ ID NOs: 289, 290, 282, 283, 284 and 99 (according to IMGT);3) SEQ ID NOs: 431, 432, 427, 428, 284 and 404 (according to Chothia); or4) SEQ ID NOs: 587, 588, 578, 579, 589 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively,the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 710 and 711 (antibody SCT1.9).

[0148] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 126, 139, 128, 140, 141 and 99 (according to Kabat);2) SEQ ID NOs: 289, 291, 292, 293, 255 and 99 (according to IMGT);3) SEQ ID NOs: 431, 433, 427, 434, 255 and 404 (according to Chothia); or4) SEQ ID NOs: 587, 590, 578, 591, 592 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 712 and 713 (antibody SCT1.10).

[0149] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 142, 143, 128, 145, 141 and 99 (according to Kabat);2) SEQ ID NOs: 294, 295, 296, 297, 255 and 99 (according to IMGT);3) SEQ ID NOs: 431, 435, 436, 437, 255 and 404 (according to Chothia); or4) SEQ ID NOs: 593, 594, 595, 596, 597 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 714 and 715 (antibody SCT1.19).

[0150] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chainvariable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 126, 146, 147, 140, 141 and 99 (according to Kabat);2) SEQ ID NOs: 289, 298, 299, 293, 255 and 99 (according to IMGT);3) SEQ ID NOs: 431, 438, 439, 434, 255 and 404 (according to Chothia); or4) SEQ ID NOs: 587, 598, 599, 591, 597 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 716 and 717 (antibody SCT2.2).

[0151] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 148, 149, 150, 129, 151 and 99 (according to Kabat);2) SEQ ID NOs: 289, 300, 301, 283, 284 and 99 (according to IMGT);3) SEQ ID NOs: 431, 438, 440, 428, 284 and 404 (according to Chothia); or4) SEQ ID NOs: 587, 600, 601, 579, 602 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to one or both of CD4 D2 and CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 718 and 719 (antibody SCT2.3).Antigen Binding Domains That Specifically Bind to CD4 D3

[0152] Provided are antibodies or antigen-binding fragments thereof that specifically bind to CD4 D3. Antibodies or antigen-binding fragments thereof that specifically bind to CD4 D3 are useful in combination therapies with molecules that comprise a CD4 DI or a CD4 D1D2 extracellular domain, e.g., a CD4 Dl-Fc fusion protein, e.g., a molecule comprising CD4 DI.22 (with or without a D2), described in Chen, et al., J. Virol. (2014) 88(2): 1125-1139. Forexample, antibodies or antigen-binding fragments thereof that specifically bind to CD4 D3 are useful in combination therapies with molecules comprising CD4 DI or CD4 D1D2 described, e.g, in U.S. Patent No. 7,368,114; and Inti. Publ. Nos. WO 2011 / 146891, WO 2019 / 183387, WO 2022 / 046644 (e.g., amtabafusp alfa (GS-8588)) and WO 2024 / 094690. In some embodiments, the antibodies or antigen-binding fragments thereof that specifically bind to CD4 D3, described herein, are insensitive to the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C), wherein the amino acid positions are with reference to SEQ ID NO: 1120. In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope within CD4 D3 comprising amino acid residues at positions 218, 220, 260, 271, 274-277, 279, 283 and 285, wherein the residue positions are with reference to SEQ ID NO: 1120. In some embodiments, the antibodies or antigen-binding fragments thereof that specifically bind to CD4 D3 bind to CD4 D3 with a binding equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

[0153] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 158, 159, 160, 145, 161 and 162; (1.20)2) SEQ ID NOs: 163, 164, 160, 165, 166 and 162; (1.21)3) SEQ ID NOs: 163, 164, 160, 165, 161 and 162; (1.22)4) SEQ ID NOs: 158, 167, 168, 145, 98 and 169; (1.23)5) SEQ ID NOs: 170, 171, 172, 173, 141 and 99; (2.1) or6) SEQ ID NOs: 25, 174, 175, 176, 29 and 177; (2.8).

[0154] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 306, 307, 1083, 297, 308 and 162; (1.20)2) SEQ ID NOs: 309, 310, 311, 312, 313 and 162; (1.21)3) SEQ ID NOs: 309, 310, 311, 312, 308 and 162; (1.22)4) SEQ ID NOs: 314, 315, 316, 297, 255 and 169; (1.23)5) SEQ ID NOs: 317, 318, 319, 320, 255 and 99; (2.1) or6) SEQ ID NOs: 196, 321, 322, 199, 200 and 177; (2.8).

[0155] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 446, 447, 448, 437, 308 and 449; (1.20)2) SEQ ID NOs: 450, 451, 448, 452, 313 and 449; (1.21)3) SEQ ID NOs: 450, 451, 448, 452, 308 and 449; (1.22)4) SEQ ID NOs: 453, 454, 455, 437, 255 and 456; (1.23)5) SEQ ID NOs: 457, 458, 459, 460, 255 and 404; (2.1) or6) SEQ ID NOs: 343, 350, 461, 347, 200 and 462; (2.8).

[0156] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 608, 609, 610, 596, 611 and 449; (1.20)2) SEQ ID NOs: 612, 613, 610, 614, 615 and 449; (1.21)3) SEQ ID NOs: 612, 613, 610, 614, 611 and 449; (1.22)4) SEQ ID NOs: 616, 617, 618, 596, 550 and 456; (1.23)5) SEQ ID NOs: 619, 620, 621, 622, 597 and 404; (2.1) or6) SEQ ID NOs: 484, 623, 624, 487, 492 and 462; (2.8).

[0157] In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 722 and 723; (1.20)2) SEQ ID NOs: 724 and 725; (1.21)3) SEQ ID NOs: 724 and 726; (1.22)4) SEQ ID NOs: 727 and 728; (1.23)5) SEQ ID NOs: 727 and 729; (1.23 VL C36Y)6) SEQ ID NOs: 730 and 731; (2.1) or7) SEQ ID NOs: 732 and 733; (2.8).

[0158] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 158, 159, 160, 145, 161 and 162 (according to Kabat);2) SEQ ID NOs: 306, 307, 1083, 297, 308 and 162 (according to IMGT);3) SEQ ID NOs: 446, 447, 448, 437, 308 and 449 (according to Chothia); or4) SEQ ID NOs: 608, 609, 610, 596, 611 and 449 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 722 and 723 (antibody SCT1.20).

[0159] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 163, 164, 160, 165, 166 and 162 (according to Kabat);2) SEQ ID NOs: 309, 310, 311, 312, 313 and 162 (according to IMGT);3) SEQ ID NOs: 450, 451, 448, 452, 313 and 449 (according to Chothia); or4) SEQ ID NOs: 612, 613, 610, 614, 615 and 449 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 724 and 725 (antibody SCT1.21).

[0160] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 163, 164, 160, 165, 161 and 162 (according to Kabat);2) SEQ ID NOs: 309, 310, 311, 312, 308 and 162 (according to IMGT);3) SEQ ID NOs: 450, 451, 448, 452, 308 and 449 (according to Chothia); or4) SEQ ID NOs: 612, 613, 610, 614, 611 and 449 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 724 and 726 In some embodiments, the antibody or antigen-binding fragment thereof binds to an epitope within CD4 D3 comprising amino acid residues at positions 218, 220, 260, 271, 274-277, 279, 283 and 285, wherein the residue positions are with reference to SEQ ID NO: 1120 (antibody SCT1.22).

[0161] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 158, 167, 168, 145, 98 and 169 (according to Kabat);2) SEQ ID NOs: 314, 315, 316, 297, 255 and 169 (according to IMGT);3) SEQ ID NOs: 453, 454, 455, 437, 255 and 456 (according to Chothia); or4) SEQ ID NOs: 616, 617, 618, 596, 550 and 456 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 727 and 728 or 727 and 729 (antibody SCT1.23 and SCT1.23 VL C36Y).

[0162] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 170, 171, 172, 173, 141 and 99 (according to Kabat);2) SEQ ID NOs: 317, 318, 319, 320, 255 and 99 (according to IMGT);3) SEQ ID NOs: 457, 458, 459, 460, 255 and 404 (according to Chothia); or4) SEQ ID NOs: 619, 620, 621, 622, 597 and 404 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 730 and 731 (antibody SCT2.1).

[0163] In some embodiments, provided is an antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:1) SEQ ID NOs: 25, 174, 175, 176, 29 and 177 (according to Kabat);2) SEQ ID NOs: 196, 321, 322, 199, 200 and 177 (according to IMGT);3) SEQ ID NOs: 343, 350, 461, 347, 200 and 462 (according to Chothia); or4) SEQ ID NOs: 484, 623, 624, 487, 492 and 462 (according to Honegger).In some embodiments, provided is an antibody or antigen-binding fragment that specifically binds to CD4 D3, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 732 and 733 (antibody SCT2.8).

[0164] As appropriate or desired, alternative framework regions can be grafted onto the CDRs (e.g., according to Kabat) that maintain the desired function of the anti-CD4 antigen binding domains. Applicable approaches for humanization and re-humanization (e.g., grafting alternative framework regions onto selected CDRs) that can be used for humanization or rehumanization of the herein described anti-CD4 antigen binding domains are described e.g., inGupta, et al., J Biol Chem (2024) 300(1): 105555; Tennenhouse, et al., Nat Biomed Eng. (2024) 8(l):30-44; Jiacomini, et al., Int J Biol Macromol . (2022) 216:465-474; Marks, et al., Bioinformatics (2021) 37(22): 4041-4047; Aubrey, et al., Methods Mol Biol (2019) 1904:231-252; Kuramochi, et al., Methods Mol Biol (2019) 1904:213-230; Apgar, et al., MAbs (2016) 8(7): 1302-1318; Choi, et al., MAbs (2015) 7(6): 1045-57; Hanf, etal., Methods (2014) 65(l):68-76; Ahmadzadeh, etal., Monoclon Antib Immunodiagn Immunother (2014) 33(2):67-73; Safdari, et al., Biotechnol Genet Eng Rev (2013) 29:175-86; Kim, et al., Methods Mol Biol. (2012) 907:237-45; Almagro, etal., Front Biosci. (2008) 13:1619-33; Kashmiri, et al., Methods (2005) 36(l):25-34, Foote and Winter, J Mol Biol (1992) 224(2):487-99, as well as in U.S. Patent Nos. 8,323,651; 8,324,350; 9,550,986; and 10,174,121, which are herein incorporated by reference in their entireties for all purposes. A software platform useful for antibody design, humanization, and humanness evaluation that can be used for humanization or re-humanization of the herein described anti-CD4 antigen binding domains is BioPhi (reviewed in Prihoda, et al. MAbs (2022) 14(l):2020203 and accessible atbiophi.dichlab.org). In some embodiments, the alternative framework regions useful for grafting have at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to a reference framework region amino acid sequence. In some embodiments, the humanized or re-humanized VH and VL amino acid sequences have at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to reference VH and VL amino acid sequences.

[0165] Illustrative sequences of the CDRs of the anti-CD4 antigen binding domains are provided in Tables A1-A4. Illustrative sequences of the VH and VL of the anti-CD4 antigen binding domains described herein are provided in Table B.TABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1Binds to CD4 DI1 NYAMS SINX1X2GSTFYX3DSVKX4 HYGGSYDPMDY X5ASQDINKYIA YTSXeLHP LQYDNPLX7T SEQ ID Xi is A, D or E SEQ ID NO: 3 X5 is K or R Xe is I or T X7 is F, Q NO: 1 X2is A, G, W or Y SEQ ID NO: 4 SEQ ID NO: 5 or YX3 is A or P SEQ ID NO: 6 X4is G or SSEQ ID N0: 22 NYAMS SINX1X2GSTFYX3DSVKX4 HYGGSYDPMDY X5ASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID Xi is A, D or E SEQ ID NO: 3 X5 is K or R SEQ ID NO: 8 SEQ ID NO: 9 NO: 1 X2is A or G SEQ ID NO: 4X3 is A or PX4is G or SSEQ ID NO: 73 NYAMS SINEX2GSTFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSXeLHP LQYDNPLX7T SEQ ID X2is W or Y SEQ ID NO: 3 SEQ ID NO: 11 Xe is I or T X7is F, Q, Y NO: 1 SEQ ID NO: 10 SEQ ID NO: 5 SEQ ID NO: 6 4 NYAMS SINEX2GSTFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSILHP LQYDNPLX7T SEQ ID X2is W or Y SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 12 X7is F, Q, Y NO: 1 SEQ ID NO: 10 SEQ ID NO: 6 5 NYAMS SINEX2GSTFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID X2is W or Y SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 1 SEQ ID NO: 106 NYAMS S INEGGS TFYADSVKX4 HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID X4is G or S SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 1 SEQ ID NO: 137 NYAMS S INEGGS TFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 14 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 18 NYAMS SINEWGS TFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYTTABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID SEQ ID NO: 15 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 19 NYAMS SINEYGSTFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 16 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 110 NYAMS SINEWGSTFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSILHP LQYDNPLQT SEQ ID SEQ ID NO: 15 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 12 SEQ ID NO: 17 NO: 111 NYAMS SINEYGSTFYADSVKS HYGGSYDPMDY RASQDINKYIA YTSILHP LQYDNPLFT SEQ ID SEQ ID NO: 16 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 12 SEQ ID NO: 18 NO: 112 NYAMS S INEGGS TFYADSVKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1078 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 113 NYAMS S INDGGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1079 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 114 NYAMS S INDGGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1079 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 115 NYAMS S INAGGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1080 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 116 NYAMS S INDAGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1081 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 117 NYAMS S INDGGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1079 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9NO: 1TABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR118 NYAMS S INDGGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1079 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 119 NYAMS S INDGGS T FYADS VKG HYGGSYDPMDY RASQDINKYIA YTSTLHP LQYDNPLYT SEQ ID SEQ ID NO: 1079 SEQ ID NO: 3 SEQ ID NO: 11 SEQ ID NO: 8 SEQ ID NO: 9 NO: 1SCT1 . DYGMS GINWNGDSTGYADSVRG DGAIGGMDV RASQDIRDDLG SASTLQS LQDYNYPWT 17 SEQ ID SEQ ID NO: 20 SEQ ID NO: 21 SEQ ID NO: 22 SEQ ID NO: 23 SEQ ID NO: 24 NO: 19SCT1 . ELSMH YFDPRGGETIYAQKFQG GGDRDYYYYYMDV KASQDIDDDMN EATTLVP LQHDSFPYT 25 SEQ ID SEQ ID NO: 26 SEQ ID NO: 27 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 30 NO: 25SCT1 . KLSMH FFDPRDGERIYAQKFQG GGDYDYYYYYMGV KASQDIDDDLN EATTLVP LQHDNFPYT 26 SEQ ID SEQ ID NO: 32 SEQ ID NO: 33 SEQ ID NO: 34 SEQ ID NO: 29 SEQ ID NO: 35 NO: 31SCT1 . ELSMH S FHPRDDE 11 YAQKFQG GGNPDYYFYYMDV KASQDIDDDMN EATTLVP LQHDNFPLT 27 SEQ ID SEQ ID NO: 36 SEQ ID NO: 37 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 38 NO: 25SCT1 . ELSMH SFHPRDGET I YAQKFQG GGNKDYYFYYMDV KASQDIDDDMN EATTLVP LQHDNFPLT 28 SEQ ID SEQ ID NO: 1082 SEQ ID NO: 39 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 38 NO: 25SCT1 . ALSMH YFNPRDGET I YAQKFQG GGDSDYYYYYMDV KASQDIDDDMN EATTLVP LQHDNFPYT 29 SEQ ID SEQ ID NO: 41 SEQ ID NO: 42 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 35 NO: 40SCT1 . ELSMH YFNPRDDETIYTQKFQG GGNKDYYFYYMDV KASQDIDDDMN EATTLVP LQHDNFPLT 30 SEQ ID SEQ ID NO: 43 SEQ ID NO: 39 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 38 NO: 25SCT1 . ELSMH VFDPKYGETTYAQKFQD GGNYEYFYYYMDV KASQDIDDDMN EATTLVP LQHDNFPYT31 SEQ ID NO: 44 SEQ ID NO: 45 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 35TABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID NO: 25SCT1 . ELSMH I FDPKYGETMYAQKFQG GGSPDYFYYYMDV KASQDIDDDMN EATTLVP LQHDNFPYT 32 SEQ ID SEQ ID NO: 46 SEQ ID NO: 47 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 35 NO: 25SCT1 . ELSMH I FDPRNGETIYAQKFQG GGSPDYYYWYMDV KASQDIDDDMN EATTLVP LQHDNFPYT 33 SEQ ID SEQ ID NO: 48 SEQ ID NO: 49 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 35 NO: 25SCT1 . ELSMH I FDPRNGETIYAQKFQG GGSPDYYFWYMDV KASQDIDDDMN EATTLVP LQHDNFPYT 34 SEQ ID SEQ ID NO: 48 SEQ ID NO: 50 SEQ ID NO: 28 SEQ ID NO: 29 SEQ ID NO: 35 NO: 25SCT1 . SYDIN WMNPNSGNTGSTQKFQG GVLKGDYYYMDV RASQSISSSYLS GSSTRAT QQDDHLPLT 45 SEQ ID SEQ ID NO: 52 SEQ ID NO: 53 SEQ ID NO: 54 SEQ ID NO: 55 SEQ ID NO: 56 NO: 51SCT1 . SYDIN WVNPNSGNTGSTQKFQG GVLKGDYYYMDV RASQSISSTYLS GSSTRAT QQDDHLPLT 46 SEQ ID SEQ ID NO: 57 SEQ ID NO: 53 SEQ ID NO: 58 SEQ ID NO: 55 SEQ ID NO: 56 NO: 51SCT1 . SYDIN WVNPNSGNTGSTQKFQG GVLKGDYYYMDV RASQSISSTYLS GSSTRAT QQDDHLPLT 47 SEQ ID SEQ ID NO: 57 SEQ ID NO: 53 SEQ ID NO: 58 SEQ ID NO: 55 SEQ ID NO: 56 NO: 51SCT1 . SYDIN WVNPNSGNTGSTQKFQG GVLKGDYYYMDV RASQSISSTYLS GSSTRAT QQDDHLPLT 48 SEQ ID SEQ ID NO: 57 SEQ ID NO: 53 SEQ ID NO: 58 SEQ ID NO: 55 SEQ ID NO: 56 NO: 51kelix GDYYWF YIYGSGGGTNYNPSLNN NILKYLHWLLY GGDNVGRKSVQ ADSERPS QVWDSTADHWV i-mab SEQ ID SEQ ID NO: 60 SEQ ID NO: 61 SEQ ID NO: 62 SEQ ID NO: 63 SEQ ID NO: 64NO: 59UB- DYVIH EIYPGSGSAYSNAKFKD RGNGTGFAY KAGQSVDYDGDSY VASNLES QQSYKDPLT 421 SEQ ID SEQ ID NO: 66 SEQ ID NO: 67 MN SEQ ID NO: 69 SEQ ID NO: 70NO: 65 SEQ ID NO: 68TABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1Binds to CD4 D2ibali SYVIH YINPYNDGTDYDEKFKG EKDNYATGAWFAY KSSQSLLYSTNQK WAS T RES QQYYSYRT zumab SEQ ID SEQ ID NO: 72 SEQ ID NO: 73 NYLA SEQ ID NO: 75 SEQ ID NO: 76NO: 71 SEQ ID NO: 74trega DCRMY VISVKSENYGANYAESVRG SYYRYDVGAWFAY RASKSVSTSGYSY LAS I LES QHSRELPWT lizum SEQ ID SEQ ID NO: 78 SEQ ID NO: 79 IY SEQ ID NO: 81 SEQ ID NO: 82 ab NO: 77 SEQ ID NO: 80SCT1 . ELSMH GFDPEDGKTIYAPKFQG GHNWNDGYYFYYYMDL KSSQSLLHTDGKT EVSNRFS MQSLQLPLT 1 SEQ ID SEQ ID NO: 83 SEQ ID NO: 84 YLY SEQ ID NO: 86 SEQ ID NO: 87 NO: 25 SEQ ID NO: 85SCT1 . DYYMN YISSSGNTIFYVDSVEG E G YNN YN Y S Y Y Y FMDV RASQSVSRKLA AASTRAT QQYNNWPYT 4 SEQ ID SEQ ID NO: 89 SEQ ID NO: 90 SEQ ID NO: 91 SEQ ID NO: 92 SEQ ID NO: 93 NO: 88SCT1 . SFGMH I IWYDGTNKYYADSVKG EIAVDGTDYYMDV RASQGIRSGLG AASTLQS LQDYNYPYT 5 SEQ ID SEQ ID NO: 95 SEQ ID NO: 96 SEQ ID NO: 97 SEQ ID NO: 98 SEQ ID NO: 99 NO: 94SCT2 . DYYMN YISSSGLTIFYVDSVKG EGYSGFDDHYYYYTDV RASQSVSSNLA GAS I RAT QHYKNWPYT 9 SEQ ID SEQ ID NO: 100 SEQ ID NO: 101 SEQ ID NO: 102 SEQ ID SEQ ID NO: 88 NO: 103 NO: 104 SCT2 . DYYMN YISSSGSTIFYTDSVKG EDYSNYEDYYYYYTGV RASQSVSSKFA NAS T RAT QQYNNWPYT 10 SEQ ID SEQ ID NO: 105 SEQ ID NO: 106 SEQ ID NO: 107 SEQ ID SEQ ID NO: 93 NO: 88 NO: 108SCT2 . DYYMN YISSSGITIFYTDSVKG EDYSNYEDHYYYYTGV RASQSVSNKFA NAS T RAT QHYNNWPYT 11 SEQ ID SEQ ID NO: 109 SEQ ID NO: 110 SEQ ID NO: 111 SEQ ID SEQ ID NO: 88 NO: 108 NO: 112 SCT2 . DYYMN YISSSGITIFYTDSVKG EDYSNYEDHYYYYTGV RASQSVSNKFA GAST RAT QHYNNWPYT 11 SEQ ID SEQ ID NO: 109 SEQ ID NO: 110 SEQ ID NO: 111 SEQ ID SEQ ID VL NO: 88 NO: 113 NO: 112N50GTABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SCT2 . DYYMN YISSSGKTIFYTDSVKG EDYSNYEDYYYYYTGV RASQSVSSKFA NAS T RAT HQYKNWPYT 12 SEQ ID SEQ ID NO: 114 SEQ ID NO: 106 SEQ ID NO: 107 SEQ ID SEQ ID NO: 88 NO: 108 NO: 115 SCT2 . DYYMN YISSSGKTIFYTDSVKG EDYSNYEDYYYYYTGV RASQSVSSKFA GAST RAT HQYKNWPYT 12 SEQ ID SEQ ID NO: 114 SEQ ID NO: 106 SEQ ID NO: 107 SEQ ID SEQ ID VL NO: 88 NO: 113 NO: 115 N50GSCT2 . DYYMN YISISGQTIYYGDSVKG EGYSNYGVKYYYYMDV RASQSISSNLA NAS T RAT QQYNAWTYT 13 SEQ ID SEQ ID NO: 116 SEQ ID NO: 117 SEQ ID NO: 118 SEQ ID SEQ ID NO: 88 NO: 108 NO : 119 SCT2 . DHYMN YISISGNTIYYTDSVKG EGYSSSSRGDYSYYTDV RASQSVSSNLA GAST RAT QQYKNWPYT 14 SEQ ID SEQ ID NO: 121 SEQ ID NO: 122 SEQ ID NO: 102 SEQ ID SEQ ID NO: 120 NO: 113 NO: 123 SCT2 . DYYMN YISISGRTIYYIDSVKG EGYSSSSRGDYSYYTDV RASQGVSSNLA GAST RAT QHYKNWPYT 15 SEQ ID SEQ ID NO: 124 SEQ ID NO: 122 SEQ ID NO: 125 SEQ ID SEQ ID NO: 88 NO: 113 NO: 104 Binds to CD4 D2 and / or D3SCT1 . SYGMH I IWFDGSNKYYADSLTG EVALEGYYYYMDV RASQDIRNGLG TTSSLQT LQDYNYPYT 6 SEQ ID SEQ ID NO: 127 SEQ ID NO: 128 SEQ ID NO: 129 SEQ ID SEQ ID NO: 99 NO: 126 NO: 130SCT1 . SYGMH I LWFDGSNKFYADSVKG ELALEGYYYYMDV RASQDIRNGLG TTSSLQS LQDYNYPYT 7 SEQ ID SEQ ID NO: 131 SEQ ID NO: 132 SEQ ID NO: 129 SEQ ID SEQ ID NO: 99 NO: 126 NO: 133SCT1 . SYGMH I LWFDGSNQFYADSVKG EIALEGYYYYMDV RSSQDIRNGLG TTSSLQS LQDYNYPYT 8 SEQ ID SEQ ID NO: 134 SEQ ID NO: 135 SEQ ID NO: 136 SEQ ID SEQ ID NO: 99 NO: 126 NO: 133SCT1 . SYGMH I IWYDGSNKYYADSVKG EVALEGYYYYMDV RASQDIRNGLG TTSNLQS LQDYNYPYT 9 SEQ ID SEQ ID NO: 137 SEQ ID NO: 128 SEQ ID NO: 129 SEQ ID SEQ ID NO: 99NO: 126 NO: 138TABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SCT1 . SYGMH I IWYDGNNKYYADSVKG EVALEGYYYYMDV RASQGIRNGLG AASSLQS LQDYNYPYT 10 SEQ ID SEQ ID NO: 139 SEQ ID NO: 128 SEQ ID NO: 140 SEQ ID SEQ ID NO: 99 NO: 126 NO: 141SCT1 . SYAMS GISGSVGSTYYADSVKG EGYDWSGMDV RASQGIRNDLG AASSLQS LQDYNYPYT 19 SEQ ID SEQ ID NO: 143 SEQ ID NO: 144 SEQ ID NO: 145 SEQ ID SEQ ID NO: 99 NO: 142 NO: 141SCT2 . SYGMH LIWFDGTTRFYADSVKG EVAIQGRDYYIDV RASQGIRNGLG AASSLQS LQDYNYPYT 2 SEQ ID SEQ ID NO: 146 SEQ ID NO: 147 SEQ ID NO: 140 SEQ ID SEQ ID NO: 99 NO: 126 NO: 141SCT2 . SYGIH I IWFDGTNKFYADSVKG EVAIQGYYYYMDV RASQDIRNGLG TTSNLQN LQDYNYPYT 3 SEQ ID SEQ ID NO: 149 SEQ ID NO: 150 SEQ ID NO: 129 SEQ ID SEQ ID NO: 99 NO : 148 NO: 151Binds to CD4 D30KT4 NYGMN WINTNTGEPTYAEEFKG LGI YYDYGYYAMDY RASESVDSYGNSF LASNLES QQNNEDPYT SEQ ID SEQ ID NO: 153 SEQ ID NO: 154 MH SEQ ID SEQ ID NO: 152 SEQ ID NO: 155 NO: 156 NO: 157 SCT1 . TYAMS GISGSGDNTYYADSVKG EGYNWNYMDV RASQGIRNDLG EASSLQS LQDYTYPYT 20 SEQ ID SEQ ID NO: 159 SEQ ID NO: 160 SEQ ID NO: 145 SEQ ID SEQ ID NO: 158 NO: 161 NO: 162 SCT1 . TEAMS GISGSGENTYYADSVKG EGYNWNYMDV RASHGIRNDLG ETSSLQS LQDYTYPYT 21 SEQ ID SEQ ID NO: 164 SEQ ID NO: 160 SEQ ID NO: 165 SEQ ID SEQ ID NO: 163 NO: 166 NO: 162 SCT1 . TEAMS GISGSGENTYYADSVKG EGYNWNYMDV RASHGIRNDLG EASSLQS LQDYTYPYT 22 SEQ ID SEQ ID NO: 164 SEQ ID NO: 160 SEQ ID NO: 165 SEQ ID SEQ ID NO: 163 NO: 161 NO: 162 SCT1 . TYAMS TISDNIGNTYYADSVKG DNEDYYMDV RASQGIRNDLG AASTLQS LQDYNYPRT 23 SEQ ID SEQ ID NO: 167 SEQ ID NO: 168 SEQ ID NO: 145 SEQ ID NO: 98 SEQ IDC36Y NO: 158 NO: 169TABLE Al - CDRs for illustrative anti-CD4 binding domains (Rabat)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SCT2 . TNAMS GISGSNGNTYYADSVKG ERDNWNGFDY RASHVIRNDLG AASSLQS LQDYNYPYT 1 SEQ ID SEQ ID NO: 171 SEQ ID NO: 172 SEQ ID NO: 173 SEQ ID SEQ ID NO: 99 NO : 170 NO: 141SCT2 . ELSMH I FDPRDGQI I YAEKFQG GGNEDYYFYYMDV KASQDIDDDVN EATTLVP LQHDHFPYT 8 SEQ ID SEQ ID NO: 174 SEQ ID NO: 175 SEQ ID NO: 176 SEQ ID NO: 29 SEQ IDNO: 25 NO: 177TABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameBinds to CD4 DI1 GFSFSNYA INX1X2GST SRHYGGSYDPMDY QDINKY YTS LQYDNPLXvT SEQ ID Xi is A, D, E SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID X7is F, Q, Y NO: 178 X2is A, G, W, Y NO: 182 SEQ ID NO: 6 SEQ ID NO: 1792 GFSFSNYA INX1X2GST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID Xi is A, D, E SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 X2is A or G NO: 182SEQ ID NO: 1833 GFSFSNYA INEX2GST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID X2is W or Y SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 SEQ ID NO: 184 NO: 1824 GFSFSNYA INEX2GST SRHYGGSYDPMDY QDINKY YTS LQYDNPLX7T SEQ ID X2is W or Y SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID X7is F, Q, Y NO: 178 SEQ ID NO: 184 NO: 182 SEQ ID NO: 65 GFSFSNYA INEX2GST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYTTABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameSEQ ID X2 is W or Y SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 SEQ ID NO: 184 NO: 1826 GFSFSNYA INEGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 185 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 1827 GFSFSNYA INEGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 185 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 1828 GFSFSNYA INEWGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 186 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 1829 GFSFSNYA INEYGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 187 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18210 GFSFSNYA INEWGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLQT SEQ ID SEQ ID NO: 186 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 17 NO: 178 NO: 18211 GFSFSNYA INEYGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLFT SEQ ID SEQ ID NO: 187 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 18 NO: 178 NO: 18212 GFSFSNYA INEGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 185 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18213 GFSFSNYA INDGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 188 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18214 GFSFSNYA INDGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 188 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9NO: 178 NO: 182TABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name15 GFSFSNYA INAGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 189 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18216 GFSFSNYA INDAG ST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 190 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18217 GFSFSNYA INDGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 188 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18218 GFSFSNYA INDGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 188 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 18219 GFSFSNYA INDGGST SRHYGGSYDPMDY QDINKY YTS LQYDNPLYT SEQ ID SEQ ID NO: 188 SEQ ID NO: 180 SEQ ID NO: 181 SEQ ID SEQ ID NO: 9 NO: 178 NO: 182SCT1 . 17 GFTFDDYG INWNGDST ARDGAIGGMDV QDIRDD SAS LQDYNYPWT SEQ ID SEQ ID NO: 192 SEQ ID NO: 193 SEQ ID NO: 194 SEQ ID SEQ ID NO: 24 NO: 191 NO: 195SCT1 .25 GHTLTELS FDPRGGET ATGGDRDYYYYYMDV QDIDDD EAT LQHDSFPYT SEQ ID SEQ ID NO: 197 SEQ ID NO: 198 SEQ ID NO: 199 SEQ ID SEQ ID NO: 30 NO: 196 NO: 200SCT1 .26 GFTLTKLS FDPRDGER ATGGDYDYYYYYMGV QDIDDD EAT LQHDNFPYT SEQ ID SEQ ID NO: 202 SEQ ID NO: 203 SEQ ID NO: 199 SEQ ID SEQ ID NO: 35 NO: 201 NO: 200SCT1 .27 GHTVTELS FHPRDDEI ATGGNPDYYFYYMDV QDIDDD EAT LQHDNFPLT SEQ ID SEQ ID NO: 205 SEQ ID NO: 206 SEQ ID NO: 199 SEQ ID SEQ ID NO: 38 NO: 204 NO: 200SCT1 .28 GHTLTELS FHPRDGET ATGGNKDYYFYYMDV QDIDDD EAT LQHDNFPLTSEQ ID NO: 207 SEQ ID NO: 208 SEQ ID NO: 199 SEQ ID NO: 38TABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameSEQ ID SEQ ID NO: 196 NO: 200SCT1 .29 GYTLTALS FNPRDGET ATGGDSDYYYYYMDV QDIDDD EAT LQHDNFPYT SEQ ID SEQ ID NO: 210 SEQ ID NO: 211 SEQ ID NO: 199 SEQ ID SEQ ID NO: 35 NO: 209 NO: 200SCT1 .30 GHTLTELS FNPRDDET ATGGNKDYYFYYMDV QDIDDD EAT LQHDNFPLT SEQ ID SEQ ID NO: 212 SEQ ID NO: 208 SEQ ID NO: 199 SEQ ID SEQ ID NO: 38 NO: 196 NO: 200SCT1 .31 GHTLTELS FDPKYGET ATGGNYEYFYYYMDV QDIDDD EAT LQHDNFPYT SEQ ID SEQ ID NO: 213 SEQ ID NO: 214 SEQ ID NO: 199 SEQ ID SEQ ID NO: 35 NO: 196 NO: 200SCT1 . 32 GHTLTELS FDPKYGET ATGGSPDYFYYYMDV QDIDDD EAT LQHDNFPYT SEQ ID SEQ ID NO: 213 SEQ ID NO: 215 SEQ ID NO: 199 SEQ ID SEQ ID NO: 35 NO: 196 NO: 200SCT1 . 33 GHTLTELS FDPRNGET ATGGSPDYYYWYMDV QDIDDD EAT LQHDNFPYT SEQ ID SEQ ID NO: 216 SEQ ID NO: 217 SEQ ID NO: 199 SEQ ID SEQ ID NO: 35 NO: 196 NO: 200SCT1 . 34 GHTLTELS FDPRNGET ATGGSPDYYFWYMDV QDIDDD EAT LQHDNFPYT SEQ ID SEQ ID NO: 216 SEQ ID NO: 218 SEQ ID NO: 199 SEQ ID SEQ ID NO: 35 NO: 196 NO: 200SCT1 .45 GYTFTSYD MNPNSGNT ARGVLKGDYYYMDV QSISSSY GSS QQDDHLPLT SEQ ID SEQ ID NO: 220 SEQ ID NO: 221 SEQ ID NO: 222 SEQ ID SEQ ID NO: 56 NO : 219 NO: 223SCT1 .46 GYTFTSYD VNPNSGNT ARGVLKGDYYYMDV QSISSTY GSS QQDDHLPLT SEQ ID SEQ ID NO: 224 SEQ ID NO: 221 SEQ ID NO: 225 SEQ ID SEQ ID NO: 56 NO : 219 NO: 223SCT1 .47 GYTFTSYD VNPNSGNT ARGVLKGDYYYMDV QSISSTY GSS QQDDHLPLT SEQ ID SEQ ID NO: 224 SEQ ID NO: 221 SEQ ID NO: 225 SEQ ID SEQ ID NO: 56NO : 219 NO: 223TABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameSCT1 .48 GYTFTSYD VNPNSGNT ARGVLKGDYYYMDV QSISSTY GSS QQDDHLPLT SEQ ID SEQ ID NO: 224 SEQ ID NO: 221 SEQ ID NO: 225 SEQ ID SEQ ID NO: 56 NO : 219 NO: 223kelixi- GGSISGDYY IYGSGGGT ASNILKYLHWLLY NVGRKS ADS QVWDSTADHWV mab SEQ ID SEQ ID NO: 227 SEQ ID NO: 228 SEQ ID NO: 229 SEQ ID SEQ ID NO: 64NO: 226 NO: 230UB-421 GYTFTDYV IYPGSGSA ARRGNGTGFAY QSVDYDGDSY VAS QQSYKDPLT SEQ ID SEQ ID NO: 232 SEQ ID NO: 233 SEQ ID NO: 234 SEQ ID SEQ ID NO: 70 NO: 231 NO: 235Binds to CD4 D2ibalizu GYTFTSYV INPYNDGT ARE KDN YAT GAW FAY QSLLYSTNQKNY WAS QQYYSYRT mab SEQ ID SEQ ID NO: 237 SEQ ID NO: 238 SEQ ID NO: 239 SEQ ID SEQ ID NO: 76NO: 236 NO: 240tregali GFSFSDCR ISVKSENYGA SASYYRYDVGAWFAY KSVSTSGYSY LAS QHSRELPWT zumab SEQ ID SEQ ID NO: 242 SEQ ID NO: 243 SEQ ID NO: 244 SEQ ID SEQ ID NO: 82NO: 241 NO: 245SCT1 . 1 GYTLTELS FDPEDGKT ATGHNWNDGYYFYYYM QSLLHTDGKTY EVS MQSLQLPLT SEQ ID SEQ ID NO: 247 DL SEQ ID NO: 249 SEQ ID SEQ ID NO: 87 NO: 246 SEQ ID NO: 248 NO: 250SCT1 . 4 GFTFSDYY ISSSGNTI ARE G YNN YN Y S Y Y Y EM QSVSRK AAS QQYNNWPYT SEQ ID SEQ ID NO: 252 DV SEQ ID NO: 254 SEQ ID SEQ ID NO: 93 NO: 251 SEQ ID NO: 253 NO: 255SCT1 . 5 GFTVSSFG IWYDGTNK ARE IAVDGTDYYMDV QGIRSG AAS LQDYNYPYT SEQ ID SEQ ID NO: 257 SEQ ID NO: 258 SEQ ID NO: 259 SEQ ID SEQ ID NO: 99 NO: 256 NO: 255SCT2 . 9 GFTFSDYY ISSSGLTI AREGYSGFDDHYYYYT QSVSSN GAS QHYKNWPYT SEQ ID SEQ ID NO: 260 DV SEQ ID NO: 262 SEQ ID SEQ IDNO: 251 SEQ ID NO: 261 NO: 263 NO: 104TABLE A2 - Illustrative CDRs for anti-CD4 binding domains ( IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameSCT2 . 10 GFTFSDYY I SSSGSTI AREDYSNYEDYYYYYT QSVSSK NAS QQYNNWPYT SEQ ID SEQ ID NO : 264 GV SEQ ID NO : 266 SEQ ID SEQ ID NO : 93 NO : 251 SEQ ID NO : 265 NO : 267SCT2 . 11 GFTFSDYY I SSSGITI AREDYSNYEDHYYYYT QSVSNK NAS QHYNNWPYT SEQ ID SEQ ID NO : 268 GV SEQ ID NO : 270 SEQ ID SEQ ID NO : 251 SEQ ID NO : 269 NO : 267 NO : 112 SCT2 . 11 GFTFSDYY I SSSGITI AREDYSNYEDHYYYYT QSVSNK GAS QHYNNWPYT VL N50G SEQ ID SEQ ID NO : 268 GV SEQ ID NO : 270 SEQ ID SEQ ID NO : 251 SEQ ID NO : 269 NO : 263 NO : 112 SCT2 . 12 GFTFSDYY I SSSGKTI AREDYSNYEDYYYYYT QSVSSK NAS HQYKNWPYT SEQ ID SEQ ID NO : 271 GV SEQ ID NO : 266 SEQ ID SEQ ID NO : 251 SEQ ID NO : 265 NO : 267 NO : 115 SCT2 . 12 GFTFSDYY I SSSGKTI AREDYSNYEDYYYYYT QSVSSK GAS HQYKNWPYT VL N50G SEQ ID SEQ ID NO : 271 GV SEQ ID NO : 266 SEQ ID SEQ ID NO : 251 SEQ ID NO : 265 NO : 263 NO : 115 SCT2 . 13 GFTFSDYY I S ISGQTI AREGYSNYGVKYYYYM QS ISSN NAS QQYNAWTYT SEQ ID SEQ ID NO : 272 DV SEQ ID NO : 274 SEQ ID SEQ ID NO : 251 SEQ ID NO : 273 NO : 267 NO : 119 SCT2 . 14 GFTFSDHY I S ISGNTI VREGYSSSSRGDYSYY QSVSSN GAS QQYKNWPYT SEQ ID SEQ ID NO : 276 TDV SEQ ID NO : 262 SEQ ID SEQ ID NO : 275 SEQ ID NO : 277 NO : 263 NO : 123 SCT2 . 15 GFTFSDYY I S ISGRTI VREGYSSSSRGDYSYY QGVSSN GAS QHYKNWPYT SEQ ID SEQ ID NO : 278 TDV SEQ ID NO : 279 SEQ ID SEQ ID NO : 251 SEQ ID NO : 277 NO : 263 NO : 104 Binds to CD4 D2 and / or D3SCT1 . 6 GFTVSSYG IWFDGSNK AREVALEGYYYYMDV QDIRNG TTS LQDYNYPYT SEQ ID SEQ ID NO : 281 SEQ ID NO : 282 SEQ ID NO : 283 SEQ ID SEQ ID NO : 99 NO : 280 NO : 284SCT1 . 7 GFTVSSYG LWFDGSNK ARELALEGYYYYMDV QDIRNG TTS LQDYNYPYTTABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameSEQ ID SEQ ID NO: 285 SEQ ID NO: 286 SEQ ID NO: 283 SEQ ID SEQ ID NO: 99 NO : 280 NO: 284SCT1 . 8 GFTVSSYG LWFDGSNQ ARE IALEGYYYYMDV QDIRNG TTS LQDYNYPYT SEQ ID SEQ ID NO: 287 SEQ ID NO: 288 SEQ ID NO: 283 SEQ ID SEQ ID NO: 99 NO : 280 NO: 284SCT1 . 9 GFTFSSYG IWYDGSNK AREVALEGYYYYMDV QDIRNG TTS LQDYNYPYT SEQ ID SEQ ID NO: 290 SEQ ID NO: 282 SEQ ID NO: 283 SEQ ID SEQ ID NO: 99 NO : 289 NO: 284SCT1 .10 GFTFSSYG IWYDGNNK TREVALEGYYYYMDV QGIRNG AAS LQDYNYPYT SEQ ID SEQ ID NO: 291 SEQ ID NO: 292 SEQ ID NO: 293 SEQ ID SEQ ID NO: 99 NO : 289 NO: 255SCT1 .19 GFTFSSYA ISGSVGST AKEGYDWSGMDV QGIRND AAS LQDYNYPYT SEQ ID SEQ ID NO: 295 SEQ ID NO: 296 SEQ ID NO: 297 SEQ ID SEQ ID NO: 99 NO: 294 NO: 255SCT2 . 2 GFTFSSYG IWFDGTTR ARE VAI QGRD Y Y I DV QGIRNG AAS LQDYNYPYT SEQ ID SEQ ID NO: 298 SEQ ID NO: 299 SEQ ID NO: 293 SEQ ID SEQ ID NO: 99 NO : 289 NO: 255SCT2 . 3 GFTFSSYG IWFDGTNK AREVAI QGYYYYMDV QDIRNG TTS LQDYNYPYT SEQ ID SEQ ID NO: 300 SEQ ID NO: 301 SEQ ID NO: 283 SEQ ID SEQ ID NO: 99 NO : 289 NO: 284Binds to CD4 D3OKT4 GYTFTNYG INTNTGEP ARLG I Y YD YG Y YAMD Y ESVDSYGNSF LAS QQNNEDPYT SEQ ID SEQ ID NO: 303 SEQ ID NO: 304 SEQ ID NO: 305 SEQ ID SEQ ID NO: 302 NO: 245 NO: 157 SCT1 .20 EIIFSTYA ISGSGDNT VKEGYNWNYMDV QGIRND EAS LQDYTYPYT SEQ ID SEQ ID NO: 307 SEQ ID NO: 1083 SEQ ID NO: 297 SEQ ID SEQ ID NO: 306 NO: 308 NO: 162 SCT1 .21 GLTFSTFA ISGSGENT AKEGYNWNYMDV HGIRND ETS LQDYTYPYTSEQ ID NO: 310 SEQ ID NO: 311 SEQ ID NO: 312TABLE A2 - Illustrative CDRs for anti-CD4 binding domains (IMGT)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 NameSEQ ID SEQ ID SEQ ID NO: 309 NO: 313 NO: 162 SCT1 .22 GLTFSTFA ISGSGENT AKEGYNWNYMDV HGIRND EAS LQDYTYPYT SEQ ID SEQ ID NO: 310 SEQ ID NO: 311 SEQ ID NO: 312 SEQ ID SEQ ID NO: 309 NO: 308 NO: 162 SCT1 .23 GFTFSTYA ISDNIGNT TKDNEDYYMDV QGIRND AAS LQDYNYPRT C36Y SEQ ID SEQ ID NO: 315 SEQ ID NO: 316 SEQ ID NO: 297 SEQ ID SEQ ID NO: 314 NO: 255 NO: 169 SCT2 . 1 GFTFSTNA ISGSNGNT AKERDNWNGFDY HVIRND AAS LQDYNYPYT SEQ ID SEQ ID NO: 318 SEQ ID NO: 319 SEQ ID NO: 320 SEQ ID SEQ ID NO: 99 NO: 317 NO: 255SCT2 . 8 GHTLTELS FDPRDGQI ATGGNEDYYFYYMDV QDIDDD EAT LQHDHFPYT SEQ ID SEQ ID NO: 321 SEQ ID NO: 322 SEQ ID NO: 199 SEQ ID SEQ IDNO: 196 NO: 200 NO: 177TABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR11 GFSFSNY X1X2G YGGSYDPMD SQDINKY YTS YDNPLXvSEQ ID Xi is A, D, E SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID X7is F, Q, Y NO: 323 X2is A, G, W, Y NO: 182 SEQ ID NO: 327SEQ ID NO: 3242 GFSFSNY X1X2G YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID Xi is A, D, E SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 X2is A or G NO: 182SEQ ID NO: 3284 GFSFSNY EX2G YGGSYDPMD SQDINKY YTS YDNPLX7X2 is W or Y SEQ ID NO: 325 SEQ ID NO: 326 X7 is F, Q, YTABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID SEQ ID NO: 330 SEQ ID SEQ ID NO: 327 NO: 323 NO: 1825 GFSFSNY EX2G YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID X2is W or Y SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 SEQ ID NO: 330 NO: 1826 GFSFSNY EGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 331 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 1827 GFSFSNY EGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 331 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 1828 GFSFSNY EWG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 332 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 1829 GFSFSNY EYG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 333 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18210 GFSFSNY EWG YGGSYDPMD SQDINKY YTS YDNPLQSEQ ID SEQ ID NO: 332 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 334 NO: 323 NO: 18211 GFSFSNY EYG YGGSYDPMD SQDINKY YTS YDNPLFSEQ ID SEQ ID NO: 333 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 335 NO: 323 NO: 18212 GFSFSNY EGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 331 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18213 GFSFSNY DGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 336 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329NO: 323 NO: 182TABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR114 GFSFSNY DGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 336 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18215 GFSFSNY AGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 337 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18216 GFSFSNY DAG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 338 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18217 GFSFSNY DGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 336 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18218 GFSFSNY DGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 336 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 18219 GFSFSNY DGG YGGSYDPMD SQDINKY YTS YDNPLYSEQ ID SEQ ID NO: 336 SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID SEQ ID NO: 329 NO: 323 NO: 182SCT1 . 17 GFTFDDY WNGD GAIGGMD SQDIRDD SAS DYNYPWSEQ ID SEQ ID NO: 340 SEQ ID NO: 341 SEQ ID NO: 342 SEQ ID SEQ ID NO: 339 NO: 195 NO: 1131 SCT1 .25 GHTLTEL PRGG GDRDYYYYYMD SQDIDDD EAT HDSFPYSEQ ID SEQ ID NO: 345 SEQ ID NO: 346 SEQ ID NO: 347 SEQ ID SEQ ID NO: 348 NO: 344 NO: 200SCT1 .26 GFTLTKL PRDG GDYDYYYYYMG SQDIDDD EAT HDNFPYSEQ ID SEQ ID NO: 350 SEQ ID NO: 351 SEQ ID NO: 347 SEQ ID SEQ ID NO: 352 NO: 349 NO: 200SCT1 .27 GHTVTEL PRDD GNPDYYFYYMD SQDIDDD EAT HDNFPLSEQ ID NO: 354 SEQ ID NO: 355 SEQ ID NO: 347 SEQ ID NO: 356TABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID SEQ ID NO: 353 NO: 200SCT1 .28 GHTLTEL PRDG GNKDYYFYYMD SQDIDDD EAT HDNFPLSEQ ID SEQ ID NO: 350 SEQ ID NO: 357 SEQ ID NO: 347 SEQ ID SEQ ID NO: 356 NO: 344 NO: 200SCT1 .29 GYTLTAL PRDG GDSDYYYYYMD SQDIDDD EAT HDNFPYSEQ ID SEQ ID NO: 350 SEQ ID NO: 359 SEQ ID NO: 347 SEQ ID SEQ ID NO: 352 NO: 358 NO: 200SCT1 .30 GHTLTEL PRDD GNKDYYFYYMD SQDIDDD EAT HDNFPLSEQ ID SEQ ID NO: 354 SEQ ID NO: 357 SEQ ID NO: 347 SEQ ID SEQ ID NO: 356 NO: 343 NO: 200SCT1 .31 GHTLTEL PKYG GNYEYFYYYMD SQDIDDD EAT HDNFPYSEQ ID SEQ ID NO: 360 SEQ ID NO: 361 SEQ ID NO: 347 SEQ ID SEQ ID NO: 352 NO: 343 NO: 200SCT1 . 32 GHTLTEL PKYG GSPDYFYYYMD SQDIDDD EAT HDNFPYSEQ ID SEQ ID NO: 360 SEQ ID NO: 362 SEQ ID NO: 347 SEQ ID SEQ ID NO: 352 NO: 343 NO: 200SCT1 . 33 GHTLTEL PRNG GSPDYYYWYMD SQDIDDD EAT HDNFPYSEQ ID SEQ ID NO: 363 SEQ ID NO: 364 SEQ ID NO: 347 SEQ ID SEQ ID NO: 352 NO: 343 NO: 200SCT1 . 34 GHTLTEL PRNG GSPDYYFWYMD SQDIDDD EAT HDNFPYSEQ ID SEQ ID NO: 363 SEQ ID NO: 365 SEQ ID NO: 347 SEQ ID SEQ ID NO: 352 NO: 343 NO: 200SCT1 .45 GYTFTSY PNSG VLKGDYYYMD SQSISSSY GSS DDHLPLSEQ ID SEQ ID NO: 367 SEQ ID NO: 368 SEQ ID SEQ ID SEQ ID NO: 369 NO : 366 NO: 1084 NO: 223SCT1 .46 GYTFTSY PNSG VLKGDYYYMD SQSISSTY GSS DDHLPLSEQ ID SEQ ID NO: 367 SEQ ID NO: 368 SEQ ID NO: 370 SEQ ID SEQ ID NO: 369NO : 366 NO: 223TABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SCT1 .47 GYTFTSY PNSG VLKGDYYYMD SQSISSTY GSS DDHLPLSEQ ID SEQ ID NO: 367 SEQ ID NO: 368 SEQ ID NO: 370 SEQ ID SEQ ID NO: 369 NO : 366 NO: 223SCT1 .48 GYTFTSY PNSG VLKGDYYYMD SQSISSTY GSS DDHLPLSEQ ID SEQ ID NO: 367 SEQ ID NO: 368 SEQ ID NO: 370 SEQ ID SEQ ID NO: 369 NO : 366 NO: 223kelixi- GGSISGDY GSGG ILKYLHWLL GDNVGRKS ADS WDSTADHW mab SEQ ID SEQ ID NO: 372 SEQ ID NO: 373 SEQ ID NO: 374 SEQ ID SEQ ID NO: 375NO: 371 NO: 230UB-421 GYTFTDY PGSG GNGTGFA GQSVDYDGDSY VAS SYKDPLSEQ ID SEQ ID NO: 377 SEQ ID NO: 378 SEQ ID NO: 379 SEQ ID SEQ ID NO: 380 NO: 376 NO: 235Binds to CD4 D2ibalizu GYTFTSY PYND KDNYATGAWFA SQSLLYSTNQKNY WAS YYSYRmab SEQ ID SEQ ID NO: 381 SEQ ID NO: 382 SEQ ID NO: 383 SEQ ID SEQ ID NO: 384NO : 366 NO: 240tregali GFSFSDC VKSENY YYRYDVGAWFA SKSVSTSGYSY LAS SRELPW zumab SEQ ID SEQ ID NO: 386 SEQ ID NO: 387 SEQ ID NO: 388 SEQ ID SEQ ID NO: 389NO: 385 NO: 245SCT1 . 1 GYTLTEL PEDG HNWNDGYYFYYYMD SQSLLHTDGKTY EVS SLQLPLSEQ ID SEQ ID NO: 391 SEQ ID NO: 392 SEQ ID NO: 393 SEQ ID SEQ ID NO: 394 NO: 390 NO: 250SCT1 . 4 GFTFSDY SSGN GYNNYNYSYYYFMD SQSVSRK AAS YNNWPYSEQ ID SEQ ID NO: 396 SEQ ID NO: 397 SEQ ID NO: 398 SEQ ID SEQ ID NO: 399 NO: 395 NO: 255SCT1 . 5 GFTVSSF YDGT IAVDGTDYYMD SQGIRSG AAS DYNYPYSEQ ID SEQ ID NO: 401 SEQ ID NO: 402 SEQ ID NO: 403 SEQ ID SEQ ID NO: 404 NO: 400 NO: 255SCT2 . 9 GFTFSDY SSGL GYSGFDDHYYYYTD SQSVSSN GAS YKNWPYTABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID SEQ ID NO: 405 SEQ ID NO: 406 SEQ ID NO: 407 SEQ ID SEQ ID NO: 408 NO: 395 NO: 263SCT2 .10 GFTFSDY SSGS DYSNYEDYYYYYTG SQSVSSK NAS YNNWPYSEQ ID SEQ ID NO: 409 SEQ ID NO: 410 SEQ ID NO: 411 SEQ ID SEQ ID NO: 399 NO: 395 NO: 267SCT2 .11 GFTFSDY SSGI DYSNYEDHYYYYTG SQSVSNK NAS YNNWPYSEQ ID SEQ ID NO: 412 SEQ ID NO: 413 SEQ ID NO: 414 SEQ ID SEQ ID NO: 399 NO: 395 NO: 267SCT2 .11 GFTFSDY SSGI DYSNYEDHYYYYTG SQSVSNK GAS YNNWPYVL N50G SEQ ID SEQ ID NO: 412 SEQ ID NO: 413 SEQ ID NO: 414 SEQ ID SEQ ID NO: 399NO: 395 NO: 263SCT2 . 12 GFTFSDY SSGK DYSNYEDYYYYYTG SQSVSSK NAS YKNWPYSEQ ID SEQ ID NO: 415 SEQ ID NO: 410 SEQ ID NO: 411 SEQ ID SEQ ID NO: 408 NO: 395 NO: 267SCT2 . 12 GFTFSDY SSGK DYSNYEDYYYYYTG SQSVSSK GAS YKNWPYVL N50G SEQ ID SEQ ID NO: 415 SEQ ID NO: 410 SEQ ID NO: 411 SEQ ID SEQ ID NO: 408NO: 395 NO: 263SCT2 . 13 GFTFSDY ISGQ GYSNYGVKYYYYMD SQSISSN NAS YNAWTYSEQ ID SEQ ID NO: 416 SEQ ID NO: 417 SEQ ID NO: 418 SEQ ID SEQ ID NO: 419 NO: 395 NO: 267SCT2 . 14 GFTFSDH ISGN GYSSSSRGDYSYYTD SQSVSSN GAS YKNWPYSEQ ID SEQ ID NO: 421 SEQ ID NO: 422 SEQ ID NO: 407 SEQ ID SEQ ID NO: 408 NO: 420 NO: 263SCT2 . 15 GFTFSDY ISGR GYSSSSRGDYSYYTD SQGVSSN GAS YKNWPYSEQ ID SEQ ID NO: 423 SEQ ID NO: 422 SEQ ID NO: 424 SEQ ID SEQ ID NO: 408 NO: 395 NO: 263Binds to CD4 D2 and / or D3SCT1 . 6 GFTVSSY FDGS VALEGYYYYMD SQDIRNG TTS DYNYPYSEQ ID NO: 426 SEQ ID NO: 427 SEQ ID NO: 428 SEQ ID NO: 404TABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID SEQ ID NO: 425 NO: 284SCT1 . 7 GFTVSSY FDGS LALEGYYYYMD SQDIRNG TTS DYNYPYSEQ ID SEQ ID NO: 426 SEQ ID NO: 429 SEQ ID NO: 428 SEQ ID SEQ ID NO: 404 NO: 425 NO: 284SCT1 . 8 GFTVSSY FDGS IALEGYYYYMD SQDIRNG TTS DYNYPYSEQ ID SEQ ID NO: 426 SEQ ID NO: 430 SEQ ID NO: 428 SEQ ID SEQ ID NO: 404 NO: 425 NO: 284SCT1 . 9 GFTFSSY YDGS VALEGYYYYMD SQDIRNG TTS DYNYPYSEQ ID SEQ ID NO: 432 SEQ ID NO: 427 SEQ ID NO: 428 SEQ ID SEQ ID NO: 404 NO: 431 NO: 284SCT1 .10 GFTFSSY YDGN VALEGYYYYMD SQGIRNG AAS DYNYPYSEQ ID SEQ ID NO: 433 SEQ ID NO: 427 SEQ ID NO: 434 SEQ ID SEQ ID NO: 404 NO: 431 NO: 255SCT1 .19 GFTFSSY GSVG GYDWSGMD SQGIRND AAS DYNYPYSEQ ID SEQ ID NO: 435 SEQ ID NO: 436 SEQ ID NO: 437 SEQ ID SEQ ID NO: 404 NO: 431 NO: 255SCT2 . 2 GFTFSSY FDGT VAIQGRDYYID SQGIRNG AAS DYNYPYSEQ ID SEQ ID NO: 438 SEQ ID NO: 439 SEQ ID NO: 434 SEQ ID SEQ ID NO: 404 NO: 431 NO: 255SCT2 . 3 GFTFSSY FDGT VAIQGYYYYMD SQDIRNG TTS DYNYPYSEQ ID SEQ ID NO: 438 SEQ ID NO: 440 SEQ ID NO: 428 SEQ ID SEQ ID NO: 404 NO: 431 NO: 284Binds to CD4 D3OKT4 GYTFTNY TNTG GIYYDYGYYAMD SESVDSYGNSF LAS NNEDPYSEQ ID SEQ ID NO: 442 SEQ ID NO: 443 SEQ ID NO: 444 SEQ ID SEQ ID NO: 445 NO: 441 NO: 245SCT1 .20 EIIFSTY GSGD GYNWNYMD SQGIRND EAS DYTYPYSEQ ID NO: 447 SEQ ID NO: 448 SEQ ID NO: 437 SEQ ID NO: 449TABLE A3 - Illustrative CDRs for anti-CD4 binding domains (Chothia)Ab VH - VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - CDR3 Name CDR1SEQ ID SEQ ID NO: 446 NO: 308SCT1 .21 GLTFSTF GSGE GYNWNYMD SHGIRND ETS DYTYPYSEQ ID SEQ ID NO: 451 SEQ ID NO: 448 SEQ ID NO: 452 SEQ ID SEQ ID NO: 449 NO: 450 NO: 313SCT1 .22 GLTFSTF GSGE GYNWNYMD SHGIRND EAS DYTYPYSEQ ID SEQ ID NO: 451 SEQ ID NO: 448 SEQ ID NO: 452 SEQ ID SEQ ID NO: 449 NO: 450 NO: 308SCT1 .23 GFTFSTY DNIG NEDYYMD SQGIRND AAS DYNYPRC36Y SEQ ID SEQ ID NO: 454 SEQ ID NO: 455 SEQ ID NO: 437 SEQ ID SEQ ID NO: 456 NO: 453 NO: 255SCT2 . 1 GFTFSTN GSNG RDNWNGFD SHVIRND AAS DYNYPYSEQ ID SEQ ID NO: 458 SEQ ID NO: 459 SEQ ID NO: 460 SEQ ID SEQ ID NO: 404 NO: 457 NO: 255SCT2 . 8 GHTLTEL PRDG GNEDYYFYYMD SQDIDDD EAT HDHFPYSEQ ID SEQ ID NO: 350 SEQ ID NO: 461 SEQ ID NO: 347 SEQ ID SEQ ID NO: 462NO: 343 NO: 200TABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 1 ASGFSFSNYA INX1X2GSTFYX3DSVKX4 HYGGSYDPMD ASQDINKY YTSXeLHPGVPSR YDNPLX7 SEQ ID Xi is A, D or E SEQ ID NO: 465 SEQ ID NO: 466 Xe is I or T X? is NO: 463 X2is A, G, W or Y SEQ ID F, Q, Y X3is G or S NO: 467 SEQ ID X4 is A or P NO: 327 SEQ ID NO: 4642 ASGFSFSNYA INX1X2GSTFYX3DSVKX4 HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLYTABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 SEQ ID Xi is A, D or E SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 X2 is A or G NO: 469 NO: 329X3is G or SX4 is A or PSEQ ID NO: 4683 ASGFSFSNYA INEX2GSTFYADSVK HYGGSYDPMD ASQDINKY YTSXeLHPGVPSR YDNPLX7 SEQ ID X2 is W or Y SEQ ID NO: 465 SEQ ID NO: 466 Xe is I or T X? is NO: 463 SEQ ID NO: 470 SEQ ID F, Q, Y NO: 467 SEQ ID NO: 327 4 ASGFSFSNYA INEX2GSTFYADSVK HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLX7 SEQ ID X2 is W or Y SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID X7 is NO: 463 SEQ ID NO: 470 NO: 469 F, Q, Y SEQ ID NO: 327 5 ASGFSFSNYA INEX2GSTFYADSVK HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID X2 is W or Y SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 SEQ ID NO: 470 NO: 469 NO: 329 6 ASGFSFSNYA INEGGS TFYADSVKX4R HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID X4is G or S SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 SEQ ID NO: 1132 NO: 469 NO: 329 7 ASGFSFSNYA INEGGSTFYADSVKSR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 471 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 8 ASGFSFSNYA INEWGSTFYADSVKSR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 472 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 9 ASGFSFSNYA INEYGSTFYADSVKSR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLYSEQ ID NO: 473 SEQ ID NO: 465 SEQ ID NO: 466TABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 SEQ ID SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 10 ASGFSFSNYA INEWGSTFYADSVKSR HYGGSYDPMD ASQDINKY YTSILHPGVPSR YDNPLQ SEQ ID SEQ ID NO: 472 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 474 NO: 334 11 ASGFSFSNYA INEYGSTFYADSVKSR HYGGSYDPMD ASQDINKY YTSILHPGVPSR YDNPLF SEQ ID SEQ ID NO: 473 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 474 NO: 335 12 ASGFSFSNYA INEGGS TFYADSVKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 475 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 13 ASGFSFSNYA INDGGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 478 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 14 ASGFSFSNYA INDGGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 478 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 15 ASGFSFSNYA INAGGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 476 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 16 ASGFSFSNYA INDAGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 477 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 17 ASGFSFSNYA INDGGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 478 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 18 ASGFSFSNYA INDGGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 478 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ IDNO: 463 NO: 469 NO: 329TABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 19 ASGFSFSNYA INDGGS T FYADS VKGR HYGGSYDPMD ASQDINKY YTSTLHPGVPSR YDNPLY SEQ ID SEQ ID NO: 478 SEQ ID NO: 465 SEQ ID NO: 466 SEQ ID SEQ ID NO: 463 NO: 469 NO: 329 SCT1 . 1 PSGFTFDDYG INWNGDSTGYADSVRGR DGAIGGMD ASQDIRDD SASTLQSGVPSR DYNYPW 7 SEQ ID SEQ ID NO: 480 SEQ ID NO: 481 SEQ ID NO: 482 SEQ ID SEQ ID NO: 479 NO: 483 NO: 343 SCT1 . 2 VSGHTLTELS FDPRGGETIYAQKFQGR GGDRDYYYYYMD ASQDIDDD EATTLVPGVPPR HDSFPY 5 SEQ ID SEQ ID NO: 485 SEQ ID NO: 486 SEQ ID NO: 487 SEQ ID SEQ ID NO: 484 NO : 488 NO: 348 SCT1 . 2 VSGFTLTKLS FDPRDGERIYAQKFQGR GGDYDYYYYYMG ASQDIDDD EATTLVPGIPPR HDNFPY 6 SEQ ID SEQ ID NO: 490 SEQ ID NO: 491 SEQ ID NO: 487 SEQ ID SEQ ID NO : 489 NO: 492 NO: 352 SCT1 . 2 VSGHTVTELS FHPRDDEI IYAQKFQGR GGNPDYYFYYMD ASQDIDDD EATTLVPGIPPR HDNFPL 7 SEQ ID SEQ ID NO: 494 SEQ ID NO: 495 SEQ ID NO: 487 SEQ ID SEQ ID NO: 493 NO: 492 NO: 356 SCT1 . 2 VSGHTLTELS FHPRDGET IYAQKFQGR GGNKDYYFYYMD ASQDIDDD EATTLVPGIPPR HDNFPL 8 SEQ ID SEQ ID NO: 496 SEQ ID NO: 497 SEQ ID NO: 487 SEQ ID SEQ ID NO: 484 NO: 492 NO: 356 SCT1 . 2 VSGYTLTALS FNPRDGET IYAQKFQGR GGDSDYYYYYMD ASQDIDDD EATTLVPGIPPR HDNFPY 9 SEQ ID SEQ ID NO: 499 SEQ ID NO: 500 SEQ ID NO: 487 SEQ ID SEQ ID NO: 498 NO: 492 NO: 352 SCT1 . 3 VSGHTLTELS FNPRDDETIYTQKFQGR GGNKDYYFYYMD ASQDIDDD EATTLVPGIPPR HDNFPL 0 SEQ ID SEQ ID NO: 501 SEQ ID NO: 497 SEQ ID NO: 487 SEQ ID SEQ ID NO: 484 NO: 492 NO: 356 SCT1 . 3 VSGHTLTELS FDPKYGETTYAQKFQDR GGNYEYFYYYMD ASQDIDDD EATTLVPGIPPR HDNFPY 1 SEQ ID SEQ ID NO: 502 SEQ ID NO: 503 SEQ ID NO: 487 SEQ ID SEQ ID NO: 484 NO: 492 NO: 352 SCT1 . 3 VSGHTLTELS FDPKYGETMYAQKFQGR GGSPDYFYYYMD ASQDIDDD EATTLVPGIPRR HDNFPY2 SEQ ID NO: 504 SEQ ID NO: 505 SEQ ID NO: 487TABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 SEQ ID SEQ ID SEQ ID NO: 484 NO: 506 NO: 352 SCT1 . 3 VSGHTLTELS FDPRNGETIYAQKFQGR GGSPDYYYWYMD ASQDIDDD EATTLVPGIPPR HDNFPY 3 SEQ ID SEQ ID NO: 507 SEQ ID NO: 508 SEQ ID NO: 487 SEQ ID SEQ ID NO: 484 NO: 492 NO: 352 SCT1 . 3 VSGHTLTELS FDPRNGETIYAQKFQGR GGSPDYYFWYMD ASQDIDDD EATTLVPGIPPR HDNFPY 4 SEQ ID SEQ ID NO: 507 SEQ ID NO: 509 SEQ ID NO: 487 SEQ ID SEQ ID NO: 484 NO: 492 NO: 352 SCT1 . 4 ASGYTFTSYD MNPNSGNTGSTQKFQGR GVLKGDYYYMD ASQSISSSY GSSTRATGIPAR DDHLPL 5 SEQ ID SEQ ID NO: 511 SEQ ID NO: 512 SEQ ID NO: 513 SEQ ID SEQ ID NO: 510 NO: 514 NO: 369 SCT1 . 4 ASGYTFTSYD VNPNSGNTGSTQKFQGR GVLKGDYYYMD ASQSISSTY GSSTRATGIPAR DDHLPL 6 SEQ ID SEQ ID NO: 515 SEQ ID NO: 512 SEQ ID NO: 516 SEQ ID SEQ ID NO: 510 NO: 514 NO: 369 SCT1 . 4 ASGYTFTSYD VNPNSGNTGSTQKFQGR GVLKGDYYYMD ASQSISSTY GSSTRATGIPAR DDHLPL 7 SEQ ID SEQ ID NO: 515 SEQ ID NO: 512 SEQ ID NO: 516 SEQ ID SEQ ID NO: 510 NO: 514 NO: 369 SCT1 . 4 ASGYTFTSYD VNPNSGNTGSTQKFQGR GVLKGDYYYMD ASQSISSTY GSSTRATGIPAR DDHLPL 8 SEQ ID SEQ ID NO: 515 SEQ ID NO: 512 SEQ ID NO: 516 SEQ ID SEQ ID NO: 510 NO: 514 NO: 369 Kelixi VSGGSISGDYY IYGSGGGTNYNPSLNNR NILKYLHWLL GDNVGRKS ADSERPSGIPAR WDSTADH -mab SEQ ID SEQ ID NO: 518 SEQ ID NO: 519 SEQ ID NO: 374 SEQ ID W NO: 517 NO: 520 SEQ ID NO: 375 UB-421 ASGYTFTDYV IYPGSGSAYSNAKFKDR RGNGTGFA AGQSVDYDGDSY VASNLESGIPAR SYKDPL SEQ ID SEQ ID NO: 522 SEQ ID NO: 523 SEQ ID NO: 524 SEQ ID SEQ ID NO: 521 NO: 525 NO: 380Binds to CD4 D2TABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 ibaliz ASGYTFTSYV INPYNDGTDYDEKFKGK EKDNYATGAWFA SSQSLLYSTNQKNY WASTRESGVPDR YYSYR umab SEQ ID SEQ ID NO: 527 SEQ ID NO: 528 SEQ ID NO: 529 SEQ ID SEQ ID NO: 526 NO: 530 NO: 384 tregal ASGFSFSDCR ISVKSENYGANYAESVRGR SYYRYDVGAWFA ASKSVSTSGYSY LASILESGVPDR SRELPW i zumab SEQ ID SEQ ID NO: 532 SEQ ID NO: 533 SEQ ID NO: 534 SEQ ID SEQ ID NO: 531 NO: 535 NO: 389 SCT1 . 1 VSGYTLTELS FDPEDGKTIYAPKFQGR GHNWNDGYYFYYYMD SSQSLLHTDGKTY EVSNRFSGVPDR SLQLPL SEQ ID SEQ ID NO: 537 SEQ ID NO: 538 SEQ ID NO: 539 SEQ ID SEQ ID NO: 536 NO: 540 NO: 394 SCT1 . 4 ASGFTFSDYY ISSSGNTIFYVDSVEGR EGYNNYNYSYYYFMD ASQSVSRK AASTRATGIPAR YNNWPY SEQ ID SEQ ID NO: 542 SEQ ID NO: 543 SEQ ID NO: 544 SEQ ID SEQ ID NO: 541 NO: 545 NO: 399 SCT1 . 5 ASGFTVSSFG IWYDGTNKYYADSVKGR EIAVDGTDYYMD ASQGIRSG AASTLQSGVPSR DYNYPY SEQ ID SEQ ID NO: 547 SEQ ID NO: 548 SEQ ID NO: 549 SEQ ID SEQ ID NO: 546 NO: 550 NO: 404 SCT2 . 9 ASGFTFSDYY ISSSGLTI FYVDS VKGR EGYSGFDDHYYYYTD ASQSVSSN GAS I RAT G I PAR YKNWPY SEQ ID SEQ ID NO: 551 SEQ ID NO: 552 SEQ ID NO: 553 SEQ ID SEQ ID NO: 541 NO: 554 NO: 408 SCT2 . 1 ASGFTFSDYY ISSSGSTIFYTDSVKGR EDYSNYEDYYYYYTG ASQSVSSK NAS T RAT G I PAR YNNWPY 0 SEQ ID SEQ ID NO: 555 SEQ ID NO: 556 SEQ ID NO: 557 SEQ ID SEQ ID NO: 541 NO: 558 NO: 399 SCT2 . 1 ASGFTFSDYY ISSSGITIFYTDSVKGR EDYSNYEDHYYYYTG ASQSVSNK NAS T RAT SI PAR YNNWPY 1 SEQ ID SEQ ID NO: 559 SEQ ID NO: 560 SEQ ID NO: 561 SEQ ID SEQ ID NO: 541 NO: 562 NO: 399 SCT2 . 1 ASGFTFSDYY ISSSGITIFYTDSVKGR EDYSNYEDHYYYYTG ASQSVSNK GAST RAT SI PAR YNNWPY 1 SEQ ID SEQ ID NO: 559 SEQ ID NO: 560 SEQ ID NO: 561 SEQ ID SEQ ID VL NO: 541 NO: 563 NO: 399N50GTABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 SCT2 . 1 ASGFTFSDYY ISSSGKTIFYTDSVKGR EDYSNYEDYYYYYTG ASQSVSSK NAS T RAT G I PAR YKNWPY 2 SEQ ID SEQ ID NO: 564 SEQ ID NO: 556 SEQ ID NO: 557 SEQ ID SEQ ID NO: 541 NO: 558 NO: 408 SCT2 . 1 ASGFTFSDYY ISSSGKTIFYTDSVKGR EDYSNYEDYYYYYTG ASQSVSSK GAS T RAT G I PAR YKNWPY 2 SEQ ID SEQ ID NO: 564 SEQ ID NO: 556 SEQ ID NO: 557 SEQ ID SEQ ID VL NO: 541 NO : 565 NO: 408 N50GSCT2 . 1 ASGFTFSDYY ISISGQTIYYGDSVKGR EGYSNYGVKYYYYMD ASQSISSN NAS T RAT DI PAR YNAWTY 3 SEQ ID SEQ ID NO: 566 SEQ ID NO: 567 SEQ ID NO: 568 SEQ ID SEQ ID NO: 541 NO : 569 NO: 419 SCT2 . 1 ASGFTFSDHY ISISGNTIYYTDSVKGR EGYSSSSRGDYSYYTD ASQSVSSN GAS T RAT G I PAR YKNWPY 4 SEQ ID SEQ ID NO: 571 SEQ ID NO: 572 SEQ ID NO: 553 SEQ ID SEQ ID NO: 570 NO : 565 NO: 408 SCT2 . 1 ASGFTFSDYY ISISGRTIYYIDSVKGR EGYSSSSRGDYSYYTD ASQGVSSN GAST RAT DI PAR YKNWPY 5 SEQ ID SEQ ID NO: 573 SEQ ID NO: 572 SEQ ID NO: 574 SEQ ID SEQ ID NO: 541 NO: 575 NO: 408 Binds to CD4 D2 and / or D3SCT1 . 6 ASGFTVSSYG IWFDGSNKYYADSLTGL EVALEGYYYYMD ASQDIRNG TTSSLQTGVPSR DYNYPY SEQ ID SEQ ID NO: 577 SEQ ID NO: 578 SEQ ID NO: 579 SEQ ID SEQ ID NO: 576 NO: 580 NO: 404 SCT1 . 7 ASGFTVSSYG LWFDGSNKFYADSVKGR ELALEGYYYYMD ASQDIRNG TTSSLQSGVPSR DYNYPY SEQ ID SEQ ID NO: 581 SEQ ID NO: 582 SEQ ID NO: 579 SEQ ID SEQ ID NO: 576 NO: 583 NO: 404 SCT1 . 8 ASGFTVSSYG LWFDGSNQFYADSVKGR EIALEGYYYYMD SSQDIRNG TTSSLQSGVPSR DYNYPY SEQ ID SEQ ID NO: 584 SEQ ID NO: 585 SEQ ID NO: 586 SEQ ID SEQ ID NO: 576 NO: 583 NO: 404 SCT1 . 9 ASGFTFSSYG IWYDGSNKYYADSVKGR EVALEGYYYYMD ASQDIRNG TTSNLQSGVPSR DYNYPY SEQ ID SEQ ID NO: 588 SEQ ID NO: 578 SEQ ID NO: 579 SEQ ID SEQ IDNO: 587 NO: 589 NO: 404TABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 SCT1 . 1 ASGFTFSSYG IWYDGNNKYYADSVKGR EVALEGYYYYMD ASQGIRNG AASSLQSGVPSS DYNYPY 0 SEQ ID SEQ ID NO: 590 SEQ ID NO: 578 SEQ ID NO: 591 SEQ ID SEQ ID NO: 587 NO: 592 NO: 404 SCT1 . 1 ASGFTFSSYA ISGSVGSTYYADSVKGR EGYDWSGMD ASQGIRND AASSLQSGVPSR DYNYPY 9 SEQ ID SEQ ID NO: 594 SEQ ID NO: 595 SEQ ID NO: 596 SEQ ID SEQ ID NO: 593 NO: 597 NO: 404 SCT2 . 2 ASGFTFSSYG IWFDGTTRFYADSVKGR EVAIQGRDYYID ASQGIRNG AASSLQSGVPSR DYNYPY SEQ ID SEQ ID NO: 598 SEQ ID NO: 599 SEQ ID NO: 591 SEQ ID SEQ ID NO: 587 NO: 597 NO: 404 SCT2 . 3 ASGFTFSSYG IWFDGTNKFYADSVKGR EVAIQGYYYYMD ASQDIRNG TTSNLQNGVPSR DYNYPY SEQ ID SEQ ID NO: 600 SEQ ID NO: 601 SEQ ID NO: 579 SEQ ID SEQ ID NO: 587 NO: 602 NO: 404 Binds to CD4 D30KT4 ASGYTFTNYG INTNTGEPTYAEEFKGR LGI YYDYGYYAMD ASESVDSYGNSF LASNLESGVPAR NNEDPY SEQ ID SEQ ID NO: 604 SEQ ID NO: 605 SEQ ID NO: 606 SEQ ID SEQ ID NO: 603 NO: 607 NO: 445 SCT1 . 2 ASEIIFSTYA ISGSGDNTYYADSVKGR EGYNWNYMD ASQGIRND EASSLQSGVPSR DYTYPY 0 SEQ ID SEQ ID NO: 609 SEQ ID NO: 610 SEQ ID NO: 596 SEQ ID SEQ ID NO: 608 NO: 611 NO: 449 SCT1 . 2 ASGLTFSTFA ISGSGENTYYADSVKGR EGYNWNYMD ASHGIRND ETSSLQSGVPSR DYTYPY 1 SEQ ID SEQ ID NO: 613 SEQ ID NO: 610 SEQ ID NO: 614 SEQ ID SEQ ID NO: 612 NO: 615 NO: 449 SCT1 . 2 ASGLTFSTFA ISGSGENTYYADSVKGR EGYNWNYMD ASHGIRND EASSLQSGVPSR DYTYPY 2 SEQ ID SEQ ID NO: 613 SEQ ID NO: 610 SEQ ID NO: 614 SEQ ID SEQ ID NO: 612 NO: 611 NO: 449 SCT1 .2 ASGFTFSTYA ISDNIGNTYYADSVKGR DNEDYYMD ASQGIRND AASTLQSGVPSR DYNYPR 3 SEQ ID SEQ ID NO: 617 SEQ ID NO: 618 SEQ ID NO: 596 SEQ ID SEQ ID NO: 616 NO: 550 NO: 456SCT2 . 1 ASGFTFSTNA ISGSNGNTYYADSVKGR ERDNWNGFD ASHVIRND AASSLQSGVPSR DYNYPYTABLE A4 - Illustrative CDRs for anti-CD4 binding domains (Honegger)Ab VH - CDR1 VH - CDR2 VH - CDR3 VL - CDR1 VL - CDR2 VL - Name CDR3 SEQ ID SEQ ID NO: 620 SEQ ID NO: 621 SEQ ID NO: 622 SEQ ID SEQ ID NO: 619 NO: 597 NO: 404 SCT2 . 8 VSGHTLTELS FDPRDGQI I YAEKFQGR GGNEDYYFYYMD ASQDIDDD EATTLVPGIPPR HDHFPY SEQ ID SEQ ID NO: 623 SEQ ID NO: 624 SEQ ID NO: 487 SEQ ID SEQ IDNO: 484 NO: 492 NO: 462TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VLBinds to CD4 DI1 SEQ ID NO: 625 SEQ ID NO: 626 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCX5ASQDINKYIAWYQ KGLEWVASINX1X2GSTFYX3DSVKX4RFTISRDNSKNTLYLE QKPGKGPKLLIHYTSXeLHPGVPSRFSGSGSGTDYTLT MNSLRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS ISSLQPEDFATYYCLQYDNPLX7TFGQGTKLEIKXi is A, D or E X5 is K or RX2is A, G, W or Y Xe is I or TX3 is A or P X? is F, Q or YX4is G or S2 SEQ ID NO: 627 SEQ ID NO: 628 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCX5ASQDINKYIAWYQ KGLEWVASINX1X2GSTFYX3DSVKX4RFTISRDNSKNTLYLE QKPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTI MNSLRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SSLQPEDFATYYCLQYDNPLYTFGQGTKLEIKXi is A, D or E X5 is K or RX2is A or GX3 is A or PX4is G or STABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL3 SEQ ID NO : 629 SEQ ID NO : 630 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEX2GS TFYADSVKSRFT I SRDNSKNTLYLEMN KPGKGPKLLIHYTSXeLHPGVPSRFSGSGSGTDYTLTI SLRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SSLQPEDFATYYCLQYDNPLX7TFGQGTKLEIK X2 is W or Y Xe is I or TX? is F, Q or Y4 SEQ ID NO : 629 SEQ ID NO : 631 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEX2GS TFYADSVKSRFT I SRDNSKNTLYLEMN KPGKGPKLLIHYTSILHPGVPSRFSGSGSGTDYTLTIS SLRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLX7TFGQGTKLEIKX2 is W or Y X7 is F, Q or Y5 SEQ ID NO : 629 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEX2GS TFYADSVKSRFT I SRDNSKNTLYLEMN KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS SLRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIKX2 is W or Y6 SEQ ID NO : 633 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEGGS TFYADSVKX4RFT I SRDNSKNTLYLEMN KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS SLRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIKX4is G or S7 SEQ ID NO : 634 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEGGS TFYADSVKSRFT I SRDNSKNTLYLEMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK8 SEQ ID NO : 635 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEWGS TFYADSVKSRFT I SRDNSKNTLYLEMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK9 SEQ ID NO : 636 SEQ ID NO : 632TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEYGSTFYADSVKSRFT I SRDNSKNTLYLEMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK10 SEQ ID NO : 635 SEQ ID NO : 637 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEWGSTFYADSVKSRFT I SRDNSKNTLYLEMNS KPGKGPKLLIHYTSILHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLQTFGQGTKLEIK11 SEQ ID NO : 636 SEQ ID NO : 638 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEYGSTFYADSVKSRFT I SRDNSKNTLYLEMNS KPGKGPKLLIHYTSILHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLFTFGQGTKLEIK12 SEQ ID NO : 639 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INEGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK13 SEQ ID NO : 640 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INDGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK14 SEQ ID NO : 641 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INDGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVYYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK15 SEQ ID NO : 642 SEQ ID NO : 632 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INAGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK16 SEQ ID NO : 643 SEQ ID NO : 632TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INDAGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK17 SEQ ID NO : 640 SEQ ID NO : 644 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQQ KGLEWVAS INDGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKAPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK18 SEQ ID NO : 640 SEQ ID NO : 645 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQH KGLEWVAS INDGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKAPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK19 SEQ ID NO : 640 SEQ ID NO : 646 EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYAMSWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDINKYIAWYQH KGLEWVAS INDGGS TFYADSVKGRFT I SRDNSKNTLYLQMNS KPGKGPKLLIHYTSTLHPGVPSRFSGSGSGTDYTLTIS LRAEDTAVFYCSRHYGGSYDPMDYWGQGTTVTVSS SLQPEDFATYYCLQYDNPLYTFGQGTKLEIK SCT1 . 17 SEQ ID NO : 647 SEQ ID NO : 648EVQLVESGGGWRPGGSLRLSCAPSGFTFDDYGMSWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQDIRDDLGWYQQ KGLEWVSGINWNGDSTGYADSVRGRFTISRDNAKNSLYLQMN KPGKAPKLLIYSASTLQSGVPSRFSGSESGTDFTLTIS SLRAEDTALYHCARDGAIGGMDVWGKGTTVTVSS SLQPEDFAAYYCLQDYNYPWTFGQGTRVEIK SCT1 .25 SEQ ID NO : 649 SEQ ID NO : 650QVQLVQSGAEVRKPGASVKVSCKVSGHTLTELSMHWIRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWFQR EGLEWMGYFDPRGGETIYAQKFQGRVTLTEDTSTDTAYMELT KPGEAAIFIIQEATTLVPGVPPRFSGSGYGTDFTLTIS SLTSEDTAVYYCATGGDRDYYYYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDSFPYTFGQGTKLEIK SCT1 .26 SEQ ID NO : 651 SEQ ID NO : 652QVQLLQSGAEVKRPGASVRVSCKVSGFTLTKLSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDLNWYQQ KGLEWMGFFDPRDGERIYAQKFQGRVTMTEDTSTDTAYMELS KPGEAAIFIVQEATTLVPGIPPRFSGSGYGTDFTLTIN SLRSEDTAVYYCATGGDYDYYYYYMGVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPYTFGQGTKLEIKSCT1 .27 SEQ ID NO : 653 SEQ ID NO : 654TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL QVQLVQSGAEVKKPGASVKVSCKVSGHTVTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGS FHPRDDE 11 YAQKFQGRVTMTEDS FTDTAYMELS KPGEAAI FI IQEATTLVPGIPPRFSGSGYGTDFTLT IN SLTSEDTAVYYCATGGNPDYYFYYMDVWGKGTPVTVSS NIESEDAAYYFCLQHDNFPLTFGQGTKVEIK SCT1 .28 SEQ ID NO : 655 SEQ ID NO : 656QVQLLQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGS FHPRDGET I YAQKFQGRVTLTEDTSKDTAFMELS KPGEAAI FI IQEATTLVPGIPPRFSGSGYGTDFTLT IN RLRSEDTAVYYCATGGNKDYYFYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPLTFGGGTKVEIK SCT1 .29 SEQ ID NO : 657 SEQ ID NO : 658QVQLVQSGAEVKKPGASVKVSCKVSGYTLTALSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGYFNPRDGETIYAQKFQGRVTMTEDTFTDTAYMELS KPGEAAI FI IQEATTLVPGIPPRFSGSGYGTDFTLI IN SLRSEDTAIYYCATGGDSDYYYYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPYTFGQGTKLEIK SCT1 .30 SEQ ID NO : 659 SEQ ID NO : 660QVQLVQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVTISCKASQDIDDDMNWYQQ TGLEWMGYFNPRDDETIYTQKFQGRVTMTEDTSTDTAYMELR KPGEAAI FI IQEATTLVPGIPPRFSGSGYGTDFTLT IN SLRSEDTAVYYCATGGNKDYYFYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPLTFGQGTKVEIK SCT1 .31 SEQ ID NO : 661 SEQ ID NO : 662QVQLVQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGVFDPKYGETTYAQKFQDRVTMTEDTSTDTAYMELS KPGEAAI FI IQEATTLVPGIPPRFSGSGYGTDFTLT IN SLRSEDTAVYYCATGGNYEYFYYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPYTFGQGTKLEIK SCT1 . 32 SEQ ID NO : 663 SEQ ID NO : 664QVQLIQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGIFDPKYGETMYAQKFQGRVTLTEDTSTDTAYMELS KPGEAAI FVIQEATTLVPGIPRRFSGSGYGTDFTLT IN SLRSEDTAVYYCATGGSPDYFYYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPYTFGQGTKLEIK SCT1 . 33 SEQ ID NO : 665 SEQ ID NO : 666QVQLLQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGIFDPRNGETIYAQKFQGRVTMTEDTSTDTAYMELS KPGEPAI FI IQEATTLVPGIPPRFSGSGYGTDFTLT IN SLRSEDTAVYYCATGGSPDYYYWYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPYTFGQGTKLEIKSCT1 . 34 SEQ ID NO : 667 SEQ ID NO : 666TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL QVQLLQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDMNWYQQ KGLEWMGIFDPRNGETIYAQKFQGRVTMTEDTSTDTAYMELS KPGEPAIFIIQEATTLVPGIPPRFSGSGYGTDFTLTIN SLSSEDTAVYYCATGGSPDYYFWYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDNFPYTFGQGTKLEIK SCT1 .45 SEQ ID NO : 668 SEQ ID NO : 669QVQLVQS GAE VKKPGAS VKVS CKAS GYTFTSYDI NWVRQAT G EIVMTQSPATLSLSPGERATLSCRASQSISSSYLSWYQ QGLEWMGWMNPNSGNTGSTQKFQGRVTMTRNTSITTAYMELS QKPGQAPRLLIYGSSTRATGIPARFSGSGSGTDFTLTI SLRSEDTAVYYCARGVLKGDYYYMDVWGKGTTVTVSS SSLQPEDFAVYYCQQDDHLPLTFGGGTKVEIK SCT1 .46 SEQ ID NO : 670 SEQ ID NO : 671QVQLVHS GAE VKKPGAS VKVS CKAS GYTFTSYDI NWVRQAT G EIVMTQSPATLSLSPGERATLSCRASQSISSTYLSWYQ QGLEWMGWVNPNSGNTGSTQKFQGRVTMTRNTSISTAYMELS QKPGQAPRLLIYGSSTRATGIPARFSGSGSGTDFTLTI SLRSEDTAVYYCARGVLKGDYYYMDVWGKGTTVTVSS SSLQPEDFAVYYCQQDDHLPLTFGGGTKVEIK SCT1 .47 SEQ ID NO : 672 SEQ ID NO : 673QVQLVQS GAE VKKPGAS VKVS CKAS GYTFTSYDI NWVRQAT G EIVMTQSPATLSLSPGERATLSCRASQSISSTYLSWYQ QGLEWMGWVNPNSGNTGSTQKFQGRVTMTRNTSISTAYMELS QKPGQAPRLLIYGSSTRATGIPARFRGSGSGTDFTLTI SLRSEDTAVYYCARGVLKGDYYYMDVWGKGTTVTVSS SSLQPEDFAVYYCQQDDHLPLTFGGGTKVEIK SCT1 .48 SEQ ID NO : 672 SEQ ID NO : 671QVQLVQS GAE VKKPGAS VKVS CKAS GYTFTSYDI NWVRQAT G EIVMTQSPATLSLSPGERATLSCRASQSISSTYLSWYQ QGLEWMGWVNPNSGNTGSTQKFQGRVTMTRNTSISTAYMELS QKPGQAPRLLIYGSSTRATGIPARFSGSGSGTDFTLTI SLRSEDTAVYYCARGVLKGDYYYMDVWGKGTTVTVSS SSLQPEDFAVYYCQQDDHLPLTFGGGTKVEIKkelixi- SEQ ID NO : 674 SEQ ID NO : 675mab MKHLWFFLLLVAAPRWVLSQVQLQEAGPGLVKPSETLSLTCS MAWALLLLGLLAHFTDSAASYELSQPRSVSVSPGQTAG VSGGSISGDYYWFWIRQSPGKGLEWIGYIYGSGGGTNYNPSL FTCGGDNVGRKSVQWYQQKPPQAPVLVIYADSERPSGI NNRVSISIDTSKNLFSLKLRSVTAADTAVYYCASNILKYLHW PARFSGSNSGNTATLTISGVEAGDEADYYCQVWDSTAD LLYWGQGVLVTVS HWVFGGGTRLTVLG UB-421 SEQ ID NO : 676 SEQ ID NO : 677QVQLVQSGPELKKPGASVKVSCKASGYTFTDYVIHWVKQATG DIVLTQSPASLAVSLGQRATITCKAGQSVDYDGDSYMN QGLEWIGEIYPGSGSAYSNAKFKDRVTMTADKSSNTAYMELS WYQQKPGQPPKLLIYVASNLESGIPARFSGSGSGTDFT SLTSDDTAVYFCARRGNGTGFAYWGQGTLVTVSS LNIHPVEENDAATYYCQQSYKDPLTFGQGTKLEIKBinds to CD4 D2TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VLibalizu SEQ ID NO : 678 SEQ ID NO : 679mab QVQLQQSGPEWKPGASVKMSCKASGYTFTSYVIHWVRQKPG DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNY QGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELS LAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTD SLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSS FTLT I S SVQAEDVAVYYCQQYYS YRT FGGGTKLE IK tregali SEQ ID NO : 680 SEQ ID NO : 681zumab EEQLVESGGGLVKPGGSLRLSCAASGFSFSDCRMYWLRQAPG DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSYIY KGLEWI GVI SVKSENYGANYAESVRGRFT I SRDDSKNTVYLQ WYQQKPGQPPKLLI YLAS ILESGVPDRFSGSGSGTDFT MNSLKTEDTAVYYCSASYYRYDVGAWFAYWGQGTLVTVSS LTISSLQAEDVAVYYCQHSRELPWTFGQGTKVEIK SCT1 . 1 SEQ ID NO : 682 SEQ ID NO : 683QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPE DIVMTQTPLSLSVTPGQPASISCKSSQSLLHTDGKTYL KGLEWMGGFDPEDGKTIYAPKFQGRVTMTEDTSTDTAYMDLS YWYLQKPGQPPHLLIYEVSNRFSGVPDRLSGSGSGTDF SLRSEDTAVYYCATGHNWNDGYYFYYYMDLWGKGTTVTVSS TLKISRVEAEDVGVYYCMQSLQLPLTFGGGTMVEIK SCT1 . 4 SEQ ID NO : 684 SEQ ID NO : 685QVQLVESGGDSVKPGGSLRLSCAASGFTFSDYYMNWIRQAPG EIVMTQSPATLSVSPGERATLSCRASQSVSRKLAWYQQ KGLEWI SYISSSGNT I FYVDSVEGRFTVSRDNAKNSLYLQMN KPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREGYNNYNYSYYYFMDVWGKGTTVTVSS SLQSEDFAVYFCQQYNNWPYTFGRGTKLEIK SCT1 . 5 SEQ ID NO : 686 SEQ ID NO : 687QVQLVE S GGGWQPGRS LRL S CAAS G FT VS S FGMHWVRQAPG AIQMTQSPSSLSASVGDRVTFTCRASQGIRSGLGWYQQ KGLEWVAI I WYDGTNKYYADSVKGRFT I SRDNSKNTLYLQLN KPGKAPNLLIYAASTLQSGVPSRFSGSGSGTDFTLTIT SLRGEDTAVYYCAREIAVDGTDYYMDVWGRGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT2 . 9 SEQ ID NO : 688 SEQ ID NO : 689QVQLVE S GGGLVT PGGS LRL S CAAS G FT FS D Y YMNW I RQAPG EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQ KGLEWLSYISSSGLTIFYVDSVKGRFTVSRDNAKNSLYLQMN KPGQAPRLLIYGASIRATGIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREGYSGFDDHYYYYTDVWGKGTTVTVSS SLQSEDFAVYYCQHYKNWPYTFGQGTRLEIK SCT2 . 10 SEQ ID NO : 690 SEQ ID NO : 691QVQLVE S GGGLVKPGGS LRL S CAAS G FT FS DY YMNW I RQAPG EIVMTQSPAALSVSPGERATLSCRASQSVSSKFAWYQQ KGLEWVSYISSSGSTIFYTDSVKGRFTISRDNAKNSLYLQMN KPGQAPRLLIYNASTRATGIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREDYSNYEDYYYYYTGVWGKGTTVTVSS SLQSEDFAVYYCQQYNNWPYTFGQGTKLEIKSCT2 . 11 SEQ ID NO : 692 SEQ ID NO : 693TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VLQVQLVE S GGGLVKPGGS LRL S C SAS G FT FS D Y YMNW I RQAPG EIVMTQSPAALSVSPGERATLSCRASQSVSNKFAWYQQ KGLEWVSYISSSGITIFYTDSVKGRFTISRDNAKNSLYLQMN KPGQAPRLLIYNASTRATSIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREDYSNYEDHYYYYTGVWGKGTTVTVSS SLQSEDFAVYYCQHYNNWPYTFGQGTKLEIK SCT2 . 11 SEQ ID NO : 692 SEQ ID NO : 694VL N50G QVQLVE S GGGLVKPGGS LRL S C SAS G FT FS DY YMNW I RQAPG EIVMTQSPAALSVSPGERATLSCRASQSVSNKFAWYQQ KGLEWVSYISSSGITIFYTDSVKGRFTISRDNAKNSLYLQMN KPGQAPRLLIYGASTRATSIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREDYSNYEDHYYYYTGVWGKGTTVTVSS SLQSEDFAVYYCQHYNNWPYTFGQGTKLEIK SCT2 . 12 SEQ ID NO : 695 SEQ ID NO : 696QVQLVE S GGGLVKPGGS LRL S CAAS G FT FS DY YMNW I RQAPG EIVMTQSPAALSVSPGERATLSCRASQSVSSKFAWYQQ KGLEWVSYISSSGKTIFYTDSVKGRFTISRDNAKNSLFLQMN KPGQAPRLLIYNASTRATGIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREDYSNYEDYYYYYTGVWGKGTTVTVSS SLQSEDFAVYYCHQYKNWPYTFGQGTKLEIK SCT2 . 12 SEQ ID NO : 695 SEQ ID NO : 697VL N50G QVQLVE S GGGLVKPGGS LRL S CAAS G FT FS DY YMNW I RQAPG EIVMTQSPAALSVSPGERATLSCRASQSVSSKFAWYQQ KGLEWVSYISSSGKTIFYTDSVKGRFTISRDNAKNSLFLQMN KPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCAREDYSNYEDYYYYYTGVWGKGTTVTVSS SLQSEDFAVYYCHQYKNWPYTFGQGTKLEIK SCT2 . 13 SEQ ID NO : 698 SEQ ID NO : 699QVQLVE S GGGLVKPGGS LRL S CAAS G FT FS DY YMNW I RQAPG EILMTQSPATLSVSPGERTTLSCRASQSISSNLAWYQQ KGLEWISYISISGQTIYYGDSVKGRFTVSRDNAKNSLFLEMN NPGQAPRLLIYNASTRATDIPARFSGGGSGTEFTLTIS SLRAEDSAVYFCAREGYSNYGVKYYYYMDVWGKGTTVTVSS SLQSEDFAVYYCQQYNAWTYTFGQGTKLEIK SCT2 . 14 SEQ ID NO : 700 SEQ ID NO : 701QVQLVE S GGGLVKPGGS LRL S CAAS G FT FS DH YMNWVRQVPG EIMMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQ KGLEWISYISISGNTIYYTDSVKGRFTVSRDNAKNSLYLQMT KPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTIS SLRAEDTAVYYCVREGYSSSSRGDYSYYTDVWGKGTTVTVSS SLQSEDFAVYYCQQYKNWPYTFGQGTKLEIK SCT2 . 15 SEQ ID NO : 702 SEQ ID NO : 703QVQLVE S GGGLVKPGGS LRL S CAAS G FT FS DY YMNWVRQVPG EIVMTQSPATLSASPGERVNLSCRASQGVSSNLAWYQQ KGLEWISYISISGRTIYYIDSVKGRFTVSRDNAKNSLYLQMT KVGQAPRLLIYGASTRATDIPARFSGSGSGSEFTLTIS NLRAEDTAVYYCVREGYSSSSRGDYSYYTDVWGKGTTVTVSS SLQSEDFAVYYCQHYKNWPYTFGQGTKLEIKBinds to CD4 D2 and / or D3SCT1 . 6 SEQ ID NO : 704 SEQ ID NO : 705TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VLQVQLVE S GGGWQPGRS LRL S CAAS G FT VS S YGMHWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQDIRNGLGWYQQ KGLEWVAI IWFDGSNKYYADSLTGLFTISRDSSKNTLFLQMN KPGKAPKLLIYTTSSLQTGVPSRFSGSGSGTDFTLTIS SLSLEDTAVYYCAREVALEGYYYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT1 . 7 SEQ ID NO : 706 SEQ ID NO : 707QVQLVE S GGGWQPGRS L S L S CAAS G FT VS S YGMHWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQDIRNGLGWYQQ KGLEWVAI LWFDGSNKFYADSVKGRFT I SRDNSKNTLYLQMN NPGKAPKLLIYTTSSLQSGVPSRFSGSGSGTDFTLTIS SLRVEDTAVYYCARELALEGYYYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT1 . 8 SEQ ID NO : 708 SEQ ID NO : 709QVQLVE S GGGWQPGRS LRL S CAAS G FT VS S YGMHWVRQAPG AIQMTQSPSSLSASVGDRVTITCRSSQDIRNGLGWYQQ KGLEWVAI LWFDGSNQFYADSVKGRFT I SRDNSKNTLYLQMN KPGKAPKLLIYTTSSLQSGVPSRFSGSGSGTDFTLTIS SLRVEDTAVYYCAREIALEGYYYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT1 . 9 SEQ ID NO : 710 SEQ ID NO : 711QVQLVE S GGGWQPGRALRL S CAAS G FT FS S YGMHWVRQAPG DIQMTQSPSSLSASVGDRVTITCRASQDIRNGLGWYQQ KGLEWVAI I WYDGSNKYYADSVKGRFT I SRDNSKNTLYLQMN KPGKAPKLLIYTTSNLQSGVPSRFSGSGSGTDFTLTIS SLRAEDTAVYYCAREVALEGYYYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT1 . 10 SEQ ID NO : 712 SEQ ID NO : 713QVQLVE S GGGWQPGRS LRL S CAAS G FT FS S YGMHWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQGIRNGLGWYQL KGLEWVAI I WYDGNNKYYADSVKGRFT I SRDNSKNTLYLQMN KPGKAPKLLIYAASSLQSGVPSSFSGSGSGTDFTLTIS SLRAEDTAVYYCTREVALEGYYYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT1 . 19 SEQ ID NO : 714 SEQ ID NO : 715EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPG AIQMTQSPSSLSAFVGDRVTITCRASQGIRNDLGWYQQ KGLEWVSGISGSVGSTYYADSVKGRFTISRDKSKNTLYLQMN KPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTIS SLRAEDTAVYYCAKEGYDWSGMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT2 . 2 SEQ ID NO : 716 SEQ ID NO : 717QVLLVESGGGWQPGRSLRLSCAASGFTFSS YGMHWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQGIRNGLGWYQQ KGLEWVTLIWFDGTTRFYADSVKGRFTVSRDNSKKTLYLQMN KPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTIS S LRAE DTAVY YCARE VAI QGRD Y Y I DVWGKGT TVTVS S SLQPADFATYYCLQDYNYPYTFGQGTKLEIRSCT2 . 3 SEQ ID NO : 718 SEQ ID NO : 719TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGIHWFRQAPG AIQMTQSPSSLSASVGDRVTITCRASQDIRNGLGWYQQ KGLEWVAI I WFDGTNKFYADSVKGRFT I SRDNSKNTVNLQMN KPGKAPMLLIYTTSNLQNGVPSRFSGSRSGTDFTLTIS S LRVE DTAI Y YCARE VAI QGYYYYMDVWGNGT TVTVS S GLQPEDFAAYFCLQDYNYPYTFGQGTKLDVKBinds to CD4 D30KT4 SEQ ID NO : 720 SEQ ID NO : 721QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPG NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMH KGLKCMGWINTNTGEPTYAEEFKGRFAFSLETSATTAFLQIN WYQQKPGQPPKLFIYLASNLESGVPARFSGSGSRTDFT NLKDEDTATYFCARLGI YYDYGYYAMDYWGQGASVTVSS LTIDPVEADDAATYYCQQNNEDPYTFGGGTKLEIK SCT1 .20 SEQ ID NO : 722 SEQ ID NO : 723EVQLLESGGGLVQPGGSLRLSCAASEIIFSTYAMSWVRQAPG AIQMTQSPYSLSASVGDRVTITCRASQGIRNDLGWYQQ KGLEWVSGISGSGDNTYYADSVKGRFTISSDNSKNTLYLQMN KPGKAPKVLIYEASSLQSGVPSRFSGSRSGTDFTLTIS SLRAEDTAVYYCVKEGYNWNYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYTYPYTFGQGTKLEIK SCT1 .21 SEQ ID NO : 724 SEQ ID NO : 725EVELLESGGGLVQPGGSLRLSCAASGLTFSTFAMSWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASHGIRNDLGWYQQ KGLEWVSGISGSGENTYYADSVKGRFTITSDNSKNTLYLQMN KPGKAPKVLISETSSLQSGVPSRFSGSRSGTDFTLTIS SLRAEDTAVYYCAKEGYNWNYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYTYPYTFGQGTKLEIK SCT1 .22 SEQ ID NO : 724 SEQ ID NO : 726EVELLESGGGLVQPGGSLRLSCAASGLTFSTFAMSWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASHGIRNDLGWYQQ KGLEWVSGISGSGENTYYADSVKGRFTITSDNSKNTLYLQMN KPGKAPKVLIYEASSLQSGVPSRFSGSRSGTDFTLTIS SLRAEDTAVYYCAKEGYNWNYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYTYPYTFGQGTKLEIK SCT1 .23 SEQ ID NO : 727 SEQ ID NO : 728EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWCQQ KGLEWVS T I SDNI GNT YYADSVKGRFT I SRDNSKNTLYLQMN KPGKAPKFLIYAASTLQSGVPSRFSGSGYGTDFTLTIS SLRAEDTAVYYCTKDNEDYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPRTFGQGTKVEIK SCT1 .23 SEQ ID NO : 727 SEQ ID NO : 729C36Y EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQ KGLEWVS T I SDNI GNT YYADSVKGRFT I SRDNSKNTLYLQMN KPGKAPKFLIYAASTLQSGVPSRFSGSGYGTDFTLTIS SLRAEDTAVYYCTKDNEDYYMDVWGKGTTVTVSS SLQPEDFATYYCLQDYNYPRTFGQGTKVEIKSCT2 . 1 SEQ ID NO : 730 SEQ ID NO : 731TABLE B - Illustrative VH / VL for anti-CD4 binding domainsAb Name VH VL EVQLLESGGGLVQPGGSLRLSCAASGFTFSTNAMSWVRQAPG AIQMTQSPSSLSASVGDRVTITCRASHVIRNDLGWYQQ KGLEWVSGISGSNGNTYYADSVKGRFI ISRDISKNTLYLEMN KPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTIS SLRAEDTAVYYCAKERDNWNGFDYWGQGTLVTVSS SLQPEDFATYYCLQDYNYPYTFGQGTKLEIK SCT2 . 8 SEQ ID NO: 732 SEQ ID NO: 733QVQLVQSGAEVKKPGASVKVSCKVSGHTLTELSMHWVRQAPG ETTLTQSPAFMSATPGDKVNISCKASQDIDDDVNWYQQ KGLEWMGI FDPRDGQI I YAEKFQGRVTVTEDTSTDTAYMELS KPGEAAIFIIQEATTLVPGIPPRFSGSGYGTDFTLTINSLRFDDTAVYYCATGGNEDYYFYYMDVWGKGTTVTVSS NIESEDAAYYFCLQHDHFPYTFGQGTKLEIK3. Interleukin- 15 (IL-15) Variants and Fusion Polypeptides Thereof

[0166] Provided are interleukin- 15 (IL- 15) variants (IL-15v) with attenuated binding to IL-2RPY (CD122, NCBI Gene ID: 3560; CD132, NCBI Gene ID: 3561), e.g, in comparison to wild-type IL-15 (SEQ ID NO: 740). In some embodiments, the IL-15v binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM. In some embodiments, the IL-15v binds to IL-2RPY with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM. In some embodiments, the IL-15v described herein induce CD4+ T cell proliferation with an ECso of less than 5 nM, e.g., less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, e.g., wherein CD4+ T cell proliferation potency is measured by marker of proliferation Ki-67 activation (MKI67; NCBI Gene ID: 4288). In some embodiments, the IL-15v induce CD8+ T cells and / or natural killer (NK) cell proliferation with an EC50 of greater than 100 nM, e.g., wherein CD8+ T cell and / or NK cell proliferation potency is measured by Ki-67 activation. In some embodiments, the IL-15v described herein induce CD4+ T cell proliferation with a potency that is at least100-fold, e.g., at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 600-fold, or more, in comparison to the potency for inducing CD8+ T cell or NK cell proliferation, e.g., wherein cell proliferation potency is measured by Ki-67 activation.

[0167] A polypeptide “variant,” as the term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and insertions. Such variants may be naturally occurring or may be synthetically generated, for example, by modifying one or more of the above polypeptide sequences described herein and evaluating one or more biological activities of the polypeptide as described herein, e.g., using any of a number of technique...

Claims

CLAIMSWhat is claimed is:

1. An interleukin- 15 variant (IL-15v) comprising the amino acid sequence of any one of SEQ IDNOs: 743, 750-752, 754-756, 758, 768-771, 774, 777, 779, 783-788, 790-798, 801-808, 810-813 and 1125.

2. The IL-15v of claim 1, wherein the IL-15v binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM.

3. The IL-15v of any one of claims 1 to 2, wherein the IL-15v binds to IL-2RPY with a binding equilibrium dissociation constant (KD) of at least 1 nM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM.

4. A fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain and (ii) an IL-15 variant (IL-15v), the fusion protein comprising the amino acid sequence of any one of SEQ ID NOs: 817, 824-826, 828-830, 832, 842-845, 848, 851, 853, 857-862, 864-872, 875-882, 884-887 and 1127.

5. The fusion protein of claim 4, comprising the amino acid sequence of any one of SEQ ID NOs: 1136, 1143-1145, 1147-1149, 1151, 1162-1165, 1168, 1171, 1173-1174, 1178-1183, 1185-1193 and 1196-1203 and 1205-1208.

6. The fusion protein of any one of claims 4 to 5, wherein the IL-15v binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM.

7. The fusion protein of any one of claims 4 to 6, wherein the IL-15v binds to IL-2RPy with a binding equilibrium dissociation constant (KD) of at least 1 nM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, atleast 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM.

8. The fusion protein of any one of claims 4 to 7, wherein the IL-15v induces CD4+ T cell proliferation with an ECso of less than 5 nM, e.g., less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, e.g., wherein CD4+ T cell proliferation potency is measured by marker of proliferation Ki-67 activation (MKI67; NCBI Gene ID: 4288).

9. The fusion protein of any one of claims 4 to 8, wherein the IL-15v induces CD8+ T cells and / or natural killer (NK) cell proliferation with an ECso of greater than 100 nM, e.g., wherein CD8+ T cell and / or NK cell proliferation potency is measured by Ki-67 activation.

10. The IL-15v of any one of claims 1 to 3 or the fusion protein of any one of claims 4 to 9, wherein the IL-15v is PEGylated.

11. The IL-15v of any one of claims 1 to 3 or the fusion protein of any one of claims 4 to 9, wherein the IL-15v is fused to an immunoglobulin crystallizable fragment (Fc).

12. The fusion protein of any one of claims 4 to 9, further comprising (iii) a transmembrane domain.

13. A chimeric antigen receptor (CAR) comprising the IL-15v of any one of claims 1 to 3 or the fusion protein of any one of claims 4 to 9.

14. A CAR-T cell transfected with a polynucleotide that encodes the IL-15v of any one of claims 1 to 3 or the fusion protein of any one of claims 4 to 9 and 12.

15. A host cell transfected with a polynucleotide that encodes the fusion protein of claim 12.

16. An antibody or antigen-binding fragment thereof that specifically binds to CD4 DI comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 1, 2, 3, 4, 5 and 6; (1)2) SEQ ID NOs: 1, 7, 3, 4, 8 and 9; (2)3) SEQ ID NOs: 1, 10, 3, 11, 5 and 6; (3)4) SEQ ID NOs: 1, 10, 3, 11, 12 and 6; (4)5) SEQ ID NOs: 1, 10, 3, 11, 8 and 9; (5)6) SEQ ID NOs: 1, 13, 3, 11, 8 and 9; (6)7) SEQ ID NOs: 1, 14, 3, 11, 8 and 9; (7)8) SEQ ID NOs: 1, 15, 3, 11, 8 and 9; (8)9) SEQ ID NOs: 1, 16, 3, 11, 8 and 9; (9)10) SEQ ID NOs: 1, 15, 3, 11, 12 and 17; (10)11) SEQ ID NOs: 1, 16, 3, 11, 12 and 18; (11)12) SEQ ID NOs: 1, 1078, 3, 11, 8 and 9; (12)13) SEQ ID NOs: 1, 1079, 3, 11, 8 and 9; (13, 14, 17, 18 and 19)14) SEQ ID NOs: 1, 1080, 3, 11, 8 and 9; (15)15) SEQ ID NOs: 1, 1081, 3, 11, 8 and 9; (16)16) SEQ ID NOs: 19, 20, 21, 22, 23 and 24; (1.17)17) SEQ ID NOs: 25, 26, 27, 28, 29 and 30; (1.25)18) SEQ ID NOs: 31, 32, 33, 34, 29 and 35; (1.26)19) SEQ ID NOs: 25, 36, 37, 28, 29 and 38; (1.27)20) SEQ ID NOs: 25, 1082, 39, 28, 29 and 38; (1.28)21) SEQ ID NOs: 40, 41, 42, 28, 29 and 35; (1.29)22) SEQ ID NOs: 25, 43, 39, 28, 29 and 38; (1.30)23) SEQ ID NOs: 25, 44, 45, 28, 29 and 35; (1.31)24) SEQ ID NOs: 25, 46, 47, 28, 29 and 35; (1.32)25) SEQ ID NOs: 25, 48, 49, 28, 29 and 35; (1.33)26) SEQ ID NOs: 25, 48, 50, 28, 29 and 35; (1.34)27) SEQ ID NOs: 51, 52, 53, 54, 55 and 56; (1.45) or28) SEQ ID NOs: 51, 57, 53, 58, 55 and 56; (1.46, 1.47, 1.48).

17. The antibody or antigen-binding fragment thereof of claim 16, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 625 and 626; (1)2) SEQ ID NOs: 627 and 628; (2)3) SEQ ID NOs: 629 and 630; (3)4) SEQ ID NOs: 629 and 631 ; (4)5) SEQ ID NOs: 629 and 632; (5)6) SEQ ID NOs: 633 and 632; (6)7) SEQ ID NOs: 634 and 632; (7)8) SEQ ID NOs: 635 and 632; (8)9) SEQ ID NOs: 636 and 632; (9)10) SEQ ID NOs: 635 and 637; (10)11) SEQ ID NOs: 636 and 638; (11)12) SEQ ID NOs: 639 and 632; (12)13) SEQ ID NOs: 640 and 632; (13)14) SEQ ID NOs: 641 and 632; (14)15) SEQ ID NOs: 642 and 632; (15)16) SEQ ID NOs: 643 and 632; (16)17) SEQ ID NOs: 640 and 644; (17)18) SEQ ID NOs: 640 and 645; (18)19) SEQ ID NOs: 640 and 646; (19)20) SEQ ID NOs: 647 and 648; (1.17)21) SEQ ID NOs: 649 and 650; (1.25)22) SEQ ID NOs: 651 and 652; (1.26)23) SEQ ID NOs: 653 and 654; (1.27)24) SEQ ID NOs: 655 and 656; (1.28)25) SEQ ID NOs: 657 and 658; (1.29)26) SEQ ID NOs: 659 and 660; (1.30)27) SEQ ID NOs: 661 and 662; (1.31)28) SEQ ID NOs: 663 and 664; (1.32)29) SEQ ID NOs: 665 and 666; (1.33)30) SEQ ID NOs: 667 and 666; (1.34)31) SEQ ID NOs: 668 and 669; (1.45)32) SEQ ID NOs: 670 and 671; (1.46)33) SEQ ID NOs: 672 and 673; (1.47) or34) SEQ ID NOs: 672 and 671; (1.48).

18. An antibody or antigen-binding fragment thereof that specifically binds to CD4 D2 comprising a heavy chain variable region (VH)-complementarity determining region(CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 25, 83, 84, 85, 86 and 87; (1.1)2) SEQ ID NOs: 88, 89, 90, 91, 92 and 93; (1.4)3) SEQ ID NOs: 94, 95, 96, 97, 98 and 99; (1.5)4) SEQ ID NOs: 88, 100, 101, 102, 103 and 104; (2.9)5) SEQ ID NOs: 88, 105, 106, 107, 108 and 93; (2.10)6) SEQ ID NOs: 88, 109, 110, 111, 108 and 112; (2.11)7) SEQ ID NOs: 88, 109, 110, 111, 113 and 112; (2.11 VL N50G)8) SEQ ID NOs: 88, 114, 106, 107, 108 and 115; (2.12)9) SEQ ID NOs: 88, 114, 106, 107, 113 and 115; (2.12 VLN50G)10) SEQ ID NOs: 88, 116, 117, 118, 108 and 119; (2.13)11) SEQ ID NOs: 120, 121, 122, 102, 113 and 123; (2.14) or 12) SEQ ID NOs: 88, 124, 122, 125, 113 and 104; (2.15).

19. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 682 and 683; (1.1)2) SEQ ID NOs: 684 and 685; (1.4)3) SEQ ID NOs: 686 and 687; (1.5)4) SEQ ID NOs: 688 and 689; (2.9)5) SEQ ID NOs: 690 and 691; (2.10)6) SEQ ID NOs: 692 and 693; (2.11)7) SEQ ID NOs: 692 and 694; (2.11 VL N50G)8) SEQ ID NOs: 695 and 696; (2.12)9) SEQ ID NOs: 695 and 697; (2.12 VL N50G)10) SEQ ID NOs: 698 and 699; (2.13)11) SEQ ID NOs: 700 and 701; (2.14) or12) SEQ ID NOs: 702 and 703; (2.15).

20. The antibody or antigen-binding fragment thereof of any one of claims 18 to 19, wherein the antibody or antigen-binding fragment thereof is insensitive to ( / .< ., binds toCD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant ID rsl 1064416 (F123L).

21. Means for binding to CD4 D2 that is insensitive to amino acid substitution resulting from polymorphism variant ID rsl 1064416 (F123L).

22. An antibody or antigen-binding fragment thereof that specifically binds to one or both of CD4 D2 and CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 126, 127, 128, 129, 130 and 99; (1.6)2) SEQ ID NOs: 126, 131, 132, 129, 133 and 99; (1.7)3) SEQ ID NOs: 126, 134, 135, 136, 133 and 99; (1.8)4) SEQ ID NOs: 126, 137, 128, 129, 138 and 99; (1.9)5) SEQ ID NOs: 126, 139, 128, 140, 141 and 99; (1.10)6) SEQ ID NOs: 142, 143, 128, 145, 141 and 99; (1.19)7) SEQ ID NOs: 126, 146, 147, 140, 141 and 99; (2.2) or8) SEQ ID NOs: 148, 149, 150, 129, 151 and 99; (2.3).

23. The antibody or antigen-binding fragment thereof of claim 22, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 704 and 705; (1.6)2) SEQ ID NOs: 706 and 707; (1.7)3) SEQ ID NOs: 708 and 709; (1.8)4) SEQ ID NOs: 710 and 711; (1.9)5) SEQ ID NOs: 712 and 713; (1.10)6) SEQ ID NOs: 714 and 715; (1.19)7) SEQ ID NOs: 716 and 717; (2.2) or8) SEQ ID NOs: 718 and 719; (2.3).

24. The antibody or antigen-binding fragment thereof of any one of claims 22 to 23, wherein the antibody or antigen-binding fragment thereof is insensitive to (i.e., binds toCD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

25. Means for binding to one or both of CD4 D2 and D3 that is insensitive to amino acid substitution resulting from polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

26. An antibody or antigen-binding fragment thereof that specifically binds to CD4 D3 comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDRl, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of1) SEQ ID NOs: 158, 159, 160, 145, 161 and 162; (1.20)2) SEQ ID NOs: 163, 164, 160, 165, 166 and 162; (1.21)3) SEQ ID NOs: 163, 164, 160, 165, 161 and 162; (1.22)4) SEQ ID NOs: 158, 167, 168, 145, 98 and 169; (1.23)5) SEQ ID NOs: 170, 171, 172, 173, 141 and 99; (2.1) or6) SEQ ID NOs: 25, 174, 175, 176, 29 and 177; (2.8).

27. The antibody or antigen-binding fragment thereof of claim 26, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 722 and 723; (1.20)2) SEQ ID NOs: 724 and 725; (1.21)3) SEQ ID NOs: 724 and 726; (1.22)4) SEQ ID NOs: 727 and 728; (1.23)5) SEQ ID NOs: 727 and 729; (1.23 VL C36Y)6) SEQ ID NOs: 730 and 731; (2.1) or7) SEQ ID NOs: 732 and 733; (2.8).

28. The antibody or antigen-binding fragment thereof of any one of claims 26 to 27, wherein the antibody or antigen-binding fragment thereof is insensitive to ( / .< ., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C).

29. The antibody or antigen-binding fragment thereof of any one of claims 26 to 28, wherein the antibody or antigen-binding fragment thereof binds to an epitope within CD4 D3 comprising amino acid residues at positions 218, 220, 260, 271, 274-277, 279, 283 and 285, wherein the residue positions are with reference to SEQ ID NO: 1120.

30. The antibody or antigen-binding fragment thereof of any one of claims 1 to 29, wherein the antibody or antigen-binding fragment thereof binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

31. Means for binding to CD4 D3 that is insensitive to amino acid substitution resulting from polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C).

32. The means of claim 31, wherein the means binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

33. A CD4-targeted interleukin- 15 (IL-15) molecule comprising:a) a first polypeptide comprising an immunoglobulin heavy chain comprising a first immunoglobulin fragment crystallizable domain (Fc domain);b) a second polypeptide comprising an immunoglobulin light chain (VL- CL), wherein the first polypeptide and the second polypeptide form an antigen binding domain that specifically binds to CD4; andc) a third polypeptide comprising a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL-15 or variant thereof (IL-15v), and (iii) a second Fc domain, wherein the first Fc domain and the second Fc domain heterodimerize to form a bispecific molecule that binds to CD4 and an IL-2PY complex (CD122 and CD132).

34. The CD4-targeted IL-15 molecule of claim 33, wherein the antigen binding domain that specifically binds to CD4 competes with or comprises a heavy chainvariable region (VH) and a light chain variable region (VL) from an antibody selected from the group consisting of ibalizumab, tregalizumab, keliximab, zanolimumab, clenoliximab, priliximab, UB-421, RPA-T4, SK3, MEM241 and OKT-4.

35. The CD4-targeted IL- 15 molecule of claim 33, wherein the antigen binding domain that specifically binds to CD4 specifically binds to the CD4 DI domain.

36. The CD4-targeted IL-15 molecule of claim 35, wherein the antigen binding domain specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 1, 2, 3, 4, 5 and 6; (1)2) SEQ ID NOs: 1, 7, 3, 4, 8 and 9; (2)3) SEQ ID NOs: 1, 10, 3, 11, 5 and 6; (3)4) SEQ ID NOs: 1, 10, 3, 11, 12 and 6; (4)5) SEQ ID NOs: 1, 10, 3, 11, 8 and 9; (5)6) SEQ ID NOs: 1, 13, 3, 11, 8 and 9; (6)7) SEQ ID NOs: 1, 14, 3, 11, 8 and 9; (7)8) SEQ ID NOs: 1, 15, 3, 11, 8 and 9; (8)9) SEQ ID NOs: 1, 16, 3, 11, 8 and 9; (9)10) SEQ ID NOs: 1, 15, 3, 11, 12 and 17; (10)11) SEQ ID NOs: 1, 16, 3, 11, 12 and 18; (11)12) SEQ ID NOs: 1, 1078, 3, 11, 8 and 9; (12)13) SEQ ID NOs: 1, 1079, 3, 11, 8 and 9; (13, 14, 17, 18 and 19) 14) SEQ ID NOs: 1, 1080, 3, 11, 8 and 9; (15)15) SEQ ID NOs: 1, 1081, 3, 11, 8 and 9; (16)16) SEQ ID NOs: 19, 20, 21, 22, 23 and 24; (1.17)17) SEQ ID NOs: 25, 26, 27, 28, 29 and 30; (1.25)18) SEQ ID NOs: 31, 32, 33, 34, 29 and 35; (1.26)19) SEQ ID NOs: 25, 36, 37, 28, 29 and 38; (1.27)20) SEQ ID NOs: 25, 1082, 39, 28, 29 and 38; (1.28)21) SEQ ID NOs: 40, 41, 42, 28, 29 and 35; (1.29)22) SEQ ID NOs: 25, 43, 39, 28, 29 and 38; (1.30)23) SEQ ID NOs: 25, 44, 45, 28, 29 and 35; (1.31)24) SEQ ID NOs: 25, 46, 47, 28, 29 and 35; (1.32)25) SEQ ID NOs: 25, 48, 49, 28, 29 and 35; (1.33)26) SEQ ID NOs: 25, 48, 50, 28, 29 and 35; (1.34)27) SEQ ID NOs: 51, 52, 53, 54, 55 and 56; (1.45)28) SEQ ID NOs: 51, 57, 53, 58, 55 and 56; (1.46, 1.47, 1.48) 29) SEQ ID NOs: 59, 60, 61, 62, 63 and 64; (keliximab) or30) SEQ ID NOs: 65, 66, 67, 68, 69 and 70; (UB-421).

37. The CD4-targeted IL-15 molecule of claim 35, wherein the antigen binding domain specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 178, 179, 180, 181, 182 and 6; (1)2) SEQ ID NOs: 178, 183, 180, 181, 182 and 9; (2)3) SEQ ID NOs: 178, 184, 180, 181, 182 and 6; (4)4) SEQ ID NOs: 178, 184, 180, 181, 182 and 9; (3, 5)5) SEQ ID NOs: 178, 185, 180, 181, 182 and 9; (6, 7, 12)6) SEQ ID NOs: 178, 186, 180, 181, 182 and 9; (8)7) SEQ ID NOs: 178, 187, 180, 181, 182 and 9; (9)8) SEQ ID NOs: 178, 186, 180, 181, 182 and 17; (10)9) SEQ ID NOs: 178, 187, 180, 181, 182 and 18; (11)10) SEQ ID NOs: 178, 188, 180, 181, 182 and 9; (13, 14, 17, 18, 19)11) SEQ ID NOs: 178, 189, 180, 181, 182 and 9; (15)12) SEQ ID NOs: 178, 190, 180, 181, 182 and 9; (16)13) SEQ ID NOs: 191, 192, 193, 194, 195 and 24; (1.17)14) SEQ ID NOs: 196, 197, 198, 199, 200 and 30; (1.25)15) SEQ ID NOs: 201, 202, 203, 199, 200 and 35; (1.26)16) SEQ ID NOs: 204, 205, 206, 199, 200 and 38; (1.27)17) SEQ ID NOs: 196, 207, 208, 199, 200 and 38; (1.28)18) SEQ ID NOs: 209, 210, 211, 199, 200 and 35; (1.29)19) SEQ ID NOs: 196, 212, 208, 199, 200 and 38; (1.30)20) SEQ ID NOs: 196, 213, 214, 199, 200 and 35; (1.31)21) SEQ ID NOs: 196, 213, 215, 199, 200 and 35; (1.32)22) SEQ ID NOs: 196, 216, 217, 199, 200 and 35; (1.33)23) SEQ ID NOs: 196, 216, 218, 199, 200 and 35; (1.34)24) SEQ ID NOs: 219, 220, 221, 222, 223 and 56; (1.45)25) SEQ ID NOs: 219, 224, 221, 225, 223 and 56; (1.46, 1.47, 1.48)26) SEQ ID NOs: 226, 227, 228, 229, 230 and 64; (keliximab) or27) SEQ ID NOs: 231, 232, 233, 234, 235 and 70; (UB-421).

38. The CD4-targeted IL-15 molecule of claim 35, wherein the antigen binding domain that specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 323, 324, 325, 326, 182 and 327; (1)2) SEQ ID NOs: 323, 328, 325, 326, 182 and 329; (2)3) SEQ ID NOs: 323, 330, 325, 326, 182 and 327; (4)4) SEQ ID NOs: 323, 330, 325, 326, 182 and 329; (5)5) SEQ ID NOs: 323, 331, 325, 326, 182 and 329; (6, 7, 12) 6) SEQ ID NOs: 323, 332, 325, 326, 182 and 329; (8)7) SEQ ID NOs: 323, 333, 325, 326, 182 and 329; (9)8) SEQ ID NOs: 323, 332, 325, 326, 182 and 334; (10)9) SEQ ID NOs: 323, 333, 325, 326, 182 and 335; (11)10) SEQ ID NOs: 323, 336, 325, 326, 182 and 329; (13, 14, 17, 18 and 19) 11) SEQ ID NOs: 323, 337, 325, 326, 182 and 329; (15)12) SEQ ID NOs: 323, 338, 325, 326, 182 and 329; (16)13) SEQ ID NOs: 339, 340, 341, 342, 195 and 1131; (1.17) 14) SEQ ID NOs: 344, 345, 346, 347, 200 and 348; (1.25)15) SEQ ID NOs: 349, 350, 351, 347, 200 and 352; (1.26)16) SEQ ID NOs: 353, 354, 355, 347, 200 and 356; (1.27)17) SEQ ID NOs: 344, 350, 357, 347, 200 and 356; (1.28)18) SEQ ID NOs: 358, 350, 359, 347, 200 and 352; (1.29)19) SEQ ID NOs: 343, 354, 357, 347, 200 and 356; (1.30)20) SEQ ID NOs: 343, 360, 361, 347, 200 and 352; (1.31)21) SEQ ID NOs: 343, 360, 362, 347, 200 and 352; (1.32)22) SEQ ID NOs: 343, 363, 364, 347, 200 and 352; (1.33)23) SEQ ID NOs: 343, 363, 365, 347, 200 and 352; (1.34)24) SEQ ID NOs: 366, 367, 368, 1084, 223 and 369; (1.45)25) SEQ ID NOs: 366, 367, 368, 370, 223 and 369; (1.46, 1.47, 1.48) 26) SEQ ID NOs: 371, 372, 373, 374, 230 and 375; (keliximab) or 27) SEQ ID NOs: 376, 377, 378, 379, 235 and 380; (UB-421).

39. The CD4-targeted IL-15 molecule of claim 35, wherein the antigen binding domain that specifically binds to CD4 DI and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:31) SEQ ID NOs: 463, 464, 465, 466, 467 and 327; (1)32) SEQ ID NOs: 463, 468, 465, 466, 469 and 329; (2)33) SEQ ID NOs: 463, 470, 465, 466, 467 and 327; (3)34) SEQ ID NOs: 463, 470, 465, 466, 469 and 327; (4)35) SEQ ID NOs: 463, 470, 465, 466, 469 and 329; (5)36) SEQ ID NOs: 463, 1132, 465, 466, 469 and 329; (6)37) SEQ ID NOs: 463, 471, 465, 466, 469 and 329; (7)38) SEQ ID NOs: 463, 472, 465, 466, 469 and 329; (8)39) SEQ ID NOs: 463, 473, 465, 466, 469 and 329; (9)40) SEQ ID NOs: 463, 472, 465, 466, 474 and 334; (10)41) SEQ ID NOs: 463, 473, 465, 466, 474 and 335; (11)42) SEQ ID NOs: 463, 475, 465, 466, 469 and 329; (12)43) SEQ ID NOs: 463, 478, 465, 466, 469 and 329; (13, 14, 17, 18 and 19) 44) SEQ ID NOs: 463, 476, 465, 466, 469 and 329; (15)45) SEQ ID NOs: 463, 477, 465, 466, 469 and 329; (16)46) SEQ ID NOs: 479, 480, 481, 482, 483 and 1131; (1.17) 47) SEQ ID NOs: 484, 485, 486, 487, 488 and 348; (1.25)48) SEQ ID NOs: 489, 490, 491, 487, 492 and 352; (1.26)49) SEQ ID NOs: 493, 494, 495, 487, 492 and 356; (1.27)50) SEQ ID NOs: 484, 496, 497, 487, 492 and 356; (1.28)51) SEQ ID NOs: 498, 499, 500, 487, 492 and 352; (1.29)52) SEQ ID NOs: 484, 501, 497, 487, 492 and 356; (1.30)53) SEQ ID NOs: 484, 502, 503, 487, 492 and 352; (1.31)54) SEQ ID NOs: 484, 504, 505, 487, 506 and 352; (1.32)55) SEQ ID NOs: 484, 507, 508, 487, 492 and 352; (1.33)56) SEQ ID NOs: 484, 507, 509, 487, 492 and 352; (1.34)57) SEQ ID NOs: 510, 511, 512, 513, 514 and 369; (1.45)58) SEQ ID NOs: 510, 515, 512, 516, 514 and 369; (1.46, 1.47, 1.48) 59) SEQ ID NOs: 517, 518, 519, 374, 520 and 375; (keliximab) or60) SEQ ID NOs: 521, 522, 523, 524, 525 and 380; (UB-421).

40. The CD4-targeted IL-15 molecule of any one of claims 35 to 39, wherein the antigen binding domain that specifically binds to CD4 DI and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 625 and 626; (1)2) SEQ ID NOs: 627 and 628; (2)3) SEQ ID NOs: 629 and 630; (3)4) SEQ ID NOs: 629 and 631 ; (4)5) SEQ ID NOs: 629 and 632; (5)6) SEQ ID NOs: 633 and 632; (6)7) SEQ ID NOs: 634 and 632; (7)8) SEQ ID NOs: 635 and 632; (8)9) SEQ ID NOs: 636 and 632; (9)10) SEQ ID NOs: 635 and 637; (10)11) SEQ ID NOs: 636 and 638; (11)12) SEQ ID NOs: 639 and 632; (12)13) SEQ ID NOs: 640 and 632; (13)14) SEQ ID NOs: 641 and 632; (14)15) SEQ ID NOs: 642 and 632; (15)16) SEQ ID NOs: 643 and 632; (16)17) SEQ ID NOs: 640 and 644; (17)18) SEQ ID NOs: 640 and 645; (18)19) SEQ ID NOs: 640 and 646; (19)20) SEQ ID NOs: 647 and 648; (1.17)21) SEQ ID NOs: 649 and 650; (1.25)22) SEQ ID NOs: 651 and 652; (1.26)23) SEQ ID NOs: 653 and 654; (1.27)24) SEQ ID NOs: 655 and 656; (1.28)25) SEQ ID NOs: 657 and 658; (1.29)26) SEQ ID NOs: 659 and 660; (1.30)27) SEQ ID NOs: 661 and 662; (1.31)28) SEQ ID NOs: 663 and 664; (1.32)29) SEQ ID NOs: 665 and 666; (1.33)30) SEQ ID NOs: 667 and 666; (1.34)31) SEQ ID NOs: 668 and 669; (1.45)32) SEQ ID NOs: 670 and 671; (1.46)33) SEQ ID NOs: 672 and 673; (1.47)34) SEQ ID NOs: 672 and 671; (1.48)35) SEQ ID NOs: 674 and 675; (keliximab) or36) SEQ ID NOs: 676 and 677; (UB-421).

41. The CD4-targeted IL- 15 molecule of claim 33, wherein the antigen binding domain that specifically binds to CD4 specifically binds to the CD4 D2 domain.

42. The CD4-targeted IL- 15 molecule of claim 41, wherein the antigen binding domain specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 71, 72, 73, 74, 75 and 76; (ibalizumab)2) SEQ ID NOs: 77, 78, 79, 80, 81 and 82; (tregalizumab)3) SEQ ID NOs: 25, 83, 84, 85, 86 and 87; (1.1)4) SEQ ID NOs: 88, 89, 90, 91, 92 and 93; (1.4)5) SEQ ID NOs: 94, 95, 96, 97, 98 and 99; (1.5)6) SEQ ID NOs: 88, 100, 101, 102, 103 and 104; (2.9)7) SEQ ID NOs: 88, 105, 106, 107, 108 and 93; (2.10)8) SEQ ID NOs: 88, 109, 110, 111, 108 and 112; (2.11)9) SEQ ID NOs: 88, 109, 110, 111, 113 and 112; (2.11 VL N50G)10) SEQ ID NOs: 88, 114, 106, 107, 108 and 115; (2.12)11) SEQ ID NOs: 88, 114, 106, 107, 113 and 115; (2.12 VLN50G)12) SEQ ID NOs: 88, 116, 117, 118, 108 and 119; (2.13)13) SEQ ID NOs: 120, 121, 122, 102, 113 and 123; (2.14) or14) SEQ ID NOs: 88, 124, 122, 125, 113 and 104; (2.15).

43. The CD4-targeted IL- 15 molecule of claim 41, wherein the antigen binding domain specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 236, 237, 238, 239, 240 and 76; (ibalizumab) 2) SEQ ID NOs: 241, 242, 243, 244, 245 and 82; (tregalizumab)3) SEQ ID NOs: 246, 247, 248, 249, 250 and 87; (1.1)4) SEQ ID NOs: 251, 252, 253, 254, 255 and 93; (1.4)5) SEQ ID NOs: 256, 257, 258, 259, 255 and 99; (1.5)6) SEQ ID NOs: 251, 260, 261, 262, 263 and 104; (2.9)7) SEQ ID NOs: 251, 264, 265, 266, 267 and 93; (2.10)8) SEQ ID NOs: 251, 268, 269, 270, 267 and 112; (2.11)9) SEQ ID NOs: 251, 268, 269, 270, 263 and 112; (2.11 VLN50G)10) SEQ ID NOs: 251, 271, 265, 266, 267 and 115; (2.12)11) SEQ ID NOs: 251, 271, 265, 266, 263 and 115; (2.12 VLN50G)12) SEQ ID NOs: 251, 272, 273, 274, 267 and 119; (2.13)13) SEQ ID NOs: 275, 276, 277, 262, 263 and 123; (2.14) or 14) SEQ ID NOs: 251, 278, 277, 279, 263 and 104; (2.15).

44. The CD4-targeted IL- 15 molecule of claim 41, wherein the antigen binding domain that specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 366, 381, 382, 383, 240 and 384; (ibalizumab) 2) SEQ ID NOs: 385, 386, 387, 388, 245 and 389; (tregalizumab)3) SEQ ID NOs: 390, 391, 392, 393, 250 and 394; (1.1)4) SEQ ID NOs: 395, 396, 397, 398, 255 and 399; (1.4)5) SEQ ID NOs: 400, 401, 402, 403, 255 and 404; (1.5)6) SEQ ID NOs: 395, 405, 406, 407, 263 and 408; (2.9)7) SEQ ID NOs: 395, 409, 410, 411, 267 and 399; (2.10)8) SEQ ID NOs: 395, 412, 413, 414, 267 and 399; (2.11)9) SEQ ID NOs: 395, 412, 413, 414, 263 and 399; (2.11 VLN50G)10) SEQ ID NOs: 395, 415, 410, 411, 267 and 408; (2.12)11) SEQ ID NOs: 395, 415, 410, 411, 263 and 408; (2.12 VLN50G) 12) SEQ ID NOs: 395, 416, 417, 418, 267 and 419; (2.13)13) SEQ ID NOs: 420, 421, 422, 407, 263 and 408; (2.14) or 14) SEQ ID NOs: 395, 423, 422, 424, 263 and 408; (2.15).

45. The CD4-targeted IL- 15 molecule of claim 41, wherein the antigen binding domain that specifically binds to CD4 D2 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 526, 527, 528, 529, 530 and 384; (ibalizumab)2) SEQ ID NOs: 531, 532, 533, 534, 535 and 389; (tregalizumab)3) SEQ ID NOs: 536, 537, 538, 539, 540 and 394; (1.1)4) SEQ ID NOs: 541, 542, 543, 544, 545 and 399; (1.4)5) SEQ ID NOs: 546, 547, 548, 549, 550 and 404; (1.5)6) SEQ ID NOs: 541, 551, 552, 553, 554 and 408; (2.9)7) SEQ ID NOs: 541, 555, 556, 557, 558 and 399; (2.10)8) SEQ ID NOs: 541, 559, 560, 561, 562 and 399; (2.11)9) SEQ ID NOs: 541, 559, 560, 561, 563 and 399; (2.11 VLN50G) 10) SEQ ID NOs: 541, 564, 556, 557, 558 and 408; (2.12)11) SEQ ID NOs: 541, 564, 556, 557, 565 and 408; (2.12 VLN50G) 12) SEQ ID NOs: 541, 566, 567, 568, 569 and 419; (2.13)13) SEQ ID NOs: 570, 571, 572, 553, 565 and 408; (2.14) or 14) SEQ ID NOs: 541, 573, 572, 574, 575 and 408; (2.15).

46. The CD4-targeted IL-15 molecule of any one of claims 41 to 45, wherein the antigen binding domain that specifically binds to CD4 D2 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 678 and 679; (ibalizumab)2) SEQ ID NOs: 680 and 681; (tregalizumab)3) SEQ ID NOs: 682 and 683; (1.1)4) SEQ ID NOs: 684 and 685; (1.4)5) SEQ ID NOs: 686 and 687; (1.5)6) SEQ ID NOs: 688 and 689; (2.9)7) SEQ ID NOs: 690 and 691; (2.10)8) SEQ ID NOs: 692 and 693; (2.11)9) SEQ ID NOs: 692 and 694; (2.11 VL N50G)10) SEQ ID NOs: 695 and 696; (2.12)11) SEQ ID NOs: 695 and 697; (2.12 VLN50G)12) SEQ ID NOs: 698 and 699; (2.13)13) SEQ ID NOs: 700 and 701; (2.14) or14) SEQ ID NOs: 702 and 703; (2.15).

47. The CD4-targeted IL-15 molecule of any one of claims 41 to 46, wherein the antibody or antigen-binding fragment thereof is insensitive to ( / .< ., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant ID rsl 1064416 (F123L).

48. The CD4-targeted IL-15 molecule of claim 33, wherein the antigen binding domain that specifically binds to CD4 specifically binds to one or both of the CD4 D2 domain and the CD4 D3 domain.

49. The CD4-targeted IL-15 molecule of claim 48, wherein the antigen binding domain specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 126, 127, 128, 129, 130 and 99; (1.6)2) SEQ ID NOs: 126, 131, 132, 129, 133 and 99; (1.7)3) SEQ ID NOs: 126, 134, 135, 136, 133 and 99; (1.8)4) SEQ ID NOs: 126, 137, 128, 129, 138 and 99; (1.9)5) SEQ ID NOs: 126, 139, 128, 140, 141 and 99; (1.10)6) SEQ ID NOs: 142, 143, 128, 145, 141 and 99; (1.19)7) SEQ ID NOs: 126, 146, 147, 140, 141 and 99; (2.2) or8) SEQ ID NOs: 148, 149, 150, 129, 151 and 99; (2.3).

50. The CD4-targeted IL-15 molecule of claim 48, wherein the antigen binding domain specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 280, 281, 282, 283, 284 and 99; (1.6)2) SEQ ID NOs: 280, 285, 286, 283, 284 and 99; (1.7)3) SEQ ID NOs: 280, 287, 288, 283, 284 and 99; (1.8)4) SEQ ID NOs: 289, 290, 282, 283, 284 and 99; (1.9)5) SEQ ID NOs: 289, 291, 292, 293, 255 and 99; (1.10)6) SEQ ID NOs: 294, 295, 296, 297, 255 and 99; (1.19)7) SEQ ID NOs: 289, 298, 299, 293, 255 and 99; (2.2) or8) SEQ ID NOs: 289, 300, 301, 283, 284 and 99; (2.3).

51. The CD4-targeted IL- 15 molecule of claim 48, wherein the antigen binding domain that specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 425, 426, 427, 428, 284 and 404; (1.6) 2) SEQ ID NOs: 425, 426, 429, 428, 284 and 404; (1.7) 3) SEQ ID NOs: 425, 426, 430, 428, 284 and 404; (1.8) 4) SEQ ID NOs: 431, 432, 427, 428, 284 and 404; (1.9) 5) SEQ ID NOs: 431, 433, 427, 434, 255 and 404; (1.10) 6) SEQ ID NOs: 431, 435, 436, 437, 255 and 404; (1.19) 7) SEQ ID NOs: 431, 438, 439, 434, 255 and 404; (2.2) or 8) SEQ ID NOs: 431, 438, 440, 428, 284 and 404; (2.3).

52. The CD4-targeted IL- 15 molecule of claim 48, wherein the antigen binding domain that specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 576, 577, 578, 579, 580 and 404; (1.6)2) SEQ ID NOs: 576, 581, 582, 579, 583 and 404; (1.7)3) SEQ ID NOs: 576, 584, 585, 586, 583 and 404; (1.8)4) SEQ ID NOs: 587, 588, 578, 579, 589 and 404; (1.9)5) SEQ ID NOs: 587, 590, 578, 591, 592 and 404; (1.10)6) SEQ ID NOs: 593, 594, 595, 596, 597 and 404; (1.19)7) SEQ ID NOs: 587, 598, 599, 591, 597 and 404; (2.2) or8) SEQ ID NOs: 587, 600, 601, 579, 602 and 404; (2.3).

53. The CD4-targeted IL-15 molecule of any one of claims 48 to 52, wherein the antigen binding domain that specifically binds to one or both of CD4 D2 and CD4 D3 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 704 and 705; (1.6)2) SEQ ID NOs: 706 and 707; (1.7)3) SEQ ID NOs: 708 and 709; (1.8)4) SEQ ID NOs: 710 and 711; (1.9)5) SEQ ID NOs: 712 and 713; (1.10)6) SEQ ID NOs: 714 and 715; (1.19)7) SEQ ID NOs: 716 and 717; (2.2) or8) SEQ ID NOs: 718 and 719; (2.3).

54. The CD4-targeted IL-15 molecule of any one of claims 48 to 53, wherein the antibody or antigen-binding fragment thereof is insensitive to ( / .< ., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

55. The CD4-targeted IL- 15 molecule of claim 33, wherein the antigen binding domain that specifically binds to CD4 specifically binds to the CD4 D3 domain.

56. The CD4-targeted IL-15 molecule of claim 55, wherein the antigen binding domain specifically binds to CD4 D3 and comprises a VH-complementarity determiningregion (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Kabat) of:1) SEQ ID NOs: 152, 153, 154, 155, 156 and 157; (OKT4)2) SEQ ID NOs: 158, 159, 160, 145, 161 and 162; (1.20)3) SEQ ID NOs: 163, 164, 160, 165, 166 and 162; (1.21)4) SEQ ID NOs: 163, 164, 160, 165, 161 and 162; (1.22)5) SEQ ID NOs: 158, 167, 168, 145, 98 and 169; (1.23)6) SEQ ID NOs: 170, 171, 172, 173, 141 and 99; (2.1) or7) SEQ ID NOs: 25, 174, 175, 176, 29 and 177; (2.8).

57. The CD4-targeted IL-15 molecule of claim 55, wherein the antigen binding domain specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to IMGT) of:1) SEQ ID NOs: 302, 303, 304, 305, 245 and 157; (OKT4)2) SEQ ID NOs: 306, 307, 1083, 297, 308 and 162; (1.20)3) SEQ ID NOs: 309, 310, 311, 312, 313 and 162; (1.21)4) SEQ ID NOs: 309, 310, 311, 312, 308 and 162; (1.22)5) SEQ ID NOs: 314, 315, 316, 297, 255 and 169; (1.23)6) SEQ ID NOs: 317, 318, 319, 320, 255 and 99; (2.1) or7) SEQ ID NOs: 196, 321, 322, 199, 200 and 177; (2.8).

58. The CD4-targeted IL-15 molecule of claim 55, wherein the antigen binding domain that specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Chothia) of:1) SEQ ID NOs: 441, 442, 443, 444, 245 and 445; (OKT4)2) SEQ ID NOs: 446, 447, 448, 437, 308 and 449; (1.20)3) SEQ ID NOs: 450, 451, 448, 452, 313 and 449; (1.21)4) SEQ ID NOs: 450, 451, 448, 452, 308 and 449; (1.22)5) SEQ ID NOs: 453, 454, 455, 437, 255 and 456; (1.23)6) SEQ ID NOs: 457, 458, 459, 460, 255 and 404; (2.1) or7) SEQ ID NOs: 343, 350, 461, 347, 200 and 462; (2.8).

59. The CD4-targeted IL-15 molecule of claim 55, wherein the antigen binding domain that specifically binds to CD4 D3 and comprises a VH-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences (according to Honegger) of:1) SEQ ID NOs: 603, 604, 605, 606, 607 and 445; (OKT4) 2) SEQ ID NOs: 608, 609, 610, 596, 611 and 449; (1.20)3) SEQ ID NOs: 612, 613, 610, 614, 615 and 449; (1.21)4) SEQ ID NOs: 612, 613, 610, 614, 611 and 449; (1.22)5) SEQ ID NOs: 616, 617, 618, 596, 550 and 456; (1.23)6) SEQ ID NOs: 619, 620, 621, 622, 597 and 404; (2.1) or7) SEQ ID NOs: 484, 623, 624, 487, 492 and 462; (2.8).

60. The CD4-targeted IL-15 molecule of any one of claims 55 to 59, wherein the antigen binding domain that specifically binds to CD4 D3 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 720 and 721; (OKT4)2) SEQ ID NOs: 722 and 723; (1.20)3) SEQ ID NOs: 724 and 725; (1.21)4) SEQ ID NOs: 724 and 726; (1.22)5) SEQ ID NOs: 727 and 728; (1.23)6) SEQ ID NOs: 727 and 729; (1.23 VL C36Y)7) SEQ ID NOs: 730 and 731; (2.1) or8) SEQ ID NOs: 732 and 733; (2.8).

61. The CD4-targeted IL- 15 molecule of any one of claims 55 to 60, wherein the antibody or antigen-binding fragment thereof is insensitive to ( / .< ., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C).

62. The CD4-targeted IL-15 molecule of any one of claims 33 to 61, wherein the antibody or antigen-binding fragment thereof binds to an epitope within CD4 D3 comprisingamino acid residues at positions 218, 220, 260, 271, 274-277, 279, 283 and 285, wherein the residue positions are with reference to SEQ ID NO: 1120.

63. The CD4-targeted IL-15 molecule of any one of claims 33 to 62, wherein the antigen binding domain that specifically binds to CD4 binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

64. Means for targeting IL-15 to CD4 D2 that is insensitive to ( / .< ., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant ID rsl 1064416 (F123L).

65. Means for targeting IL- 15 to one or both of CD4 D2 and D3 that is insensitive to ( / .< ., binds to CD4 in the presence or absence of) the amino acid substitutions resulting from one or more of CD4 polymorphism variant IDs rs28919570 (R265W), rsl 1064419 (F227S or F227C) and rsl 1064416 (F123L).

66. Means for targeting IL- 15 to CD4 D3 that is insensitive to ( / .< ., binds to CD4 in the presence and absence of) the amino acid substitution resulting from CD4 polymorphism variant IDs rs28919570 (R265W) and rsl 1064419 (F227S or F227C).

67. The means of claim 66, wherein the means specifically binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g., lower than 100 pM, lower than 90 pM, lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

68. The CD4-targeted IL- 15 molecule of any one of claims 33 to 63, wherein the fusion protein comprises an IL- 15 receptor alpha subunit (IL15RA) SUSHI domain that binds to IL- 15, is no longer than 65 amino acids, and comprises the amino acid sequence of SEQ ID NO: 734, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 734.

69. The CD4-targeted IL-15 molecule of claim 68, wherein the IL15RA SUSHI domain comprises the amino acid sequence of SEQ ID NO: 735, or an amino acidsequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 735.

70. The CD4-targeted IL-15 molecule of any one of claims 68 to 69, wherein the IL15RA SUSHI domain comprises an amino acid sequence of any one of SEQ ID NOs: 736-739.

71. The CD4-targeted IL-15 molecule of any one of claims 33 to 70, wherein the fusion protein comprises an IL-15 variant comprising one or more of the following amino acid substitutions:• an aspartic acid (Asp; D) at position 1 (N1D);• an aspartic acid (Asp; D) at position 4 (N4D);• a glycine (Gly; G) at position 7 (S7G);• a glycine (Gly;G) or an asparagine (Asn; N) at position 8 (D8N);• an asparagine (Asn; N) at position 30 (D30N);• an asparagine (Asn; N) at position 61 (D61N);• a glutamine (Gin; Q) at position 64 (E64Q);• an alanine (Ala; A) or an aspartic acid (Asp; D) at position 65 (N65A or N65D);• an alanine (Ala; A) at position 68 (I68A);• a leucine (Leu; L) or a glutamic acid (Glu; E) at position 71 (N71L or N71E);• an aspartic acid (Asp; D) at position 72 (N72D);• a leucine (Leu; L) at position 77 (N77L);• a glycine (Gly; G) or a proline (Pro; P) at position 79 (N79G or N79P);• a glutamic acid (Glu; E) at position 108 (Q108E);• an alanine (Ala; A), a glycine (Gly; G), an aspartic acid (Asp; D), a serine (Ser; S) or a lysine (Lys; K) at position 112 (N112 A, N112G, N112D, N112S orN112K);• N1D, N4D and D8N;• NlD andD61N;• N1D and E64Q;• N1D and N65D;• N4D andD61N;• N4D and E64Q;• N4D and N65D;• S7G and N65D;• D8G andD61N;• D8G and E64Q;• D8G and N65D;• D8N andD61N;• D8N and E64Q• D8N and N65D;• D30N andN65D;• D61N andE64Q;• D61N andN65D;• E64Q and N65D;• E64Q and Q108E;• N65A and I68A;• N65D and I68A;• N71L andN79P;• N71L andN112D;• N79P andN112D;• S7G, N65A and I68A;• S7G, N65D and I68A;• D30N, E64Q andN65D; • D61N, E64Q andN65D; • D61N, N65D and 168 A; • N71Q, N79Q andN112Q;• N71A, N79A andN112A;• N71G, N79G andN112G;• N71S, N79L and N112E;• N71E, N79P andN112K;• N71L, N79P andN112K;• N71L, N79P and N112D;• N71K, N79P andN112D;• N71E, N79P and N112S;• N71E, N79P andN112D;• N1D, D61N, E64Q and Q108E;• N4D, D6 IN, E64Q and Q 108E;• N71Q, N77L, N79Q and N112Q;• N71 A, N77L, N79A and N112A;• N71G, N77L, N79G and N112G;• N71S, N77L, N79L and N112E;• N71E, N77L, N79P and N112K;• N71L, N77L, N79P and N112K;• N71E, N77L, N79P and N112S;• N71E, N77L, N79P and N112D;• S7G, N65D, N71L, N79P and N112D;• S7G, N65D, N71E, N77L, N79P and N112D;• S7G, N65D, N71E, N77L, N79P and N112S;• S7G, N65D, N71L, N77L, N79P and N112K; or• S7G, N65D, N71E, N77L, N79P and N112K; wherein the position numbers are with respect to SEQ ID NO: 740.

72. The CD4-targeted IL-15 molecule of any one of claims 33 to 71, wherein the fusion protein comprises an IL-15 variant comprising one or more of the following amino acid substitutions:• S7G and N65D;• N65D and I68A;• S7G, N65D and I68A;• S7G, N65D, N71L, N79P and N112D;• S7G, N65D, N71E, N77L, N79P and N112D;• S7G, N65D, N71E, N77L, N79P and N112S;• S7G, N65D, N71L, N77L, N79P and N112K; or• S7G, N65D, N71E, N77L, N79P, N112K; wherein the position numbers are with respect to SEQ ID NO: 740.

73. The CD4-targeted IL-15 molecule of any one of claims 33 to 72, comprising an IL-15 or IL-15v of any one of SEQ ID NOs: 740-813, 1124 and 1125.

74. The CD4-targeted IL-15 molecule of any one of claims 33 to 73, comprising an IL-15 or IL-15v of any one of SEQ ID NOs: 743, 750-752, 754-756, 758, 768-771, 774, 777, 779, 783-788, 790-798, 801-808, 810-813 and 1125.

75. The CD4-targeted IL- 15 molecule of any one of claims 33 to 74, wherein the fusion protein comprises in sequential order from N-terminus to C-terminus, (i) the IL15RA SUSHI domain, (ii) the IL-15 or variant thereof, and (iii) Fc domain.

76. The CD4-targeted IL-15 molecule of any one of claims 33 to 75, comprising a flexible linker between the IL15RA SUSHI domain and the IL-15 or variant thereof.

77. The CD4-targeted IL- 15 molecule of claim 76, wherein the linker has a length of from about 4 to about 50 amino acids, e.g., from about 5 amino acids to about 25 amino acids, e.g., from about 15 amino acids to about 25 amino acids.

78. The CD4-targeted IL-15 molecule of any one of claims 76 to 77, wherein the linker comprises from 1 to 10 units, e.g., 1 to 5 units, e.g., 3 to 5 units, of a poly-glycine serine linker selected from GGGS, GGGGS and combinations thereof.

79. The CD4-targeted IL- 15 molecule of any one of claims 76 to 78, wherein the linker comprises 5 units of GGGGS (GGGGSGGGGSGGGGSGGGGSGGGGS; SEQ ID NO: 1085).

80. The CD4-targeted IL-15 molecule of any one of claims 33 to 79, comprising a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL-15 or variant thereof (IL-15v) of any one of SEQ ID NOs: 814-887, 1126 and 1127.

81. The CD4-targeted IL- 15 molecule of any one of claims 33 to 80, comprising a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL-15 or variant thereof (IL-15v) of any one of SEQ ID NOs: 1133-1208.

82. The CD4-targeted IL-15 molecule of any one of claims 33 to 80, comprising a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL- 15 or variant thereof (IL-15v) of any one of SEQ ID NOs: 817, 824-826, 828-830, 832, 842-845, 848, 851, 853, 857-862, 864-872, 875-882, 884-887 and 1127.

83. The CD4-targeted IL-15 molecule of any one of claims 33 to 82, comprising a fusion protein comprising: (i) an IL-15 receptor alpha subunit (IL15RA) SUSHI domain, (ii) an IL-15 or variant thereof (IL-15v) of any one of SEQ ID NOs: 1136, 1143-1145, 1147-1149, 1151, 1162-1165, 1168, 1171, 1173-1174, 1178-1183, 1185-1193 and 1196-1203, 1205-1208.

84. The CD4-targeted IL-15 molecule of any one of claims 33 to 83, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RP with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g, a KD of at least 1.5 pM, at least 2 pM, at least 2.5 pM, at least 3 pM, at least 3.5 pM, at least 4 pM, at least 4.5 pM or at least 5 pM.

85. The CD4-targeted IL-15 molecule of any one of claims 33 to 84, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RPy with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g., a KD of at least 3 nM, e.g., at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM.

86. The CD4-targeted IL-15 molecule of any one of claims 33 to 85, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RPy with a KD that is at least 1000-fold to the KD of the antigen binding domain specifically binding to CD4.

87. The CD4-targeted IL-15 molecule of any one of claims 33 to 86, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein binds to IL-2RPy with a binding equilibrium dissociation constant (KD) of at least 1 pM, e.g, a KD of at least 3 nM, e.g, at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 11 nM, at least 12 nM, at least 13 nM, at least 14 nM, or at least 15 nM, and the antigen binding domain that specifically binds to CD4 binds to CD4 with an equilibrium dissociation constant (KD) of lower than 1 nM, e.g, lower than 100 pM, lower than 90 pM,lower than 80 pM, lower than 70 pM, lower than 60 pM, lower than 50 pM, lower than 40 pM, or lower than 30 pM.

88. The CD4-targeted IL-15 molecule of any one of claims 33 to 87, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein induces CD4+ T cell proliferation with an ECso of less than 5 nM, e.g., less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, e.g., wherein CD4+ T cell proliferation potency is measured by marker of proliferation Ki-67 activation (MKI67; NCBI Gene ID: 4288).

89. The CD4-targeted IL-15 molecule of any one of claims 33 to 88, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein activates both naive CD4+ T cells and memory CD4+ T cells.

90. The CD4-targeted IL-15 molecule of any one of claims 33 to 89, wherein the IL-15v or the IL-15RA SUSHI domain-IL-15v fusion protein induces CD8+ T cells and / or natural killer (NK) cell proliferation with an ECso of greater than 100 nM, e.g., wherein CD8+ T cell and / or NK cell proliferation potency is measured by Ki-67 activation.

91. The CD4-targeted IL- 15 molecule of any one of claims 33 to 90, wherein the first Fc domain and the second Fc domain are human IgGl.

92. The CD4-targeted IL- 15 molecule of claim 91, wherein one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L234A, L234V, L234F, L235A, L235E, G237A, P331S, and any combination thereof, wherein the numbering of the residues is according to Eu numbering.

93. The CD4-targeted IL- 15 molecule of any one of claims 33 to 82, wherein the first Fc domain and the second Fc domain are human IgG4.

94. The CD4-targeted IL-15 molecule of claim 93, wherein one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, G237A, S228P, and any combination thereof, wherein the numbering of the residues is according to Eu numbering.

95. The CD4-targeted IL- 15 molecule of any one of claims 91 to 94, wherein the first Fc domain and the second Fc domain comprise the following amino acid substitutions (Eu numbering), respectively:a) T366W and T366S / L368A / Y407V;b) T366S / L368A / Y407V and T366W;c) T366W / S354C and T366S / L368A / Y407V / Y349C;d) T366S / L368A / Y407V / Y349C and T366W / S354C;e) S364H / F405A and Y349T / T394;f) Y349T / T394 and S364H / F405A;g) T350V / L351Y / F405A / Y407V and T350V / T366L / K392L / T394W; h) T350V / T366L / K392L / T394W and T350V / L351 Y / F405A / Y407V; i) K360D / D399M / Y407A and E345R / Q347R / T366V / K409V;j) E345R / Q347R / T366V / K409V and K360D / D399M / Y407A;k) K409D / K392D and D399K / E356K;l) D399K / E356K and K409D / K392D;m) K360E / K409W and Q347R / D399V / F405T;n) Q347R / D399V / F405T and K360E / K409W;o) K360E / K409W / Y349C and Q347R / D399V / F405T / S354C;p) Q347R / D399V / F405T / S354C and K360E / K409W / Y349C;q) K370E / K409W and E357N / D399V / F405T; orr) E357N / D399V / F405T and K370E / K409W.

96. The CD4-targeted IL- 15 molecule of any one of claims 91 to 95, wherein one or both of the first Fc domain and the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering):a) tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (252Y, 254T and 256E);b) leucine at position 428 (428L);c) glutamine at position 250 and leucine at position 428 (250Q and 428L); d) leucine at position 428 and serine at position 434 (428L and 434S); e) leucine at position 428 and alanine at position 434 (428L and 434A); f) arginine at position 311 and leucine at position 428 (311R and 428L); g) glycine at position 309 and leucine at position 428 (309G and 428L);h) glutamine at position 307, valine at position 311 and valine at position 378 (307Q, 31 IV and 378V); ori) aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311 and valine at position 378 (256D, 286D, 307R, 31 IV and 378V).

97. The CD4-targeted IL-15 molecule of any one of claims 91 to 96, wherein one of the first Fc domain or the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering): one or both of an arginine at position 435 (H435R) and a phenylalanine or an alanine at position 436 (Y436F or Y436A).

98. The CD4-targeted IL- 15 molecule of any one of claims 33 to 97, comprising a heavy chain (HC1) and a light chain (LC1) that bind to CD4 DI and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 921, 922 and 923; (100)2) SEQ ID NOs: 924, 922 and 925; (101)3) SEQ ID NOs: 926, 922 and 925; (102)4) SEQ ID NOs: 926, 922 and 1074; (103)5) SEQ ID NOs: 926, 922 and 1075; (104)6) SEQ ID NOs: 926, 922 and 1076; (105)7) SEQ ID NOs: 926, 922 and 974; (106)8) SEQ ID NOs: 926, 929 and 1076; (107)9) SEQ ID NOs: 927, 928 and 925; (108)10) SEQ ID NOs: 926, 929 and 925; (109)11) SEQ ID NOs: 926, 922 and 985; (110)12) SEQ ID NOs: 930, 922 and 923; (111)13) SEQ ID NOs: 931, 922 and 925; (112)14) SEQ ID NOs: 932, 922 and 933; (113)15) SEQ ID NOs: 934, 922 and 935; (114)16) SEQ ID NOs: 936, 937 and 923; (115)17) SEQ ID NOs: 938, 939 and 923; (116)18) SEQ ID NOs: 940, 941 and 923; (117)19) SEQ ID NOs: 942, 943 and 923; (118)20) SEQ ID NOs: 944, 945 and 923; (119)21) SEQ ID NOs: 946, 947 and 923; (120)22) SEQ ID NOs: 948, 949 and 923; (121)23) SEQ ID NOs: 950, 951 and 923; (122)24) SEQ ID NOs: 952, 953 and 923; (123)25) SEQ ID NOs: 954, 955 and 923; (124)26) SEQ ID NOs: 956, 955 and 923; (125)27) SEQ ID NOs: 957, 958 and 923; (126)28) SEQ ID NOs: 959, 960 and 923; (127)29) SEQ ID NOs: 961, 962 and 923; (128)30) SEQ ID NOs: 961, 960 and 923; (129)31) SEQ ID NOs: 926, 922 and 1091; (249)32) SEQ ID NOs: 926, 922 and 1092; (251)33) SEQ ID NOs: 926, 922 and 1093; (252)34) SEQ ID NOs: 926, 922 and 1094; (253)35) SEQ ID NOs: 926, 922 and 1095; (254)36) SEQ ID NOs: 926, 922 and 1096; (255)37) SEQ ID NOs: 926, 922 and 1097; (259)38) SEQ ID NOs: 926, 922 and 1098; (260)39) SEQ ID NOs: 926, 922 and 1099; (261) or40) SEQ ID NOs: 926, 922 and 1100; (262).

99. The CD4-targeted IL-15 molecule of any one of claims 33 to 97, comprising a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D2 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 1086, 1087 and 1088; (245)2) SEQ ID NOs: 963, 964 and 923; (130)3) SEQ ID NOs: 965, 966 and 923; (131)4) SEQ ID NOs: 967, 968 and 923; (132)5) SEQ ID NOs: 969, 970 and 923; (133)6) SEQ ID NOs: 969, 970 and 971; (134)7) SEQ ID NOs: 969, 970 and 972; (135)8) SEQ ID NOs: 973, 970 and 974; (136)9) SEQ ID NOs: 975, 976 and 923; (137)10) SEQ ID NOs: 977, 978 and 923; (138)11) SEQ ID NOs: 977, 978 and 971; (139)12) SEQ ID NOs: 977, 978 and 972; (140)13) SEQ ID NOs: 977, 979 and 972; (141)14) SEQ ID NOs: 980, 979 and 974; (142)15) SEQ ID NOs: 981, 982 and 923; (143)16) SEQ ID NOs: 981, 982 and 971; (144)17) SEQ ID NOs: 981, 982 and 972; (145)18) SEQ ID NOs: 981, 983 and 972; (146)19) SEQ ID NOs: 984, 983 and 974; (147)20) SEQ ID NOs: 984, 983 and 985; (148)21) SEQ ID NOs: 986, 987 and 923; (149)22) SEQ ID NOs: 988, 989 and 923; (150)23) SEQ ID NOs: 988, 989 and 971; (151)24) SEQ ID NOs: 988, 989 and 972; (152)25) SEQ ID NOs: 990, 991 and 923; (153)26) SEQ ID NOs: 990, 991 and 971; (154)27) SEQ ID NOs: 990, 991 and 972; (155) or28) SEQ ID NOs: 992, 991 and 974; (156).

100. The CD4-targeted IL-15 molecule of any one of claims 33 to 97, comprising a heavy chain (HC1) and a light chain (LC1) that bind to one or both of CD4 D2 and CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 993, 994 and 923; (157)2) SEQ ID NOs: 995, 996 and 923; (158)3) SEQ ID NOs: 997, 998 and 923; (159)4) SEQ ID NOs: 999, 1000 and 923; (160)5) SEQ ID NOs: 1001, 1002 and 923; (161)6) SEQ ID NOs: 1003, 1004 and 923; (162)7) SEQ ID NOs: 1005, 1006 and 923; (163) or8) SEQ ID NOs: 1007, 1008 and 923; (164).

101. The CD4-targeted IL- 15 molecule of any one of claims 33 to 97, comprising a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 1089, 1090 and 1088; (246)2) SEQ ID NOs: 1009, 1010 and 923; (165)3) SEQ ID NOs: 1009, 1010 and 971; (166)4) SEQ ID NOs: 1009, 1010 and 972; (167)5) SEQ ID NOs: 1011, 1012 and 923; (168)6) SEQ ID NOs: 1011, 1012 and 971; (169)7) SEQ ID NOs: 1011, 1012 and 972; (170)8) SEQ ID NOs: 1013, 1012 and 974; (171)9) SEQ ID NOs: 1011, 1014 and 923; (172)10) SEQ ID NOs: 1011, 1014 and 971; (173)11) SEQ ID NOs: 1011, 1014 and 972; (174)12) SEQ ID NOs: 1013, 1014 and 974; (175)13) SEQ ID NOs: 1015, 1016 and 923; (176)14) SEQ ID NOs: 1015, 1016 and 971; (177)15) SEQ ID NOs: 1015, 1017 and 971; (178)16) SEQ ID NOs: 1015, 1016 and 972; (179)17) SEQ ID NOs: 1015, 1017 and 972; (180)18) SEQ ID NOs: 1018, 1017 and 974; (181)19) SEQ ID NOs: 1018, 1017 and 985; (182)20) SEQ ID NOs: 1019, 1020 and 923; (183)21) SEQ ID NOs: 1019, 1020 and 971; (184)22) SEQ ID NOs: 1019, 1020 and 972; (185)23) SEQ ID NOs: 1021, 1020 and 974; (186) 24) SEQ ID NOs: 1022, 1023 and 923; (187) 25) SEQ ID NOs: 1024, 1025 and 923; (188) 26) SEQ ID NOs: 1011, 1014 and 1026; (189) 27) SEQ ID NOs: 1027, 1014 and 1028; (190) 28) SEQ ID NOs: 1027, 1014 and 1029; (191) 29) SEQ ID NOs: 1011, 1014 and 1030; (192) 30) SEQ ID NOs: 1011, 1014 and 1031; (193) 31) SEQ ID NOs: 1011, 1014 and 1032; (194) 32) SEQ ID NOs: 1011, 1014 and 1077; (220) 33) SEQ ID NOs: 1011, 1014 and 1033; (195) 34) SEQ ID NOs: 1011, 1014 and 1034; (196) 35) SEQ ID NOs: 1011, 1014 and 1035; (197) 36) SEQ ID NOs: 1011, 1014 and 1036; (198) 37) SEQ ID NOs: 1011, 1014 and 1037; (199) 38) SEQ ID NOs: 1011, 1014 and 1038; (200) 39) SEQ ID NOs: 1011, 1014 and 1039; (201) 40) SEQ ID NOs: 1011, 1014 and 1040; (202) 41) SEQ ID NOs: 1011, 1014 and 1041; (203) 42) SEQ ID NOs: 1011, 1014 and 1042; (204) 43) SEQ ID NOs: 1011, 1014 and 1043; (205) 44) SEQ ID NOs: 1011, 1014 and 1044; (206) 45) SEQ ID NOs: 1011, 1014 and 1045; (207) 46) SEQ ID NOs: 1011, 1014 and 1046; (208) 47) SEQ ID NOs: 1011, 1014 and 1047; (209) 48) SEQ ID NOs: 1011, 1014 and 1048; (210) 49) SEQ ID NOs: 1011, 1014 and 1049; (211) 50) SEQ ID NOs: 1011, 1014 and 1050; (212) 51) SEQ ID NOs: 1011, 1014 and 1051; (213) 52) SEQ ID NOs: 1011, 1014 and 1052; (214) 53) SEQ ID NOs: 1011, 1014 and 1053; (215) 54) SEQ ID NOs: 1011, 1014 and 1054; (216) 55) SEQ ID NOs: 1011, 1014 and 1055; (217) or56) SEQ ID NOs: 1011, 1014 and 1056; (218).

102. The CD4-targeted IL-15 molecule of any one of claims 33 to 97, comprising a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth in SEQ ID NOs: 1011, 1014 and 1057; (219).

103. The CD4-targeted IL-15 molecule of claim 102, comprising a heavy chain (HC1) and a light chain (LC1) that bind to CD4 D3 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 1011, 1014 and 923; (172)2) SEQ ID NOs: 1011, 1014 and 971; (173)3) SEQ ID NOs: 1011, 1014 and 972; (174)4) SEQ ID NOs: 1011, 1014 and 1026; (189)5) SEQ ID NOs: 1011, 1014 and 1030; (192)6) SEQ ID NOs: 1011, 1014 and 1031; (193)7) SEQ ID NOs: 1011, 1014 and 1032; (194)8) SEQ ID NOs: 1011, 1014 and 1077; (220)9) SEQ ID NOs: 1011, 1014 and 1033; (195)10) SEQ ID NOs: 1011, 1014 and 1034; (196)11) SEQ ID NOs: 1011, 1014 and 1035; (197)12) SEQ ID NOs: 1011, 1014 and 1036; (198)13) SEQ ID NOs: 1011, 1014 and 1037; (199)14) SEQ ID NOs: 1011, 1014 and 1038; (200)15) SEQ ID NOs: 1011, 1014 and 1039; (201)16) SEQ ID NOs: 1011, 1014 and 1040; (202)17) SEQ ID NOs: 1011, 1014 and 1041; (203)18) SEQ ID NOs: 1011, 1014 and 1042; (204)19) SEQ ID NOs: 1011, 1014 and 1043; (205)20) SEQ ID NOs: 1011, 1014 and 1044; (206)21) SEQ ID NOs: 1011 , 1014 and 1045; (207)22) SEQ ID NOs: 101 1 , 1014 and 1046; (208)23) SEQ ID NOs: 101 1 , 1014 and 1047; (209)24) SEQ ID NOs: 101 1 , 1014 and 1048; (210)25) SEQ ID NOs: 101 1 , 1014 and 1049; (211)26) SEQ ID NOs: 101 1 , 1014 and 1050; (212)27) SEQ ID NOs: 101 1 , 1014 and 1051; (213)28) SEQ ID NOs: 101 1 , 1014 and 1052; (214)29) SEQ ID NOs: 101 1 , 1014 and 1053; (215)30) SEQ ID NOs: 101 1 , 1014 and 1054; (216)31) SEQ ID NOs: 101 1 , 1014 and 1055; (217) or32) SEQ ID NOs: 101 1 , 1014 and 1056; (218).

104. The CD4-targeted IL-15 molecule of claim 33, comprising a heavy chain (HC1) and a light chain (LC1) that bind to Rhesus CD4 and an IL15RASushi-IL15v-Fc fusion protein (HC2) comprising, respectively, the amino acid sequences set forth below, or amino acid sequences at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequences set forth below:1) SEQ ID NOs: 1101, 1102 and 1103; (247)2) SEQ ID NOs: 1058, 1059 and 1060 (221) or3) SEQ ID NOs: 1221, 1222 and 1223 (277).

105. The CD4-targeted IL- 15 molecule of any one of claims 33 to 104, wherein the CD4-targeted IL-15 has a serum half-life in a human or a non-human primate of less than 24 hours, e.g., less than 20 hours, less than 18 hours, less than 16 hours.

106. A polynucleotide or multiple polynucleotides encoding the IL-15v of any one of claims 1 to 3, the fusion protein of any one of claims 4 to 7, the CAR of claim 14, the antibody or antigen-binding fragment of any one of claims 16 to 30, or the CD4-targeted IL- 15 molecule of any one of claims 33 to 105.

107. The polynucleotide or polynucleotides according to claim 106 encoding a CD4-targeted IL- 15 molecule, wherein the polynucleotide encoding the heavy chain comprising the antigen binding domain that specifically binds to CD4 comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1104, 1107, 1109, 1112, 1115, 1118 and1228, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1104, 1107, 1109, 1112, 1115, 1118 and 1228.

108. The polynucleotide or polynucleotides according to any one of claims 106 to 107, wherein the polynucleotide encoding the light chain comprising the antigen binding domain that specifically binds to CD4 comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1105, 1110, 1113, 1116 and 1229, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1105, 1110, 1113, 1116 and 1229.

109. The polynucleotide or polynucleotides according to any one of claims 106 to 108, wherein the polynucleotide encoding the IL15RASushi-IL15v-Fc fusion protein comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1106, 1108, 1111, 1114, 1117, 1119 and 1230, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1106, 1108, 1111, 1114, 1117, 1119 and 1230.

110. The polynucleotide or polynucleotides of any one of claims 106 to 109, comprising the following polynucleotide sequences, or polynucleotide sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the polynucleotide sequences set forth, respectively, below:1) SEQ ID NOs: 1104, 1105 and 1106;2) SEQ ID NOs: 1107, 1105 and 1108;3) SEQ ID NOs: 1109, 1110 and 1111;4) SEQ ID NOs: 1112, 1113 and 1114;5) SEQ ID NOs: 1115, 1116 and 1117;6) SEQ ID NOs: 1118, 1113 and 1119; or7) SEQ ID NOs: 1228, 1229 and 1230.

111. The polynucleotide or polynucleotides of any one of claims 106 to 110, wherein polynucleotide or polynucleotides are selected from the group consisting of DNA, cDNA, RNA and mRNA.

112. An expression cassette or multiple expression cassettes comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides of any one of claims 106 to 111.

113. A vector comprising the polynucleotide or polynucleotides of any one of claims 106 to 111, or the expression cassette of claim 112.

114. The vector of claim 113, wherein the vector is a plasmid vector or a viral vector.

115. The vector of claim 114, wherein the viral vector comprises a DNA virus or an RNA virus.

116. The vector of any one of claims 114 to 115, wherein the viral vector is from a viral family selected from the group consisting of: Adenoviridae (e.g., Adenovirus), Arenaviridae (e.g., lymphocytic choriomeningitis mammarenavirus, Cali mammarenavirus (a.k.a., Pichinde mammarenavirus), Poxviridae (e.g., Vaccinia virus), Herpesviridae (e.g., Herpesvirus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus Hl), Reoviridae (e.g., Reovirus), Retroviridae (e.g., Lentivirus), Picornaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., Measles virus, Newcastle disease virus (NDV)), Rhabdoviridae (e.g., Vesicular stomatitis virus (VSV)), Togaviridae (e.g., Alphavirus, Sindbis virus) and Enteroviridae (e.g., Echovirus).

117. A lipoplex, e.g., lipid nanoparticle (LNP), comprising the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, or the vector of any one of claims 113 to 116.

118. The lipoplex, e.g., lipid nanoparticle (LNP) of claim 117, wherein the polynucleotide or polynucleotides are mRNA.

119. A cell or population of cells comprising the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, or thevector of any one of claims 113 to 116, wherein the cell or population of cells expresses the CD4-targeted IL- 15 molecule of any one of claims 33 to 105.

120. The cell or population of cells of claim 119, wherein the cell or population of cells is a eukaryotic cell.

121. The cell or population of cells of any one of claims 119 to 120, wherein the cell or population of cells comprises a mammalian cell, an insect cell, a plant cell or a yeast cell.

122. The cell or population of cells of any one of claims 119 to 121, wherein the mammalian cell is a Chinese Hamster Ovary (CHO) cell.

123. The cell or population of cells of any one of claims 119 to 121, wherein the mammalian cell is a human cell.

124. The cell or population of cells of claim 123, wherein the cell is a human embryonic kidney cell.

125. The cell or population of cells of any one of claims 119 to 124, wherein the population of cells produces at least 4 g / L, e.g., at least 5 g / L, at least 6 g / L, at least 7 g / L, at least 8 g / L, at least 9 g / L, or more, CD4-targeted IL- 15 molecule.

126. A method of producing a CD4-targeted IL-15 molecule, the method comprising:a) culturing a cell or population of cells of any one of claims 119 to 124 transformed with the polynucleotide or polynucleotides of any one of claims 106 to 111, or the expression cassette or multiple expression cassettes of claim 112, in a cell culture under conditions sufficient to express the CD4-targeted IL-15 molecules; andb) isolating or purifying the CD4-targeted IL-15 molecules from the cell culture.

127. The method of any claim 126, wherein the polypeptide comprising the antigen binding domain that specifically binds to CD4 and the polypeptide comprising the IL15RASushi-IL15v-Fc fusion protein are expressed and assembled in the same cell.

128. The method of any one of claims 126 to 127, wherein the isolating or purifying step comprises Protein A chromatography.

129. The method of any one of claims 126 to 128, wherein at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, of the CD4-targeted IL-15 molecules are isolated or purified.

130. The method of any one of claims 126 to 129, wherein the cell or population of cells are cultured in a culture volume of at least 2L, e.g., at least 5L, 10L, 50L, 100L, 150L, 200L, 250L, or more.

131. The method of any one of claims 126 to 130, wherein the population of cells produces at least 4 g / L, e.g., at least 5 g / L, at least 6 g / L, at least 7 g / L, at least 8 g / L, at least 9 g / L, or more, CD4-targeted IL-15 molecule.

132. The method of any one of claims 126 to 131, further comprising formulating the CD4-targeted IL-15 molecules into a sterile pharmaceutical composition suitable for administration to a human subject.

133. A pharmaceutical composition comprising the IL-15v of any one of claims 1 to 3, the fusion protein of any one of claims 4 to 9, the CD4-targeted IL-15 molecule of any one of claims 33 to 105, the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, the vector of any one of claims 113 to 116, or the lipoplex (e.g., LNP) of claim 117, and a pharmaceutically acceptable carrier.

134. The pharmaceutical composition of claim 133, wherein the composition comprises an aqueous formulation.

135. The pharmaceutical composition of claim 133, wherein the composition is lyophilized.

136. The pharmaceutical composition of any one of claims 133 to 135, formulated for intravenous, subcutaneous, intramuscular, intradermal, or mucosal (e.g. buccal, intranasal, intrarectal, intravaginal) administration.

137. The pharmaceutical composition of any one of claims 133 to 136, further comprising one or more additional therapeutic agents.

138. The pharmaceutical composition of any one of claims 133 to 137, further comprising a second therapeutic agent.

139. The pharmaceutical composition of any one of claims 133 to 138, further comprising second and third therapeutic agents.

140. The pharmaceutical composition of any one of claims 137 to 139, further comprising a latency reversal agent (LRA).

141. The pharmaceutical composition of any one of claims 137 to 140, further comprising a toll-like receptor (TLR) agonist.

142. The pharmaceutical composition of claim 141, wherein the TLR agonist is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist.

143. The pharmaceutical composition of claim 142, wherein the TLR3 agonist is selected from the group consisting of rintatolimod and Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose (poly ICLC (HILTONOL®)).

144. The pharmaceutical composition of claim 142, wherein the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, resiquimod and NKTR-262.

145. The pharmaceutical composition of claim 142, wherein the TLR8 agonist is selected from the group consisting of selgantolimod, motolimod, resiquimod and NKTR-262.

146. The pharmaceutical composition of claim 142, wherein the TLR9 agonist is selected from the group consisting of cavrotolimod, cobitolimod, agatolimod, leftolimod, litenimod and tilsotolimod.

147. The pharmaceutical composition of any one of claims 137 to 146, further comprising a multispecific T-cell engager, e.g., abispecific T-cell engager.

148. The pharmaceutical composition of any one of claims 137 to 146, further comprising a CD4-Fc fusion protein.

149. The pharmaceutical composition of any one of claims 147 to 148, further comprising amtabafusp alfa (GS-8588).

150. The pharmaceutical composition of any one of claims 137 to 149, further comprising a lipid nanoparticle (LNP) comprising an HIV tat mRNA.

151. The pharmaceutical composition of any one of claims 137 to 150, further comprising a non-nucleoside reverse transcriptase inhibitor (NNRTI) as targeted activator of cell kill (TACK).

152. The pharmaceutical composition of claim 151, wherein the TACK is selected from efavirenz (EFV), rilpivirine (RPV), pyrimidone pyrOl, and pyrimidone pyr02.

153. The pharmaceutical composition of any one of claims 137 to 152, further comprising a Second Mitochondria-derived Activator of Caspase (SMAC) mimetic or an inhibitor of cellular inhibitor of apoptosis proteins (cIAP).

154. The pharmaceutical composition of claim 153, wherein the SMAC mimetic or cIAP inhibitor is selected from xevinapant, dasminapant, birinapant, tolinapant lactate, ciapavir and AZD5582.

155. The pharmaceutical composition of any one of claims 137 to 154, further comprising an inhibitor of one or both of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2).

156. The pharmaceutical composition of claim 155, wherein the inhibitor of one or both of PTPN1 and PTPN2 is selected from 3-Hydroxy-l,2,3-benzotriazin-4(3H)-one (HODHBt), avarol, osunprotafib, trodusquemine, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, talaramide Q, aurothiomalate disodium, daiokanzoto, berberine chloride, and alpha-tocopherolquinone.

157. The pharmaceutical composition of any one of claims 137 to 156, further comprising one or more anti-HIV vaccines.

158. The pharmaceutical composition of claim 157, wherein the anti-HIV vaccine is a viral vector vaccine.

159. The pharmaceutical composition of any one of claims 157 to 158, wherein the viral vector is selected from an arenavirus vector, a modified vaccinia virus Ankara (MV A)) vector, and a simian (e.g., chimpanzee, gorilla, rhesus) adenovirus vector.

160. The pharmaceutical composition of any one of claims 137 to 146, further comprising one or more anti-HIV broadly neutralizing antibodies that bind to different epitopes or regions of gpl20 selected from the group consisting of:(i) third variable loop (V3) (e.g., high mannose patch) comprising a N332 oligomannose glycan;(ii) second variable loop (V2) (e.g., Env trimer apex);(iii) CD4 binding site (CD4bs);(iv) gpl20 / gp41 interface; or(v) silent face of gpl20.

161. The pharmaceutical composition of claim 160, comprising an anti-HIV broadly neutralizing antibody that binds to the third variable loop (V3) (e.g., high mannose patch) comprising a N332 oligomannose glycan and the second antigen binding molecule binds to the CD4 binding site (CD4bs).

162. The pharmaceutical composition of any one of claims 160 to 161, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03.

163. The pharmaceutical composition of any one of claims 160 to 162, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), 10-1074, 10-1074-J, elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-128 and PGT-134.

164. The pharmaceutical composition of any one of claims 160 to 163, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS-9723, 3BNC117, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04); CH103, 44-VRC13.01, 1NC9,12A12, N6, 1-18, N49-P7, NC-Cowl, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25.

165. The pharmaceutical composition any one of claims 160 to 164, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS-9723, 3BNC117, VRC07 and VRC07-523.

166. The pharmaceutical composition of any one of claims 160 to 165, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 second variable loop (V2) (e.g., Env trimer apex).

167. The pharmaceutical composition of any one of claims 160 to 166, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01.

168. The pharmaceutical composition of any one of claims 160 to 167, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 / gp41 interface.

169. The pharmaceutical composition of any one of claims 160 to 168, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01.

170. The pharmaceutical composition of any one of claims 160 to 169, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to an epitope or region of gp41 in the membrane proximal region (MPER).

171. The pharmaceutical composition of any one of claims 160 to 170, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH andVL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-lOOcF, 4E10, DH511.11P, 2F5, A32, 7b2, andLNOl.

172. A method of inducing, stimulating or promoting the proliferation of CD4+ T cells, comprising contacting the CD4+ T cells with an effective amount of the CD4-targeted IL- 15 molecule of any one of claims 33 to 105 or the pharmaceutical composition of any one of claims 133 to 139.

173. The method of claim 172, wherein the CD4+ T cells are in vivo.

174. The method of claim 172, wherein the CD4+ T cells are in vitro.

175. The method of any one of claims 172 to 174, wherein CD4+ T cell proliferation is induced, stimulated or promoted with a potency that is at least 100 fold, e.g., at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 600-fold, or more, in comparison to the potency for inducing, stimulating or promoting CD8+ T cell or NK cell proliferation.

176. The method of claim 175, wherein cell proliferation potency is measured by Ki-67 activation.

177. A method of activating a latent viral reservoir in a subject infected with human immunodeficiency virus (HIV), comprising administering to the subject a therapeutically effective amount of the CD4-targeted IL-15 molecule of any one of claims 33 to 105, the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, the vector of any one of claims 113 to 116, or the lipoplex (e.g„ LNP) of claim 117 or the pharmaceutical composition of any one of claims 133 to 139.

178. A method of treating or preventing human immunodeficiency virus (HIV) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the CD4-targeted IL- 15 molecule of any one of claims 33 to 105, the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, the vector of any one of claims 113 to 116, or the lipoplex (e.g„ LNP) of claim 117 or the pharmaceutical composition of any one of claims 133 to 139.

179. Use of the CD4-targeted IL-15 molecule of any one of claims 33 to 105, the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, the vector of any one of claims 113 to 116, the lipoplex (e.g„ LNP) of claim 117 or the pharmaceutical composition of any one of claims 133 to 139 in a method of activating a latent viral reservoir in a subject infected with human immunodeficiency virus (HIV).

180. Use of the CD4-targeted IL-15 molecule of any one of claims 33 to 105, the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, the vector of any one of claims 113 to 116, the lipoplex (e.g„ LNP) of claim 117 or the pharmaceutical composition of any one of claims 133 to 139 in a method of treating or preventing human immunodeficiency virus (HIV) in a subject in need thereof.

181. The method of any one of claims 177 to 178 or the use of any one of claims 179 to 180, further comprising administering to the subject one or more additional therapeutic agents.

182. The method or use of any one of claims 177 to 181, further comprising administering an HIV latency reversing agent (LRA).

183. The method or use of any one of claims 177 to 182, further comprising a toll-like receptor (TLR) agonist.

184. The method or use of claim 183, wherein the TLR agonist is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist.

185. The method or use of claim 184, wherein the TLR3 agonist is selected from the group consisting of rintatolimod and Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose (poly ICLC (HILTONOL®)).

186. The method or use of claim 184, wherein the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, resiquimod and NKTR-262.

187. The method or use of claim 184, wherein the TLR8 agonist is selected from the group consisting of selgantolimod, motolimod resiquimod and NKTR-262.

188. The method or use of claim 184, wherein the TLR9 agonist is selected from the group consisting of cavrotolimod, cobitolimod, agatolimod, leftolimod, litenimod and tilsotolimod.

189. The method or use of any one of claims 183 to 188, wherein the method achieves synergistic HIV virion RNA production.

190. The method or use of any one of claims 177 to 188, further comprising administering a multispecific T-cell engager, e.g., abispecific T-cell engager.

191. The method or use of any one of claims 177 to 188, further comprising a CD4-Fc fusion protein.

192. The method or use of any one of claims 190 to 191, further comprising administering amtabafusp alfa (GS-8588).

193. The method or use of any one of claims 177 to 192, further comprising administering a lipid nanoparticle (LNP) comprising an HIV tat mRNA.

194. The method or use of any one of claims 177 to 193, further comprising a non-nucleoside reverse transcriptase inhibitor (NNRTI) as targeted activator of cell kill (TACK).

195. The method of claim 194, wherein the TACK is selected from efavirenz (EFV), rilpivirine (RPV), pyrimidone pyrOl, and pyrimidone pyr02.

196. The method or use of any one of claims 177 to 195, further comprising administering a Second Mitochondria-derived Activator of Caspase (SMAC) mimetic or an inhibitor of cellular inhibitor of apoptosis proteins (cIAP).

197. The method or use of claim 196, wherein the SMAC mimetic or cIAP inhibitor is selected from xevinapant, dasminapant, birinapant, tolinapant lactate, ciapavir and AZD5582.

198. The method or use of any one of claims 196 to 197, wherein the method achieves synergistic HIV virion RNA production.

199. The method or use of any one of claims 177 to 197, further comprising administering an inhibitor of one or both of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2).

200. The method of claim 199, wherein the inhibitor of one or both of PTPN1 and PTPN2 is selected from 3-Hydroxy-l,2,3-benzotriazin-4(3H)-one (HODHBt), avarol, osunprotafib, trodusquemine, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, talaramide Q, aurothiomalate disodium, daiokanzoto, berberine chloride, and alpha-tocopherolquinone.

201. The method or use of any one of claims 177 to 200, further comprising administering one or more anti -HIV vaccines.

202. The method or use of claim 201, wherein the anti -HIV vaccine is a viral vector vaccine.

203. The method or use of any one of claims 201 to 202, wherein the viral vector is selected from an arenavirus vector, modified vaccinia virus Ankara (MV A)) vector, and a simian (e.g., chimpanzee, gorilla, rhesus) adenovirus vector.

204. The method or use of any one of claims 201 to 203, comprising a primeboost regimen, comprising:a) Priming at a first time point by co-administering a first viral vector with the CD4-targeted IL- 15 molecule; andb) Boosting at a second time point by co-administering a second viral vector with the CD4-targeted IL- 15 molecule.

205. The method or use of claim 204, wherein the first viral vector and the second viral vector are the same.

206. The method or use of claim 204, wherein the first viral vector and the second viral vector are different.

207. The method or use of any one or claims 177 to 206, further comprising administering to the subject one or more anti -HIV broadly neutralizing antibodies.

208. The method or use of claim 207, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 selected from the group consisting of:i. third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan;ii. second variable loop (V2) and / or Env trimer apex;iii. CD4 binding site (CD4bs);iv. gpl20 / gp41 interface; orv. silent face of gpl20.

209. The method or use of any one of claims 207 to 208, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the third variable loop (V3) and / or high mannose patch comprising aN332 oligomannose glycan and competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab, GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03.

210. The method or use of any one of claims 207 to 209, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the second variable loop (V2) and / or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01.

211. The method or use of any one of claims 207 to 210, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the CD4 binding site (CD4bs) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), 3BNC117, GS-9723, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 and N60P25.

212. The method or use of any one of claims 207 to 211, wherein the one or more anti -HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the gpl20 / gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01.

213. The method or use of any one of claims 207 to 212, wherein the one or more anti -HIV broadly neutralizing antibodies bind to an epitope or region of the gpl20 silent face and competes with or comprises VH and VL regions from an antibody selected from VRC-PG05 and SF12.

214. The method or use of any one of claims 207 to 213, wherein the one or more anti -HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER).

215. The method or use of any one of claims 207 to 214, wherein the one or more anti -HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, A32, 7b2, andLNOl.

216. The method or use of any one of claims 207 to 215, wherein the one or more anti -HIV broadly neutralizing antibodies bind to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202.

217. The method or use of any one of claims 181 to 216, wherein the subject is not receiving antiretroviral therapy (ART) or ART is discontinued prior to administration of the CD4-targeted IL-15, the polynucleotide or polynucleotides, the expression cassette, the vector, the LNP or the pharmaceutical composition.

218. The method or use of any one of claims 181 to 217, wherein ART is discontinued after one or more administrations of the CD4-targeted IL-15, the polynucleotide or polynucleotides, the expression cassette, the vector, the LNP or the pharmaceutical composition.

219. The method or use of any one of claims 181 to 218, further comprising administering one or more antiretroviral therapy (ART) agents to the subject.

220. The method or use of any one of claims 177 to 219, further comprising co-administering one or more innate immune activators.

221. The method or use of claim 220 wherein the one or more innate immune activators comprises an agonist of a receptor selected from the group consisting of firns related tyrosine kinase 3 (FLT3), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotide binding oligomerization domain containing 2 (N0D2).

222. The method or use of claim 221, wherein the method achieves synergistic HIV virion RNA production.

223. The method or use of any one of claims 220 to 221, comprising coadministering one or both of GS-3583 and inarigivir soproxil (GS-9992).

224. The method or use of any one of claims 177 to 223, further comprising co-administering one or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor.

225. The method or use of claim 224, wherein the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated(BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD 150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI 6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9).

226. The method or use of any one of claims 224 to 225, further comprising co-administering one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors.

227. The method or use of claim 226, wherein the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274,PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1).

228. The method or use of any one of claims 224 to 227, further comprising co-administering one or more agonists or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors.

229. The method or use of claim 228, wherein the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155).

230. The method or use of any one of claims 224 to 229, further comprising co-administering one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors.

231. The method or use of claim 230, wherein the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1(KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD 161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94), killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9).

232. The method or use of any one of claims 224 to 231, further comprising co-administering one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors.

233. The method or use of claim 232, wherein the NK-cell stimulatory immune checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7).

234. The method or use of any one of claims 224 to 233, wherein the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

235. The method or use of claim 234, wherein the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).

236. The method or use of claim 234, wherein the proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from the group consisting of zimberelimab (AB 122), pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, ASC22, durvalumab, BMS-936559, CK-301, envafolimab (ASC-22, KN-035), PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT- 1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-l / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFP-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

237. The method or use of any one of claims 224 to 233, wherein the one or more immune checkpoint inhibitors comprises a small molecule inhibitor of CD274 (PDL1, PD-Ll), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4.

238. The method or use of claim 237, wherein the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181.

239. The method or use of claim 237, wherein the small molecule inhibitor of CTLA4 comprises BPI-002.

240. The method or use of any one of claims 177 to 239, wherein the subject is chronically infected with HIV.

241. The method or use of any one of claims 177 to 240, wherein the subject is heavily treatment experienced (HTE).

242. The method or use of any one of claims 177 to 241, wherein the CD4-targeted IL- 15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition are administered systemically or locally.

243. The method or use of any one of claims 177 to 242, wherein the CD4-targeted IL- 15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition is administered via a route selected from intravenous, subcutaneous, intramuscular, intradermal, and mucosal (e.g. buccal, intranasal, intrarectal, intravaginal).

244. The method or use of any one of claims 177 to 243, wherein the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by the same routes of administration.

245. The method or use of any one of claims 177 to 243, wherein the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by different routes of administration.

246. The method or use of any one of claims 177 to 245, wherein the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are co-administered according to the same schedule (e.g., co-administered at the same time intervals).

247. The method or use of any one of claims 177 to 245, wherein the CD4-targeted IL- 15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition and the one or more additional therapeutic agents are co-administered according to different schedules (e.g., co-administered at different time intervals).

248. The method or use of any one of claims 177 to 247, comprising multiple administrations of the CD4-targeted IL-15, the polynucleotide, the vector, the LNP and / or the pharmaceutical composition, optionally with one or more additional therapeutic agents, at predetermined intervals.

249. The method or use of any one of claims 177 to 248, wherein the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v have a serum half-life in a human of less than 24 hours, e.g., less than 20 hours, less than 18 hours, less than 16 hours.

250. The method or use of any one of claims 177 to 249, wherein the subject or the mammal is a human.

251. A kit comprising one or more unitary doses of a CD4-targeted IL- 15 molecule as claimed in any one of claims 33 to 105, the polynucleotide or polynucleotides of any one of claims 106 to 111, the expression cassette of claim 112, the vector of any one ofclaims 113 to 116, the lipoplex (e.g„ LNP) of claim 117 or the pharmaceutical composition of any one of claims 133 to 139.

252. The kit of claim 251, wherein the one or more unitary doses are in a single container.

253. The kit of claim 251, wherein the one or more unitary doses are in two or more separate containers.

254. The kit of any one of claim 251 to 253, comprising one or more containers selected from the group consisting of vials, ampoules and pre-loaded syringes.

255. The kit of any one of claim 251 to 254, comprising one or more containers comprising the IL-15v, IL-15Ra Sushi domain - IL-15v fusion protein or CD4-targeted IL-15v in an aqueous solution.

256. The kit of any one of claim 251 to 255, wherein the one or more unitary doses are the same.

257. The kit of any one of claim 251 to 256, comprising two or more unitary doses, wherein the unitary doses are the same.

258. The kit of any one of claim 251 to 255, wherein the one or more unitary doses are different.

259. The kit of any one of claim 251 to 256, comprising two or more unitary doses, wherein the unitary doses are different.

260. The kit of any one of claim 251 to 259, further comprising one or more unitary doses of one or more additional therapeutic agents.

261. The kit of claim 260, further comprising at least one latency reversal agent (LRA).

262. The kit of any one of claims 260 to 261, further comprising at least one toll-like receptor (TLR) agonist.

263. The kit of claim 262, wherein the TLR agonist is a TLR2 agonist, a TLR3 agonist, a TLR7 agonist, a TLR8 agonist or a TLR9 agonist.

264. The kit of claim 263, wherein the TLR3 agonist is selected from the group consisting of rintatolimod and Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose (poly ICLC (HILTONOL®)).

265. The kit of claim 263, wherein the TLR7 agonist is selected from the group consisting of vesatolimod, imiquimod, resiquimod and NKTR-262.

266. The kit of claim 263, wherein the TLR8 agonist is selected from the group consisting of selgantolimod, motolimod resiquimod and NKTR-262.

267. The kit of claim 263, wherein the TLR9 agonist is selected from the group consisting of cavrotolimod, cobitolimod, agatolimod, leftolimod, litenimod and tilsotolimod.

268. The kit of any one of claims 260 to 267, further comprising a multispecific T-cell engager, e.g., a bispecific T-cell engager.

269. The kit of any one of claims 260 to 267, further comprising a CD4-Fc fusion protein.

270. The kit of any one of claims 260 to 269, further comprising amtabafusp alfa (GS-8588).

271. The kit of any one of claims 260 to 270, further comprising a lipid nanoparticle (LNP) comprising an HIV tat mRNA.

272. The kit of any one of claims 260 to 271, further comprising a nonnucleoside reverse transcriptase inhibitor (NNRTI) as targeted activator of cell kill (TACK).

273. The kit of claim 272, wherein the TACK is selected from efavirenz (EFV), rilpivirine (RPV), pyrimidone pyrOl, and pyrimidone pyr02.

274. The kit of any one of claims 260 to 273, further comprising a Second Mitochondria-derived Activator of Caspase (SMAC) mimetic or an inhibitor of cellular inhibitor of apoptosis proteins (cIAP).

275. The kit of claim 274, wherein the SMAC mimetic or cIAP inhibitor is selected from xevinapant, dasminapant, birinapant, tolinapant lactate, ciapavir and AZD5582.

276. The kit of any one of claims 260 to 275, further comprising an inhibitor of one or both of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and protein tyrosine phosphatase non-receptor type 2 (PTPN2).

277. The kit of claim 276, wherein the inhibitor of one or both of PTPN1 and PTPN2 is selected from 3-Hydroxy-l,2,3-benzotriazin-4(3H)-one (HODHBt), avarol, osunprotafib, trodusquemine, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, talaramide Q, aurothiomalate disodium, daiokanzoto, berberine chloride, and alpha-tocopherolquinone.

278. The kit of any one of claims 260 to 277, further comprising one or more anti-HIV vaccines.

279. The kit of claim 278, wherein the anti-HIV vaccine is a viral vector vaccine.

280. The kit of any one of claims 278 to 279, wherein the viral vector is selected from an arenavirus vector, modified vaccinia virus Ankara (MV A)) vector, and a simian (e.g., chimpanzee, gorilla, rhesus) adenovirus vector.

281. The kit of any one of claims 260 to 267, further comprising one or more anti-HIV broadly neutralizing antibodies that bind to different epitopes or regions of gpl20 selected from the group consisting of:(i) third variable loop (V3) (e.g., high mannose patch) comprising a N332 oligomannose glycan;(ii) second variable loop (V2) (e.g., Env trimer apex);(iii) CD4 binding site (CD4bs);(iv) gpl20 / gp41 interface; or(v) silent face of gpl20.

282. The kit of claim 281, comprising an anti-HIV broadly neutralizing antibody that binds to the third variable loop (V3) (e.g., high mannose patch) comprising a N332 oligomannose glycan and the second antigen binding molecule binds to the CD4 binding site (CD4bs).

283. The kit of any one of claims 281 to 282, comprising an anti -HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03.

284. The kit of any one of claims 281 to 283, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of zinlirvimab (GS-2872), 10-1074, 10-1074-J, elipovimab (GS-9722), PGT-121, PGT-121.66, PGT-121.414, PGT-128 and PGT-134.

285. The kit of any one of claims 281 to 284, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS-9723, 3BNC117, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, PGV04 (VRC-PG04); CH103, 44-VRC13.01, 1NC9, 12A12, N6, 1-18, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 andN60P25.

286. The kit of any one of claims 281 to 285, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of teropavimab (GS-5423), GS-9723, 3BNC117, VRC07 and VRC07-523.

287. The kit of any one of claims 281 to 286, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 second variable loop (V2) (e.g., Env trimer apex).

288. The kit of any one of claims 281 to 287, comprising an anti-HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01.

289. The kit of any one of claims 281 to 288, comprising an anti -HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to the gpl20 / gp41 interface.

290. The kit of any one of claims 281 to 289, comprising an anti -HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01.

291. The kit of any one of claims 281 to 290, comprising an anti -HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody that binds to an epitope or region of gp41 in the membrane proximal region (MPER).

292. The kit of any one of claims 281 to 291, comprising an anti -HIV broadly neutralizing antibody that competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, A32, 7b2, andLNOl.

293. The kit of any one of claims 260 to 292, comprising one or more innate immune activators.

294. The kit of claim 293, comprising an agonist of a receptor selected from the group consisting of fms related tyrosine kinase 3 (FLT3), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotide binding oligomerization domain containing 2 (N0D2).

295. The kit of any one of claims 293 to 294, comprising one or both of GS-3583 and inarigivir soproxil (GS-9992).

296. The kit of any one of claims 260 to 295, comprising one or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor.

297. The kit of claim 296, wherein the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2,CD28H), CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD 150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI 6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor,two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9).

298. The kit of any one of claims 296 to 297, comprising one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors.

299. The kit of claim 298, wherein the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1).

300. The kit of any one of claims 296 to 299, comprising one or more agonists or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors.

301. The kit of claim 300, wherein the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155).

302. The kit of any one of claims 296 to 301, comprising one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors.

303. The kit of claim 302, wherein the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9).

304. The kit of any one of claims 296 to 303, comprising one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors.

305. The kit of claim 304, wherein the NK-cell stimulatory immune checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7).

306. The kit of any one of claims 296 to 304, comprising a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

307. The kit of claim 306, wherein the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBL5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).

308. The kit of claim 306, wherein the proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1) is selected from the group consisting of zimberelimab (AB 122), pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP -224, MED 10680 (AMP-514), spartalizumab, atezolizumab, avelumab, ASC22, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN2034 (balstilimab), JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-l / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFP-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

309. The kit of any one of claims 296 to 304, comprising a small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4.

310. The kit of claim 307, wherein the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181.

311. The kit of claim 307, wherein the small molecule inhibitor of CTLA4 comprises BPI-002.