Fusions containing CD8 antigen binding molecules for the treatment of

Abstract

Provided herein are methods of treating chronic viral infection (e.g., hepatitis B virus (HBV) and / or human immunodeficiency virus (HIV) infection), comprising administering to an individual in need thereof an effective amount of a fusion protein comprising: (a) a first portion comprising an antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof specifically binds to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second portion comprising a cytokine, a chemokine, or a growth factor.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 411,321, filed on September 29, 2022; and U.S. Provisional Application No. 63 / 421,879, filed on November 2, 2022; each of which is hereby incorporated by reference in its entirety.

[0003] Reference to an electronic sequence listing

[0004] The contents of the electronic sequence listing (182842000740seqlist.xml; size: 560,146 bytes; and creation date: September 27, 2023) are incorporated herein by reference in its entirety. Technical Field

[0005] The present disclosure provides a method for treating chronic viral infection (e.g., hepatitis B virus infection and / or human immunodeficiency virus infection), the method comprising administering to an individual in need thereof an effective amount of a fusion protein comprising: (a) a first part comprising an antibody or an antigen-binding fragment thereof, which specifically binds to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part comprising a cytokine, a chemokine or a growth factor. Background Art

[0006] HBV is a DNA virus that causes acute and chronic liver disease. In HBV infection, T cell- and antibody-mediated responses are responsible for resolving acute infection. CD4+ T cells promote the induction and maintenance of CD8+ T cells and neutralizing antibodies by interacting with B cells, and effector CD8+ T cells induce viral clearance by secreting antiviral cytokines and killing infected hepatocytes. Neutralizing antibodies may contain residual cell-borne virus that has not been eliminated by CD8+ T cells.

[0007] Although CD8+ T cells are essential for the antiviral activity of HBV, their response to HBV antigens may be defective in chronically infected patients (Iannacone, M. and Guidotti, LG (2022) Nat Rev Imm 22(1):19-32; Thimme, R. et al. (2003) J. Virol. 77(1):68-76; Rehermann, B. et al. (1995) J. Exp. Med. 181(3):1047-1058). CD8+ T cells recognize HBV antigens on the major histocompatibility complex (MHC) on infected hepatocytes; however, activation / priming of CD8+ T cells in the liver is thought to result in T cell anergy or dysfunction, and the inability of CD8+ T cells to clear infected hepatocytes.

[0008] In preclinical HBV models that recapitulate HBV-induced CD8+ T cell dysfunction, IL-2-based therapy (but not checkpoint blockade) reversed this CD8+ T cell defect (Bénéchet, AP et al. (2019) Nature 574(7777):200-205), suggesting that IL-2 therapy may be a promising approach to reinvigorate HBV immunity. However, IL-2-based therapeutics are limited by pleiotropic effects because IL-2 receptors are expressed on many immune cell types, including immunosuppressive regulatory T cells (Tregs) and cytotoxic natural killer (NK) cells. Due to toxicity, the administration of non-targeted IL-2-based therapeutics in patients may be limited, and therefore, the ability of these therapeutics to deliver sufficient CD8+ T cell activation in patients may be compromised.

[0009] Human immunodeficiency viruses HIV-1 and HIV-2 are enveloped retroviruses that cause acquired immunodeficiency syndrome (AIDS). In 2021, more than 38 million people were considered HIV-infected. It is also believed that 5-20% of all HIV-infected people worldwide are also co-infected with HBV (see, for example, Singh, KP et al. (2017) AIDS 31 (15): 2035-2052). The liver-related mortality rate of this co-infected population can be 19 times higher than that of people infected with HBV alone, and 8 times higher than that of people infected with HIV alone, and the overall mortality rate and hepatocellular carcinoma (HCC) risk are also higher. Although CD8+T cells are believed to be able to recognize and kill HIV-infected T cells, HIV can escape the immune system by virtue of its high mutation rate, ability to downregulate surface MHC-I expression, and destruction of CD8+T cell signaling (Gulzar, N. and Copeland, KFT (2004) Curr. HIV Res. 2 (1): 23-37).

[0010] Therefore, there is still a need to provide cytokine / chemokine / growth factor-based therapeutic agents for treatment (e.g., for HBV and / or HIV infection) to activate CD8+T cell responses without activating other immune subtypes, such as Treg and / or NK cells. For example, such therapeutic agents can include fusion proteins that activate CD8+T cells in a targeted manner, such as by delivering cytokines (including but not limited to IL-2 and IL-21).

[0011] All references cited herein (including patent applications, patent publications, and UniProt KB / Swiss-Prot accession numbers) are hereby incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. Summary of the invention

[0012] The present disclosure describes, among other things, methods for treating chronic viral infections. As described above, better treatments are needed for HBV (e.g., chronic HBV) and HIV infections, including HBV / HIV co-infections. Although IL-2-based therapeutics are promising, IL-2 receptors are expressed on many immune cell types, so widespread activation of IL-2 may have pleiotropic effects. The present disclosure demonstrates that cis-targeted IL-2 fusion proteins selectively act on CD8+ T cells and are sufficient to produce antiviral activity in a mouse viral infection (HBV) model.

[0013] In some aspects, the present disclosure provides a method for treating hepatitis B virus (HBV) and / or human immunodeficiency virus (HIV) infection, the method comprising administering to an individual in need thereof an effective amount of a fusion protein comprising: (a) a first portion comprising an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second portion comprising a cytokine, a chemokine, or a growth factor. In some embodiments, the first portion is fused to the second portion directly or via a linker. In some aspects, the present disclosure provides a fusion protein comprising: (a) a first part, the first part comprising an antibody or an antigen-binding fragment thereof, the antibody or its antigen-binding fragment specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part, the second part comprising a cytokine, a chemokine or a growth factor, for use in a method of treating HBV and / or HIV infection in an individual in need thereof, the method comprising administering an effective amount of the fusion protein to the individual. In some aspects, the present disclosure provides a fusion protein comprising: (a) a first part, the first part comprising an antibody or an antigen-binding fragment thereof, the antibody or its antigen-binding fragment specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part, the second part comprising a cytokine, a chemokine or a growth factor, for use in the manufacture of a medicament for treating HBV and / or HIV infection in an individual in need thereof.

[0014] In some aspects, the present disclosure provides a method for treating HBV infection, the method comprising administering an effective amount of a fusion protein to an individual in need thereof, the fusion protein comprising: (a) a first part comprising an antibody or an antigen-binding fragment thereof, the antibody or its antigen-binding fragment specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part comprising a cytokine, a chemokine or a growth factor. In some embodiments, the first part is fused to the second part directly or via a linker. In some aspects, the present disclosure provides a fusion protein comprising: (a) a first part, the first part comprising an antibody or an antigen-binding fragment thereof, the antibody or its antigen-binding fragment specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part, the second part comprising a cytokine, a chemokine or a growth factor, for use in a method of treating HBV infection in an individual in need thereof, the method comprising administering an effective amount of the fusion protein to the individual. In some aspects, the present disclosure provides a fusion protein comprising: (a) a first part, the first part comprising an antibody or an antigen-binding fragment thereof, the antibody or its antigen-binding fragment specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part, the second part comprising a cytokine, a chemokine or a growth factor, for use in the manufacture of a medicament for treating HBV infection in an individual in need thereof.

[0015] In some embodiments according to any embodiment described herein, HBV infection is chronic HBV infection. In some embodiments, administration results in an increase in HBV reactive CD8+T cells in the liver of the individual. In some embodiments, administration results in a decrease in serum HBV DNA levels in the individual.

[0016] In some embodiments according to any of the embodiments described herein, the HIV infection is HIV-1 or HIV-2 infection. In some embodiments, administration results in an increase in HIV-reactive CD8+T cells in the individual. In some embodiments, administration results in a decrease in serum HIV RNA and / or serum HIV antigen levels in the individual. In some embodiments, the infection is HBV / HIV co-infection.

[0017] In some embodiments according to any embodiment described herein, the individual is a human. In some embodiments, the second part induces the activation of CD8+T cells. In some embodiments, the fusion protein induces the activation of cells expressing human CD8ab heterodimers with a potency at least 10 times higher than the activation of cells expressing human CD8aa homodimers. In some embodiments, the fusion protein induces the activation of CD8+T cells with a potency at least 10 times higher than the activation of NK cells. In some embodiments, the activation potency is measured by EC50, as assessed by cell proliferation, STAT5 phosphorylation and / or cytotoxic function. In some embodiments, cytotoxic function includes the expression of IFNγ and / or granzyme B. In some embodiments, for example, before administering the fusion protein, the individual suffers from or has been diagnosed with HBV infection.

[0018] In some embodiments according to any embodiment described herein, the first part specifically binds to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa. In some embodiments, the first part specifically binds to the extracellular domain of human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to the extracellular domain of human CD8a and / or human CD8aa. In some embodiments, the first part is bound to cells expressing human CD8ab heterodimers on the surface with an EC50 of less than 1000nM. In some embodiments, the first part binds to human CD8+T cells. In some embodiments, the first part specifically binds to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa expressed on the surface of natural killer (NK) cells. In some embodiments, the first portion specifically binds to cells expressing human CD8b and / or human CD8ab on their surface (e.g., T cells) with an affinity at least 10-fold greater than its binding to cells expressing human CD8a and / or human CD8aa on their surface (e.g., NK cells).

[0019] In some embodiments according to any of the embodiments described herein, the first portion comprises an antibody or antigen-binding fragment (e.g., a humanized or human antibody or antigen-binding fragment). In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 15; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 63. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24.In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 65. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 67.In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:31, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:32, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:33; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 54, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 68, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 69. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:37, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:38, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:39; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42.In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 56, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 70, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 71. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:43, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:44, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:45; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQID NO:48. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 57, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 45; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 72, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 73.In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 183, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 184, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182.In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:185, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:186.

[0020] In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: CDR-H1, which comprises the amino acid sequence X 1 X 2 AIS, where X 1 is S, K, G, N, R, D, T or G, and wherein X 2 is Y, L, H or F (SEQ ID NO: 259); CDR-H2 comprises the amino acid sequence X 1 X 2 X 3 PX 4 X 5 X 6 X 7 X 8 X 9 YX 10 QKFX 11 G, where X 1 G or H, X 2 I or F, X 3 I, N or M, X 4 is G, N, H, S, R, I or A, X 5 A, N, H, S, T, F or Y, X 6 A, D or G, X 7 is T, E, K, V, Q or A, X 8 A or T, X 9 is N or K, X 10 is A or N, and X 11 is Q or T (SEQ ID NO: 260); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 , where X 1 D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 I or L, X 5 R, A, Q or S, X6 is A or D, and X 7 D, E, A or S (SEQ ID NO: 261); and wherein the VL domain comprises: CDR-L1, which comprises the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, where X 1 R or G, X 2 A or T, X 3 Q or E, X 4 is E, N, T, S, A, K, D, G, R or Q, X 5 is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2, which comprises the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 , where X 1 A or S, X 2 is T, S, E, Q or D, X 3 N, R, A, E or H, X 4 is Q or A, and X 5 is S or D (SEQ ID NO: 263); and CDR-L3, which comprises the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, where X 1 is S, N, D, Q, A or E, X 2 is T, I or S, X 3 Y, L or F, X 4 is D, G, T, E, Q, A, or Y, and X 5A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 227; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 245, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 246. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 252. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:251; and the VL domain comprises the amino acid sequence of SEQ ID NO:252.In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 253, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 254. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO:274), FW-2 comprising the sequence WVRQAPGQGLEWMG (SEQ ID NO:275), FW-3 comprising the sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO:276), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0021] In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: CDR-H1, which comprises the amino acid sequence GX 1 X 2 FX 3 X 4 X 5 , where X 1 G, Y, S or A, X 2 is T, S, G, R, N or H, X 3 S, T, R, H, Y, G or P, X4 is S, K, G, N, R, D, T, or G, and X 5 is Y, L, H or F (SEQ ID NO: 265); CDR-H2 comprises the amino acid sequence X 1 PX 2 X 3 X 4 X 5 , where X 1 I, N or M, X 2 is G, N, H, S, R, I or A, X 3 A, N, H, S, T, F or Y, X 4 is A, D, or G, and X 5 is T, E, K, V, Q or A (SEQ ID NO: 266); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 , where X 1 D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 I or L, X 5 R, A, Q or S, X 6 is A or D, and X 7 D, E, A or S (SEQ ID NO: 267); and wherein the VL domain comprises: CDR-L1, which comprises the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, where X 1 R or G, X 2 A or T, X 3 Q or E, X 4 is E, N, T, S, A, K, D, G, R or Q, X 5 is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2, which comprises the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 , where X 1 A or S, X 2 is T, S, E, Q or D, X3 N, R, A, E or H, X 4 is Q or A, and X 5 is S or D (SEQ ID NO: 263); and CDR-L3, which comprises the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, where X 1 is S, N, D, Q, A or E, X 2 is T, I or S, X 3 is Y, L or F, X 4 is D, G, T, E, Q, A, or Y, and X 5is A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 239, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 245; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 246. In some embodiments, the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 251; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 252. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 251; and the VL domain comprises the amino acid sequence of SEQ ID NO: 252. In some embodiments, the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:243, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:233; and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:228.In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO: 253; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence SEQ ID NO: 254. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEV KKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising the sequence AISWV RQAPGQGLEWMGGI (SEQ ID NO: 279), FW-3 comprising the sequence ANYA QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WY QQKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GVPSRFS GSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0022] In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: CDR-H1, which comprises the amino acid sequence X 1 YX 2 MS, where X 1 is S, D, E, A, or Q, and X 2 is A, G or T (SEQ ID NO: 268); CDR-H2 comprises the amino acid sequence DIX 1 X 2 X 3 GX 4 X 5 TX 6 YA DSVKG, where X 1 is T, N, S, Q, E, H, R or A, X 2 is Y, W, F or H, X 3 is A, S, Q, E or T, X 4 G or E, X 5 is S or I, and X 6is A or G (SEQ ID NO: 269); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 , where X 1 S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 D or S, X 6 is D, N, Q, E, S, T or L, X 7 is L, F, or M, and X 8is I, Y or V (SEQ ID NO: 270); and the VL domain comprises: a CDR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), a CDR-L2 comprising the amino acid sequence GASS RAT (SEQ ID NO: 41), and a CDR-L3 comprising the amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence SEQ ID NO: 230, and a CDR-H3 comprising the amino acid sequence SEQ ID NO: 231; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 247, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 248. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 249, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 250. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 249; and wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:231; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42.In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 255, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 256. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 257, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 258. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO:281), FW-2 comprising the sequence WVR QAPGKGLEWVS (SEQ ID NO:282), FW-3 comprising the sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:283), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO:293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO:294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO:295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO:296).

[0023] In some embodiments, the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; wherein the VH domain comprises: CDR-H1, which comprises the amino acid sequence GFTFX 1 X 2 Y, where X 1 is S, D, E, Q, S, or A, and X 2 is S, D, E, A or Q (SEQ ID NO: 271); CDR-H2 comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 , where X 1 is T, N, S, Q, E, H, R or A, X2 is Y, W, F or H, X 3 is A, S, Q, E or T, X 4 is G or E, and X 5 is S or I (SEQ ID NO: 272); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 , where X 1 S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 D or S, X 6 is D, N, Q, E, S, T or L, X 7 is L, F or M, and X 8I, Y or V (SEQ ID NO: 273); and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), a CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and a CDR-L3 comprising the amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the VH domain comprises: a CDR-H1 comprising the amino acid sequence SEQ ID NO: 240, a CDR-H2 comprising the amino acid sequence SEQ ID NO: 241, and a CDR-H3 comprising the amino acid sequence SEQ ID NO: 242; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 247; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 248. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 249; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 250. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 249; and wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 244, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 242; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 255; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 256.In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 257; and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 258. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 286), FW-2 comprising the sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO: 287), FW-3 comprising the sequence TAYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO: 284) or WGQGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO:293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO:294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO:295), and FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO:296).

[0024] In some embodiments according to any of the embodiments described herein, the antibody or fragment is a multispecific antibody or fragment (eg, a bispecific antibody or fragment).

[0025] In some embodiments according to any embodiment described herein, the fusion protein comprises a first portion according to any one of the above embodiments and a second portion comprising a cytokine, chemokine or growth factor. In some embodiments, the first portion is fused to the second portion directly or via a linker. In some embodiments, the first portion comprises a human or humanized antibody or antigen-binding fragment thereof that specifically binds to CD8b and / or CD8ab, wherein the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein: the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 15; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 18; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 21; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 22, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 23, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 24. NO:23, and a CDR-L2 comprising an amino acid sequence of SEQ ID NO:24; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO:25, a CDR-H2 comprising an amino acid sequence of SEQ ID NO:26, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:27; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO:30; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO:31, a CDR-H2 comprising an amino acid sequence of SEQ ID NO:32, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:33; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:34, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:35, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: NO:36; the VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:37, CDR-H2 comprising the amino acid sequence of SEQ ID NO:38, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:39;wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 43, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 44, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 45; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 46, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 47, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 48; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 3; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 4, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 44, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 45 NO:5 and a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:179; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:182; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:226, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:227; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: NO:228; the VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, CDR-H2 comprising the amino acid sequence of SEQ ID NO:230, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:231;and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), a CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and a CDR-L3 comprising the amino acid sequence QQYGSSPPVT (SEQ ID NO: 42); the VH domain comprises: a CDR-H1 comprising the amino acid sequence SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence SEQ ID NO: 233; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence SEQ ID NO: 236; the VH domain comprises: a CDR-H1 comprising the amino acid sequence SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence SEQ ID NO: NO:233; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:228; or the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:231, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of RASQSVSSNLA (SEQ ID NO:40), a CDR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:41), and a CDR-L3 comprising the amino acid sequence of QQYGSSPPVT (SEQ ID NO:42). In some embodiments, the first portion comprises a human or humanized antibody or antigen-binding fragment thereof that specifically binds to CD8b and / or CD8ab, wherein the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein: the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 53, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 21, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 24; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 49, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 27, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 30; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 54, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: NO:52, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:33, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:36; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:56, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:39, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:57, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: NO:45, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 49, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 50, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 3, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 6; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 183, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 184, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 179, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 182; the VH domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 181, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 182 NO:238, CDR-H1 comprising the amino acid sequence of SEQ ID NO:239, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:233, and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:228; the VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:240, CDR-H2 comprising the amino acid sequence of SEQ ID NO:241, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:242, and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:42; the VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:238, CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:42 NO:243 and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:233, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:236;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 233, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 228; or the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 244, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 242, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42. ;

[0026] In some embodiments according to any embodiment described herein (e.g., fusion proteins of the present disclosure), the second portion induces activation of CD8+T cells. In some embodiments, the fusion protein induces activation of cells expressing human CD8ab heterodimers with a potency at least 10 times higher than that of cells expressing human CD8aa homodimers. In some embodiments, the fusion protein induces activation of CD8+T cells with a potency at least 10 times higher than that of NK cell activation. In some embodiments, the activation potency is measured by EC50, as assessed by cell proliferation, STAT5 phosphorylation and / or cytotoxic function. In some embodiments, the first portion comprises: two antibody heavy chain polypeptides, the antibody heavy chain polypeptides comprising a structure according to formula [I] from N-terminus to C-terminus:

[0027] VH-CH1-hinge-CH2-CH3[I]

[0028] and two antibody light chain polypeptides, the antibody light chain polypeptides comprising, from N-terminus to C-terminus, a structure according to formula [II]:

[0029] VL-CL[II]

[0030] wherein VH is an antibody heavy chain variable (VH) domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is an antibody light chain variable (VL) domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second portion is fused to the C-terminus of one of the two CH3 domains (e.g., via a linker disclosed herein). In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide, the first antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [I]:

[0031] VH-CH1-hinge-CH2-CH3[I],

[0032] An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus:

[0033] VL-CL[II],

[0034] and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]:

[0035] Hinge-CH2-CH3[III],

[0036] wherein VH is an antibody heavy chain variable (VH) domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is an antibody light chain variable (VL) domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide (e.g., via a linker disclosed herein). In some embodiments, the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide (e.g., via a linker disclosed herein). In some embodiments, the first portion comprises a first antibody heavy chain polypeptide, and the first antibody heavy chain polypeptide comprises, from the N-terminus to the C-terminus, a structure according to formula [I]:

[0037] VH-CH1-hinge-CH2-CH3[I],

[0038] An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus:

[0039] VL-CL[II],

[0040] and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]:

[0041] Hinge-CH2-CH3[III],

[0042] Wherein VH is an antibody heavy chain variable (VH) domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is an antibody light chain variable (VL) domain, and wherein CL is an antibody constant light chain domain; and wherein the C-terminus of the second portion is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide (e.g., via a linker disclosed herein). In some embodiments, the first portion comprises one or two antibody heavy chain polypeptides and one or two antibody light chain polypeptides. In some embodiments, the first portion comprises a single-chain antibody or a single-chain variable fragment (scFv). In some embodiments, the first portion comprises a VHH antibody. In some embodiments according to any embodiment described herein (e.g., the fusion protein described above), VH and VL form an antigen binding site (e.g., specifically binds CD8b and / or CD8ab). In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide, the first antibody heavy chain polypeptide comprising a structure according to formula [I] from N-terminus to C-terminus:

[0043] VH-CH1-hinge-CH2-CH3[I],

[0044] An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus:

[0045] VL-CL[II],

[0046] and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]:

[0047] Hinge-CH2-CH3[III],

[0048] wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and wherein the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide. In some embodiments, the VH domains of two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15, and wherein the VL domains of two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18; the VH domains of two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21, and wherein the VL domains of two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: NO:24; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:31, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:32, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:33, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:34, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:35 CDR-L2 of NO:35 and CDR-L3 comprising the amino acid sequence of SEQ ID NO:36;The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 37, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 43, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 44, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 45, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: NO:48; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:179, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: CDR-L3 of ID NO:182;The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 227, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 230, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 231, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: NO:42; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:233, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:236; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:233, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:236. CDR-L2 of NO:17 and CDR-L3 comprising the amino acid sequence of SEQ ID NO:228;Or the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:231, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, the VH domains of two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15, and wherein the VL domains of two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18; the VH domains of two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21, and wherein the VL domains of two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: NO:24; the VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30;The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 54, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 56, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39; and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: NO:42; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:57, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:45, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: CDR-L3 of IDNO:6;The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 183, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 184, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 239, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 241, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 242, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42; the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: CDR-L2 of NO:235 and CDR-L3 comprising the amino acid sequence of SEQ ID NO:236;The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; or the VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 244, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 242, and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: NO:42. In some embodiments, the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO:13, a CDR-H2 comprising an amino acid sequence of SEQ ID NO:14, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:15, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO:18; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO:19, a CDR-H2 comprising an amino acid sequence of SEQ ID NO:20, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:21, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:22, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:23, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO:24; the VH domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:19, a CDR-H2 comprising an amino acid sequence of SEQ ID NO:20, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:21, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:22, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:23, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO:24 NO:25, a CDR-H1 comprising the amino acid sequence of SEQ ID NO:26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 31, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 32, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 33, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 34, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 35, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 36; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 37, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 38, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 39, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 43, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 44, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 45. NO:44, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: NO:179, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:182;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 227, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 228; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 230, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 231, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; the VH domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 41, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 42, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 43. ID NO: 225 CDR-H1, comprising the amino acid sequence of SEQ ID NO: 232, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228;Or the VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:231, and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 51, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 15, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 18; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 53, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 52, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 21, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 24; the VH domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 2 NO:49, a CDR-H1 comprising an amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:27, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO:30; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO:54, a CDR-H2 comprising an amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO:33, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO:34, a CDR-L2 comprising an amino acid sequence of SEQ ID NO:35, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO:36;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 55, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 56, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 39, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 55, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 57, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 45, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 46, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 47, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 48; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 49, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42 NO:50 and a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:183, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:184, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:179, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:182; the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:239, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: NO:233, and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:228;The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 241, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 242, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; the VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 233, and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 236; the VH domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 236 NO:238, CDR-H1 comprising the amino acid sequence of SEQ ID NO:243, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:233, and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:228; or the VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:240, CDR-H2 comprising the amino acid sequence of SEQ ID NO:244, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:242, and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, the VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to sequence SEQ ID NO: 62, and wherein the VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to sequence SEQ ID NO: 63;The VH domains of the two antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:64, and wherein the VL domains of the two antibody light chain polypeptides both comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:65; the VH domains of the two antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:66, and wherein the VL domains of the two antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:67; the VH domains of the two antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:68, and wherein the VL domains of the two antibody light chain polypeptides both comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: NO:69 is at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO:69; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:70, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:71; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:72, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:73; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:74. NO:185, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:186; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:245, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:246;The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 251, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 252; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 253, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 254; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 255. NO:247 is at least 90%, at least 95%, at least 99% or 100% identical to an amino acid sequence, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:248; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:249, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:250; the VH domains comprise the amino acid sequence of SEQ ID NO:249, and wherein the VL domains comprise the amino acid sequence of SEQ ID NO:250; the VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: NO:255 is at least 90%, at least 95%, at least 99% or 100% identical to an amino acid sequence, and wherein the VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:256;Or the VH domains of the two antibody heavy chain polypeptides both comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO: 257, and wherein the VL domains of the two antibody light chain polypeptides both comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO: 258. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:63; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:65; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:67; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO: NO:68 is at least 90%, at least 95%, at least 99% or 100% identical to an amino acid sequence, and wherein the VL domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:69; the VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:70, and wherein the VL domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:71; the VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:72, and wherein the VL domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:73; the VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO: NO:185 is at least 90%, at least 95%, at least 99% or 100% identical to an amino acid sequence, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:186;The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 245, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 246; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 252; the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 253, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: NO:254 is at least 90%, at least 95%, at least 99% or 100% identical to an amino acid sequence; the VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:247, and wherein the VL domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:248; the VH domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:249, and wherein the VL domain comprises an amino acid sequence at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:250; the VH domain comprises the amino acid sequence of SEQ ID NO:249, and wherein the VL domain comprises the amino acid sequence of SEQ ID NO:250; the VH domain comprises the amino acid sequence of SEQ ID NO: NO:255 is at least 90%, at least 95%, at least 99% or 100% identical to an amino acid sequence, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:256;or the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 257, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 258. In some embodiments, one or both of the antibody heavy chain polypeptides comprise the following amino acid substitutions: L234A, L235A and G237A, numbered according to the EU index. In some embodiments, the first of the antibody heavy chain polypeptides comprises amino acid substitutions Y349C and T366W, and the second of the antibody heavy chain polypeptides comprises amino acid substitutions S354C, T366S, L368A and Y407V, numbered according to the EU index. ;

[0049] In some embodiments according to any of the embodiments described herein, the second portion comprises an IL-2 polypeptide. In some embodiments, the IL-2 polypeptide is a mutant IL-2 polypeptide comprising one or more mutations relative to a human IL-2 polypeptide comprising the sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNIN VIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 81). In some embodiments, the mutant IL-2 polypeptide has a binding affinity for IL-2Rα that is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence SEQ ID: 81 for IL-2Rα. In some embodiments, the binding affinity of the mutant IL-2 polypeptide to IL-2Rβ is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rβ; and / or the binding affinity of the mutant IL-2 polypeptide to IL-2Rγ is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rγ. In some embodiments, the IL-2 polypeptide comprises the sequence SEQ ID NO:81 having one, two, three, four or five amino acid substitutions relative to SEQ ID NO:81, and wherein the one, two, three, four or five substitutions comprise substitutions at positions of SEQ ID NO:81 selected from the group consisting of: Q11, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129, and S130. In some embodiments, the IL-2 polypeptide comprises a sequence SEQ ID NO: 81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO: 81): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F42A, and N88S; R38E, F42A, and N88A; R38E, F42A, and N88G; R38E, F42A, and N88R; R38E, F42A, and N88T; R38E, F42A, and N88D; R38E, F42A, and V91E; R38E, F42A, and D84H; R38E, F42A, and D84K; R38E, F42A, and D84R; H16D, R38E, and F42A;H16E, R38E and F42A; R38E, F42A and Q126S; R38D, F42A and N88S; R38D, F42A and N88A; R38D, F42A and N88G; R38D, F42A and N88R; R38D, F42A and N88T; R38D, F42A and N88D; R38D, F42A and V91E; R38D, F42A and D84H; R38 D, F42A and D84K; R38D, F42A and D84R; H16D, R38D and F42A; H16E, R38D and F42A; R38D, F42A and Q126S; R38A, F42K and N88S; R38A, F42K and N88A; R38A, F42K and N88G; R38A, F42K and N88R; R38A, F42K and N88T; R38A, F4 2K and N88D; R38A, F42K and V91E; R38A, F42K and D84H; R38A, F42K and D84K; R38A, F42K and D84R; H16D, R38A and F42K; H16E, R38A and F42K; R38A, F42K and Q126S; F42A, E62Q and N88S; F42A, E62Q and N88A; F42A, E62Q and N 88G; F42A, E62Q and N88R; F42A, E62Q and N88T; F42A, E62Q and N88D; F42A, E62Q and V91E; F42A, E62Q and D84H; F42A, E62Q and D84K; F42A, E62Q and D84R; H16D, F42A and E62Q; H16E, F42A and E62Q; F42A, E62Q and Q126S. In some embodiments, the IL-2 polypeptide comprises the sequence SEQ ID NO: 81 having another amino acid substitution at position C125 relative to SEQ ID NO: 81. In some embodiments, the IL-2 polypeptide comprises the sequence SEQ ID NO: 81 having one of the following amino acid substitution sets (relative to the sequence SEQ ID NO: 81): NO:81: R38E, F42A and C125A; R38D, F42A and C125A; F42A, E62Q and C125A; R38A, F42K and C125A; R38E, F42A, N88S and C125A; R38E, F42A, N88A and C125A; R38E, F42A, N88G and C125A; R38E, F42A, N88R and C125A; R38E, F42A, N88T and C125A; R38E, F42A, N88D and C125A; R38E, F42A, V91E and C125A; R38E, F42A, D84H and C125A;R38E, F42A, D84K and C125A; R38E, F42A, D84R and C125A; H16D, R38E, F42A and C125A; H16E, R38E, F42A and C125A; R38E, F42A, C125A and Q126S; R38D, F42A, N88S and C12 5A; R38D, F42A, N88A and C125A; R38D, F42A, N88G and C125A; R38D, F42A, N88R and C125A; R38D, F42A, N88T and C125A; R38D, F42A, N88D and C125A; R38D, F42A, V91E and C 125A; R38D, F42A, D84H and C125A; R38D, F42A, D84K and C125A; R38D, F42A, D84R and C125A; H16D, R38D, F42A and C125A; H16E, R38D, F42A and C125A; R38D, F42A, C125 A and Q126S; R38A, F42K, N88S and C125A; R38A, F42K, N88G and C125A; R38A, F42K, N88R and C125A; R38A, F42K, N88T and C125A; R38A, F42K, N88D and C125A; R38A, F42K, N 88A and C125A; R38A, F42K, V91E and C125A; R38A, F42K, D84H and C125A; R38A, F42K, D84K and C125A; R38A, F42K, D84R and C125A; H16D, R38A, F42K and C125A; H16E, R38A , F42K and C125A; R38A, F42K, C125A and Q126S; F42A, E62Q, N88S and C125A; F42A, E62Q, N88A and C125A; F42A, E62Q, N88G and C125A; F42A, E62Q, N88R and C125A; F42A, E 62Q, N88T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V91E and C125A; F42A, E62Q and D84H and C125A; F42A, E62Q and D84K and C125A; F42A, E62Q and D84R and C125A; H16D , F42A and E62Q and C125A; H16E, F42A, E62Q and C125A; F42A, E62Q, C125A and Q126S; F42A, N88S and C125A; F42A, N88A and C125A; F42A, N88G and C125A; F42A, N88R and C125A;In some embodiments, the IL-2 polypeptide comprises the sequence APT SSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPK KATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLE LKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 80). In some embodiments, the IL-2 polypeptide comprises the sequence APTSSSTKKTQL QLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQ CLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 297). In some embodiments, the IL-2 polypeptide comprises a sequence selected from the group consisting of SEQ ID Nos: 85-155 and 190-216. In some embodiments, the IL-2 polypeptide comprises a sequence selected from the group consisting of SEQ ID Nos: 80, 85-155, 190-216, 297, and 354-383. In some embodiments, the second portion comprises a polypeptide that induces signaling through IL2Rβγ. In some embodiments, the second portion comprises an IL-21 polypeptide. ;

[0050] In some embodiments according to any embodiment described herein (e.g., fusion proteins of the present disclosure), one or both of the antibody Fc domains include human IgG1 Fc domains with the following amino acid substitutions: L234A, L235A, G237A, and K322A, numbered according to the EU index. In some embodiments, one or both of the antibody Fc domains do not have a C-terminal lysine. In some embodiments, one or both of the antibody Fc domains include human IgG1 Fc domains with the following amino acid substitutions: L234A, L235A, and G237A, numbered according to the EU index. In some embodiments, one or both of the antibody Fc domains do not have a C-terminal lysine. In some embodiments, the first of the two Fc domains includes human IgG1 Fc domains with amino acid substitutions Y349C and T366W, and the second of the two Fc domains includes human IgG1 Fc domains with amino acid substitutions S354C, T366S, L368A, and Y407V, numbered according to the EU index. In some embodiments, one or both of the antibody Fc domains do not have a C-terminal lysine. In some embodiments (e.g., fusion proteins of the present disclosure), the linker comprises the sequence (GGGS)xGn (SEQ ID NO: 74), (GGGGS)xGn (SEQ ID NO: 75) or (GGGGGS)xGn (SEQ ID NO: 76), S(GGGS)xGn (SEQ ID NO: 386), S(GGGGS)xGn (SEQ ID NO: 387) or S(GGGGGS)xGn (SEQ ID NO: 388), wherein x=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein n=0, 1, 2 or 3. In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 79) or SGGGGSGGGGSGGGGS (SEQ ID NO: 389). In some embodiments (e.g., in a fusion protein of the present disclosure), the linker connects the first part of the present disclosure (e.g., a human or humanized antibody or antigen-binding fragment thereof that specifically binds to CD8b and / or CD8ab) with the second part of the present disclosure (e.g., an IL-2 polypeptide of the present disclosure, an IL-21 polypeptide of the present disclosure, or a polypeptide of the present disclosure that induces signaling via IL2Rβγ).

[0051] In some embodiments according to any of the embodiments described herein, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 156, a heavy chain comprising the amino acid sequence of SEQ ID NO: 157, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 156, a heavy chain comprising the amino acid sequence of SEQ ID NO: 157, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 159, a heavy chain comprising the amino acid sequence of SEQ ID NO: 160, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 161. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 159, a heavy chain comprising the amino acid sequence of SEQ ID NO: 160, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 162, a heavy chain comprising the amino acid sequence of SEQ ID NO: 163, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 164. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 162, a heavy chain comprising the amino acid sequence of SEQ ID NO: 163, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 219. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 165, a heavy chain comprising the amino acid sequence of SEQ ID NO: 166, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 167. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 165, a heavy chain comprising the amino acid sequence of SEQ ID NO: 166, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 220. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 168, a heavy chain comprising the amino acid sequence of SEQ ID NO: 169, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 170. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 168, a heavy chain comprising the amino acid sequence of SEQ ID NO: 169, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 221.In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 171, a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 173. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 171, a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 222. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 174, a heavy chain comprising the amino acid sequence of SEQ ID NO: 175, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 176. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 174, a heavy chain comprising the amino acid sequence of SEQ ID NO: 175, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 223. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 187, a heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 189. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 187, a heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 298, a heavy chain comprising the amino acid sequence of SEQ ID NO: 299, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 300. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 298, a heavy chain comprising the amino acid sequence of SEQ ID NO: 299, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 301. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 302, a heavy chain comprising the amino acid sequence of SEQ ID NO: 303, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 304. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 302, a heavy chain comprising the amino acid sequence of SEQ ID NO: 303, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 305.In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 306, a heavy chain comprising the amino acid sequence of SEQ ID NO: 307, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 308. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 306, a heavy chain comprising the amino acid sequence of SEQ ID NO: 307, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 309. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 310, a heavy chain comprising the amino acid sequence of SEQ ID NO: 311, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 312. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 310, a heavy chain comprising the amino acid sequence of SEQ ID NO: 311, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 314, a heavy chain comprising the amino acid sequence of SEQ ID NO: 315, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 316. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 314, a heavy chain comprising the amino acid sequence of SEQ ID NO: 315, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 318, a heavy chain comprising the amino acid sequence of SEQ ID NO: 319, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 320. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 318, a heavy chain comprising the amino acid sequence of SEQ ID NO: 319, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 321. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 322, a heavy chain comprising the amino acid sequence of SEQ ID NO: 323, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 324. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 322, a heavy chain comprising the amino acid sequence of SEQ ID NO: 323, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 325.In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 326, a heavy chain comprising the amino acid sequence of SEQ ID NO: 327, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 328. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 326, a heavy chain comprising the amino acid sequence of SEQ ID NO: 327, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 329. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 330, a heavy chain comprising the amino acid sequence of SEQ ID NO: 331, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 332. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 330, a heavy chain comprising the amino acid sequence of SEQ ID NO: 331, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 333. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 334, a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 336. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 334, a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 338, a heavy chain comprising the amino acid sequence of SEQ ID NO: 339, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 340. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 338, a heavy chain comprising the amino acid sequence of SEQ ID NO: 339, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 341. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 342, a heavy chain comprising the amino acid sequence of SEQ ID NO: 343, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 344. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 342, a heavy chain comprising the amino acid sequence of SEQ ID NO: 343, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 345.In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 346, a heavy chain comprising the amino acid sequence of SEQ ID NO: 347, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 348. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 346, a heavy chain comprising the amino acid sequence of SEQ ID NO: 347, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 349. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 350, a heavy chain comprising the amino acid sequence of SEQ ID NO: 351, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 352. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 156, a heavy chain comprising the amino acid sequence of SEQ ID NO: 157, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 159, a heavy chain comprising the amino acid sequence of SEQ ID NO: 160, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 162, a heavy chain comprising the amino acid sequence of SEQ ID NO: 163, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 219. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 165, a heavy chain comprising the amino acid sequence of SEQ ID NO: 166, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 220. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 168, a heavy chain comprising the amino acid sequence of SEQ ID NO: 169, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 221. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 171, a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 222. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 174, a heavy chain comprising the amino acid sequence of SEQ ID NO: 175, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 223.In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 187, a heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 298, a heavy chain comprising the amino acid sequence of SEQ ID NO: 299, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 301. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 302, a heavy chain comprising the amino acid sequence of SEQ ID NO: 303, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 305. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 306, a heavy chain comprising the amino acid sequence of SEQ ID NO: 307, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 309. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 310, a heavy chain comprising the amino acid sequence of SEQ ID NO: 311, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 314, a heavy chain comprising the amino acid sequence of SEQ ID NO: 315, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 318, a heavy chain comprising the amino acid sequence of SEQ ID NO: 319, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 321. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 322, a heavy chain comprising the amino acid sequence of SEQ ID NO: 323, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 325. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 326, a heavy chain comprising the amino acid sequence of SEQ ID NO: 327, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 329. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 330, a heavy chain comprising the amino acid sequence of SEQ ID NO: 331, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 333.In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 334, a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 338, a heavy chain comprising the amino acid sequence of SEQ ID NO: 339, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 341. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 342, a heavy chain comprising the amino acid sequence of SEQ ID NO: 343, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 345. In some embodiments, the fusion proteins of the present disclosure comprise one or two light chains comprising the amino acid sequence of SEQ ID NO: 346, a heavy chain comprising the amino acid sequence of SEQ ID NO: 347, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 349. In some embodiments, the fusion protein of the present disclosure comprises one or two light chains comprising the amino acid sequence of SEQ ID NO: 350, a heavy chain comprising the amino acid sequence of SEQ ID NO: 351, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 353. In some embodiments, the fusion protein comprises one or two antigen binding sites, each antigen binding site comprising a VL domain from one of the light chains and a VH domain from one of the heavy chains (e.g., the fusion protein comprises two antigen binding sites: one comprising a VL domain from one of the two light chains and a VH domain from one of the heavy chains, and the other comprising a VL domain from the other light chain and a VH domain from the other heavy chain).

[0052] In some embodiments according to any of the embodiments described herein, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 156, a polypeptide comprising the amino acid sequence of SEQ ID NO: 157, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 156, a polypeptide comprising the amino acid sequence of SEQ ID NO: 157, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 217. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 159, a polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 161. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 159, a polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 162, a polypeptide comprising the amino acid sequence of SEQ ID NO: 163, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 164. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 162, a polypeptide comprising the amino acid sequence of SEQ ID NO: 163, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 219. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 165, a polypeptide comprising the amino acid sequence of SEQ ID NO: 166, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 167. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 165, a polypeptide comprising the amino acid sequence of SEQ ID NO: 166, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 220. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 168, a polypeptide comprising the amino acid sequence of SEQ ID NO: 169, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 170. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 168, a polypeptide comprising the amino acid sequence of SEQ ID NO: 169, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 221.In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 171, a polypeptide comprising the amino acid sequence of SEQ ID NO: 172, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 173. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 171, a polypeptide comprising the amino acid sequence of SEQ ID NO: 172, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 222. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 174, a polypeptide comprising the amino acid sequence of SEQ ID NO: 175, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 176. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 174, a polypeptide comprising the amino acid sequence of SEQ ID NO: 175, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 223. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 187, a polypeptide comprising the amino acid sequence of SEQ ID NO: 188, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 189. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 187, a polypeptide comprising the amino acid sequence of SEQ ID NO: 188, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 224. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 298, a polypeptide comprising the amino acid sequence of SEQ ID NO: 299, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 300. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 298, a polypeptide comprising the amino acid sequence of SEQ ID NO: 299, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 301. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 302, a polypeptide comprising the amino acid sequence of SEQ ID NO: 303, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 304. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 302, a polypeptide comprising the amino acid sequence of SEQ ID NO: 303, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 305.In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 306, a polypeptide comprising the amino acid sequence of SEQ ID NO: 307, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 308. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 306, a polypeptide comprising the amino acid sequence of SEQ ID NO: 307, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 309. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 310, a polypeptide comprising the amino acid sequence of SEQ ID NO: 311, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 312. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 310, a polypeptide comprising the amino acid sequence of SEQ ID NO: 311, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 313. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 314, a polypeptide comprising the amino acid sequence of SEQ ID NO: 315, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 316. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 314, a polypeptide comprising the amino acid sequence of SEQ ID NO: 315, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 317. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 318, a polypeptide comprising the amino acid sequence of SEQ ID NO: 319, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 320. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 318, a polypeptide comprising the amino acid sequence of SEQ ID NO: 319, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 321. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 322, a polypeptide comprising the amino acid sequence of SEQ ID NO: 323, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 324. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 322, a polypeptide comprising the amino acid sequence of SEQ ID NO: 323, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 325.In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 326, a polypeptide comprising the amino acid sequence of SEQ ID NO: 327, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 328. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 326, a polypeptide comprising the amino acid sequence of SEQ ID NO: 327, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 329. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 330, a polypeptide comprising the amino acid sequence of SEQ ID NO: 331, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 332. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 330, a polypeptide comprising the amino acid sequence of SEQ ID NO: 331, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 333. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 334, a polypeptide comprising the amino acid sequence of SEQ ID NO: 335, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 336. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 334, a polypeptide comprising the amino acid sequence of SEQ ID NO: 335, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 337. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 338, a polypeptide comprising the amino acid sequence of SEQ ID NO: 339, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 340. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 338, a polypeptide comprising the amino acid sequence of SEQ ID NO: 339, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 341. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 342, a polypeptide comprising the amino acid sequence of SEQ ID NO: 343, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 344. In some embodiments, the fusion protein of the present disclosure comprises one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 342, a polypeptide comprising the amino acid sequence of SEQ ID NO: 343, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 345.In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 346, a polypeptide comprising the amino acid sequence of SEQ ID NO: 347, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 348. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 346, a polypeptide comprising the amino acid sequence of SEQ ID NO: 347, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 349. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 350, a polypeptide comprising the amino acid sequence of SEQ ID NO: 351, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 352. In some embodiments, the fusion proteins of the present disclosure comprise one or two polypeptides comprising the amino acid sequence of SEQ ID NO: 350, a polypeptide comprising the amino acid sequence of SEQ ID NO: 351, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 353.

[0053] In some embodiments according to any of the embodiments described herein, the fusion protein comprises a first portion that binds to human CD8b and a second portion that comprises an IL2 polypeptide, wherein the fusion protein comprises four polypeptide chains, wherein: (1) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334; (2) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334; (3) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 338, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 339, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 340, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 338; or (4) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 338, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: NO:339, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:341, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:338.

[0054] In some embodiments according to any of the embodiments described herein, the fusion protein is administered in a pharmaceutical composition comprising the fusion protein and a pharmaceutically acceptable carrier.

[0055] In some embodiments according to any embodiment described herein, the method further comprises administering a second antiviral agent or immunomodulator to the individual. In some embodiments, the second antiviral agent or immunomodulator is a nucleoside or nucleotide analog, a capsid assembly regulator or inhibitor, a TLR agonist, a vaccine, an RNAi-based agent, an interferon-α, an HBV entry inhibitor, a covalently closed circular DNA (cccDNA) disruptor, an HBV transcription inhibitor, a CD3 bispecific T cell redirector, an HBV antigen targeting agent, a PD1 and / or PDL1 blocker, an agent that reduces PDL1 expression in hepatocytes, an RNA destabilizer, or a hepatitis B surface antigen (HBsAg) release inhibitor. In some embodiments, the second antiviral agent or immunomodulator is an antiretroviral therapy (ART), a PD1 and / or PDL1 blocker, or an agent that reduces PDL1 expression. In some embodiments, the ART comprises a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor (INSTI), an attachment inhibitor, a post-attachment inhibitor, a pharmacokinetic enhancer, or a combination thereof.

[0056] It should be understood that one, some or all of the features of the various embodiments described herein can be combined to form other embodiments of the present disclosure. These and other aspects of the present disclosure will become apparent to those skilled in the art. These and other embodiments of the present disclosure are further described by the following specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The general mechanism of how targeted fusions of mutant IL-2 polypeptides with CD8 antigen binding molecules (CD8-targeted IL-2 fusions) as well as non-targeted IL-2 fusions stimulate cells that do or do not express the CD8 antigen is shown.

[0058] Figure 2A Three different fusion protein formats (Formats A, B, and C) according to some embodiments are depicted.

[0059] Figure 2B Depicted are the in vitro activity profiles of a murine CD8+ T cell targeted IL-2 fusion protein (mCD8-mIL2v1) and a control non-targeted IL-2 fusion protein representing the "non-alpha" IL-2 class (CTRL-mIL2v2) in Format A. Signaling as assessed by pSTAT5 staining of murine splenocytes after 25 minutes of stimulation is shown.

[0060] Figure 3 The study design for testing CD8-targeted IL-2 fusion proteins in a hepatitis B virus (HBV) mouse model is shown, as described in Example 3. Native T cell receptor (TCR) transgenic HBV core antigen reactive CD8+ T cells (Cor93 T cells) were adoptively transferred into transgenic mice with HBV replication competence, which constitutively expressed all HBV antigens in the liver. Mice were treated with CD8-IL2 fusion proteins or control interventions, and viral levels and CD8+ T cell responses were assessed.

[0061] Figures 4A-4D Shown as Figure 3 The experimental results of HBV transgenic mice are described in . 5 Cor93 T cells were injected intravenously with 0.3 mg / kg of CD8-targeted IL-2 fusion protein mCD8-mIL2v1 on day 1 for treatment. Serum HBV core DNA ( Figure 4A ), serum ALT activity ( Figure 4B ),weight( Figure 4C ) and liver staining for HBV core antigen (HBcAg) by immunohistochemistry (IHC) ( Figure 4D ), comparing mice treated with CD8-IL2 fusion protein or control intervention.

[0062] Figures 5A-5D Show Figures 4A-4D Additional results from the experiments in , describing HBV antigen reactive CD8+ T cells in the liver. The number of HBV antigen reactive CD8+ T cells ( Figure 5A ), their PD-1 expression ( Figure 5B ), the percentage of cells expressing IFNγ in response to ex vivo stimulation with HBV peptides ( Figure 5C ) and the percentage of cells expressing GzmB ( Figure 5D ).

[0063] Figures 6A-6C Shown as Figure 3 The results of Example 4 using HBV transgenic mice are described in the following. 5 Cor93 T cells were injected intravenously with 0.1 or 0.3 mg / kg of mCD8-mIL2v1 fusion protein or control non-targeted "non-α" IL-2 fusion protein CTRL-mIL2v2 on day 1. Serum HBV core DNA ( Fig. 6A), serum ALT activity ( Figure 6B ) and liver staining for HBV core antigen (HBcAg) by immunohistochemistry (IHC) ( Figure 6C ).

[0064] Figures 7A-7C Additional results of Example 4 are shown, describing HBV antigen reactive CD8+ T cells in the liver. The number of HBV antigen reactive CD8+ T cells ( Fig. 7A ), the percentage of cells expressing IFNγ in response to ex vivo stimulation with HBV peptides ( Figure 7B ) and the percentage of cells expressing GzmB ( Figure 7C ).

[0065] Fig. 8A and Figure 8B Additional results of Example 4 are shown, describing NK cells in the liver and T regulatory (Treg) cells in the spleen. The frequency of NK cells in the liver as part of the intrahepatic white blood cells is shown ( Fig. 8A ) and absolute Treg cell counts in the spleen ( Figure 8B ). DETAILED DESCRIPTION

[0066] definition

[0067] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "molecule" optionally includes a combination of two or more such molecules, and so forth.

[0068] It should be understood that aspects and embodiments of the present disclosure include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0069] As used herein, the term "about" refers to the typical error range for individual values ​​that is readily known to those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments for the value or parameter itself.

[0070] As used herein, "immune cells" are cells of the immune system that react to organisms or other entities that are considered foreign to the host's immune system. They protect the host from foreign pathogens, organisms, and disease effects. Immune cells, also known as leukocytes, participate in the innate and adaptive immune responses against pathogens. The innate immune response occurs immediately after exposure to the pathogen without additional initiation or learning processes. The adaptive immune process requires initial initiation, and then produces memory, which then causes enhanced reactivity when the same pathogen is encountered later. Innate immune cells include, but are not limited to, monocytes, macrophages, dendritic cells, innate lymphoid cells (ILCs) including natural killer (NK) cells, neutrophils, megakaryocytes, eosinophils, and basophils. Adaptive immune cells include B and T lymphocytes / cells. T cell subsets include, but are not limited to, αβCD4+T (naive CD4+, memory CD4+, effector memory CD4+, effector CD4+, regulatory CD4+) and αβCD8+T (naive CD8+, memory CD8+, effector memory CD8+, effector CD8+). B cell subsets include, but are not limited to, naive B cells, memory B cells, and plasma cells. NK T cells and Tγδ (T gamma delta) cells exhibit the characteristics of both innate and adaptive lymphocytes.

[0071] "T cells" or "T lymphocytes" are immune cells that play a key role in coordinating immune responses in health and disease. There are two major subsets of T cells with unique functions and properties: T cells expressing the CD8 antigen (CD8 + T cells) are cytotoxic or killer T cells that can lyse target cells using cytotoxic proteins such as granzymes and perforins; and T cells expressing the CD4 antigen (CD4 + T cells) are able to regulate CD8 + T cells, B cells, macrophages, and many other immune cell types function as helper T cells. + T cells are further subdivided into several subsets, such as T regulatory (Treg) cells, which are able to suppress immune responses, and T helper 1 (Th1), T helper 2 (Th2), and T helper 17 (Th17) cells, which regulate different types of immune responses by secreting immunomodulatory proteins such as cytokines. T cells recognize their targets via αβ T cell receptors that bind to unique antigen-specific motifs, and this recognition mechanism is usually required in order to trigger their cytotoxic and cytokine secretion functions. "Innate lymphocytes" may also display CD8 + and CD4 +Characteristics of T cells, such as cytotoxic activity or secretion of Th1, Th2 and Th17 cytokines. Some of these innate lymphocyte subsets include NK cells and ILC1, ILC2 and ILC3 cells; and innate T cells such as Tγδ cells; and NK T cells. Typically, these cells can quickly respond to inflammatory stimuli (such as immunomodulatory cytokines) from infected or injured tissues, but unlike αβT cells, they can respond without the need to recognize antigen-specific patterns.

[0072] "Cytokine" is an immunomodulatory polypeptide form that mediates crosstalk between initiation / primary cells and target / effector cells. It can act as a soluble form or cell surface associated with binding to a "cytokine receptor" on a target immune cell to activate signal transduction. As used herein, a "cytokine receptor" is a polypeptide on the cell surface that activates intracellular signal transduction after binding to a cytokine on the extracellular cell surface. Cytokines include, but are not limited to, chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by a variety of cells including immune cells, endothelial cells, fibroblasts, and stromal cells. A given cytokine can be produced by more than one cell type. Cytokines are pleiotropic; because receptors are expressed on multiple immune cell subsets, a cytokine can activate signal transduction pathways in multiple cells. However, depending on the cell type, the signal transduction events of cytokines can produce different downstream cellular events, such as activation, proliferation, survival, apoptosis, secretion of effector functions and other immunomodulatory proteins.

[0073] As used herein, "amino acid" refers to the naturally occurring carboxyl α-amino acids, including alanine (three letter code: ala, single letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine ​​(cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y) and valine (val, V).

[0074] As used herein, "polypeptide" or "protein" refers to a molecule in which monomers (amino acids) are linearly linked to each other via peptide bonds (also called amide bonds). The term "polypeptide" refers to any chain of two or more amino acids, and does not refer to a specific length of the product. Therefore, the definition of "polypeptide" includes peptides, dipeptides, tripeptides, oligopeptides, "proteins", "amino acid chains" or any other terms used to refer to chains of two or more amino acids, and the term "polypeptide" can be used to replace any of these terms, or the term "polypeptide" can be used interchangeably with any of these terms. The term "polypeptide" is also intended to refer to a product of a polypeptide that can be derived from a natural biological source or produced by recombinant technology, but is not necessarily translated from a specified nucleic acid sequence. It can be produced in any way, including chemical synthesis. A polypeptide generally has a defined three-dimensional structure, but it does not necessarily have such a structure. The size of the polypeptides of the present disclosure may be about 3 or more, 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 100 or more, 200 or more, 500 or more, 1,000 or more, or 2,000 or more amino acids. Polypeptides with a defined three-dimensional structure are referred to as folded, and polypeptides that do not have a defined three-dimensional structure but can adopt many different conformations are referred to as unfolded. Polypeptides may further form multimers, such as dimers, trimers, and higher oligomers, i.e., consisting of more than one polypeptide molecule. The polypeptide molecules that form such dimers, trimers, etc. may be the same or different. Therefore, the corresponding higher-order structures of such multimers are referred to as homo- or hetero-dimers, homo- or hetero-trimers, etc. The terms "polypeptide" and "protein" also refer to modified polypeptides / proteins wherein post-expression modifications are effected including, but not limited to, glycosylation, acetylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, or modification with non-naturally occurring amino acids.

[0075] As used herein, "residue" means a position in a protein and its associated amino acid identity. For example, Leu 234 (also known as Leu234 or L234) is the residue at position 234 in human antibody IgG1.

[0076] "Wild type" herein means an amino acid sequence or nucleotide sequence found in nature, including allelic gene variations. A wild type protein has an amino acid sequence or nucleotide sequence that has not been intentionally modified.

[0077] "Substitution" or "mutation" refers to a change in the backbone of a polypeptide, wherein an amino acid naturally occurring in the wild-type sequence of a polypeptide is replaced by another amino acid that is not naturally occurring at the same position in the polypeptide. Preferably, one or more mutations are introduced to modify the affinity of the polypeptide for its receptor, thereby changing its activity so that its affinity and activity become different from those of the wild-type homologous polypeptide. Mutations may also improve the biophysical properties of a polypeptide. Amino acid mutations may be produced using genetic or chemical methods well known in the art. Genetic methods may include site-directed mutagenesis, PCR, gene synthesis, and the like. It is contemplated that methods of altering amino acid side chain groups by methods other than genetic engineering (such as chemical modification) may also be applicable.

[0078] As used herein, "CD8" refers to any natural human CD8. Unless otherwise clearly indicated or contextually indicated, reference to "CD8" refers to CD8aa and / or CD8ab. The amino acid sequence of exemplary human CD8b (beta chain of human CD8) is described under UniProtP10966 (CD8B_HUMAN). "CD8a" refers to the alpha chain of human CD8 (e.g., described under UniProt P01732 (CD8A_HUMAN)). "CD8aa" refers to the homodimer of CD8a. "CD8ab" refers to the heterodimer of CD8a and CD8b. "CD8", "CD8a", "CD8b", "CD8aa" and "CD8ab" cover untreated forms and mature forms produced by the processing in cells. "CD8", "CD8a", "CD8b", "CD8aa" and "CD8ab" also include, but are not limited to, naturally occurring variants, such as one or more alleles or splice variants.

[0079] Unless otherwise indicated, as used herein, "interleukin-2" or "IL-2" refers to any native human IL-2. "IL-2" encompasses unprocessed IL-2 as well as "mature IL-2" which is a form of IL-2 produced by processing in cells. Figure 1 A depicts the sequence of "mature IL-2". An exemplary form of untreated human IL-2 comprises an additional N-terminal amino acid signal peptide linked to mature IL-2. "IL-2" also includes, but is not limited to, naturally occurring IL-2 variants, such as one or more alleles or splice variants. The amino acid sequence of an exemplary human IL-2 is described under UniProt P60568 (IL2_HUMAN).

[0080] "Affinity" or "binding affinity" refers to the strength of the total amount of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). Affinity can generally be expressed by the dissociation constant (K D ) indicates that the dissociation constant is the ratio of the dissociation rate constant to the association rate constant (kdissociation and kassociation, respectively). Therefore, equivalent affinity can include different rate constants as long as the ratio of the rate constants remains the same. Affinity can be measured by common methods known in the art, such as enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) technology (e.g., BIAcore), biolayer interferometry (BLI) technology (e.g., Octet), and other traditional binding assays (Heeley, Endocr Res 28, 217-229 (2002).

[0081] As used herein, "binding" or "specific binding" refers to the ability of a polypeptide or antigen binding molecule to selectively interact with a receptor of a polypeptide or target antigen, respectively, and this specific interaction may be different from non-targeted or non-desired or non-specific interactions. Examples of specific binding include, but are not limited to, IL-2 cytokines binding to their specific receptors (e.g., IL-2Rα, IL-2Rβ, and IL-2Rγ) and antigen binding molecules binding to specific antigens (e.g., CD8 or PD-1).

[0082] "Mutant IL-2 polypeptide" refers to an IL-2 polypeptide with reduced affinity for its receptor, wherein such reduced affinity will result in reduced biological activity of the mutant. Reduced affinity and thus reduced activity can be obtained by introducing a small number of amino acid mutations or substitutions. Mutant IL-2 polypeptides may also have other modifications to the peptide backbone, including but not limited to amino acid deletions, permutations, cyclizations, disulfide bonds or post-translational modifications (e.g., glycosylation or altered carbohydrates) of the polypeptide, chemical or enzymatic modifications of the polypeptide (e.g., attachment of PEG to the polypeptide backbone), addition of peptide tags or labels, or fusion with proteins or protein domains to produce a final construct with desired characteristics (such as reduced IL-2Rβγ affinity). The desired activity may also include improved biophysical properties compared to the wild-type IL-2 polypeptide. A variety of modifications may be combined to achieve the desired activity modification, such as reduced affinity or improved biophysical properties. As a non-limiting example, an amino acid sequence for consensus N-linked glycosylation may be incorporated into the polypeptide to allow glycosylation. Another non-limiting example is that lysine may be incorporated into the polypeptide to enable PEGylation. Preferably, one or more mutations are introduced into the polypeptide to modify its activity.

[0083] The terms "antibody" and "immunoglobulin" are used interchangeably and are used herein in the broadest sense and encompass various antibody structures, including but not limited to monoclonal antibodies (e.g., full-length or intact monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, and single domain antibodies (as described in more detail herein), so long as they exhibit the desired antigen-binding activity.

[0084] Antibodies (immunoglobulins) refer to proteins with structures that are substantially similar to native antibody structures. "Native antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, the native immunoglobulin of the IgG class is a heterotetrameric glycoprotein of about 150,000 daltons, which is composed of two light chains and two heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy chain domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3), also referred to as a heavy chain constant region. Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain, also referred to as a light chain constant region. The subunit structure and three-dimensional configuration of different classes of immunoglobulins are well known and generally described in, for example, Abbas et al., 2000, Cellular and Mol and Kindt et al., Kuby Immunology, 6th edition, WH Freeman and Co., page 91 (2007). Antibodies (immunoglobulins) are classified into different classes depending on the amino acid sequence of the heavy chain constant domain. There are five main classes of antibodies: α (IgA), δ (IgD), ε (IgE), γ (IgG) or μ (IgM), some of which can be further divided into subtypes, such as γ1 (IgG1), γ2 (IgG2), γ3 (IgG3), γ4 (IgG4), α1 (IgA1) and α2 (IgA2). The light chain of an immunoglobulin can be classified into one of two types (called κ (kappa) and λ (lambda)) based on the amino acid sequence of its constant domain. Immunoglobulins are essentially composed of two Fab molecules and an Fc domain connected via an immunoglobulin hinge region.

[0085] As used herein, "Fc" or "Fc region" or "Fc domain" refers to the C-terminal region of an antibody heavy chain that contains at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. Fc may refer to the last two constant region immunoglobulin domains (e.g., CH2 and CH3) of IgA, IgD, and IgG; the last three constant region immunoglobulin domains of IgE and IgM; and optionally, all or part of the flexible hinge at the N-terminus of these domains. For IgA and IgM, Fc may include a J chain. The IgG Fc region includes the IgG CH2 and IgG CH3 domains, and in some cases, includes a hinge. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. The "hinge" region generally extends from about the amino acid residue at position 216 to about the amino acid residue at position 230. The hinge region herein may be a native hinge domain or a variant hinge domain. The "CH2 domain" of the human IgG Fc region generally extends from about the amino acid residue at position 231 to about the amino acid residue at position 340. The CH2 domain herein may be a native sequence CH2 domain or a variant CH2 domain. The "CH3 domain" comprises an extension of the C-terminal residue of the CH2 domain in the Fc region, from about the amino acid residue at position 341 of IgG to about the amino acid residue at position 447. The CH3 region herein may be a native sequence CH3 domain or a variant CH3 domain (e.g., a CH3 domain having an introduced "protrusion" ("knob") in one of its chains and a correspondingly introduced "cavity" ("mortise") in the other chain; see U.S. Patent No. 5,821,333, expressly incorporated herein by reference). Thus, the definition of "Fc domain" includes amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3) or fragments thereof. An "Fc fragment" herein may contain fewer amino acids from either or both of the N-terminus and the C-terminus, but still be able to form a dimer with another Fc domain or Fc fragment, as can be detected using standard methods, typically based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.). In the present disclosure, a human IgG Fc domain has a specific use and may be an Fc domain from human IgG1, IgG2, or IgG4.

[0086] "Variant Fc domain" or "Fc variant" or "variant Fc" contains amino acid modifications (e.g., substitutions, additions, and deletions) compared to the parent Fc domain. The term also includes naturally occurring allele variants of the Fc region of an immunoglobulin. In general, the variant Fc domain has at least about 80%, 85%, 90%, 95%, 97%, 98% or 99% identity to the corresponding parent human IgG Fc domain (using the identity algorithm discussed below, one embodiment utilizing the BLAST algorithm as known in the art, using default parameters). Alternatively, the variant Fc domain may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid modifications compared to the parent Fc domain. For example, the N-terminus or C-terminus of the Fc region of an immunoglobulin may lack one or more amino acids without substantial loss of biological function. Additionally, as discussed herein, the variant Fc domains herein are still capable of forming a dimer with another Fc domain as measured using known techniques such as non-denaturing gel electrophoresis as described herein.

[0087] As used herein, "Fcγ receptor," "FcγR," or "FcγR" means any member of a family of proteins that binds to the Fc region of an IgG antibody and is encoded by a FcγR gene. In humans, this family includes, but is not limited to, FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, incorporated by reference in its entirety), as well as any undiscovered human FcγR or FcγR isoform or allotype. FcγRs can be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcγRs include but are not limited to FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as any undiscovered mouse FcγR or FcγR isoform or allotype.

[0088] As used herein, "effector function" refers to a biochemical event caused by the interaction of an antibody Fc region with an Fc receptor or ligand, which varies with the antibody isotype. Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), cytokine secretion, antigen uptake by antigen-presenting cells mediated by immune complexes, cell surface receptors (e.g., B cell receptors) downregulation, and B cell activation. "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcR (such as natural killer (NK) cells, neutrophils, and macrophages) recognize antibodies bound to target cells and subsequently dissolve the target cells. ADCC is associated with FcγRIIIa binding; FcγRIIIa binding increases ADCC activity. In order to assess the ADCC activity of related molecules, an in vitro ADCC analysis, such as that described in U.S. Patent Nos. 5,500,362 or 5,821,337, may be performed. As used herein, "ADCP" or antibody-dependent cell-mediated phagocytosis refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγRs recognize bound antibodies on a target cell and subsequently induce phagocytosis of the target cell.

[0089] "Fc null" and "Fc null variant" are used interchangeably and are used herein to describe a modified Fc with reduced or abolished effector function. Such Fc null or Fc null variants have reduced or abolished FcγR and / or complement receptors. Preferably, the effector function of such Fc null or Fc null variant is abolished. Exemplary methods of modification include, but are not limited to, chemical alteration, amino acid residue substitution, insertion, and deletion. Exemplary amino acid positions (numbered based on the Eu numbering scheme) of Fc molecules where one or more modifications are introduced to reduce the effector function of the resulting variant are the following positions: i) IgG1: C220, C226, C229, E233, L234, L235, G237, P238, S239 D265, S267, N297, L328, P331, K322, A327 and P329, ii) IgG2: V234, G237, D265, H268, N297, V309, A330, A331, K322, and iii) IgG4: L235, G237, D265 and E318.Exemplary Fc molecules with reduced effector function include those with one or more of the following substitutions: i) IgG1: N297A, N297Q, N297G, D265A / N297A, D265A / N297Q, C220S / C226S / C229S / P238S, S267E / L328F, C226S / C229S / E233P / L234V / L235A, L234F / L235E / P 331S, L234A / L235A, L234A / L235A / G237A, L234A / L235A / G237A / K322A, L234A / L235A / G237A / A330 S / A331S, L234A / L235A / P329G, E233P / L234V / L235A / G236del / S239K, E233P / L234V / L235A / G236de l / S267K, E233P / L234V / L235A / G236del / S239K / A327G, E233P / L234V / L235A / G236del / S267K / A32 7G and E233P / L234V / L235A / G236del, L234A / L235A / G237 are missing; ii) IgG2: A330S / A331S, V234A / G237A, V2 34A / G237A / D265A, D265A / A330S / A331S, V234A / G237A / D265A / A330S / A331S and H268Q / V309L / A330S / A331S; iii) IgG4: L235A / G237A / E318A, D265A, L235A / G237A / D265A and L235A / G237A / D265A / E318A.

[0090] As used herein, "epitope" refers to a determinant that can specifically bind to the variable region of an antibody molecule called a paratope. An epitope is a molecular grouping such as an amino acid or a sugar side chain and generally has specific structural features and charge-to-mass ratio characteristics. A single antigen may have more than one epitope. An epitope may include amino acid residues that are directly involved in binding and other amino acid residues that are not directly involved in binding, such as amino acid residues that are effectively blocked by an antigen-binding peptide (in other words, the amino acid residues are within the footprint of the antigen-binding peptide). An epitope may be conformational or linear. An epitope generally includes at least 3 and more often includes at least 5 or 8-10 amino acids. Antibodies that recognize the same epitope can be verified in a simple immunoassay (e.g., "warehouse building") that shows the ability of one antibody to block the binding of another antibody to the target antigen.

[0091] As used herein, "joint" refers to a molecule that connects two polypeptide chains. The joint can be a polypeptide joint or a synthetic chemical joint (for example, see Protein Engineering, 9 (3), 299-305, disclosed in 1996). The length and sequence of the polypeptide joint are not particularly limited and can be selected by those skilled in the art according to the purpose. The polypeptide joint comprises one or more amino acids. In some embodiments, the polypeptide joint is a peptide with a length of at least 5 amino acids, preferably a length of 5 to 100, more preferably 10 to 50 amino acids. In one embodiment, the peptide joint is G, S, GS, SG, SGG, GGS and GSG (wherein G = glycine and S = serine). In another embodiment, the peptide linker is (GGGS)xGn (SEQ ID NO: 74) or (GGGGS)xGn (SEQ ID NO: 75) or (GGGGGS)xGn (SEQ ID NO: 76) or S(GGGS)xGn (SEQ ID NO: 386) or S(GGGGS)xGn (SEQ ID NO: 387) or S(GGGGGS)xGn (SEQ ID NO: 388), wherein x = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and n = 0, 1, 2 or 3. Preferably, the linker is (GGGGS)xGn, wherein x = 2, 3 or 4, and n = 0 (SEQ ID NO: 77); more preferably, the linker is (GGGGS)xGn, wherein x = 3 and n = 0 (SEQ ID NO: 78). In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:79) or SGGGGSGGGGSGGGGS (SEQ ID NO:389). Synthetic chemical linkers include cross-linking agents routinely used to cross-link peptides, such as N-hydroxysuccinimide (NHS), disuccinimidyl suberate (DSS), bis(succinimidyl) suberate (BS3), dithiobis(succinimidyl propionate) (DSP), dithiobis(succinimidyl propionate) (DTSSP), ethylene glycol bis(succinimidyl succinate) (EGS), ethylene glycol bis(sulfosuccinimidyl succinate) (sulfo-EGS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), bis[2-(succinimidyloxycarbonyloxy)ethyl]sulfone (BSOCOES), and bis[2-(succinimidyloxycarbonyloxy)ethyl]sulfone (sulfo-BSOCOES).

[0092] The term "polynucleotide" refers to an isolated nucleic acid molecule or construct encoding a polypeptide of the present disclosure, such as messenger RNA (mRNA), viral RNA or plasmid DNA (pDNA). A polynucleotide may contain conventional phosphodiester bonds or unconventional bonds (e.g., amide bonds, such as those found in peptide nucleic acids (PNA)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments present in a polynucleotide, such as DNA or RNA fragments. In some aspects, one or more vectors (especially expression vectors) comprising such nucleic acids are provided. On the one hand, a method for preparing a polypeptide of the present disclosure is provided, wherein the method includes culturing a host cell comprising a nucleic acid encoding the polypeptide under conditions suitable for expressing the polypeptide and recovering the polypeptide from the host cell. "Recombinant" means producing a protein in an exogenous host cell using recombinant nucleic acid technology. For the purposes of the present disclosure, a recombinantly produced protein expressed in a host cell is considered to be isolated, and a native or recombinant protein that has been separated, fractionated, or partially or substantially purified by any suitable technique is also considered to be isolated.

[0093] "Isolated," when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and / or recovered from a cell or cell culture expressing the polypeptide. Typically, an isolated polypeptide will be purified by at least one purification step. There is no desired level of purity; "purified" or "purified" means that the concentration of the target protein in the composition is increased relative to the concentration of contaminants compared to the starting material. As used herein, "isolated protein" refers to a target protein that is substantially free of other proteins with different binding specificities.

[0094] method

[0095] Certain aspects of the present disclosure relate to methods for treating chronic viral infections. In some embodiments, the method comprises administering an effective amount of a fusion protein of the present disclosure to an individual in need thereof. In some embodiments, the fusion protein comprises: a first part, the first part comprising an antibody or an antigen-binding fragment thereof, the antibody or its antigen-binding fragment specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and a second part, the second part comprising a cytokine, a chemokine or a growth factor, wherein the first part is fused to the second part directly or via a linker. In some embodiments, the individual is a human.

[0096] In some embodiments, the chronic viral infection is a chronic HBV infection. In some embodiments, the chronic HBV infection of the present disclosure refers to an HBV infection present in an individual for 6 months or longer.

[0097] In some embodiments, for example, before the fusion protein is applied, the individual suffers from or has been diagnosed with HBV infection, such as chronic HBV infection. Analysis for detecting HBV and diagnosing HBV infection is known in the art, and includes but is not limited to detecting HBV antigens in blood or plasma samples, such as detecting HBV nucleic acids (such as HBV DNA) and / or proteins, or detecting anti-HBV antigen antibodies. Exemplary HBV serology and virology markers include but are not limited to HBsAg, HBeAg, HBV DNA, anti-HBc IgM or IgG antibodies, anti-HBs and anti-HBe.

[0098] In some embodiments, the method results in an increase in HBV reactive CD8+T cells in the liver of an individual. In some embodiments, the method results in a decrease in the serum HBV DNA level of an individual, such as a decrease in the HBV DNA level in a serum sample obtained from an individual (e.g., as compared to the HBV DNA level in a serum sample obtained from an individual before administration, or as compared to a reference or reference value).

[0099] In some embodiments, the chronic viral infection is a human immunodeficiency virus (HIV) infection. In some embodiments, the HIV is HIV-1 or HIV-2.

[0100] In some embodiments, the individual suffers from or has been diagnosed with HIV infection, e.g., prior to administering the fusion protein. Assays for detecting HIV and diagnosing HIV infection are known in the art and include, but are not limited to, detecting HIV antigens (e.g., p24) in blood or plasma samples, e.g., detecting HIV nucleic acids (e.g., HIV RNA) and / or proteins, or detecting antibodies against HIV antigens.

[0101] In some embodiments, the method results in an increase in HIV-reactive CD8+ T cells in the individual. In some embodiments, the method results in a decrease in serum HIV RNA levels in the individual and / or a decrease in serum HIV antigen levels in the individual, e.g., as compared to HIV RNA or HIV antigen levels in a serum sample obtained from the individual prior to administration, or as compared to a reference or reference value).

[0102] In some embodiments, the chronic viral infection is a HBV / HIV co-infection. It is believed that 5-20% of all HIV-infected people worldwide are also co-infected with HBV (see, e.g., Singh, KP et al. (2017) AIDS 31(15):2035-2052). The liver-related mortality rate of this co-infected population can be 19 times higher than that of people infected with HBV alone, and 8 times higher than that of people infected with HIV alone, and the overall mortality rate and risk of hepatocellular carcinoma (HCC) are also higher. In some embodiments, for example, before administering the fusion protein, the individual suffers from or has been diagnosed with HBV / HIV co-infection.

[0103] In some embodiments, the methods of the present disclosure include administering an effective amount of a fusion protein described herein to an individual in need thereof. In some embodiments, the fusion protein comprises any of the anti-CD8 antibodies, antigen binding domains, or antibody fragments disclosed herein. Exemplary fusion proteins and their properties are provided below.

[0104] In some embodiments, the fusion protein induces the activation of cells expressing human CD8ab heterodimers with a potency at least 2 times, at least 5 times or at least 10 times higher than the activation of cells expressing human CD8aa homodimers. In some embodiments, the fusion protein induces the activation of CD8+T cells with a potency at least 2 times, at least 5 times or at least 10 times higher than the activation of NK cells. In some embodiments, the activation potency is measured by EC50, as assessed by cell proliferation, STAT5 phosphorylation and / or cytotoxic function (e.g., expression of IFNγ and / or granzyme B). Exemplary analysis is further described below.

[0105] The preferential activity of the targeted IL-2 fusion protein comprising a mutant IL-2 polypeptide on cells expressing the antigen is confirmed in an analysis containing antigen-expressing and antigen-non-expressing cells that also express IL-2Rβγ or IL-2Rαβγ. One such analysis is an in vitro analysis that measures STAT5 (pSTAT5) phosphorylation and / or expression of the proliferation marker Ki-67 in human immune cells (such as human peripheral blood and / or tumor-infiltrating immune cells) after exposure to the IL-2 polypeptide. In one form of analysis, the activity of the targeted IL-2 fusion protein on cells expressing the antigen and cells not expressing the antigen is measured to confirm the selectivity for cells expressing the antigen. In another form of analysis, the activity of the targeted IL-2 fusion protein comprising a mutant IL-2 polypeptide on cells expressing the antigen is compared with the activity of a non-targeted IL-2 fusion protein comprising the same mutant IL-2 polypeptide and a control antibody that does not recognize any antigen on cells expressing the antigen to confirm the extent of rescue of the mutant IL-2 polypeptide in signal transduction when fused to an antigen binding molecule.

[0106] In some embodiments, the activation of CD8b+IL-2Rβ+ cells by the fusion protein of the present disclosure containing a CD8b antigen binding molecule is at least 10 times, at least 50 times, or at least 100 times higher than the activation of CD8b-IL-2Rβ+ cells. In some embodiments, the activation of CD8b+IL-2Rβ+ cells by the fusion protein is 50 times, 100 times, or 200 times higher than that of a control antibody comprising a fusion molecule of the IL-2 mutant polypeptide and not binding to any antigen expressed on the cell. The cell activation by the IL-2 fusion protein is determined by measuring the expression of pSTAT5 or the cell proliferation marker Ki67 in the cell after treatment with the IL-2 fusion protein.

[0107] In some embodiments, the fusion proteins of the present disclosure show one or more of the following: binding to human CD8 and not blocking the interaction of CD8 with MHC class I; and, for example, activating CD8+T cells with a potency at least 10 times, 25 times, 50 times, 100 times, 250 times, 500 times, or 1000 times higher than the activation of NK cells. In some embodiments, the anti-CD8 antibodies or fusion proteins of the present disclosure can be analyzed, for example, by analyzing the activation state of CD8+T cells (e.g., after antigen stimulation) in the presence or absence of anti-CD8 antibodies or fusion proteins to determine whether they block the interaction of CD8 with MHC class I. In some embodiments, the activation of CD8+T cells and / or NK cells can be measured, for example, by analyzing one or more markers of proliferation (e.g., Ki67) (e.g., the proportion of treated cells expressing one or more markers), IL-2Rβ / γ downstream signaling, and / or STAT5 downstream signaling.

[0108] In some embodiments, the fusion protein of the present disclosure comprises: a first part, the first part comprising a human or humanized antibody or an antigen-binding fragment thereof that specifically binds to CD8b and / or CD8ab (e.g., any of the anti-CD8 antibodies described above); and a second part, the second part comprising a cytokine, a chemokine, or a growth factor. In some embodiments, the first part is directly fused to the second part. In some embodiments, the first part is fused to the second part via a linker. Exemplary and non-limiting illustrations of the fusion proteins of the present disclosure are depicted in Figure 2A Any anti-CD8 antibody disclosed herein (eg, specifically binding to human CD8b and / or human CD8ab) can be used in the methods and fusion proteins disclosed herein.

[0109] In some embodiments, the anti-CD8 antibodies of the present disclosure specifically bind to human CD8b and / or human CD8ab with an affinity at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or at least 200 times higher than their binding to human CD8a and / or human CD8aa expressed on, for example, natural killer (NK) cells (e.g., human NK cells). In some embodiments, the anti-CD8 antibodies of the present disclosure specifically bind to human CD8b and / or human CD8ab with an affinity at least 10 times higher than their binding to human CD8a and / or human CD8aa expressed on, for example, natural killer (NK) cells. In some embodiments, the human CD8b and / or human CD8ab are expressed on the surface of human cells (e.g., human T cells).

[0110] In some embodiments, the anti-CD8 antibodies of the present disclosure specifically bind to cells (e.g., human T cells) expressing human CD8ab heterodimers on the surface with an EC50 of less than 1000 nM. In some embodiments, the anti-CD8 antibodies of the present disclosure specifically bind to human CD8+T cells.

[0111] In some embodiments, the anti-CD8 antibodies of the present disclosure are human antibodies or antibody fragments. In some embodiments, human antibodies or antibody fragments include human CDR and framework sequences in the variable domain, such as isolated from humans or produced using a library containing human antibody sequences (such as CDR sequences). In some embodiments, the anti-CD8 antibodies of the present disclosure are humanized antibodies or antibody fragments. In some embodiments, humanized antibodies or antibody fragments include non-human CDRs (such as from mice, rabbits, goats, etc.) and human framework sequences in the variable domain. In some embodiments, people or humanized antibodies also include human Fc regions. In some embodiments, the human Fc region also includes one or more Fc mutations, for example, as disclosed herein. There are five main complete antibody categories: IgA, IgD, IgE, IgG, and IgM, and several of these categories can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant domains corresponding to different classes of antibodies are referred to as α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0112] A variety of definitions of CDR sequences of antibody variable domains are known in the art. Unless otherwise specified, CDR sequences are described herein according to the Kabat definition (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, NIH publication 91-3242, Bethesda MD (1991), volumes 1-3). However, other definitions are known and contemplated for use. For example, in some embodiments, the CDR sequences can be described by the Chothia definition (see, e.g., Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987). Depending on the specific CDR definition used, the precise framework sequences may also vary, but as known in the art, the first framework sequence (FW-1) refers to the sequence from the N-terminus of the VH or VL domain to the start of CDR-H1 / CDR-L1, the second framework sequence (FW-2) refers to the sequence from the end of CDR-H1 / CDR-L1 to the start of CDR-H2 / CDR-L2, the third framework sequence (FW-3) refers to the sequence from the end of CDR-H2 / CDR-L2 to the start of CDR-H3 / CDR-L3, and the fourth framework sequence (FW-4) refers to the sequence from the end of CDR-H3 / CDR-L3 to the C-terminal boundary of the VH or VL domain.

[0113] In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 3; and a VL domain comprising: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2, or 3 heavy chain CDRs of antibody xhCD8v1 (e.g., as shown in Tables 1-3) and / or 1, 2, or 3 light chain CDRs of antibody xhCD8v1 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising CDR-H1, CDR-H2, and CDR-H3 from sequence SEQ ID NO:58; and a VL domain comprising CDR-L1, CDR-L2, and CDR-L3 from sequence SEQ ID NO:59.

[0114] In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 179; and a VL domain comprising: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 182. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2, or 3 heavy chain CDRs of antibody xhCD8v8 (e.g., as shown in Tables 1-3) and / or 1, 2, or 3 light chain CDRs of antibody xhCD8v8 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising CDR-H1, CDR-H2, and CDR-H3 from sequence SEQ ID NO: 185; and a VL domain comprising CDR-L1, CDR-L2, and CDR-L3 from sequence SEQ ID NO: 186.

[0115] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 62, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 63. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v2 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v2 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 62; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 63.

[0116] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 64, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 65. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v3 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v3 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 64; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 65.

[0117] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 66, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 67. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v4 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v4 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 66; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 67.

[0118] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 31, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 32, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 68, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 69. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v5 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v5 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 68; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 69.

[0119] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 37, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 70, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 71. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v6 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v6 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are human. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 70; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 71.

[0120] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 43, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 44, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 45; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 72, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 73. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v7 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v7 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are human. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 72; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 73.

[0121] In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising: a CDR-H1 comprising an amino acid sequence X 1 X 2 AIS, where X 1 is S, K, G, N, R, D, T or G, and wherein X 2 is Y, L, H or F (SEQ ID NO: 259); CDR-H2 comprises the amino acid sequence X 1 X 2 X 3 PX 4 X 5 X 6 X 7 X 8 X 9 YX 10 QX 11 G, where X 1 G or H, X 2 I or F, X 3 I, N or M, X 4is G, N, H, S, R, I or A, X 5 A, N, H, S, T, F or Y, X 6 A, D or G, X 7 is T, E, K, V, Q or A, X 8 A or T, X 9 is N or K, X 10 is A or N, and X 11 is Q or T (SEQ ID NO: 260); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 , where X 1 D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 I or L, X 5 R, A, Q or S, X 6 is A or D, and X 7 is D, E, A or S (SEQ ID NO: 261); and a VL domain, the VL domain comprising: CDR-L1, which comprises the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, where X 1 R or G, X 2 A or T, X 3 For Q or E, X 4 is E, N, T, S, A, K, D, G, R or Q, X 5 is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2, which comprises the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 , where X 1 A or S, X 2 is T, S, E, Q or D, X 3 N, R, A, E or H, X 4 is Q or A, and X 5 is S or D (SEQ ID NO: 263); and CDR-L3, which comprises the amino acid sequence QX 1 X2 X 3 X 4 X 5 PWT, where X 1 is S, N, D, Q, A or E, X 2 is T, I or S, X 3 is Y, L or F, X 4 is D, G, T, E, Q, A, or Y, and X 5 is A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQL VQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 274), FW-2 comprising the sequence WVRQAPGQGLEWMG (SEQ ID NO: 275), FW-3 comprising the sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 276), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WYQ QKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GVPSRFSG SGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0122] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 227; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 245, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 246. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v9 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v9 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 245; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 246. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO:274), FW-2 comprising the sequence WVRQAPGQGLEWMG (SEQ ID NO:275), FW-3 comprising the sequence RVTITADESTSTAYMELSSLRSEDTA VYYCAR (SEQ ID NO:276), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0123] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 251, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 252. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO: 251; and the VL domain comprises the amino acid sequence SEQ ID NO: 252. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v12 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v12 (e.g., as shown in Tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 251; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 252. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO:274), FW-2 comprising the sequence WVRQAPGQGLEWMG (SEQ ID NO:275), FW-3 comprising the sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO:276), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277).In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GV PSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0124] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 253, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 254. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v13 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v13 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 253; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 254. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO:274), FW-2 comprising the sequence WVRQAPGQGLEWMG (SEQ ID NO:275), FW-3 comprising the sequence RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO:276), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0125] In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising: a CDR-H1 comprising an amino acid sequence X 1 YX 2 MS, where X 1 is S, D, E, A, or Q, and X 2 is A, G or T (SEQ ID NO: 268); CDR-H2 comprises the amino acid sequence DIX 1 X 2 X 3 GX 4 X 5 TX 6 YADSVKG, where X 1 is T, N, S, Q, E, H, R or A, X 2 is Y, W, F or H, X 3 is A, S, Q, E or T, X 4 G or E, X 5 is S or I, and X 6 is A or G (SEQ ID NO: 269); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 , where X 1 S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 D or S, X 6 is D, N, Q, E, S, T or L, X 7 is L, F, or M, and X 8is I, Y or V (SEQ ID NO: 270); and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), a CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and a CDR-L3 comprising the amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO:281), FW-2 comprising the sequence WVRQAPGKGLEWVS (SEQ ID NO:282), FW-3 comprising the sequence RF TISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:283), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO:284) or WGQG TLVTVSS (SEQ ID NO:285). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO:293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO:294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO:295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO:296).

[0126] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 230, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 231; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 247, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 248. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v10 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v10 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 247; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 248. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO:281), FW-2 comprising the sequence WVRQAPGKGLEWVS (SEQ ID NO:282), FW-3 comprising the sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:283), and / or FW-4 comprising the sequence WGQGTMVT VSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285).In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGT LSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising the sequence WYQQKP GQAPRLLIY (SEQ ID NO: 294), FW-3 comprising the sequence GIPDRFSGSGS GTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO: 296).

[0127] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 230, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 231; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 249, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 250. In some embodiments, the VH domain comprises the amino acid sequence SEQ ID NO: 249; and the VL domain comprises the amino acid sequence SEQ ID NO: 250. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v11 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v11 (e.g., as shown in Tables 1-3). In some embodiments, the antibody is humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 249; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 250. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO:281), FW-2 comprising the sequence WVRQAPGKGLEWVS (SEQ ID NO:282), FW-3 comprising the sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:283), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285).In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAV YYC (SEQ ID NO: 295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO: 296).

[0128] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 237, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 231; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 255, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 256. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v14 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v14 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 255; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 256. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO:281), FW-2 comprising the sequence WVRQAPGKGLEWVS (SEQ ID NO:282), FW-3 comprising the sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:283), and / or FW-4 comprising the sequence WGQGTMVT VSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285).In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGT LSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising the sequence WYQQKP GQAPRLLIY (SEQ ID NO: 294), FW-3 comprising the sequence GIPDRFSGSGS GTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO: 296).

[0129] In some embodiments, an anti-CD8 antibody of the present disclosure comprises: a VH domain comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 237, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 231; and a VL domain comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 257, and / or the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 258. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise 1, 2 or 3 heavy chain CDRs of antibody xhCD8v15 (e.g., as shown in Tables 1-3) and / or 1, 2 or 3 light chain CDRs of antibody xhCD8v15 (e.g., as shown in Tables 1-3). In some embodiments, the antibodies are humanized. In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 from sequence SEQ ID NO: 257; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 from sequence SEQ ID NO: 258. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO:281), FW-2 comprising the sequence WVRQAPGKGLEWVS (SEQ ID NO:282), FW-3 comprising the sequence RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:283), and / or FW-4 comprising the sequence WGQGTMVT VSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285).In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGT LSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising the sequence WYQQKP GQAPRLLIY (SEQ ID NO: 294), FW-3 comprising the sequence GIPDRFSGSGS GTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO: 296).

[0130] In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:15; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:18. In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:53, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:21; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:24. In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30.In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:54, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:52, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:33; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:56, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:39; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:55, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:57, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:45; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48. In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 183, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 184, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182.

[0131] In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising: a CDR-H1 comprising the amino acid sequence GX 1 X 2 FX 3 X 4 X 5 , where X1 G, Y, S or A, X 2 is T, S, G, R, N or H, X 3 S, T, R, H, Y, G or P, X 4 is S, K, G, N, R, D, T, or G, and X 5 is Y, L, H or F (SEQ ID NO: 265); CDR-H2 comprises the amino acid sequence X 1 PX 2 X 3 X 4 X 5 , where X 1 I, N or M, X 2 is G, N, H, S, R, I or A, X 3 A, N, H, S, T, F or Y, X 4 is A, D, or G, and X 5 is T, E, K, V, Q or A (SEQ ID NO: 266); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 , where X 1 D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 I or L, X 5 R, A, Q or S, X 6 is A or D, and X 7 is D, E, A or S (SEQ ID NO: 267); and a VL domain, the VL domain comprising: CDR-L1, which comprises the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, where X 1 R or G, X 2 A or T, X 3 For Q or E, X 4 is E, N, T, S, A, K, D, G, R or Q, X 5 is Y or S, and X 6 A or V (SEQ ID NO: 262); CDR-L2, which comprises the amino acid sequence GX 1 X 2 X 3LX 4 X 5 , where X 1 A or S, X 2 is T, S, E, Q or D, X 3 N, R, A, E or H, X 4 is Q or A, and X 5 is S or D (SEQ ID NO: 263); and CDR-L3, which comprises the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, where X 1 is S, N, D, Q, A or E, X 2 is T, I or S, X 3 Y, L or F, X 4 is D, G, T, E, Q, A, or Y, and X 5 is A, T, R, S, K or Y (SEQ ID NO: 264). In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO: 278), FW-2 comprising the sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO: 279), FW-3 comprising the sequence ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 280), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO: 277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO:290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO:291), and / or FW-4 comprising the sequence FGGGTKVEIK (SEQ ID NO:292).

[0132] In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 239, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO:278), FW-2 comprising the sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO:279), FW-3 comprising the sequence ANYAQKFQGRVTITADEST STAYMELSSLRSEDTAVYYCAR (SEQ ID NO:280), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTIT C (SEQ ID NO: 289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO: 291), and / or FW-4 comprising the sequence FGGGTKVEI K (SEQ ID NO: 292).

[0133] In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO:278), FW-2 comprising the sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO:279), FW-3 comprising the sequence ANYAQKFQGRVTITADEST STAYMELSSLRSEDTAVYYCAR (SEQ ID NO:280), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTIT C (SEQ ID NO: 289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO: 291), and / or FW-4 comprising the sequence FGGGTKVEI K (SEQ ID NO: 292).

[0134] In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 238, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence QVQLVQSGAEVKKPGSSVKVSCKAS (SEQ ID NO:278), FW-2 comprising the sequence AISWVRQAPGQGLEWMGGI (SEQ ID NO:279), FW-3 comprising the sequence ANYAQKFQGRVTITADEST STAYMELSSLRSEDTAVYYCAR (SEQ ID NO:280), and / or FW-4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:277). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence DIQMTQSPSSLSASVGDRVTIT C (SEQ ID NO: 289), FW-2 comprising the sequence WYQQKPGKAPKLLIY (SEQ ID NO: 290), FW-3 comprising the sequence GVPSRFSGSGSGTDFTLTISSLQP EDFATYYC (SEQ ID NO: 291), and / or FW-4 comprising the sequence FGGGTKVEI K (SEQ ID NO: 292).

[0135] In some embodiments, the anti-CD8 antibodies of the present disclosure comprise: a VH domain comprising: a CDR-H1 comprising the amino acid sequence GFTFX 1 X 2 Y, where X 1 is S, D, E, Q, S, or A, and X 2 is S, D, E, A or Q (SEQ ID NO: 271); CDR-H2 comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 , where X 1 is T, N, S, Q, E, H, R or A, X 2 is Y, W, F or H, X 3 is A, S, Q, E or T, X 4is G or E, and X 5 is S or I (SEQ ID NO: 272); and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 , where X 1 S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 D or S, X 6 is D, N, Q, E, S, T or L, X 7 is L, F, or M, and X 8 is I, Y or V (SEQ ID NO: 273); and a VL domain, the VL domain comprising: a CDR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), a CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and a CDR-L3 comprising the amino acid sequence QQYGSSPPVT (SEQ ID NO: 42). In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGG SLRLSCAAS (SEQ ID NO: 286), FW-2 comprising the sequence AMSWVRQAP GKGLEWVSDI (SEQ ID NO: 287), FW-3 comprising the sequence TAYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 288), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO: 284) or WG QGTLVTVSS (SEQ ID NO: 285). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO:293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO:294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO:295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO:296).

[0136] In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:240, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:241, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:242; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:286), FW-2 comprising the sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO:287), FW-3 comprising the sequence TAYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:288), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO:293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO:294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO:295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO:296).

[0137] In some embodiments, the anti-CD8 antibody of the present disclosure comprises: a VH domain, wherein the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 244, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 242; and a VL domain, wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VH domain further comprises: FW-1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:286), FW-2 comprising the sequence AMSWVRQAPGKGLEWVSDI (SEQ ID NO:287), FW-3 comprising the sequence TAYADSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO:288), and / or FW-4 comprising the sequence WGQGTMVTVSS (SEQ ID NO:284) or WGQGTLVTVSS (SEQ ID NO:285). In some embodiments, the VL domain further comprises: FW-1 comprising the sequence EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 293), FW-2 comprising the sequence WYQQKPGQAPRLLIY (SEQ ID NO: 294), FW-3 comprising the sequence GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 295), and / or FW-4 comprising the sequence FGQGTKVEIK (SEQ ID NO: 296). In some embodiments, the present disclosure provides an anti-CD8 antibody comprising: a VH domain comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of the single antibodies listed in Table 1; and a VL domain comprising the CD R-L1, CDR-L2, and CDR-L3 sequences of the single antibodies listed in Table 1. For example, the anti-CD8 antibody comprises six CDRs of antibodies xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xh CD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xh CD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14, ​​xhCD8v15, V9 family or V11 family shown in Table 1.In some embodiments, the present disclosure provides an anti-CD8 antibody comprising: a VH domain comprising CDR-H1, CDR-H2 and CDR-H3 sequences of a single antibody listed in Table 2; and a VL domain comprising CDR-L1, CDR-L2 and CDR-L3 sequences of a single antibody listed in Table 2. For example, the anti-CD8 antibody comprises six CDRs of antibodies xhCD8v1, xhCD 8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14, ​​xhCD8v15, V9 family or V11 family shown in Table 2. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD8 antibody, wherein the anti-CD8 antibody comprises: a VH domain, wherein the VH domain comprises the CDR-H1, CDR-H2 and CDR-H3 sequences of the single antibodies listed in Table 1; and a VL domain, wherein the VL domain comprises the CDR-L1, CDR-L2 and CDR-L3 sequences of the single antibodies listed in Table 1. For example, the anti-CD8 antibody of the fusion protein comprises six CD Rs of the antibodies xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14, ​​xhCD8v15, V9 family or V11 family shown in Table 1. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD8 antibody, wherein the anti-CD8 antibody comprises: a VH domain, wherein the VH domain comprises the CDR-H1, CDR-H2 and CDR-H3 sequences of the single antibodies listed in Table 2; and a VL domain, wherein the VL domain comprises the CDR-L1, CDR-L2 and CDR-L3 sequences of the single antibodies listed in Table 2. For example, the anti-CD8 antibody of the fusion protein comprises six CDRs of antibodies xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD 8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14, ​​xhCD8v15, V9 family or V11 family shown in Table 2.In some embodiments, the present disclosure provides an anti-CD8 antibody comprising: a VH domain, wherein the VH domain comprises the CDR-H1, CDR-H2 and CDR-H3 sequences of the VH domain listed in Table 3; and a VL domain, wherein the VL domain comprises the CDR-L1, CDR-L2 and CDR-L3 sequences of the VL domain listed in Table 3 (in some embodiments, the VH and VL domains are from the same single antibody listed in Table 3). For example, the anti-CD8 antibody comprises the VH and VL of antibody xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14 or xhCD8v15 shown in Table 3. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD8 antibody, the anti-CD8 antibody comprising: a VH domain, the VH domain comprising the CDR-H1, CDR-H2 and CDR-H3 sequences of the VH domain listed in Table 3; and a VL domain, the VL domain comprising the CDR-L1, CDR-L2 and CDR-L3 sequences of the VL domain listed in Table 3 (in some embodiments, the VH and VL domains are from the same single antibody listed in Table 3). In some embodiments, the present disclosure provides an anti-CD8 antibody comprising the VH domain sequence and the VL domain sequence of the single antibody as listed in Table 3. In some embodiments, the present disclosure provides a fusion protein comprising an anti-CD8 antibody, the anti-CD8 antibody comprising the VH domain sequence and the VL domain sequence of the single antibody as listed in Table 3. For example, the anti-CD8 antibody of the fusion protein comprises the VH and VL of the antibody xhCD8v1, xhCD8v1.1, xhCD8v2, xhCD8v3, xhCD8v4, xhCD8v5, xhCD8v6, xhCD8v7, xhCD8v8, xhCD8v9, xhCD8v10, xhCD8v11, xhCD8v12, xhCD8v13, xhCD8v14 or xhCD8v15 shown in Table 3.

[0138] Table 1. Anti-CD8 Antibody CDR (Kabat)

[0139]

[0140]

[0141]

[0142] Table 2. Anti-CD8 Antibody CDR (Chothia)

[0143]

[0144]

[0145]

[0146] Table 3. Anti-CD8 antibody variable domain sequences

[0147]

[0148]

[0149]

[0150] In some embodiments, the first part comprises an antibody (e.g., an anti-CD8 antibody of the present disclosure). In some embodiments, the first part comprises an antibody fragment (e.g., an anti-CD8 antibody fragment of the present disclosure). In some embodiments, the first part comprises a single-chain antibody or a single-chain variable fragment (scFv). In some embodiments, the first part comprises a VHH antibody. In some embodiments, the first part comprises one or two antibody heavy chain polypeptides (e.g., an anti-CD8 antibody of the present disclosure) and one or two antibody light chain polypeptides. In some embodiments, the first part comprises 3 heavy chain CDRs and / or 3 light chain CDRs of a single anti-CD8 antibody of the present disclosure, for example, as shown in Tables 1-3. In some embodiments, the first part comprises the VH and / or VL domains of a single anti-CD8 antibody of the present disclosure, for example, as shown in Table 3. In some embodiments, the first part also comprises one or two human IgG Fc domains. In some embodiments, the one or two human IgG Fc domains are IgG1, IgG2, IgG3, or IgG4 Fc domains. In some embodiments, the one or two human IgG Fc domains do not have a C-terminal lysine residue. In some embodiments, the one or both human IgG Fc domains comprise amino acid modifications (such as substitutions, deletions, additions, etc.). In some embodiments, the Fc domain modifications promote heterodimer formation (e.g., as shown in Table 4). In some embodiments, the one or both Fc domains comprise Fcγ null mutations.

[0151] In some embodiments, the first portion comprises: two antibody heavy chain polypeptides, the antibody heavy chain polypeptides comprising, from N-terminus to C-terminus, a structure according to formula [I]:

[0152] VH-CH1-hinge-CH2-CH3[I]

[0153] and two antibody light chain polypeptides, the antibody light chain polypeptides comprising, from N-terminus to C-terminus, a structure according to formula [II]:

[0154] VL-CL[II]

[0155] wherein VH is the VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain. In some embodiments, the N-terminus of the second portion is fused to the C-terminus of one of the two CH3 domains (see, e.g., Figure 2A Form A).

[0156] In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide, the first antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [I]:

[0157] VH-CH1-hinge-CH2-CH3[I],

[0158] An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus:

[0159] VL-CL[II],

[0160] and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]:

[0161] Hinge-CH2-CH3[III],

[0162] wherein VH is the VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain. In some embodiments, the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide (see, e.g., Figure 2A In some embodiments, the N-terminus of the second portion is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide.

[0163] In some embodiments, the first portion comprises: a first antibody heavy chain polypeptide, the first antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [I]:

[0164] VH-CH1-hinge-CH2-CH3[I],

[0165] An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus:

[0166] VL-CL[II],

[0167] and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]:

[0168] Hinge-CH2-CH3[III],

[0169] wherein VH is the VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is the VL domain, and wherein CL is an antibody constant light chain domain. In some embodiments, the C-terminus of the second portion is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide (see, e.g., Figure 2A in the form C).

[0170] In some embodiments, the anti-CD8 antibodies of the present disclosure are multispecific (e.g., bispecific) antibodies or antibody fragments. For example, in some embodiments, the multispecific antibody (e.g., bispecific antibody) comprises a first antigen binding domain that binds to CD8 (e.g., as described above) and a second antigen binding domain that binds to a target of interest. In some embodiments, bispecific antibodies can be produced by fusing additional binding sites to the heavy or light chains of immunoglobulins. Examples of additional binding sites include, but are not limited to, variable regions, scFv, Fab, VHH, and peptides.

[0171] In some embodiments, the recombinant bispecific antibodies disclosed herein can be classified into two categories, i.e., i) a form produced by a combination of only variable regions and ii) a form of combining variable regions with Fc domains. Representatives of the first category are tandem scFv (taFv), bifunctional antibodies (Db), DART, single-chain bifunctional antibodies (scDb), Fab-Fc, tandem Fab, dual variable region Fab, and tandem dAb / VHH. The two variable regions can be linked together via covalent bonds or non-covalent interactions.

[0172] Non-covalent interactions can involve the use of heterodimerization modules such as leucine zippers, dock-and-lock approaches using regulatory subunits of cAMP-dependent protein kinase (PKA) and the anchor domain or knob-in-hole CH3 domain of A kinase anchoring protein (AKAP) (U.S. Pat. No. 5,731,168; U.S. Pat. No. 7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996) and Carter, J Immunol Meth 248, 7-15 (2001)) to pair the variable regions.

[0173] In some embodiments, bispecific antibodies are produced on a natural immunoglobulin framework containing two pairs of heavy and light chain combinations, each pair having different binding specificities. The homodimerization of the two heavy chains in IgG is mediated by CH3 interactions. To promote heterodimer formation, genetic modifications are introduced into two separate CH3 regions. These heterodimerization mutations generally involve steric repulsion, charge steering interactions, or interchain disulfide bond formation. Exemplary and non-limiting Fc modifications that promote heterodimerization include the following:

[0174] Table 4. Exemplary Fc modifications that promote heterodimerization.

[0175]

[0176]

[0177]

[0178] In some embodiments, bispecific antibodies can be produced by post-production assembly of half antibodies, thereby solving the heavy chain and light chain mispairing problem. These antibodies generally contain modifications that are conducive to heterodimerization of half antibodies. Exemplary systems include, but are not limited to, knobs and holes, IgG1 (EEE-RRR), IgG2 (EEE-RRRR) (Strop et al. J Mol Biol (2012)) and DuoBody (F405L-K409R), listed in Table 5. In such cases, half antibodies are individually produced in separate cell lines and purified. The purified antibodies are then mildly reduced to obtain half antibodies, which are then assembled into bispecific antibodies. The heterodimeric bispecific antibodies are then purified from the mixture using conventional purification methods.

[0179] In some embodiments, strategies for producing bispecific antibodies that do not rely on preferential chain pairing can also be employed. These strategies generally involve introducing genetic modifications on the antibody in such a way that the heterodimer will have different biochemical or biophysical properties than the homodimer; thus, the heterodimer can be selectively purified from the homodimer after assembly or expression. An example is the introduction of H435R / Y436F in the IgG1 CH3 domain to eliminate the binding of Fc to the protein A resin and the subsequent co-expression of the H435R / Y436F variant with a wild-type Fc. The resulting homodimeric antibody containing two copies of H435R / Y436F cannot bind to the protein A column, while the heterodimeric antibody containing one copy of the H435R / Y436F mutation will have a reduced affinity for protein A compared to the strong interaction of the homodimeric wild-type antibody (Tustian et al. Mabs 2016). Other examples include kappa / lambda antibodies (Fischer et al., Nature Communication 2015) and the introduction of different charges on individual chains (E357Q, S267K or N208D / Q295E / N384D / Q418E / N421D) (US 2018 / 0142040 A1; (Strop et al. J Mol Biol (2012)).

[0180] In some embodiments, bispecific antibodies can be generated by fusing additional binding sites to the heavy or light chains of immunoglobulins.Examples of additional binding sites include, but are not limited to, variable regions, scFv, Fab, VHH, and peptides.

[0181] In some embodiments, the antibody or fusion protein of the present disclosure includes an Fc region. In some embodiments, the Fc region includes one or more mutations that reduce or eliminate FcγR binding and / or effector function. In some embodiments, the Fc region (e.g., IgG1 Fc region) includes a substitution at one or more of the following positions: C220, C226, C229, E233, L234, L235, G237, P238, S239, D265, S267, N297, L328, P331, K322, A327, and P329. In some embodiments, the Fc region (e.g., IgG2 Fc region) includes a substitution at one or more of the following positions: V234, G237, D265, H268, N297, V309, A330, A331, K322. In some embodiments, the Fc region (e.g., IgG4 Fc region) comprises a substitution at one or more of the following positions: L235, G237, D265, and E318. In some embodiments, the Fc region (e.g., IgG1 Fc region) comprises one or more of the following mutations or mutation groups: N297A, N297Q, N297G, D265A / N297A, D265A / N297Q, C220S / C226S / C229S / P238S, S267E / L328F, C226S / C229S / E233P / L234V / L235A, L234F / L235E / P331S, L234A / L235A, L234A / L235A / G237A, L234A / L235A / G237A / K322A, L234A / L235A / G237A / K322A, L234A / L235A / G237A / K322A. 7A / A330S / A331S, L234A / L235A / P329G, E233P / L234V / L235A / G236del / S239K, E233P / L234V / L235A / G236del / S267K, E233P / L234V / L235A / G236del / S239K / A327G, E233P / L234V / L235A / G236del / S267K / A327G and E233P / L234V / L235A / G236del, L234A / L235A / G237 are missing. In some embodiments, the Fc region (e.g., an IgG2 Fc region) comprises one or more of the following mutations or groups of mutations: A330S / A331S, V234A / G237A, V234A / G237A / D265A, D265A / A330S / A331S, V234A / G237A / D265A / A330S / A331S, and H268Q / V309L / A330S / A331S.In some embodiments, the Fc region (e.g., IgG4 Fc region) comprises one or more of the following mutations or mutation groups: L235A / G237A / E318A, D265A, L235A / G237A / D265A, and L235A / G237A / D265A / E318A. In some embodiments, the Fc region comprises one, two, three, or all of the following mutations: L234A, L235A, G237A, and K322A, numbered according to the EU index. In some embodiments, the Fc region comprises one, two, or all of the following mutations: L234A, L235A, and G237A, numbered according to the EU index.

[0182] In some embodiments, the first and second Fc domains of the fusion protein contain one or more of the following Fc mutations that reduce effector function according to EU numbering: L234A, L235A, G237A, and K322A. In some embodiments, the first and second Fc domains of the fusion protein contain the following Fc mutations that reduce effector function according to EU numbering: L234A, L235A, and G237A. In some embodiments, the first and second Fc domains of the fusion protein contain the following Fc mutations that reduce effector function according to EU numbering: L234A, L235A, G237A, and K322A. In some embodiments, the first and second Fc domains of the fusion protein contain the following amino acid substitutions that promote heterodimer formation: Y349C / T366W (knob) and S354C, T366S, L368A, and Y407V (hole).

[0183] In some embodiments, heterodimerization mutations and / or mutations that modify Fcγ receptor binding reduce Fc stability. Therefore, one or more additional mutations are added to the Fc region to increase its stability. For example, one or more disulfide bond pairs (such as A287C and L306C, V259C and L306C, R292C and V302C, and V323C and I332C) are introduced into the Fc region. Another example is the introduction of S228P into a bispecific antibody based on IgG4 to stabilize the hinge disulfide bond. Additional examples include the introduction of K338I, A339K, and K340S mutations to enhance Fc stability and aggregation resistance (Gao et al., 2019 Mol Pharm. 2019; 16: 3647).

[0184] In some embodiments, the second portion induces activation of CD8+T cells. In some embodiments, the second portion comprises a polypeptide that induces signal transduction via IL2Rβγ. For example, in some embodiments, the second portion comprises an IL-15 polypeptide (e.g., a human IL-15 polypeptide or a derivative thereof) or a neoleukin. In some embodiments, the second portion comprises an IL-21 polypeptide (e.g., a human IL-21 polypeptide or a derivative thereof).

[0185] In some embodiments, the second moiety comprises an IL-2 polypeptide (eg, a human IL-2 polypeptide or a derivative thereof).

[0186] In some embodiments, the binding affinity of the mutant IL-2 polypeptide to IL-2Rα is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rα. In some embodiments, the binding affinity of the mutant IL-2 polypeptide to IL-2Rβ is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rβ. In some embodiments, the binding affinity of the mutant IL-2 polypeptide to IL-2Rγ is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rγ. The difference in binding affinity of the wild-type and disclosed mutant polypeptides to IL-2Rα and IL-2Rβ can be measured, for example, in a standard surface plasmon resonance (SPR) assay that measures the affinity of protein-protein interactions familiar to those skilled in the art. The difference in binding affinity of the wild-type and disclosed mutant polypeptides to IL-2Rγ cannot be reliably measured by SPR analysis because the wild-type IL-2 polypeptide has a very low affinity for IL-2Rγ. Alternatively, its reduced IL-2Rγ affinity can be inferred by performing an in vitro assay that measures pSTAT5 and compares the activity of the IL-2 polypeptide in the presence and absence of IL-2Rγ affinity-reducing substitutions on IL-2R expressing cells. Exemplary sequences of IL-2Rα, IL-2Rβ, and IL-2Rγ are provided below.

[0187] IL-2Rα:

[0188] MDSYLLMWGLLTFIMVPGCQAELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATER IYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQVAVAGCVFLLISVLLLSGLTWQRRQRKSRRTI(SEQ ID NO:82)

[0189] IL-2Rβ:

[0190] (SEQ ID NO:83)

[0191] IL-2Rγ:

[0192] MLKPSLPFTSLLFLQLPLLGVGLNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET(SEQID NO:84)

[0193] In some embodiments, the IL-2 polypeptide is a mutant IL-2 polypeptide comprising one or more mutations relative to a human IL-2 polypeptide comprising the sequence APTSS STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKK ATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLEL KGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 81). In some embodiments, the mutant IL-2 polypeptide of the present disclosure has one or more, two or more, or three or more affinity-reducing amino acid substitutions relative to, for example, a wild-type mature IL-2 polypeptide having the amino acid sequence of SEQ ID NO: 81. In some embodiments, one or more, two or more, or three or more substituted residues are selected from the group consisting of Q11, H16, L18, L19, D20, D84, S87, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129, and S130. A reduced affinity for IL-2Rα may be obtained by substituting one or more of the following residues in the sequence of a wild-type mature IL-2 polypeptide: R38, F42, K43, Y45, E62, P65, E68, V69, and L72. Reduced affinity for IL-2Rβ may be obtained by substituting one or more of the following residues: E15, H16, L19, D20, D84, S87, N88, V91, and 192. Reduced affinity for IL-2Rγ may be obtained by substituting one or more of the following residues in the sequence of the wild-type mature IL-2 polypeptide: Q11, L18, Q22, T123, Q126, S127, 1129, and S130.

[0194] In some embodiments, the mutant IL-2 polypeptide comprises an F42A or F42K amino acid substitution relative to the wild-type mature IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises an F42A or F42K amino acid substitution and an R38A, R38D, R38E, E62Q, E68A, E68Q, E68K or E68R amino acid substitution relative to the wild-type mature IL-2 amino acid sequence. For example, in some embodiments, the mutant IL-2 polypeptide comprises F42A; R38A and F42A; R38D and F42A; R38E and F42A; F42A and E62Q; F42A and E68A; F42A and E68Q; F42A and E68K; F42A and E68R; or R38A and F42K amino acid substitutions relative to the wild-type mature IL-2 amino acid sequence, e.g., as shown in SEQ ID NO: 81. In some embodiments, the mutant IL-2 polypeptide comprises R38E and F42A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38D and F42A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises F42A and E62Q amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38A and F42K amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38D and F42A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38A and F42K amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises F42A and E62Q amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises H16E, H16D, D20N, M23A, M23R, M23K, D84L, D84N, D84V, D84H, D84Y, D84R, D84K, S87K, S87A, N88A, N88D, N88G, N88S, N88T, N88R, N88I, V91A, V91T, V91E, I92A, E95S, E95A, E95R, T123A, T123E, T123K, T123Q, Q126A, Q126S, Q126T, Q126E, S127A, S127E,S127K or S127Q amino acid substitution. In some embodiments, the mutant IL-2 polypeptide comprises F42A; R38A and F42A; R38D and F42A; R38E and F42A; F42A and E62Q; F42A and E68A; F42A and E68Q; F42A and E68K; F42A and E68R; or R38A and F42K amino acid substitutions relative to the wild-type mature IL-2 amino acid sequence; and relative to, for example, SEQ The wild-type mature IL-2 amino acid sequence shown in ID NO:81 comprises H16E, H16D, D20N, M23A, M23R, M23K, D84L, D84N, D84V, D84H, D84Y, D84R, D84K, S87K, S87A, N88A, N88D, N88G, N88S, N88T, N88R, N88I, V91A, V91T, V91E, I92A, E95S, E95A, E95R, T123A, T123E, T123K, T123Q, Q126A, Q126S, Q126T, Q126E, S127A, S127E, S127K or S127Q amino acid substitutions. For example, in some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and H16E amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and H16D amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and D84K amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and D84R amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and N88S amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and N88A amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and N88G amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and N88R amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and N88T amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A, and N88T amino acid substitutions relative to the wild-type IL-2 amino acid sequence.In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A and N88D amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A and V91E amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises R38E, F42A and Q126S amino acid substitutions relative to the wild-type IL-2 amino acid sequence. In some embodiments, the mutant IL-2 polypeptide comprises SEQ ID NO: 81 with one of the following amino acid substitution sets: The amino acid sequence of NO:81: R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F42A and N88S; R38E, F42A and N88A; R38E, F42A and N88G; R38E, F42A and N88R; R38E, F42A and N88T; R38E, F42A and N88D; R38E, F42A and V91E; R38E, F42A and D84H; R38E, F42A and D84K; R38E, F42A and D84R; H16D, R38E and F42A; H16E, R38E and F42A; R38E, F42A and Q126S; R38D, F42A and N88S; R38D, F42A and N88A; R38D, F42A and N88G; R38D, F42A and N88R; R38D, F42A and N88T; R38D, F42A and N88D; R38D, F42A and V91E; R38D, F42A and D84H; R38D, F42A and D84K; R38D, F42A and D84R; H16D, R3 8D and F42A; H16E, R38D and F42A; R38D, F42A and Q126S; R38A, F42K and N88S; R38A, F42K and N88A; R38A, F42K and N88G; R38A, F42K and N88R; R38A, F42K and N88T; R38A, F42K and N88D; R38A, F42K and V91E; R38A, F42K and D84H; R38A, F42K and D84K; R38A, F42K and D84R; H16D, R38A and F42 K; H16E, R38A and F42K; R38A, F42K and Q126S; F42A, E62Q and N88S; F42A, E62Q and N88A; F42A, E62Q and N88G; F42A, E62Q and N88R; F42A, E62Q and N88T; F42A, E62Q and N88D; F42A, E62Q and V91E; F42A, E62Q and D84H; F42A, E62Q and D84K; F42A, E62Q and D84R; H16D, F42A and E62Q; H16E,F42A and E62Q; F42A, E62Q and Q126S; R38E, F42A and C125A; R38D, F42A and C125A; F42A, E62Q and C125A; R38A, F42K and C125A; R38E, F42A, N88S and C125A; R38E, F42A, N88A and C125A; R38E, F42A, N88G and C125A; R38E, F42A, N88R and C125A; R38E, F42A, N88T and C125A; R38E, F42A, N88D and C125A; R38E, F42A, V91E and C125A; R38E, F42A, D84 H and C125A; R38E, F42A, D84K and C125A; R38E, F42A, D84R and C125A; H16D, R38E, F42A and C125A; H16E, R38E, F42A and C125A; R38E, F42A, C125A and Q126S; R38D, F42A, N 88S and C125A; R38D, F42A, N88A and C125A; R38D, F42A, N88G and C125A; R38D, F42A, N88R and C125A; R38D, F42A, N88T and C125A; R38D, F42A, N88D and C125A; R38D, F42A, V91E and C125A; R38D, F42A, D84H and C125A; R38D, F42A, D84K and C125A; R38D, F42A, D84R and C125A; H16D, R38D, F42A and C125A; H16E, R38D, F42A and C125A; R38D, F42A , C125A and Q126S; R38A, F42K, N88S and C125A; R38A, F42K, N88A and C125A; R38A, F42K, N88G and C125A; R38A, F42K, N88R and C125A; R38A, F42K, N88T and C125A; R38A, F4 2K, N88D and C125A; R38A, F42K, V91E and C125A; R38A, F42K, D84H and C125A; R38A, F42K, D84K and C125A; R38A, F42K, D84R and C125A; H16D, R38A, F42K and C125A; H16E, R 38A, F42K and C125A; R38A, F42K, C125A and Q126S; F42A, E62Q, N88S and C125A; F42A, E62Q, N88A and C125A; F42A, E62Q, N88G and C125A; F42A, E62Q, N88R and C125A; F42A,E62Q, N88T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V91E and C125A; F42A, E62Q and D84H and C125A; F42A, E62Q and D84K and C125A; F42A, E62Q and D84R and C125A; H16D, F42A, E62Q and C125A; H16E, F42A, E62Q and C125A; F42A, E62Q, C125A and Q126S; F42A, N88S and C12 5A; F42A, N88A and C125A; F42A, N88G and C125A; F42A, N88R and C125A; F42A, N88T and C125A; F42A, N88D and C125A; F42A, V91E and C125A; F42A, D84H and C125A; F42A, D84K and C125A; F42A, D84R and C125A; H16D, F42A and C125A; H16E, F42A and C125A; and F42A, C125A and Q126S. In some embodiments, the IL-2 polypeptide comprises a sequence of SEQ ID NO: 81 having one, two, three, four or five amino acid substitutions relative to SEQ ID NO: 81, and wherein the one, two, three, four or five substitutions comprise substitutions at positions of SEQ ID NO: 81 selected from the group consisting of: Q11, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, I92, T123, Q126, S127, I129 and S130. In some embodiments, the IL-2 polypeptide comprises a sequence of SEQ ID NO: 81 having one of the following amino acid substitution sets (relative to sequence SEQ ID NO: 81): NO:81: R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F42A and N88S; R38E, F42A and N88A; R38E, F42A and N88G; R38E, F42A and N88R; R38E, F42A and N88T; R38E, F42A and N88D; R38E, F42A and V91E; R3 8E, F42A and D84H; R38E, F42A and D84K; R38E, F42A and D84R; H16D, R38E and F42A; H16E, R38E and F42A; R38E, F42A and Q126S; R38D, F42A and N88S; R38D, F42A and N88A; R38D, F42A and N88G; R38D, F42A and N88R; R38D,F42A and N88T; R38D, F42A and N88D; R38D, F42A and V91E; R38D, F42A and D84H; R38D, F42A and D84K; R38D, F42A and D84R; H16D, R38D and F42A; H16E, R38D and F42A; R38D, F42A and Q126S; R38A, F42K and N88S; R38A, F42K and N88A; R38A, F42K and N88G; R38A, F42K and N88R; R38A, F42K and N88T; R38A, F42K and N88D; R38A, F42K and V91E; R38 A, F42K and D84H; R38A, F42K and D84K; R38A, F42K and D84R; H16D, R38A and F42K; H16E, R38A and F42K; R38A, F42K and Q126S; F42A, E62Q and N88S; F42A, E62Q and N88A; F42A, E62Q and N88G; F42A, E62Q and N88R; F42A, E62Q and N88T; F42A, E62Q and N88D; F42A, E62Q and V91E; F42A, E62Q and D84H; F42A, E62Q and D84K; and F42A, E62Q and D84R.

[0195] In some embodiments, the IL-2 polypeptide comprises the sequence SEQ ID NO: 81 having another amino acid substitution at position C125 relative to SEQ ID NO: 81. In some embodiments, the IL-2 polypeptide comprises the sequence SEQ ID NO: 81 having one of the following amino acid substitution sets (relative to the sequence SEQ ID NO: 81): NO:81: R38E, F42A and C125A; R38D, F42A and C125A; F42A, E62Q and C125A; R38A, F42K and C125A; R38E, F42A, N88S and C125A; R38E, F42A, N88A and C125A; R38E, F42A, N88G and C125A; R38E, F42A, N88R and C125A; R38E, F42A, N88D and C125A; R38E, F42A, N88T and C125A; R38E, F42A, V91E and C125A; R38E, F42A, D84H and C125A; R38E, F42A, D84K and C125A; R38E, F42A, D84R and C125A; H16D, R38E, F42A and C125A; H16E, R38E, F42A and C125A; R38E, F42A, C125A and Q126S; R38D, F42A, N88S and C125A; R38D, F42A, N88A and C125A; R38D, F42A, N88G and C125A; R38D, F42A, N88R and C125A; R38D, F42A 2A, N88T and C125A; R38D, F42A, N88D and C125A; R38D, F42A, V91E and C125A; R38D, F42A, D84H and C125A; R38D, F42A, D84K and C125A; R38D, F42A, D84R and C125A; H16D, R38D, F42A and C125A; H16E, R38D, F42A and C125A; R38D, F42A, C125A and Q126S; R38A, F42K, N88S and C125A; R38A, F42K, N88 G and C125A; R38A, F42K, N88R and C125A; R38A, F42K, N88T and C125A; R38A, F42K, N88D and C125A; R38A, F42K, N88A and C125A; R38A, F42K, V91E and C125A; R38A, F42K, D84H and C125A; R38A, F42K, D84K and C125A; R38A, F42K, D84R and C125A; H16D, R38A, F42K and C125A; H16E, R38A, F42K and C125A;R38A, F42K, C125A and Q126S; F42A, E62Q, N88S and C125A; F42A, E62Q, N88A and C125A; F42A, E62Q, N88G and C125A; F42A, E62Q, N88R and C125A; F42A, E62Q, N88T and C125A ; F42A, E62Q, N88D and C125A; F42A, E62Q, V91E and C125A; F42A, E62Q and D84H and C125A; F42A, E62Q and D84K and C125A; F42A, E62Q and D84R and C125A; H16D, F42A, E62Q and C125A; H16E, F42A, E62Q and C125A; F42A, E62Q, C125A and Q126S; F42A, N88S and C125A; F42A, N88A and C125A; F42A, N88G and C125A; F42A, N88R and C125A; F42A, N88T and C125A; F42A , N88D and C125A; F42A, V91E and C125A; F42A, D84H and C125A; F42A, D84K and C125A; F42A, D84R and C125A; H16D, F42A and C125A; H16E, F42A and C125A; and F42A, C125A and Q126S. ;

[0196] In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 80). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 85). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 86). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 87). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 88).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSST KKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKAT ELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKG SETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 89). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELK HLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSET TFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 90). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQ LQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 91). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQ CLEEELKPLEEVLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 92). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMC EYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 93).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLE EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 94). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLE EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCSSIISTLT (SEQ ID NO: 95). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLL LDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEE LKPLEEVLNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYA DETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 96). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLL DLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEEL KPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 97). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDL QMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKP LEEVLNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADET ATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 98).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEE VLNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATI VEFLNRWITFCQSIISTLT (SEQ ID NO: 99). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 100). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 101). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCSSIISTLT (SEQ ID NO: 102). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 103).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 104). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 105). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 106). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 107). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 108).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCSSIISTLT (SEQ ID NO: 109). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 110). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 111). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 112). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 113).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 114). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 115). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCSSIISTLT (SEQ ID NO: 116). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 117). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 118).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 119). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 120). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 121). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 122). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 123).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 124). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 125). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 126). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 127). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 128).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 129). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 130). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 131). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 132). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 133).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFASSIISTLT (SEQ ID NO: 134). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 135). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 136). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 137). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 138).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 139). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 140). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFASSIISTLT (SEQ ID NO: 141). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 142). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 143).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 144). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 145). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 146). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 147). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 148).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISSINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 149). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 150). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINEIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 151). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRHLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 152). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEDLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 153).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 154). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFASSIISTLT (SEQ ID NO: 155). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 190). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 191). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 192).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 193). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 194). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 195). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 196). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 197).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 198). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 199). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 200). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 201). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 202).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 203). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 204). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 205). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 206). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 207).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 208). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 209). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 210). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 211). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 212).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 213). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISGINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 214). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRKLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 215). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRRLISNINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 216). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 297).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 354). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 355). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 356). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 357). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 358).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 359). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 360). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 361). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 362). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 363).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 364). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 365). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 366). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFCQSIISTLT (SEQ ID NO: 367). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIV EFLNRWITFCQSIISTLT (SEQ ID NO: 368).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 369). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 370). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 371). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 372). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 373).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTDMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 374). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 375). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 376). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTKKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 377). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 378).In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 379). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEQLKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 380). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 381). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISTINVIVLELKGSETTFMCEYADETATIVE FLNRWITFAQSIISTLT (SEQ ID NO: 382). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISDINVIVLELKGSETTFMCEYADETATIV EFLNRWITFAQSIISTLT (SEQ ID NO: 383). In some embodiments, the mutant IL-2 polypeptide comprises the amino acid sequence of an IL-2 polypeptide listed in Table 7.

[0197] Table 7. Exemplary IL-2 polypeptide sequences

[0198]

[0199]

[0200]

[0201] In some embodiments, the mutant IL-2 polypeptides of the present disclosure also contain other modifications that provide additional advantages such as improved biophysical properties, including but not limited to mutations and deletions. Improved biophysical properties include, but are not limited to, improved thermal stability, aggregation tendency, acid reversibility, viscosity, and yield in mammalian or bacterial or yeast cells. For example, residue C125 can be replaced with a neutral amino acid such as serine, alanine, threonine, or valine; and the N-terminal A1 residue may be deleted, both of which are described in U.S. Patent No. 4,518,584. The mutant IL-2 polypeptide may also include a mutation of residue M104, such as M104A, as described in U.S. Patent No. 5,206,344. Therefore, in certain embodiments, the mutant IL-2 polypeptides of the present disclosure comprise the amino acid substitution C125A. In other embodiments, one, two, or three N-terminal residues are deleted.

[0202] In some embodiments, the fusion protein of the present disclosure comprises a linker. In some embodiments, the linker is a chemical linker (eg, as disclosed in Protein Engineering, 9(3), 299-305, 1996). Synthetic chemical linkers include cross-linking agents routinely used to cross-link peptides, such as N-hydroxysuccinimide (NHS), disuccinimidyl suberate (DSS), bis(succinimidyl) suberate (BS3), dithiobis(succinimidyl propionate) (DSP), dithiobis(succinimidyl propionate) (DTSSP), ethylene glycol bis(succinimidyl succinate) (EGS), ethylene glycol bis(sulfosuccinimidyl succinate) (sulfo-EGS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), bis[2-(succinimidyloxycarbonyloxy)ethyl]sulfone (BSOCOES), and bis[2-(succinimidyloxycarbonyloxy)ethyl]sulfone (sulfo-BSOCOES).

[0203] In some embodiments, the linker is an amino acid-based or peptide-based linker. In some embodiments, the polypeptide linker is a peptide of at least 5 amino acids in length, preferably 5 to 100, more preferably 10 to 50 amino acids in length. In one embodiment, the peptide linker is G, S, GS, SG, SGG, GGS and GSG (wherein G = glycine and S = serine). In some embodiments, the linker comprises the sequence (GGGS)xGn (SEQ ID NO: 74), (GGGGS)xGn (SEQ ID NO: 75), (GGGGGS)xGn (SEQ ID NO: 76), S (GGGS)xGn (SEQ ID NO: 386), S (GGGGS)xGn (SEQ ID NO: 387) or S (GGGGGS)xGn (SEQ ID NO: 388), wherein x = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein n = 0, 1, 2 or 3. In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:79) or SGGGGSGGGGSGGGGS (SEQ ID NO:389).

[0204] In some embodiments, the fusion proteins of the present disclosure comprise one, two or all three polypeptides shown in Table 5 for a single fusion protein. In some embodiments, the fusion proteins of the present disclosure comprise two light chains of a single fusion protein in Table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain that does not comprise an IL-2 fusion. As is known in the art, the C-terminal lysine of some antibody heavy chain species can be cleaved in a portion of the molecule. Therefore, in some embodiments, the fusion proteins of the present disclosure comprise two light chains of a single fusion protein in Table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain that does not comprise an IL-2 fusion, wherein the heavy chain that does not comprise an IL-2 fusion comprises the sequence of the respective fusion protein SEQ ID No: 158, 161, 164, 167, 170, 173, 176, 189, 300, 304, 308, 312, 326, 320, 324, 328, 332, 336, 340, 344, 348 or 352. In some embodiments, the fusion protein of the present disclosure comprises two light chains of a single fusion protein in Table 5, a heavy chain comprising an IL-2 fusion, and a heavy chain not comprising an IL-2 fusion, wherein the heavy chain not comprising an IL-2 fusion comprises the sequence of the respective fusion protein SEQ ID No: 217-224, 301, 305, 309, 313,...

Claims

1. A method for treating hepatitis B virus (HBV) and / or human immunodeficiency virus (HIV) infection, the method comprising administering to an individual in need thereof an effective amount of a fusion protein, the fusion protein comprising: (a) a first part, the first part comprising an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof specifically binding to human CD8b and / or human CD8ab with an affinity at least 10 times higher than its binding to human CD8a and / or human CD8aa; and (b) a second part, the second part comprising a cytokine, a chemokine or a growth factor, wherein the first part is fused to the second part directly or via a linker.

2. The method of claim 1, wherein the HBV infection is a chronic HBV infection.

3. The method of claim 1 or claim 2, wherein the administration results in an increase in HBV-reactive CD8+ T cells in the liver of the individual.

4. The method of any one of claims 1-3, wherein the administration results in a reduction in serum HBV DNA levels in the individual.

5. The method of claim 1, wherein the HIV infection is HIV-1 or HIV-2 infection.

6. The method of claim 1 or claim 5, wherein the administration results in an increase in HIV-reactive CD8+ T cells in the individual.

7. The method of any one of claims 1-6, wherein the infection is HBV / HIV co-infection.

8. The method of any one of claims 1-7, wherein the individual is a human.

9. The method of any one of claims 1-8, wherein the second portion induces activation of CD8+ T cells.

10. The method of claim 9, wherein the fusion protein induces activation of cells expressing human CD8ab heterodimers with a potency at least 10-fold higher than activation of cells expressing human CD8aa homodimers.

11. The method of claim 9, wherein the fusion protein induces activation of CD8+ T cells with a potency at least 10 times higher than activation of NK cells.

12. The method of claim 10 or claim 11, wherein the activation potency is measured by EC50 as assessed by cell proliferation.

13. The method of claim 10 or claim 11, wherein the activation potency is measured by EC50 as assessed by STAT5 phosphorylation.

14. The method of claim 10 or claim 11, wherein the activation potency is measured by EC50 as assessed by cytotoxic function.

15. The method of claim 14, wherein the cytotoxic function comprises expression of IFNγ and / or granzyme B.

16. The method of any one of claims 1-15, wherein the second portion comprises an IL-2 polypeptide.

17. The method of claim 16, wherein the IL-2 polypeptide is a mutant IL-2 polypeptide comprising one or more mutations relative to a human IL-2 polypeptide comprising the sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 81).

18. The method of claim 17, wherein the binding affinity of the mutant IL-2 polypeptide to IL-2Rα is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rα.

19. The method of claim 18, wherein the binding affinity of the mutant IL-2 polypeptide to IL-2Rβ is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rβ; and / or The binding affinity of the mutant IL-2 polypeptide to IL-2Rγ is reduced by 50% or more compared to the binding affinity of the wild-type IL-2 polypeptide comprising the sequence of SEQ ID: 81 to IL-2Rγ.

20. The method of any one of claims 17-19, wherein the IL-2 polypeptide comprises the sequence SEQ ID NO:81 having one, two, three, four or five amino acid substitutions relative to SEQ ID NO:81, and wherein the one, two, three, four or five substitutions comprise substitutions at positions of SEQ ID NO:81 selected from the group consisting of: Q11, H16, L18, L19, D20, Q22, R38, F42, K43, Y45, E62, P65, E68, V69, L72, D84, S87, N88, V91, 192, T123, Q126, S127, 1129, and S130.

21. The method of claim 20, wherein the IL-2 polypeptide comprises a sequence SEQ ID NO: 81 having one of the following sets of amino acid substitutions (relative to sequence SEQ ID NO: 81): R38E and F42A; R38D and F42A; F42A and E62Q; R38A and F42K; R38E, F42A, and N88S; R38E, F42A, and N88A; R38E, F42A, and N88G; R38E, F42A, and N88R; R38E, F42A, and N88T; R38E, F42A, and N88D; R38E, F42A, and V91E; R38E, F42A, and D84H; R38E, F42A, and D84K; R38E, F42A, and D84R; H16D, R38E and F42A; H16E, R38E and F42A; R38E, F42A and Q126S; R38D, F42A and N88S; R38D, F42A and N88A; R38D, F42A and N88G; R38D, F42A and N88R; R38D, F42A and N88T; R38D, F42A and N88D; R38D, F42A and V91E; R38D, F42A and D84H; R38D, F42A and D84K; R38D, F42A and D84R; H 16D, R38D and F42A; H16E, R38D and F42A; R38D, F42A and Q126S; R38A, F42K and N88S; R38A, F42K and N88A; R38A, F42K and N88G; R38A, F42K and N88R; R38A, F42K and N88T; R38A, F42K and N88D; R38A, F42K and V91E; R38A, F42K and D84H; R38A, F42K and D84K; R38A, F42K and D84R; H 16D, R38A and F42K; H16E, R38A and F42K; R38A, F42K and Q126S; F42A, E62Q and N88S; F42A, E62Q and N88A; F42A, E62Q and N88G; F42A, E62Q and N88R; F42A, E62Q and N88T; F42A, E62Q and N88D; F42A, E62Q and V91E; F42A, E62Q and D84H; F42A, E62Q and D84K; and F42A, E62Q and D84R.

22. The method of claim 20, wherein the IL-2 polypeptide comprises the sequence SEQ ID NO: 81 having another amino acid substitution at position C125 relative to SEQ ID NO:

81.

23. The method of claim 22, wherein the IL-2 polypeptide comprises a sequence of SEQ ID NO: 81 having one of the following amino acid substitutions: NO:81: R38E, F42A and C125A; R38D, F42A and C125A; F42A, E62Q and C125A; R38A, F42K and C125A; R38E, F42A, N88S and C125A; R38E, F42A, N88A and C125A; R38E, F42A, N88G and C125A; R38E, F42A, N88R and C125A; R38E, F42A, N88D and C125A; R38E, F42A, N88T and C125A; R38E, F42A, V91E and C125A; R38E, F42A, D 84H and C125A; R38E, F42A, D84K and C125A; R38E, F42A, D84R and C125A; H16D, R38E, F42A and C125A; H16E, R38E, F42A and C125A; R38E, F42A, C125A and Q126S; R38D, F42A, N88S and C125A; R38D, F42A, N88A and C125A; R38D, F42A, N88G and C125A; R38D, F42A, N88R and C125A; R38D, F42A, N88T and C125A; R38D, F42A 2A, N88D and C125A; R38D, F42A, V91E and C125A; R38D, F42A, D84H and C125A; R38D, F42A, D84K and C125A; R38D, F42A, D84R and C125A; H16D, R38D, F42A and C125A; H16E, R38D, F42A and C125A; R38D, F42A, C125A and Q126S; R38A, F42K, N88S and C125A; R38A, F42K, N88G and C125A; R38A, F42K, N88R and C125A; R38 A, F42K, N88T and C125A; R38A, F42K, N88D and C125A; R38A, F42K, N88A and C125A; R38A, F42K, V91E and C125A; R38A, F42K, D84H and C125A; R38A, F42K, D84K and C125A; R38A, F42K, D84R and C125A; H16D, R38A, F42K and C125A; H16E, R38A, F42K and C125A; R38A, F42K, C125A and Q126S; F42A, E62Q, N88S and C125A;F42A, E62Q, N88A and C125A; F42A, E62Q, N88G and C125A; F42A, E62Q, N88R and C125A; F42A, E62Q, N88T and C125A; F42A, E62Q, N88D and C125A; F42A, E62Q, V91E and C125A; F42A, E62Q and D84H and C125A; F42A, E62Q and D84K and C125A; F42A, E62Q and D84R and C125A; H16D, F42A and E62Q and C125A; H16E, F42A, E62Q and C125A; F 42A, E62Q, C125A and Q126S; F42A, N88S and C125A; F42A, N88A and C125A; F42A, N88G and C125A; F42A, N88R and C125A; F42A, N88T and C125A; F42A, N88D and C125A; F42A, V91E and C125A; F42A, D84H and C125A; F42A, D84K and C125A; F42A, D84R and C125A; H16D, F42A and C125A; H16E, F42A and C125A; and F42A, C125A and Q126S. ; 24. The method of any one of claims 17-19, wherein the IL-2 polypeptide comprises the sequence APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISAINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 80) or the sequence APTSSSTKKTQLQLEELLLDLQMILNGINNYKNPKLTEMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFAQSIISTLT (SEQ ID NO: 297).

25. The method of any one of claims 17-19, wherein the IL-2 polypeptide comprises a sequence selected from the group consisting of SEQ ID NOs: 80, 85-155, 190-216, 297, and 354-383.

26. The method of any one of claims 1-25, wherein the first moiety binds to cells expressing human CD8ab heterodimers on their surface with an EC50 of less than 1000 nM.

27. The method of any one of claims 1-26, wherein the first portion binds to human CD8+ T cells.

28. The method of any one of claims 1-27, wherein the antibody or antigen-binding fragment thereof is humanized or human.

29. The method of any one of claims 1-28, wherein the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, and in: (a) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18; (b) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24; (c) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 30; (d) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 31, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 32, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 33, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 36; (e) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 37, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42; (f) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:43, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:44, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:45, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48; (g) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; (h) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182; (i) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 227, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; (j) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236; (k) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; (l) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:230, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:231, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of RASQSVSSNLA (SEQ ID NO:40), a CDR-L2 comprising the amino acid sequence of GAS SRAT (SEQ ID NO:41), and a CDR-L3 comprising the amino acid sequence of QQYGSSPPVT (SEQ ID NO:42); or (m) the VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:231, and the VL domain comprises: a CDR-L1 comprising the amino acid sequence of RASQSVSSNLA (SEQ ID NO:40), a CDR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:41), and a CDR-L3 comprising the amino acid sequence of QQYGSS PPVT (SEQ ID NO:42).

30. The method of any one of claims 1-28, wherein the antibody or fragment comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, and in: (a) the VH domain comprises: CDR-H1, which comprises the amino acid sequence X 1 X 2 AIS, where X 1 is S, K, G, N, R, D, T or G, and wherein X 2 is Y, L, H or F (SEQ ID NO: 259), CDR-H2, which comprises the amino acid sequence X 1 X 2 X 3 PX 4 X 5 X 6 X 7 X 8 X 9 YX 10 QKFX 11 G, where X 1 G or H, X 2 I or F, X 3 I, N or M, X 4 is G, N, H, S, R, I or A, X 5 A, N, H, S, T, F or Y, X 6 A, D or G, X 7 is T, E, K, V, Q or A, X 8 A or T, X 9 is N or K, X 10 is A or N, and X 11 is Q or T (SEQ ID NO: 260), and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 GX 4 X 5 LFX 6 X 7 , where X 1 D or A, X 2 A, G, E, R, Y, K, N, Q, L or F, X 3 A, L, P or Y, X 4 I or L, X 5 R, A, Q or S, X 6 is A or D, and X 7 is D, E, A or S (SEQ ID NO: 261); and wherein the VL domain comprises: CDR-L1, which comprises the amino acid sequence X 1 X 2 SX 3 X 4 IX 5 GX 6 LN, where X 1 R or G, X 2 A or T, X 3 For Q or E, X 4 is E, N, T, S, A, K, D, G, R or Q, X 5 is Y or S, and X 6 is A or V (SEQ ID NO: 262), CDR-L2, which comprises the amino acid sequence GX 1 X 2 X 3 LX 4 X 5 , where X 1 A or S, X 2 is T, S, E, Q or D, X 3 N, R, A, E or H, X 4 is Q or A, and X 5 is S or D (SEQ ID NO: 263), and CDR-L3, which comprises the amino acid sequence QX 1 X 2 X 3 X 4 X 5 PWT, where X 1 is S, N, D, Q, A or E, X 2 is T, I or S, X 3 is Y, L or F, X 4 is D, G, T, E, Q, A, or Y, and X 5 is A, T, R, S, K or Y (SEQ ID NO: 264); or (b) the VH domain comprises: CDR-H1, which comprises the amino acid sequence X 1 YX 2 MS, where X 1 is S, D, E, A, or Q, and X 2 is A, G or T (SEQ ID NO: 268), CDR-H2, which comprises the amino acid sequence DIX 1 X 2 X 3 GX 4 X 5 TX 6 YADSVKG, where X 1 is T, N, S, Q, E, H, R or A, X 2 is Y, W, F or H, X 3 is A, S, Q, E or T, X 4 G or E, X 5 is S or I, and X 6 is A or G (SEQ ID NO: 269), and CDR-H3, which comprises the amino acid sequence X 1 X 2 X 3 YX 4 WX 5 X 6 AX 7 DX 8 , where X 1 S or A, X 2 N, H, A, D, L, Q, Y or R, X 3 A, N, S or G, X 4 A, V, R, E or S, X 5 D or S, X 6 is D, N, Q, E, S, T or L, X 7 is L, F, or M, and X 8 is I, Y or V (SEQ ID NO: 270); and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 40), a CDR-L2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 41), and A CDR-L3 comprising the amino acid sequence QQYGSSPPVT (SEQ ID NO: 42).

31. The method of claim 29 or claim 30, in: (a) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 62, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 63; (b) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 64, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 65; (c) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 66, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 67; (d) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 68, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 69; (e) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 70, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 71; (f) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 72, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 73; (g) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 185, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 186; (h) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 245, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 246; (i) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 251, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 252; (j) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 253, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 254; (k) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 247, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 248; (l) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 249, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 250; (m) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 255, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 256; or (n) the VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:257, and the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO:

258.

32. The method of any one of claims 1-31, wherein the antibody or antigen-binding fragment thereof is multispecific.

33. The method of claim 32, wherein the antibody or antigen-binding fragment thereof is bispecific.

34. The method of any one of claims 1-33, wherein the first portion comprises: two antibody heavy chain polypeptides, the antibody heavy chain polypeptides comprising, from N-terminus to C-terminus, a structure according to formula [I]: VH-CH1-hinge-CH2-CH3[I] and two antibody light chain polypeptides, the antibody light chain polypeptides comprising, from N-terminus to C-terminus, a structure according to formula [II]: VL-CL[II] wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and The N-terminus of the second part is fused to the C-terminus of one of the two CH3 domains.

35. The method of any one of claims 1-33, wherein the first portion comprises a first antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [I]: VH-CH1-hinge-CH2-CH3[I], An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus: VL-CL[II], and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]: Hinge-CH2-CH3[III], wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and The N-terminus of the second part is fused to the C-terminus of the CH3 domain of the second antibody heavy chain polypeptide.

36. The method of any one of claims 1-33, wherein the first portion comprises a first antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [I]: VH-CH1-hinge-CH2-CH3[I], An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus: VL-CL[II], and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]: Hinge-CH2-CH3[III], wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and The C-terminus of the second part is fused to the N-terminus of the hinge domain of the second antibody heavy chain polypeptide.

37. The method of any one of claims 1-33, wherein the first portion comprises a first antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [I]: VH-CH1-hinge-CH2-CH3[I], An antibody light chain polypeptide, comprising a structure according to formula [II] from N-terminus to C-terminus: VL-CL[II], and a second antibody heavy chain polypeptide, the second antibody heavy chain polypeptide comprising, from N-terminus to C-terminus, a structure according to formula [III]: Hinge-CH2-CH3[III], wherein VH is said VH domain, wherein CH1 is an antibody CH1 domain, wherein hinge is an antibody hinge domain, wherein CH2-CH3 is an antibody Fc domain, wherein VL is said VL domain, and wherein CL is an antibody constant light chain domain; and The N-terminus of the second part is fused to the C-terminus of the CH3 domain of the first antibody heavy chain polypeptide.

38. The method of claim 34, in: The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:25, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:26, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:27; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:29, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:30; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:31, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:32, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:33; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:34, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:35, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:36; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:37, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:38, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:39; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:42; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO:43, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:44, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:45; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 179; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 182; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 227; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 230, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 231; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42; The VH domains of the two antibody heavy chain polypeptides each comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and wherein the VL domains of the two antibody light chain polypeptides each comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 236; The VH domains of the two antibody heavy chain polypeptides both comprise: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and wherein the VL domains of the two antibody light chain polypeptides both comprise: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; or The VH domains of the two antibody heavy chain polypeptides both comprise: CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:231; and wherein the VL domains of the two antibody light chain polypeptides both comprise: CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:

42.

39. The method of claim 34 or claim 38, in: The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 62, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 63; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 62, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 63; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 64, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 65; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 64, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 65; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:66, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:67; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO:66, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO:67; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:68, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO:69; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO:68, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO:69; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 70, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 71; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 70, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 71; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 72, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 73; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 72, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 73; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 185, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 186; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 185, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 186; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 245, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 246; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 245, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 246; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 251, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 252; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 251, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 252; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 253, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 254; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 253, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 254; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 247, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 248; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 247, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 248; The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 249, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 250; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 249, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 250; The VH domains of both antibody heavy chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 255, and wherein the VL domains of both antibody light chain polypeptides comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 256; optionally, the VH domains of both antibody heavy chain polypeptides comprise the amino acid sequence of SEQ ID NO: 255, and the VL domains of both antibody light chain polypeptides comprise the amino acid sequence of SEQ ID NO: 256; or The VH domains of the two antibody heavy chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 257, and wherein the VL domains of the two antibody light chain polypeptides each comprise an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 258; optionally, the VH domains of the two antibody heavy chain polypeptides each comprise the amino acid sequence of SEQ ID NO: 257, and the VL domains of the two antibody light chain polypeptides each comprise the amino acid sequence of SEQ ID NO:

258.

40. The method of any one of claims 35 to 37, in: The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 13, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 14, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 15; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 18; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 20, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 21; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 23, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 24; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 25, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 26, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 27; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 28, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 29, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 30; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 31, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 32, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 33; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 34, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 35, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 36; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 37, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 38, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 39; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 43, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 44, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 45; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 46, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 47, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 48; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 2, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 3; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 6; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 177, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 178, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 179; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 180, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 181, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 182; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 226, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 227; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 228; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 229, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 230, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 231; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 42; The VH domain comprises: a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 233; and wherein the VL domain comprises: a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 234, a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 235, and a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 236; The VH domain comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 232, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 233; and wherein the VL domain comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 228; or The VH domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:229, CDR-H2 comprising the amino acid sequence of SEQ ID NO:237, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:231; and wherein the VL domain comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO:40, CDR-L2 comprising the amino acid sequence of SEQ ID NO:41, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:

42.

41. The method of any one of claims 35 to 37 and 40, in: The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 62, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 63; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 62, and the VL domain comprises the amino acid sequence of SEQ ID NO: 63; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 64, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 65; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 64, and the VL domain comprises the amino acid sequence of SEQ ID NO: 65; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 66, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 67; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 66, and the VL domain comprises the amino acid sequence of SEQ ID NO: 67; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 68, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 69; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 68, and the VL domain comprises the amino acid sequence of SEQ ID NO: 69; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 70, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 71; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 70, and the VL domain comprises the amino acid sequence of SEQ ID NO: 71; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 72, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 73; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 72, and the VL domain comprises the amino acid sequence of SEQ ID NO: 73; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 185, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 186; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 185, and the VL domain comprises the amino acid sequence of SEQ ID NO: 186; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 245, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 246; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 245, and the VL domain comprises the amino acid sequence of SEQ ID NO: 246; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 251, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 252; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 251, and the VL domain comprises the amino acid sequence of SEQ ID NO: 252; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 253, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 254; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 253, and the VL domain comprises the amino acid sequence of SEQ ID NO: 254; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 247, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 248; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 247, and the VL domain comprises the amino acid sequence of SEQ ID NO: 248; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 249, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 250; optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 249, and the VL domain comprises the amino acid sequence of SEQ ID NO: 250; The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 255, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the sequence of SEQ ID NO: 256; or optionally, the VH domain comprises the amino acid sequence of SEQ ID NO: 255 and the VL domain comprises the amino acid sequence of SEQ ID NO: 256; or The VH domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO: 257, and wherein the VL domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to sequence SEQ ID NO: 258; optionally, the VH domain comprises the amino acid sequence SEQ ID NO: 257, and the VL domain comprises the amino acid sequence SEQ ID NO:

258.

42. The method of any one of claims 34-41, wherein one or both of the antibody heavy chain polypeptides comprise the following amino acid substitutions: L234A, L235A, and G237A, numbered according to the EU index.

43. The method of any one of claims 34-42, wherein a first of the antibody heavy chain polypeptides comprises amino acid substitutions Y349C and T366W, and a second of the antibody heavy chain polypeptides comprises amino acid substitutions S354C, T366S, L368A, and Y407V, numbered according to the EU index.

44. The method of any one of claims 1-33, wherein the first portion comprises one or two antibody heavy chain polypeptides and one or two antibody light chain polypeptides.

45. The method of any one of claims 1-33, wherein the first portion comprises a single chain antibody or a single chain variable fragment (scFv).

46. ​​The method of any one of claims 1-33, wherein the first portion comprises a VHH antibody.

47. The method of any one of claims 1-46, wherein the linker comprises the sequence (GGGS)xGn (SEQ ID NO:74), (GGGGS)xGn (SEQ ID NO:75), or (GGGGGS)xGn (SEQ ID NO:76), S(GGGS)xGn (SEQ ID NO:386), S(GGGGS)xGn (SEQ ID NO:387), or S(GGGGGS)xGn (SEQ ID NO:388), wherein x=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and wherein n=0, 1, 2, or 3.

48. The method of any one of claims 1-46, wherein the linker comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 79) or SGGGGSGGGGSGG GGS (SEQ ID NO: 389).

49. The method of any one of claims 1-33, wherein the fusion protein comprises: One or two light chains comprising the amino acid sequence of SEQ ID NO: 156, a heavy chain comprising the amino acid sequence of SEQ ID NO: 157, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 158; One or two light chains comprising the amino acid sequence of SEQ ID NO: 159, a heavy chain comprising the amino acid sequence of SEQ ID NO: 160, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 161; One or two light chains comprising the amino acid sequence of SEQ ID NO: 162, a heavy chain comprising the amino acid sequence of SEQ ID NO: 163, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 164; One or two light chains comprising the amino acid sequence of SEQ ID NO: 165, a heavy chain comprising the amino acid sequence of SEQ ID NO: 166, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 167; One or two light chains comprising the amino acid sequence of SEQ ID NO: 168, a heavy chain comprising the amino acid sequence of SEQ ID NO: 169, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 170; One or two light chains comprising the amino acid sequence of SEQ ID NO: 171, a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 173; One or two light chains comprising the amino acid sequence of SEQ ID NO: 174, a heavy chain comprising the amino acid sequence of SEQ ID NO: 175, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 176; one or two light chains comprising the amino acid sequence of SEQ ID NO: 187, a heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 189; One or two light chains comprising the amino acid sequence of SEQ ID NO:298, a heavy chain comprising the amino acid sequence of SEQ ID NO:299, and a heavy chain comprising the amino acid sequence of SEQ ID NO:300; One or two light chains comprising the amino acid sequence of SEQ ID NO:302, a heavy chain comprising the amino acid sequence of SEQ ID NO:303, and a heavy chain comprising the amino acid sequence of SEQ ID NO:304; One or two light chains comprising the amino acid sequence of SEQ ID NO:306, a heavy chain comprising the amino acid sequence of SEQ ID NO:307, and a heavy chain comprising the amino acid sequence of SEQ ID NO:308; One or two light chains comprising the amino acid sequence of SEQ ID NO: 310, a heavy chain comprising the amino acid sequence of SEQ ID NO: 311, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 312; One or two light chains comprising the amino acid sequence of SEQ ID NO: 314, a heavy chain comprising the amino acid sequence of SEQ ID NO: 315, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 316; One or two light chains comprising the amino acid sequence of SEQ ID NO: 318, a heavy chain comprising the amino acid sequence of SEQ ID NO: 319, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 320; One or two light chains comprising the amino acid sequence of SEQ ID NO: 322, a heavy chain comprising the amino acid sequence of SEQ ID NO: 323, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 324; One or two light chains comprising the amino acid sequence of SEQ ID NO:326, a heavy chain comprising the amino acid sequence of SEQ ID NO:327, and a heavy chain comprising the amino acid sequence of SEQ ID NO:328; One or two light chains comprising the amino acid sequence of SEQ ID NO: 330, a heavy chain comprising the amino acid sequence of SEQ ID NO: 331, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 332; One or two light chains comprising the amino acid sequence of SEQ ID NO: 334, a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 336; one or two light chains comprising the amino acid sequence of SEQ ID NO: 338, a heavy chain comprising the amino acid sequence of SEQ ID NO: 339, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 340; One or two light chains comprising the amino acid sequence of SEQ ID NO: 342, a heavy chain comprising the amino acid sequence of SEQ ID NO: 343, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 344; One or two light chains comprising the amino acid sequence of SEQ ID NO:346, a heavy chain comprising the amino acid sequence of SEQ ID NO:347, and a heavy chain comprising the amino acid sequence of SEQ ID NO:348; One or two light chains comprising the amino acid sequence of SEQ ID NO: 350, a heavy chain comprising the amino acid sequence of SEQ ID NO: 351, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 352; One or two light chains comprising the amino acid sequence of SEQ ID NO: 156, a heavy chain comprising the amino acid sequence of SEQ ID NO: 157, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 217; one or two light chains comprising the amino acid sequence of SEQ ID NO: 159, a heavy chain comprising the amino acid sequence of SEQ ID NO: 160, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 218; One or two light chains comprising the amino acid sequence of SEQ ID NO: 162, a heavy chain comprising the amino acid sequence of SEQ ID NO: 163, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 219; One or two light chains comprising the amino acid sequence of SEQ ID NO: 165, a heavy chain comprising the amino acid sequence of SEQ ID NO: 166, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 220; One or two light chains comprising the amino acid sequence of SEQ ID NO: 168, a heavy chain comprising the amino acid sequence of SEQ ID NO: 169, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 221; one or two light chains comprising the amino acid sequence of SEQ ID NO: 171, a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 222; One or two light chains comprising the amino acid sequence of SEQ ID NO: 174, a heavy chain comprising the amino acid sequence of SEQ ID NO: 175, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 223; One or two light chains comprising the amino acid sequence of SEQ ID NO: 187, a heavy chain comprising the amino acid sequence of SEQ ID NO: 188, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 224; one or two light chains comprising the amino acid sequence of SEQ ID NO:298, a heavy chain comprising the amino acid sequence of SEQ ID NO:299, and a heavy chain comprising the amino acid sequence of SEQ ID NO:301; One or two light chains comprising the amino acid sequence of SEQ ID NO:302, a heavy chain comprising the amino acid sequence of SEQ ID NO:303, and a heavy chain comprising the amino acid sequence of SEQ ID NO:305; One or two light chains comprising the amino acid sequence of SEQ ID NO:306, a heavy chain comprising the amino acid sequence of SEQ ID NO:307, and a heavy chain comprising the amino acid sequence of SEQ ID NO:309; One or two light chains comprising the amino acid sequence of SEQ ID NO: 310, a heavy chain comprising the amino acid sequence of SEQ ID NO: 311, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 313; One or two light chains comprising the amino acid sequence of SEQ ID NO: 314, a heavy chain comprising the amino acid sequence of SEQ ID NO: 315, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 317; one or two light chains comprising the amino acid sequence of SEQ ID NO:318, a heavy chain comprising the amino acid sequence of SEQ ID NO:319, and a heavy chain comprising the amino acid sequence of SEQ ID NO:321; One or two light chains comprising the amino acid sequence of SEQ ID NO: 322, a heavy chain comprising the amino acid sequence of SEQ ID NO: 323, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 325; One or two light chains comprising the amino acid sequence of SEQ ID NO:326, a heavy chain comprising the amino acid sequence of SEQ ID NO:327, and a heavy chain comprising the amino acid sequence of SEQ ID NO:329; One or two light chains comprising the amino acid sequence of SEQ ID NO: 330, a heavy chain comprising the amino acid sequence of SEQ ID NO: 331, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 333; One or two light chains comprising the amino acid sequence of SEQ ID NO: 334, a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 337; one or two light chains comprising the amino acid sequence of SEQ ID NO: 338, a heavy chain comprising the amino acid sequence of SEQ ID NO: 339, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 341; One or two light chains comprising the amino acid sequence of SEQ ID NO: 342, a heavy chain comprising the amino acid sequence of SEQ ID NO: 343, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 345; One or two light chains comprising the amino acid sequence of SEQ ID NO: 346, a heavy chain comprising the amino acid sequence of SEQ ID NO: 347, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 349; or One or two light chains comprising the amino acid sequence of SEQ ID NO:350, a heavy chain comprising the amino acid sequence of SEQ ID NO:351, and a heavy chain comprising the amino acid sequence of SEQ ID NO:

353.

50. The method of any one of claims 1-33, wherein the fusion protein comprises: (1) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 334, a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 335, a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 336, and a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO: 334; (2) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 334, a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 335, a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 337, and a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO: 334; (3) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 338, a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 339, a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 340, and a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO: 338; or (4) a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 338, a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 339, a third polypeptide chain comprising the amino acid sequence of SEQ ID NO: 341, and a fourth polypeptide chain comprising the amino acid sequence of SEQ ID NO:

338.

51. The method of any one of claims 1-50, wherein the fusion protein is administered in a pharmaceutical composition comprising the fusion protein and a pharmaceutically acceptable carrier.

52. The method of any one of claims 1-51, further comprising administering to the individual a second antiviral agent or an immunomodulatory agent.

53. A method as claimed in claim 52, wherein the second antiviral agent or immunomodulator is a nucleoside or nucleotide analog, a capsid assembly regulator or inhibitor, a TLR agonist, a vaccine, an RNAi-based agent, interferon-α, an HBV entry inhibitor, a covalently closed circular DNA (cccDNA) disruptor, an HBV transcription inhibitor, a CD3 bispecific T cell redirector, an HBV antigen targeting agent, a PD1 and / or PDL1 blocker, an agent that reduces PDL1 expression in hepatocytes, an RNA destabilizer, or a hepatitis B surface antigen (HBsAg) release inhibitor.

54. The method of claim 52, wherein the second antiviral agent or immunomodulator is an antiretroviral therapy (ART), a PD1 and / or PDL1 blocker, or an agent that reduces PDL1 expression.

55. The method of claim 54, wherein the ART comprises a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor (INSTI), an attachment inhibitor, a post-attachment inhibitor, a pharmacokinetic enhancer, or a combination thereof.

56. A kit comprising the fusion protein of any one of claims 1-50, for use in the method of any one of claims 1-55.

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