Antibodies specific for the delta 1 chain of the T cell receptor

Abstract

Disclosed herein are antibodies specific for the δ-1 chain of the γδ T cell receptor and methods of using such antibodies to modulate the biological activity of γδ T cells. Such anti-δ1 antibodies can also be used to treat diseases associated with γδ T cell activation, such as solid tumors, or to detect the presence of γδ1 T cells.

Description

Background of the Invention

[0002] Immune checkpoint blockade has achieved unprecedented success as a cancer treatment in the past few years. Antibodies are commonly used to block immunosuppressive pathways, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) pathways. Although therapies targeting these two pathways have been shown to be successful in treating several cancer types, the response rate of anti-CTLA-4 and anti-PD-1 therapies to treated patients depends on the cancer type, which is 10% to 60%, but it has not yet been shown to exceed a response rate of 60%, even when used in combination (Kyvistborg et al., Enhancing responses to cancer immunotherapy; Science. 2018 Feb 2; 359 (6375): 516-517). In addition, a large number of cancer types are refractory to these therapies.

[0003] γδT cells are a subpopulation of T cells with different T cell receptors (TCR) γ and δ chains on their surface. This distinguishes them from CD4+ helper T cells and CD8+ cytotoxic T cells, which express αβTCR on their cell surfaces. Recent studies have found that γδT cells have tumor-promoting activity (Zhao et al. J Transl Med (2018) 16: 3). For example, in human pancreatic ductal carcinoma, it has been found that γδT cells constitute a large part of tumor-infiltrating T cells and suppress the anti-cancer immune response mediated by alpha beta (αβ) T cells (Daley et al., Cell, 2016, 166: 1485-1499). In the tumor microenvironment (TME), it has been shown that γδT cells express IL-4, IL-10 and TGF-β, resulting in inhibition of anti-tumor responses (Kuhl et al., Immunol., 2009, 128 (4): 580-588). It has been shown that the expression of both IL-10 and TGF-β is increased in various cancer types (Lafont et al., Front Immunol., 2014, 5: 622). γδT17 cells are the main source of IL-17 in the tumor microenvironment, and they play a role in promoting angiogenesis in various cancer types (Silva-Santos B. Eur J Immunol. 2010; 40: 1873-6; Zhao et al. J Transl Med (2018) 16: 3, and references therein). In addition, it has been found that γδT cells induce senescence of naive T cells and effector T cells, which become suppressive in the TME and increase immunosuppression in the TME (Ye et al., J Immunol., 2013, 190 (5): 2403-2414). Finally, studies have shown that γδ T cells increase the presence of myeloid-derived suppressor cells (MDSCs) in the TME, thereby promoting a pro-tumor microenvironment (Yan and Huang, Oncoimmunology. 2014;3:e953423; Qu P, et al., Cancer Lett. 2016;380:253–6, and references therein).

[0004] Given the average response rates and the large number of cancer types that are refractory to current treatments, there remains a need for new cancer therapies. Modulating the activity of one or more of γδ T cells and / or their T cell receptors offers a new approach to cancer treatment. SUMMARY OF THE INVENTION

[0006] Modulation of one or more of the γδ T cell activity and / or its T cell receptor can be used alone or in combination with existing therapies as a means of cancer treatment. Described herein are novel human antibodies that bind to human γδ T cell receptors and their therapeutic uses in treating cancer. The present disclosure is based, at least in part, on the development of antibodies that specifically bind to the delta-1 chain of the γδ T cell receptor (TCR). Such antibodies were found to effectively inhibit γδ T cells, thereby rescuing immunosuppression mediated by γδ T cells.

[0007] Thus, one aspect of the present disclosure provides an isolated antibody that specifically binds to the delta-1 chain of a T cell receptor. In some cases, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2, and HC CDR3. In some embodiments, HC CDR1 comprises the motif of FTX1X2X3X4X5IH (SEQ ID NO: 46), wherein X1 is F or V, X2 is S or T, X3 is G, A or S, X4 is T, N or S, and X5 is D or S. In some embodiments, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively or additionally, in some embodiments, HC CDR3 comprises PGX6YYWYYSGSAYEGYGLDY (SEQ ID NO: 48), wherein X6 comprises S or M.

[0008] Alternatively or additionally, the isolated antibodies disclosed herein comprise a light chain variable region (V L ), which comprises LC CDR1, LC CDR2, and LC CDR3. In some embodiments, LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). In some embodiments, LC CDR2 comprises X7ASSLX8S (SEQ ID NO: 50), wherein X7 is S or A and X8 is Y or Q. Alternatively or additionally, in some embodiments, LC CDR3 comprises QQX9X 10 X 11 X 12 X 13 X 14 LIT (SEQ ID NO: 51), wherein X9 is S or Q, X 10 Is G, S or T, X 11 Is D, K or S, X 12 Is Y, W or does not exist, X 13 is P or not present, and X 14 is D, F, or Y. In some cases, the isolated antibody does not comprise the same heavy and light chain CDRs as delta 1-17.

[0009] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 comprises the motif of FTFX1X2X3X4IH (SEQ ID NO: 93), wherein X1 is S or T, X2 is S, G or A, X3 is T, N or S, and X4 is D or S. Alternatively or additionally, in some embodiments, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively or additionally, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). Alternatively or additionally, in some embodiments, the isolated antibodies disclosed herein comprise a light chain variable region (V L ), comprising a LC CDR1, a LC CDR2, and a LC CDR3, wherein the LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). Alternatively or additionally, in some embodiments, the LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, in some embodiments, the LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0010] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 comprises the motif of FTFX1X2X3X4IH (SEQ ID NO: 93), wherein X1 is S or T, X2 is S, G or A, X3 is T, N or S, and X4 is D or S, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). In some embodiments, the isolated antibody comprises a light chain variable region (V L ), which comprises LC CDR1, LC CDR2 and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55), LC CDR2 comprises AASSLQS (SEQ ID NO: 56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0011] In some embodiments, the antibody comprises a heavy chain variable region (V H), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 is selected from the group consisting of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72. Alternatively or additionally, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO:53). Alternatively or additionally, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO:54). Alternatively or additionally, the isolated antibodies disclosed herein comprise a light chain variable region (V L ), comprising LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). Alternatively or additionally, LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0012] In some embodiments, the antibody comprises a heavy chain variable region (V H ), comprising HC CDR1, HC CDR2, and HC CDR3, wherein HC CDR1 is selected from the group consisting of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, and SEQ ID NO:72, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO:53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO:54). In some embodiments, the isolated antibody further comprises a light chain variable region (V L ), which comprises LC CDR1, LC CDR2 and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55), LC CDR2 comprises AASSLQS (SEQ ID NO: 56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0013] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 comprises the motif of FTFX1X2X3X4IH (SEQ ID NO: 94), wherein X1 is S or T, X2 is S or A, X3 is N or S, and X4 is D or S, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). In some embodiments, the isolated antibody comprises a light chain variable region (V L ), which comprises LC CDR1, LC CDR2 and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55), LC CDR2 comprises AASSLQS (SEQ ID NO: 56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0014] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 is selected from the group consisting of SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71 and SEQ ID NO: 72. Alternatively or additionally, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively or additionally, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). Alternatively or additionally, the isolated antibodies disclosed herein comprise a light chain variable region (V L ), comprising LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). Alternatively or additionally, LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0015] In some embodiments, the antibody comprises a heavy chain variable region (V H), comprising HC CDR1, HC CDR2, and HC CDR3, wherein HC CDR1 is selected from the group consisting of SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). In some embodiments, the isolated antibody further comprises a light chain variable region (V L ), which comprises LC CDR1, LC CDR2 and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55), LC CDR2 comprises AASSLQS (SEQ ID NO: 56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0016] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of an anti-δ1 antibody disclosed herein comprise no more than 10 amino acid variations in total (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid changes) relative to the HC CDRs of a reference antibody. Alternatively or additionally, the LC CDR1, LC CDR2, and LC CDR3 of the antibody comprise no more than 8 amino acid variations (e.g., no more than 7, 6, 5, 4, 3, 2, or 1 amino acid variation) in total relative to the light chain CDRs of a reference antibody selected from the group consisting of δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43.

[0017] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of an anti-δ1 antibody disclosed herein comprise no more than 10 amino acid variations (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in total relative to the HC CDRs of a reference antibody. Alternatively or additionally, the LC CDR1, LC CDR2, and LC CDR3 of the antibody comprise no more than 8 amino acid variations (e.g., no more than 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in total relative to the light chain CDRs of a reference antibody selected from the group consisting of δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43.

[0018] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of an anti-δ1 antibody disclosed herein comprise no more than 10 amino acid changes (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid changes) in total relative to the HC CDRs of a reference antibody. Alternatively or additionally, the LC CDR1, LC CDR2, and LC CDR3 of the antibody comprise no more than 8 amino acid changes (e.g., no more than 7, 6, 5, 4, 3, 2, or 1 amino acid changes) in total relative to the light chain CDRs of a reference antibody selected from the group consisting of δ1-38, δ1-39, δ1-40, and δ1-41.

[0019] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of an antibody are at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of a reference antibody and / or the CDR1, CDR2, and CDR3 collectively share at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity.

[0020] In some examples, the anti-δ1 antibody may comprise the same heavy chain complementarity determining regions (CDRs) and the same light chain CDRs as the reference antibody. In a specific example, the anti-δ1 antibody comprises the same heavy chain variable region and the same light chain variable region as the reference antibody.

[0021] In some embodiments, the anti-δ1 antibodies disclosed herein bind to the human δ1 chain. In some embodiments, the anti-δ1 antibodies disclosed herein are selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. Each of these antibodies is referred to herein as a "reference antibody." In some embodiments, an anti-δ1 antibody disclosed herein binds to the same epitope as any of the δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies and / or competes for binding to the epitope with any of the just-mentioned reference antibodies.

[0022] In some embodiments, the anti-δ1 antibodies disclosed herein are selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. Each of these antibodies is referred to herein as a "reference antibody." In some embodiments, the anti-δ1 antibodies disclosed herein bind to the same epitope as any of the δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies and / or compete for binding to the epitope with any of the just-mentioned reference antibodies.

[0023] In some embodiments, the anti-δ1 antibodies disclosed herein are selected from δ1-38, δ1-39, δ1-40, and δ1-41 antibodies. Each of these antibodies is referred to herein as a "reference antibody." In some embodiments, the anti-δ1 antibodies disclosed herein bind to the same epitope as any of the δ1-38, δ1-39, δ1-40, and δ1-41 antibodies and / or compete for binding to the epitope with any of the just-mentioned reference antibodies.

[0024] In some embodiments, an anti-δ1 antibody comprises a heavy chain variable domain (V H), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) that are collectively at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of the reference antibody; and / or the antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the light chain CDRs of the reference antibody.

[0025] In some embodiments, an anti-δ1 antibody comprises a heavy chain variable domain (V H ), which includes heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2) and heavy chain complementary determining region 3 (HC CDR3) that are collectively at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the heavy chain CDRs of an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 and δ1-43 antibodies; and / or the antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3, which together bind to a member selected from the group consisting of δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38 The light chain CDRs of the antibodies in the 1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies are at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical.

[0026] In some embodiments, an anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3), which together are at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of an antibody selected from the group consisting of δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies; and / or the antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that, collectively, are at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the light chain CDRs of an antibody selected from the group consisting of δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies.

[0027] In some embodiments, an anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3), which together are at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies; and / or the antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that, collectively, are at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the light chain CDRs of an antibody selected from the group consisting of δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies.

[0028] In some embodiments, the anti-δ1 antibody comprises the same heavy chain complementary determining regions (CDRs) and the same light chain CDRs as the reference antibody. In some embodiments, the anti-δ1 antibody comprises the same heavy chain variable region and the same light chain variable region as an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. In some embodiments, the anti-δ1 antibody comprises the same heavy chain variable region and the same light chain variable region as an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies.

[0029] In a specific embodiment, an anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) identical to the heavy chain CDRs of delta 1-39. In some embodiments, the anti-delta 1 antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, light CDR2, and light chain CDR3 identical to the light chain CDRs of delta 1-39. In some embodiments, the anti-delta 1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3), which together are at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of delta 1-39; and / or the antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the light chain CDRs of delta 1-39.

[0030] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence selected from the group consisting of SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72. In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence of SEQ ID NO: 68. In some embodiments, the anti-δ1 antibody comprises a VH CDR2 having a sequence of SEQ ID NO: 53. In some embodiments, the anti-δ1 antibody comprises a VH CDR3 having a sequence of SEQ ID NO: 54. In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence of SEQ ID NO: 68, a VH CDR2 having a sequence of SEQ ID NO: 53, and a VH CDR3 having a sequence of SEQ ID NO: 54. In some embodiments, the anti-δ1 antibody comprises a light chain variable domain (V H ), which comprises a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 68, 53 and 54, respectively.

[0031] In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 55. In some embodiments, the anti-δ1 antibody comprises a VL CDR2 having the sequence of SEQ ID NO: 56 or 58. In some embodiments, the anti-δ1 antibody comprises a VL CDR3 having a sequence selected from any one of SEQ ID NOs: 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60. In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 55, a VL CDR2 having the sequence of SEQ ID NO: 56 or 58, and a VL CDR3 having a sequence selected from any one of SEQ ID NOs: 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60. In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 55, a VL CDR2 having the sequence of SEQ ID NO: 56, and a VL CDR3 having a sequence selected from any one of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a light chain variable domain (V L), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56, and 57, respectively.

[0032] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence selected from the group consisting of SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72. In some embodiments, the anti-δ1 antibody comprises a VH CDR2 having a sequence of SEQ ID NO: 53. In some embodiments, the anti-δ1 antibody comprises a VH CDR3 having a sequence of SEQ ID NO: 54. In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence of SEQ ID NO: 68. In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence of SEQ ID NO: 68, a VH CDR2 having a sequence of SEQ ID NO: 53, and a VH CDR3 having a sequence of SEQ ID NO: 54. In some embodiments, the anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 68, 53 and 54, respectively.

[0033] In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having a sequence of SEQ ID NO: 55. In some embodiments, the anti-δ1 antibody comprises a VL CDR2 having a sequence of SEQ ID NO: 56. In some embodiments, the anti-δ1 antibody comprises a VL CDR3 having a sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having a sequence of SEQ ID NO: 55, a VL CDR2 having a sequence of SEQ ID NO: 56, and a VL CDR3 having a sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a light chain variable domain (V L), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56, and 57, respectively.

[0034] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence selected from the group consisting of SEQ ID NOs: 67, 68, 69, and 70. In some embodiments, the anti-δ1 antibody comprises a VH CDR2 having a sequence of SEQ ID NO: 53. In some embodiments, the anti-δ1 antibody comprises a VH CDR3 having a sequence of SEQ ID NO: 54. In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence of SEQ ID NO: 68. In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence of SEQ ID NO: 68, a VH CDR2 having a sequence of SEQ ID NO: 53, and a VH CDR3 having a sequence of SEQ ID NO: 54. In some embodiments, the anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 68, 53 and 54, respectively.

[0035] In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having a sequence of SEQ ID NO: 55. In some embodiments, the anti-δ1 antibody comprises a VL CDR2 having a sequence of SEQ ID NO: 56. In some embodiments, the anti-δ1 antibody comprises a VL CDR3 having a sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a VL CDR1 having a sequence of SEQ ID NO: 55, a VL CDR2 having a sequence of SEQ ID NO: 56, and a VL CDR3 having a sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a light chain variable domain (V L), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56, and 57, respectively.

[0036] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence selected from the group consisting of SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a VH CDR2 having a sequence of SEQ ID NO: 53, and a VH CDR3 having a sequence of SEQ ID NO: 54. Alternatively or additionally, the anti-δ1 antibody comprises a VLCDR1 having a sequence of SEQ ID NO: 55, a VL CDR2 having a sequence of SEQ ID NOs: 56 or 58, and a VL CDR3 having a sequence selected from any one of SEQ ID NOs: 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60. In some embodiments, the anti-δ1 antibody comprises a heavy chain variable domain (V H ), comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72 (CDR1), 53 (CDR2), and 54 (CDR3), respectively. Alternatively or additionally, the anti-delta 1 antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the light chain CDRs of SEQ ID NO: 55 (CDR1), 56 or 58 (CDR2) and 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60 (CDR3), respectively.

[0037] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence selected from the group consisting of SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a VH CDR2 having a sequence of SEQ ID NO: 53, and a VH CDR3 having a sequence of SEQ ID NO: 54. Alternatively or additionally, the anti-δ1 antibody comprises a VLCDR1 having a sequence of SEQ ID NO: 55, a VL CDR2 having a sequence of SEQ ID NO: 56, and a VL CDR3 having a sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72 (CDR1), 53 (CDR2), and 54 (CDR3), respectively. Alternatively or additionally, the anti-δ1 antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56, and 57, respectively.

[0038] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having a sequence selected from SEQ ID NOs: 67, 68, 69, and 70, a VH CDR2 having a sequence of SEQ ID NO: 53, and a VH CDR3 having a sequence of SEQ ID NO: 54. Alternatively or additionally, the anti-δ1 antibody comprises a VL CDR1 having a sequence of SEQ ID NO: 55, a VL CDR2 having a sequence of SEQ ID NO: 56, and a VL CDR3 having a sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a heavy chain variable domain (V H), which comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 67, 68, 69, and 70 (CDR1), 53 (CDR2), and 54 (CDR3), respectively. Alternatively or additionally, the anti-δ1 antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56, and 57, respectively.

[0039] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having the sequence shown in SEQ ID NO: 68, a VH CDR2 having the sequence of SEQ ID NO: 53, and a VH CDR3 having the sequence of SEQ ID NO: 54. Alternatively or additionally, the anti-δ1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 55, a VL CDR2 having the sequence of SEQ ID NO: 56, and a VL CDR3 having the sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a heavy chain variable domain (V H ), which comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of SEQ ID NOS 68 (CDR1), 53 (CDR2), and 54 (CDR3), respectively. Alternatively or additionally, the anti-δ1 antibody comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56, and 57, respectively.

[0040] In some embodiments, the anti-δ1 antibody comprises a VH CDR1 having the sequence of SEQ ID NO: 68, a VH CDR2 having the sequence of SEQ ID NO: 53, and a VH CDR3 having the sequence of SEQ ID NO: 54, and further comprises a VL CDR1 having the sequence of SEQ ID NO: 55, a VL CDR2 having the sequence of SEQ ID NO: 56, and a VL CDR3 having the sequence of SEQ ID NO: 57. In some embodiments, the anti-δ1 antibody comprises a light chain variable domain (V H ), which comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 that, collectively, are at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the heavy chain CDRs of SEQ ID NOs: 68, 53, and 54, respectively, and further comprises a light chain variable domain (V L ), which comprises a light chain CDR1, a light chain CDR2 and a light chain CDR3 that are collectively at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the light chain CDRs of SEQ ID NOs: 55, 56 and 57, respectively.

[0041] In any of these embodiments, the anti-δ1 antibody binds to δ1. In some embodiments, the anti-δ1 antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3 comprising no more than 10 (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid variations in total relative to the HC CDRs of a reference antibody; and / or wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3 comprising no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) amino acid variations in total relative to the light chain CDRs of the reference antibody. In some embodiments, the reference antibody is δ1-39.

[0042] In some embodiments, the anti-δ1 antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3 comprising no more than 10 (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid variations relative to the HC CDRs of an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43; and / or wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3. CDR3, which comprises no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) amino acid variations relative to the light chain CDRs of an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43.

[0043] In some embodiments, the anti-δ1 antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3 comprising no more than 10 (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid variations relative to the HC CDRs of an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43; and / or wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3. CDR3, which comprises no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2 or 1) amino acid variations relative to the light chain CDRs of an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 and δ1-43.

[0044] In some embodiments, the anti-δ1 antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3 comprising no more than 10 (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid variations collectively relative to the HC CDRs of an antibody selected from δ1-38, δ1-39, δ1-40, and δ1-41, and / or wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3 comprising no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) amino acid variations collectively relative to the light chain CDRs of an antibody selected from δ1-38, δ1-39, δ1-40, and δ1-41.

[0045] In some embodiments, the anti-δ1 antibody comprises a HC CDR1, a HC CDR2, and a HC CDR3 that comprise no more than 10 (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid variations total relative to the HC CDRs of δ1-39; and / or wherein the antibody comprises a LC CDR1, a LC CDR2, and a LC CDR3 that comprise no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) amino acid variations total relative to the light chain CDRs of δ1-39.

[0046] In some embodiments, the anti-δ1 antibody comprises a V that is identical to that of a reference antibody. L is at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to V L , and / or with the reference antibody V H is at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98%, 99%, or 100%) identical to V H .

[0047] In some embodiments, the anti-delta 1 antibody has a binding agent selected from the group consisting of delta 1-18, delta 1-19, delta 1-20, delta 1-21, delta 1-22, delta 1-23, delta 1-24, delta 1-25, delta 1-26, delta 1-27, delta 1 -28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 and δ1-43 7 Antibodies Antibodies V HThe sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. H Sequence, and / or with a sequence selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-3 1. V of antibodies of δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 and δ1-43 antibodies L The sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. L sequence.

[0048] In some embodiments, the anti-δ1 antibody has a V with an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. H The sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. H Sequence, and / or with a V sequence of an antibody selected from the group consisting of δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies L The sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. L sequence.

[0049] In some embodiments, the anti-δ1 antibody has a V similar to that of an antibody selected from the group consisting of δ1-38, δ1-39, δ1-40, and δ1-41 antibodies. H The sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. HSequence, and / or with a V sequence of an antibody selected from the group consisting of δ1-38, δ1-39, δ1-40 and δ1-41 antibodies L The sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. L sequence.

[0050] In some embodiments, the anti-δ1 antibody has a V similar to that of δ1-39. L The sequences are at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical. L Sequence, and / or V with δ1-39 antibody H is at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to V H .

[0051] In some embodiments, an anti-δ1 antibody disclosed herein has the same VL sequence as an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. In some embodiments, an anti-δ1 antibody disclosed herein is an antibody having the same VL sequence as an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. In some embodiments, the disclosed anti-δ1 antibodies have the same VH sequence and the same VL sequence as an antibody selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies.

[0052] In some embodiments, the anti-δ1 antibodies disclosed herein have the same VL sequence as an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. In some embodiments, the anti-δ1 antibodies disclosed herein are antibodies that have the same VL sequence as an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies. In some embodiments, the disclosed anti-δ1 antibodies have the same VH sequence and the same VL sequence as an antibody selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43 antibodies.

[0053] In some embodiments, the anti-δ1 antibodies disclosed herein have the same VL sequence as an antibody selected from δ1-38, δ1-39, δ1-40, and δ1-41 antibodies. In some embodiments, the anti-δ1 antibodies disclosed herein are antibodies that have the same VL sequence as an antibody selected from δ1-38, δ1-39, δ1-40, and δ1-41 antibodies. In some embodiments, the anti-δ1 antibodies disclosed herein have the same VH sequence and the same VL sequence as an antibody selected from δ1-38, δ1-39, δ1-40, and δ1-4 antibodies.

[0054] In some embodiments, the anti-δ1 antibody is selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43. In some embodiments, the anti-δ1 antibody is selected from δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, and δ1-43. In some embodiments, the anti-δ1 antibody is selected from δ1-38, δ1-39, δ1-40, and δ1-41. In a specific embodiment, the anti-δ-1 antibody is δ1-39.

[0055] In some embodiments, the anti-δl antibody comprises a VH region having a sequence selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the anti-δl antibody comprises a VL region having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some embodiments, the anti-δl antibody comprises a VH region having a sequence selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and a VL region having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some embodiments, the anti-δ1 antibody comprises a VH region having a sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the anti-δ1 antibody comprises a VL region having a sequence selected from the group consisting of SEQ ID NOs: 9. In some embodiments, the anti-δ1 antibody comprises a VH region selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and a VL region having a sequence of SEQ ID NO: 9.

[0056] In some embodiments, the anti-δ1 antibody comprises a VH region having the sequence of SEQ ID NO: 24. In some embodiments, the anti-δ1 antibody comprises a VL region having the sequence of SEQ ID NO: 9. In some embodiments, the anti-δ1 antibody comprises a VH region having the sequence of SEQ ID NO: 24 and a VL region having the sequence of SEQ ID NO: 9.

[0057] In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. HIn some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. L In some embodiments, the anti-δ1 antibody has a V sequence comprising a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H In some embodiments, the anti-δ1 antibody has a V sequence comprising a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. L In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of a sequence selected from SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. L sequence.

[0058] In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H A sequence and a sequence having V that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. LIn some embodiments, the isolated antibody has a V sequence comprising a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H Sequences and V sequences comprising a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9 L In some embodiments, the isolated antibody has a V sequence consisting essentially of a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H Sequence and V consisting essentially of a sequence selected from SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9 L In some embodiments, the isolated antibody has a V sequence consisting of a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H A sequence and a V consisting of a sequence selected from SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9 L sequence.

[0059] In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the sequence of SEQ ID NO: 9. L In some embodiments, the anti-δ1 antibody has a V sequence comprising a sequence selected from SEQ ID NO: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H In some embodiments, the anti-δ1 antibody has a V sequence comprising SEQ ID NO: 9. LIn some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of the sequence of SEQ ID NO: 9. L sequence.

[0060] In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H A sequence and a sequence having a V sequence that is at least 80 or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the sequence of SEQ ID NO: 9. L In some embodiments, the isolated antibody has a V sequence comprising a sequence selected from SEQ ID NO: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H Sequence and V comprising the sequence of SEQ ID NO: 9 L In some embodiments, the isolated antibody has a V sequence consisting essentially of a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H Sequence and V consisting essentially of the sequence of SEQ ID NO:9 L In some embodiments, the isolated antibody has a V sequence consisting of a sequence selected from SEQ ID NO: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H Sequence and V consisting of the sequence of SEQ ID NO:9 L sequence.

[0061] In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NOs: 22, 23, 24, 25, and 43. H In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the sequence of SEQ ID NO: 9. L In some embodiments, the anti-δ1 antibody has a V sequence comprising a sequence selected from SEQ ID NO: 22, 23, 24, 25, and 43. H In some embodiments, the anti-δ1 antibody has a V sequence comprising SEQ ID NO: 9. L In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of a sequence selected from SEQ ID NOs: 22, 23, 24, 25, and 43. H In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of the sequence of SEQ ID NO: 9. L sequence.

[0062] In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NOs: 22, 23, 24, 25, and 43. H A sequence and a V sequence that is at least 80 or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the sequence of SEQ ID NO: 9. L In some embodiments, the isolated antibody has a V sequence comprising a sequence selected from SEQ ID NOs: 22, 23, 24, 25, and 43. H Sequence and V comprising the sequence of SEQ ID NO: 9 LIn some embodiments, the isolated antibody has a V sequence consisting essentially of a sequence selected from SEQ ID NOs: 22, 23, 24, 25, and 43. H Sequence and V consisting essentially of the sequence of SEQ ID NO: 9 L In some embodiments, the isolated antibody has a V sequence consisting of a sequence selected from SEQ ID NO: 22, 23, 24, 25, and 43. H Sequence and V consisting of the sequence of SEQ ID NO:9 L sequence.

[0063] In some embodiments, the anti-δ1 antibody has a V that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 24. H In some embodiments, the anti-δ1 antibody has a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 9. L In some embodiments, the anti-δ1 antibody has a V sequence comprising SEQ ID NO: 24. H In some embodiments, the anti-δ1 antibody has a V sequence comprising SEQ ID NO: 9. L In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of SEQ ID NO: 24. H In some embodiments, the isolated antibody has a V sequence consisting essentially of or consisting of SEQ ID NO: 9. L sequence.

[0064] In some embodiments, the anti-δ1 antibody has a V that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 24. HA sequence having a V sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 9 L In some embodiments, the isolated antibody has a V sequence comprising SEQ ID NO: 24. H Sequence and V comprising SEQ ID NO: 9 L In some embodiments, the isolated antibody has a V sequence consisting essentially of SEQ ID NO: 24. H Sequence and V consisting essentially of SEQ ID NO: 9 L In some embodiments, the isolated antibody has a V sequence consisting of SEQ ID NO: 24. H Sequence and V consisting of SEQ ID NO:9 L sequence.

[0065] In some embodiments, the anti-δ1 antibody has a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 78. In some embodiments, the anti-δ1 antibody has a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 79. In some embodiments, the anti-δ1 antibody has a light chain sequence comprising SEQ ID NO: 78. In some embodiments, the anti-δ1 antibody has a heavy chain sequence comprising SEQ ID NO: 79. In some embodiments, the isolated antibody has a light chain sequence consisting essentially of or consisting of SEQ ID NO: 78. In some embodiments, the isolated antibody has a heavy chain sequence consisting essentially of or consisting of SEQ ID NO: 79.

[0066] In some embodiments, the anti-delta 1 antibody has a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:78 and a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:79. In some embodiments, the isolated antibody has a light chain sequence comprising SEQ ID NO: 78 and a heavy chain sequence comprising SEQ ID NO: 79. In some embodiments, the isolated antibody has a light chain sequence consisting essentially of SEQ ID NO: 78 and a heavy chain sequence consisting essentially of SEQ ID NO: 79. In some embodiments, the isolated antibody has a light chain sequence consisting of SEQ ID NO: 78 and a heavy chain sequence consisting of SEQ ID NO: 79.

[0067] In some embodiments, the anti-δ1 antibody preferentially binds to a γδ1 TCR relative to a γδ2 TCR or a or γδ3 TCR. In a specific embodiment, the anti-δ1 antibody does not bind to a T cell receptor comprising a δ-2 chain and a γ chain.

[0068] In some embodiments, the anti-δ1 antibodies described herein cross-react with human δ-1 chains and non-human mammalian δ-1 chains; for example, non-human primate δ-1 chains. In a specific example, the non-human primate δ-1 chain is a cynomolgus monkey δ-1 chain.

[0069] In some embodiments, the anti-δ1 antibodies described herein are capable of binding to γδ1 TCRs comprising various γ chains, including γ3, 4, 5, 8, or 9. In some embodiments, the anti-δ1 antibodies described herein are capable of binding to γδ1 TCRs comprising various γ chains, including γ3, 4, 5, and 8. In some embodiments, the anti-δ1 antibodies described herein cross-react with human δ-1 chains and non-human mammalian δ-1 chains, such as non-human primate δ-1 chains, and are capable of binding to γδ1 TCRs comprising various γ chains, including γ3, 4, 5, and 8. Non-limiting examples of such antibodies described herein include δ1-39 and δ1-41. In some examples, such antibodies are δ1-38, δ1-39, δ1-40, and δ1-41.

[0070] Any anti-δ1 antibody described herein can be a full-length antibody (e.g., an IgG molecule) or an antigen-binding fragment thereof. In some examples, the antibody is a Fab, F(ab')2, or a single-chain antibody. In any case, the antibody can be a human antibody or a humanized antibody. In some embodiments, the antibody is an antibody drug conjugate. In some embodiments, the antibody is an antibody mimetic.

[0071] On the other hand, the present disclosure provides isolated nucleic acids or nucleic acid groups that encode or co-encode any anti-δ1 antibody disclosed herein. In some cases, the heavy chain and light chain of the antibody are encoded by two separate nucleic acid molecules (a set of nucleic acids). In other cases, the heavy chain and light chain of the antibody are encoded by one nucleic acid molecule, which can be in a polycistronic form or under the control of different promoters. Therefore, in one aspect, the present disclosure provides an isolated nucleic acid molecule comprising one or more nucleic acid sequences encoding the heavy chain variable region (VH) and / or light chain variable region (VL) of the anti-δ1 antibodies described herein. In some embodiments, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the heavy chain variable region (VH) of the anti-δ1 antibodies described herein. Alternatively or in addition, in some embodiments, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the light chain variable region (VL) of the anti-δ1 antibodies described herein. In a specific embodiment, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL (or heavy chain and / or light chain) of an antibody comprising the heavy chain complementary determining region 1 (CDR1) of SEQ ID NO: 68, the heavy chain complementary determining region 2 (CDR2) of SEQ ID NO: 53, and the heavy chain complementary determining region 3 (CDR3) of SEQ ID NO: 54, and / or comprising the light chain complementary determining region 1 (CDR1) of SEQ ID NO: 55, the light chain complementary determining region 2 (CDR2) of SEQ ID NO: 56, and the light chain complementary determining region 3 (CDR3) of SEQ ID NO: 57. Thus, in some embodiments, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL (or heavy chain and / or light chain) of an antibody comprising the VH of SEQ ID NO: 24 and / or the VL of SEQ ID NO: 9. In one example, the one or more nucleic acid sequences encode the VH and / or VL (or heavy chain and / or light chain) of G9.2-17.

[0072] In some embodiments, the nucleic acid or nucleic acid group is located on one or two vectors, for example, one or two vectors can be one or two expression vectors. Thus, the vector can comprise any of the isolated one or more nucleic acid molecules described herein. In addition, the present disclosure provides host cells comprising any of the isolated nucleic acids or nucleic acid groups encoding the anti-delta 1 antibodies described herein. In some embodiments, the host cell is selected from Escherichia coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells.

[0073] Also provided herein is a method of producing an anti-δ1 antibody, comprising culturing the host cell described herein under suitable conditions that allow expression of the antibody, and harvesting the antibody thereby produced from the cell culture (eg, from the culture medium).

[0074] Furthermore, the present disclosure provides a pharmaceutical composition comprising any anti-δ1 antibody or nucleic acid(s) encoding such an antibody, and a pharmaceutically acceptable carrier.

[0075] In yet another aspect, the present disclosure features a method of inhibiting the activity and function of immunosuppressive γδT cells, such as γδ1 T cells, in a subject, the method comprising administering to a subject in need thereof an effective amount of any anti-δ1 antibody disclosed herein or a pharmaceutical composition comprising such an antibody. Alternatively or in addition, the present disclosure features a method of eliminating or depleting immunosuppressive γδT cells, such as γδ1 T cells, in a subject, the method comprising administering to a subject in need thereof an effective amount of any anti-δ1 antibody disclosed herein or a pharmaceutical composition comprising such an antibody. In some embodiments, the subject in need thereof is a human patient having, suspected of having, or at risk of having a solid cancer. In some embodiments, the present disclosure features a method of treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of any anti-δ1 antibody disclosed herein or a pharmaceutical composition comprising such an antibody. Exemplary solid tumors include, but are not limited to, pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, glioblastoma, upper and lower gastrointestinal malignancies, squamous cell head and neck cancer, genitourinary cancer, ovarian cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, neuroendocrine cancer, adrenocortical carcinoma, or sarcoma. In some examples, an effective amount of the pharmaceutical composition is sufficient to inhibit or block the activity and function of immunosuppressive γδT cells, such as γδ1 T cells.

[0076] Any of the treatment methods described herein may also include administering to the subject an inhibitor of a checkpoint molecule, an activator of a co-stimulatory receptor, an inhibitor of an innate immune cell target, a chemotherapeutic agent, and / or any other anti-cancer therapeutic agent, including but not limited to biologics, small molecule inhibitors, and / or any form of radiotherapy and / or cell-based therapy. Examples of checkpoint molecules include but are not limited to PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIM-3, A2aR, TIGIT, and VISTA. Examples of co-stimulatory receptors include but are not limited to OX40, GITR, CD137, CD40, CD27, and ICOS. Examples of innate immune cell targets include but are not limited to KIR, NKG2A, CD96, TLR, IDO, and galectin-9.

[0077] The scope of the present disclosure also includes (i) pharmaceutical compositions for treating diseases associated with activation of immunosuppressive γδ T cells (e.g., γδ1 T cells), wherein the pharmaceutical composition comprises any of the anti-δ1 antibodies described herein or nucleic acids encoding them (one or more), and a pharmaceutically acceptable carrier; and (ii) use of the anti-δ1 antibodies or encoding nucleic acids in the preparation of a medicament for treating a target disease described herein.

[0078] Another aspect of the present disclosure provides a method for analyzing a biological sample from a subject suspected of having a solid tumor (e.g., a metastatic solid tumor or a recurrent or refractory solid tumor), the method comprising: (i) providing a biological sample from a subject suspected of having a solid tumor; and (ii) measuring the level of δ1 in the biological sample with an antibody that specifically binds to δ1. In some embodiments, the subject is suspected of having a solid tumor, such as a metastatic solid tumor or a recurrent or refractory solid tumor. Examples include, but are not limited to, pancreatic adenocarcinoma (PDA), colorectal cancer (CRC), hepatocellular carcinoma (HCC), breast cancer (e.g., ductal carcinoma), and bile duct cancer. In some embodiments, the subject is suspected of having a metastatic solid tumor. In other embodiments, the subject is suspected of having a recurrent or refractory solid tumor. Examples include, but are not limited to, metastatic pancreatic adenocarcinoma (PDA), metastatic colorectal cancer (CRC), metastatic hepatocellular carcinoma (HCC), breast cancer (e.g., ductal carcinoma), and bile duct cancer.

[0079] In some embodiments, the biological sample can be a serum sample or a plasma sample. In other embodiments, the biological sample can be a tumor biopsy sample. For example, in some embodiments, the tumor biopsy sample comprises a patient-derived organotypic tumor spheroid (PDOT). For example, in some embodiments, the tumor biopsy sample comprises TIL.

[0080] The antibody can be any antibody described herein, e.g., comprising the same heavy and light chain complementary determining regions (CDRs) as the reference antibody delta 1-39, e.g., comprising a heavy chain variable domain of SEQ ID NO: 24, and / or a light chain variable domain of SEQ ID NO: 9. In some cases, the antibody can be a Fab molecule. In some embodiments, the antibody is a different anti-delta 1 antibody known in the art.

[0081] In some embodiments, an immunoassay is used to determine the level of δ 1 in a biological sample. In some embodiments, the assay is flow cytometry.

[0082] In some embodiments, if the level of δ1 measured in step (ii) is elevated relative to the control level, the methods disclosed herein further comprise identifying the subject as a suitable candidate for treatment involving an anti-δ1 antibody. The suitable candidate is administered an effective amount of an anti-δ1 antibody, such as those described herein, alone or in combination with a checkpoint inhibitor, such as those described herein.

[0083] In some embodiments, the δ1 level measured in step (ii) is used to identify or select cancer patients who may respond to anti-δ1 targeted therapy. In some embodiments, the δ1 level is measured in blood, serum and / or plasma. In some embodiments, the δ1 level is measured on the surface of cancer cells or immune cells derived from tumors and / or the blood of cancer patients. In some examples, the cancer cells are in tumor organoids derived from human patients. In some examples, the immune cells are in tumor organoids derived from human patients. In some embodiments, the immune cells include macrophages, α / β T cells and / or γ / δ T cells.

[0084] The details of one or more embodiments of the present invention are set forth in the following description. Other features and advantages of the present invention will be apparent from the following drawings and detailed description of several embodiments, as well as from the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] The following drawings constitute part of this specification and are included to further illustrate certain aspects of the present disclosure, which may be better understood by reference to the drawings in combination with the detailed description of specific embodiments presented herein.

[0087] Figure 1 The figure shows an immunohistochemical analysis of human pancreatic cancer tissue compared with normal pancreas, demonstrating the enrichment of γδ T cells in pancreatic cancer tissue compared with normal tissue.

[0088] Figure 2 is a bar graph depicting the percentage of total T cells in peripheral blood and tumors, demonstrating the enrichment of γδ T cells in pancreatic cancer tissue compared to peripheral blood.

[0089] Figures 3A-3C Depicted are bar graphs showing co-culture assays of γδ (gdT) and αβ T cells (abT). γδ cells were derived from tumor or blood, and as indicated, αβ T cells were derived from the blood of the same patient. The graph depicts the % TNF-α+ cells obtained when blood αβ T cells were cultured alone or co-cultured with intratumoral and blood γδ T cells. Activation of blood αβ T cells by ligation with CD3 / CD28 resulted in an increase in TNF-α measured by FACS. Column 1: unactivated αβ T cells; Column 2: activated αβ T cells; Column 3: activated αβ T cells co-cultured with blood γδ T cells; Column 4: activated αβ T cells co-cultured with tumor γδ T cells. Figure 3A : Cells derived from colorectal cancer patients. Figure 3B and 3C : Cells derived from two individual pancreatic cancer patients.

[0090] Figures 4A-4C Depicted are bar graphs showing immune profile expression in gastrointestinal neuroendocrine tumor samples (PDOTS) untreated (Utx) and treated with isotype (hIgG1) compared to two anti-δ1 IgG1 antibodies (δ1-23 and δ1-17 as examples). CD8 + The percentage of TNF-α in T cells ( Figure 4A ), CD8 + The percentage of IFNγ in T cells ( Figure 4B ) and CD8 + The percentage of CD44 in T cells ( Figure 4C ).

[0091] Figure 5A and 5B The bar graph depicts immune profile expression in breast cancer liver metastasis tumor samples (PDOTS) untreated (Utx) and treated with isotype (hIgG1) compared to two anti-δ1 IgG1 antibodies (δ1-23 and δ1-17 as examples). CD3 + The percentage of TNF-α in T cells ( Figure 5A ) and CD3 + The percentage of CD44 in T cells ( Figure 5B ).

[0092] Figures 6A-6N Depicted are binding titrations of anti-δ1 antibodies to purified γ / δ TCRs, as measured using a bead binding assay. Human γ9 / δ1C (denoted "human D1"), cynomolgus monkey γ / δ1A ("cynomolgus D1"), and cynomolgus monkey γ / δ2 ("cynomolgus D2") were tested.

[0093] Figures 7A-7L Depicted are binding titrations of the anti-δ1 antibodies δ1-17 and δ1-23 to purified γ / δ TCRs composed of different subunits.

[0094] Figure 8 Shown are traces of thermal shift assays used to determine the thermal stability of delta 1 -specific IgG.

[0095] Figures 9A-9I Binding titration of anti-δ1 antibodies to purified γ / δ TCRs, as measured by bead binding assay, is shown. Human γ9 / δ1C (denoted "human D1") and cynomolgus monkey γ / δ1A ("cynomolgus D1") were tested.

[0096] Figures 10A-10D The anti-δ1 antibodies disclosed herein were shown to have high affinity and specificity for δ1. Figure 10A is a surface plasmon resonance (SPR) graph showing that, for example, anti-δ1-17 antibodies have high affinity for human δ1 TCR. Figure 10B Figure 1 shows that the δ1-17 antibody is specific for the δ1 TCR and does not bind to (cross-react with) the δ2 TCR. Three different δ1 variants (D1A, D1B, and D1C) were generated that differ from each other only in the CDR3 loop. δ1 and δ2 Fc fusion proteins were attached to streptavidin-coated beads, and binding titrations were performed with δ1-17 hIgG1. Figure 10C is a graph showing cross-reactivity of the delta 1-41 antibody between humans and monkeys ("cynomolgus monkeys"). Figure 10D is a graph showing that the δ1 antibodies δ1-17, δ1-39, and δ1-41 are specific for the δ1 TCR relative to the δ2 TCR.

[0097] Figure 11A and 11B The anti-delta 1 antibodies disclosed herein were shown to be gamma-independent. Figure 11A It is a diagram showing that δ1-17 is δ1-specific, regardless of the γ chain in the purified δγTCR. Figure 11B Figure 1 demonstrates that several anti-δ1 antibodies (including δ1-39 and δ1-41) are δ1-specific using the cell-surface δγ TCR. Untransduced J.RT3-T3.5 (TIB153) were used as a control to demonstrate the absence of background binding to any other cell-surface receptors found on T cells (data not shown).

[0098] Figures 12A-12D Included are bar graphs showing immune profile expression in tumor samples (PDOTS) treated with an isotype (hIgG1) compared to an anti-δ1 IgG1 antibody (δ1-17 as an example). Figure 12A ), hepatic neuroendocrine tumors ( Figure 12B), colorectal neuroendocrine tumors ( Figure 12C ) and hepatocellular carcinoma ( Figure 12D ) shows CD3 + The percentage of TNF-α in T cells, CD3 + IFNγ percentage and CD3 in T cells + Percentage of CD44 in T cells.

[0099] Figures 13A-13D Included are figures showing the impact of γδ T cells on checkpoint inhibition responses in lung (LLC) and subcutaneous melanoma (B16F10) syngeneic models. Figure 13A and 13B : Graph showing the anti-tumor effects of anti-CTLA-4 antibodies compared to wild-type counterparts in a γδ knockout Lewis lung cancer mouse model versus untreated (13A) or IgG isotype control (13B). Figure 13C and 13D : Graph showing the anti-tumor effects of anti-PD-1 antibodies compared to wild-type counterparts in a γδ knockout melanoma mouse model versus untreated (13C) or IgG isotype control (13D).

[0100] Figures 14A-14G Included are graphs showing the stability of anti-δ1 antibodies δ1-17, δ1-41, and δ1-39 following freeze / thaw, concentration, and filtration. Figure 14A and 14B Stability curves for δ1-41 and δ1-17, respectively. From top to bottom: freeze / thaw once, 3 mg / ml; freeze / thaw once, concentrated to 12 mg / ml; and freeze / thaw once, concentrated to 12 mg / ml, and filtered. Figure 14C and 14D Stability curves of δ1-41 and δ1-17 after 10 days of incubation at 4°C, respectively. From top to bottom: freeze / thaw once, 3 mg / ml; freeze / thaw once, concentrated to 12 mg / ml; and freeze / thaw once, concentrated to 12 mg / ml, and filtered. Figure 14E and Figure 14F The stability curves of δ1-41 and δ1-17 after high temperature storage and freezing and thawing, respectively. From top to bottom: freeze / thaw once; overnight at 37°C (O / N); overnight at room temperature (RT); and freeze / thaw four times. Figure 14G Shown are the stability curves of δ1-39 fresh, frozen and thawed five times, and after 18 hours at 24°C.

[0101] Figures 15A-15CIncluded are graphs showing the antibody-dependent cellular phagocytosis (ADCP) effects of δ1-17 and δ1-41 against targets immobilized on beads. 15A: 1000 nM target on beads. 15B: 100 nM target on beads. 15C: 10 nM target on beads.

[0102] Figures 16A-16C Included are graphs showing the ADCP effect of delta 1-17 and delta 1-41 at various time points, including 1 hour (16A), 4 hours (16B), and 24 hours (16C) at various antibody concentrations as indicated.

[0103] Figure 17 is a graph showing the ADCP effects observed for various anti-δ1 antibodies (eg, δ1-17, δ1-39, and δ1-41) against different target proteins in a bead-based ADCP assay.

[0104] Figure 18A and 18B Included are graphs showing the ADCP effect of anti-delta 1 antibodies in a cell-based ADCP assay. Figure 18A : ADCP effects at different time points as indicated. Figure 18B : ADCP effect of different antibody concentrations.

[0105] Figure 19 Included are graphs showing the antibody-dependent cellular cytotoxicity (ADCC) effect of delta 1-41 at various antibody concentrations as indicated.

[0106] Figures 20A-20B Included are bar graphs showing the level of αβ T cell activation in tumor samples (PDOTS) treated with an isotype (hIgG1) compared to an anti-δ1 IgG1 antibody (δ1-41 as an example) or an anti-PD1 antibody. Figure 20A ) and hepatocellular carcinoma ( Figure 20B ), CD8 + The percentage of TNF-α in T cells, CD8 + IFNγ percentage and CD8 T cells + Percentage of CD44 in T cells.

[0107] Figures 21A-21C Included are bar graphs showing the level of αβ T cell activation in hepatocellular carcinoma tumor samples (PDOTS) treated with anti-δ1 IgG1 antibodies (δ1-17 as an example) in the presence of a co-stimulatory receptor agonist (ICOS agonist) compared to isotype (hIgG1) as a control. + The percentage of CD44 in T cells ( Figure 21A ), CD3 + The percentage of TNF-α in T cells ( Figure 21B ) and CD3 + The percentage of IFNγ in T cells ( Figure 21C ).

[0108] Figures 22A-22C The anti-δ1 antibody δ1-39 disclosed herein was shown to be cross-reactive between humans and monkeys and to have a high affinity for δ1. Figure 22A : Binding of the delta 1-39 antibody to the human delta-1 chain. Figure 22B : Binding of anti-delta 1-39 to monkey ("cynomolgus") delta-1 chain. Figure 22C : List K D Table of values, rate constants, and fitting parameters.

[0109] Figure 23 We show that δ1-39 is specific for δ1 and is independent of the γ chain in purified δγ TCRs.

[0110] Figures 24A-24H The anti-δ1 antibodies disclosed herein were shown to be specific regardless of the gamma combination used in the δγ TCR on the cell surface. Figures 24A-24F : A diagram showing the binding of the δ1-39 antibody to δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9 expressed on the cell surface, respectively. Figure 24G and 24H : Graph showing binding studies where cell surface expressed δ2γ9 and TCRαβ (from the parental Jurkat (E6-1) cell line) served as negative controls and showed no binding by δ1-39.

[0111] Figure 25A and 25B Included are graphs showing the antibody-dependent cellular cytotoxicity (ADCC) effects of δ1-17, δ1-39, and δ1-41 compared to isotype-treated and untreated cells. NK-92 cells expressing additional FcγRs were used as effector cells. Jurkat (J.RT3-T3.5) cell lines expressing δ1 / γ9 were used as target cells and labeled with CFSE dye. Cells were mixed at a 4:1 effector to target ratio and anti-δ1 antibodies or isotypes were added at 100 nM for 1 hour ( Figure 25A ) or 3.5 hours ( Figure 25B After incubation, cells were stained with a fixable viability dye (FVD660) and quantified by flow cytometry.

[0112] Figure 26Included are bar graphs showing the ADCP effect of anti-δ1 antibodies in cell-based ADCP assays using anti-δ antibodies, isotypes, or vehicle on cells expressing δ1 / γ-4, δ1 / γ-9, δ2 / γ-9, or no TCR. For each set of columns, from left to right are: δ1-17, δ1-38, δ1-39, δ1-40, δ1-41, isotype, and no antibody.

[0113] Figure 27 Included figures show specific cell killing in peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors that were treated with delta 1-39, isotypes, or left untreated after isolation. Healthy PBMCs purchased from Stemcell (Cat. No. 70025.1) were treated at 37°C for 1 hour and stained and processed for flow cytometry.

[0114] Figure 28A -C includes graphs showing delta 1-39 mediated killing in various patient samples. Figures 28A-28C Includes graphs showing specific cell killing in patient samples. Figure 28A ), pancreatic ductal carcinoma (PDA; Figure 28B ) and gastrointestinal neuroendocrine tumors (GI-NET; Figure 28C ) Single cell tumor suspensions were treated with delta 1-39, isotypes as indicated overnight at 37°C or left untreated and processed for staining and flow cytometry.

[0115] Figure 29 Results of a receptor internalization assay are shown. Cells expressing the δ1 / γ9 T cell receptor on their surface were incubated in the presence of 100 nM δ-39, isotype antibodies, anti-CD3 (clone OKT3) (azide-free) antibodies, or no antibody. Cells were harvested 1, 3.5, and 24 hours after incubation and processed for staining with anti-δ1 (clone TS8.2) antibodies for flow cytometry.

[0116] Figure 30 A bar graph is shown showing binding of various δ1 clones as indicated to stable cell lines expressing monkey γ / δ TCRs. Jurkat cells lacking TCR expression on their surface were transduced to express monkey δ1 / γ or δ2 / γ receptors. Cells expressing only the γ chain or no TCR were stained as negative controls. Anti-δ1-17 showed no binding to any cynomolgus monkey TCR, while anti-δ1-23 and anti-δ1-32-41 showed specific binding to monkey δ1 containing TCRs on the cell surface.

[0117] Figures 31A-31B Includes demonstration of the use of anti-delta 1 antibodies (anti-delta-39 as an example) from human donors with colorectal cancer ( Figure 31A ) and healthy human donors ( Figure 31B) Graph showing specific δ1 detection in isolated PBMCs.

[0118] Figure 32 Depicted are three bar graphs showing flow cytometric analysis of PBMCs with Dylight-650-conjugated anti-δ1-39 and commercially available anti-δ1 (clone TS8.2), anti-δ2-PE (clone B6), anti-CD3 (clone UCHT-1), and anti-TCR AB (clone IP26). The results show that the staining profiles of directly conjugated anti-δ1-39 and anti-δ1 (clone TS8.2) are similar.

[0119] Figure 33 Flow cytometric analysis of commercially available anti-δ1 (clone TS8.2) is described to determine the levels of δ1-positive T cells in PBMCs from healthy and patients. For most patients tested, δ1 levels were higher than those in healthy donors. The percentage of δ1 T cells was calculated as the fraction of total viable single cells.

[0120] Figure 34 Flow cytometric analysis of δ1 T cell levels in healthy PBMCs versus tumors is described. δ1 levels were measured by staining with a commercially available anti-δ1 antibody (clone TS8.2). Results show that δ1 levels were higher in tumor single-cell suspensions than in healthy donor PBMCs. The percentage of δ1 T cells was calculated as the fraction of total viable CD3-positive single cells. Detailed Description of the Invention

[0122] T cell receptors (TCRs) are disulfide-linked, membrane-anchored heterodimeric proteins expressed on the surface of T cells, where they recognize fragments of antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs) or other types of ligands presented on the cell surface. Most T cells have TCRs that contain an alpha (α) chain and a beta (β) chain (called αβ T cells), while a minority of T cells have TCRs composed of a gamma (γ) chain and a delta (δ) chain (called γδ T cells).

[0123] γδTCT recognizes a variety of self and non-self antigens, such as small peptides, soluble or membrane proteins, phospholipids, pyrophosphate pentenyl esters and sulfatides. Due to its antigenic diversity, γδT cells can play a wide range of different roles. For example, since γδT cell activation does not require antigen presenting cells (APCs) for antigen processing and presentation, γδT cells can be rapidly activated and play a role in the early stages of the immune response. Similar to natural killer (NK) cells, γδT cells also respond to the stimulation of stress and / or infection-induced ligands (Lafont et al., Front Immunol., 2014, 5: 622). Such ligands are usually weakly expressed or not expressed in the normal state because they are only upregulated when there is stress (DNA damage, heat stress) or infection. In addition, human γδT cells also express pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), which regulate their activation (Shojaei et al., Cancer Res., 2009, 69 (22): 8710-8717).

[0124] It has been found that γδT cells are anti-tumorigenic and pro-tumorigenic depending on widely different conditions (Lafont et al., Front Immunol., 2014, 5: 622). With regard to pancreatic ductal adenocarcinoma (PDA), it has been found that γδT cells account for a considerable proportion of tumor-infiltrating T cells, and they have an inhibitory function on αβT cell-mediated anti-cancer immunity. In mouse models, it was found that the loss, depletion or blocking of γδT cell recruitment was protective against PDA and led to an increase in the infiltration, activation and Th1 polarization of αβT cells (Daley et al., Cell, 2016, 166: 1485-1499). In particular, it was found that the δ1 subtype of the γδT cell receptor was enriched in tumor-infiltrating T cells.

[0125] Thus, antibodies specific for γδ T cells (e.g., specific for the δ-1 chain of a TCR comprising a δ-1 chain and a γ chain; "anti-δ-1 antibodies") may be promising therapeutic agents for treating diseases associated with tumor-infiltrating γδ T cells (e.g., diseases in which tumor-infiltrating γδ T cells play an immunosuppressive role) or circulating γδ T cells, which can block conventional T cell activation and thereby block the immune response to pathological cells (e.g., cancer cells). Without being bound by theory, anti-δ1 antibodies may block the suppressive function of γδ T cells expressing this class, thereby enhancing the anti-tumor immune response. Thus, the antibodies may prevent the direct or indirect inhibition of α-β T cell activity. The antibodies may inhibit γδ T cell cytokine secretion (e.g., IL-17), thereby preventing the induction of angiogenesis and the attraction of MDSCs, neutrophils, and TAMs. The antibodies may inhibit the Treg / Th2 type activity of γδ T cells, thereby preventing the restriction of anti-tumor γδ T cells. In addition, the antibody can prevent the interface of tumor-promoting γδ T cells with dendritic cells (DCs), thereby preventing the inhibition of DC maturation, the induction of DC and / or T cell senescence, and preventing the limitation of DC antigen presentation due to the presence of γδ T cells. Alternatively, the anti-δ1 antibody can also exert its therapeutic effect by inducing cytotoxicity (e.g., ADCC, ADCP and / or CDC) against target γδ T cells. Pathological cells refer to cells that directly or indirectly contribute to the initiation and / or development of the disease. In some embodiments, the anti-δ1 antibody is an antibody drug conjugate and exerts its effect by targeting the chemotherapeutic agent to the tumor site.

[0126] Thus, described herein are antibodies specific for γδ T cells (eg, anti-δ1 antibodies) and their therapeutic use to rescue the suppression of conventional T cell activity mediated by γδ T cells and / or to treat diseases associated with γδ T cell activation.

[0127] Antibodies that bind to the δ1 chain of γδ T cells

[0128] The present disclosure provides antibodies specific for γδT cells of an appropriate species (e.g., humans or non-human primates, such as monkeys, chimpanzees, or apes), for example, antibodies specific for γδ1T cells. Such antibodies can specifically bind to the δ1 chain of the TCR expressed on γδ1T cells. In some embodiments, the antibodies described herein bind to the δ1 chain in a γδ1 heterodimer (e.g., a δ1 / and γ chain, such as a γ9 heterodimer) that can be expressed on the surface of γδ1T cells.

[0129] The anti-δ1 chain antibodies disclosed herein may exhibit one or more advantageous characteristics, including but not limited to: (i) high binding affinity to a variety of human δ1 TCRs, regardless of their CDR sequences, and in particular regardless of their CDR3 sequences (e.g., a K of less than 12 nM);D , such as clones δ1-19, δ1-26, δ1-29, and δ-39); (ii) cross-reactivity of human δ1 TCR and non-human primate δ1 TCR, such as cynomolgus monkey δ1 TCR (e.g., K D (iii) are able to bind to γδ1 TCRs containing various γ chains, including γ3, 4, 5, 8, or 9, such as δ1-38, δ1-39, δ1-40, and δ1-41; and / or (iv) bind to δ-1 with high specificity, such as with very high specificity compared to other targets. Little or no binding, for example, as determined by protein array analysis; (v) inhibiting γδ-T cell activity, i.e., inhibiting γδ-T cell-mediated inhibition of T cell activation, such as CD4+ and / or CD8+ cells (e.g., δ1-23, δ1-39) (vi) promoting inflammatory T cell activation (i.e., promoting activation of CD4+ helper cells and / or CD8+ effector cells) (vii) depleting γδ-T cells, for example, by ADCC, CDC and / or ADCP.

[0130] Accordingly, in some embodiments, the anti-δ1 chain antibodies disclosed herein (also referred to herein as "anti-δ1 antibodies") exhibit one or more advantageous characteristics. In some embodiments, the anti-δ1 chain antibodies disclosed herein have high binding affinity to a variety of human δ1 TCRs, regardless of their CDR sequences, and in particular, regardless of their CDR3 sequences. In some embodiments, the K of human δ-1 is D In some embodiments, the K for human δ-1 is less than 10 nM. D The value is less than 5 nM or less than 2 nM. In some embodiments, the K for human delta-1 D The value is less than 1 nM. The K D A non-limiting example of an antibody with a K value below 1 nM is δ1-39. In some embodiments, the cross-reactivity of a human δ1 TCR and a non-human primate δ1 TCR, such as a cynomolgus monkey δ1 TCR (e.g., K for human and cynomolgus monkey δ1 TCR) is D The difference in values is within one order of magnitude. D The K values for cynomolgus monkey δ1 TCR D A non-limiting example of an antibody with a K value within an order of magnitude is δ1-39. In some embodiments, the anti-δ1 chain antibodies disclosed herein have high binding affinity to a variety of cynomolgus monkey δ1 TCRs regardless of their CDR sequences, and in particular regardless of their CDR3 sequences. In some embodiments, the K value for cynomolgus monkey δ-1 is within an order of magnitude. DIn some embodiments, the K for cynomolgus monkey delta-1 is less than 10 nM. D The value is less than 5 nm or less than 2 nm. In some embodiments, the K value of cynomolgus monkey delta-1 is less than 5 nm or less than 2 nm. D The value is less than 1nm. D A non-limiting example of an antibody with a value below 1 nm is δ1-39. In some embodiments, the anti-δ1 chain antibodies disclosed herein are capable of binding to γδ1 TCRs containing various γ chains. In some embodiments, the anti-δ1 chain antibodies disclosed herein are capable of binding to γδ1 TCRs containing γ chains 3, 4, 5, 8, and / or 9. For example, in a specific embodiment, the anti-δ1 chain antibodies disclosed herein are capable of binding to γδ1 TCRs containing γ chains 3, 4, 5, and 8, for example, including δ-38, δ1-39, δ1-40, and δ1-41. A non-limiting example of an anti-δ1 antibody disclosed herein that is capable of binding to γδ1 TCRs containing γ chains 3, 4, 5, 8, and 9 is δ1-39. In some embodiments, the anti-δ1 antibodies described herein cross-react with human δ-1 chains and non-human mammalian δ-1 chains (e.g., non-human primate δ-1 chains) and are capable of binding to γδ1 TCRs containing various γ chains, including γ3, 4, 5, and 8. Non-limiting examples of such antibodies described herein include δ1-39 and δ1-41. Other examples include δ1-38 and δ1-40. In some embodiments, the antibody binds to δ-1 with high specificity, for example, as determined by protein array analysis. A non-limiting example of such antibodies is clone δ1-39. In some embodiments, the anti-δ1 chain antibodies disclosed herein inhibit γδ-T cell-mediated inhibition or suppression of T cell activation. In some embodiments, the anti-δ1 antibodies described herein inhibit the inhibitory activity of γδ-T cells. In some embodiments, the anti-δ1 chain antibodies disclosed herein can promote inflammatory T cell activation, for example, as shown herein for δ1-39. In some embodiments, the anti-δ1 chain antibodies disclosed herein can activate CD4+ helper cells and / or CD8+ effector cells, for example, in tumors or peripheral blood. In some embodiments, the anti-δ1 chain antibodies disclosed herein can deplete γδ-T cells, for example, by ADCC, CDC, and / or ADCP.

[0131] Antibodies (singular and plural forms are used interchangeably) are immunoglobulin molecules that are able to specifically bind to targets, such as carbohydrates, polynucleotides, lipids, polypeptides, etc., through at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" includes not only complete (i.e., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (e.g., Fab, Fab', F(ab')2, Fv), single chains (scFv), mutants thereof, fusion proteins comprising antibody portions, humanized antibodies, chimeric antibodies, diabodies, nanobodies, linear antibodies, single-chain antibodies, multispecific antibodies (e.g., bispecific antibodies), and any other modified configuration of immunoglobulin molecules comprising antigen recognition sites of desired specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. Antibodies include antibodies of any class, such as IgD, IgE, IgG, IgA, or IgM (or subclasses thereof), and antibodies do not need to be of any particular class. Based on the antibody amino acid sequence of the constant domain of its heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[0132] The term "antibody" is also meant to include so-called antibody mimetics. Antibody mimetics refer to small molecules, for example 3-30 kDa, which can be single amino acid chain molecules that can specifically bind to antigens but do not have antibody-related structures. Antibody mimetics and their protein scaffolds, include but are not limited to Affibody molecules (Z domain of protein A), Affilin (γ-B crystal), ubiquitin, Affimer (cysteine protease inhibitor), Affitin (Sac7d (from Sulfolobus acidocaldarius)), Alphabodies (triple helical coiled coil), Anticalin (liposoluble protein), Avimers (domains of various membrane receptors), DARPin (ankyrin repeat motif), Fynomer (SH3 domain of Fyn), Kunitz domain peptide (Kunitz domain of various protease inhibitors), Ecalantide (Kalbitor) and monomer (fibronectin type III domain). Therefore, in some embodiments, the anti-δ1 antibody is an antibody mimetic.

[0133] In some embodiments, the anti-δ1 antibody is an antibody drug conjugate (ADC). ADCs typically include a monoclonal antibody directed against a target present on a cell, a cytotoxic drug, and a linker for attaching the antibody to the drug. Carter & Senter (2008), Cancer J. 14 (3): 154-69 and Chari et al (2014) Angewandte Chemie International Edition 53: 3751 review antibody drug conjugates for cancer therapy. The cytotoxic moiety can be a polypeptide that can be directly or indirectly cytotoxic. When indirectly cytotoxic, the polypeptide can have enzymatic activity and can convert a relatively nontoxic prodrug into a cytotoxic drug (e.g., antibody-directed enzyme prodrug therapy; ADEPT). The cytotoxic moiety may comprise a drug selected from the group consisting of: cytostatics (e.g., taxanes (e.g., docetaxel, particularly paclitaxel)); alkylating agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., 25-thiopurine, methotrexate); antimitotics (e.g., vincristine); topoisomerase inhibitors (e.g., doxorubicin, etoposide, etc.). The cytotoxic moiety may be any known chemotherapeutic agent. The cytotoxic moiety may be an enteric bacterial toxin, particularly Pseudomonas exotoxin 20A or calicheamicin. The cytotoxic moiety may also comprise a radioactive atom. The radioactive atom is typically selected from the group consisting of iodine-123; iodine-125; iodine-131; indium-111; bromine-77; copper-67; arsenic-77; astatine-211; actinium-15225; bismuth-212; bismuth-213; bismuth-217; lutetium-177; holmium-166; phosphorus-33; platinum-193; platinum-195; rhenium-186; rhenium-188; strontium-89; yttrium-90; gold-199, palladium-100; and antimony-211. In some embodiments, the cytotoxic moiety is capable of inhibiting at least one activity of a cell expressing a delta 1 TCR. In some embodiments, the cytotoxic moiety is capable of inactivating or killing a cell. To facilitate coupling between the cytotoxic moiety and the antibody, the two agents can be directly conjugated, or a spacer molecule can be introduced between them. Suitable spacers include polyalkylene glycols (eg polyethylene glycol) and peptide linkers.Many suitable coupling techniques are well known in the art.Suitable reagents that allow for covalent, electrostatic, or non-covalent binding of moieties to antibodies include benzoquinones, carbodiimides and more specifically EDC (1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide hydrochloride), dimaleimides, dithiodinitrobenzoic acid (DTNB), N-succinimidyl S-acetylthioacetic acid (SATA), ultraviolet (UV)-reactive bridging agents having one or more phenyl azide groups and preferably N-[-4-(azidosalicylamino)butyl]-3'-(2'-pyridyldithio)-propionamide (APDP), N-succinimidyl-3-(2-25 pyridyldithio) propionate (SPDP), 6-hydrazinonicotinamide (HYNIC). Another form of coupling, particularly for radioactive elements, involves the use of bifunctional ion chelators. For example, chelates derived from EDTA or DTPA have been developed for binding metals, particularly radioactive metals, to immunoglobulins. Therefore, DTPA and its derivatives can be substituted with different groups on the carbon chain to increase the stability and rigidity of the ligand-metal complex, which is well known in the art.

[0134] In some embodiments, anti-δ1 antibodies are conjugated to drugs to produce antibody drug conjugates (ADCs). In some embodiments, anti-δ1 antibodies are antibody drug conjugates (ADCs). Suitable cytotoxic agents that can be conjugated to anti-δ1 antibodies are described herein and are known in the art. In some embodiments, the linker is cleavable. Non-limiting examples of linkers include disulfide-bond-containing linkers that can be cleaved by disulfide exchange, acid-resistant linkers that can be cleaved at acidic pH, and linkers that can be cleaved by hydrolases (e.g., glycosyl hydrolases, such as glucuronidase), esterases, and peptidases (e.g., peptide linkers and glucuronide linkers). In some embodiments, the linker is non-cleavable. In some embodiments, the drug is released via a proteolytic antibody degradation mechanism.

[0135] A typical antibody molecule includes a heavy chain variable region (V H ) and light chain variable region (V L ), which are usually involved in antigen binding. H and V L The V region can be further subdivided into regions of high variability, also called "complementarity determining regions" ("CDRs"), interspersed with more conserved regions, called "framework regions" ("FRs"). H and V LTypically, it is composed of three CDRs and four FRs, arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework regions and CDRs can be precisely identified using methods known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, the EU definition, and / or the contact definition, all of which are well known in the art. For example, see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242, Chothia et al. (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al. (1997) J. Molec. Biol. 273:927-948; Edelman et al., Proc Natl Acad Sci US A. 1969 May; 63(1):78-85; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs). For example, the correspondence or comparison between C numbers according to different definitions can be found at http: / / www.imgt.org / .

[0136] The antibodies described herein may be capable of binding to a T cell receptor delta-1 polypeptide (anti-delta-1 antibody), which may be of a suitable origin, such as human or non-human mammals (e.g., rabbits, primates such as monkeys, etc.).

[0137] The anti-δ1 antibodies described herein may be full-length antibodies comprising two heavy chains and two light chains, each comprising a variable domain and a constant domain. Alternatively, the anti-δ1 antibodies may be antigen-binding fragments of full-length antibodies. Examples of binding fragments encompassed by the term "antigen-binding fragment" of a full-length antibody include (i) Fab fragments, which consist of V L 、V H 、C L and C H 1 domain; (ii) F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bond in the hinge region; (iii) H and C H1 domain; (iv) a V fragment consisting of a single arm of the antibody L and V H (v) dAb fragments (Ward et al., (1989) Nature 341: 544-546), which consist of one or more V H domain composition (e.g., including but not limited to VHH domains (camelid or nanobodies); and (vi) separate complementarity determining regions (CDRs) that retain functionality. In addition, although the two domains V L and V H are encoded by separate genes, but they can be linked using recombinant methods with synthetic linkers, enabling them to form a single protein chain, where V L and V H The regions pair to form a monovalent molecule known as a single-chain Fv (scFv). See, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0138] In some embodiments, the antibodies described herein specifically bind to the corresponding target antigen or epitope thereof, for example, specifically bind to the delta-1 chain of the T cell gamma delta 1 receptor. An antibody that "specifically binds" to an antigen or epitope is a term well known in the art. If a molecule reacts more frequently, more rapidly, longer-lastingly, and / or with a higher affinity to a specific target antigen than to other targets, the molecule is said to exhibit "specific binding." If an antibody binds to a target antigen or epitope with a higher affinity, a higher avidity, more readily, and / or longer-lasting affinity than it binds to other substances, the antibody "specifically binds" to the target antigen or epitope. For example, an antibody that specifically (or preferentially) binds to an antigen (e.g., the delta-1 chain of a human TCR) or an antigenic epitope therein is an antibody that binds to the target antigen with a higher affinity, a higher avidity, more readily, and / or longer-lasting affinity than it binds to other antigens (e.g., the delta-2 chain of a human TCR) or other epitopes in the same antigen. It can also be understood from this definition that, for example, an antibody that specifically binds to a first target antigen may or may not specifically or preferentially bind to a second target antigen. Therefore, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. In some examples, an antibody that "specifically binds" to a target antigen or an epitope thereof may not bind to other antigens or other epitopes on the same antigen, i.e., only baseline binding activity may be detected in conventional methods. Baseline binding activity refers to the binding activity detected in conventional methods when no antigen (blank control) or a different antigen (negative control) is used.

[0139] The specificity of the anti-δ1 antibodies described herein can be measured using protein arrays to generate specificity scores (S scores) as described herein and known in the art (see, e.g., Jeong et al., Mol Cell Proteomics. 2012 Jun; 11(6):0111.016253). In addition, by comparing the K values of the anti-δ1 antibodies for binding to d1, the specificity scores (S scores) can be calculated. D and K bound to d2 D , to assess the specificity of the anti-δ1 antibodies described herein.

[0140] In some embodiments, the anti-δ1 antibodies described herein bind to a motif shared by the TCRδ-1 chain. The sequences of the TCRδ-1 chain (e.g., human TCRδ-1 chain, cynomolgus monkey TCRδ-1 chain, or TCRδ chains from other species) are well known in the art and can be found in publicly available databases, such as the International Immunogenetics Information System. Database (imgt.org) or GenBank. In some instances, anti-δ1 antibodies may cross-react with different human or cynomolgus monkey δ1 chains.

[0141] Exemplary amino acid sequences of the extracellular region (lacking the transmembrane domain and cytoplasmic tail) of the delta 1 chain (human and cynomolgus monkey) are provided below:

[0142] Human TCR:

[0143] AQKVTQAQSSVSMPVRKAVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSDEQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFCALGVYAHSLTGGYRGGADKLIFGKGTR VTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISSPGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDDFEVKTDSTDHVKPKETENTKQPSKS(SEQ ID NO:26)

[0144] Human TCR:

[0145] AQKVTQAQSSVSMPVRKAVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSDEQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFCALGPRPSYSEELGDTHRADKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKS(SEQ ID NO:27)

[0146] Human TCR:

[0147] AQKVTQAQSSVSMPVRKAVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSDEQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFCALGEPNHFLNTDKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKS(SEQ ID NO:28)

[0148] Cynomolgus macaque TCR:

[0149] AQKVTQAQSSVSMPVEKAVTLNCQYETSSWSYDLFWYKQLPGKEMIFLIRQGSSEQNARDGRYSVNFKKEASFIALTISALQLEDSATYFCALRRPFTAQLFFGKGTQLIVEPERQPHTKPSVFVMKNGTNVACLVKDFYPKDIRINLESSKKITEFDPAIVVSPSGKYNAVKLGQYADSNSVTCSVQHNKEVVYSTDFEVKTNSTDHLKPTETENTKQPSKS(SEQ ID NO:32)

[0150] Cynomolgus macaque TCR:

[0151] AQKVTQAQSSVSMPVGKAVTLNCQYETSSWSYYLFWYKQLPGKEMIFLIHQGSSQQNARNGRYSVNFQKAASSITLTISALQLEDSATYFCALRERPPNPGPFVLGVYATAQLFFGKGT QLIVEPERQPHTKPSVFVMKNGTNVACLVKDFYPKDIRINLESSKKITEFDPAIVVSPSGKYNAVKLGQYADSNSVTCSVQHNKEVVYSTDFEVKTNSTDHLKPTETENTKQPSKS(SEQ ID NO:33)

[0152] Cynomolgus monkey TCR:

[0153] AQKVTQAQSSVSMPVEKAVTLNCQYETSWWSYDLFWYKQLPGKEMIFLIRQSSSEQNARDGRYSANFKKEASSKSFIALTISALQLEDSATYFCALPLQVRGPTGGIRVYDKLIFGKGT RVTVEPKRQPHTKPSVFVMKNGTNVACLVKDFYPKDIRINLESSKKITEFDPAIVVSPSGKYNAVKLGQYADSNSVTCSVQHNKEVVYSTDFEVKTNSTDHLKPTETENTKQPSKS(SEQ ID NO:34)

[0154] As used herein, "cross-reactivity" refers to an antibody that exhibits binding activity (detectable by conventional assays) to two or more different antigen sequences (e.g., human δ1 and δ2). Such antibodies may have substantially similar binding affinities to these antigens, for example, having a binding affinity for one antigen determined under the same assay conditions that is higher than <10 times (e.g., <5 times or <2 times) the binding affinity for the other antigen. Alternatively, such an antibody may have a substantially higher binding affinity for one of these antigens relative to the other, for example, having a binding affinity for one antigen determined under the same assay conditions that is at least 10 times higher (e.g., 20 times higher, 50 times higher, 100 times higher, or 1000 times higher) than the binding affinity for the other antigen.

[0155] In some embodiments, the anti-δ1 antibodies described herein preferentially bind to a single human δ1 chain. In some embodiments, the antibody binds to the δ1 chain, regardless of the sequence of the CDR region (e.g., CDR3 region). In some embodiments, the anti-δ1 antibody preferentially binds to human δ1 relative to human δ-2 chain, human δ-3 chain, γ chain (e.g., γ-9 chain) and / or non-human δ1 chain. As used herein, an antibody "preferentially binds" to a first antigen or an epitope thereof, as compared to a second antigen or another epitope, means that the binding affinity of the antibody to the first antigen or an epitope thereof is significantly higher, e.g., at least 10 times higher (e.g., >20 times, >50 times, >100 times, >1000 times, or more), relative to the second antigen or another epitope, as measured under the same assay conditions.

[0156] The anti-δ1 antibodies described herein may preferentially bind to human δ1 chains relative to their non-human counterparts (e.g., non-human primate δ1 chains), or vice versa. In other cases, the anti-δ1 antibodies described herein may cross-react with both human and non-human δ1 chains. For example, the antibodies may cross-react with both human δ1 chains and non-human primate δ1 chains.

[0157] In some cases, the anti-δ1 antibodies described herein do not bind to human δ-2 chains, human δ-3 chains, or gamma chains (e.g., gamma-9 chains). In some embodiments, the anti-δ1 antibodies do not bind to the δ-2 chain (referred to herein as δ2). In some embodiments, the anti-δ1 antibodies do not bind to the δ-3 chain (referred to herein as δ3). In some embodiments, the anti-δ1 antibodies do not bind to either the δ-2 chain or the δ-3 chain. An antibody that does not bind to an antigen means that no meaningful binding can be detected using conventional assays (e.g., ELISA or surface plasmon resonance) (e.g., only background binding or no binding at all).

[0158] In some embodiments, the antibodies described herein - anti-δ1 antibodies bind to a T cell receptor comprising a δ1 chain and a γ chain. The sequences of γ chains are known in the art (e.g., see imgt.org / IMGTrepertoire). Non-limiting examples of γ chains include γ1, γ2, γ3, γ4, γ5, γ5P, γ8, γ9, γ10, γ11, γ-a. Non-limiting examples of γ chains are encoded by the following genes: TRGV1, TRGV2, TRGV3, TRGV4, TRGV5, TRGV5P, TRGV8, TRGV9, TRGV10, TRGV11, and TRGVA. In some embodiments, the antibodies described herein - anti-δ1 antibodies bind to a T cell receptor comprising a δ1 chain and a γ chain known in the art. In some embodiments, the anti-δ1 antibodies described herein may bind to a TCR comprising any γ chain. In some embodiments, the anti-δ1 antibodies described herein may bind to a TCR comprising γ3, 4, 5, 8, and 9. In some embodiments, the anti-δ1 antibodies described herein can bind to TCRs comprising γ3, 4, 5, and 8. The anti-δ1 antibodies described herein preferably have suitable binding affinity for the target antigen (e.g., human δ1 chain) or an antigenic epitope thereof. As used herein, "binding affinity" refers to the apparent binding constant or K A .K A is the dissociation constant (K D The anti-δ1 antibodies described herein may have a specific affinity for the target antigen or antigenic epitope of at least 10 -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 Binding affinity (K D ). The increase in binding affinity corresponds to K D The reduction of K for binding to the second antigen A (or value K D ) compared to the K for binding to the first antigen A Higher (or numerical K D 1, 2, 3, 4, 5, 10, 15, 20, 37.5, 50, 70, 80, 91, 100, 500, 1000, 10000, or 10,000, respectively. 5In some embodiments, any anti-δ1 antibody can be further affinity matured to increase the binding affinity of the antibody to the target antigen or its antigenic epitope.

[0159] Binding affinity (or binding specificity) can be determined by a variety of methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance or spectroscopy (e.g., using fluorescence analysis). Exemplary conditions for assessing binding affinity are in HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P20). These techniques can be used to measure the concentration of bound binding protein as a function of the concentration of target protein. The concentration of bound binding protein ([bound]) is generally related to the concentration of free target protein ([free]) by the following equation:

[0160] [Bound] = [Free] / (Kd + [Free])

[0161] However, it is not always necessary to precisely determine K A , because sometimes quantitative measurements of affinity (e.g., using methods such as ELISA or FACS analysis) are obtained and K A It is sufficient that it is proportional and can therefore be used for comparison, e.g., to determine whether the affinity is higher, e.g., 2-fold higher, to obtain a qualitative measure of affinity, or to obtain an inference of affinity, e.g., by activity in a functional assay such as an in vitro or in vivo assay.

[0162] The anti-δ1 antibodies described herein can inhibit γδT cell activation, that is, reduce the overall activity of γδT cells (e.g., immunosuppressive γδT cells). Without being bound by theory, the anti-δ1 antibodies described herein can inhibit the biological activity of γδ1T cells by directly blocking the activity of γδ1TCR expressed on T cells. Alternatively or in addition, by binding to γδ1TCR, anti-δ1 antibodies can trigger cytotoxicity, such as ADCC and / or ADCP and / or CDC, to eliminate T cells expressing γδ1TCR, resulting in the consumption of γδ1T cells. Therefore, the anti-δ1 antibodies described herein can rescue immunosuppression mediated by γδT cells, for example in a cancer setting.

[0163] In some embodiments, the anti-δ1 antibodies described herein inhibit the activity of γδ1 T cells. In some embodiments, the anti-δ1 antibodies described herein inhibit the activity of γδ1 T cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). In some embodiments, the inhibitory or suppressive efficacy of the anti-δ1 antibody is measured by examining the ability of the antibody to "rescue" immune cells, such as αβ T cells, from the inhibitory activity of γδ T cells. In some embodiments, the anti-δ1 antibodies described herein can rescue immunosuppression induced by γδ1 T cells. The anti-δ1 antibodies described herein can rescue immunosuppression induced by γδ1 T cells by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0164] In some embodiments, the anti-δ1 antibodies as described herein are capable of eliminating γδ1 T cells, i.e., consuming γδ1 T cells, for example, from the tumor microenvironment and / or serum, blood, or circulation. In some embodiments, the anti-δ1 antibodies as described herein are capable of eliminating γδ1 T cells from the tumor microenvironment, i.e., consuming γδ1 T cells. In some embodiments, the anti-δ1 antibodies described herein deplete γδ1 T cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). In some embodiments, the ability of the anti-δ1 antibody is measured by examining the ability of the antibody to "rescue" immune cells, such as αβ T cells, from the inhibitory activity of γδ T cells. In some embodiments, the anti-δ1 antibodies described herein can rescue immunosuppression induced by γδ1 T cells. The anti-δ1 antibodies described herein can rescue immunosuppression induced by γδ1 T cells by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0165] In some embodiments, the anti-δ1 antibodies described herein are capable of eliminating γδ1 T cells from the tumor microenvironment, i.e., depleting γδ1 T cells. In some embodiments, the anti-δ1 antibodies as described herein deplete γδ1 T cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). In some embodiments, the inhibitory or suppressive efficacy of the anti-δ1 antibody is measured by examining the ability of the antibody to "rescue" immune cells, such as αβ T cells, from the inhibitory activity of γδ T cells. In some embodiments, the anti-δ1 antibodies described herein can rescue immunosuppression induced by γδ1 T cells. The anti-δ1 antibodies described herein can rescue immunosuppression induced by γδ1 T cells by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0166] In some embodiments, the anti-δ1 antibodies described herein activate ADCC. In some embodiments, the anti-δ1 antibodies described herein activate ADCC by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). In some embodiments, the ability of an antibody to activate ADCC is measured according to one or more methods described herein.

[0167] In some embodiments, the anti-δ1 antibodies described herein activate ADCP. In some embodiments, the anti-δ1 antibodies described herein activate ADCP by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). In some embodiments, the ability of an antibody to activate ADCP is measured according to one or more methods described herein.

[0168] In some embodiments, the anti-δ1 antibodies described herein activate or reactivate CD4+ helper cells and / or CD8+ effector cells in tumors and / or peripheral blood. In some embodiments, the anti-δ1 antibodies described herein activate or reactivate CD4+ helper cells and / or CD8+ effector cells in tumors and / or peripheral blood by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In some embodiments, the ability of anti-δ1 antibodies to activate CD4+ and / or CD8+ cells is measured by examining the levels of proinflammatory cytokines. In some embodiments, anti-δ1 antibodies are capable of increasing the production of proinflammatory cytokines in tumors, including but not limited to IFNγ, TNF-α, and CD44. In some embodiments, the anti-δ1 antibody is capable of increasing the production of proinflammatory cytokines in a tumor by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein), including but not limited to IFNγ, TNF-α, and CD44.

[0169] In some embodiments, the anti-δ1 antibodies described herein can modulate, for example, reduce the ratio of γδ1 T cells to γδ2 T cells. In some embodiments, the anti-δ1 antibodies described herein modulate, for example, reduce the ratio of γδ1 T cells to γδ2 T cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0170] In some embodiments, the anti-δ1 antibodies described herein can modulate, for example, reduce the fraction of γδ1 T cells present in PBMCs and / or the fraction of γδ1 T cells present in tumor-localized immune cells. In some embodiments, the anti-δ1 antibodies described herein modulate, for example, reduce the fraction of γδ1 T cells present in PBMCs and / or the fraction of γδ1 T cells present in tumor-localized immune cells by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0171] In some embodiments, an anti-δ1 antibody as described herein can deplete γδ T cells of a tumor. In some embodiments, an anti-δ1 antibody as described herein depletes γδ T cells of a tumor by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0172] In some embodiments, the anti-δ1 antibodies described herein can prevent direct or indirect inhibition of α-βT cell activity. In some embodiments, the anti-δ1 antibodies as described herein can inhibit γδT cell cytokine secretion (e.g., IL-17), thereby preventing the induction of angiogenesis and the attraction of MDSC, neutrophils, and TAMs. In some embodiments, the anti-δ1 antibodies described herein can inhibit the Treg / Th2 type activity of γδT cells, thereby preventing anti-tumor γδT cells from being restricted. In some embodiments, the anti-δ1 antibodies described herein can prevent the junction interface of tumor-promoting γδT cells with dendritic cells (DCs), and thus prevent the inhibition of DC maturation and / or the induction of DC or T cell aging. In some embodiments, the anti-δ1 antibodies described herein can prevent the restriction of DC antigen presentation due to the presence of γδT cells.

[0173] Apparent inhibition constant (Ki app or K i,app ) provides a measure of inhibitor potency that is related to the concentration of inhibitor required to reduce enzyme activity and is independent of enzyme concentration. The inhibitory activity of the anti-δ1 antibodies described herein can be determined by routine methods known in the art.

[0174] Antibody K i , app The value can be determined by measuring the inhibitory effect of varying concentrations of the antibody on the extent of a reaction (e.g., enzyme activity); the change in the pseudo-first-order rate constant (v) as a function of inhibitor concentration is fitted to the modified Morrison equation (Equation 1) to yield an estimate of the apparent Ki value. For competitive inhibitors, Ki app Can be obtained since K i , app The y-intercept was extracted from the linear regression analysis of the plot versus substrate concentration.

[0175]

[0176] where A equals vo / E, which is the initial velocity of the enzymatic reaction (vo) in the absence of inhibitor (I) divided by the total enzyme concentration (E).

[0177] In some embodiments, the anti-delta 1 antibodies described herein may have a Ki of 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 pM or less for the target antigen or antigenic epitope. app In some embodiments, an anti-δ1 antibody may have a lower Ki for a first target (e.g., a specific epitope of δ1) relative to a second target (e.g., a different specific epitope of δ1). app 。Ki app The difference (e.g., for specificity or other comparisons) can be at least 1.5, 2, 3, 4, 5, 10, 15, 20, 37.5, 50, 70, 80, 91, 100, 500, 1000, 10,000, or 10 5 In some examples, the anti-δ1 antibody inhibits the first antigen (e.g., the first protein or its mimetic in a first conformation) better than the second antigen (e.g., the same first protein or its mimetic in a second conformation; or a second protein). In some embodiments, any anti-δ1 antibody can be further affinity matured to reduce the Ki of the antibody to the target antigen or its antigenic epitope. app .

[0178] The antibodies described herein can be of murine, rat, monkey, human, or any other origin (including chimeric or humanized antibodies). Such antibodies are non-naturally occurring, i.e., they are not produced in animals without human action (e.g., immunizing such animals with the desired antigen or fragment thereof or isolating them from an antibody library).

[0179] Any antibody described herein can be monoclonal or polyclonal. "Monoclonal antibody" refers to a homogeneous antibody population, while "polyclonal antibody" refers to a heterogeneous antibody population. These two terms do not limit the source of the antibody or its production method.

[0180] In one example, the antibody used in the methods described herein is a humanized antibody.Humanized antibody refers to the form of non-human (such as mouse) antibody, which is a specific chimeric immunoglobulin, immunoglobulin chain or its antigen-binding fragment, which comprises the minimum sequence derived from non-human immunoglobulin. For most parts, humanized antibody is human immunoglobulin (acceptor antibody), wherein the residues from the CDR of the acceptor are replaced by the residues of the CDR with required specificity, affinity and ability from non-human species (donor antibody) (such as mouse, rat or rabbit). In some cases, the Fv framework region (FR) residues of human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibody can include residues that are neither found in the CDR or framework sequence of the acceptor antibody nor in the imported one, but is included to further improve and optimize antibody performance. Generally speaking, humanized antibody will include substantially all at least one, typically two variable domains, wherein all or substantially all of the CDR regions correspond to those of non-human immunoglobulins and all or substantially all of the FR regions are those of human immunoglobulin consensus sequences. The humanized antibody preferably also comprises at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. The antibody may have a modified Fc region as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (1, 2, 3, 4, 5, or 6) that are altered relative to the original antibody, also referred to as one or more CDRs "derived from" one or more CDRs of the original antibody. Humanized antibodies may also involve affinity maturation.

[0181] Methods for constructing humanized antibodies are also well known in the art. See, for example, Queen et al., Proc. Natl. Acad. Sci. USA, 86: 10029-10033 (1989). In one example, the V of the parent non-human antibody is modified according to methods known in the art. H and V L The variable regions of the parent V sequences were subjected to three-dimensional molecular modeling analysis. Next, the same molecular modeling analysis was used to identify the framework amino acid residues predicted to be important for forming the correct CDR structure. H and V L The sequence is used as a search query to identify human V antibodies with amino acid sequences homologous to those of the parent non-human antibody from any antibody gene database. H and V L Then select Person V H and V L Acceptor gene.

[0182] The CDR regions in the selected human acceptor gene can be replaced with CDR regions from a parental non-human antibody or a functional variant thereof. If necessary, residues in the framework region of the parental chain that are predicted to be important in interacting with the CDR region can be used to replace the corresponding residues in the human acceptor gene.

[0183] In another example, the antibodies described herein are chimeric antibodies, which may include a heavy chain constant region and a light chain constant region from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of an antibody derived from a mammal (e.g., a non-human mammal, such as a mouse, rabbit, and rat), while the constant regions are homologous to sequences in an antibody derived from another mammal (e.g., a human). In some embodiments, amino acid modifications may be made in the variable and / or constant regions.

[0184] In some embodiments, the anti-δ1 antibodies described herein may comprise a heavy chain variable region (V H ), which comprises a heavy chain (HC) CDR1, HC CDR2, and HC CDR3. HC CDR1 may comprise the motif shown as FTX1X2X3X4X5IH (SEQ ID NO: 46), wherein X1 may be F or V, X2 may be S or T, X3 may be G, A or S, X4 may be T, N or S, and X5 may be D or S. In a specific example, HC CDR1 may be FTVSSSSIH (SEQ ID NO: 52). HC CDR2 may comprise the motif shown as SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively or additionally, HC CDR3 may comprise the motif shown as PGX6YYWYYSGSAYEGYGLDY (SEQ ID NO: 48), wherein X6 may be S or M. In a specific example, HC CDR3 may comprise the sequence of DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54).

[0185] Alternatively or additionally, the anti-δ1 antibodies described herein may comprise a light chain variable region (VL) comprising a light chain (LC) CDR1, a LC CDR2, and a LC CDR3. In some cases, the LC CDR1 may comprise the motif shown as RASQSVSSAVA (SEQ ID NO: 55). The LC CDR2 may comprise the motif shown as X7ASSLX8S (SEQ ID NO: 50), wherein X7 may be S or A, and X8 may be Y or Q. In some examples, the LC CDR2 may comprise the sequence of AASSLQS (SEQ ID NO: 56). Alternatively or additionally, the LC CDR3 may comprise the sequence of QQX9X10 X 11 X 12 X 13 X 14 LIT (SEQ ID NO: 51), wherein X9 can be S or Q, X 10 Can be G, S or T, X 11 Can be D, K or S, X 12 Can be Y, W or not exist, X 13 Can be P or not exist, and X 14 It can be D, F, or Y. In some examples, the LC CDR3 can comprise the sequence of QQQSKYPFLIT (SEQ ID NO: 57).

[0186] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 comprises the motif of FTFX1X2X3X4IH (SEQ ID NO: 93), wherein X1 is S or T, X2 is S, G or A, X3 is T, N or S, and X4 is D or S. Alternatively or additionally, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively or additionally, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). Alternatively or additionally, the isolated antibodies disclosed herein comprise a light chain variable region (V L ), comprising LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). Alternatively or additionally, LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0187] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 comprises the motif of FTFX1X2X3X4IH (SEQ ID NO: 93), wherein X1 is S or T, X2 is S, G or A, X3 is T, N or S, and X4 is D or S, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). In some embodiments, the isolated antibody further comprises a light chain variable region (VL ), which comprises LC CDR1, LC CDR2 and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55), LC CDR2 comprises AASSLQS (SEQ ID NO: 56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0188] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 comprises the motif of FTFX1X2X3X4IH (SEQ ID NO: 94), wherein X1 is S or T, X2 is S or A, X3 is N or S, and X4 is D or S, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). In some embodiments, the isolated antibody comprises a light chain variable region (V L ), which comprises LC CDR1, LC CDR2 and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55), LC CDR2 comprises AASSLQS (SEQ ID NO: 56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0189] In some embodiments, the antibody comprises a heavy chain variable region (V H ), which comprises HC CDR1, HC CDR2 and HC CDR3, wherein HC CDR1 is selected from the group consisting of SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71 and SEQ ID NO: 72. Alternatively or additionally, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively or additionally, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). Alternatively or additionally, the isolated antibodies disclosed herein comprise a light chain variable region (V L), comprising LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). Alternatively or additionally, LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0190] In some embodiments, the anti-δ1 antibodies described herein comprise all of the heavy chain and / or all of the light chain CDR motifs described herein. In some instances, the antibodies do not have the same heavy and light chain CDRs as δ1-17 or do not have the same heavy and light chain variable regions as δ1-17.

[0191] A number of exemplary anti-delta 1 antibodies are provided below (CDR residues based on Kabat numbering are indicated in bold). A list of CDRs is provided in Table 1.

[0192] δ1-17

[0193] V H :

[0194]

[0195] V L :

[0196]

[0197] δ1-18

[0198] V H :

[0199]

[0200] V L :

[0201]

[0202] δ1-19

[0203] V H :

[0204]

[0205]

[0206] V L :

[0207]

[0208] δ1-20

[0209] V H :

[0210]

[0211] V L :

[0212]

[0213] δ1-21

[0214] V H :

[0215]

[0216]

[0217] V L :

[0218]

[0219] δ1-22

[0220] V H :

[0221]

[0222] V L :

[0223]

[0224] δ1-23

[0225] V H :

[0226]

[0227] V L :

[0228]

[0229] δ1-24

[0230] V H :

[0231]

[0232] V L :

[0233]

[0234] δ1-25

[0235] V H :

[0236]

[0237] V L :

[0238]

[0239]

[0240] δ1-26

[0241] V H :

[0242]

[0243] V L :

[0244]

[0245] δ1-27

[0246] V H :

[0247]

[0248] V L :

[0249]

[0250] δ1-28

[0251] V H :

[0252]

[0253] V L :

[0254]

[0255] δ1-29

[0256] V H :

[0257]

[0258] V L :

[0259]

[0260] δ1-30

[0261] V H :

[0262]

[0263] V L :

[0264]

[0265] δ1-31

[0266] V H :

[0267]

[0268] V L :

[0269]

[0270] δ1-32

[0271] V H :

[0272]

[0273]

[0274] V L :

[0275]

[0276] δ1-33

[0277] V H :

[0278]

[0279] V L :

[0280]

[0281] δ1-34

[0282] V H :

[0283]

[0284]

[0285] V L :

[0286]

[0287] δ1-35

[0288] V H :

[0289]

[0290] V L :

[0291]

[0292] δ1-36

[0293] V H :

[0294]

[0295] V L :

[0296]

[0297] δ1-37

[0298] V H :

[0299]

[0300] V L :

[0301]

[0302] δ1-38

[0303] V H :

[0304]

[0305] V L :

[0306]

[0307] δ1-39

[0308] V H :

[0309]

[0310] V L :

[0311]

[0312] δ1-40

[0313] VH :

[0314]

[0315] V L :

[0316]

[0317]

[0318] δ1-41

[0319] V H :

[0320]

[0321] V L :

[0322]

[0323] δ1-42

[0324] V H :

[0325]

[0326] V L :

[0327]

[0328] δ1-43

[0329] V H :

[0330]

[0331] V L :

[0332]

[0333] Table 1. Selected antibody CDR sequences

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340] In some embodiments, the anti-δ1 antibodies described herein bind to the same epitope as any of the exemplary antibodies listed above or compete with the exemplary antibodies for binding to the δ-1 chain. An "epitope" refers to a site on a target antigen that is recognized and bound by an antibody. The site may be composed entirely of amino acid components, entirely of chemical modifications of the amino acids of a protein (e.g., a glycosyl moiety), or a combination thereof. Overlapping epitopes include at least one common amino acid residue. An epitope may be linear, typically 6-15 amino acids in length. Alternatively, an epitope may be conformational. The epitope to which an antibody binds can be determined by conventional techniques, such as epitope mapping methods (see, for example, as described below). An antibody that binds to the same epitope as an exemplary antibody described herein may bind to exactly the same epitope or a substantially overlapping epitope (e.g., containing less than 3 non-overlapping amino acid residues, less than 2 non-overlapping amino acid residues, or only 1 non-overlapping amino acid residue) as an exemplary antibody. Whether two antibodies compete with each other for binding to the same antigen can be determined by competition assays well known in the art.

[0341] In some examples, the anti-δ1 antibodies described herein comprise the same V domains as the exemplary antibodies listed above. H and / or V L CDR. With the same V H and / or V L CDRs of two antibodies are identical when determined by the same method (e.g., the Kabat method or the Chothia method known in the art). Such anti-δ1 antibodies may have the same V H , the same V L or both.

[0342] Also within the scope of the present disclosure are functional variants of any of the exemplary anti-delta 1 antibodies disclosed herein. Such functional variants are substantially similar in structure and function to the exemplary antibodies. Functional variants comprise V sequences substantially identical to those of the exemplary antibodies. H and / or V L CDR. For example, it can comprise only up to 10 (e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid residue variations in the total CDR region of the antibody and bind with substantially similar affinity (e.g., with a K of the same order of magnitude). DValue) binds to the same epitope of δ1. Alternatively or in addition, the amino acid residue variation is a conservative amino acid residue substitution. As used herein, a "conservative amino acid substitution" refers to an amino acid substitution that does not change the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods known to those of ordinary skill in the art for altering polypeptide sequences, such as those found in references compiling these methods, such as Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., ed., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989 or Current Protocols in Molecular Biology, FM Ausubel, et al., ed., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions between amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0343] In some embodiments, an anti-δ1 antibody may comprise a V domain that is identical to the exemplary antibodies described herein. H Alternatively or in addition, an anti-δ1 antibody may comprise a heavy chain CDR that is at least 80% (e.g., 85%, 90%, 95%, or 98%) identical to the V CDRs of an exemplary antibody described herein. L "Individually" refers to a light chain CDR that has at least 80% (e.g., 85%, 90%, 95% or 98%) sequence identity compared to the CDRs of the respective heavy or light chains of the respective antibodies. "Individually" refers to a light chain CDR that has at least 80% (e.g., 85%, 90%, 95% or 98%) sequence identity compared to the CDRs of the respective heavy or light chains of the respective antibodies (e.g., disclosed herein). "Collectively ... (e.g., disclosed herein). Such antibodies may also include one or more of the heavy chain CDR1, CDR2 and CDR3 motifs described herein and / or all of the heavy chain CDR1, CDR2 and CDR3 motifs described herein and / or all of the light chain CDR1, CDR2 and CDR3 motifs.

[0344] In some embodiments, the anti-δ1 antibodies described herein may comprise V sequences that are identical to the exemplary antibodies described herein. HV having at least 80% (e.g., 85%, 90%, 95% or 98%) sequence identity H Alternatively or in addition, the anti-δ1 antibody may comprise a V sequence that is identical to the exemplary antibodies described herein. L V having at least 80% (e.g., 85%, 90%, 95% or 98%) sequence identity L Such antibodies may further comprise one or more of the heavy chain CDR1, CDR2, and CDR3 motifs described herein and / or one or more of the light chain CDR1, CDR2, and CDR3 motifs described herein, e.g., all of the heavy chain CDR1, CDR2, and CDR3 motifs described herein and / or all of the light chain CDR1, CDR2, and CDR3 motifs described herein.

[0345] The "percent identity" of two amino acid sequences is determined using the algorithm of Karlin and Altschul, Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, as modified in Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul, et al., J. Mol. Biol. 215:403-10, 1990. BLAST protein searches can be performed using the XBLAST program with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the protein molecule of interest. In cases where there are gaps between the two sequences, Gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1997. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0346] In some embodiments, the heavy chain of any anti-δ1 antibody as described herein may further comprise a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). The heavy chain constant region may be from any suitable source, such as human, mouse, rat, or rabbit. In a specific example, the heavy chain constant region is from human IgG (γ heavy chain) of any IgG subfamily as described herein, such as IgG1. Several mutations in antibody heavy chains for modulating effector function are known in the art (e.g., as listed in Table 1 and described in Wang et al., Protein Cell 2018, 9(1): 63–73, the contents of which are incorporated herein by reference in their entirety).

[0347] Depending on the specific mutations to include, there are many known mutations that can be used to enhance ADCC, ADCP, and CDC. I have attached a review article that details all of these situations (see Table 1). Non-limiting examples of human IgG1 heavy chain mutations include (1) E333A mutation (improved binding to FcγRIIIa and enhanced ADCC and CDC); (2) S239D / A330L / I332E mutation (improved binding to FcγRIIIa and enhanced ADCC); (3) K326W / E333S mutation (improved binding to C1q and enhanced CDC); (4) S239D / I332E / G236A mutation (increased FcγRIIa / FcγRIIb ratio and enhanced macrophage phagocytosis). Alternatively, the LALA mutation blocks all effector functions, i.e., essentially ADCC, ADCP, and CDC. The LALA sequence of hIgG1 includes two mutations L234A and L235A (EU numbering) that inhibit FcgR binding, and a P329G mutation (EU numbering) to eliminate complement C1q binding, thereby eliminating all immune effector functions. An exemplary mutation in IgG4 is the Fab arm exchange mutant sequence of hIgG4, which includes a mutation (S228P; EU numbering) to inhibit Fab arm exchange. For the purpose of manufacture, it may be desirable to delete the C-terminal lysine (" K ") residue in the following heavy chain sequence. Therefore, in some embodiments, the C-terminal lysine (" K ") residue may not be present in each heavy chain sequence given below. In one example, the constant region is from human IgG1, and its exemplary heavy chain amino acid sequence (SEQ ID NO:31) is provided below. In some embodiments, one or more mutations described in 1-4 above are introduced. In some embodiments, the heavy chain constant region of the anti-δ1 antibodies described herein may comprise a single domain (e.g., CH1, CH2, or CH3) of a constant region (e.g., SEQ ID NOs: 31, 74-77) or a combination of any single domains. In some embodiments, the light chain constant region of the antibodies described herein may comprise a single domain (e.g., CL) of a constant region (e.g., SEQ ID NO: 73). Exemplary light and heavy chain sequences are listed below.

[0348] Exemplary constant region sequences

[0349] Ig kappa light chain (LC) (SEQ ID NO: 73):

[0350] TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0351] IgG1 heavy chain (HC) (SEQ ID NO:31):

[0352] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0353] IgG1 heavy chain (HC) LALA (SEQ ID NO:74):

[0354] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0355] IgG4 HC (SEQ ID NO:75):

[0356] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0357] IgG4 HC Fab-arm exchange mutant (SEQ ID NO:76):

[0358] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0359] hIgG4 HC Fab-arm exchange mutant constant region (SEQ ID NO:77)

[0360] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0361] δ1-39, with Igκ-type light chain (LC) (SEQ ID NO: 78)

[0362]

[0363] δ1-39, with IgG1 heavy chain (HC) (SEQ ID NO: 79)

[0364]

[0365] δ1-39, with IgG4 HC (SEQ ID NO:47)

[0366]

[0367] δ1-39, with IgG4 HC Fab arm swap mutant HC (SEQ ID NO: 49)

[0368]

[0369]

[0370] δ1-39, with IgG4 HC Fab arm swap mutant (SEQ ID NO:80)

[0371]

[0372] In any of the embodiments described herein, the anti-δ1 antibodies of the present disclosure may comprise a light chain constant region having the sequence of SEQ ID NO: 73. In any of the embodiments described herein, the anti-δ1 antibodies of the present disclosure may comprise a heavy chain constant region having the sequence of SEQ ID NO: 31. In any of the embodiments described herein, the anti-δ1 antibodies of the present disclosure may comprise a heavy chain constant region having the sequence of SEQ ID NO: 74. In any of the embodiments described herein, the anti-δ1 antibodies of the present disclosure may comprise a heavy chain constant region having the sequence of SEQ ID NO: 75. In any of the embodiments described herein, the anti-δ1 antibodies of the present disclosure may comprise a heavy chain constant region having the sequence of SEQ ID NO: 76.

[0373] In some embodiments, the anti-δ1 antibody has a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 78. In some embodiments, the anti-δ1 antibody has a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 79. In some embodiments, the anti-δ1 antibody has a light chain sequence comprising SEQ ID NO: 78. In some embodiments, the anti-δ1 antibody has a heavy chain sequence comprising SEQ ID NO: 79. In some embodiments, the isolated antibody has a light chain sequence consisting essentially of or consisting of SEQ ID NO: 78. In some embodiments, the isolated antibody has a heavy chain sequence consisting essentially of or consisting of SEQ ID NO: 79.

[0374] In some embodiments, the anti-δ1 antibody has a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:78 and a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:79. In some embodiments, the isolated antibody has a light chain sequence comprising SEQ ID NO: 78 and has a heavy chain sequence comprising SEQ ID NO: 79. In some embodiments, the isolated antibody has a light chain sequence consisting essentially of SEQ ID NO: 78 and has a heavy chain sequence consisting essentially of SEQ ID NO: 79. In some embodiments, the isolated antibody has a light chain sequence consisting of SEQ ID NO: 78 and has a heavy chain sequence consisting of SEQ ID NO: 79.

[0375] In some embodiments, the anti-δ1 antibody has a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the antibody has a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NO: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45.

[0376] In some embodiments, the anti-δ1 antibody has a light chain sequence comprising a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some embodiments, the anti-delta 1 antibody has a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a light chain sequence comprising a constant region having the sequence of SEQ ID NO:31 and a VL region having a sequence selected from SEQ ID NOs:4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9.

[0377] In some embodiments, the anti-δ1 antibody has a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the anti-δ1 antibody has a light chain sequence comprising a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some embodiments, the isolated antibody has a heavy chain sequence that consists essentially of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, or consists of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the isolated antibody has a light chain sequence that consists essentially of, or consists of, a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9.

[0378] In some embodiments, the anti-delta 1 antibody has a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 73 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: The light chain sequences of the VL regions of sequences of NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9 are at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical. In some embodiments, the isolated antibody has a heavy chain sequence and a light chain sequence, wherein the heavy chain sequence comprises a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and the light chain sequence comprises a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some embodiments, the isolated antibody has a heavy chain sequence and a light chain sequence, wherein the heavy chain sequence consists essentially of a constant region having the sequence of SEQ ID NO:31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs:3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and the light chain sequence consists essentially of a constant region having the sequence of SEQ ID NO:73 and a VL region having a sequence selected from the group consisting of SEQ ID NOs:4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9.In some embodiments, the isolated antibody has a heavy chain sequence and a light chain sequence, wherein the heavy chain sequence consists of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44 and 45, and the light chain sequence consists of a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9.

[0379] In some embodiments, the anti-δ1 antibody has a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the antibody has a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45.

[0380] In some embodiments, the anti-δ1 antibody has a light chain sequence comprising a constant region having the sequence of SEQ ID NO: 73 and a VL region having the sequence of SEQ ID NO: 9. In some embodiments, the anti-δ1 antibody has a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a light chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VL region having the sequence of SEQ ID NO: 9.

[0381] In some embodiments, the anti-δ1 antibody has a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the anti-δ1 antibody has a light chain sequence comprising a constant region having the sequence of SEQ ID NO: 73 and a VL region having the sequence of SEQ ID NO: 9. In some embodiments, the isolated antibody has a heavy chain sequence consisting essentially of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, or consisting of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the isolated antibody has a light chain sequence consisting essentially of a constant region having the sequence of SEQ ID NO: 73 and a VL region having the sequence of SEQ ID NO: 9, or consisting of a constant region having the sequence of SEQ ID NO: 73 and a VL region having the sequence of SEQ ID NO: 9.

[0382] In some embodiments, the anti-δ1 antibody has a heavy chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and a light chain sequence that is at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84%, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a heavy chain sequence comprising a constant region having the sequence of SEQ ID NO: 73 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: The light chain sequences of the VL regions of sequences of NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9 are at least 80% or 85% (e.g., at least 80%, 81%, 82%, 83%, 84% or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical. In some embodiments, the isolated antibody has a heavy chain sequence and a light chain sequence, wherein the heavy chain sequence comprises a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44 and 45, and the light chain sequence comprises a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9. In some embodiments, the isolated antibody has a heavy chain sequence and a light chain sequence, wherein the heavy chain sequence consists essentially of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and the light chain sequence consists essentially of a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9.In some embodiments, the isolated antibody has a heavy chain sequence and a light chain sequence, wherein the heavy chain sequence consists of a constant region having the sequence of SEQ ID NO: 31 and a VH region having a sequence selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44 and 45, and the light chain sequence consists of a constant region having the sequence of SEQ ID NO: 73 and a VL region having a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16 and 9.

[0383] If necessary, the anti-δ1 antibodies described herein may comprise a modified constant region. For example, the antibody may comprise a modified constant region that is immunologically inert, such as one that does not trigger complement-mediated lysis or does not stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). In other embodiments, the constant region is modified as described in Eur. J. Immunol. (1999) 29: 2613-2624; PCT application number PCT / GB99 / 01441; and / or UK patent application number 9809951.8. In other examples, the antibodies described herein may comprise a modified constant region with enhanced ADCC activity. Accordingly, the anti-δ1 antibodies described herein may comprise a modified constant region that improves effector function, i.e., improves complement-mediated lysis, improves stimulation of antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, the antibody is an IgG1 molecule and comprises one or more mutations described in 1-4 above or in Wang et al. ADCC activity can be assessed using the method disclosed in US Pat. No. 5,500,362.

[0384] Any anti-δ1 antibody described herein may comprise a light chain further comprising a light chain constant region, which may be any CL known in the art. In some examples, the CL is a kappa-type light chain. In other examples, the CL is a lambda-type light chain.

[0385] Antibody heavy and light chain constant regions are well known in the art, such as those provided in the IMGT database (www.imgt.org) or at www.vbase2.org / vbstat.php., both of which are incorporated herein by reference.

[0386] Preparation of anti-δ1 antibodies

[0387] Antibodies capable of binding to the delta-1 chain of the γδ TCR as described herein can be prepared by any method known in the art. For example, see Harlow and Lane, (1998) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.

[0388] In some embodiments, specific antibodies to a target antigen (e.g., a suitable species such as human delta-1 chain or a fragment thereof) can be prepared by conventional hybridoma technology. The full-length target antigen or a fragment thereof, optionally coupled to a carrier protein such as KLH, can be used to immunize a host animal to produce antibodies that bind to the antigen. As further described herein, the immunization pathway and immunization program of the host animal are generally consistent with established and conventional techniques for antibody stimulation and production. General techniques for producing mouse antibodies, humanized antibodies, and human antibodies are known in the art and are described herein. It is contemplated that any mammalian subject, including humans or their antibody-producing cells, is manipulated as a basis for producing mammals, including human hybridoma cell lines. Typically, a host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantarly, and / or intradermally with an amount of an immunogen, including an immunogen as described herein.

[0389] Hybridomas can be prepared from lymphocytes and immortalized myeloma cells using the general somatic cell hybridization technique of Kohler, B. and Milstein, C. (1975) Nature 256:495-497 or the modified technique of Buck, DW et al., In Vitro, 18:377-381 (1982). Existing myeloma cell lines, including but not limited to X63-Ag8.653 and myeloma cell lines from the Salk Institute, Cell Distribution Center, San Diego, Calif., USA, can be used for hybridization. Generally, this technique involves fusing myeloma cells and lymphocytes using a fusing agent such as polyethylene glycol or by electrical means familiar to those skilled in the art. After fusion, the cells are separated from the fusion medium and grown in a selective growth medium such as hypoxanthine-aminopterin-thymidine (HAT) medium to remove unhybridized parental cells. Any culture medium described herein, whether or not supplemented with serum, can be used to culture hybridomas that secrete monoclonal antibodies. As another alternative to the cell fusion technique, EBV immortalized B cells can be used to produce the anti-δ1 monoclonal antibodies described herein. The hybridoma cells are expanded and subcloned (if desired), and the supernatant is assayed for anti-immunogen activity by conventional immunoassay procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescent immunoassay).

[0390] Hybridomas that can be used as sources of antibodies include all derivatives and progeny cells of parent hybridomas that produce monoclonal antibodies capable of interfering with δ1 (γδT cell) activity. Hybridomas that produce such antibodies can be grown in vitro or in vivo using known procedures. If desired, monoclonal antibodies can be isolated from culture medium or body fluids by conventional immunoglobulin purification procedures such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration. If undesirable activity is present, it can be removed by, for example, running the preparation through an adsorbent made of an immunogen attached to a stationary phase and eluting or releasing the desired antibody from the immunogen. Populations of antibodies (e.g., monoclonal antibodies) can be obtained by immunizing a host animal with a target antigen or a fragment containing a target amino acid sequence conjugated to a protein that is immunogenic in the species to be immunized (e.g., keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor) using a bifunctional or derivatizing agent (e.g., maleimidobenzoylsulfosuccinimide ester (conjugation through cysteine residues), N-hydroxysuccinimide (conjugation through lysine residues), glutaraldehyde, succinic anhydride, SOCl, or R1N=C=NR, wherein R and R1 are different alkyl groups).

[0391] If desired, the antibody of interest (monoclonal or polyclonal) (e.g., produced by a hybridoma) can be sequenced and the polynucleotide sequence cloned into a vector for expression or amplification. The sequence encoding the antibody of interest can be maintained in a vector of a host cell, which can then be amplified and frozen for future use. In an alternative, the polynucleotide sequence can be used for genetic manipulation to "humanize" or improve the affinity (affinity maturation) or other characteristics of the antibody. For example, if the antibody is used for human clinical trials and treatment, the constant region can be engineered to be more similar to a human constant region to avoid an immune response. It may be necessary to genetically manipulate the antibody sequence to obtain a higher affinity for the target antigen and to suppress the activity of the target γδ1TCR (thereby suppressing the activity of the target γδT cells) with greater efficacy. It will be apparent to those skilled in the art that one or more polynucleotide changes can be made to the antibody and still maintain its binding specificity to the target antigen.

[0392] In other embodiments, fully human antibodies can be obtained by using commercially available mice that have been engineered to express specific human immunoglobulins. Transgenic animals designed to produce a more desirable (e.g., fully human antibodies) or more robust immune response can also be used to produce humanized or human antibodies. Examples of such technology are the Xenomouse® from Amgen, Inc. (Fremont, Calif.). RTMand HuMAb-Mouse from Medarex, Inc. (Princeton, NJ) RTM and TC Mouse TM In another alternative, antibodies can be produced recombinantly by phage display or yeast technology. For example, see U.S. Patent Nos. 5,565,332; 5,580,717; 5,733,743; and 6,265,150; and Winter et al. (1994) Annu. Rev. Immunol. 12: 433-455. Alternatively, phage display technology (McCafferty et al. (1990) Nature 348: 552-553) can be used to produce human antibodies and antibody fragments in vitro from immunoglobulin variable (V) domain gene repertoires from unimmunized donors.

[0393] Alternatively, antibodies that can be combined with target antigens as described herein can be isolated from suitable antibody libraries by routine operations. According to conventional selection processes known in the art, antibody libraries comprising multiple antibody components can be used to identify antibodies combined with specific target antigens (e.g., the epitope of δ-1 chains in this case). In the selection process, the antibody library can be probed with the target antigen or its fragment, and the antibody library members that can be combined with the target antigen can be separated, usually by retaining on a support. This screening process can be carried out for many rounds (e.g., including positive and negative selections) to enrich the antibody pool that can be combined with the target antigen. Then, the individual clones of the enrichment pool can be separated and further characterized to identify those clones with required binding activity and biological activity. The sequence of heavy chain and light chain variable domains can also be determined by conventional methodology.

[0394] There are many conventional methods known in the art to identify and isolate antibodies capable of binding to the target antigens described herein, including phage display, yeast display, ribosome display, or mammalian display technologies.

[0395] As an example, phage display typically uses covalent bonds to bind protein (e.g., antibody) components to phage coat proteins. This connection is generated by translation of nucleic acids encoding the antibody component fused to the coat protein. This connection can include flexible peptide linkers, protease sites, or amino acids incorporated due to suppression of stop codons. Phage display is described in, for example, U.S. Pat. No. 5,223,409; Smith (1985) Science 228:1315-1317; WO 92 / 18619; WO 91 / 17271; WO 92 / 20791; WO 92 / 15679; WO 93 / 01288; WO 92 / 01047; WO 92 / 09690; WO 90 / 02809; de Haard et al. (1999) J. Biol. Chem 274:18218-30; Hoogenboom et al. (1998) Immunotechnology 4:1-20; Hoogenboom et al. (2000) Immunol Today 2:371-8 and Hoet et al. (2005) Nat Biotechnol. 23(3):344-8. Phage displaying the protein component can be cultured and harvested using standard phage preparation methods, such as PEG precipitation from the growth medium. After selecting individual displaying phage, nucleic acids encoding the selected protein component can be isolated from cells infected with the selected phage or from the phage itself (after amplification). Individual colonies or plaques can be selected, and the nucleic acids can then be isolated and sequenced.

[0396] Other display formats include cell-based display (see, e.g., WO 03 / 029456), protein-nucleic acid fusion (see, e.g., U.S. Pat. No. 6,207,446), ribosome display (see, e.g., Mattheakis et al. (1994) Proc. Natl. Acad. Sci. USA 91:9022 and Hanes et al. (2000) Nat Biotechnol. 18:1287-92; Hanes et al. (2000) Methods Enzymol. 328:404-30; and Schaffitzel et al. (1999) J Immunol Methods. 231(1-2):119-35), and E. coli periplasmic display (J Immunol Methods. 2005 Nov 22; PMID: 16337958), and yeast display (Feldhaus et al., Nat Biotechnol. 18:1287-92). Biotechnol. 2003; 21: 163-70). After the display library members are isolated based on their binding to the target antigen, each isolated library member can also be tested for its ability to bind to non-target molecules to assess its binding specificity. Examples of non-target molecules include streptavidin on magnetic beads, blocking agents such as bovine serum albumin, fat-free milk, soy protein, any monoclonal antibody that captures or immobilizes the target, or non-transfected cells that do not express the target. For example, high-throughput ELISA screening can be used to obtain data. ELISA screening can also be used to obtain quantitative data on the binding of each library member to the target and cross-species reactivity with related targets or target antigen subunits. The non-target and target binding data are compared (e.g., using a computer and software) to identify library members that specifically bind to the target.

[0397] After selecting candidate library members that bind to the target, each candidate library member can be further analyzed, e.g., to further characterize its binding properties to the target, e.g., δ1 chain (referred to herein as δ1). Each candidate library member can be subjected to one or more secondary screening assays. The assays can be directed to binding properties, catalytic properties, inhibitory properties, physiological properties (e.g., cytotoxicity, renal clearance, immunogenicity), structural properties (e.g., stability, conformation, oligomerization state), or other functional properties. The same assay can be used repeatedly but under different conditions, e.g., to measure pH, ion or thermal sensitivity.

[0398] In appropriate circumstances, the assay can directly use a display library member, a recombinant polypeptide produced by the nucleic acid encoding the selected polypeptide, or a synthetic peptide synthesized based on the sequence of the selected polypeptide. For selected Fab, the Fab can be assessed or can be modified and produced as complete IgG protein. Exemplary assays for binding properties are described below.

[0399] The bound protein can also be assessed using an ELISA assay. For example, each protein is contacted with a microplate whose bottom surface has been coated with a target (such as a limited amount of target). The plate is washed with a buffer solution to remove non-specifically bound polypeptides. The plate is then probed with an antibody that recognizes the bound protein (such as a tag or a constant portion of the bound protein) to determine the amount of bound protein on the plate that is bound to the target. The antibody is connected to a detection system (for example, an enzyme that produces a colorimetric product when a suitable substrate is provided, such as alkaline phosphatase or horseradish peroxidase (HRP)).

[0400] Alternatively, the ability of binding protein as described herein to bind target antigen can be analyzed using homogeneous assays, that is, after all the components of the assay are added, no additional liquid operation is required. For example, fluorescence resonance energy transfer (FRET) can be used as a homogeneous assay (as seen in, Lakowicz et al., U.S. Patent No. 5,631,169; Stavrianopoulos et al., U.S. Patent No. 4,868,103). The fluorophore marker on the selected first molecule (e.g., the molecule identified in the fraction) is such that if the second molecule (e.g., target) is near the first molecule, the fluorescent energy emitted by it can be absorbed by the fluorescent marker on the second molecule. The fluorescent marker on the second molecule emits fluorescence when absorbing the transferred energy. Since the efficiency of energy transfer between the markers is related to the distance separated between the molecules, the spatial relationship between the molecules can be assessed. In the case of binding between molecules, the fluorescent emission of the "acceptor" molecular marker in the assay should be the maximum. The binding events configured to be monitored by FRET can be conveniently measured by standard fluorescence measurement detection means (e.g., using a fluorometer). By titrating the amount of the first or second binding molecule, a binding curve can be generated to estimate the equilibrium binding constant.

[0401] Surface plasmon resonance (SPR) can be used to analyze the interaction between binding proteins and target antigens. SPR or biomolecular interaction analysis (BIA) detects biospecific interactions in real time without labeling any interactors. The mass change at the binding surface of the BIA chip (indicating that a binding event has occurred) causes the refractive index of light near the surface to change (the optical phenomenon of SPR). The change in refractive index produces a detectable signal, which is measured as an indicator of the real-time reaction between biomolecules. The method using SPR is described in, for example, U.S. Patent No. 5,641,640; Raether, 1988, Surface Plasmons Springer Verlag; Sjolander and Urbaniczky, 1991, Anal. Chem. 63: 2338-2345; Szabo et al., 1995, Curr. Opin. Struct. Biol. 5: 699-705 and online resources provided by BIAcore International AB (Uppsala, Sweden).

[0402] Information from SPR can be used to provide the equilibrium dissociation constant (K) for binding of the binding protein to the target. D ) and kinetic parameters (including K on and K off Such data can be used to compare different biomolecules. For example, proteins selected from expression libraries can be compared to identify proteins with high affinity for the target or with slow K off This information can also be used to establish structure-activity relationships (SAR). For example, the kinetic and equilibrium binding parameters of the mature form of the parent protein can be compared with those of the parent protein. Variant amino acids at given positions that are associated with specific binding parameters such as high affinity and slow K can be identified. off This information can be combined with structural modeling (e.g., using homology modeling, energy minimization, or structure determination by X-ray crystallography or NMR). Thus, an understanding of the physical interactions between a protein and its target can be systematically elaborated and used to guide other design processes.

[0403] As another example, a cell-based assay can be used. Binding proteins can be screened based on their ability to bind to cells that transiently or stably express and display the target of interest on their cell surface. For example, a δ1 binding protein can be fluorescently labeled and then used to detect binding to δ1 in the presence or absence of an antagonist antibody by changes in fluorescence intensity using a flow cytometer (e.g., a FACS instrument).

[0404] Antigen-binding fragments of intact antibodies (full-length antibodies) can be prepared by conventional methods. For example, F(ab')2 fragments can be produced by pepsin digestion of antibody molecules, while Fab fragments can be generated by reducing the disulfide bridges of F(ab')2 fragments.

[0405] Genetically engineered antibodies, such as humanized antibodies, chimeric antibodies, single-chain antibodies and bispecific antibodies, can be produced via conventional recombinant techniques. In one example, using conventional procedures (such as, by using oligonucleotide probes that can specifically bind the heavy chain and light chain of encoding monoclonal antibodies), the DNA of the monoclonal antibodies specific to the target antigen can be easily separated and sequenced. Once separated, DNA can be placed in one or more expression vectors, then transfected into host cells such as Escherichia coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells or the myeloma cells that do not otherwise produce immunoglobulin (Ig), to obtain the synthesis of monoclonal antibodies in recombinant host cells. See, for example, PCT Publication No. WO 87 / 04462. The DNA can then be modified, for example, by replacing the homologous murine sequences with coding sequences for human heavy and light chain constant domains (Morrison et al., (1984) Proc. Nat. Acad. Sci. 81:6851), or by covalently linking the immunoglobulin coding sequence to all or part of the coding sequence for a non-immunoglobulin polypeptide. In this way, genetically engineered antibodies with binding specificity for the target antigen, such as "chimeric" or "hybrid" antibodies, can be prepared.

[0406] Techniques developed for producing "chimeric antibodies" are well known in the art. See, for example, Morrison et al. (1984) Proc. Natl. Acad. Sci. USA 81, 6851; Neuberger et al. (1984) Nature 312, 604; and Takeda et al. (1984) Nature 314: 452.

[0407] Methods for constructing humanized antibodies are also well known in the art. For example, see Queen et al., Proc. Natl. Acad. Sci. USA, 86: 10029-10033 (1989). In one example, the V of the parent non-human antibody is modified according to methods known in the art. H and V L The variable region was subjected to three-dimensional molecular modeling analysis. Then, the same molecular modeling analysis was used to identify the framework amino acid residues that were predicted to be important for forming the correct CDR structure. H and V LThe sequence is used as a search query to identify human V antibodies with amino acid sequences homologous to those of the parent non-human antibody from any antibody gene database. H and V L Then, select the person V H and V L Acceptor gene.

[0408] The CDR region in the selected human acceptor gene can be replaced with the CDR region or its functional variant from parental non-human antibody. If necessary, the residues in the parental chain framework region that are predicted to be important in interacting with the CDR region (see above description) can be used to replace the corresponding residues in the human acceptor gene.

[0409] The nucleotide sequence encoding the heavy chain variable region and the nucleotide sequence encoding the light chain variable region can be linked together via recombinant technology to prepare a single-chain antibody. Preferably, a flexible linker is added between the two variable regions. Alternatively, the technology described for producing single-chain antibodies (U.S. Patents Nos. 4,946,778 and 4,704,692) can be adapted to produce phage or yeast scFv libraries, and scFv clones specific for δ1 can be identified from the library according to conventional procedures. Positive clones can be further screened to identify those that inhibit γδT cell activity.

[0410] In some examples, any anti-δ1 antibody described herein can be a binding portion of a bispecific or trispecific antibody. In other examples, any anti-δ1 antibody can be used to construct a chimeric antigen receptor (CAR), which can be expressed on immune cells such as T cells. Any bispecific antibody or CAR-T cell comprising an anti-δ1 antibody is also within the scope of the present disclosure.

[0411] The antibodies obtained and described herein according to methods known in the art can be characterized using methods well known in the art. For example, one method is to identify the epitope to which the antigen binds, or "epitope mapping". There are many known methods in the art for identifying and characterizing the location of epitopes on proteins, including crystal structures of antibody-antigen complexes, competitive assays, gene fragment expression assays, and assays based on synthetic peptides, such as those described in Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. In another example, epitope mapping can be used to determine the sequence to which the antibody binds. Such an epitope can be a linear epitope, i.e., contained in a single segment of amino acids, or a conformational epitope formed by the three-dimensional interaction of amino acids, which is not necessarily contained in a single segment of amino acids (primary structure linear sequence). Peptides of different lengths (e.g., at least 4-6 amino acids long) can be isolated or synthesized (e.g., recombinant) and used for binding assays with antibodies. In another example, the epitope of antibody binding can be determined by using overlapping peptides derived from the target antigen sequence and determining the combination of the antibody in a system screening. According to the gene fragment expression assay, the open reading frame encoding the target antigen is randomly or fragmented by a specific gene construction, and the reactivity of the expressed fragment of the antigen and the antibody to be tested is measured. The gene fragment can be produced by, for example, PCR, and then transcribed and translated into protein in vitro in the presence of radioactive amino acids. Next, the combination of the antibody and the radiolabeled antigen fragment is determined by immunoprecipitation and gel electrophoresis. Some epitopes can also be identified by using a large-capacity random peptide sequence library (phage library) displayed on the surface of phage particles. Alternatively, the combination of the library defined by the overlapping peptide fragments and the antibody to be tested can be tested in a simple binding assay. In another example, mutagenesis, domain exchange experiments and alanine scanning mutagenesis of the antigen-binding domain can be carried out to identify the epitope in combination with required, sufficient and / or necessary residues. For example, domain swapping experiments can be performed using mutants of the target antigen in which various fragments of the delta 1 polypeptide have been replaced (exchanged) with sequences from closely related but antigenically distinct proteins (e.g., another member of the soluble β-galactoside-binding lectin family). By assessing antibody binding to the mutant delta 1, the importance of a particular antigen fragment for antibody binding can be assessed.

[0412] Alternatively, competition assays can be performed using other antibodies known to bind to the same antigen to determine whether the antibody binds to the same epitope as the other antibodies.Competition assays are well known to those skilled in the art.

[0413] In some instances, the anti-δ1 antibody is produced by recombinant techniques as exemplified below.

[0414] The nucleic acids encoding the heavy and light chains of the anti-δ1 antibodies as described herein can be cloned into an expression vector, and each nucleotide sequence is operably linked to a suitable promoter. In one example, the nucleotide sequences encoding the heavy and light chains are each operably linked to a different promoter. Alternatively, the nucleotide sequences encoding the heavy and light chains can be operably linked to a single promoter so that both the heavy and light chains are expressed from the same promoter. If necessary, an internal ribosome entry site (IRES) can be inserted between the heavy and light chain coding sequences.

[0415] In some examples, the nucleotide sequences encoding the two antibody chains are cloned into two vectors, which can be introduced into the same or different cells. When the two chains are expressed in different cells, each of them can be isolated from the host cells expressing the chains. The isolated heavy and light chains can then be mixed and incubated under appropriate conditions to form antibodies.

[0416] Typically, methods known in the art can be used to clone the nucleic acid sequence of one or all chains of the antibody encoding the antibody into a suitable expression vector, operably connected with a suitable promoter. For example, the nucleotide sequence and the carrier can be contacted with a restriction enzyme under appropriate conditions to produce complementary ends on each molecule, and these ends can be paired with each other and linked together by a ligase. Alternatively, a synthetic nucleic acid linker can be connected to the end of the gene. These synthetic joints contain the nucleic acid sequence corresponding to a specific restriction site in the carrier. The selection of the expression vector / promoter will depend on the type of the host cell used to produce the antibody.

[0417] A variety of promoters can be used to express the antibodies described herein, including but not limited to the cytomegalovirus (CMV) immediate early promoter, viral LTRs (e.g., Rous sarcoma virus LTR, HIV-LTR, HTLV-1 LTR), simian virus 40 (SV40) early promoter, Escherichia coli lac UV5 promoter, and herpes simplex tk virus promoter.

[0418] Regulatable promoters can also be used. Such regulatable promoters include those that use the lac repressor from E. coli as a transcriptional regulator to regulate transcription from a mammalian cell promoter carrying the lac operator [Brown, M. et al., Cell, 49:603-612 (1987)], and those that use the tetracycline repressor (tetR) [Gossen, M. and Bujard, H., Proc. Natl. Acad. Sci. USA 89:5547-5551 (1992); Yao, F. et al., Human Gene Therapy, 9:1939-1950 (1998); Shockelt, P. et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)]. Other systems include FK506 dimers, VP16 or p65, using astradiol, RU486, diphenol murislerone or rapamycin. Inducible systems are available from Invitrogen, Clontech and Ariad.

[0419] A regulatable promoter comprising a repressor with an operator can be used. In one embodiment, the lac repressor from Escherichia coli can be used as a transcriptional regulator to regulate transcription from a mammalian cell promoter carrying the lac operator [M. Brown et al., Cell, 49: 603-612 (1987)]; Gossen and Bujard (1992); [M. Gossen et al., Natl. Acad. Sci. USA, 89: 5547-5551 (1992)] The tetracycline repressor (tetR) is combined with a transcription activator (VP16) to generate a tetR-mammalian cell transcription activator fusion protein, i.e., tTa (tetR-VP 16), with a minimal promoter carrying tetO derived from the major immediate early promoter of human cytomegalovirus (hCMV), to generate a tetR-tet operator system to control gene expression in mammalian cells. In one embodiment, a tetracycline inducible switch is used. When the tetracycline operator is appropriately positioned downstream of the TATA element of the CMVIE promoter, the tetracycline repressor (tetR) itself, rather than a tetR-mammalian cell transcription factor fusion derivative, can act as a potent trans-regulator to regulate gene expression in mammalian cells (Yao et al., Human Gene Therapy, 10(16):1392-1399(2003)). A particular advantage of this tetracycline-inducible switch is that it does not require the use of a tetracycline repressor-mammalian cell transactivator or repressor fusion protein (which may be toxic to cells in some cases) to achieve its regulatable effect (Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551(1992); Shockett et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526(1995)).

[0420] In addition, the vector may comprise, for example, some or all of the following: a selective marker gene, such as the neomycin gene for selecting stable or transient transfectants in mammalian cells; an enhancer / promoter sequence from the immediate early gene of human CMV for high-level transcription; transcription termination and RNA processing signals from SV40 for mRNA stabilization; an SV40 polyoma virus origin of replication and ColE1 for appropriate episomal replication; an internal ribosome binding site (IRES), a universal multiple cloning site; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Suitable vectors and methods for generating vectors containing transgenes are well known and available in the art.

[0421] Examples of polyadenylation signals that can be used to practice the methods described herein include, but are not limited to, the human type I collagen polyadenylation signal, the human type II collagen polyadenylation signal, and the SV40 polyadenylation signal.

[0422] One or more vectors (e.g., expression vectors) comprising nucleic acids encoding any antibody can be imported into appropriate host cells to produce the antibody. Host cells can be cultured under appropriate conditions for expressing the antibody or any of its polypeptide chains. Such antibodies or their polypeptide chains can be recovered by cultured cells (e.g., from cells or culture supernatant) via conventional methods such as affinity purification. If necessary, the polypeptide chains of the antibody can be incubated under appropriate conditions for a suitable time to produce the antibody.

[0423] In some embodiments, the methods for preparing the antibodies described herein involve recombinant expression vectors encoding both the heavy and light chains of the anti-δ1 antibody, as also described herein. The recombinant expression vector can be introduced into a suitable host cell (e.g., dhfr-CHO cells) by conventional methods such as calcium phosphate-mediated transfection. Positive transformant host cells can be selected and cultured under appropriate conditions to express the two polypeptide chains that form the antibody, which can be recovered from the cells or from the culture medium. If necessary, the two chains recovered from the host cells can be incubated under appropriate conditions to form the antibody.

[0424] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of an anti-δ1 antibody and the other encoding the light chain of an anti-δ1 antibody. Both recombinant expression vectors can be introduced into suitable host cells (e.g., dhfr-CHO cells) by conventional methods such as calcium phosphate-mediated transfection. Alternatively, each expression vector can be introduced into a suitable host cell. Positive transformants can be selected and cultured under appropriate conditions to express the polypeptide chains of the antibody. When the two expression vectors are introduced into the same host cell, the antibodies produced therein can be recovered from the host cell or from the culture medium. If necessary, the polypeptide chains can be recovered from the host cell or from the culture medium and then incubated under appropriate conditions to form antibodies. When the two expression vectors are introduced into different host cells, each of the two polypeptide chains can be recovered from the corresponding host cell or from the corresponding culture medium. The two polypeptide chains can then be incubated under appropriate conditions for forming antibodies.

[0425] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select the transformants, culture the host cells and recover the antibodies from the culture medium. For example, some antibodies can be isolated by affinity chromatography using a protein A or protein G coupled matrix.

[0426] Any nucleic acid encoding the heavy chain, light chain, or both chains of an anti-delta 1 antibody as described herein, vectors (eg, expression vectors) containing such nucleic acids; and host cells comprising these vectors are within the scope of the present disclosure.

[0427] The anti-δ1 antibodies thus prepared can be characterized using methods known in the art to detect and / or measure the reduction, improvement, or neutralization of γδ T cell biological activity. For example, ELISA-type assays can be used to qualitatively or quantitatively measure the inhibition, or lack thereof, of αβ T cell activation by γδ T cells.

[0428] The biological activity of the anti-δ1 antibody can be verified by incubating the candidate antibody with stimulated conventional (αβ) T cells and isolated γδ T cells and monitoring any one or more of the following characteristics: (a) binding between the candidate antibody and γδ T cells; (b) subsequent increase in the levels of T cell activation markers; (c) prevention, amelioration or treatment of any aspect of solid tumors; (d) blocking or reducing the activation of γδ T cells; and (e) inhibition (reduction) of the synthesis, production or release of γδ T cells, and (f) reduction or depletion of γδ T cell levels.

[0429] Thus, in one aspect, the present disclosure provides a nucleic acid or a set of nucleic acids that encode or co-encode any anti-δ1 antibody disclosed herein. In some cases, the heavy chain and light chain of the antibody are encoded by two separate nucleic acid molecules (a set of nucleic acids). In other cases, the heavy chain and light chain of the antibody are encoded by a nucleic acid molecule, which can be in a polycistronic form or under the control of different promoters. Accordingly, in one aspect, the present disclosure provides an isolated nucleic acid molecule comprising one or more nucleic acid sequences encoding the heavy chain variable region (VH) and / or light chain variable region (VL) of the anti-δ1 antibodies described herein. In some embodiments, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the heavy chain variable region (VH) of the anti-δ1 antibodies described herein. Alternatively or additionally, in some embodiments, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the light chain variable region (VL) of the anti-δ1 antibodies described herein.

[0430] In some embodiments, the isolated nucleic acid encodes an antibody that binds to δ1 (regardless of the γ chain). In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of a full-length antibody or an antigen-binding fragment thereof. In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL regions of a single-chain antibody. In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of a human antibody or a humanized antibody. In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an IgG molecule, such as an IgG1 molecule. In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising an HC constant region as shown in SEQ ID NO: 31 and / or a light chain constant region as shown in SEQ ID NO: 71.

[0431] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding a heavy chain variable region (VH) and / or a light chain variable region (VL) of an antibody that binds to the delta 1 chain of the gamma / delta T cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as set forth in a sequence selected from the group consisting of SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 53, and a heavy chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 54 and / or comprises a light chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO: 55, a light chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 56 or 58, and a light chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 57. The light chain complementary determining region 3 (CDR3) shown in the sequences of NO:83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59 and 60.

[0432] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding a heavy chain variable region (VH) and / or a light chain variable region (VL) of an antibody that binds to the delta 1 chain of the gamma / delta T cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as set forth in a sequence selected from SEQ ID NOs: 5 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 53, and a heavy chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 54 and / or comprises a light chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO: 55, a light chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 56, and a light chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 57.

[0433] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding a heavy chain variable region (VH) and / or a light chain variable region (VL) of an antibody that binds to the δ1 chain of the gamma / delta T-cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO:68, a heavy chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO:53, and a heavy chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO:54 and / or comprises a light chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO:55, a light chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO:56, and a light chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO:57.

[0434] In some nucleic acid embodiments described herein, the nucleic acid molecules comprise one or more nucleic acid sequences encoding the VH of an antibody comprising a VH and / or VL selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and / or a VL selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some nucleic acid embodiments described herein, the nucleic acid molecules comprise one or more nucleic acid sequences encoding the VH of an antibody comprising a VH and / or VL selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and / or a VL shown in SEQ ID NO: 9.

[0435] In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising the VH and / or VL set forth in SEQ ID NO: 24 and / or the VL set forth in SEQ ID NO: 9. In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising the VH and / or VL set forth in SEQ ID NO: 55 and / or the VL set forth in SEQ ID NO: 54.

[0436] In some embodiments, the one or more nucleic acid sequences encode the VH and / or VL of an antibody comprising a VH as set forth in SEQ ID NO: 24 and a VL as set forth in SEQ ID NO: 9, and a heavy chain constant region as set forth in SEQ ID NO: 31 and a light chain constant region as set forth in SEQ ID NO: 71. In some embodiments, the one or more nucleic acid sequences encode the VH and / or VL of an antibody comprising a heavy chain as set forth in SEQ ID NO: 79 and a light chain as set forth in SEQ ID NO: 78. In some embodiments, the one or more nucleic acid sequences encode the VH and / or VL of delta 1-39.

[0437] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding a heavy chain and / or light chain of an antibody that binds to the delta 1 chain of the gamma / delta T cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as set forth in a sequence selected from the group consisting of SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 53, and a heavy chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 54 and / or comprises a light chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO: 55, a light chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 56 or 58, and a light chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 57. The light chain complementary determining region 3 (CDR3) shown in the sequences of NO:83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59 and 60.

[0438] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding the heavy and / or light chains of an antibody that binds to the δ1 chain of the gamma / delta T-cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as set forth in a sequence selected from the group consisting of SEQ ID NOs: 5 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 53, and a heavy chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 54 and / or comprises a light chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO: 55, a light chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO: 56, and a light chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO: 57.

[0439] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding the heavy and / or light chains of an antibody that binds to the δ1 chain of the gamma / delta T-cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO:68, a heavy chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO:53, and a heavy chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO:54 and / or comprises a light chain complementary determining region 1 (CDR1) as set forth in SEQ ID NO:55, a light chain complementary determining region 2 (CDR2) as set forth in SEQ ID NO:56, and a light chain complementary determining region 3 (CDR3) as set forth in SEQ ID NO:57.

[0440] In some nucleic acid embodiments described herein, the nucleic acid molecules comprise one or more nucleic acid sequences encoding the heavy chain of an antibody comprising a VH and / or VL selected from the group consisting of SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and / or a light chain selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some nucleic acid embodiments described herein, the nucleic acid molecules comprise one or more nucleic acid sequences encoding the heavy chain of an antibody comprising a VH and / or VL selected from the group consisting of SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and / or a light chain shown in SEQ ID NO: 9.

[0441] In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the heavy and / or light chains of an antibody comprising VH and / or VL as set forth in SEQ ID NO: 24 and / or VL as set forth in SEQ ID NO: 9. In some nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the heavy and / or light chains of an antibody comprising VH and / or VL as set forth in SEQ ID NO: 55 and / or VL as set forth in SEQ ID NO: 54.

[0442] In some embodiments, the one or more nucleic acid sequences encode the heavy and / or light chains of an antibody comprising a VH as set forth in SEQ ID NO: 24 and a VL as set forth in SEQ ID NO: 9, and a heavy chain constant region as set forth in SEQ ID NO: 31 and a light chain constant region as set forth in SEQ ID NO: 71. In some embodiments, the one or more nucleic acid sequences encode the heavy and / or light chains of an antibody comprising a heavy chain as set forth in SEQ ID NO: 79 and a light chain as set forth in SEQ ID NO: 78. In some embodiments, the one or more nucleic acid sequences encode the heavy and / or light chains of delta 1-39.

[0443] Any isolated nucleic acid described herein is suitable for cloning into a vector. In some embodiments, the vector is an expression vector. In some embodiments, the vector comprises an isolated nucleic acid comprising one or more nucleic acid sequences encoding a heavy chain variable region (VH) and / or a light chain variable region (VL) of an antibody that binds to the delta 1 chain of the gamma / delta T cell receptor, wherein the antibody comprises: a heavy chain complementary determining region 1 (CDR1) as shown in SEQ ID NO: 68, a heavy chain complementary determining region 2 (CDR2) as shown in SEQ ID NO: 53, and a heavy chain complementary determining region 3 (CDR3) as shown in SEQ ID NO: 54 and / or comprises a light chain complementary determining region 1 (CDR1) as shown in SEQ ID NO: 55, a light chain complementary determining region 2 (CDR2) as shown in SEQ ID NO: 56, and a light chain complementary determining region 3 (CDR3) as shown in SEQ ID NO: 57. In some embodiments, the vector comprises an isolated nucleic acid encoding VH. In some embodiments, the vector comprises an isolated nucleic acid encoding VL. In some embodiments, the vector comprises an isolated nucleic acid encoding both VL and VH. The present disclosure also encompasses compositions comprising any isolated nucleic acid or vector described herein, including but not limited to, for example, the vectors or nucleic acids described in this paragraph. The present disclosure also encompasses host cells comprising any isolated nucleic acid or vector described herein, including but not limited to, the vectors and nucleic acids described in this paragraph. In some embodiments, the host cell is selected from the group consisting of Escherichia coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells.

[0444] Also provided herein are methods for producing antibodies or antigen-binding fragments thereof that bind to human delta-1 as described herein, comprising expressing one or more nucleic acid molecules described herein (including but not limited to those described in the previous paragraph) in a host cell, thereby producing the antibody. In one embodiment, the method for producing a monoclonal antibody or antigen-binding fragment thereof that binds to human galectin-9 comprises (i) culturing the host cell under conditions that allow expression of the anti-delta 1 antibody; and (ii) harvesting the anti-delta 1 antibody produced thereby from the cell culture. Antibodies produced according to this method are also encompassed.

[0445] Pharmaceutical composition and use thereof

[0446] The present disclosure provides pharmaceutical compositions comprising the anti-δ1 antibodies described herein and their use for inhibiting signaling mediated by γδ1 T cells or inhibiting activity mediated by γδ1 T cells, and / or eliminating δ1-positive cells. Such antibodies can be used to treat diseases associated with activated γδ1 T cells, or to determine the presence / level of γδT cells in a biological sample.

[0447] Pharmaceutical composition

[0448] Antibodies as described herein, as well as encoding nucleic acids or nucleic acid groups, vectors comprising these nucleic acids, or host cells comprising these vectors can be mixed with pharmaceutically acceptable carriers (excipients) to form pharmaceutical compositions for treating targeted diseases. "Acceptable" means that the carrier must be compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) without harming the subject being treated. Pharmaceutically acceptable excipients (carriers) include buffers well known in the art. For example, see Remington: The Science and Practice of Pharmacy 20th edition (2000) Lippincott Williams and Wilkins, ed. KE Hoover.

[0449] The pharmaceutical compositions used in the methods of the present invention may comprise a pharmaceutically acceptable carrier, excipient or stabilizer in the form of a lyophilized formulation or an aqueous solution. (Remington: The Science and Practice of Pharmacy 20th edition (2000) Lippincott Williams and Wilkins, ed. KE Hoover). Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations used and may include: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0450] In some examples, the pharmaceutical compositions described herein include liposomes containing antibodies (or encoding nucleic acids), which can be prepared by methods known in the art, such as those described in Epstein et al., Proc. Natl. Acad. Sci. USA 82: 3688 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with extended circulation time are disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomes can be generated by reverse phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of limited pore size to produce liposomes with the desired diameter.

[0451] Antibodies or encoding nucleic acids (one or more) can also be encapsulated in, for example, microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly (methyl methacrylate) microcapsules) prepared by coacervation techniques or by interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or coarse emulsions. Such techniques are known in the art, for example, referring to Remington, The Science and Practice of Pharmacy 20th edition, Mack Publishing (2000).

[0452] In other examples, the pharmaceutical compositions described herein can be formulated in a sustained-release form. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing antibodies in the form of molded articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPOT®. TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0453] Pharmaceutical compositions for in vivo administration must be sterile. This is easily achieved, for example, by filtration through a sterile filtration membrane. The therapeutic antibody composition is typically placed in a container with a sterile access port, such as an intravenous fluid bag or a vial with a stopper pierceable by a hypodermic needle.

[0454] The pharmaceutical compositions described herein may be in unit dosage form, such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

[0455] In order to prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulated composition containing a homogeneous mixture of the compound of the present invention or its pharmaceutically acceptable non-toxic salt. When these preformulated compositions are referred to as homogeneous, this means that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules. This solid preformulated composition is then subdivided into unit dosage forms of the above type, which contain 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of this novel composition can be coated or otherwise compounded to provide a dosage form with a long-lasting effect advantage. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter covering the former in the form of a film. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including certain polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0456] Suitable surfactants include, among others, nonionic agents such as polyoxyethylene sorbitan (e.g., Tween TM 20, 40, 60, 80 or 85) and other sorbitans (e.g., Span TM 20, 40, 60, 80 or 85). Compositions containing surfactants will conveniently contain 0.05% to 5% surfactant, and may be 0.1% to 2.5%. It will be appreciated that other ingredients, such as mannitol or other pharmaceutically acceptable vehicles, may also be added if necessary.

[0457] Commercially available fat emulsions such as Intralipid TM , Liposyn TM Infonutrol TM 、Lipofundin TM and Lipiphysan TM, to prepare a suitable emulsion. The active ingredient can be dissolved in a premixed emulsion composition, or the active ingredient can also be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and in an emulsion formed after mixing with a phospholipid (e.g., egg lecithin, soybean lecithin or soybean lecithin) and water. It should be understood that other ingredients, such as glycerol or glucose, can also be added to adjust the tension of the emulsion. Suitable emulsions typically contain up to 20% oil, for example 5% to 20%.

[0458] The emulsion composition can be prepared by combining the antibody with the intralipid TM or those emulsion compositions prepared by mixing their components (soybean oil, egg lecithin, glycerol and water).

[0459] Pharmaceutical compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect.

[0460] Compositions in preferably sterile pharmaceutically acceptable solvents can be aerosolized using gases. The aerosolized solution can be inhaled directly from the aerosolizing device, or the aerosolizing device can be connected to a face mask, face tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered from a device that delivers the formulation in an appropriate manner, preferably by oral or nasal administration.

[0461] Therapeutic applications

[0462] The present disclosure provides pharmaceutical compositions comprising at least one anti-δ1 antibody or antigen-binding fragment thereof described herein, and uses of such compositions for inhibiting and / or reducing activity mediated by T cells expressing γδ1 TCRs and / or reducing signal transduction mediated by T cells expressing γδ1 TCRs and / or clearing or reducing the number of γδ1 T cells. In some embodiments, the antibodies can be used to treat diseases associated with γδ1 T cells. In some embodiments, the antibodies can be used to treat diseases associated with γδ1 T cells. Any anti-δ1 antibody described herein can be used in the methods described herein. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-30, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a combination thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a combination thereof. Non-limiting examples of such antibodies include, for example, δ1-23. In another aspect, the antibody is δ1-41. In another aspect, the antibody is δ1-39. In some aspects, the present invention provides a method for treating cancer. In some embodiments, the present disclosure provides a method for reducing, improving or eliminating one or more symptoms associated with cancer and / or prolonging survival (disease-free survival, progression-free survival, overall survival) associated with cancer.

[0463] In some embodiments, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the present disclosure provides a method for treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a combination thereof. Non-limiting examples of such antibodies include δ1-23. In certain examples, the anti-δ1 antibody is δ1-17 or a functional variant thereof as disclosed herein. In other certain examples, the anti-δ1 antibody is δ1-39 or a functional variant thereof as disclosed herein. In still other certain examples, the anti-δ1 antibody is δ1-41 or a functional variant thereof as disclosed herein.

[0464] The present disclosure provides a method for inhibiting γδ1 TCR-mediated cell signaling in a subject, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an anti-δ1 antibody described herein (including but not limited to δ1-23, δ1-17, δ1-39 and / or δ1-41). In one aspect, the antibody is δ1-41. In another aspect, the antibody is δ1-39.

[0465] To practice the methods disclosed herein, an effective amount of the pharmaceutical compositions described herein is administered to a subject (e.g., a human) in need of treatment via an appropriate route, such as intravenous administration (e.g., as a bolus or by continuous infusion over a period of time), by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, inhalation, or topical routes. Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers, can be used for administration. Liquid formulations can be directly atomized, while lyophilized powders can be atomized after reconstitution. Alternatively, anti-δ1 antibodies as described herein are atomized using a fluorocarbon formulation and a metered dose inhaler, or inhaled in the form of a lyophilized powder and a ground powder.

[0466] In some embodiments, the subject treated by the methods described herein is a mammal, more preferably a human. Mammals include, but are not limited to, farm animals, sports animals, pets, primates, horses, dogs, cats, mice, and rats. The human subject in need of treatment can be a human patient who has, is at risk of, or is suspected of having a target disease / disorder, such as a solid tumor.

[0467] In some embodiments, the cancer is selected from adrenal cancer, adrenocortical cancer, anal cancer, appendix cancer, bile duct cancer, cancer), bladder cancer, bone cancer (e.g., Ewing sarcoma, osteosarcoma, malignant fibrous histiocytoma), brain cancer (e.g., astrocytoma, brain stem glioma, craniopharyngioma, ependymoma), bronchial cancer, cholangiocarcinoma, cholangiosarcoma, central nervous system cancer, breast cancer, Castleman disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, genitourinary cancer, gestational trophoblastic disease, heart cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia), liver cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), lymphoma (e.g., AIDS-related lymphoma), lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, pancreatic duct adenocarcinoma (PDA), nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, liposarcoma, liposarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma Myoma, rhabdoid tumor, salivary gland cancer, sarcoma, skin cancer (e.g., basal cell carcinoma, melanoma), squamous cell head and neck cancer, small intestine cancer, stomach cancer, teratoma, testicular cancer, laryngeal cancer, thymic cancer, thyroid cancer, rare childhood cancers, upper and lower gastrointestinal malignancies (including but not limited to esophageal cancer, gastric cancer, and hepatobiliary cancer), urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, cancer of unknown primary, Waldenstrom macroglobulinemia, and Wilms tumor. In some embodiments, the cancer is selected from hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, such as essential thrombocythemia, polycythemia vera, and myelofibrosis. In some embodiments, symptoms associated therewith include, but are not limited to, anemia, loss of appetite, irritation of the bladder lining, bleeding and bruising (thrombocytopenia), changes in taste or smell, constipation, diarrhea, dry mouth, difficulty swallowing, edema, fatigue, hair loss (alopecia), infection, infertility, lymphedema, mouth ulcers, nausea, pain, peripheral neuropathy, tooth decay, urinary tract infection, and / or problems with memory and concentration. The method may comprise preparing a pharmaceutical composition with an anti-delta 1 antibody as described herein, and administering the pharmaceutical composition to a subject in a therapeutically effective amount.In certain embodiments, administration of the pharmaceutical composition, e.g., one or more anti-δ1 antibodies described herein, including but not limited to antibody δ1-23, to a subject reduces cell proliferation, tumor growth, and / or tumor volume in the subject, or reduces the number of metastatic lesions over time. In some embodiments, administration of the composition results in a complete response, a partial response, or stable disease.

[0468] Examples of solid tumor cancers include pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer (e.g., non-small cell lung cancer NSCLC and small cell lung cancer SCLC), glioblastoma, upper and lower gastrointestinal malignancies (including but not limited to esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, bile duct cancer (cholangiocarcinoma) and hepatobiliary cancer), squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer (carcinoid and pancreatic neuroendocrine tumors), adrenocortical carcinoma and sarcoma. Hematological malignancies include acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasms such as essential thrombocythemia, polycythemia vera and myelofibrosis. Subjects with solid tumors or hematologic malignancies can be identified by routine medical examinations, such as laboratory tests, imaging modalities associated with organ function tests. In some embodiments, the subject to be treated by the methods described herein can be a human cancer patient who has undergone or is currently undergoing anti-cancer therapy (e.g., chemotherapy, radiotherapy, immunotherapy, cell-based therapy, surgery, or any combination thereof).

[0469] Increased numbers of γδT cells have been found in many cancers, including but not limited to gliomas, melanomas, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, neuroendocrine tumors (e.g., carcinoid tumors), breast cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, and prostate cancer. In some cases, as explained below, the proportion or number of γδ1 T cells in cancer is increased relative to non-cancerous controls, and / or the proportion or number of γδ2 T cells in cancer is decreased relative to non-cancerous controls. Without wishing to be bound by theory, for example, by using or administering anti-δ1 antibodies, blocking or targeting the δ1 chain TCR and thereby reducing the immunosuppressive function of γδT cells expressing the δ1 TCR (γδ1 cells) may provide an effective new therapeutic approach for treating certain cancers, such as cancers with high levels of γδT cells. Accordingly, any anti-δ-1 antibody disclosed herein is suitable for inhibiting the immunosuppression of γδT cells and reactivating effector T cell responses. Accordingly, the anti-δ1 antibodies described herein are suitable for treating cancer, such as cancers associated with γδT cells (e.g., cancers in which γδT cells play a role in the occurrence and progression of cancer). Accordingly, provided herein are methods for treating cancer, comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody administered to the subject is selected from δ1-17, δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43, or a functional variant thereof, as disclosed herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is δ1-41.

[0470] Non-limiting exemplary cancers treated by the anti-delta 1 antibodies disclosed herein are provided below.

[0471] Gliomas, tumors of glial cells in the brain or spine, are a deadly form of brain cancer, accounting for approximately 80% of all malignant brain tumors and 50% of primary brain tumors (Goodenberger and Jenkins, Genetics of adult glioma. Cancer Genet. 2012 Dec; 205(12): 613-21). This cancer is characterized by the tumor's infiltrating growth without boundaries in the brain, leaving extensive necrosis and often disrupting the blood-brain barrier. Glioblastoma (glioblastoma multiforme, GBM) is the most aggressive type of glioma. Even after complete surgical resection, high-grade gliomas often regenerate. Although other treatments, such as radiotherapy and chemotherapy, have been used, they have little success.

[0472] Studies have found that although the total γδT cell ratio in the peripheral blood of glioma patients is not significantly different from that of healthy controls, the γδ1T cell ratio in the peripheral blood of glioma patients is significantly increased, while the γδ2T cell ratio is significantly decreased compared with healthy controls (Liu et al., γδT Cells in Peripheral Blood of Glioma Patients. Med Sci Monit. 2018; 24: 1784-92). Without wishing to be bound by theory, for example, by administering antibodies that bind to δ1, blocking or targeting δ1 and thereby potentially reducing the immunosuppressive function of γδ1 cells may provide a new therapeutic approach for treating gliomas.

[0473] In some embodiments, the present disclosure provides a method for treating a glioma (e.g., a glioblastoma) in a subject, the method comprising administering an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one aspect, the antibody is δ1-41. In another aspect, the antibody is δ1-39.

[0474] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is a glioma (e.g., glioblastoma). In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0475] Melanoma is the most deadly form of skin cancer, and its incidence has been increasing over the past 30 years, especially in young adults. The accumulation of genetic disorders in melanocytes, most commonly mutations in B-Raf and N-Ras, is a hallmark of melanoma (Rodríguez-Cerdeira et al., Advances in Immunotherapy for Melanoma: A Comprehensive Review; Mediators Inflamm. 2017; 2017: 3264217, and references therein). These changes subsequently lead to the transformation of dysplastic melanocytes into melanoma cells, which then invade and metastasize.

[0476] Similar to glioma, the frequency of γδ1 cells in melanoma patients is higher than that in healthy controls (Wistuba-Hamprecht et al., Eur J Cancer. 2016 September; 64: 116-26). This was found regardless of whether the patients had been treated with ipilimumab. In contrast, the levels of γδ2 cells were lower in melanoma patients compared to healthy controls, and ipilimumab reduced the levels of γδ2 cells in patients with worse outcomes. In this study, the high frequency of γδ2 cells and the low frequency of γδ1 cells were associated with good overall survival (OS) in melanoma patients. Without wishing to be bound by theory, for example, by administering antibodies that bind to δ1, blocking or targeting δ1 and potentially reducing the immunosuppressive function of γδ1 cells may provide new treatments for melanoma, which may prolong the overall survival of patients (including but not limited to patients treated with ipilimumab).

[0477] In some embodiments, the present disclosure provides a method for treating melanoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or functional variants thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0478] In some embodiments, the present disclosure provides for the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is melanoma. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0479] Sarcomas are tumors of mesenchymal (connective) tissue and include malignancies of bone (eg, osteosarcoma), cartilage (chondrosarcoma), fat (liposarcoma), muscle (eg, leiomyosarcoma), blood vessels, and hematopoietic tissue. Sarcomas are typically treated with surgery, but chemotherapy and radiation may be given before and / or after surgery to improve outcomes.

[0480] In some embodiments, the present disclosure provides a method for treating a sarcoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0481] In some embodiments, the present disclosure provides for the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is a sarcoma. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0482] Gastrointestinal (GI) cancers include, but are not limited to, esophageal cancer, stomach cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, and liver cancer. GI cancers represent the largest number of cancers and the highest number of cancer deaths compared to any other system of the body.

[0483] Esophageal cancer is the sixth most common cancer worldwide, and its incidence is increasing. There are two main types of esophageal cancer: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Although the cause of this cancer is unknown, certain risk factors have been identified, such as smoking or drinking, as well as reflux, Barrett's esophagus, achalasia, Plummer-Vinson syndrome, or esophageal scarring (American Cancer Society, Esophageal Cancer, June 14, 2017). Current treatments typically include surgery, as well as chemotherapy, radiotherapy, and / or stent placement (Short et al., Esophageal Cancer. Am Fam Physician. January 1, 2017; 95(1): 22-28).

[0484] Studies have found that adhesion molecules recruit γδ1 T cells from the peripheral blood of patients with esophageal cancer to tumor tissue, just as γδ1 T cells were found to be detained in the tumor tissue of patients with esophageal cancer (Thomas et al., Role of adhesion molecules in recruitment of γδ1 T cells from the peripheral blood to the tumor tissue of esophageal cancer patients. Cancer Immunol Immunother. 2001 Jun;50(4):218-25). Given the elevated levels of γδ1 T cells, blocking or targeting δ1, for example by administering antibodies that bind to δ1, may provide a new treatment for esophageal cancer, which may prolong overall patient survival.

[0485] In some embodiments, the present disclosure provides a method for treating esophageal cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0486] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is esophageal cancer. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0487] Gastric cancer, which develops in the lining of the stomach, was the leading cause of cancer death until the 1980s and is now the third most common cause of cancer-related death worldwide (World Health Organization, Fact Sheets – Cancer, Sep 12, 2018). There are many factors that contribute to gastric cancer, including Helicobacter pylori infection, smoking, diet, and genetics. One genetic risk factor for gastric cancer is a genetic defect in the CDH1 gene. Treatment for gastric cancer generally involves surgery, chemotherapy, and radiation therapy, but cure rates are low. Studies have shown that treatment with the human epidermal growth factor receptor 2 (HER2) inhibitor trastuzumab prolongs overall survival in patients with inoperable locally advanced or metastatic gastric cancer (overexpressing the HER2 / neu gene) (Orditura et al., Treatment of gastric cancer. World J Gastroenterol. 2014 Feb 21;20(7):1635–1649). However, further strategies for resistant gastric cancer are needed to improve outcomes for patients with gastric cancer.

[0488] It has been found that γδT cells promote the formation of gastric cancer. In particular, γδT cells are the main source of IL-17 in the tumor microenvironment, and IL-17 promotes angiogenesis in gastric cancer, thereby promoting cancer growth (Wu et al., IL-17 promotes angiogenesis through Stat3 pathway mediated upregulation of VEGF ingastric cancer. Tumour Biol. 2016 April; 37 (4): 5493-501). Therefore, without wishing to be bound by theory, γδT cells are key producers of immunosuppressive cytokines in gastric cancer and propose new targets for immunotherapy.

[0489] In some embodiments, the present disclosure provides a method for treating gastric cancer in a subject, the method comprising administering an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0490] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or functional variants thereof, such as those described herein), and wherein the cancer is gastric cancer. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0491] Colorectal cancer (CRC), also known as intestinal cancer, colon cancer, or rectal cancer, is any cancer that affects the colon and rectum. CRC is known to be driven by genetic alterations in tumor cells and is also influenced by tumor-host interactions. Recent reports have demonstrated a direct correlation between the density of certain T lymphocyte subsets and good clinical outcomes in CRC, supporting the primary role of T cell-mediated immunity in inhibiting CRC tumor progression. As with most cancers, current treatments for CRC include surgery, chemotherapy, and radiation. In addition, drugs that target specific mutations (e.g., bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, and ziv-aflibercept) can be administered. Immunotherapeutic antibodies, such as, but not limited to, pembrolizumab and nivolumab, can also be administered. However, further anti-tumor therapies are needed to improve patient outcomes.

[0492] In rectal tumor tissues of patients with rectal cancer, the frequency of γδ1 cells is high and has been found to be positively correlated with T stage (Rong et al., Analysis of tumor-infiltrating gamma delta T cells in rectal cancer. World J Gastroenterol. 2016 Apr 7;22(13):3573–3580). In contrast, the level of γδ2 cells is lower in patients with rectal cancer compared with healthy controls and is negatively correlated with T stage. Studies have found that tumor-infiltrating γδ1 T cells have a strong inhibitory effect, and it is therefore believed that an imbalance in the ratio of γδ1 T cells to γδ2 T cells in patients with rectal cancer may promote the occurrence of rectal cancer. Without wishing to be bound by theory, for example, by administering antibodies that bind to δ1, blocking or targeting δ1 and potentially reducing the inhibitory function of γδ1 cells may provide new treatments for CRC, which may prolong the overall survival of patients.

[0493] In some embodiments, the present disclosure provides a method for treating colorectal cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0494] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or functional variants thereof, such as those described herein), and wherein the cancer is colorectal cancer. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0495] Pancreatic cancer, including pancreatic ductal adenocarcinoma (PDA), accounts for approximately 3% of all cancers and 7% of all cancer deaths in the United States (American Cancer Society, 2019). In PDA, which accounts for approximately 85% of all pancreatic cancers, mutations in four genes have been found in the majority of cases: KRAS, CDKN2A, TP53, and SMAD4 (Wolfgang et al., CA Cancer J Clin. 2013 Sep;63(5):318–348). Treatment of pancreatic cancer typically consists of surgical resection and adjuvant therapy; currently, the median overall survival of patients with resected pancreatic cancer remains approximately 20-22 months. Therefore, additional anti-tumor strategies are needed to further improve outcomes for patients with pancreatic cancer.

[0496] In human pancreatic ductal adenocarcinoma (PDA), activated γδT cell populations account for up to 75% of tumor-infiltrating T cells (Daley et al., Cell. 2016 Sep 8; 166(6): 1485-1499.e15), and γδT cells produce high levels of tumor-promoting IL-17 in PDA (McAllister et al., Cancer Cell. 2014 May 12; 25(5): 621-37). Depletion of γδT cells in the pancreas can significantly prevent tumorigenesis in vivo and lead to the influx of immunogenic Th1 cells and CD8+ T cells into the tumor microenvironment (TME). Without wishing to be bound by theory, pancreatic infiltrating γδT cells promote PDA progression by inducing adaptive immunosuppression, and accordingly, γδT cells are key regulators of effector T cell activation in pancreatic cancer and new targets for cancer immunotherapy.

[0497] In some embodiments, the present disclosure provides a method for treating pancreatic cancer (e.g., PDA) in a subject, the method comprising administering an effective amount of an anti-δ1 antibody or its antigen-binding fragment as described herein to a subject in need thereof. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or its functional variants, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0498] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is pancreatic cancer (e.g., PDA). In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0499] Cholangiocarcinoma (CCA) is an epithelial cancer that forms in the bile ducts and is the most common bile duct malignancy and the second most common liver malignancy after hepatocellular carcinoma. The overall incidence of CCA has been increasing worldwide over the past four decades. CCA is divided into three subtypes based on its anatomical location: intrahepatic cholangiocarcinoma (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA) (e.g., see Loeuillard et al., Animal models of cholangiocarcinoma; Biochim Biophys Acta Mol Basis Dis. 2018 Apr 5, and Rizvi et al., Cholangiocarcinoma—evolving concepts and therapeutic strategies; Nat Rev Clin Oncol. 2018 Feb;15(2):95–111). Currently, the disease is incurable and fatal unless the tumor can be completely resected at an early stage. Other treatment options include adjuvant chemotherapy and radiotherapy.

[0500] In some embodiments, the present disclosure provides a method for treating cholangiocarcinoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0501] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or a functional variant thereof, such as those described herein), and wherein the cancer is cholangiocarcinoma. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0502] Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It is the sixth most common cancer and the second leading cause of cancer death. HCC most often develops in people with chronic liver disease, such as cirrhosis caused by hepatitis B or C infection. HCC is often accompanied by cirrhosis caused by chronic viral infection and extensive lymphocytic infiltration. Current treatment options for liver cancer include partial surgical resection, liver transplantation, percutaneous ablation, local and systemic chemotherapy (e.g., transarterial chemoembolization), small molecule TKIs, and immunotherapy. However, additional anti-tumor treatment strategies are needed to further improve the outcomes of patients with liver cancer.

[0503] It has been found that γδ T cells accumulate in liver tumors, as patients with liver malignancies have elevated levels of γδ T cells compared to healthy controls (Kenna et al., Distinct subpopulations of gamma delta T cells are present in normal and tumor-bearing human liver. Clin Immunol. 2004; 113: 56–63 and Hammerich et al., World J Gastrointest Pathophysiol. 2014 May 15; 5(2): 107–113). Furthermore, different γδ chains can lead to either protective or damaging effects of γδ T cells. Studies have found that in patients with hepatitis C virus, γδ1 T cells are associated with higher necroinflammatory scores, which may indicate how these cells behave in liver cancer (Rajoriya et al., Front Immunol. 2014; 5: 400). Without wishing to be bound by theory, it may be possible to provide a new therapeutic approach for liver cancer by, for example, blocking certain populations of γδ T cells with anti-δ1 antibodies, which could potentially prolong overall patient survival.

[0504] In some embodiments, the present disclosure provides a method for treating liver cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0505] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is liver cancer. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0506] Neuroendocrine tumors (NETs) originate from neuroendocrine cells and most commonly occur in the intestines, but can also occur in the pancreas, lungs, and other parts of the body. Carcinoid tumors are slow-growing neuroendocrine tumors that arise in enterochromaffin cells of the gastrointestinal and bronchopulmonary systems. Although rare, they are the most common type of gastrointestinal neuroendocrine tumor. There are many different types of carcinoid tumors, including bronchopulmonary carcinoids, gastric carcinoids, small intestinal carcinoids, appendiceal carcinoids, and colorectal carcinoid tumors. Typically, treatment includes surgical resection, hepatic chemoembolization (if appropriate), and medical therapy (Pinchot et al., Carcinoid tumors. Oncologist. 2008 Dec;13(12):1255–1269). In addition to some chemotherapeutic agents (Maroun et al., J Curr Oncol. 2006 Apr; 13(2): 67-76) and a limited number of small molecule inhibitors, patients have been found to respond to somatostatin analogs (Aparicio et al., Antitumor activity of somatostatin analogues in progressive metastatic neuroendocrinegastroenteropancreatic tumors. Gut. 1996; 38: 430–438). However, other antitumor strategies are needed to improve the outcomes of patients with NET and carcinoid tumors.

[0507] In some embodiments, the present disclosure provides a method for treating a neuroendocrine tumor (e.g., a carcinoid tumor) in a subject, the method comprising administering an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0508] In some embodiments, the present disclosure provides for the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is a neuroendocrine tumor (e.g., a carcinoid tumor). In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0509] Breast cancer is the second leading cause of cancer death in women. It is caused by genetic mutations in the DNA of breast cancer cells and is the most common type of cancer in women. Depending on the severity of the cancer, treatment can include surgery, chemotherapy, hormone therapy (e.g., hormone-blocking therapy, selective estrogen receptor modulators, aromatase inhibitors), and / or radiation. However, additional anti-tumor strategies are needed to improve outcomes for patients with NETs and carcinoid tumors.

[0510] Studies have found that γδ1 cells are the dominant tumor-infiltrating T cells in tumor cells of breast cancer patients compared with normal controls (Peng et al., Tumor-infiltrating γδT cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity. 2007 Aug; 27(2): 334-48). In contrast, the level of γδ2 cells is lower in breast cancer patients compared with healthy controls. Another study specifically examining triple-negative breast cancer found that the number of γδT cells was increased compared with the level in normal breast tissue (Hidalgo et al., Histological analysis of γδT lymphocytes infiltrating human triple-negative breast carcinomas. Front Immunol. 2014; 5: 632). In fact, it has been found that the γδ1 T cell subtype promotes tumor growth and spread through its immunosuppressive effects (Morrow et al., The role of gamma delta T lymphocytes in breast cancer: a review. Transl Res. 2019 January; 203: 88-96). Without wishing to be bound by theory, for example, by administering antibodies that bind to δ1, blocking or targeting δ1 and potentially reducing the immunosuppressive effects of γδ1 T cells in breast cancer may provide new treatments for breast cancer, which may improve overall patient survival.

[0511] In some embodiments, the present disclosure provides a method for treating breast cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as selected from δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0512] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is breast cancer. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0513] Lung cancer is the most common cause of cancer-related death in men and the second most common cause of cancer-related death in women. Approximately 30% of cancers involve mutations in the Kras oncogene, while mutations in c-MET, NKX2-1, LIB1, PIK3CA, and BRAF have also been implicated in cancer (Herbst et al., Lung cancer. N Eng J Med. 2008. 359(13):1367–80). Treatment of lung cancer varies depending on its severity and may include surgery, radiotherapy, chemotherapy, targeted drug therapy (e.g., erlotinib, gefitinib, afatinib, denosumab), and bronchoscopy. However, the prognosis for people with lung cancer is less than 20% five years after diagnosis. Therefore, additional anti-tumor strategies are needed to further improve patient outcomes.

[0514] In a study of patients with non-small cell lung cancer (NSCLC), an enrichment of the γδ1 T cell population relative to the γδ2 T cell population was found (Bao et al., Characterization of γδT cells in patients with non-small cell lung cancer. Oncol Lett. 2017 Jul;14(1):1133–1140). In another study, it has been shown that lung cancer cells overexpress tumor-infiltrating γδT lymphocytes and that these cells constitute a “substantial fraction” of the tumor-infiltrating cells in lung cancer (Ferrarini et al., Killing of laminin receptor-positive human lung cancers by tumor infiltrating lymphocytes bearing gammadelta(+)t-cell receptors. J Natl Cancer Inst. 1996 Apr 3;88(7):436-41). Without wishing to be bound by theory, blocking or targeting δ1 and potentially reducing the suppressive effect of γδ1 T cells in breast cancer, such as by administering antibodies that bind δ1, may provide new therapeutic approaches for lung cancer, which may improve overall patient survival.

[0515] In some embodiments, the present disclosure provides a method for treating lung cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0516] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is lung cancer. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0517] Genitourinary cancers include, for example, ovarian cancer, endometrial cancer, kidney cancer, bladder cancer, and prostate cancer.

[0518] Ovarian cancer is the most common cause of gynecologic death in Europe and North America, with a diverse progression that makes it challenging to treat and manage. Typically, treatment begins with surgery, followed by chemotherapy (e.g., platinum-based chemotherapy). Similarly, uterine cancer (e.g., endometrial cancer, uterine sarcoma) is the most common gynecologic cancer in the United States and presents with a diverse disease progression. Treatment typically includes surgery, chemotherapy, hormone therapy, and radiation therapy. Kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma) accounts for approximately 2% of all cancers worldwide and has the highest prevalence in North America. Treatment typically consists of surgery, biologic therapies (e.g., everolimus, torisel, sorafenib, sutent, axitinib), immunotherapies (e.g., interferon, interleukin-2), and sunitinib and pazopanib. Kidney cancer generally does not respond to chemotherapy or radiation therapy. Bladder cancer is one of the most common cancers and, if diagnosed early, is highly treatable. Current treatments include surgery, chemotherapy, radiation therapy, and immunotherapy (e.g., Bacillus Calmette-Guérin (BCG), interferon α-2b, atezolizumab). Prostate cancer is the most common cancer and the second leading cause of cancer death in men in the United States and can be treated with surgery, radiation therapy, hormone therapy, chemotherapy, and / or immunotherapy. Therefore, further anti-tumor strategies are needed to improve outcomes for patients with genitourinary cancers.

[0519] In one study, gamma delta T cells were found among the intratumoral T cells of untreated primary advanced ovarian serous carcinoma, whereas alpha beta T cells were absent (Raspollini et al., Tumour-infiltrating gamma / delta T-lymphocytes are correlated with a brief disease-free interval in advanced ovarian serous carcinoma. Ann Oncol. 2005 Apr;16(4):590-6). In a murine ovarian cancer model, delta gamma T cells were found to accumulate at the late stage of tumor progression (Rei et al., Murine CD27(-)Vgamma6(+)gammadelta T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages. Proc Natl Acad Sci USA 2014;111:E3562–E3570). Elevated levels of γδ1 T cells have been found in renal cell carcinoma and prostate cancer (Groh et al., Broad tumor-associated expression and recognition by tumor-derived γδT cells of MICA and MICB. Proc Natl Acad Sci USA. 1999 Jun 8; 96(12): 6879–6884). Conversely, an increase in Vδ2 T cells after BCG administration has been found to be beneficial in bladder cancer (Pauza et al., Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local. Front Immunol. 2018; 9: 1305).

[0520] In some embodiments, the present disclosure provides a method for treating urogenital cancer (e.g., ovarian cancer, endometrial (uterine) cancer, kidney cancer, bladder cancer, prostate cancer) in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or a functional variant thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is δ1-41.

[0521] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or functional variants thereof, such as those described herein), and wherein the cancer is a genitourinary cancer (e.g., ovarian cancer, endometrial (uterine) cancer, kidney cancer, bladder cancer, prostate cancer). In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0522] Lymphoma is a cancer of the lymphocytes and includes chronic lymphocytic leukemia, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma (Hodgkin's disease), non-Hodgkin's lymphoma, and Waldenstrom's macroglobulinemia. Treatment of lymphoma includes chemotherapy, radiation therapy, and immunotherapy. A rare type of lymphoma, gamma delta T-cell lymphoma, is often fatal, although it can be treated with allogeneic stem cell transplantation. However, other anti-tumor therapies are needed to further improve the outcomes of lymphoma patients.

[0523] In some embodiments, the present disclosure provides a method for treating lymphoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or functional variants thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0524] In some embodiments, the present disclosure provides for the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is lymphoma. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0525] Adrenocortical carcinoma is a rare but aggressive form of cancer. This cancer is treated with surgical resection, although most patients are not candidates for this treatment and are instead treated with radiation and radiofrequency ablation. Chemotherapy (eg, mitotane, cisplatin, doxorubicin, etoposide, and mitotane, streptozotocin, and mitotane) can also be administered; however, overall survival remains low. Therefore, additional antitumor strategies are needed to further improve outcomes for patients with adrenocortical carcinoma.

[0526] In some embodiments, the present disclosure provides a method for treating adrenocortical carcinoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-δ1 antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the anti-δ1 antibody is one or more of the anti-δ1 antibodies disclosed herein, such as δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42 or δ1-43 or functional variants thereof, such as those described herein. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is delta 1-39. In yet another example, the antibody is delta 1-41.

[0527] In some embodiments, the present disclosure provides the use of an anti-δ1 antibody as a medicament for treating cancer, wherein the anti-δ1 antibody is selected from one or more of any of the antibodies described herein (e.g., δ1-18, δ1-19, δ1-20, δ1-21, δ1-22, δ1-23, δ1-24, δ1-25, δ1-26, δ1-27, δ1-28, δ1-31, δ1-32, δ1-33, δ1-34, δ1-35, δ1-36, δ1-37, δ1-38, δ1-39, δ1-40, δ1-41, δ1-42, or δ1-43, or functional variants thereof, such as those described herein), and wherein the cancer is adrenocortical carcinoma. In one example, the antibody is δ1-23. In another example, the antibody is δ1-17. In yet another example, the antibody is δ1-39. In yet another example, the antibody is delta 1-41.

[0528] In specific examples, administration of an effective amount of delta 1-17 to a subject in need thereof using the methods disclosed herein can treat pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer (e.g., non-small cell lung cancer NSCLC and small cell lung cancer SCLC), glioblastoma, upper and lower gastrointestinal malignancies (including but not limited to esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, bile duct cancer (cholangiocarcinoma) and hepatobiliary cancer), squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer (carcinoid and pancreatic neuroendocrine tumors), adrenocortical carcinoma, sarcoma, or a combination thereof.

[0529] In other specific examples, pancreatic duct adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer (e.g., non-small cell lung cancer NSCLC and small cell lung cancer SCLC), glioblastoma, upper and lower gastrointestinal malignancies (including but not limited to esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, bile duct cancer (cholangiocarcinoma) and hepatobiliary cancer), squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer (carcinoid and pancreatic neuroendocrine tumors), adrenocortical cancer, sarcoma, or a combination thereof can be treated using the methods disclosed herein.

[0530] In yet other specific examples, pancreatic duct adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer (e.g., non-small cell lung cancer NSCLC and small cell lung cancer SCLC), glioblastoma, upper and lower gastrointestinal malignancies (including but not limited to esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, bile duct cancer (cholangiocarcinoma) and hepatobiliary cancer), squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer (carcinoid and pancreatic neuroendocrine tumors), adrenocortical cancer, sarcoma, or a combination thereof can be treated using the methods disclosed herein.

[0531] In yet other specific examples, pancreatic duct adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer (e.g., non-small cell lung cancer NSCLC and small cell lung cancer SCLC), glioblastoma, upper and lower gastrointestinal malignancies (including but not limited to esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, bile duct cancer (cholangiocarcinoma) and hepatobiliary cancer), squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer (carcinoid and pancreatic neuroendocrine tumors), adrenocortical cancer, sarcoma, or a combination thereof can be treated using the methods disclosed herein.

[0532] A subject suspected of having any such disease / disorder of interest may or may not exhibit one or more symptoms of the disease / disorder. A subject at risk of the disease / disorder may be a subject having one or more risk factors for the disease / disorder.

[0533] As used herein, "effective amount" refers to the amount of each active agent required to give a subject a therapeutic effect, either alone or in combination with one or more other active agents. In some embodiments, the therapeutic effect is to reduce the activity and / or number / expression of γδT cells or to increase the anti-tumor immune response (e.g., activation and / or activity increase of αβT cells) in the tumor microenvironment. It will be obvious to those skilled in the art to determine whether the amount of the antibody achieves a therapeutic effect. As will be appreciated by those skilled in the art, the effective amount varies, depending on the specific condition being treated, the severity of the condition, individual patient parameters (including age, physical condition, body shape, sex and weight), the duration of treatment, the nature of the co-therapy (if any), the specific route of administration, and similar factors within the knowledge and expertise of health practitioners. These factors are well known to those of ordinary skill in the art and can be solved simply by routine experiments. It is generally preferred to use the maximum dose of a single component or a combination thereof, i.e., the highest safe dose based on reasonable medical judgment.

[0534] Empirical considerations such as half-life will usually help determine dosage. For example, antibodies compatible with the human immune system, such as humanized antibodies or fully human antibodies, can be used to extend the half-life of the antibody and prevent the antibody from being attacked by the host immune system. The frequency of administration can be determined and adjusted during the course of treatment, and is usually but not necessarily based on the treatment and / or suppression and / or improvement and / or delay of the target disease / illness. Alternatively, the persistence of the antibody continuous release formulation may be suitable. Various preparations and devices for achieving sustained release are known in the art.

[0535] In one example, the dosage of an anti-delta 1 antibody as described herein can be determined empirically in an individual who has received one or more administrations of the antibody. The individual is given increasing doses of the antagonist. To assess the efficacy of the antagonist, indicators of the disease / disorder can be followed.

[0536] Typically, for administration of any anti-δ1 antibody described herein, an initial candidate dose may be about 2 mg / kg to about 10 mg / kg or 1 mg / kg to about 20 mg / kg. For the purposes of this disclosure, a typical dose may be about any dose from 0.1 μg / kg to 3 μg / kg to 30 μg / kg to 300 μg / kg to 3 mg / kg, to 30 mg / kg to 100 mg / kg, or higher, depending on the factors described above. In some embodiments, any anti-δ1 antibody described herein may be administered to a subject in need of treatment in one or more fixed doses, i.e., independent of the subject's weight, body surface area, or other similar factors. For repeated administration over several days or longer, depending on the condition, treatment is continued until the desired symptom suppression occurs or until sufficient therapeutic levels are achieved to alleviate the target disease or condition or its symptoms. Exemplary dosing regimens include administration of an initial dose of about 3 mg / kg, followed by weekly maintenance doses of about 1 mg / kg of the antibody, or thereafter maintenance doses of about 1 mg / kg every other week. However, other dosing regimens may also be useful, depending on the pharmacokinetic decay pattern that the practitioner wishes to achieve. For example, administration is contemplated one to four times per week. In some embodiments, the dosage range that can be used is from about 3 μg / mg to about 2 mg / kg (e.g., about 3 μg / mg, about 10 μg / mg, about 30 μg / mg, about 100 μg / mg, about 300 μg / mg, about 1 mg / kg, and about 2 mg / kg). In other embodiments, a fixed dose (giving a patient a determined amount of antibody without considering body weight, body surface area, and other similar factors) can be used to treat a target disease as described herein.

[0537] In some embodiments, the dosing frequency is once a week, once every 2 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks; or once a month, once every 2 months, or once every 3 months or longer. The progress of this therapy is easily monitored by conventional techniques and assays. The dosing regimen (including the antibody used) can change over time.

[0538] In some embodiments, for adult patients of normal weight, a dose range of about 0.3 mg / kg to 5.00 mg / kg may be administered. In some examples, the dose of the anti-δ1 antibody described herein may be 10 mg / kg. The specific dosing regimen, i.e., dose, timing, and repetition, will depend on the specific individual and the individual's medical history as well as the properties of the respective agent (e.g., the half-life of the agent and other considerations well known in the art).

[0539] For the purposes of this disclosure, the appropriate dosage of an antibody as described herein will depend on the specific antibody, antibody and / or non-antibody peptide (or combination thereof) employed, the type and severity of the disease / disorder, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to antagonists, and the discretion of the attending physician. Clinicians will typically administer the antibody until a dosage that achieves the desired result is reached. In some embodiments, the desired result is an increase in the anti-tumor immune response in the tumor microenvironment. Methods for determining whether a dosage produces the desired result will be apparent to those skilled in the art. Administration of one or more antibodies can be continuous or intermittent, depending on, for example, the physiological condition of the recipient, whether the purpose of administration is therapeutic or preventive, and other factors known to skilled practitioners. Administration of the antibody can be substantially continuous over a preselected time period, or a series of spaced doses can be employed, for example, before, during, or after the target disease or disorder develops.

[0540] As used herein, the term "treat" refers to applying or administering a composition comprising one or more active agents to a subject suffering from a target disease or condition, symptoms of the disease / condition, or susceptibility to the disease / condition, in order to treat, cure, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the condition, symptoms of the disease, or susceptibility to the disease or condition.

[0541] Alleviate the target disease / illness and comprise delaying the formation or progress of disease, or reducing disease severity, or prolonging survival.Alleviate disease or prolong survival and do not necessarily need to cure effect.As used herein, "delaying" the formation of target disease or illness means to postpone, hinder, slow down, slow down, stabilize and / or postpone the progress of disease.The time of this delay can be of different lengths, and this depends on the history of disease and / or the individual being treated.The method of "delaying" or alleviating the formation of disease or delaying the onset of disease is the method for reducing the probability of forming one or more symptoms of disease and / or reducing the degree of symptom in a given time frame compared with not using this method.This comparison is normally based on clinical research, and the number of subjects used is enough to provide the result with statistical significance.

[0542] The "development / occurrence" or "progression" of a disease refers to the initial manifestation and / or subsequent progression of the disease. The development of a disease can be detected and assessed using standard clinical techniques as are well known in the art. However, development also refers to progression that may not be detected. For the purposes of this disclosure, development or progression refers to the biological progression of symptoms. "Development" includes appearance, recurrence, and onset. As used herein, "onset" or "occurrence" of a disease or condition of interest includes initial onset and / or recurrence.

[0543] In some embodiments, the present disclosure provides a method for inhibiting γδT cell activity. In some embodiments, the anti-δ1 antibodies described herein are administered to a subject in need of treatment in an amount sufficient to inhibit the activity of γδT cells. In some embodiments, the anti-δ1 antibodies described herein are administered to a subject in need of treatment in an amount sufficient to inhibit the activity of γδT cells by at least 10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more). In other embodiments, anti-δ1 antibodies are administered in an amount that effectively rescues immunosuppression induced by γδT cells. In other embodiments, anti-δ1 antibodies are administered in an amount that effectively rescues immunosuppression induced by γδT cells by at least 10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0544] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-41 and δ1-39, for inhibiting the activity of γδT cells. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to inhibit the activity of γδT cells. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to inhibit the activity of γδT cells in vivo by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) (compared to the level before treatment or in a control subject). In some embodiments, the antibody is δ1-39.

[0545] In some embodiments, the present disclosure provides a method for reducing tumor volume, tumor size and / or tumor burden, comprising providing or administering to a subject an anti-δ1 antibody as described herein (e.g., in Table 1 and / or Table 2) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-39, and δ1-41. In some embodiments, the method reduces tumor volume, tumor size, and / or tumor burden by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increments therein).

[0546] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-41 and δ1-39, for reducing tumor volume, tumor size and / or tumor load. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to reduce tumor volume, tumor size and / or tumor load. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need of treatment in an amount sufficient to reduce tumor volume, tumor size and / or tumor load by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) in vivo (compared to the level before treatment or in a control subject). In some embodiments, the antibody is δ1-39.

[0547] In some embodiments, the present disclosure provides a method for depleting target cells (e.g., γδT cells, such as Vδ1T cells) in a tumor and / or blood, the method comprising providing or administering to a subject an anti-δ1 antibody as described herein (e.g., in Table 1 and / or Table 2) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-39, and δ1-41. In some embodiments, the method depletes γδT cells, such as Vδ1T cells, by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0548] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-41 and δ1-39, for depleting target cells in tumors and / or blood, such as γδT cells, such as γδ1T cells. In some embodiments, the antibodies described herein, such as those in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to deplete γδT cells such as γδ1T cells in tumors and / or blood. In some embodiments, the antibodies described herein, such as those in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to deplete γδT cells such as γδ1T cells in tumors and / or blood by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) (compared to the level before treatment or in a control subject). In some embodiments, the antibody is delta 1-39.

[0549] In some embodiments, the present disclosure provides a method for regulating the ratio of γδT cells in a tumor, for example, regulating, such as reducing, the ratio of γδ1T cells to γδ2T cells, the method comprising providing or administering to a subject an anti-δ1 antibody as described herein (e.g., in Table 1 and / or Table 2) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-39, and δ1-41. In some embodiments, the method regulates, for example, reducing the ratio of γδ1T cells to γδ2T cells in a tumor by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0550] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-17, δ1-39 or δ1-41, for regulating the ratio of γδT cells in tumors, for example, regulating such as reducing the ratio of Vδ1T cells to Vδ2T cells. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to regulate, for example, reduce the ratio of γδ1T cells to γδ2T cells in tumors. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to subjects in need thereof in an amount sufficient to regulate, for example, reduce the ratio of γδ1T cells to γδ2T cells in tumors in vivo by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) (compared to the level before treatment or in a control subject). In some embodiments, the antibody is delta 1-39.

[0551] In some embodiments, the present disclosure provides a method for regulating the ratio of γδ1 T cells in PBMCs and / or the ratio of γδ1 T cells in immune cells present in tumors (e.g., isolated from a subject with cancer), for example, regulating, such as reducing, the ratio of γδ1 T cells in PBMCs and / or the ratio of γδ1 T cells in immune cells present in tumors, the method comprising providing or administering to the subject an anti-δ1 antibody as described herein (e.g., in Table 1) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-39, and δ1-41. In some embodiments, the method regulates, for example, reducing the ratio of γδ1 T cells in PBMCs and / or the ratio of γδ1 T cells in immune cells present in tumors by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0552] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-17, δ1-39 or δ1-41, for regulating the ratio of γδ1 T cells in PBMCs and / or the ratio of γδ1 T cells in immune cells present in tumors, for example, regulating, such as reducing, the ratio of γδ1 to PBMCs or to immune cells in tumors. In some embodiments, the antibodies described herein, such as those in Table 1, including but not limited to δ1-23, δ1-41 and δ1-39, are administered to a subject in need thereof in an amount sufficient to regulate, for example, reduce the ratio of γδ1 T cells in PBMCs and / or the ratio of γδ1 T cells in immune cells present in tumors. In some embodiments, an antibody described herein, such as in Table 1, including but not limited to δ1-23, δ1-41, and δ1-39, is administered to a subject in need of treatment in an amount sufficient to modulate, for example, reduce the ratio of γδ1 T cells in PBMCs and / or the ratio of γδ1 T cells in immune cells present in tumors by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) in vivo compared to levels before treatment or in a control subject. In some embodiments, the antibody is δ1-39.

[0553] In some embodiments, the present disclosure provides a method for clearing or depleting target cells, wherein the target cells are immunosuppressive immune cells, such as γδT cells, such as γδ1T cells, the method comprising providing or administering to a subject an anti-δ1 antibody as described herein (e.g., in Table 1 and / or Table 2) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is δ1-39. In some embodiments, the method promotes the clearance or depletion of target cells (e.g., immunosuppressive immune cells, such as γδT cells, such as γδ1T cells) by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0554] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-17, δ1-39 or δ1-41, for clearing or depleting target cells, wherein the target cells are immunosuppressive immune cells, such as γδT cells, such as γδ1T cells. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-17, δ1-39 or δ1-41, are administered to a subject in need thereof in an amount sufficient to clear or deplete γδT cells such as γδ1T cells in the tumor and / or circulation (e.g., serum or blood). In some embodiments, an antibody described herein, such as in Table 1, including but not limited to δ1-23, δ1-41, and δ1-39, is administered to a subject in need of treatment in an amount sufficient to eliminate or deplete γδ T cells, such as γδ1 T cells, in the tumor in vivo by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to levels before treatment or in a control subject. In some embodiments, the antibody is δ1-39.

[0555] In some embodiments, the present disclosure provides a method for inducing cytotoxicity, such as ADCC, in a target cell, wherein the target cell is an immunosuppressive immune cell, such as a γδT cell, such as a γδ1T cell, the method comprising providing or administering to a subject an anti-δ1 antibody as described herein (e.g., in Table 1 and / or Table 2) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-39, and δ1-41. In some embodiments, the method induces cytotoxicity, such as ADCC, in γδT cells (e.g., γδ1T cells) by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein).

[0556] In some embodiments, the present disclosure provides one or more anti-δ1 antibodies described herein, including but not limited to δ1-23, δ1-17, δ1-39 or δ1-41, for inducing cytotoxicity such as ADCC in target cells, wherein the target cells are immunosuppressive immune cells, such as γδT cells, such as γδ1T cells. In some embodiments, the antibodies described herein, such as in Table 1, including but not limited to δ1-23, δ1-17, δ1-39 or δ1-41, are administered to a subject in need thereof in an amount sufficient to promote ADCC in γδT cells such as γδ1T cells in the tumor and / or circulation (e.g., serum or blood). In some embodiments, an antibody described herein, such as in Table 1, including but not limited to δ1-23, δ1-41, and δ1-39, is administered to a subject in need of treatment in an amount sufficient to promote ADCC by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) in the tumor and / or circulating (e.g., serum or blood) γδ T cells, such as γδ1 T cells, in vivo (compared to levels before treatment or in a control subject). In some embodiments, the antibody is δ1-39.

[0557] In some embodiments, the present disclosure provides a method for inducing cytotoxicity, such as complement-dependent cytotoxicity (CDC), against target cells expressing δ1 (i.e., γδT cells, such as γδ1T cells) in a subject, the method comprising providing or administering to the subject an anti-δ1 antibody as described herein (e.g., in Table 1) or an antigen-binding fragment thereof. In some embodiments, the anti-δ1 antibody is selected from δ1-23, δ1-39, and δ1-41. In some embodiments, the anti-δ1 antibody is δ1-17. In some embodiments, the anti-δ1 antibody is δ1-39. In some embodiments, the anti-δ1 antibody is δ1-41. In some embodiments, the m...

Claims

1. An isolated antibody that binds to the delta 1 chain of a T cell receptor, wherein the antibody comprises a heavy chain complementary determining region 1 (VH-CDR1) as set forth in SEQ ID NO: 68, a heavy chain complementary determining region 2 (VH-CDR2) as set forth in SEQ ID NO: 53, and a heavy chain complementary determining region 3 (VH-CDR3) as set forth in SEQ ID NO: 54, and further comprises a light chain complementary determining region 1 (VL-CDR1) as set forth in SEQ ID NO: 55, a light chain complementary determining region 2 (VL-CDR2) as set forth in SEQ ID NO: 56, and a light chain complementary determining region 3 (VL-CDR3) as set forth in SEQ ID NO:

57.

2. The isolated antibody of claim 1, which is a full-length antibody or an antigen-binding fragment thereof.

3. The isolated antibody of claim 1, which is a single-chain antibody.

4. The isolated antibody of claim 1, which is a human antibody or a humanized antibody.

5. The isolated antibody of claim 1, which is an IgG molecule.

6. The isolated antibody of claim 5, wherein the antibody is an IgG1 or IgG4 molecule.

7. The isolated antibody of claim 6, wherein the antibody is an IgG1 molecule.

8. The isolated antibody of claim 7, wherein the IgG1 has one or more mutations selected from the group consisting of: (1) E333A mutation; (2) S239D / A330L / I332E mutation; (3) K326W / E333S mutation; and (4) S239D / I332E / G236A mutation.

9. The isolated antibody of claim 7, wherein the antibody comprises a heavy chain constant region as shown in SEQ ID NO: 31 and a light chain constant region as shown in SEQ ID NO:

73.

10. The isolated antibody of any one of claims 1-9, wherein the antibody comprises a heavy chain variable region (VH) as shown in SEQ ID NO: 24 and a light chain variable region (VL) as shown in SEQ ID NO:

9.

11. The isolated antibody of claim 1, wherein the antibody comprises a VH as shown in SEQ ID NO: 24 and a VL as shown in SEQ ID NO: 9, and comprises a heavy chain constant region as shown in SEQ ID NO: 31 and a light chain constant region as shown in SEQ ID NO:

73.

12. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain as set forth in SEQ ID NO: 79 and a light chain as set forth in SEQ ID NO:

78.

13. The isolated antibody of claim 11 or 12, wherein the C-terminal lysine residue of the heavy chain is deleted.

14. A pharmaceutical composition comprising the antibody of any one of claims 1 to 9 and 11 to 13 and a pharmaceutically acceptable carrier. 15 . The pharmaceutical composition of claim 14 , wherein the antibody comprises a heavy chain variable region (VH) as shown in SEQ ID NO: 24 and a light chain variable region (VL) as shown in SEQ ID NO:

9.

16. Use of an antibody that binds to the delta 1 chain of a T cell receptor as described in any one of claims 1 to 9 and 11 to 13 in the preparation of a medicament for treating cancer in a subject, wherein the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, esophageal cancer, gastric cancer, hepatobiliary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer and ovarian cancer.

17. The use of claim 16, wherein the antibody comprises a heavy chain variable region (VH) as shown in SEQ ID NO: 24 and a light chain variable region (VL) as shown in SEQ ID NO:

9.

18. The use of claim 16, wherein the subject is a human patient suffering from the cancer.

19. Use of an antibody that binds to the delta 1 chain of the T cell receptor as described in any one of claims 1-9 and 11-13 and an inhibitor of a checkpoint molecule, an activator of a co-stimulatory receptor, an inhibitor of an innate immune cell target, a chemotherapeutic agent, or an antihypertensive agent in the preparation of a kit for treating cancer in a subject, wherein the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, esophageal cancer, gastric cancer, hepatobiliary cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, and ovarian cancer.

20. The method of claim 19, wherein: (a) the checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIM-3, A2aR, TIGIT and VISTA; (b) the co-stimulatory receptor is selected from the group consisting of OX40, GITR, CD137, CD40, CD27 and ICOS; and / or (c) The innate immune cell target is selected from the group consisting of KIR, NKG2A, CD96, TLR, IDO and Galectin-9.

21. The use of claim 20, wherein the subject is a human patient suffering from the cancer.

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