Antibodies specific to delta 1 chain of t cell receptor

Abstract

To provide an isolated antibody which binds to a delta-1 chain of a T cell receptor.SOLUTION: In one aspect, provided is an isolated antibody, comprising: a heavy chain variable region in which HC CDR1 comprises FTX1X2X3X4X5IH (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), HC CDR2 comprises SIYSSSGYTYYADSVKG, and HC CDR3 comprises PGX6YYWYYSGSAYEGYGLDY (X6 is S or M); and / or a light chain variable region in which LC CDR1 comprises RASQSVSSAVA, LC CDR2 comprises X7ASSLX8S (X7 is S or A, X8 is Y or Q), and LC CDR3 comprises QQX9X10X11X12X13X14LIT (X9 is S or Q, X10 is G, S, or T, X11 is D, K, or S, X12 is Y, W, or absent, X13 is P or absent, and X14 is D, F, or Y).SELECTED DRAWING: None

Description

[Background technology]

[0001] 2. Background of the Invention Immune checkpoint blockade has demonstrated unprecedented success as a cancer treatment in the past few years. In many cases, antibodies are used to block immune inhibitory pathways, such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) pathways. Although therapies targeting those two pathways have shown success in treating several cancer types, anti-CTLA-4 and anti-PD-1 therapies have response rates of 10-60% of treated patients, depending on the cancer type, and have yet to demonstrate the ability to exceed a 60% response rate, even when used in combination (Kyvistborg et al., "Enhancing Anti-cancer Drugs," 2013). "Scientific evidence supports the efficacy and safety of immunized cancer therapy," Science. 2018 Feb. 2; 359(6375):516-517. Additionally, many cancer types are refractory to these therapies.

[0002] γδ T cells are a subgroup of T cells that have distinct T cell receptor (TCR) γ and δ chains on their surface. This separates them from CD4+ helper T cells and CD8+ cytotoxic T cells that express αβ TCR on the cell surface. Recent studies have found that γδ T cells have tumor-promoting activity (Zhao et al., J Transl Med (2018) 16:3). For example, in human pancreatic ductal adenocarcinoma, γδ T cells have been found to constitute a substantial proportion of tumor-infiltrating T cells and to inhibit anti-cancer immune responses mediated by alpha beta (αβ) T cells (Daley et al., Cell, 2016, 166:1485-1499). In the tumor microenvironment (TME), gamma delta T cells have been shown to express IL-4, IL-10, and TGF-β leading to suppression of antitumor responses (Kuhl et al., Immunol., 2009, vol. 128(4):580-588). Expression of both IL-10 and TGF-β has been shown to be increased in various cancer types (Lafont et al., Front Immunol., 2014, vol. 5:622). gamma delta T17 cells are the major source of IL-17 in the tumor microenvironment, where they function to promote angiogenesis in numerous cancer types (Silva-Santos B. Eur J Immunol. 2010; vol. 40:1873-6; Zhao et al., J Transl Med (2018) 16:3, and references therein). Additionally, γδ T cells have been found to induce senescence of naive and effector T cells such that these cells become suppressive in the TME, increasing immunosuppression (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, promoting a tumor-promoting microenvironment (Yan and Huang, Oncoimmunology. 2014;3:e953423; Qu P et al., Cancer Lett. 2016;380:253-6, and references therein). Summary of the Invention [Problem to be solved by the invention]

[0003] Given the average response rate 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 gamma delta T cells and / or their T cell receptors provides a novel cancer therapy approach. [Means for solving the problem]

[0004] Summary of the Invention Modulation of gamma delta T cell activity and / or one or more of its T cell receptors may be used alone or in combination with existing therapies as a means for cancer treatment. Described herein are novel human antibodies that bind to human gamma delta T cell receptors and their therapeutic use in the treatment of cancer. The disclosure is based, at least in part, on the development of antibodies that specifically bind to the delta-1 chain of the gamma delta T cell receptor (TCR). Such antibodies have been found to effectively suppress gamma delta T cells, thereby rescuing the immunosuppression mediated by gamma delta T cells.

[0005] Thus, one embodiment of the present disclosure provides an isolated antibody that specifically binds to the delta-1 chain of the T cell receptor. In some cases, the antibody comprises a heavy chain variable region (V) comprising HC CDR1, HC CDR2, and HC CDR3. H In some embodiments, HC CDR1 comprises FTX. 1 X 2 X 3 X 4 X 5 IH (SEQ ID NO: 46) motif, 1 is F or V, and X 2 is S or T, and X 3 is G, A, or S, and X 4 is T, N, or S, and X 5is D or S. In some embodiments, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively, or additionally, in some embodiments, HC CDR3 comprises PGX 6 YYWYYSGSAYEGYGLDY (SEQ ID NO: 48), 6 contains S or M.

[0006] Alternatively or additionally, the isolated antibody disclosed herein comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L In some embodiments, LC CDR1 comprises RASQSVSSAVA (SEQ ID NO: 55). In some embodiments, LC CDR2 comprises X 7 ASSLX 8 S (SEQ ID NO: 50), 7 is S or A, and X 8 is Y or Q. Alternatively or additionally, in some embodiments, LC CDR3 is QQX 9 X 10 X 11 X 12 X 13 X 14 LIT (SEQ ID NO:51), 9 is S or Q, and X 10 is G, S, or T, and X 11 is D, K, or S, and X 12 is Y, W, or absent, X 13 is P or absent and X 14 is D, F, or Y. In some cases, the isolated antibody does not contain the same heavy and light chain CDRs as Delta 1-17.

[0007] In some embodiments, the antibody comprises a heavy chain variable region (V H ) and HC CDR1 is FTFX 1 X 2 X 3 X 4 IH (SEQ ID NO: 93) motif, 1 is S or T, and X2 is S, G or A, and X 3 is T, N, or S, and X 4 is D or S, V H 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 antibody disclosed herein comprises LC CDR1, LC The light chain variable region (V L LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55), L 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).

[0008] In some embodiments, the antibody comprises a heavy chain variable region (V H ) and HC CDR1 is FTFX 1 X 2 X 3 X 4 IH (SEQ ID NO: 93) motif, 1 is S or T, and X 2 is S, G or A, and X 3 is T, N, or S, and X 4 is D or S, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54); H In some embodiments, the isolated antibody comprises LC CDR1, LC CDR2, and LC CDR3. The light chain variable region (V LLC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55), LC CDR2 comprises AASSLQS (SEQ ID NO:56), and LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO:57), L Includes.

[0009] In some embodiments, the antibody comprises a heavy chain variable region (V H 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. H 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 antibody disclosed herein comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55), L Alternatively or additionally, LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO: 57).

[0010] In some embodiments, the antibody comprises a heavy chain variable region (V H 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), HIn some embodiments, the isolated antibody comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L 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), L Further includes:

[0011] In some embodiments, the antibody comprises a heavy chain variable region (V H ) and HC CDR1 is FTFX 1 X 2 X 3 X 4 IH (SEQ ID NO: 94) motif, 1 is S or T, and X 2 is S or A and X 3 is N or S and X 4 is D or S, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53), and HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54); H In some embodiments, the isolated antibody comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L 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), L Includes.

[0012] In some embodiments, the antibody comprises a heavy chain variable region (V H 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. HAlternatively 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 antibody disclosed herein comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55), L Alternatively or additionally, LC CDR2 comprises AASSLQS (SEQ ID NO: 56). Alternatively or additionally, LC CDR3 comprises QQQSKY PFLIT (SEQ ID NO:57).

[0013] In some embodiments, the antibody comprises a heavy chain variable region (V H 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), H In some embodiments, the isolated antibody comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L 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), L Further includes:

[0014] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of the anti-Delta1 antibodies disclosed herein together contain 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) compared to the HC CDRs of a reference antibody. Alternatively or additionally, the LC CDR1, LC CDR2, and LC CDR3 of the antibody together contain no more than 8 amino acid changes (e.g., no more than 7, 6, 5, 4, 3, 2, or 1 amino acid change) compared to the light chain CDRs of a reference antibody, the reference antibody being 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

[0015] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of the anti-delta 1 antibody disclosed herein contain 10 or less amino acid changes (e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less amino acid changes) in combination with the HC CDR of the reference antibody. Alternatively or additionally, the LC CDR1, LC CDR2, and LC CDR3 of the antibody contain 8 or less amino acid changes (e.g., 7, 6, 5, 4, 3, 2, or 1 or less amino acid changes) in combination with the light chain CDR of the reference antibody, the reference antibody being selected from the group consisting of delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

[0016] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of the anti-delta 1 antibody disclosed herein contain 10 or less amino acid changes (e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less amino acid changes) in combination with the HC CDR of the reference antibody.Alternatively or additionally, the LC CDR1, LC CDR2, and LC CDR3 of the antibody contain 8 or less amino acid changes (e.g., 7, 6, 5, 4, 3, 2, or 1 or less amino acid changes) in combination with the light chain CDR of the reference antibody, and the reference antibody is selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

[0017] In some embodiments, the HC CDR1, HC CDR2, and HC CDR3 of the 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 the reference antibody, and / or the CDR1, CDR2, and CDR3 together 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 the reference antibody. 8%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%).

[0018] In some examples, the anti-delta1 antibody may comprise the same heavy chain complementarity determining region (CDR) and the same light chain CDR as the reference antibody. In one particular example, the anti-delta1 antibody comprises the same heavy chain variable region and the same light chain variable region as the reference antibody.

[0019] In some embodiments, the anti-delta1 antibodies disclosed herein bind to human delta1 chain. In some embodiments, the anti-delta1 antibodies disclosed herein are selected from delta1-18, delta1-19, delta1-20, delta1-21, delta1-22, delta1-23, delta1-24, delta1-25, delta1-26, delta1-27, delta1-28, delta1-31, delta1-32, delta1-33, delta1-34, delta1-35, delta1-36, delta1-37, delta1-38, delta1-39, delta1-40, delta1-41, delta1-42, and delta1-43 antibodies. Each of these antibodies is referred to herein as a "reference antibody." In some embodiments, the anti-delta 1 antibodies disclosed herein bind to the same epitope as any one of the 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies, and / or compete for binding to the epitope against any of the reference antibodies listed immediately above.

[0020] In some embodiments, the anti-delta 1 antibody disclosed herein is selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. Each of these antibodies is referred to herein as a "reference antibody." In some embodiments, the anti-delta 1 antibody disclosed herein binds to the same epitope as any one of the delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies and / or competes for binding to the epitope against any one of the reference antibodies described immediately above.

[0021] In some embodiments, the anti-delta 1 antibody disclosed herein is selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies. Each of these antibodies is referred to herein as a "reference antibody." In some embodiments, the anti-delta 1 antibody disclosed herein binds to the same epitope as any one of the delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies and / or competes for binding to the epitope against any one of the reference antibodies described immediately above.

[0022] In some embodiments, the anti-Delta1 antibody comprises a heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3). H ), wherein HC CDR1, HC CDR2, and HC CDR3 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 the reference antibody, and / or the antibody comprises a light chain variable domain (V L ), wherein the light chain CDR1, light chain CDR2, and light chain CDR3 together 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.

[0023] In some embodiments, the anti-Delta1 antibody comprises a heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3). H), including HC CDR1, HC CDR2, and HC and / or the antibody comprises a light chain variable domain (VD) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3, the CDR3 together being 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 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. L ), and the light chain CDR1, light chain CDR2, and light chain CDR3 collectively comprise 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta and / or a light chain CDR of an antibody selected from Delta 1-38, Delta 1-39, Delta 1-40, Delta 1-41, Delta 1-42, and Delta 1-43 antibodies.

[0024] In some embodiments, the anti-Delta1 antibody comprises a heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3). H), wherein HC CDR1, HC CDR2, and HC CDR3 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 delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies, and / or the antibody comprises a light chain variable domain (V L ), wherein the light chain CDR1, light chain CDR2, and light chain CDR3 together 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 delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies.

[0025] In some embodiments, the anti-Delta1 antibody comprises a heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3). H ), wherein HC CDR1, HC CDR2, and HC CDR3 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 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 ) and includes light chain CDR1, light chain CDR R2 and the light chain CDR3 together 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 delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies.

[0026] In some embodiments, the anti-delta 1 antibody comprises the same heavy chain complementarity determining regions (CDRs) and the same light chain CDRs as the reference antibody. In some embodiments, the anti-delta 1 antibody comprises the same heavy chain variable region and the same light chain variable region as an antibody selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. In some embodiments, the anti-Delta 1 antibody comprises the same heavy chain variable region and the same light chain variable region as an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies.

[0027] In one specific embodiment, the anti-Delta1 antibody comprises a heavy chain variable domain (VD) that contains heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) identical to the heavy chain CDRs of Delta1-39. H In some embodiments, the anti-Delta1 antibody comprises a light chain variable domain (V) that comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 identical to the light chain CDRs of Delta1-39. LIn some embodiments, the anti-Delta1 antibody comprises a heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3). H ), including HC CDR1, HC CDR2, and HC and / or the antibody comprises a light chain variable domain (V CDR1, V CDR2, and V CDR3) that is 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. L ), wherein the light chain CDR1, light chain CDR2, and light chain CDR3 together 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 delta 1-39.

[0028] In some embodiments, the anti-Delta1 antibody has a VH sequence selected from SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72. In some embodiments, the anti-delta 1 antibody comprises a VH CDR1 having the sequence of SEQ ID NO:68. In some embodiments, the anti-delta 1 antibody comprises a VH CDR2 having the sequence of SEQ ID NO:53. In some embodiments, the anti-delta 1 antibody comprises a VH CDR3 having the sequence of SEQ ID NO:54. In some embodiments, the anti-delta 1 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. In some embodiments, the anti-delta 1 antibody comprises a light chain variable domain (VH CDR1) having a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H), wherein the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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.

[0029] In some embodiments, the anti-delta 1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 55. In some embodiments, the anti-delta 1 antibody comprises a VL CDR2 having the sequence of SEQ ID NO: 56 or 58. In some embodiments, the anti-delta 1 antibody comprises a VL CDR3 having a sequence selected from any of SEQ ID NOs: 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60. In some embodiments, the anti-delta 1 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 of SEQ ID NOs: 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60. In some embodiments, the anti-Delta1 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 of SEQ ID NO:57. In some embodiments, the anti-Delta1 antibody comprises a light chain variable domain (V CDR1) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. L ), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0030] In some embodiments, the anti-Delta1 antibody comprises a VH CDR1 having a sequence selected from SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72. In some embodiments, the anti-Delta1 antibody comprises a VH CDR1 having a sequence selected from SEQ ID NO: 53. In some embodiments, the anti-delta1 antibody comprises a VH CDR3 having the sequence of SEQ ID NO:54. In some embodiments, the anti-delta1 antibody comprises a VH CDR1 having the sequence of SEQ ID NO:68. In some embodiments, the anti-delta1 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. In some embodiments, the anti-delta1 antibody comprises a heavy chain variable domain (VH CDR1) having a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H ), wherein heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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.

[0031] In some embodiments, the anti-delta 1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO:55. In some embodiments, the anti-delta 1 antibody comprises a VL CDR2 having the sequence of SEQ ID NO:56. In some embodiments, the anti-delta 1 antibody comprises a VL CDR3 having the sequence of SEQ ID NO:57. In some embodiments, the anti-delta 1 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-delta 1 antibody comprises a light chain variable domain (VL CDR1) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. L), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0032] In some embodiments, the anti-Delta1 antibody is selected from the group consisting of SEQ ID NOs: 67, 68, 69, and 70. In some embodiments, the anti-delta 1 antibody comprises a VH CDR2 having the sequence of SEQ ID NO:53. In some embodiments, the anti-delta 1 antibody comprises a VH CDR3 having the sequence of SEQ ID NO:54. In some embodiments, the anti-delta 1 antibody comprises a VH CDR1 having the sequence of SEQ ID NO:68. In some embodiments, the anti-delta 1 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. In some embodiments, the anti-delta 1 antibody comprises a heavy chain variable domain (VH CDR1) comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H ), wherein heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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.

[0033] In some embodiments, the anti-delta 1 antibody comprises a VL CDR1 having the sequence of SEQ ID NO:55. In some embodiments, the anti-delta 1 antibody comprises a VL CDR2 having the sequence of SEQ ID NO:56. In some embodiments, the anti-delta 1 antibody comprises a VL CDR3 having the sequence of SEQ ID NO:57. In some embodiments, the anti-delta 1 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-delta 1 antibody comprises a light chain variable domain (VL CDR1) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. L ), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0034] In some embodiments, the anti-Delta1 antibody has a VH sequence selected from SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72. In some embodiments, the anti-Delta1 antibody comprises a light chain variable domain (VCDR1) comprising a heavy chain CDR1, 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-Delta1 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 of SEQ ID NOs:83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60. In some embodiments, the anti-Delta1 antibody comprises a light chain variable domain (VCDR1) comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H), wherein the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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: 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-Delta1 antibody comprises a light chain variable domain (V) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. L ), wherein the light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55 (CDR1), 56 or 58 (CDR2), and 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60 (CDR3), respectively.

[0035] In some embodiments, the anti-Delta1 antibody is selected from SEQ ID NOs: 61, 62, 63, 64, 65, 6 6, 67, 68, 69, 70, 71, and 72, 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-Delta1 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-Delta1 antibody comprises a heavy chain variable domain (VL CDR1) comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H), wherein the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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: 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-Delta1 antibody comprises a light chain variable domain (V) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. L ), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0036] In some embodiments, the anti-Delta1 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-Delta1 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-Delta1 antibody comprises a heavy chain variable domain (VL CDR1) comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H), wherein the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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: 67, 68, 69, and 70 (CDR1), 53 (CDR2), and 54 (CDR3), respectively. Alternatively or additionally, the anti-Delta1 antibody comprises a light chain variable domain (V) comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. L ), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0037] In some embodiments, the anti-Delta1 antibody has a VH having the sequence set forth in SEQ ID NO:68. In some embodiments, the anti-Delta1 antibody comprises a heavy chain variable domain (V CDR1 having the sequence of SEQ ID NO: 53, a VH CDR2 having the sequence of SEQ ID NO: 54, and a VL CDR3 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. H ), wherein the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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 (CDR1), 53 (CDR2), and 54 (CDR3), respectively. Alternatively or additionally, the anti-Delta1 antibody comprises a light chain variable domain comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3. In (VL ), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0038] In some embodiments, the anti-Delta1 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. In some embodiments, the anti-Delta1 antibody further comprises a light chain variable domain (V CDR1) comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, 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-Delta1 antibody further comprises a light chain variable domain (V CDR1) comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3. H ), wherein the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 together 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 the antibody comprises a light chain variable domain (V L ), wherein light chain CDR1, light chain CDR2, and light chain CDR3 together 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 SEQ ID NOs: 55, 56, and 57, respectively.

[0039] In any of these embodiments, the anti-delta 1 antibody binds to delta 1. In some embodiments, the anti-delta 1 antibody comprises HC CDR1, HC CDR2, and HC CDR3, where HC CDR1, HC CDR2, and HC CDR3 together contain 10 or less (e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less) amino acid changes compared to the HC CDRs of the reference antibody, and / or the antibody comprises LC CDR1, LC CDR2, and LC CDR3, where LC CDR1, LC CDR2, and LC CDR3 together contain 8 or less (e.g., 7, 6, 5, 4, 3, 2, or 1 or less) amino acid changes compared to the light chain CDRs of the reference antibody. In some embodiments, the reference antibody is delta 1-39.

[0040] In some embodiments, the anti-delta 1 antibody comprises an HC CDR1, an HC CDR2, and an HC CDR3, where the HC CDR1, HC CDR2, and HC CDR3, taken together, contain 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) compared to the HC CDRs of an antibody selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43, and / or the antibody comprises an LC CDR1, an LC CDR2, and an HC CDR3, where the HC CDR1, HC CDR2, and HC CDR3, taken together, contain 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) compared to the HC CDRs of an antibody selected from 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, del and LC CDR1, LC CDR2, and LC CDR3, which together contain no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) amino acid changes compared to the light chain CDRs of an antibody selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

[0041] In some embodiments, the anti-delta 1 antibody comprises an HC CDR1, an HC CDR2, and an HC CDR3, which together contain 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) compared to the HC CDRs of an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43, and / or the antibody comprises an LC CDR1, an LC CDR2, and an LC CDR3, which together contain 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) compared to the HC CDRs of an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43. The CDR3s contain, in total, no more than 8 (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) amino acid changes compared to the light chain CDRs of an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

[0042] In some embodiments, the anti-delta 1 antibody comprises an HC CDR1, an HC CDR2, and an HC CDR3, which together contain no more than 10 amino acid changes (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) compared to the HC CDRs of an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41; and / or the antibody comprises an LC CDR1, an LC CDR2, and an LC CDR3, which together contain no more than 8 amino acid changes (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) compared to the light chain CDRs of an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

[0043] In some embodiments, the anti-delta 1 antibody comprises an HC CDR1, an HC CDR2, and an HC CDR3, where the HC CDR1, HC CDR2, and HC CDR3 together contain no more than 10 amino acid changes (e.g., no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1) compared to the HC CDRs of delta 1-39, and / or the antibody comprises an LC CDR1, an LC CDR2, and an LC CDR3, where the LC CDR1, LC CDR2, and LC CDR3 together contain no more than 8 amino acid changes (e.g., no more than 7, 6, 5, 4, 3, 2, or 1) compared to the light chain CDRs of delta 1-39.

[0044] In some embodiments, the anti-Delta1 antibody is a VI of the reference antibody. L V that 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 L , and / or the V of the reference antibody H V that 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 H Includes.

[0045] In some embodiments, the anti-delta 1 antibody is a V of an antibody selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. H V that 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 the sequence Hand / or the sequences 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, delta 1-31, delta 1-32 , delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. L V that 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 the sequence L It has an array.

[0046] In some embodiments, the anti-delta 1 antibody is a V of an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. H V that 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 the sequence H and / or V of an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. L V that 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 the sequence L It has an array.

[0047] In some embodiments, the anti-delta 1 antibody is an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies. H V that 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 the sequence H sequence, and / or V of an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies L V that 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 the sequence L It has an array.

[0048] In some embodiments, the anti-delta 1 antibody is a V L V that 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 the sequence L Sequence, and / or V of Delta 1-39 antibody H V that 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 H has.

[0049] In some embodiments, the anti-delta 1 antibodies disclosed herein have the same VL sequence as an antibody selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. In some embodiments, the anti-delta 1 antibody disclosed herein is selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. In some embodiments, the disclosed anti-delta 1 antibodies have the same VH sequence and the same VL sequence as an antibody selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies.

[0050] In some embodiments, the anti-delta 1 antibody disclosed herein has the same VL sequence as an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. In some embodiments, the anti-delta 1 antibody disclosed herein has the same VL sequence as an antibody selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43 antibodies. In some embodiments, the disclosed anti-Delta 1 antibodies have the same VH sequence and the same VL sequence as an antibody selected from Delta 1-32, Delta 1-33, Delta 1-34, Delta 1-35, Delta 1-36, Delta 1-37, Delta 1-38, Delta 1-39, Delta 1-40, Delta 1-41, Delta 1-42, and Delta 1-43 antibodies.

[0051] In some embodiments, the anti-delta 1 antibodies disclosed herein have the same VL sequence as an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies. In some embodiments, the anti-delta 1 antibodies disclosed herein are antibodies having the same VL sequence as an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41 antibodies. In some embodiments, the disclosed anti-delta 1 antibodies have the same VH sequence and the same VL sequence as an antibody selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-4 antibodies.

[0052] In some embodiments, the anti-delta 1 antibody is selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43. In some embodiments, the anti-delta 1 antibody is selected from delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43. In some embodiments, the anti-delta 1 antibody is selected from delta 1-38, delta 1-39, delta 1-40, and delta 1-41. In one specific embodiment, the anti-delta-1 antibody is delta 1-39.

[0053] In some embodiments, the anti-delta 1 antibody comprises 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. In some embodiments, the anti-delta 1 antibody comprises 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 comprises 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 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 embodiments, the anti-delta 1 antibody comprises 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 anti-delta 1 antibody comprises a VL region having a sequence of SEQ ID NO: 9. In some embodiments, the anti-delta 1 antibody comprises 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 a VL region having a sequence of SEQ ID NO: 9.

[0054] In some embodiments, the anti-Delta 1 antibody comprises a VH region having the sequence of SEQ ID NO: 24. In some embodiments, the anti-Delta 1 antibody comprises a VL region having the sequence of SEQ ID NO: 9. In some embodiments, the anti-Delta 1 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.

[0055] In some embodiments, the anti-Delta1 antibody is 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 In some embodiments, the anti-Delta1 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: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. L In some embodiments, the anti-Delta1 antibody has a V sequence comprising 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-Delta1 antibody has a V 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 NOs: 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 NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. L It has an array.

[0056] In some embodiments, the anti-Delta1 antibody is 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 and 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: 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 comprising a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H V comprising a sequence selected from SEQ ID NOs: 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 consisting essentially of a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H and SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. V consisting essentially of the sequence selected L In some embodiments, the isolated antibody has a V sequence consisting of a sequence selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H V consisting of a sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. L It has an array.

[0057] In some embodiments, the anti-Delta1 antibody is 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-Delta1 antibody has a V sequence 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-Delta1 antibody has a V sequence comprising 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-Delta1 antibody has the sequence of SEQ ID NO:9. LIn some embodiments, the isolated antibody has the sequence V 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 the sequence V consisting essentially of or consisting of the sequence of SEQ ID NO:9. L It has an array.

[0058] In some embodiments, the anti-Delta1 antibody is 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 9, and 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: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H 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 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 NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. H V consisting of the sequence SEQ ID NO:9 L It has an array.

[0059] In some embodiments, the anti-Delta1 antibody is 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-Delta1 antibody has a V sequence 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 antibody has the sequence The Delta1 antibody comprises a V sequence selected from SEQ ID NOs: 22, 23, 24, 25, and 43. H In some embodiments, the anti-Delta1 antibody has the sequence of 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 the sequence V consisting essentially of or consisting of the sequence of SEQ ID NO:9. L It has an array.

[0060] In some embodiments, the anti-Delta1 antibody is 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. H9, and 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 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: 22, 23, 24, 25, and 43. H 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 NOs: 22, 23, 24, 25, and 43. H V consisting of the sequence SEQ ID NO:9 L It has an array.

[0061] In some embodiments, the anti-Delta1 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:24. H In some embodiments, the anti-Delta1 antibody has a V sequence 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-Delta1 antibody has the sequence V comprising SEQ ID NO:24. H In some embodiments, the anti-Delta1 antibody has the sequence V comprising SEQ ID NO:9. LIn some embodiments, the isolated antibody has the sequence V consisting essentially of or consisting of SEQ ID NO:24. H In some embodiments, the isolated antibody has the sequence V consisting essentially of or consisting of SEQ ID NO:9. L It has an array.

[0062] In some embodiments, the anti-Delta1 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:24. H 9, and 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 V comprising sequence and SEQ ID NO:9 L In some embodiments, the isolated antibody has the sequence V consisting essentially of SEQ ID NO:24. H V consisting essentially of sequence SEQ ID NO:9 L In some embodiments, the isolated antibody has the sequence V consisting of SEQ ID NO:24. H V consisting of sequence SEQ ID NO:9 L It has an array.

[0063] 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. 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 SEQ ID NO: 79. In some embodiments, the anti-Delta 1 antibody has a light chain sequence comprising SEQ ID NO: 78. In some embodiments, the anti-Delta 1 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.

[0064] In some embodiments, the anti-Delta1 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.

[0065] In some embodiments, the anti-delta1 antibody preferentially binds to the γδ1 TCR compared to the γδ2 TCR or (or a or) the γδ3 TCR. In one particular embodiment, the anti-delta1 antibody does not bind to a T cell receptor that includes the delta-2 chain and the gamma chain.

[0066] In some embodiments, the anti-delta-1 antibody described herein cross-reacts with human delta-1 chain and non-human mammalian delta-1 chain, for example, non-human primate delta-1 chain.In one particular example, the non-human primate delta-1 chain is cynomolgus monkey delta-1 chain.

[0067] In some embodiments, the anti-delta1 antibodies described herein can bind to γδ1 TCRs containing various gamma chains, including gamma 3, 4, 5, 8, or 9. In some embodiments, the anti-delta1 antibodies described herein can bind to γδ1 TCRs containing various gamma chains, including gamma 3, 4, 5, and 8. In some embodiments, the anti-delta1 antibodies described herein cross-react with human delta-1 chains and non-human mammalian delta-1 chains, e.g., non-human primate delta-1 chains, and can bind to γδ1 TCRs containing various gamma chains, including gamma 3, 4, 5, and 8. Non-limiting examples of such antibodies described herein include delta 1-39 and delta 1-41. In some examples, such antibodies are delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

[0068] Any of the anti-Delta1 antibodies described herein may be full-length antibodies (e.g., IgG molecules) or antigen-binding fragments thereof. In some examples, the antibodies may be 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.

[0069] In another aspect, the disclosure provides an isolated nucleic acid or set of nucleic acids that encode or together encode any of the anti-Delta 1 antibodies disclosed herein. In some cases, the heavy and light chains of the antibody are encoded by two separate nucleic acid molecules (sets of nucleic acids). In other cases, the heavy and light chains of the antibody are encoded by one nucleic acid molecule, which may be in a multicistronic format or under the control of separate promoters. Thus, in one aspect, the 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 an anti-Delta 1 antibody described herein. In some embodiments, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the heavy chain variable region (VH) of an anti-Delta 1 antibody 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 an anti-Delta 1 antibody described herein. In one specific embodiment, the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL (or heavy and / or light chains) of an antibody comprising a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or comprises a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as 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 and / or light chains) of an antibody comprising a VH set forth as SEQ ID NO:24 and / or a VL set forth as SEQ ID NO:9. In one example, the one or more nucleic acid sequences encode the VH and / or VL (or heavy and / or light chains) of G9.2-17.

[0070] In some embodiments, the nucleic acid or set of nucleic acids is located on one or two vectors, for example, the one or two vectors may be one or two expression vectors. Thus, the vector may comprise any of the isolated nucleic acid molecules described herein. Furthermore, the present disclosure provides a host cell comprising any of the isolated nucleic acids or set of nucleic acids encoding the anti-Delta 1 antibodies described herein. In some embodiments, the host cell is selected from the group consisting of E. coli cells, Simian COS cells, Chinese Hamster Ovary (CHO) cells, or myeloma cells.

[0071] Also provided herein is a method for producing an anti-Delta1 antibody, comprising culturing a host cell described herein under suitable conditions allowing expression of the antibody, and recovering the antibody so produced from the cell culture (e.g., culture medium).

[0072] Additionally, the disclosure provides a pharmaceutical composition comprising any of the anti-Delta 1 antibodies or a nucleic acid encoding same, and a pharma- ceutically acceptable carrier.

[0073] In yet another aspect, the disclosure features a method of inhibiting the activity and function of immunosuppressive γδ T cells, e.g., γδ1 T cells, in a subject, comprising administering to a subject in need thereof an effective amount of any anti-Delta1 antibody disclosed herein or a pharmaceutical composition comprising the same. Alternatively or additionally, the disclosure features a method of eliminating or depleting immunosuppressive γδ T cells, e.g., γδ1 T cells, in a subject, comprising administering to a subject in need thereof an effective amount of any anti-Delta1 antibody disclosed herein or a pharmaceutical composition comprising the same. In some embodiments, the subject in need thereof is a human subject 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, comprising administering to a subject in need thereof an effective amount of any anti-Delta1 antibody disclosed herein or a pharmaceutical composition comprising the same. 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, the effective amount of the pharmaceutical composition is sufficient to inhibit or block the activity and function of immunosuppressive γδ T cells, e.g., γδ1 T cells.

[0074] Any of the treatment methods described herein may further include administering to the subject an inhibitor of a checkpoint molecule, an activator of a costimulatory receptor, an inhibitor of an innate immune cell target, a chemotherapeutic agent, and / or any other anti-cancer treatment, such as but not limited to biologics, small molecule inhibitors, and / or any form of radiation therapy, 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 costimulatory 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.

[0075] Also within the scope of the disclosure are (i) a pharmaceutical composition for use in treating a disease associated with activation of immunosuppressive γδ T cells (e.g., γδ1 T cells), comprising any anti-Delta1 antibody or a nucleic acid encoding same described herein, and a pharma- ceutically acceptable carrier, and (ii) the use of an anti-Delta1 antibody or an encoding nucleic acid for the manufacture of a medicament for use in treating a target disease as described herein.

[0076] Another aspect of the present disclosure provides a method of analyzing a biological sample from a subject suspected of having a solid tumor (e.g., a metastatic solid tumor or a relapsed or refractory solid tumor), comprising (i) preparing a biological sample from a subject suspected of having a solid tumor, and (ii) measuring the level of Delta1 in the biological sample using an antibody that specifically binds to Delta1. In some embodiments, the subject is a subject suspected of having a solid tumor, e.g., a metastatic solid tumor or a relapsed 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 cholangiocarcinoma. In some embodiments, the subject is a subject suspected of having a metastatic solid tumor. In other embodiments, the subject is a subject suspected of having a relapsed 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 (eg, ductal carcinoma), and cholangiocarcinoma.

[0077] 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 patient-derived organotypic tumor spheroid (PDOT).For example, in some embodiments, the tumor biopsy sample comprises TIL.

[0078] The antibody can be any of those described herein, e.g., contains the same heavy and light chain complementarity determining regions (CDRs) as the reference antibody delta 1-39, e.g., contains 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, In some embodiments, the antibody can be a Fab molecule. In some embodiments, the antibody is a different anti-Delta1 antibody known in the art.

[0079] In some embodiments, an immunoassay is used to determine the level of Delta 1 in a biological sample. In some embodiments, the assay is flow cytometry.

[0080] In some embodiments, the method disclosed herein further comprises identifying the subject as a suitable candidate for treatment with anti-delta 1 antibody if the level of delta 1 measured in step (ii) is elevated compared to the control level.Suitable candidates are given an effective amount of anti-delta 1 antibody, such as those described herein, alone or in combination with a checkpoint inhibitor, such as those described herein.

[0081] In some embodiments, the level of delta1 measured in step (ii) is used to identify or select cancer patients who may respond to anti-delta1 targeted therapy. In some embodiments, delta1 level is measured in blood, serum and / or plasma. In some embodiments, delta1 level is measured on the surface of cancer cells or immune cells derived from tumor and / or 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, alpha / beta T cells, and / or gamma / delta T cells.

[0082] The details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will be apparent from the following drawings and detailed description of some embodiments, and also from the appended claims.

[0083] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood by reference to the drawings in combination with the detailed description of specific embodiments presented herein. [Brief description of the drawings]

[0084] [Figure 1] FIG. 1 is a photograph of immunohistochemical analysis of human pancreatic cancer tissue compared to normal pancreas, demonstrating enrichment of γδ T cells in pancreatic cancer tissue compared to normal tissue. [Diagram 2] FIG. 1 is a bar graph representing the percentage of total T cells in peripheral blood and tumors, demonstrating enrichment of γδ T cells in pancreatic cancer tissue compared to peripheral blood. [Figure 3A] FIG. 3 depicts a bar graph showing a co-culture assay of gamma delta T cells (gdT) and alpha beta T cells (abT). As indicated, gamma delta cells were derived from tumor or blood, and alpha beta T cells were derived from blood of the same patient. The figure represents the % of TNF-α+ cells obtained when blood αβ T cells were cultured alone or when co-cultured with intratumoral and blood γδ T cells. Blood alpha beta T cells were activated by ligation to CD3 / CD28, resulting in an increase in TNF-α measured by FACS. Bar 1: non-activated αβ T cells; Bar 2: activated αβ T cells; Bar 3: activated αβ T cells co-cultured with blood γδ T cells; Bar 4: activated αβ T cells co-cultured with tumor γδ T cells. FIG. 3A: Cells derived from a patient with colorectal cancer. FIG. 3B and 3C: Cells derived from two individual patients with pancreatic cancer. [Figure 3B]FIG. 3 depicts a bar graph showing a co-culture assay of gamma delta T cells (gdT) and alpha beta T cells (abT). As indicated, gamma delta cells were derived from tumor or blood, and alpha beta T cells were derived from blood of the same patient. The figure represents the % of TNF-α+ cells obtained when blood αβ T cells were cultured alone or when co-cultured with intratumoral and blood γδ T cells. Blood alpha beta T cells were activated by ligation to CD3 / CD28, resulting in an increase in TNF-α measured by FACS. Bar 1: non-activated αβ T cells; Bar 2: activated αβ T cells; Bar 3: activated αβ T cells co-cultured with blood γδ T cells; Bar 4: activated αβ T cells co-cultured with tumor γδ T cells. FIG. 3A: Cells derived from a patient with colorectal cancer. FIG. 3B and 3C: Cells derived from two individual patients with pancreatic cancer. [Figure 3C] FIG. 3 depicts a bar graph showing a co-culture assay of gamma delta T cells (gdT) and alpha beta T cells (abT). As indicated, gamma delta cells were derived from tumor or blood, and alpha beta T cells were derived from blood of the same patient. The figure represents the % of TNF-α+ cells obtained when blood αβ T cells were cultured alone or when co-cultured with intratumoral and blood γδ T cells. Blood alpha beta T cells were activated by ligation to CD3 / CD28, resulting in an increase in TNF-α measured by FACS. Bar 1: non-activated αβ T cells; Bar 2: activated αβ T cells; Bar 3: activated αβ T cells co-cultured with blood γδ T cells; Bar 4: activated αβ T cells co-cultured with tumor γδ T cells. FIG. 3A: Cells derived from a patient with colorectal cancer. FIG. 3B and 3C: Cells derived from two individual patients with pancreatic cancer. [Figure 4A]FIG. 4 depicts a bar graph showing immune profile expression in untreated (Utx) and isotype (hIgG1) treated gastrointestinal neuroendocrine tumor samples (PDOTS) compared with two anti-delta 1 IgG1 antibodies (e.g. delta 1-23 and delta 1-17). Shown are the percentage of TNF-α in CD8+ T cells (FIG. 4A), the percentage of IFNγ in CD8+ T cells (FIG. 4B), and the percentage of CD44 in CD8+ T cells (FIG. 4C). [Figure 4B] FIG. 4 depicts a bar graph showing immune profile expression in untreated (Utx) and isotype (hIgG1) treated gastrointestinal neuroendocrine tumor samples (PDOTS) compared with two anti-delta 1 IgG1 antibodies (e.g. delta 1-23 and delta 1-17). Shown are the percentage of TNF-α in CD8+ T cells (FIG. 4A), the percentage of IFNγ in CD8+ T cells (FIG. 4B), and the percentage of CD44 in CD8+ T cells (FIG. 4C). [Figure 4C] FIG. 4 depicts a bar graph showing immune profile expression in untreated (Utx) and isotype (hIgG1) treated gastrointestinal neuroendocrine tumor samples (PDOTS) compared with two anti-delta 1 IgG1 antibodies (e.g. delta 1-23 and delta 1-17). Shown are the percentage of TNF-α in CD8+ T cells (FIG. 4A), the percentage of IFNγ in CD8+ T cells (FIG. 4B), and the percentage of CD44 in CD8+ T cells (FIG. 4C). [Figure 5A] 5A-5C are bar graphs showing immune profile expression in untreated (Utx) and isotype (hIgG1) treated breast cancer liver metastasis tumor samples (PDOTS) compared with two anti-delta 1 IgG1 antibodies (e.g., delta 1-23 and delta 1-17).The percentage of TNF-α in CD3+ T cells (FIG. 5A) and the percentage of CD44 in CD3+ T cells (FIG. 5B) are shown. [Figure 5B]5A-5C are bar graphs showing immune profile expression in untreated (Utx) and isotype (hIgG1) treated breast cancer liver metastasis tumor samples (PDOTS) compared with two anti-delta 1 IgG1 antibodies (e.g., delta 1-23 and delta 1-17).The percentage of TNF-α in CD3+ T cells (FIG. 5A) and the percentage of CD44 in CD3+ T cells (FIG. 5B) are shown. [Figure 6A] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6B] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6C] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6D] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6E]1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6F] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6G] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6H] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6I] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6J]1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6K] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6L] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6M] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 6N] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured using a bead binding assay, tested on human gamma 9 / delta 1C (labeled "Human D1"), cyno gamma / delta 1A ("Cyno D1"), and cyno gamma / delta 2 ("Cyno D2"). [Figure 7A] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7B]FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7C] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7D] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7E] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7F] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7G] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7H] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7I] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7J] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7K] FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 7L]FIG. 1 shows the binding titration of anti-delta 1 antibodies, delta 1-17 and delta 1-23, to purified gamma / delta TCR composed of various subunits. [Figure 8] FIG. 1 shows traces from a thermal shift assay used to determine the thermal stability of Delta1-specific IgG. [Figure 9A] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9B] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9C] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9D] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9E] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9F]1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9G] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9H] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 9I] 1 shows the binding titration of anti-delta 1 antibodies to purified gamma / delta TCRs, as measured by bead binding assay, tested on human gamma 9 / delta 1C (labeled "human D1") and cynomolgus gamma / delta 1A ("cyno D1"). [Figure 10A]10A shows that the anti-delta1 antibodies disclosed herein have high affinity and specificity for delta1. FIG. 10A is a surface plasmon resonance (SPR) graph showing that the anti-delta1-17 antibodies, for example, have high affinity for human delta1 TCR. FIG. 10B is a graph showing that the delta1-17 antibodies are specific for delta1 TCR and do not bind (cross-react) with delta2 TCR. Three different delta1 variants (D1A, D1B, and D1C) were generated that differ from each other only in the CDR3 loop. Delta1 and delta2 Fc fusion proteins were attached to streptavidin-coated beads and binding titration was performed with delta1-17 hIgG1. FIG. 10C is a graph showing that the delta1-41 antibody is cross-reactive between humans and monkeys ("cyno"). FIG. 10D is a graph showing that Delta 1 antibodies, Delta 1-17, Delta 1-39, and Delta 1-41, are specific for the Delta 1 TCR compared to the Delta 2 TCR. [Figure 10B] 10A shows that the anti-delta1 antibodies disclosed herein have high affinity and specificity for delta1. FIG. 10A is a surface plasmon resonance (SPR) graph showing that the anti-delta1-17 antibodies, for example, have high affinity for human delta1 TCR. FIG. 10B is a graph showing that the delta1-17 antibodies are specific for delta1 TCR and do not bind (cross-react) with delta2 TCR. Three different delta1 variants (D1A, D1B, and D1C) were generated that differ from each other only in the CDR3 loop. Delta1 and delta2 Fc fusion proteins were attached to streptavidin-coated beads and binding titration was performed with delta1-17 hIgG1. FIG. 10C is a graph showing that the delta1-41 antibody is cross-reactive between humans and monkeys ("cyno"). FIG. 10D is a graph showing that Delta 1 antibodies, Delta 1-17, Delta 1-39, and Delta 1-41, are specific for the Delta 1 TCR compared to the Delta 2 TCR. [Figure 10C]10A shows that the anti-delta1 antibodies disclosed herein have high affinity and specificity for delta1. FIG. 10A is a surface plasmon resonance (SPR) graph showing that the anti-delta1-17 antibodies, for example, have high affinity for human delta1 TCR. FIG. 10B is a graph showing that the delta1-17 antibodies are specific for delta1 TCR and do not bind (cross-react) with delta2 TCR. Three different delta1 variants (D1A, D1B, and D1C) were generated that differ from each other only in the CDR3 loop. Delta1 and delta2 Fc fusion proteins were attached to streptavidin-coated beads and binding titration was performed with delta1-17 hIgG1. FIG. 10C is a graph showing that the delta1-41 antibody is cross-reactive between humans and monkeys ("cyno"). FIG. 10D is a graph showing that Delta 1 antibodies, Delta 1-17, Delta 1-39, and Delta 1-41, are specific for the Delta 1 TCR compared to the Delta 2 TCR. [Figure 10D] 10A shows that the anti-delta1 antibodies disclosed herein have high affinity and specificity for delta1. FIG. 10A is a surface plasmon resonance (SPR) graph showing that the anti-delta1-17 antibodies, for example, have high affinity for human delta1 TCR. FIG. 10B is a graph showing that the delta1-17 antibodies are specific for delta1 TCR and do not bind (cross-react) with delta2 TCR. Three different delta1 variants (D1A, D1B, and D1C) were generated that differ from each other only in the CDR3 loop. Delta1 and delta2 Fc fusion proteins were attached to streptavidin-coated beads and binding titration was performed with delta1-17 hIgG1. FIG. 10C is a graph showing that the delta1-41 antibody is cross-reactive between humans and monkeys ("cyno"). FIG. 10D is a graph showing that Delta 1 antibodies, Delta 1-17, Delta 1-39, and Delta 1-41, are specific for the Delta 1 TCR compared to the Delta 2 TCR. [Figure 11A]Figures 11A-11C show that anti-delta 1 antibodies disclosed herein are gamma independent. Figure 11A is a graph showing that delta 1-17 is delta 1-specific, regardless of the gamma chain of the purified delta gamma TCR. Figure 11B is a graph demonstrating that several anti-delta 1 antibodies, including delta 1-39 and delta 1-41, are delta 1-specific using cell surface delta gamma TCR. Non-transduced J.RT3-T3.5 (TIB153) was used as a control to show no background binding to other cell surface receptors found on T cells (data not shown). [Figure 11B] Figures 11A-11C show that anti-delta 1 antibodies disclosed herein are gamma independent. Figure 11A is a graph showing that delta 1-17 is delta 1-specific, regardless of the gamma chain of the purified delta gamma TCR. Figure 11B is a graph demonstrating that several anti-delta 1 antibodies, including delta 1-39 and delta 1-41, are delta 1-specific using cell surface delta gamma TCR. Non-transduced J.RT3-T3.5 (TIB153) was used as a control to show no background binding to other cell surface receptors found on T cells (data not shown). [Figure 12A] FIG. 12 includes bar graphs showing the immune profile expression of tumor samples (PDOTS) treated with isotype (hIgG1) compared to anti-delta 1 IgG1 antibody (e.g., delta 1-17). The percentage of TNF-α in CD3+ T cells, the percentage of IFNγ in CD3+ T cells, and the percentage of CD44 in CD3+ T cells are shown for colorectal cancer liver metastasis (FIG. 12A), liver neuroendocrine tumor (FIG. 12B), colorectal cancer neuroendocrine tumor (FIG. 12C), and hepatocellular carcinoma (FIG. 12D). [Figure 12B]FIG. 12 includes bar graphs showing the immune profile expression of tumor samples (PDOTS) treated with isotype (hIgG1) compared to anti-delta 1 IgG1 antibody (e.g., delta 1-17). The percentage of TNF-α in CD3+ T cells, the percentage of IFNγ in CD3+ T cells, and the percentage of CD44 in CD3+ T cells are shown for colorectal cancer liver metastasis (FIG. 12A), liver neuroendocrine tumor (FIG. 12B), colorectal cancer neuroendocrine tumor (FIG. 12C), and hepatocellular carcinoma (FIG. 12D). [Figure 12C] FIG. 12 includes bar graphs showing the immune profile expression of tumor samples (PDOTS) treated with isotype (hIgG1) compared to anti-delta 1 IgG1 antibody (e.g., delta 1-17). The percentage of TNF-α in CD3+ T cells, the percentage of IFNγ in CD3+ T cells, and the percentage of CD44 in CD3+ T cells are shown for colorectal cancer liver metastasis (FIG. 12A), liver neuroendocrine tumor (FIG. 12B), colorectal cancer neuroendocrine tumor (FIG. 12C), and hepatocellular carcinoma (FIG. 12D). [Figure 12D] FIG. 12 includes bar graphs showing the immune profile expression of tumor samples (PDOTS) treated with isotype (hIgG1) compared to anti-delta 1 IgG1 antibody (e.g., delta 1-17). The percentage of TNF-α in CD3+ T cells, the percentage of IFNγ in CD3+ T cells, and the percentage of CD44 in CD3+ T cells are shown for colorectal cancer liver metastasis (FIG. 12A), liver neuroendocrine tumor (FIG. 12B), colorectal cancer neuroendocrine tumor (FIG. 12C), and hepatocellular carcinoma (FIG. 12D). [Figure 13A]Figures 13A and 13B include graphs showing the effect of γδ T cells on the response to checkpoint inhibition in subcutaneous syngenic models of lung (LLC) and melanoma (B16F10). Figures 13A and 13B: Graphs showing the anti-tumor efficacy of anti-CTLA-4 antibodies versus untreated (13A) or IgG isotype control (13B) in a γδ knockout Lewis lung carcinoma mouse model compared to their wild-type counterparts. Figures 13C and 13D: Graphs showing the anti-tumor efficacy of anti-PD-1 antibodies versus untreated (13C) or IgG isotype control (13D) in a γδ knockout melanoma mouse model compared to their wild-type counterparts. [Figure 13B] Figures 13A and 13B include graphs showing the effect of γδ T cells on the response to checkpoint inhibition in subcutaneous syngenic models of lung (LLC) and melanoma (B16F10). Figures 13A and 13B: Graphs showing the anti-tumor efficacy of anti-CTLA-4 antibodies versus untreated (13A) or IgG isotype control (13B) in a γδ knockout Lewis lung carcinoma mouse model compared to their wild-type counterparts. Figures 13C and 13D: Graphs showing the anti-tumor efficacy of anti-PD-1 antibodies versus untreated (13C) or IgG isotype control (13D) in a γδ knockout melanoma mouse model compared to their wild-type counterparts. [Figure 13C] Figures 13A and 13B include graphs showing the effect of γδ T cells on the response to checkpoint inhibition in subcutaneous syngenic models of lung (LLC) and melanoma (B16F10). Figures 13A and 13B: Graphs showing the anti-tumor efficacy of anti-CTLA-4 antibodies versus untreated (13A) or IgG isotype control (13B) in a γδ knockout Lewis lung carcinoma mouse model compared to their wild-type counterparts. Figures 13C and 13D: Graphs showing the anti-tumor efficacy of anti-PD-1 antibodies versus untreated (13C) or IgG isotype control (13D) in a γδ knockout melanoma mouse model compared to their wild-type counterparts. [Figure 13D]Figures 13A and 13B include graphs showing the effect of γδ T cells on the response to checkpoint inhibition in subcutaneous syngenic models of lung (LLC) and melanoma (B16F10). Figures 13A and 13B: Graphs showing the anti-tumor efficacy of anti-CTLA-4 antibodies versus untreated (13A) or IgG isotype control (13B) in a γδ knockout Lewis lung carcinoma mouse model compared to their wild-type counterparts. Figures 13C and 13D: Graphs showing the anti-tumor efficacy of anti-PD-1 antibodies versus untreated (13C) or IgG isotype control (13D) in a γδ knockout melanoma mouse model compared to their wild-type counterparts. [Figure 14A] 14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 14B]14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 14C]14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 14D]14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 14E]14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 14F]14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 14G]14A and 14B are graphs showing the stability of anti-delta 1 antibodies, delta 1-17, delta 1-41, and delta 1-39 after freeze / thaw, concentration, and filtration. Figures 14A and 14B are stability curves of delta 1-41 and delta 1-17, respectively. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14C and 14D are stability curves of delta 1-41 and delta 1-17, respectively, after 10 days of incubation at 4°C. From top to bottom panels: freeze / thaw 1x, 3 mg / ml; freeze / thaw 1x, concentrated to 12 mg / ml; and freeze / thaw 1x, concentrated to 12 mg / ml and filtered. Figures 14E and 14F are stability curves of delta 1-41 and delta 1-17, respectively, after high temperature storage and freezing and thawing. From top to bottom panels: freeze / thaw 1x; 37°C overnight (O / N); room temperature (RT) overnight (O / N); and freeze / thaw 4x. Figure 14G shows stability curves of delta 1-39 fresh, freeze-thawed 5 times, and after 18 hours at 24°C. [Figure 15A] 15A includes charts showing the antibody-dependent cellular phagocytosis (ADCP) effect of Delta 1-17 and Delta 1-41 on targets immobilized on beads. 15A: 1000 nM target on beads. 15B: 100 nM target on beads. 15C: 10 nM target on beads. [Figure 15B] 15A includes charts showing the antibody-dependent cellular phagocytosis (ADCP) effect of Delta 1-17 and Delta 1-41 on targets immobilized on beads. 15A: 1000 nM target on beads. 15B: 100 nM target on beads. 15C: 10 nM target on beads. [Figure 15C] 15A includes charts showing the antibody-dependent cellular phagocytosis (ADCP) effect of Delta 1-17 and Delta 1-41 on targets immobilized on beads. 15A: 1000 nM target on beads. 15B: 100 nM target on beads. 15C: 10 nM target on beads. [Figure 16A]16A-16C include diagrams showing the ADCP effects of delta 1-17 and delta 1-41 at different time points, including 1 hour (16A), 4 hours (16B), and 24 hours (16C), at various antibody concentrations as indicated. [Figure 16B] 16A-16C include diagrams showing the ADCP effects of delta 1-17 and delta 1-41 at different time points, including 1 hour (16A), 4 hours (16B), and 24 hours (16C), at various antibody concentrations as indicated. [Figure 16C] 16A-16C include diagrams showing the ADCP effects of delta 1-17 and delta 1-41 at different time points, including 1 hour (16A), 4 hours (16B), and 24 hours (16C), at various antibody concentrations as indicated. [Figure 17] 1 is a diagram showing the ADCP effect of various anti-delta 1 antibodies (eg, delta 1-17, delta 1-39, and delta 1-41) against various target proteins observed in a bead-based ADCP assay. [Figure 18A] 18A-B include diagrams showing the ADCP effect of anti-Delta 1 antibodies in a cell-based ADCP assay.Figure 18A: ADCP effect at different time points as indicated.Figure 18B: ADCP effect at various antibody concentrations. [Figure 18B] 18A-B include diagrams showing the ADCP effect of anti-Delta 1 antibodies in a cell-based ADCP assay.Figure 18A: ADCP effect at different time points as indicated.Figure 18B: ADCP effect at various antibody concentrations. [Figure 19] FIG. 1 includes a diagram showing the antibody-dependent cellular cytotoxicity (ADCC) effect of Delta 1-41 at various antibody concentrations as indicated. [Figure 20A]20A and 20B include bar graphs showing the level of αβ T cell activation in tumor samples (PDOTS) treated with isotype (hIgG1) compared to anti-delta 1 IgG1 antibody (e.g., delta 1-41) or anti-PD1 antibody. The percentage of TNF-α in CD8+ T cells, the percentage of IFNγ in CD8+ T cells, and the percentage of CD44 in CD8+ T cells are shown for colorectal cancer (FIG. 20A) and hepatocellular carcinoma (FIG. 20B). [Figure 20B] 20A and 20B include bar graphs showing the level of αβ T cell activation in tumor samples (PDOTS) treated with isotype (hIgG1) compared to anti-delta 1 IgG1 antibody (e.g., delta 1-41) or anti-PD1 antibody. The percentage of TNF-α in CD8+ T cells, the percentage of IFNγ in CD8+ T cells, and the percentage of CD44 in CD8+ T cells are shown for colorectal cancer (FIG. 20A) and hepatocellular carcinoma (FIG. 20B). [Figure 21A] 21A includes bar graphs showing the level of αβ T cell activation in tumor samples (PDOTS) from hepatocellular carcinoma treated with anti-delta 1 IgG1 antibody (e.g., delta 1-17) in the presence of a costimulatory receptor agonist (ICOS agonist) compared to isotype (hIgG1) (as control). The percentage of CD44 in CD3+ T cells (FIG. 21A), the percentage of TNF-α in CD3+ T cells (FIG. 21B), and the percentage of IFNγ in CD3+ T cells (FIG. 21C) are shown. [Figure 21B] 21A includes bar graphs showing the level of αβ T cell activation in tumor samples (PDOTS) from hepatocellular carcinoma treated with anti-delta 1 IgG1 antibody (e.g., delta 1-17) in the presence of a costimulatory receptor agonist (ICOS agonist) compared to isotype (hIgG1) (as control). The percentage of CD44 in CD3+ T cells (FIG. 21A), the percentage of TNF-α in CD3+ T cells (FIG. 21B), and the percentage of IFNγ in CD3+ T cells (FIG. 21C) are shown. [Figure 21C]21A includes bar graphs showing the level of αβ T cell activation in tumor samples (PDOTS) from hepatocellular carcinoma treated with anti-delta 1 IgG1 antibody (e.g., delta 1-17) in the presence of a costimulatory receptor agonist (ICOS agonist) compared to isotype (hIgG1) (as control). The percentage of CD44 in CD3+ T cells (FIG. 21A), the percentage of TNF-α in CD3+ T cells (FIG. 21B), and the percentage of IFNγ in CD3+ T cells (FIG. 21C) are shown. [Figure 22A] Figures 22A-22C show that the anti-delta 1 antibody, delta 1-39, disclosed herein is cross-reactive between humans and monkeys and has high affinity for delta 1. Figure 22A: Binding of delta 1-39 antibody to human delta-1 chain. Figure 22B: Binding of anti-delta 1-39 to monkey ("cyno") delta-1 chain. Figure 22C: Table listing KD values, rate constants and fitting parameters. [Figure 22B] Figures 22A-22C show that the anti-delta 1 antibody, delta 1-39, disclosed herein is cross-reactive between humans and monkeys and has high affinity for delta 1. Figure 22A: Binding of delta 1-39 antibody to human delta-1 chain. Figure 22B: Binding of anti-delta 1-39 to monkey ("cyno") delta-1 chain. Figure 22C: Table listing KD values, rate constants and fitting parameters. [Figure 22C] Figures 22A-22C show that the anti-delta 1 antibody, delta 1-39, disclosed herein is cross-reactive between humans and monkeys and has high affinity for delta 1. Figure 22A: Binding of delta 1-39 antibody to human delta-1 chain. Figure 22B: Binding of anti-delta 1-39 to monkey ("cyno") delta-1 chain. Figure 22C: Table listing KD values, rate constants and fitting parameters. [Figure 23] FIG. 1 shows that delta 1-39 is delta 1-specific, regardless of the gamma chain of the purified δγ TCR. [Figure 24A]Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 24B] Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 24C] Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 24D]Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 24E] Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 24F] Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 24G]Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Fig. 24H] Figures 24A-24F: Graphs showing binding of Delta1-39 antibodies to cell surface expressed δ1γ2, δ1γ3, δ1γ4, δ1γ5, δ1γ8, and δ1γ9, respectively. Figures 24G and 24H: Graphs showing binding studies using cell surface expressed δ2γ9 and TCR alpha beta (from the parental Jurkat (E6-1) cell line) as negative controls, showing no binding by Delta1-39. [Figure 25A] FIG. 25 includes diagrams showing the antibody-dependent cellular cytotoxicity (ADCC) effects of Delta 1-17, Delta 1-39, and Delta 1-41 compared to isotype-treated and untreated cells. NK-92 cells expressing extra FcγR were used as effector cells. Jurkat (J.RT3-T3.5) cell line expressing δ1 / γ9 was used as target cell line and labeled with CFSE dye. Cells were mixed at an effector to target ratio of 4:1 and anti-Delta 1 antibody or isotype was added at 100 nM for 1 hour (FIG. 25A) or 3.5 hours (FIG. 25B). After incubation, cells were stained with cell viability reagent (FVD660) and quantified by flow cytometry. [Figure 25B]FIG. 25 includes diagrams showing the antibody-dependent cellular cytotoxicity (ADCC) effects of Delta 1-17, Delta 1-39, and Delta 1-41 compared to isotype-treated and untreated cells. NK-92 cells expressing extra FcγR were used as effector cells. Jurkat (J.RT3-T3.5) cell line expressing δ1 / γ9 was used as target cell line and labeled with CFSE dye. Cells were mixed at an effector to target ratio of 4:1 and anti-Delta 1 antibody or isotype was added at 100 nM for 1 hour (FIG. 25A) or 3.5 hours (FIG. 25B). After incubation, cells were stained with cell viability reagent (FVD660) and quantified by flow cytometry. [Figure 26] 1 includes bar graphs showing the ADCP effect of anti-delta 1 antibodies in a cell-based ADCP assay using anti-delta antibodies, isotypes, or vehicle on cells expressing delta 1 / gamma-4, delta 1 / gamma-9, delta 2 / gamma-9, or no TCR. For each set of bars, from left to right, are delta 1-17, delta 1-38, delta 1-39, delta 1-40, delta 1-41, isotype, and no Ab bars. [Figure 27] FIG. 1 includes a diagram showing specific cell killing in peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors that were treated with either delta 1-39, isotype, or left untreated after isolation. Healthy PBMCs purchased from Stemcell (cat 70025.1) were treated for 1 hour at 37° C. and processed for staining and flow. [Figure 28A] 28A-28C include diagrams showing Delta 1-39 mediated killing in various patient samples. Figures 28A-28C include diagrams showing specific cell killing in patient samples. Single cell tumor suspensions of lung adenocarcinoma (Figure 28A), pancreatic ductal carcinoma (PDA; Figure 28B), and gastrointestinal neuroendocrine tumor (GI-NET; Figure 28C) were treated overnight at 37°C with either Delta 1-39, isotype as indicated, or left untreated, and processed for staining and flow cytometry. [Figure 28B]28A-28C include diagrams showing Delta 1-39 mediated killing in various patient samples. Figures 28A-28C include diagrams showing specific cell killing in patient samples. Single cell tumor suspensions of lung adenocarcinoma (Figure 28A), pancreatic ductal carcinoma (PDA; Figure 28B), and gastrointestinal neuroendocrine tumor (GI-NET; Figure 28C) were treated overnight at 37°C with either Delta 1-39, isotype as indicated, or left untreated, and processed for staining and flow cytometry. [Figure 28C] 28A-28C include diagrams showing Delta 1-39 mediated killing in various patient samples. Figures 28A-28C include diagrams showing specific cell killing in patient samples. Single cell tumor suspensions of lung adenocarcinoma (Figure 28A), pancreatic ductal carcinoma (PDA; Figure 28B), and gastrointestinal neuroendocrine tumor (GI-NET; Figure 28C) were treated overnight at 37°C with either Delta 1-39, isotype as indicated, or left untreated, and processed for staining and flow cytometry. [Figure 29] FIG. 13 depicts a graph showing the results of a receptor internalization assay. Cells expressing delta1 / gamma9 T cell receptors on their surface were incubated in the presence of 100 nM delta1-39, isotype antibody, anti-CD3 (clone OKT3) (azide-free) antibody, or in the absence of antibody. After 1, 3.5, and 24 hours of incubation, cells were harvested and processed for staining with anti-delta1 (clone TS8.2) antibody for flow cytometry. [Diagram 30] FIG. 1 shows a bar graph demonstrating that the various Delta-1 clones shown bind to stable cell lines expressing monkey gamma / delta TCR. Jurkat cells lacking expression of TCR on their surface were transduced with expressed monkey Delta 1 / gamma receptor or Delta 2 / gamma receptor. Cells expressing only the gamma chain or no TCR were stained as negative controls. Anti-Delta 1-17 shows no binding to any cynoTCR, while anti-Delta 1-23 and anti-Delta 1-32-41 show specific binding to monkey Delta 1 containing TCR on the cell surface. [Figure 31A]Figures 31A and 31B include diagrams showing specific Delta1 detection in PBMCs isolated from human donors with colorectal cancer (Figure 31A) and healthy human donors (Figure 31B) using anti-Delta1 antibodies (anti-Delta1-39 as an example). [Figure 31B] Figures 31A and 31B include diagrams showing specific Delta1 detection in PBMCs isolated from human donors with colorectal cancer (Figure 31A) and healthy human donors (Figure 31B) using anti-Delta1 antibodies (anti-Delta1-39 as an example). [Diagram 32] FIG. 1 depicts three bar graphs showing flow cytometry analysis of Dylight-650 conjugated anti-delta 1-39 and commercial anti-delta 1 (clone TS8.2), anti-delta 2-PE (clone B6), anti-CD3 (clone UCHT-1), and anti-TCR AB (clone IP26) on PBMC. The results show that the staining profiles of directly conjugated anti-delta 1-39 and anti-delta 1 (clone TS8.2) are similar. [Diagram 33] FIG. 13 shows flow cytometry analysis of commercial anti-Delta1 (clone TS8.2) to determine the levels of Delta1 positive T cells in healthy and patient PBMCs. In most patients tested, Delta1 levels were higher than in healthy donors. The percentage of Delta1 T cells is calculated as the fraction of total cells, live cells, and single cells. [Diagram 34] FIG. 13 shows flow cytometry analysis of delta1 T cell levels in healthy PBMCs versus tumors. Delta1 levels are measured by staining with a commercial anti-delta1 antibody (clone TS8.2). Results show that delta1 levels are higher in tumor single cell suspensions than in healthy donor PBMCs. The percentage of delta1 T cells is calculated as a fraction of total cells, live cells, single cells, and CD3 positive cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0085] Detailed Description of the Invention 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 alpha (α) and beta (β) chains (known as αβ T cells), while a minority of T cells have TCRs made of gamma (γ) and delta (δ) chains (known as γδ T cells).

[0086] γδ TCRs recognize a variety of self and non-self antigens, such as small peptides, soluble or membrane proteins, phospholipids, prenyl pyrophosphates, and sulfatides. Due to their antigenic diversity, γδ T cells can exert a wide range of different actions. For example, because γδ T cell activation does not require antigen processing and presentation by antigen-presenting cells (APCs), γδ T cells can be rapidly activated and act during the early stages of the immune response. Similar to natural killer (NK) cells, γδ T cells also respond to stimulation with stress- and / or infection-induced ligands (Lafont et al., Front Immunol., 2014, vol. 5:622). Such ligands are typically weakly or not expressed under normal conditions and are only upregulated in the presence of stress (DNA damage, heat stress) or infection. Additionally, human γδ T cells also express pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), that modulate their activation (Shojaei et al., Cancer Res., 2009, 69(22):8710-8717).

[0087] γδ T cells have been found to be both anti-tumorigenic and pro-tumorigenic, depending on a variety of conditions (Lafont et al., Front Immunol., 2014, vol. 5:622). With respect to pancreatic ductal adenocarcinoma (PDA), γδ T cells have been found to constitute a substantial proportion of tumor-infiltrating T cells and to have inhibitory functions against anti-cancer immunity mediated by αβ T cells. In mouse models, deletion, depletion, or blocking of γδ T cell recruitment has been found to be protective against PDA, resulting in increased infiltration, activation, and Th1 localization of αβ T cells (Daley et al., Cell, 2016, vol. 166:1485-1499). Notably, the delta 1 subtype of the γδ T cell receptor was found to be enriched among tumor-infiltrating T cells.

[0088] Therefore, antibodies specific for γδ T cells (e.g., specific for the delta-1 chain of a TCR that contains a delta-1 chain and a gamma chain; "anti-delta-1 antibodies") can block conventional T cell activation and thus the immune response against pathological cells (e.g., cancer cells), tumor-infiltrating γδ It may be a promising therapeutic agent for treating diseases associated with T cells (e.g., those in which tumor-infiltrating γδ T cells play an immunosuppressive role) or diseases associated with circulating γδ T cells. Without being bound by theory, anti-Delta1 antibodies may block the inhibitory function of γδ T cells expressing it, thereby enhancing anti-tumor immune responses. Thus, the antibodies may prevent direct or indirect suppression of alpha-beta T cell activity. The antibodies may inhibit γδ T cell cytokine secretion (e.g., IL-17), thereby preventing induction of angiogenesis, and attraction of MDSCs, neutrophils, and TAMs. The antibodies may inhibit Treg / Th2-type activity of γδ T cells, thereby preventing the restriction of anti-tumor γδ T cells. Additionally, the antibodies may prevent the interface of tumor-promoting γδ T cells with dendritic cells (DCs), thereby preventing inhibition of DC maturation, induction of DC and / or T cell senescence, or Anti-Delta1 antibodies can prevent the restriction of DC antigen presentation resulting from the presence of γδ T cells. Alternatively or additionally, anti-Delta1 antibodies can also exert their therapeutic effect by inducing cytotoxicity, such as ADCC, ADCP and / or CDC against target γδ T cells. Pathological cells refer to cells that contribute, either directly or indirectly, to the initiation and / or development of disease. In some embodiments, anti-Delta1 antibodies are antibody drug conjugates and exert their effect by targeting chemotherapeutic agents to tumor sites.

[0089] Thus, described herein are antibodies specific for γδ T cells (e.g., anti-Delta1 antibodies) and their therapeutic uses for rescuing the inhibition of conventional T cell activity mediated by γδ T cells and / or for treating diseases associated with γδ T cell activation.

[0090] Antibody that binds to the delta 1 chain of gamma delta T cells The present disclosure provides antibodies specific for γδ T cells, e.g., antibodies specific for γδ1 T cells, of a suitable species (e.g., human, or non-human primate, e.g., monkey, chimpanzee, or ape). Such antibodies may specifically bind to the delta-1 chain of the TCR expressed on γδ1 T cells. In some embodiments, the antibodies described herein are specific for γδ1 T cells. It binds to the delta-1 chain in a γδ1 heterodimer (e.g., a heterodimer of delta-1 and a gamma chain, e.g., gamma-9), which may be expressed on the surface of a T cell.

[0091] The anti-delta1 chain antibodies disclosed herein may exhibit one or more superior features, including: (i) high binding affinity (e.g., K<12 nM) to multiple human delta1 TCRs, regardless of their CDR sequences, and in particular regardless of their CDR3 sequences; D(ii) cross-reactivity of human Delta1 TCR and non-human primate Delta1 TCR, e.g., cynomolgus Delta1 TCR (e.g., K for human Delta1 TCR) D value and K against cynomolgus delta1 TCR D (iii) γδ1, which contain various gamma chains, including gamma 3, 4, 5, 8, or 9; e.g., clones delta 1-18, delta 1-19, delta 1-21, delta 1-22, delta 1-23, delta 1-25, delta 1-26, delta 1-28, delta 1-39; and / or (iv) binding to Delta-1 with high specificity, e.g., little or no binding to other targets, e.g., as determined by protein array analysis; (v) inhibiting γδ-T cell activity, i.e., inhibiting γδ-T cell mediated suppression of T cell activation, e.g., of CD4+ and / or CD8+ cells (e.g., Delta 1-23, Delta 1-39); (vi) promoting inflammatory T cell activation (i.e., promoting activation of CD4+ helper cells and / or CD8+ effector cells); (vii) depletion of γδ-T cells, e.g., through ADCC, CDC, and / or ADCP.

[0092] Thus, in some embodiments, the anti-delta1 chain antibodies disclosed herein (sometimes referred to herein as "anti-delta1 antibodies") exhibit one or more advantageous features. In some embodiments, the anti-delta1 chain antibodies disclosed herein have high binding affinity to multiple human delta1 TCRs, regardless of their CDR sequences, and in particular regardless of their CDR3 sequences. In some embodiments, the anti-delta1 chain antibodies disclosed herein have high binding affinity to multiple human delta1 TCRs, regardless of their CDR sequences, and in particular regardless of their CDR3 sequences. In some embodiments, the anti-delta1 chain antibodies disclosed herein have high binding affinity to multiple human delta1 TCRs, regardless of their CDR sequences, and in some embodiments, high binding affinity to human delta- ... D In some embodiments, the K value for human Delta-1 is less than 10 nM. D In some embodiments, the K value for human Delta-1 is less than 5 nM or less than 2 nM.D Values ​​are less than 1 nM. K for human delta-1 is less than 1 nM D Non-limiting examples of antibodies with values is delta1-39. In some embodiments, the cross-reactivity of human delta1 TCR and non-human primate delta1 TCR, e.g., cynomolgus delta1 TCR (e.g., K D value and K against cynomolgus delta1 TCR D The difference in K values ​​for human Delta1 TCR is within an order of magnitude. D value and K against cynomolgus delta1 TCR D A non-limiting example of an antibody with values ​​that differ within an order of magnitude is delta 1-39. In some embodiments, the anti-delta 1 chain antibodies disclosed herein have high binding affinity to multiple cyno delta 1 TCRs, regardless of their CDR sequences, and in particular regardless of their CDR3 sequences. In some embodiments, the K for cyno delta-1 is D In some embodiments, the K value for cyno Delta-1 is less than 10 nM. D In some embodiments, the K for cyno delta-1 is less than 5 nM or less than 2 nM. D Values ​​are less than 1 nM. K for cyno delta-1 is less than 1 nM. DA non-limiting example of an antibody having a value is delta 1-39. In some embodiments, the anti-delta 1 chain antibody disclosed herein can bind to γδ1 TCRs containing various gamma chains. In some embodiments, the anti-delta 1 chain antibody disclosed herein can bind to γδ1 TCRs containing gamma chains 3, 4, 5, 8, and / or 9. For example, in one particular embodiment, the anti-delta 1 chain antibody disclosed herein can bind to γδ1 TCRs containing gamma chains 3, 4, 5, and 8, including delta 1-38, delta 1-39, delta 1-40, and delta 1-41. A non-limiting example of an anti-delta 1 antibody disclosed herein that can bind to γδ1 TCRs containing gamma chains 3, 4, 5, and 8, and 9 is delta 1-39. In some embodiments, the anti-delta 1 antibodies described herein cross-react with human delta-1 chains and non-human mammalian delta-1 chains, e.g., non-human primate delta-1 chains, and can bind to gamma delta 1 TCRs containing various gamma chains, including gamma 3, 4, 5, and 8. Non-limiting examples of such antibodies described herein include delta 1-39 and delta 1-41. Additional examples include delta 1-38 and delta 1-40 (Delat 1-40). In some embodiments, the antibodies bind to delta-1 with high specificity, e.g., as determined by protein array analysis. A non-limiting example of such an antibody is clone delta 1-39. In some embodiments, the anti-delta 1 chain antibodies disclosed herein inhibit gamma delta-T cell-mediated suppression or inhibition of T cell activation. In some embodiments, the anti-delta 1 antibodies described herein inhibit the suppressive activity of gamma delta-T cells. In some embodiments, the anti-delta 1 chain antibodies disclosed herein can promote inflammatory T cell activation, e.g., as shown herein for delta 1-39. In some embodiments, the anti-delta1 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-delta 1 chain antibodies disclosed herein can deplete γδ-T cells, for example through ADCC, CDC, and / or ADCP.

[0093] Antibodies (used interchangeably in the plural) are immunoglobulin molecules capable of specifically binding to targets, e.g., 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" encompasses intact (i.e., full-length) polyclonal or monoclonal antibodies, as well as antigen-binding fragments thereof (e.g., Fab, Fab', F(ab')2, Fv), single chain (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 an immunoglobulin molecule comprising an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. Antibodies include antibodies of any class, e.g., IgD, IgE, IgG, IgA, or IgM (or subclasses thereof), and antibodies may be of any specific class. Depending 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, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[0094] The term "antibody" is also meant to include so-called antibody mimetics. Antibody mimetics refer to small molecules, e.g., 3-30 kDa, which may be single amino acid chain molecules that can specifically bind to an antigen but do not have the structure associated with antibodies. Antibody mimetics and their protein scaffolds include Affibody molecules (Z domain of Protein A), Affilins (Gamma-B crystalline), Ubiquitin, Affimers (Cystatin), Affitins (Sulfolobus These include, but are not limited to, Sac7d from D. acidocaldarius), Alphabodies (triple helical coiled coils), Anticalins (Lipocalins), Avimers (domains of various membrane receptors), DARPins (ankyrin repeat motifs), Fynomers (SH3 domains of Fyn), Kunitz domain peptides (Kunitz domains of various protease inhibitors), Ecallantide (Kalbitor), and Monobodies (fibronectin type III domains). Thus, in some embodiments, the anti-Delta 1 antibody is an antibody mimic.

[0095] In some embodiments, the anti-Delta 1 antibody is an antibody drug conjugate (ADC). ADCs generally include a monoclonal antibody against a target present on a cell, a cytotoxic drug, and a linker that attaches the antibody to the drug. Antibody-drug conjugates for cancer therapy are reviewed in Carter & Senter (2008), Cancer J. vol. 14(3): pp. 154-69, and Chari et al. (2014) Angewandte Chemie International Edition vol. 53: 3751. The cytotoxic moiety may be a polypeptide, which may be either directly or indirectly cytotoxic. If indirectly cytotoxic, the polypeptide may have enzymatic activity and may convert a relatively non-toxic 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 azathioprine, methotrexate); antimitotics (e.g., vincristine); topoisomerase inhibitors (e.g., doxorubicin, etoposide), and the like. The cytotoxic moiety may be any known chemotherapeutic agent. The cytotoxic moiety may be an enterobacterial toxin, particularly Pseudomonas exotoxin 20A or calicheamicin. The cytotoxic moiety may also comprise a radioactive atom. Radioactive atoms are typically iodine-123, iodine-125, iodine-131, indium-111, bromine-77, copper-67, arsenic-77, astatine-211, actinium-15 In some embodiments, the cytotoxic moiety is selected from the group consisting of chromium-225, 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 can inactivate or kill a cell. To facilitate the 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 poly(alkylene) glycols, such as polyethylene glycol, and peptide linkers. Many suitable coupling techniques are well known in the art. Suitable agents allowing for covalent, electrostatic or non-covalent attachment of moieties to antibodies include benzoquinones, carbodiimides, more particularly EDC (1-ethyl-3-[3-dimethyl-aminopropyl]-carbodiimide hydrochloride), dimaleimides, dithiobis-nitrobenzoic acid (DTNB), N-succinimidyl S-acetylthio-acetate (SATA), bridging agents with one or more phenyl azide groups that react with ultraviolet light (UV), preferably N-[-4-(azidosalicyamino)butyl]-3'-(2'-pyridyldithio)-propionamide (APDP), N-succinimidyl 3-(2-25 pyridyldithio)propionate (SPDP), 6-hydrazino-nicotinamide (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 to metals, especially radioactive metals, and immunoglobulins. Therefore, as is well known in the art, 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.

[0096] In some embodiments, the anti-Delta 1 antibody is conjugated to a drug to produce an antibody drug conjugate (ADC). In some embodiments, the anti-Delta 1 antibody is an antibody drug conjugate (ADC). Suitable cytotoxic agents that can be conjugated to the anti-Delta 1 antibody are described herein and known in the art. In some embodiments, the linker is cleavable. Non-limiting examples of linkers include disulfide-containing linkers that are cleavable through disulfide exchange, acid-labile linkers that are cleavable at acidic pH, and linkers that are cleavable by hydrolases (e.g., glycosyl hydrolases, e.g., 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.

[0097] A typical antibody molecule contains a heavy chain variable region (V H ) and the light chain variable region (V L ) is included. V H and V L The regions can be further divided into regions of hypervariability, also known as "complementarity determining regions" ("CDRs"), interspersed with more conserved regions known as "framework regions" ("FRs"). H and V L Typically, a framework region is composed of three CDRs and four FRs arranged from amino to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework regions and CDRs can be precisely identified using methodologies known in the art, such as 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. See, for example, 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. May 1969; 63(1):78-85; and Almagro, J. See Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. Correspondence or alignment between C numbering according to different definitions can be found, for example, at http: / / www.imgt.org / .

[0098] The antibodies described herein may be capable of binding to a T cell receptor delta-1 polypeptide (anti-delta-1 antibody), which may be from any suitable source, e.g., a human or non-human mammal (e.g., rabbit, primate, e.g., monkey, etc.).

[0099] The anti-Delta1 antibody as described herein may be a full-length antibody containing two heavy chains and two light chains, each of which contains a variable domain and a constant domain. Alternatively, the anti-Delta1 antibody may be an antigen-binding fragment of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding fragment" of a full-length antibody include: (i) V L , V H , C L and C H (ii) a Fab fragment, which is a monovalent fragment consisting of one domain; (ii) a F(ab') fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region. 2 Fragment; (iii)V H and C H(iv) a single-arm V of an antibody; L and V H (v) an Fv fragment consisting of one or more V H (vi) isolated complementarity determining regions (CDRs) that retain functionality. Additionally, two domains of the Fv fragment, the VHH domain (VHH domain, V ... L and V H are encoded by separate genes, they can be synthesized using recombinant methods L and V H The domains can be joined by synthetic linkers that allow them to be produced as a single protein chain that pairs to form monovalent molecules known as single-chain Fvs (scFvs). See, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0100] In some embodiments, the antibodies described herein specifically bind to a 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 understood in the art. A molecule is said to exhibit "specific binding" when it reacts more frequently, more rapidly, with a longer duration and / or with a higher affinity with a particular target antigen than with alternative targets. An antibody "specifically binds" to a target antigen or epitope when it binds with higher affinity, avidity, more readily and / or with a longer duration than it binds to other substances. For example, an antibody that specifically (or preferentially) binds to an antigen (e.g., the delta-1 chain of the human TCR) or an antigen epitope therein is an antibody that binds to this target antigen with higher affinity, avidity, more readily and / or with a longer duration than it binds to other antigens (e.g., the delta-2 chain of the human TCR) or other epitopes in the same antigen. For example, it is also understood with this definition that 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 (but can include) exclusive binding. In some cases, an antibody that "specifically binds" to a target antigen or its epitope may not bind to other antigens or other epitopes in the same antigen, i.e., only baseline binding activity can be detected in conventional methods. Baseline binding activity refers to the binding activity detected in conventional methods when no antigen is used (blank control) or a different antigen is used (negative control).

[0101] The specificity of the anti-Delta1 antibodies described herein can be determined by protein array analysis, resulting in a specificity score (S-score) as described herein and known in the art. (See, e.g., Jeong et al., Mol Cell Proteomics. 2012 June;11(6):O111.016253). Additionally, the specificity of the anti-delta1 antibodies described herein can be measured using the K D K of bond to d2 D It is evaluated by comparing with

[0102] In some embodiments, the anti-delta 1 antibodies described herein bind to a motif common to the TCR delta-1 chain. The sequences of the TCR delta-1 chain (e.g., human TCR delta-1 chain, cynomolgus monkey TCR delta-1 chain, or TCR delta chains from other species) are well known in the art and are available in public databases, such as the International These can be found in the Immunogenetics Information System® database (imgt.org), or GenBank. In some instances, anti-Delta1 antibodies may cross-react with different human or cynomolgus Delta1 chains.

[0103] 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. Human TCR: AQKVTQAQSSVSMPVRKAVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSDEQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFCALGVYAHSLTGGYRGGADKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKS (array Number 26) Human TCR: AQKVTQAQSSVSMPVRKAVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSDEQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFCALGPRPSYSEELGDTHRADKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKS (SEQ ID NO: 27) Human TCR: AQKVTQAQSSVSMPVRKAVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSDEQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFCALGEPNHFLNTDKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKS (SEQ ID NO: 2 8) Cynomolgus TCR: AQKVTQAQSSVSMPVEKAVTLNCQYETSSWSYDLFWYKQLPGKEMIFLIRQGSSEQNARDGRYSVNFKKEASFIALTISALQLEDSATYFCALRRPFTAQLFFGKGTQLIVEPERQPHTKPSVFVMKNGTNVACLVKDFYPKDIRINLESSKKITEFDPAIVVSPSGKYNAVKLGQYADSNSVTCSVQHNKEVVYSTDFEVKTNSTDHLKPTETENTKQPSKS (SEQ ID NO: 32) Cynomolgus TCR: AQKVTQAQSSVSMPVGKAVTLNCQYETSSSWSYYLFWYKQLPGKEMIFLIHQGSSQQNARNGRYSVNFQKAASSITLTISALQLEDSATYFCALRERPPNPGPFVLGVYATAQLFFGKG TQLIVEPERQPHHTKPSVFVMKNGTNVACLVKDFYPKDIRINLESSKKITEFDPAIVVSPSGKYNAVKLGQYADSNSVTCSVQHNKEVVYSTDFEVKTNSTDHLKPTETENTKQPSKS Column number 33) Cynomolgus TCR: AQKVTQAQSSVSMPVEKAVTLNCQYETSWWSYDLFWYKQLPGKEMIFLIRQSSSEQNARDGRYSANFKKEASSKSFIALTISALQLEDSATYFCALPLQVRGPTGGIRVYDKLIFGKG TRVTVEPKRQPHHTKPSVFVMKNGTNVACLVKDFYPKDIRINLESSKKITEFDPAIVVSPSGKYNAVKLGQYADSNSVTCSVQHNKEVVYSTDFEVKTNSTDHLKPTETENTKQPSKS( Column number 34) As used herein, "cross-react" means that an antibody exhibits binding activity (detectable by conventional assays) for two or more different antigen sequences (e.g., human Delta 1 and Delta 2). Such antibodies may have substantially similar binding affinities for these antigens, e.g., <10-fold (e.g., <5-fold or <2-fold) higher binding affinity for one antigen than the other, when determined under the same assay conditions. Alternatively, such an antibody may have a substantially higher binding affinity for one of the antigens compared to the other, e.g., at least 10-fold higher (e.g., 20-fold higher, 50-fold higher, 100-fold higher, or 1,000-fold higher) antigen affinity for one antigen than the other when determined under the same assay conditions.

[0104] In some embodiments, the anti-delta1 antibodies described herein preferentially bind to single chain human delta1 chain. In some embodiments, the antibodies bind to delta1 chain regardless of the sequence of the CDR region, e.g., CDR3 region. In some embodiments, the anti-delta1 antibodies preferentially bind to human delta1 compared to human delta-2 chain, human delta-3 chain, gamma chain (e.g., gamma-9 chain), and / or non-human delta1 chain. As used herein, an antibody "preferentially binds" to a first antigen or epitope thereof compared to a second antigen or another epitope means that the antibody has a substantially higher, e.g., at least 10-fold higher (e.g., >20-fold, >50-fold, >100-fold, >1,000-fold, or higher) binding affinity for the first antigen or epitope thereof compared to the second antigen or another epitope, when determined under the same assay conditions.

[0105] The anti-delta1 antibodies described herein may preferentially bind to human delta1 chains compared to non-human counterparts (e.g., non-human primate delta1 chains), or vice versa. In other examples, the anti-delta1 antibodies described herein may cross-react with human and non-human delta1 chains. For example, the antibodies may cross-react with human delta1 chains and non-human primate delta1 chains.

[0106] In some cases, the anti-delta 1 antibodies described herein do not bind to human delta-2 chain, human delta-3 chain, or gamma chain (e.g., gamma-9 chain, etc.). In some embodiments, the anti-delta 1 antibodies do not bind to delta-2 chain (also referred to herein as delta 2). In some embodiments, the anti-delta 1 antibodies do not bind to delta-3 chain (also referred to herein as delta 3). In some embodiments, the anti-delta 1 antibodies do not bind to either delta-2 chain or delta-3 chain. An antibody that does not bind to an antigen means that insignificant binding (e.g., only background binding or no binding at all) can be detected using conventional assays (e.g., ELISA or surface plasmon resonance).

[0107] In some embodiments, the anti-delta 1 antibody described herein binds to a T cell receptor comprising a delta 1 chain and a gamma chain. Gamma chain sequences are known in the art (see, for example, imgt.org / IMGTrepertoire). Non-limiting examples of gamma chains include gamma 1, gamma 2, gamma 3, gamma 4, gamma 5, gamma 5P, gamma 8, gamma 9, gamma 10, gamma 11, gamma a. Non-limiting examples of gamma chains are encoded by the following genes: TRGV1, TRGV2, TRGV3, TRGV4, TRGV5, TRGV5P, TRGV8, TRGV9, TRGV10, TRGV11, and TRGVA. In some embodiments, the anti-delta 1 antibody described herein binds to a T cell receptor comprising a delta 1 chain and a gamma chain known in the art. In some embodiments, the anti-delta1 antibodies described herein can bind to TCRs including any gamma chain. In some embodiments, the anti-delta1 antibodies described herein can bind to TCRs including gamma 3, gamma 4, gamma 5, gamma 8, and gamma 9. In some embodiments, the anti-delta1 antibodies described herein can bind to TCRs including gamma 3, gamma 4, gamma 5, and gamma 8. The anti-delta1 antibodies described herein preferably have suitable binding affinity for the target antigen (e.g., human delta1 chain) or antigenic epitope thereof. As used herein, "binding affinity" refers to the apparent Association constant or K A It means. A is the dissociation constant (K D The anti-Delta1 antibodies described herein have a binding affinity of at least 10 to a target antigen or antigen epitope. -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 M or less binding affinity (K D The increase in binding affinity can be expressed as K DA higher affinity binding of an antibody to a first antigen compared to a second antigen corresponds to a decrease in the K for binding the second antigen. A (or a number K D ) for binding the first antigen A (or a smaller number K D In such cases, the antibody has specificity for a first antigen (e.g., a first protein in a first conformation or a mimetic thereof) compared to a second antigen (e.g., the same first protein in a second conformation or a mimetic thereof; or a second protein). The difference in binding affinity (e.g., relative to specificity or other comparison) can be at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 37.5-fold, 50-fold, 70-fold, 80-fold, 91-fold, 100-fold, 500-fold, 1000-fold, 10,000-fold, or 10 5 In some embodiments, any of the anti-Delta1 antibodies can be more affinity matured to increase the binding affinity of the antigen to the target antigen or its antigenic epitope.

[0108] Binding affinity (or binding specificity) can be determined by various methods, such as equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, or spectroscopy (e.g., using a fluorescence assay). An exemplary condition for evaluating binding affinity is in HBS-P buffer (10 mM HEPES, 150 mM NaCl, 0.005% (v / v) surfactant P20 at pH 7.4). Using these techniques, the concentration of bound binding protein can be measured as a function of the target protein concentration. The concentration of bound binding protein ([Bound]) is generally related to the concentration of free target protein ([Free]) by the following formula:

[0109] [Bound]=[Free] / (Kd+[Free]) Quantitative measurements of affinity, determined using methods such as, for example, ELISA or FACS analysis, can be used to measure the K ASince it is proportional to and sometimes it is sufficient to obtain K A It is not always necessary to make an exact determination and thus, for example, a functional assay, e.g., activity in an in vitro or in vivo assay, can be used for comparison, such as determining whether a higher affinity is, e.g., 2-fold or more, to obtain a quantitative measurement of affinity or to obtain an estimate of affinity.

[0110] The anti-delta1 antibodies described herein can inhibit γδT cell activation, i.e., reduce the overall activity of γδT cells, such as immunosuppressive γδT cells. Without being bound by theory, the anti-delta1 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, the anti-delta1 antibodies can eliminate T cells expressing γδ1TCR by triggering cytotoxicity, such as ADCC and / or ADCP and / or CDC, resulting in the depletion of γδ1T cells. Thus, the anti-delta1 antibodies described herein can rescue the immunosuppression mediated by γδT cells, for example, in a cancer environment.

[0111] In some embodiments, the anti-delta1 antibodies described herein inhibit the activity of γδ1 T cells. In some embodiments, the anti-delta1 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 increment therein). In some embodiments, the inhibitory or suppressive ability of the anti-delta1 antibodies is measured by examining the ability of the antibodies to "rescue" immune cells, such as αβ T cells, from the inhibitory activity of γδ T cells. In some embodiments, the anti-delta1 antibodies 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 increment therein). In some embodiments, the inhibitory or suppressive ability of the anti-delta1 antibodies is measured by examining the ability of the antibodies to "rescue" immune cells, such as αβ T cells, from the inhibitory activity of γδ T cells. In the present invention, the anti-delta1 antibody described herein can rescue the immune inhibition induced by gamma delta1 T cells. The anti-delta1 antibody described herein can rescue the immune inhibition induced by gamma delta1 T cells by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0112] In some embodiments, the anti-delta1 antibodies described herein can eliminate γδ1 T cells from, for example, the tumor microenvironment and / or serum, blood, or circulation, i.e., can deplete γδ1 T cells. In some embodiments, the anti-delta1 antibodies described herein can eliminate γδ1 T cells from the tumor microenvironment, i.e., can deplete γδ1 T cells. In some embodiments, the anti-delta1 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 increment therein). In some embodiments, the ability of the anti-delta1 antibodies is measured by examining the ability of the antibodies to "rescue" immune cells, such as αβ T cells, from the inhibitory activity of γδ T cells. In some embodiments, the anti-delta1 antibodies described herein can rescue immune inhibition induced by γδ1 T cells. The anti-Delta1 antibodies described herein can rescue the immune inhibition induced by γδ1 T cells by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0113] In some embodiments, the anti-delta1 antibodies described herein can eliminate γδ1 T cells from the tumor microenvironment, i.e., deplete γδ1 T cells. In some embodiments, the anti-delta1 antibodies described herein can 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 increment therein). In some embodiments, the inhibitory or suppressive ability of the anti-delta1 antibodies 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-delta1 antibodies described herein can rescue immune inhibition induced by γδ1 T cells. The anti-Delta1 antibodies described herein can rescue the immune inhibition induced by γδ1 T cells by at least 10% (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0114] In some embodiments, the anti-delta 1 antibodies described herein activate ADCC. In some embodiments, the anti-delta 1 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 increment therein). In some embodiments, the ability of the antibody to activate ADCC is measured according to one or more of the methods described herein.

[0115] In some embodiments, the anti-delta 1 antibodies described herein activate ADCP. In some embodiments, the anti-delta 1 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 increment therein). In some embodiments, the ability of the antibody to activate ADCP is measured according to one or more of the methods described herein.

[0116] In some embodiments, the anti-Delta1 antibodies described herein activate or inhibit tumor and / or peripheral blood CD4+ helper cells and / or CD8+ effector cells. In some embodiments, the anti-Delta1 antibodies described herein activate or reactivate at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein) of CD4+ helper cells and / or CD8+ effector cells in tumors and / or peripheral blood. In some embodiments, the ability of anti-Delta1 antibodies to activate CD4+ cells and / or CD8+ cells is measured by examining the levels of inflammatory cytokines. In some embodiments, anti-Delta1 antibodies can increase the production of inflammatory cytokines in tumors, such as, but not limited to, IFNγ, TNF-α, and CD44. In some embodiments, the anti-Delta1 antibody can increase production of inflammatory cytokines, such as, but not limited to, IFNγ, TNF-α, and CD44, in tumors by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment thereof).

[0117] In some embodiments, the anti-delta1 antibodies described herein can modulate, e.g., decrease, the ratio of γδ1 T cells to γδ-2 T cells. In some embodiments, the anti-delta1 antibodies described herein modulate, e.g., decrease, the ratio of γδ1 T cells to γδ-2 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 increment therein).

[0118] In some embodiments, the anti-delta1 antibodies described herein can modulate, e.g., 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-delta1 antibodies described herein modulate, e.g., 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 increment therein).

[0119] In some embodiments, the anti-delta1 antibodies described herein can deplete tumors of γδ T cells. In some embodiments, the anti-delta1 antibodies described herein can deplete tumors of γδ 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 increment therein).

[0120] In some embodiments, the anti-delta1 antibodies described herein can prevent direct or indirect suppression of αβ T cell activity. In some embodiments, the anti-delta1 antibodies described herein can inhibit γδ T cell cytokine secretion (e.g., IL-17), thereby preventing induction of angiogenesis and attraction of MDSCs, neutrophils, and TAMs. In some embodiments, the anti-delta1 antibodies described herein can inhibit Treg / Th2 type activity of γδ T cells, thereby preventing the restriction of anti-tumor γδ T cells. In some embodiments, the anti-delta1 antibodies described herein can prevent the interface of tumor-inducing γδ T cells with dendritic cells (DCs), thus preventing the inhibition of DC maturation and / or the induction of senescence of DCs or T cells. In some embodiments, the anti-delta1 antibodies described herein can prevent the restriction of DC antigen presentation resulting from the presence of γδ T cells.

[0121] The apparent inhibition constant (Ki) provides an index of inhibitor potency. app or K i,app ) is related to the concentration of inhibitor required to reduce enzyme activity and is independent of enzyme concentration. The inhibitory activity of the anti-Delta1 antibodies described herein can be determined by routine methods known in the art.

[0122] Antibody K i, app The K value can be determined by measuring the inhibitory effect of different concentrations of antibody on the extent of a reaction (e.g., enzyme activity); fitting the change in the pseudo-first-order rate constant (v) as a function of inhibitor concentration to a modified Morrison equation (Equation 1), which provides an estimate of the apparent K value. For competitive inhibitors, the K app is K i, app It can be obtained from the y-intercept extracted from linear regression analysis of a plot of versus substrate concentration.

[0123]

number

[0124] where A is equal to vo / E, i.e., the initial velocity (vo) of the enzyme reaction in the absence of inhibitor (I), divided by the total enzyme concentration (E).

[0125] In some embodiments, the anti-delta antibodies described herein 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 a target antigen or antigenic epitope. app In some embodiments, an anti-delta 1 antibody may have a lower Ki value for a first target (e.g., a specific epitope of delta 1) compared to a second target (e.g., a different specific epitope of delta 1). app It may have Ki app The difference in (e.g., relative to specificity or other comparison) is at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 37.5-fold, 50-fold, 70-fold, 80-fold, 91-fold, 100-fold, 500-fold, 1000-fold, 10,000-fold, or 10 5 In some instances, the anti-Delta1 antibody inhibits a first antigen (e.g., a first protein in a first conformation or mimetic thereof) more than a second antigen (e.g., the same first protein or mimetic thereof in a second conformation; or a second protein). In some embodiments, any of the anti-Delta1 antibodies ... app It can be further affinity matured to reduce

[0126] The antibodies described herein may be murine, rat, monkey, human, or of any other origin, including chimeric or humanized antibodies. Such antibodies are not naturally occurring, i.e., would not be produced in an animal without human action (e.g., immunizing such an animal with the desired antigen or a fragment thereof or isolating it from an antibody library).

[0127] Any of the antibodies described herein can be monoclonal or polyclonal. A "monoclonal antibody" refers to a population of homogeneous antibodies, and a "polyclonal antibody" refers to a population of heterogeneous antibodies. These two terms do not limit the source of the antibody or the method by which it is made.

[0128] In one example, the antibody used in the methods described herein is a humanized antibody. Humanized antibody refers to a form of a non-human (e.g., murine) antibody that is a specific chimeric immunoglobulin, or an antigen-binding fragment thereof that contains minimal sequence derived from a non-human immunoglobulin. For the most part, a humanized antibody is an antibody in which the residues from the recipient CDRs have been modified to resemble those of a non-human species (donor antibody), e.g., mouse, rat, etc., with the desired specificity, affinity, and capacity. A humanized antibody is a human immunoglobulin (recipient antibody) in which Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. In some cases, humanized antibodies may contain residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. In general, a humanized antibody will contain substantially all of at least one, and typically two, variable regions, in which all or substantially all of the CDR regions that correspond to the CDR regions of the non-human immunoglobulin and all or substantially all of the FR regions are CDR regions of a human immunoglobulin consensus sequence. The humanized antibody will also optionally contain at least a portion of a constant region or domain (Fc) of an immunoglobulin, typically a human immunoglobulin. The antibody may have an Fc region modified as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, or six) that have been altered relative to the original antibody, also referred to as one or more CDRs "derived from" one or more CDRs from the original antibody. Humanized antibodies may also be subject to affinity maturation.

[0129] 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 a parent non-human antibody is H and V L The variable regions of the V11A ... H and V L The chain is the parent V as a search query. H and V L The sequence is then identified from any antibody gene database. H and V L The receptor gene is selected.

[0130] The CDR regions in the selected human acceptor gene can be replaced with CDR regions from a parent non-human antibody or a functional variant thereof. If necessary, residues in the framework regions of the parent chain predicted to be important in interactions with the CDR regions can be used to replace the corresponding residues in the human acceptor gene.

[0131] In another example, the antibody described herein is a chimeric antibody, which can include heavy and light chain constant regions from a human antibody. 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 mouse, rabbit, and rat), while the constant portion is homologous to the sequence of an antibody derived from another mammal, such as a human. In some embodiments, amino acid modifications can be made in the variable and / or constant regions.

[0132] In some embodiments, the anti-Delta1 antibodies described herein comprise a heavy chain variable region (V) comprising a heavy chain (HC) CDR1, a HC CDR2, and a HC CDR3. H HC CDR1 may comprise FTX 1 X 2 X 3 X 4 X 5 IH (SEQ ID NO: 46), in which case X 1 can be F or V, and X 2 can be S or T, and X 3 can be G, A, or S, and X 4 can be T, N, or S, and X 5 may be D or S. In a particular example, HC CDR1 may be FTVSSSSIH (SEQ ID NO: 52). HC CDR2 may include the motif set forth as SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively, or in addition, HC CDR3 may include PGX 6 YYWYYSGSAYEGYGLDY (SEQ ID NO: 48), in which X 6 can be S or M. In specific examples In this case, the HC CDR3 may comprise the sequence DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO:54).

[0133] Alternatively, or in addition, the anti-Delta1 antibodies described herein comprise a light chain variable region (V) comprising a light chain (LC) CDR1, a LC CDR2, and a LC CDR3. L Optionally, LC CDR1 may comprise the motif set forth as RASQSVSSAVA (SEQ ID NO: 55). LC CDR2 may comprise the motif set forth as X 7 ASSLX 8 S (SEQ ID NO:50), in which case X 7 can be S or A, and X 8can be Y or Q. In some examples, LC CDR2 can comprise a sequence of AASSLQS (SEQ ID NO:56). Alternatively, or in addition, LC CDR3 can comprise a sequence of QQX 9 X 10 X 11 X 12 X 13 X 14 LIT (SEQ ID NO:51), in which case X 9 can be S or Q, and X 10 can be G, S, or T, and X 11 can be D, K, or S, and X 12 can be Y, W, or absent, X 13 can be P or absent, and X 14 can be D, F, or Y. In some examples, the LC CDR3 can comprise the sequence of QQQSKYPFLIT (SEQ ID NO:57).

[0134] In some embodiments, the antibody comprises a heavy chain variable region (V H ), wherein HC CDR1 comprises FTFX 1 X 2 X 3 X 4 IH (SEQ ID NO: 93) motif, in which 1 is S or T, and X 2 is S, G, or A, and X 3 X4 is T, N, or S, and X5 is D or S. Alternatively, or in addition, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO: 53). Alternatively, or in addition, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO: 54). Alternatively, or in addition, the isolated antibody disclosed herein comprises a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3. L), where LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55). Alternatively, or in addition, LC CDR2 comprises AASSLQS (SEQ ID NO:56). Alternatively, or in addition, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO:57).

[0135] In some embodiments, the antibody comprises a heavy chain variable region (V H ), wherein HC CDR1 comprises FTFX 1 X 2 X 3 X 4 IH (SEQ ID NO: 93) motif, where X 1 is S or T, and X 2 is S, G, or A, and X 3 X 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 (V) comprising LC CDR1, LC CDR2, and LC CDR3. L ), where 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).

[0136] In some embodiments, the antibody comprises a heavy chain variable region (V H ), wherein HC CDR1 comprises FTFX 1 X 2 X 3 X 4 IH (SEQ ID NO: 94) motif, in which 1 is S or T, and X 2 is S or A, and X 3 is N or S, and X 4is 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) comprising LC CDR1, LC CDR2, and LC CDR3. L ), in which case 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).

[0137] In some embodiments, the antibody comprises a heavy chain variable region (V H ), where 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 in addition, HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO:53). Alternatively, or in addition, HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO:54). Alternatively, or in addition, the isolated antibodies disclosed herein comprise LC CDR1, LC CDR2, and LC The light chain variable region (V L ), where LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55). Alternatively, or in addition, LC CDR2 comprises AASSLQS (SEQ ID NO:56). Alternatively, or in addition, LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO:57).

[0138] In some embodiments, the anti-Delta1 antibodies described herein contain all of the heavy chain CDR motifs and / or all of the light chain CDR motifs described herein. In some examples, the antibodies do not contain the same heavy and light chain CDRs as Delta1-17 or do not contain the same heavy and light chain variable regions as Delta1-17.

[0139] Some exemplary anti-Delta1 antibodies are provided below (CDR residues based on Kabat numbering are shown in bold). A list of CDRs is provided in Table 1.

[0140]

number

[0141]

number

[0142]

number

[0143]

number

[0144]

number

[0145]

number

[0146] [Table 1-1]

[0147] [Table 1-2]

[0148] [Table 1-3]

[0149] [Table 1-4]

[0150] In some embodiments, the anti-delta 1 antibodies described herein bind to the same epitope as any of the exemplary antibodies listed above, or compete with the exemplary antibodies in binding to the delta-1 chain. "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 amino acids of a protein (e.g., glycosyl moieties), or a combination thereof. Overlapping epitopes contain at least one common amino acid residue. Epitopes may be linear, typically 6-15 amino acids in length. Alternatively, epitopes may be conformational. The epitope to which an antibody binds can be determined by routine techniques, such as epitope mapping methods (see, e.g., below). Antibodies that bind to the same epitope as the exemplary antibodies described herein may bind to exactly the same epitope or to a substantially overlapping epitope (e.g., containing less than three non-overlapping amino acid residues, less than two non-overlapping amino acid residues, or only one non-overlapping amino acid residue). Whether two antibodies compete with each other for binding to a cognate antigen can be determined by competition assays that are well known in the art. do.

[0151] In some instances, the anti-Delta1 antibodies described herein have the same V H and / or V L Contains CDR. Same V H and / or V L Two antibodies that have CDRs mean that their CDRs are identical as determined by the same approach (e.g., the Kabat approach or the Chothia approach, which are known in the art). Such anti-Delta1 antibodies have the same V and VD as the exemplary antibodies described herein. H , the same V L , or both.

[0152] Functional variants of any of the exemplary anti-Delta1 antibodies disclosed herein are also within the scope of the present disclosure. Such functional variants are substantially similar to the exemplary antibodies, both structurally and functionally. Functional variants have substantially the same V H and / or V L For example, a functional variant can contain only up to 10 (e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1) amino acid residue variations in the entire CDR region of an antibody and have substantially the same affinity (e.g., K D Alternatively, or in addition, the amino acid residue variations are conservative amino acid residue substitutions. As used herein, "conservative amino acid residue substitutions" refers to amino acid substitutions that do not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for modifying polypeptide sequences known to those of skill in the art, such methods being described in references compiling such methods, e.g., Molecular Cloning: A Laboratory Manual, J. Sambrook et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, or Current Protocols in Molecular Biology, FM Ausubel et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include those made for 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.

[0153] In some embodiments, the anti-Delta1 antibody has the V H Alternatively, or in addition, the anti-Delta1 antibody may comprise heavy chain CDRs that individually or collectively have at least 80% (e.g., 85%, 90%, 95%, or 98%) sequence identity when compared to the V CDRs. H The antibody may comprise light chain CDRs that are individually or collectively at least 80% (e.g., 85%, 90%, 95%, or 98%) sequence identical to the CDRs. "Individually" means that one particular heavy or light chain CDR of the antibody shares the sequence identity described for the corresponding heavy or light chain CDR in an exemplary antibody, e.g., as disclosed herein. "Collectively" means that the three heavy or light chain CDRs of the antibody, taken together, share the sequence identity described for the corresponding heavy or light chain CDR in an exemplary antibody, e.g., as described herein. Such an antibody may also comprise one or more of the heavy chain CDR1, CDR2, and CDR3 motifs 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 and / or all of the light chain CDR1, CDR2, and CDR3 motifs described herein.

[0154] In some embodiments, the anti-Delta1 antibodies described herein have the V H At least 80% (e.g., 85%, 90%, 95%, or 98%) sequence identity with V H Alternatively, or in addition, the anti-Delta1 antibody may comprise the V of the exemplary antibodies described herein. L V has at least 80% (e.g., 85%, 90%, 95%, or 98%) sequence identity to LSuch antibodies may also comprise one or more of the heavy chain CDR1, CDR2, and CDR3 motifs and / or one or more of the light chain CDR1, CDR2, and CDR3 motifs described herein, for example, all of the heavy chain CDR1, CDR2, and CDR3 motifs and / or all of the light chain CDR1, CDR2, and CDR3 motifs described herein.

[0155] 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, modified as 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 with the XBLAST program at score=50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule of interest. When gaps exist between the two sequences, Gapped BLAST can be utilized 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.

[0156] In some embodiments, the heavy chain of any of the anti-delta1 antibodies 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 of any suitable origin, e.g., human, mouse, rat, or rabbit. In a particular example, the heavy chain constant region is derived from human IgG (gamma heavy chain) of any of the IgG subfamilies described herein, e.g., IgG1. Several mutations in the heavy chain of an antibody to adjust 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).

[0157] There are many known mutations that exist to enhance ADCC, ADCP, and CDC, as well as specific mutations to include. The inventors have attached a review that details all of these (see Table 1). Non-limiting examples of human IgG1 heavy chain mutations include: (1) E333A mutation (increased binding to FcγRIIIa and increased ADCC and CDC); (2) S239D / A330L / I332E mutation (increased binding to FcγRIIIa and increased ADCC); (3) K326W / E333S mutation (increased binding to C1q and increased CDC); (4) S239D / I332E / G236A mutation (increased FcγRIIa / FcγRIIb ratio and increased macrophage phagocytosis). Alternatively, the LALA mutation prevents all effector functions, i.e., the essential functions for ADCC, ADCP, and CDC. The hIgG1 LALA sequence contains two mutations L234A and L235A (EU numbering), which inhibit FcgR binding, as well as a P329G mutation (EU numbering) to abolish binding of complement C1q, thereby abolishing all immune effector functions. IgG4 istThe hIgG4 Arm Exchange Mutant sequence includes a mutation that inhibits Fab arm exchange (S228P; EU numbering). For manufacturing purposes, the following heavy chain sequences are It may be desirable to delete the C-terminal lysine ("K") residue that is present in each of the heavy chain sequences presented below. Thus, in some embodiments, the C-terminal lysine ("K") residue may be absent in each of the heavy chain sequences presented below. In one example, the constant region is derived from human IgG1, an exemplary heavy chain amino acid sequence of which is provided below (SEQ ID NO: 31). In some embodiments, one or more of the mutations described in 1-4 above are introduced. In some embodiments, the heavy chain constant region of the anti-Delta1 antibodies described herein may comprise a single domain (e.g., CH1, CH2, or CH3) or any combination of single domains of the constant region (e.g., SEQ ID NOs: 31, 74-77). In some embodiments, the light chain constant region of the antibodies described herein may comprise a single domain (e.g., CL) of the constant region (e.g., SEQ ID NO: 73). Exemplary light and heavy chain sequences are listed below.

[0158]

number

[0159]

number

[0160] In any of the embodiments described herein, the anti-delta 1 antibody 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-delta 1 antibody 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-delta 1 antibody 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-delta 1 antibody 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-delta 1 antibody of the present disclosure may comprise a heavy chain constant region having the sequence of SEQ ID NO: 76.

[0161] In some embodiments, the anti-Delta1 antibody 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-delta1 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-delta1 antibody has a light chain sequence that comprises SEQ ID NO:78. In some embodiments, the anti-delta1 antibody has a heavy chain sequence that comprises SEQ ID NO:79. In some embodiments, the isolated antibody has a light chain sequence that consists essentially of or consists of SEQ ID NO:78. In some embodiments, the isolated antibody has a heavy chain sequence that consists essentially of or consists of SEQ ID NO:79.

[0162] In some embodiments, the anti-Delta1 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.

[0163] In some embodiments, the anti-Delta1 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: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 NOs:3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45.

[0164] In some embodiments, the anti-Delta1 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-Delta1 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.

[0165] In some embodiments, the anti-Delta1 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:3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. In some embodiments, the anti-Delta1 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 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 SEQ ID NOs:3, 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 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 consisting essentially 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, or consisting 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.

[0166] In some embodiments, the anti-Delta1 antibody 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: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 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 isolated 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: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and 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 isolated antibody has a heavy chain sequence consisting of a constant region substantially 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 a light chain sequence consisting of a constant region substantially 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 consisting 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 a light chain sequence consisting 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.

[0167] In some embodiments, the anti-Delta1 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 at least 80% or 85% (e.g., In some embodiments, the heavy chain sequence is 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 nucleic acid sequence of the present invention.

[0168] In some embodiments, the anti-delta1 antibody has a light chain sequence that includes 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-delta1 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 that includes a constant region having the sequence of SEQ ID NO:31 and a VL region having the sequence of SEQ ID NO:9.

[0169] In some embodiments, the anti-Delta1 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 anti-Delta1 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 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 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:49, 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.

[0170] In some embodiments, the anti-Delta1 antibody 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. 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 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 isolated 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, and 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 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 SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and a light chain sequence consisting essentially 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. 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 SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45. 21, 22, 23, 24, 25, 43, 44, and 45, and a light chain sequence consisting 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.

[0171] If necessary, the anti-delta1 antibodies described herein may include modified constant regions. For example, the anti-delta1 antibodies may include modified constant regions that are immunologically inactive, e.g., do not cause complement-mediated lysis or stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). In other embodiments, the constant regions are modified as described in Eur. J. Immunol. (1999) 29:2613-2624; PCT Application No. PCT / GB99 / 01441; and / or UK Patent Application No. 9809951.8. In other examples, the antibodies described herein may include modified constant regions with enhanced ADCC activity. Thus, the anti-delta1 antibodies described herein may include modified constant regions that improve effector function, i.e., improve complement-mediated lysis and improve stimulation of antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, the antibodies are IgG1 molecules and include one or more mutations described in 1-4 above or in Wang et al. ADCC activity can be assessed using the methods disclosed in US Pat. No. 5,500,362.

[0172] Any of the anti-Delta1 antibodies described herein may comprise a light chain, which further comprises a light chain constant region that may be any CL known in the art. In some instances, the CL is a kappa light chain. In other instances, the CL is a lambda light chain.

[0173] Antibody heavy and light chain constant regions are well known in the art and are provided, for example, in the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php, both of which are incorporated herein by reference.

[0174] Preparation of anti-Delta1 antibody Antibodies capable of binding to the delta-1 chain of the γδ TCR described herein can be generated by any method known in the art, see, for example, Harlow and Lane, (1998) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.

[0175] In some embodiments, antibodies specific for a target antigen (e.g., delta-1 chain or a fragment thereof of a suitable species, such as human) can be produced by conventional hybridoma technology. A full-length target antigen or a fragment thereof, optionally conjugated to a carrier protein, such as KLH, can be used to immunize a host animal to generate antibodies that bind to the antigen. The route and schedule of immunization of the host animal is generally maintained by established conventional techniques for stimulating and producing antibodies, as further described herein. General techniques for producing mouse, humanized, and human antibodies are known in the art and described herein. It is contemplated that any mammalian subject, including humans, or antibody-producing cells therefrom can be engineered to serve as a basis for the generation of mammals, including human hybridoma cell lines. Typically, a host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantarly, and / or intradermally with an amount of immunogen, e.g., an amount as described herein.

[0176] Hybridomas can be prepared from lymphocytes and immortalized bone marrow cells using the general somatic cell mating technique of Kohler, B. and Milstein, C. (1975) Nature 256:495-497, or as modified by Buck, DW, et al., In Vitro, 18:377-381 (1982). Available myeloma lines, such as, but not limited to, X63-Ag8.653 and those available from the Salk Institute, Cell Distribution Center (San Diego, Calif., USA), can be used for mating. Generally, the technique involves fusing bone marrow and lymphoid cells using fusogens such as polyethylene glycol, or by electrical means well known to those skilled in the art. After fusion, the cells are separated from the fusion medium to remove non-mating parent cells and grown in a selective culture medium, such as hypoxanthine-aminopterin thymidine (HAT) medium. Any medium described herein, supplemented or not with serum, can be used to culture the hybridomas secreting monoclonal antibodies. As another alternative to cell fusion techniques, EBV-immortalized B cells can be used to produce the anti-Delta 1 monoclonal antibodies described herein. Hybridomas are expanded and subcloned, if desired, and supernatants are assayed for anti-immunogen activity by conventional immunological procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescent immunoassay).

[0177] Hybridomas that can be used as a source of antibodies include all derivatives, progeny cells of parent hybridomas that produce monoclonal antibodies capable of blocking Delta 1 (γδ T cell) activity. Hybridomas producing such antibodies can be cultured 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. Undesirable activity, if present, can be removed, for example, by passing the preparation over an adsorbent made of immunogen attached to a solid phase, and eluting or releasing the desired antibody from the immunogen. A target antigen or fragment containing the target amino acid conjugated to a protein that is immunogenic in the species to be immunized, such as keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, with a bifunctional derivatizing agent, such as maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine ​​residues), N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride, SOCl, or R 1 N=C=NR, where R and R 1 are different alkyl groups], etc., can result in a population of antibodies (e.g., monoclonal antibodies).

[0178] If desired, the antibody of interest (monoclonal or polyclonal) (e.g., produced by a hybridoma) may be sequenced, and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest may be maintained within the vector in a host cell, and the host cell may then be propagated and frozen for future use. In the alternative, the polynucleotide sequence may be used to "humanize" the antibody by genetic engineering, or to improve the affinity (affinity maturation) or other properties of the antibody. For example, the constant region may be engineered to more closely resemble human constant regions to avoid immune responses when the antibody is used in clinical trials and treatments in humans. It may be desirable to genetically engineer the antibody sequence to obtain higher affinity for the target antigen and more efficacy in inhibiting the activity of the target gamma delta 1 TCR (and therefore the activity of the target gamma delta T cell). The antibody may be engineered to have a higher affinity for the target antigen and more efficacy in inhibiting the activity of the target gamma delta 1 TCR (and therefore the activity of the target gamma delta T cell). It will be apparent to one of skill in the art that one or more polynucleotide changes can be made to the polypeptide and still maintain binding specificity for the target antigen.

[0179] In other embodiments, fully human antibodies can be obtained by using commercially available mice that have been engineered to express specific human immunoglobulin proteins. For the generation of humanized or human antibodies, transgenic animals designed to generate more desirable (e.g., fully human) or more robust immune responses can also be used. Examples of such technology are Xenomouse® from Amgen, Inc. (Fremont, CA) and HuMAb-Mouse® and TC Mouse™ from Medarex, Inc. (Princeton, NJ). In another alternative, antibodies can be recombinantly produced by phage display or yeast technology. See, for example, 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.

[0180] Alternatively, antibodies capable of binding to the target antigen described herein can be routinely isolated from a suitable antibody library. By using an antibody library containing multiple antibody components, antibodies that bind to a specific target antigen (e.g., in this case, an epitope of the delta-1 chain) can be identified after routine selection processes known in the art. In the selection process, the antibody library can be interrogated with the target antigen or a fragment thereof, and members of the library that can bind to the target antigen can be isolated, typically by retention on a support. Such screening processes can be carried out by multiple rounds (e.g., including both positive and negative selection) to enrich the pool of antibodies that can bind to the target antigen. Individual clones of the enriched pool can then be isolated and further characterized to identify those with the desired binding and biological activities. The sequences of the heavy and light chain variable domains can also be determined by conventional methodologies.

[0181] There are several routine methods known in the art to identify and isolate antibodies capable of binding to the target antigens described herein, such as phage display, yeast display, ribosomal display, or mammalian display technologies.

[0182] As an example, phage display typically uses covalent bonds to attach protein (e.g., antibody) components to bacteriophage coat proteins. The attachment occurs by translation of a nucleic acid encoding the antibody component fused to the coat protein. The attachment may include flexible peptide linkers, protease sites, or amino acids incorporated as a result of suppression of a stop codon. Phage display has been described, for example, in 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. ol. 23(3)344-8. Bacteriophage displaying the protein component can be grown and harvested using standard phage preparation methods, such as PEG precipitation from growth medium. After selection of individual display phages, nucleic acid encoding the selected protein component can be isolated from cells infected with the selected phage after amplification or from the phage itself. Individual colonies or plaques can be selected and the nucleic acid can then be isolated and sequenced.

[0183] Other display formats include cell-based display (see, e.g., WO 03 / 029456), protein-nucleic acid fusions (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. 2003;21:163-70). After members of the display library have been isolated for binding to the target antigen, each isolated library member can also be tested for its ability to bind to a non-target molecule to assess its binding specificity. Examples of non-target molecules include streptavidin on magnetic beads, blocking agents such as bovine serum albumin, non-fat milk, soy protein, any capture or target-fixing monoclonal antibody, or non-transfected cells that do not express the target. For example, such data can be obtained by using a high-throughput ELISA screen. The ELISA screen can also be used to obtain quantitative data for binding of each library member to the target, as well as cross-species reactivity to subunits of the target or target antigen. The non-target binding data and the target binding data are compared (e.g., using a computer and software) to identify library members that specifically bind to the target.

[0184] After selecting candidate library members that bind to the target, each candidate library member can be further analyzed to further characterize its binding properties to the target, such as, for example, the delta1 chain (also referred to herein as delta1). Each candidate library member can be subjected to one or more secondary screening assays. The assays can be for binding properties, catalytic properties, inhibitory properties, physiological properties (e.g., cytotoxicity, renal clearance, immunogenicity), structural properties (e.g., stability, conformation, oligomerization state), or another functional property. The same assay can be used repeatedly, but also under different conditions, for example, to determine pH, ionic, or thermal sensitivity.

[0185] Where appropriate, the assays can use the display library members directly, or recombinant polypeptides produced from nucleic acids encoding the selected polypeptides, or synthetic peptides synthesized based on the sequence of the selected polypeptide. In the case of a selected Fab, the Fab can be assessed or modified and produced as an intact IgG protein. Exemplary assays for binding properties are described below.

[0186] Binding proteins can also be assessed using an ELISA assay. For example, each protein is contacted with a microtiter plate having a bottom surface coated with the target, e.g., a limiting amount of the target. To remove non-specifically bound polypeptides, The plate is washed with a buffer to detect the amount of binding protein bound to the target on the plate. The amount of binding protein bound to the target on the plate is then determined by probing the plate with an antibody that can recognize the binding protein, such as a tag or a constant portion of the binding protein. The antibody is conjugated to a detection system (e.g., an enzyme such as alkaline phosphatase or horseradish peroxidase (HRP) that produces a colorimetric product when provided with an appropriate substrate).

[0187] Alternatively, the ability of the binding proteins described herein to bind to target antigens can be analyzed using homogeneous assays, i.e., no further fluid manipulation is required after all the components of the assay are added. For example, fluorescence resonance energy transfer (FRET) can be used as a homogeneous assay (see, for example, Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos et al., U.S. Pat. No. 4,868,103). The fluorophore label on the first molecule (e.g., the molecule identified in the fraction) is selected so that when the second molecule is in close proximity to the first molecule, its emitted fluorescent energy can be absorbed by the fluorescent label on the second molecule (e.g., the target). The fluorescent label on the second molecule fluoresces when it absorbs the transferred energy. The efficiency of energy transfer between labels is related to the distance separating the molecules, so the spatial relationship between the molecules can be evaluated. In the situation where binding occurs between the molecules, the fluorescent emission of the "acceptor" molecule label in the assay should be maximum. The binding events that are configured for monitoring by FRET can be easily measured by using standard fluorometric detection means, such as a fluorometer. By titrating the amount of the first binding molecule or the second binding molecule, a binding curve can be generated to estimate the equilibrium binding constant.

[0188] Surface plasmon resonance (SPR) can be used to analyze the interaction of binding proteins with target antigens. SPR, or biomolecular interaction analysis (BIA), detects biospecific interactions in real time without labeling any of the interactants. A change in mass at the binding surface of the BIA chip (indicative of a binding event) results in a modulation of the refractive index of light near the surface (the optical phenomenon of SPR). The change in refractive index generates a detectable signal, which is measured as an indication of real-time reactions between biomolecules. Methods using SPR are described, for example, in U.S. Pat. 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, with online resources provided by BIAcore International AB (Uppsala, Sweden).

[0189] Information from SPR is the equilibrium dissociation constant (K D ) and kinetic parameters for binding of the binding protein to the target, e.g., K on and K. off Such data can be used to compare different biomolecules. For example, by comparing proteins selected from an expression library, those with high affinity for a target or those with slow K off This information can also be used to develop structure-activity relationships (SAR). For example, the kinetic and equilibrium binding parameters of the mature form of the parent protein can be compared to those of the parent protein. Proteins with particular binding parameters, such as high affinity and slow K offVariant amino acids at given positions that correlate with, for example, α, β ... To this end, an understanding of the physical interactions between a protein and its target can be formulated and used.

[0190] As a further example, cell assays can be used.Binding proteins can be screened for their ability to bind to cells that express and display the target of interest on the cell surface, either transiently or stably.For example, Delta1 binding proteins can be fluorescently labeled, and the binding to Delta1 in the presence or absence of antagonistic antibody can be detected by the change in fluorescence intensity using flow cytometry, e.g., FACS device.

[0191] Antigen-binding fragments of intact antibodies (full-length antibodies) can be prepared by routine methods. For example, F(ab')2 fragments can be produced by pepsin digestion of the antibody molecule and Fab fragments can be generated by reducing the disulfide bonds of the F(ab')2 fragment.

[0192] Genetically engineered antibodies, such as humanized antibodies, chimeric antibodies, single-chain antibodies, and bispecific antibodies, can be produced, for example, by conventional recombinant techniques. In one example, DNA encoding a monoclonal antibody specific to a target antigen can be easily isolated and sequenced using conventional procedures (e.g., by using an oligonucleotide probe that can specifically bind to genes encoding the heavy and light chains of a monoclonal antibody). Once isolated, the DNA can be placed into one or more expression vectors, which are then transfected into host cells that do not otherwise produce immunoglobulins, such as E. coli cells, monkey COS cells, Chinese hamster (CHO) cells, or bone marrow cells, 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 substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences, Morrison et al., (1984) Proc. Nat. Acad. Sci. 81:6851, or by covalently linking all or part of the coding sequence for a non-immunoglobulin polypeptide to an immunoglobulin coding sequence. In that manner, engineered antibodies, e.g., "chimeric" or "hybrid" antibodies, with the binding specificity of a target antigen can be prepared.

[0193] Techniques developed for the production of "chimeric antibodies" are well known in the art. See, e.g., 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.

[0194] 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 a parent non-human antibody is H and V L The variable regions of the VH1, VH2, and VH3 are subjected to three-dimensional molecular modeling analysis according to methods known in the art. Framework amino acid residues predicted to be important for the formation of the correct CDR structure are then identified using the same molecular modeling analysis. In parallel, a human VH1, VH2, and VH3 having an amino acid sequence that is homologous to the amino acid sequence of the parent non-human antibody are identified. H and V L The chain is the parent V as a search query. H and V L The sequence is then identified from any antibody gene database. H and V L The receptor gene is selected.

[0195] The CDR regions within the selected human receptor gene are used to identify the parent non-human antibody or its functional barrier. If necessary, residues in the framework regions of the parent chain predicted to be important in interactions with the CDR regions (see above) can be used to replace the corresponding residues in the human receptor gene.

[0196] Single chain antibodies can be prepared by recombinant techniques by linking the nucleotide sequence encoding the heavy chain variable region with the nucleotide sequence encoding the light chain variable region. Preferably, a flexible linker is incorporated between the two variable regions. Alternatively, the techniques described for the production of single chain antibodies (U.S. Pat. Nos. 4,946,778 and 4,704,692) can be adapted to generate phage or yeast scFv libraries, and scFv clones specific for Delta1 can be identified from the libraries according to routine procedures. Positive clones can be further screened to identify those that inhibit gamma delta T cell activity.

[0197] In some examples, any of the anti-Delta1 antibodies described herein can be the binding portion of a bispecific or trispecific antibody. In other examples, any of the anti-Delta1 antibodies can be used to construct a chimeric antigen receptor (CAR) that can be expressed on immune cells such as T cells. Any bispecific antibody or CAR-T cell that includes an anti-Delta1 antibody is also within the scope of the present disclosure.

[0198] The antibodies obtained according to the methods known in the art and described herein 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". For mapping and characterizing the location of epitopes on proteins, see, for example, Chapter 11 of Harlow and Lane, Using Antibodies, a Laboratory Manual, These include solving the crystal structure of an antibody-antigen complex, competitive assays, gene fragment expression assays, and synthetic peptide-based assays, as described in Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. In a further example, epitope mapping can be used to identify sequences to which an antibody binds. The epitope can be a linear epitope, i.e., an epitope contained in a single stretch of amino acids, or a conformational epitope formed by three-dimensional interactions of amino acids that are not necessarily contained in a single stretch of amino acids (primary structure linear sequence). Peptides of various lengths (e.g., at least 4-6 amino acids long) can be isolated or synthesized (e.g., recombinantly) and used in binding assays with the antibody. In another example, the epitope to which the antibody binds can be determined in a systematic screen by using overlapping peptides derived from the target antigen sequence and determining binding by the antibody. According to gene fragment expression assay, the open reading frame encoding the target antigen is fragmented randomly or by specific genetic construction, and the reactivity of the expressed antigen fragments with the antibody to be tested is determined. The gene fragments can be generated, for example, by PCR, and then transcribed and translated into proteins in vitro in the presence of radioactive amino acids. The binding of the antigen to the radioactively labeled antigen fragments is then determined by immunoprecipitation and gel electrophoresis. A particular epitope can also be identified by using a large library of random peptide sequences displayed on the surface of phage particles (phage libraries). Alternatively, a defined library of overlapping peptide fragments can be tested for binding to the test antibody in a single binding assay. In a further example, the binding of the antigen-binding domain to the antigen-binding domain can be determined by immunoprecipitation and gel electrophoresis. Mutagenesis, domain swapping experiments, and alanine scanning mutagenesis can be performed to identify the sufficient and / or necessary residues required for epitope binding.For example, domain swapping experiments can be performed using mutants of target antigens in which various fragments of Delta1 polypeptide are replaced with sequences from closely related but antigenically distinct proteins (e.g., other members of the β-galactoside-binding soluble lectin family).The importance of specific antigen fragments to antibody binding can be evaluated by evaluating the binding of the antibody to the mutant Delta1.

[0199] Alternatively, one can determine whether an antibody binds to the same epitope as another antibody by performing a competition assay using another antibody known to bind to the same antigen. Competition assays are well known to those of skill in the art.

[0200] In some instances, the anti-Delta1 antibodies are prepared by recombinant techniques, as exemplified below.

[0201] The nucleic acids encoding the heavy and light chains of the anti-Delta1 antibody described herein can be cloned into one expression vector, in which each nucleotide sequence is operably linked to a suitable promoter. In one example, each nucleotide sequence encoding the heavy and light chains is operably linked to a different promoter. Alternatively, the nucleotide sequences encoding the heavy and light chains are 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 encoding sequences.

[0202] In some examples, the nucleotide sequences encoding the two chains of the antibody are cloned into two vectors, which can be introduced into the same cell or different cells. When the two chains are expressed in different cells, each of them can be isolated from the host cell that expresses it, and the isolated heavy and light chains can be mixed and incubated under suitable conditions to allow the formation of the antibody.

[0203] Generally, the nucleic acid sequence encoding one or all chains of the antibody can be cloned into a suitable expression vector operably linked to a suitable promoter using methods known in the art. For example, the nucleotide sequence and the vector can be contacted with a restriction enzyme under suitable conditions to create complementary ends on each molecule that can pair with each other and be linked together by a ligase. Alternatively, synthetic nucleic acid linkers can be ligated to the ends of the gene. These synthetic linkers contain nucleic acid sequences that correspond to specific restriction sites in the vector. The choice of expression vector / promoter will depend on the type of host cell used in the production of the antibody.

[0204] A variety of promoters can be used for expression of the antibodies described herein, including, but not limited to, the cytomegalovirus (CMV) intermediate early promoter, viral LTRs, such as avian sarcoma virus LTR, HIV-LTR, HTLV-1 LTR, simian virus 40 (SV40) early promoter, E. coli lac UV5 promoter, and herpes simplex tk virus promoter.

[0205] Regulatable promoters may also be used, including those that are capable of regulating transcription from mammalian cell promoters carrying the lac operator. These include those that use the lac repressor from E. coli as a transcriptional modulator [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.

[0206] Regulatable promoters containing repressors with operons can be used. In one embodiment, the lac repressor from E. coli can function as a transcriptional modulator to regulate transcription from a lac operator-bearing mammalian cell promoter combining a tetracycline repressor (tetR) with a transcriptional activator (VP 16) to create a tetR-mammalian cell transcriptional activator fusion protein tTa (tetR-VP 16) using a tetO-bearing minimal promoter from the human cytomegalovirus (hCMV) major intermediate-early promoter to create a tetR-tet operator system to control gene expression in mammalian cells [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)]. In one embodiment, a tetracycline-inducible switch is used. When a tetracycline operator is appropriately positioned downstream to the TATA element of the CMVIE promoter, the tetracycline repressor (tetR) alone, rather than a tetR-mammalian cell transcription factor fusion derivative, can function as a potent trans-modulator of gene expression in mammalian cells (Yao et al., Human Gene Therapy, 10(16):1392-1399 (2003)). One particular advantage of this tetracycline-inducible switch is that it does not require the use of tetracycline repressor-mammalian cell transactivator or repressor fusion proteins, which in some cases may be toxic to cells, to achieve its tunable effect (Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992); Shockett et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)).

[0207] In addition, the vector may contain, for example, some or all of the following: a selectable marker gene, such as the neomycin gene for selection of stable or transient transfectants in mammalian cells; an enhancer / promoter sequence from the intermediate-early gene of human CMV for high levels of transcription; transcription termination and RNA processing signals from SV40 for mRNA stability; an SV40 polyoma origin of replication and ColE1 for proper episomal replication; internal ribosome binding sites (IRESes), a versatile multiple cloning site; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Suitable vectors and methods for making vectors containing transgenes are well known and available in the art.

[0208] Examples of polyadenylation signals useful for carrying out the methods described herein include: These include, but are not limited to, the human collagen I polyadenylation signal, the human collagen II polyadenylation signal, and the SV40 polyadenylation signal.

[0209] One or more vectors (e.g., expression vectors) containing a nucleic acid encoding any of the antibodies can be introduced into a suitable host cell for producing the antibody. The host cells can be cultured under suitable conditions for expression of the antibody or any polypeptide chains thereof. Such antibodies or polypeptide chains thereof can be recovered by the cultured cells (e.g., from the cells or culture supernatant) by conventional methods, such as, for example, affinity purification. If necessary, the polypeptide chains of the antibody can be incubated under suitable conditions for a suitable period of time to allow production of the antibody.

[0210] In some embodiments, the method for preparing the antibody described herein involves a recombinant expression vector encoding both the heavy and light chains of the anti-Delta1 antibody, as also described herein. The recombinant expression vector can be introduced into a suitable host cell (e.g., dhfr-CHO cell) by conventional methods, such as calcium phosphate-mediated transfection. Positively transformant host cells can be selected and cultured under suitable conditions that allow the expression of the two polypeptide chains that form the antibody, and the chains can be recovered from the cells or culture medium. If necessary, the two chains recovered from the host cell can be incubated under suitable conditions that allow the formation of the antibody.

[0211] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of an anti-delta 1 antibody and the other encoding the light chain of an anti-delta 1 antibody. Both of the two recombinant expression vectors can be introduced into a suitable host cell (e.g., dhfr-CHO cell) by conventional methods, such as calcium phosphate-mediated transfection. Alternatively, each of the expression vectors can be introduced into a suitable host cell. Positive transformants can be selected and cultured under suitable conditions that allow the expression of the polypeptide chains of the antibody. If the two expression vectors are introduced into the same host cell, the antibody produced therein can be recovered from the host cell or culture medium. If necessary, the polypeptide chains can be recovered from the host cell or culture medium and then incubated under suitable conditions that allow the formation of the antibody. If the two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cell or the corresponding culture medium. The two polypeptide chains can then be incubated under suitable conditions for the formation of the antibody.

[0212] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells, and recover the antibody from the culture medium. For example, some antibodies can be isolated by affinity chromatography with protein A or protein G bound to a matrix.

[0213] Any of the nucleic acids encoding the heavy chain, light chain, or both, of the anti-Delta1 antibodies described herein, vectors containing them (e.g., expression vectors), and host cells containing the vectors are within the scope of the present disclosure.

[0214] Thus, the prepared anti-Delta1 antibodies can be characterized using methods known in the art to detect and / or measure the reduction, enhancement, or neutralization of γδ T cell biological activity. For example, ELISA-type assays can be suitable for qualitative or quantitative measurement of γδ T cell inhibition or lack thereof of αβ T cell activation.

[0215] The biological activity of an anti-Delta1 antibody can be verified by incubating a 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 a solid tumor; (c) blocking or reduction of γδ T cell activation; and (d) inhibition (reduction) of the synthesis, production, or release of γδ T cells, (e) reduction or depletion of γδ T cell levels.

[0216] Thus, in one aspect, the disclosure provides an isolated nucleic acid or set of nucleic acids that encode or collectively encode any of the anti-delta 1 antibodies described herein. In some cases, the heavy and light chains of the antibody are encoded by two separate nucleic acid molecules (sets of nucleic acids). In other examples, the heavy and light chains of the antibody are encoded by one nucleic acid molecule that may be in a multicistronic format or under the control of different promoters. Thus, in one aspect, the disclosure provides an isolated nucleic acid molecule that includes one or more nucleic acid sequences that encode the heavy chain variable region (VH) and / or light chain variable region (VL) of the anti-delta 1 antibody described herein. In some embodiments, the nucleic acid molecule includes one or more nucleic acid sequences that encode the heavy chain variable region (VH) of the anti-delta 1 antibody described herein. Alternatively, or in addition, in some embodiments, the nucleic acid molecule includes one or more nucleic acid sequences that encode the light chain variable region (VL) of the anti-delta 1 antibody described herein.

[0217] In some embodiments, the isolated nucleic acid encodes an antibody that binds to Delta1 independent of the gamma chain. In some of the 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 antigen-binding fragment thereof. In some of the 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 of the 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 of the 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, e.g., an IgG1 molecule. In some of the 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 HC constant region set forth as SEQ ID NO:31 and / or the light chain constant region set forth as SEQ ID NO:71.

[0218] 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 a gamma / delta T cell receptor, wherein the antibody has a heavy chain complementarity determining region 1 (CDR) set forth in a sequence selected from SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementarity determining region 2 (CDR) set forth as SEQ ID NO: 53, and a light chain complementarity determining region 3 (CDR) set forth in a sequence selected from SEQ ID NOs: 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementarity determining region 4 (CDR) set forth as SEQ ID NO: 53, and a light chain complementarity determining region 5 (CDR) set forth in a sequence selected from SEQ ID NOs: 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a light chain complementarity determining region 5 (CDR) set forth as SEQ ID NO: 53, and a light chain complementarity determining region 6 (CDR) set forth in a sequence selected from SEQ ID NOs: 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, and / or comprises a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56 or 58, and a light chain complementarity determining region 3 (CDR3) set forth in a sequence selected from SEQ ID NOs:83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60.

[0219] In some embodiments, the isolated nucleic acid encodes 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 a gamma / delta T cell receptor. One or more nucleic acid sequences to be loaded 、 wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) 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 complementarity determining region 2 (CDR2) set forth as SEQ ID NO: 53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO: 54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO: 55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO: 56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO: 57.

[0220] 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 a gamma / delta T cell receptor, wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:57.

[0221] In some of the nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding an antibody VH comprising a VH and / or VL selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and / or a VL selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some of the nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding an antibody VH comprising a VH and / or VL selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45 and / or a VL set forth in SEQ ID NO: 9.

[0222] In some of the nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding an antibody VH and / or VL comprising the VH and / or VL set forth as SEQ ID NO:24 and / or the VL set forth as SEQ ID NO:9. In some of the nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding an antibody VH and / or VL comprising the VH and / or VL set forth as SEQ ID NO:55 and / or the VL set forth as SEQ ID NO:54.

[0223] In some embodiments, the one or more nucleic acid sequences encode the VH and / or VL of an antibody comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:9, and a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as 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 set forth as SEQ ID NO:79 and a light chain set forth as SEQ ID NO:78. In some embodiments, the one or more nucleic acid sequences encode the VH and / or VL of Delta 1-39.

[0224] In some embodiments, the isolated nucleic acid comprises one or more nucleic acid sequences encoding a heavy and / or light chain of an antibody that binds to the delta 1 chain of a gamma / delta T cell receptor, wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth in a sequence selected from SEQ ID NOs: 52, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, and 72, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO: 53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO: 54. and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO: 55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO: 56 or 58, and a light chain complementarity determining region 3 (CDR3) set forth in a sequence selected from SEQ ID NOs: 83, 84, 85, 86, 87, 57, 88, 89, 90, 91, 92, 59, and 60.

[0225] 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 delta 1 chain of a gamma / delta T cell receptor. 、wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) 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 complementarity determining region 2 (CDR2) set forth as SEQ ID NO: 53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO: 54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO: 55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO: 56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO: 57.

[0226] 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 delta 1 chain of a gamma / delta T cell receptor, wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:57. In some of the nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding an antibody heavy chain comprising a VH and / or VL selected from SEQ ID NOs: 3, 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and / or a light chain selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 2, 16, and 9. In some of the nucleic acid embodiments described herein, the nucleic acid molecule comprises one or more nucleic acid sequences encoding an antibody heavy chain comprising a VH and / or VL selected from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, 24, 25, 43, 44, and 45, and / or a light chain set forth in SEQ ID NO: 9.

[0227] In some of the 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 a VH and / or VL set forth as SEQ ID NO:24 and / or a VL set forth as SEQ ID NO:9. In some of the 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 a VH and / or VL set forth as SEQ ID NO:55 and / or a VL set forth as SEQ ID NO:54.

[0228] In some embodiments, the one or more nucleic acid sequences encode the heavy and / or light chains of an antibody comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:9, and a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as 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 set forth as SEQ ID NO:79 and a light chain set forth as 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.

[0229] Any of the isolated nucleic acids described herein are suitable for cloning into a vector. In some embodiments, the vector is an expression vector. In 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 a gamma / delta T cell receptor, where the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:57. In some embodiments, the vector comprises an isolated nucleic acid encoding a VH. In some embodiments, the vector comprises an isolated nucleic acid encoding a VL. In some embodiments, the vector comprises an isolated nucleic acid encoding both a VL and a VH. Additionally, compositions comprising any of the isolated nucleic acids or vectors described herein, including but not limited to, the vectors or nucleic acids described in this paragraph, are also contemplated in this disclosure. Additionally, host cells comprising any of the isolated nucleic acids or vectors described herein, including but not limited to, the vectors or nucleic acids described in this paragraph, are also contemplated in this disclosure. In some embodiments, the host cells are selected from the group consisting of E. coli cells, monkey COS cells, Chinese hamster (CHO) cells, or bone marrow cells.

[0230] Also provided herein is a method for producing an antibody or antigen-binding fragment thereof described herein that binds to human Delta-1, comprising expressing in a host cell one or more nucleic acid molecules described herein (such as, but not limited to, those described in the previous paragraph), 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 a host cell under conditions that allow expression of an anti-Delta1 antibody; and (ii) recovering the resulting anti-Delta1 antibody from the cell culture. Antibodies produced by such methods are also contemplated.

[0231] Pharmaceutical compositions and uses thereof The present disclosure provides pharmaceutical compositions comprising the anti-Delta1 antibodies described herein and their use for inhibiting γδ1 T cell-mediated signaling or activity and / or eliminating Delta1 positive cells. Such antibodies can be used to treat diseases associated with activated γδ1 T cells or to determine the presence / level of γδ T cells in a biological sample.

[0232] Pharmaceutical Compositions The antibodies described herein, as well as the encoding nucleic acid or set of nucleic acids, vectors containing them, or host cells containing the vectors, can be mixed with a pharma- ceutically acceptable carrier (excipient) to form a pharmaceutical composition for use in treating the target disease. By "acceptable" it is meant that the carrier must be compatible with (and preferably capable of stabilizing) the active ingredient of the composition and be non-toxic to the subject being treated. Pharmaceutically acceptable excipients (carriers) include buffers and are well known in the art. See, for example, Remington: The See Science and Practice of Pharmacy, 20th ed. (2000), edited by Lippincott Williams and Wilkins, K. E. Hoover.

[0233] The pharmaceutical compositions used in the present methods may contain pharma- ceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions (Remington: The Science and Practice of Pharmacy, 20th Edition (2011)). 000) Lippincott Williams and Wilkins, ed. K. E. Hoover. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); polypeptides of low molecular weight (less than about 10 residues); serum albumin, gelatin, and the like. The surfactant may include proteins such as antibodies, ...

[0234] In some examples, the pharmaceutical compositions described herein can be prepared using the same or similar methods as 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 containing antibodies (or encoding nucleic acids) can be prepared by methods known in the art. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be produced by reverse phase evaporation using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes can be extruded through filters with defined pore size to obtain liposomes with the desired diameter.

[0235] The antibodies or encoding nucleic acids may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as microcapsules of hydroxymethylcellulose or gelatin, and microcapsules of poly(methyl methacrylate), respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are known in the art, see, for example, Remington, The Science and Practice of Pharmacy 20th Edition, Mack Publishing (2000).

[0236] In other examples, the pharmaceutical compositions described herein can be formulated in sustained release format.Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing antibodies, said matrices being in the form of shaped 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. Pat. 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™ (injectable microspheres made of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0237] Pharmaceutical compositions to be used for in vivo administration must be sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes. Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0238] 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 for administration by inhalation or insufflation.

[0239] For the preparation of solid compositions such as tablets, the main active ingredient can be mixed with pharmaceutical carriers, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition, thereby allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the above-described type containing 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action. For example, the tablets or pills can contain an inner dose or an outer dose of the ingredients, the outer dose being in the form of an envelope that covers the inner dose. 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 a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0240] Suitable surfactants include in particular non-ionic agents such as polyoxyethylene sorbitans (e.g. Tween® 20, 40, 60, 80, or 85), and other sorbitans (e.g. Span™ 20, 40, 60, 80, or 85). Compositions containing a surfactant conveniently contain 0.05-5% surfactant, which may be 0.1-2.5%. It will be appreciated that other ingredients may be added if required, such as mannitol or other pharma- ceutically acceptable vehicles.

[0241] Suitable emulsions can be prepared using commercially available fat emulsions such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™, and Lipiphysan™. The active ingredient may be dissolved in a premixed emulsion composition or in an emulsion formed upon mixing of oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and phospholipids (e.g., egg phospholipids, soybean oil phospholipids, or soybean lecithin) with water. It will be appreciated that other ingredients, such as glycerol or glucose, may be added to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, e.g., 5-20% oil.

[0242] The emulsion composition may be a composition prepared by mixing the antibody with Intralipid™ or its components (soybean oil, egg phospholipids, glycerol, and water).

[0243] Pharmaceutical compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as set out above. In some embodiments, The compositions may be administered by the oral or nasal respiratory route for local or systemic effect.

[0244] Compositions, preferably in sterile pharma- ceutical acceptable solvents, may be nebulized by using a gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0245] therapeutic use The present disclosure provides pharmaceutical compositions comprising at least one anti-delta1 antibody or antigen-binding fragment thereof as described herein, and uses of the compositions to inhibit and / or reduce activity mediated by γδ1 TCR expressing T cells, and / or reduce signal transduction, and / or eliminate or reduce the number of γδ1 T cells. In some embodiments, the antibodies are useful for treating diseases associated with γδ1 T cells. In some embodiments, the antibodies are useful for treating diseases associated with γδ1 T cells. Any of the anti-delta1 antibodies described herein can be used in the methods described herein. In some embodiments, the anti-delta1 antibody is selected from delta1-23, delta1-30, delta1-31, delta1-32, delta1-33, delta1-34, delta1-35, delta1-36, delta1-37, delta1-38, delta1-39, delta1-40, delta1-41, delta1-42, or delta1-43, or a combination thereof. In some embodiments, the anti-delta 1 antibody is selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a combination thereof. Non-limiting examples of such antibodies include, for example, delta 1-23. In another embodiment, the antibody is delta 1-41. In another embodiment, the antibody is delta 1-39. In some embodiments, the invention provides a method of treating cancer. In some embodiments, the present disclosure provides methods of reducing, ameliorating, or eliminating one or more symptoms associated with cancer and / or prolonging survival (disease-free, progression-free, overall).

[0246] In some embodiments, the disclosure provides a method of treating cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-Delta 1 antibody or antigen-binding fragment thereof described herein. In some embodiments, the disclosure provides a method of treating cancer in a subject, the method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an anti-Delta 1 antibody or antigen-binding fragment thereof described herein. In some embodiments, the anti-Delta 1 antibody is selected from 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, Delta 1-31, Delta 1-32, Delta 1-33, Delta 1-34, Delta 1-35, Delta 1-36, Delta 1-37, Delta 1-38, Delta 1-39, Delta 1-40, Delta 1-41, Delta 1-42, or Delta 1-43, or a combination thereof. Non-limiting examples of such antibodies include Delta 1-23. In a particular example, the anti-Delta 1 antibody is Delta 1-17 or a functional variant thereof disclosed herein. In another particular example, the anti-Delta 1 antibody is Delta 1-39 or a functional variant thereof disclosed herein. In a further particular example, the anti-Delta 1 antibody is Delta 1-41 or a functional variant thereof disclosed herein.

[0247] The present disclosure provides a method of 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-Delta 1 antibody as described herein, including but not limited to Delta 1-23, Delta 1-17, Delta 1-39, and / or Delta 1-41. In one embodiment, the antibody is Delta 1-41. In another embodiment, the antibody is Delta 1-39.

[0248] To carry out the methods disclosed herein, an effective amount of the pharmaceutical composition described herein is administered to a subject (e.g., a human) in need of treatment through a suitable route, such as intravenous administration, for example, as a bolus or as a continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, inhalation, or topical routes. Commercially available atomizers for liquid formulations, including jet atomizers and ultrasonic atomizers, are useful for administration. Liquid formulations can be directly atomized, and lyophilized powders can be atomized after reconstitution. Alternatively, the anti-Delta 1 antibodies described herein can be aerosolized using fluorocarbon formulations and metered dose inhalers, or inhaled as lyophilized and milled powders.

[0249] 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, sport animals, pets, primates, horses, dogs, cats, mice, and rats.The human subject in need of treatment may be a human patient who is at risk of or suspected of having a target disease / disorder, such as a solid tumor.

[0250] In some embodiments, the cancer is adrenal gland cancer, adrenocortical carcinoma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, bone cancer (e.g., Ewing's sarcoma tumor, osteosarcoma, malignant fibrous histiocytoma), brain cancer (e.g., astrocytoma, brain stem glioma, craniopharyngioma, ependymoma), bronchial tumor, cholangiocarcinoma, cholangiosarcoma, central nervous system tumor, breast cancer, Castleman's disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, Cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, genitourinary cancer, gestational trophoblastic disease, cardiac cancer, Kaposi's sarcoma, renal 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, Burkitt's lymphoma, skin cancer, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cancer, paranasal sinus cancer, pancreatic ductal adenocarcinoma (PDA), nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, liposarcoma, lipomyosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (e.g. In some embodiments, the cancer is selected from acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, and hematologic malignancies, including myeloproliferative neoplasms such as essential thrombocytosis, polycythemia vera, myelofibrosis, and myeloproliferative neoplasms such as essential thrombocythemia, polycythemia vera, and myelofibrosis.In some embodiments, associated symptoms 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 sores, nausea, pain, peripheral neuropathy, tooth decay, urinary tract infection, and / or memory and concentration problems.The method may include 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, a pharmaceutical. Administering a composition, such as one or more of the anti-Delta 1 antibodies described herein, including but not limited to antibody Delta 1-23, to a subject reduces cell proliferation, tumor growth, and / or tumor volume, or reduces the number of metastatic lesions over time in the subject. In some embodiments, administering the composition results in a complete response, a partial response, or stabilization of the disease.

[0251] 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, gastric, colorectal, pancreatic, bile duct (cholangiocarcinoma), and hepatobiliary carcinoma), squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer (carcinoid and pancreatic neuroendocrine tumors), adrenal cortical carcinoma, and sarcoma. Hematological malignancies include acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms such as essential thrombocythemia, polycythemia vera, and myelofibrosis. Subjects with solid tumors or hematological malignancies can be identified by routine medical tests, e.g., laboratory tests, imaging procedures associated with organ function tests. In some embodiments, the subject to be treated by the methods described herein may be a human cancer patient who has undergone or is a subject to anti-cancer therapy, e.g., chemotherapy, radiation therapy, immunotherapy, cell-based therapy, surgery, or any combination thereof.

[0252] Increased numbers of γδ T cells have been found in several cancers, including but not limited to glioma, melanoma, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, neuroendocrine tumors (e.g., carcinoid tumors), breast cancer, lung cancer, ovarian cancer, rectal cancer, bladder cancer, and prostate cancer. In some cases, as described below, the percentage or number of γδ1 T cells in cancer is increased compared to non-cancer controls, and / or the percentage or number of γδ2 T cells in cancer is decreased compared to non-cancer controls. Without wishing to be bound by theory, blocking or targeting delta1 chain TCR, for example, by using or administering anti-delta1 antibodies, thereby reducing the immunosuppressive function of γδ T cells expressing delta1 TCR (γδ1 cells), may present an effective and novel therapeutic approach for the treatment of certain cancers, for example, cancers with high levels of γδ T cells. Thus, any of the anti-delta-1 antibodies disclosed herein are suitable for inhibiting immunosuppression by γδ T cells and reactivating effector T cell responses. Therefore, the anti-delta 1 antibody described herein is suitable for treating cancer, such as cancer associated with γδ T cells (e.g., cancer in which γδ T cells play a role in cancer development and progression).Therefore, a method for treating cancer is provided herein, comprising administering a therapeutically effective amount of the anti-delta 1 antibody described herein or an antigen-binding fragment thereof to a subject in need thereof. In some embodiments, the anti-delta-1 antibody administered to the subject is selected from delta 1-17, 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, delta 1-43, or a functional variant thereof disclosed herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0253] Non-limiting exemplary cancers treated by the anti-Delta1 antibodies disclosed herein are provided below.

[0254] Gliomas, tumors of the glial cells of the brain or spine, are a lethal form of brain cancer that accounts 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 infiltrative growth of tumors without borders in the brain, leaving extensive necrosis and often disrupting the blood-brain barrier. Glioblastoma (glioblastoma multiforme, GBM) is the most aggressive type of glioma. High-grade gliomas typically regrow despite complete surgical resection. Other treatments, such as radiation therapy and chemotherapy, have been used with very limited success.

[0255] Although the proportion of total γδ T cells in the peripheral blood of patients with glioma is not significantly different from that of healthy controls, it has been found that the proportion of γδ1 T cells is significantly higher, whereas the proportion of γδ2 T cells is significantly lower, in the peripheral blood of patients with glioma compared to healthy controls (Liu et al., γδ T Cells in Peripheral Blood of Glioma Patients. Med Sci Monit. 2018;24:1784-92). Without wishing to be bound by theory, blocking or targeting delta1, for example by administering an antibody that binds to delta1, thereby possibly reducing the immunosuppressive function of γδ1 cells, may present a novel therapeutic approach for the treatment of glioma.

[0256] In some embodiments, the present disclosure provides a method of treating glioma (e.g., glioblastoma) in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, e.g., selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one aspect, the antibody is delta 1-41. In another embodiment, the antibody is Delta 1-39.

[0257] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is a glioma (e.g., glioblastoma). In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0258] Melanoma is the most lethal form of skin cancer and has been increasing in incidence over the past 30 years, especially in young adults. Accumulation of mutations in α- and N-Ras is a hallmark of melanoma (Rodriguez-Cerd (Eira 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 are capable of invasion and metastasis. This is followed by:

[0259] Similar to gliomas, there is a higher frequency of Vδ1 cells in melanoma patients compared to healthy controls (Wistuba-Hamprecht et al., Eur J Cancer. 2016 Sep;64:116-26). This was found whether the patients were treated with ipilimumab or not. In contrast, the levels of γδ2 cells were lower in melanoma patients compared to healthy controls, and the levels of γδ2 cells were reduced by ipilimumab in patients with worse outcomes. In this study, a high frequency of γδ2 cells and a low frequency of γδ1 cells were associated with a favorable overall survival (OS) of melanoma patients. Without wishing to be bound by theory, blocking or targeting delta1, for example by administering an antibody that binds to delta1, and possibly reducing the immunosuppressive function of γδ1 cells, presents a novel therapeutic approach in melanoma, which may result in improved overall survival in patients, including but not limited to those treated with ipilimumab.

[0260] In some embodiments, the disclosure provides a method of treating melanoma in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or antigen-binding fragment thereof described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, e.g., selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0261] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is melanoma. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0262] Sarcomas are tumors of mesenchymal (connective) tissues and include malignant tumors of bone (e.g., osteosarcoma), cartilage (chondrosarcoma), fat (liposarcoma), muscle (e.g., leiomyosarcoma), blood vessels, and hematopoietic tissues. Sarcomas are typically treated by surgery, although chemotherapy and radiation may also be administered before and / or after surgery to improve outcome.

[0263] In some embodiments, the disclosure provides a method of treating a sarcoma in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-Delta 1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, the anti-Delta 1 antibody is any of the antibodies disclosed herein, such as 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, Delta 1-31, Delta 1-32, Delta 1-33, Delta 1-34, Delta 1-35, Delta 1-36, Delta 1-37, Delta 1-38, Delta 1-39, Delta 1-40, Delta 1-41, Delta 1-42, Delta 1-43, Delta 1-44, Delta 1-45, Delta 1-46, Delta 1-47, Delta 1-48, Delta 1-49, Delta 1-50, Delta 1-51, Delta 1-52, Delta 1-53, Delta 1-54, Delta 1-55, Delta 1-56, Delta 1-57, Delta 1-58, Delta 1-59, Delta 1-60, Delta 1-61, Delta 1-62, Delta 1-63, Delta 1-64, Delta 1-65, Delta 1-66, Delta 1-67, Delta 1-68, Delta 1-69, Delta 1-70, Delta 1-71, Delta 1-72, Delta 1-73, Delta 1-74, Delta 1-75, Delta 1-76, Delta 1-77, Delta 1-78, Delta 1-79, Delta 1-80, Delta 1-81 The antibody is one or more of an anti-Delta 1 antibody selected from Delta 1-34, Delta 1-35, Delta 1-36, Delta 1-37, Delta 1-38, Delta 1-39, Delta 1-40, Delta 1-41, Delta 1-42, or Delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is Delta 1-23. In another example, the antibody is Delta 1-17. In yet another example, the antibody is Delta 1-39. In a further example, the antibody is Delta 1-41.

[0264] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is a sarcoma. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0265] Gastrointestinal (GI) cancers include, but are not limited to, esophageal cancer, stomach cancer, colorectal cancer, pancreatic cancer, bile duct cancer, and liver cancer. GI cancers represent the largest number of cancers and the largest number of cancer deaths than any other system of the body.

[0266] Esophageal cancer is the sixth most common cancer worldwide and its incidence is increasing. There are two main types of esophageal cancer, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), and the cause of this cancer is unknown, although certain risk factors have been identified, such as tobacco or alcohol use, as well as reflux, Barrett's esophagus, achalasia, Plummer-Vinson syndrome, or esophageal scarring (American Cancer Society, Esophageal Cancer, June 14, 2017). Current treatments usually include surgery, as well as chemotherapy, radiation therapy, and / or stent insertion (Short et al., Esophageal Cancer. Am Fam Physician. 2017 Jan 1;95(1):22-28).

[0267] It has been found that adhesion molecules recruit γδ1 T cells from the peripheral blood to the tumor tissue of esophageal cancer patients, as γδ1 T cells are found sequestered 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 increased levels of γδ1 T cells, blocking or targeting Delta1, for example by administering antibodies that bind to Delta1, presents a novel therapeutic approach in esophageal cancer, which could result in improved overall survival in patients.

[0268] In some embodiments, the disclosure provides a method of treating esophageal cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-Delta 1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, the anti-Delta 1 antibody is any of the antibodies disclosed herein, such as 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, Delta 1-31, Delta 1-32, Delta 1-33, Delta 1-34, Delta 1-35, Delta 1-36, Delta 1-37, Delta 1-38, Delta 1-39, Delta 1-40, Delta 1-41, Delta 1-42, Delta 1-43, Delta 1-44, Delta 1-45, Delta 1-46, Delta 1-47, Delta 1-48, Delta 1-49, Delta 1-50, Delta 1-51, Delta 1-52, Delta 1-53, Delta 1-54, Delta 1-55, Delta 1-56, Delta 1-57, Delta 1-58, Delta 1-59, Delta 1-60, Delta 1-61, Delta 1-62, Delta 1-63, Delta 1-64, Delta 1-65, Delta 1-66, Delta 1-67, Delta 1-68, Delta 1-69, Delta 1-70, Delta 1-71, Delta 1-72, Delta 1-73, Delta 1-74, Delta 1-75, Delta 1-76, Delta 1-77, Delta 1-78, Delta 1-79, Delta 1-80, Delta 1-81, The anti-delta 1 antibody is one or more selected from delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0269] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is esophageal cancer. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0270] Gastric cancer develops in the gastric epithelium and was the leading cause of cancer death until the 1980s, and is currently the third leading cause of cancer-related deaths worldwide (World Health Organization, Fact Sheets-Cancer, September 12, 2018). Factors affecting gastric cancer include Helicobacter pylori infection, smoking, diet, and genetics. There are several factors that lead to gastric cancer. One genetic risk factor for gastric cancer is a genetic defect in the CDH1 gene. In general, treatment of gastric cancer includes surgery, chemotherapy, and radiation therapy, but cure is rare. Treatment with trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor, was found to extend overall survival in patients with locally advanced or metastatic inoperable gastric cancer that overexpresses the HER2 / neu gene (Orditura et al., Treatment of gastric cancer. World J Gastroenterol. 2014 Feb 21;20(7):1635-1649). However, further anti-treatment strategies are needed to improve outcomes for gastric cancer patients.

[0271] It has been found that γδ T cells promote the progression of gastric cancer. In particular, γδ T cells are the main source of IL-17 in the tumor microenvironment, which supports angiogenesis in gastric cancer and promotes cancer growth (Wu et al., IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer. Tumour Biol. 2016 Apr;37(4):5493-501). Thus, without wishing to be bound by theory, γδ T cells are the main source of immunosuppressive cytokines in gastric cancer, presenting a novel target for immunotherapy.

[0272] In some embodiments, the disclosure provides a method of treating gastric cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-delta 1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, the anti-delta 1 antibody is an anti-delta 1 antibody or antigen-binding fragment thereof as described herein, e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1- 43, or a functional variant thereof, such as those described herein. In one example, the antibody is Delta 1-23. In another example, the antibody is Delta 1-17. In yet another example, the antibody is Delta 1-39. In a further example, the antibody is Delta 1-41.

[0273] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is gastric cancer. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0274] 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 subpopulations and favorable clinical outcomes in CRC, supporting a key role for T cell-mediated immunity in suppressing tumor progression in CRC. 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 dib-aflibercept) may be administered. Immunotherapeutic antibodies, such as but not limited to pembrolizumab and nivolumab, may also be administered. However, there is a need for additional antitumor treatments to improve patient outcomes.

[0275] The frequency of γδ1 cells was found to be high in rectal tumor tissues of rectal cancer patients and 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 was low in rectal cancer patients compared to healthy controls and negatively correlated with T stage. Tumor-infiltrating γδ1 T cells were found to have a strong inhibitory effect, and it was concluded that an imbalanced percentage of γδ1 and γδ2 T cells in rectal cancer patients would contribute to the progression of rectal cancer. Without wishing to be bound by theory, blocking or targeting delta1, for example by administering antibodies that bind delta1, and possibly reducing the inhibitory function of γδ1 cells, could present a novel therapeutic approach for CRC, thereby resulting in improved overall survival in patients.

[0276] In some embodiments, the disclosure provides a method of treating colorectal cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of an anti-delta 1 antibody or antigen-binding fragment thereof as described herein. In some embodiments, the anti-delta 1 antibody is an anti-delta 1 antibody or antigen-binding fragment thereof as described herein, e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-36. The antibody is one or more of an anti-Delta 1 antibody selected from Delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is Delta 1-23. In another example, the antibody is Delta 1-17. In yet another example, the antibody is Delta 1-39. In a further example, the antibody is Delta 1-41.

[0277] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is colorectal cancer. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0278] Pancreatic cancer, including pancreaticobiliary adenocarcinoma (PDA), accounts for nearly 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, four genes have been found to be mutated in the majority of cases: KRAS, CDKN2A, TP53, and SMAD4 (Wolfgan (G et al., CA Cancer J Clin. 2013 Sep;63(5):318-348). Treatment of pancreatic cancer typically consists of surgical resection and adjuvant therapy, and currently the median overall survival of patients with resected pancreatic cancer remains approximately 20-22 months. Thus, there is a need for additional antitumor strategies to further improve outcomes for patients with pancreatic cancer.

[0279] In human pancreaticobiliary adenocarcinoma (PDA), activated γδ T 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 γδ T cells produce high levels of tumor-promoting IL-17 in PDA (McAllister et al., Cancer Cell. 2014 May 12;25(5):621-37). Deletion of intrapancreatic γδ T cells leads to in In vivo, they significantly protect against oncogenicity and result in the influx of immunogenic Th1 and CD8+ T cells into the tumor microenvironment (TME). Without wishing to be bound by theory, pancreatic infiltrating γδ T cells promote PDA progression by inducing adaptive immune suppression, thus γδ T cells are key regulators of effector T cell activation in pancreatic cancer and a novel target for cancer immunotherapy.

[0280] In some embodiments, the disclosure provides a method of treating pancreatic cancer (e.g., PDA) in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or antigen-binding fragment thereof described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, e.g., selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0281] In some embodiments, the disclosure provides for the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is pancreatic cancer (e.g., PDA). In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0282] Cholangiocarcinoma (CCA) is an epithelial cancer that forms in the bile duct and is the most common bile duct malignancy and the second most common liver malignancy after hepatocellular carcinoma. The overall incidence of cholangiocarcinoma has gradually increased worldwide over the past 40 years. CCA is classified into three subtypes based on its anatomical location: intrahepatic cholangiocarcinoma (iCCA), perihepatic CCA (pCCA), and distal CCA (dCCA) (see, for example, 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; Vol. 15(2): 95-111). Currently, the disease is incurable and fatal unless the tumor can be completely resected at an early stage. Other treatments include adjuvant chemotherapy and radiation therapy.

[0283] In some embodiments, the present disclosure provides a method of treating cholangiocarcinoma in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or an antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, for example, selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0284] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is cholangiocarcinoma. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0285] 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 occurs most frequently in people with chronic liver disease, such as cirrhosis caused by hepatitis B or C infection. HCC is usually accompanied by a cirrhotic liver with extensive lymphocytic infiltration due to chronic viral infection. Current treatments 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 antitumor treatment strategies are needed to further improve outcomes for liver cancer patients.

[0286] It has been found that γδ T cells accumulate in liver tumors, as patients with hepatic malignancies have increased 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 may direct γδ T cells to have protective or damaging effects. γδ1 T cells were found to correlate with high necroinflammation scores in patients with Hepatitis C virus, which may be an indication of how such cells function in liver cancer (Rajoriya et al., Front Immunol.2014;5:400). Without wishing to be bound by theory, blocking certain populations of γδ T cells, for example by anti-delta1 antibodies, may present a novel therapeutic approach in liver cancer and possibly result in an increase in overall patient survival.

[0287] In some embodiments, the present disclosure provides a method for treating liver cancer in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or an antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, for example, 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0288] In some embodiments, the present disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is liver cancer. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0289] Neuroendocrine tumors (NETs) originate from neuroendocrine cells and occur most frequently in the intestine, but can also occur in the pancreas, lungs, and other areas of the body. Carcinoid tumors, slow-growing neuroendocrine tumors that arise in the chromaffin cells of the gastrointestinal and bronchopulmonary systems, are the most common type of rare but common gastrointestinal neuroendocrine tumor. There are several different types of carcinoid tumors, including bronchopulmonary, gastric, small intestinal, appendix, and colorectal carcinoid tumors. Typically, treatment includes surgical resection, hepatic chemoembolization (if applicable), and medical therapy (Pinchot et al., Carcinoid tumors. Oncologist. 2008 Dec;13(12):1255-1269). Patients have been found to respond to somatostatin analogues (Aparicio et al., Antitumor activity of somatostatin analogues in progressive metastatic neuroendocrine gastroenteropancreatic tumors. Gut. 1996;38:430-438), in addition to several chemotherapy drugs (Maroun et al., J Curr Oncol. 2006 Apr;13(2):67-76) and a limited number of small molecule inhibitors. However, additional antitumor strategies are needed to improve outcomes for patients with NETs and carcinoid tumors.

[0290] In some embodiments, the disclosure provides a method of treating a neuroendocrine tumor (e.g., a carcinoid tumor) in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, e.g., selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0291] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is a neuroendocrine tumor (e.g., a carcinoid tumor). In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0292] 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 frequent type of cancer in women. Depending on the severity of the cancer, treatment may include surgery, chemotherapy, hormonal therapy (e.g., hormone blocking therapy, selective estrogen receptor modulators, aromatase inhibitors), and / or radiation. However, additional antitumor strategies are needed to improve outcomes for patients with NETs and carcinoid tumors.

[0293] γδ1 cells were found to be the predominant tumor-infiltrating T cells in tumor tissue from patients with breast cancer compared to normal controls (Peng et al., Tumor-infiltrating T cells, 2014). g 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 levels of γδ2 cells were lower in breast cancer patients compared to healthy controls. Further studies looking specifically at triple-negative breast cancer found an increased number of γδT cells compared to levels in normal breast tissue (Hidalgo et al., Histological analysis of γδ T lymphocytes infiltrating human triple-negative breast carcinomas.Front Immunol.2014;5:632). Indeed, the γδ1T cell subtype was found to promote tumor growth and extend its immunosuppressive effect (Morrow et al., The role of gamma delta T lymphocytes in breast cancer:a review.Transl Res.2019 Jan;203:88-96). Without wishing to be bound by theory, blocking or targeting Delta1, for example by administering antibodies that bind to Delta1, and possibly reducing the immunosuppressive effect of γδ1 T cells in breast cancer, may represent a novel therapeutic approach in breast cancer, thereby resulting in improved overall survival in patients.

[0294] In some embodiments, the disclosure provides a method of treating breast cancer in a subject, the method comprising administering an effective amount of an anti-delta 1 antibody or an antigen-binding fragment thereof as described herein to a subject in need thereof. In some embodiments, the anti-delta 1 antibody is one or more of the anti-delta 1 antibodies disclosed herein, for example, selected from 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or a functional variant thereof, such as those described herein. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0295] In some embodiments, the disclosure provides the use of an anti-delta 1 antibody as a medicament for the treatment of cancer, wherein the anti-delta 1 antibody is selected from any one or more of the antibodies described herein (e.g., 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, or delta 1-43, or functional variants thereof, such as those described herein), and the cancer is breast cancer. In one example, the antibody is delta 1-23. In another example, the antibody is delta 1-17. In yet another example, the antibody is delta 1-39. In a further example, the antibody is delta 1-41.

[0296] 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. Mutations in the Kras proto-oncogene have been implicated in approximately 30% of cancers, while c-MET, NKX2-1, LIB1, PIK3CA, and BRAF have also been implicated (Herbst et al., Lung cancer.NE ng J Med. 2008, Vol. 359 (No. 13): pp. 1367-80). Treatment of lung c...

Claims

1. 1. An isolated antibody that binds to the delta-1 chain of a T cell receptor, comprising: (i) a heavy chain variable region (V) comprising HC CDR1, HC CDR2, and HC CDR3; Ｈ and wherein the HC CDR1 is FTX １ X ２ X ３ X ４ X ５ IH (SEQ ID NO: 46), １ is F or V, and X ２ is S or T, and X ３ is G, A, or S, and X ４ is T, N, or S, and X ５ is D or S, the HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO:53), and the HC CDR3 comprises PGX ６ YYWYYSGSAYEGYGLDY (SEQ ID NO: 48), ６ The V includes S or M. Ｈ and / or (ii) a light chain variable region (V) comprising LC CDR1, LC CDR2, and LC CDR3; Ｌ wherein the LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55) and the LC CDR2 comprises X ７ ASSLX ８ S (SEQ ID NO:50), ７ is S or A, and X ８ is Y or Q, and the LC CDR3 is QQX ９ X １０ X １１ X １２ X １３ X １４ LIT (SEQ ID NO:51), ９ is S or Q, and X １０ is G, S, or T, and X １１ is D, K, or S, and X １２ is Y, W, or absent, and X １３ is P or absent and X １４ is D, F, or Y. Ｌ Including, does not contain the same heavy and light chain CDRs as Delta 1-17; Isolated antibodies.

2. the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively contain no more than 10 amino acid changes compared to the HC CDRs of a reference antibody, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody 2. The isolated antibody of claim 1, wherein CDR3 collectively contains no more than 8 amino acid changes compared to the light chain CDRs of said reference antibody, and said reference antibody is 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

3. 3. The isolated antibody of claim 1 or claim 2, wherein the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively share at least 90% sequence identity to the heavy chain CDRs of the reference antibody, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody collectively share at least 80% sequence identity to the light chain CDRs of the reference antibody.

4. The V of the reference antibody Ｈ The V Ｈ and / or the V of the reference antibody Ｌ The V Ｌ The isolated antibody of any one of claims 1 to 3, comprising:

5. The isolated antibody of any one of claims 2 to 4, comprising the same heavy chain complementarity determining region and / or the same light chain complementarity determining region as the reference antibody.

6. The isolated antibody of claim 5, comprising the same heavy chain variable region and the same light chain variable region as the reference antibody.

7. The HC CDR1, the HC CDR2, and the HC CDR3 of the antibody are collectively represented by delta 1-18, delta 1-19, delta 1-20, delta 1-21, delta 1 and / or the LC CDR1, LC CDR2, and LC CDR3 of said antibody are selected from the group consisting of: delta 1-22, delta 1-23, delta 1-24, delta 1-25, delta 1-26, delta 1-27, delta 1-28, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

2. The isolated antibody of claim 1, wherein the CDR3 collectively contains no more than 8 amino acid changes compared to the light chain CDRs of an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

8. the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively share at least 90% sequence identity to the heavy chain CDRs of an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43; and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody share at least 90% sequence identity to the heavy chain CDRs of an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

8. The isolated antibody of claim 7, wherein the CDR3s collectively share at least 80% sequence identity to the light chain CDRs of an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

9. V of an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43. Ｈ The V Ｈ , and / or the V of an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43. Ｌ The V Ｌ 9. The isolated antibody of claim 7 or claim 8, comprising:

10. The antibody has the same heavy chain complementarity determining region and / or the same light chain complementarity determining region as an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43. The isolated antibody of any one of claims 7 to 9, comprising

11. 6. The isolated antibody of claim 5, comprising the same heavy chain variable region and the same light chain variable region as an antibody 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, delta 1-31, delta 1-32, delta 1-33, delta 1-34, delta 1-35, delta 1-36, delta 1-37, delta 1-38, delta 1-39, delta 1-40, delta 1-41, delta 1-42, and delta 1-43.

12. (i) a heavy chain variable region (VH) comprising HC CDR1, HC CDR2, and HC CDR3, wherein the HC CDR1 is FTFX １ X ２ X ３ X ４ IH (SEQ ID NO: 94) motif, １ is S or T, and X ２ is S or A, and X ３ is N or S, and X ４ is D or S, the HC CDR2 comprises SIYSSSGYTYYADSVKG (SEQ ID NO:53), and the HC CDR3 comprises DPGSYYWYYSGSAYEGYGLDY (SEQ ID NO:54), and / or (ii) a light chain variable region (VL) comprising a LC CDR1, a LC CDR2, and a LC CDR3, wherein the LC CDR1 comprises RASQSVSSAVA (SEQ ID NO:55), the LC CDR2 comprises AASSLQS (SEQ ID NO:56), and the LC CDR3 comprises QQQSKYPFLIT (SEQ ID NO:51).

13. 13. The isolated antibody of claim 12, wherein the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody, collectively, contain no more than 10 amino acid changes compared to the HC CDRs of a reference antibody, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody, collectively, contain no more than 8 amino acid changes compared to the light chain CDRs of the reference antibody, and the reference antibody is selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

14. 14. The isolated antibody of claim 12 or claim 13, wherein the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively share at least 90% sequence identity to the heavy chain CDRs of the reference antibody, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody collectively share at least 80% sequence identity to the light chain CDRs of the reference antibody.

15. The V of the reference antibody Ｈ The V Ｈ and / or the V of the reference antibody Ｌ The V Ｌ The isolated antibody of any one of claims 12 to 14, comprising:

16. The isolated antibody of any one of claims 12 to 15, comprising the same heavy chain complementarity determining region and / or the same light chain complementarity determining region as the reference antibody.

17. The isolated antibody of claim 16, comprising the same heavy chain variable region and the same light chain variable region as the reference antibody.

18. the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively contain no more than 10 amino acid changes compared to the HC CDRs of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41; and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody contain no more than 10 amino acid changes compared to the HC CDRs of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

2. The isolated antibody of claim 1, wherein the CDR3s collectively contain no more than 8 amino acid changes compared to the light chain CDRs of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

19. 20. The isolated antibody of claim 18, wherein the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively share at least 90% sequence identity 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, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody collectively share at least 80% sequence identity to the light chain CDRs of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, delta 1-41, and delta 1-42.

20. V of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41 Ｈ The V Ｈ and / or the V of an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41. Ｌ The V Ｌ 20. The isolated antibody of claim 18 or claim 19, comprising:

21. 21. The isolated antibody of any one of claims 18 to 20, comprising the same heavy chain complementarity determining regions and / or the same light chain complementarity determining regions as an antibody selected from the group consisting of delta 1-38, delta 1-39, delta 1-40, and delta 1-41.

22. 22. The isolated antibody of claim 21, comprising the same heavy chain variable region and the same light chain variable region as an antibody selected from the group consisting of Delta 1-38, Delta 1-39, Delta 1-40, and Delta 1-41.

23. 23. The isolated antibody of any of claims 1-22, wherein the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively contain no more than 10 amino acid changes compared to the HC CDRs of Delta 1-39, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody collectively contain no more than 8 amino acid changes compared to the light chain CDRs of Delta 1-39.

24. the HC CDR1, the HC CDR2, and the HC CDR3 of the antibody collectively share at least 90% sequence identity to the heavy chain CDRs of delta 1-39, and / or the LC CDR1, the LC CDR2, and the LC CDR3 of the antibody 24. The isolated antibody of claim 23, wherein the CDR3s together share at least 80% sequence identity to the light chain CDRs of an antibody selected from the group consisting of Delta 1-39.

25. Delta 1-39 V Ｈ The V Ｈ and / or Delta 1-39 V Ｌ The V Ｌ 25. The isolated antibody of claim 23, comprising:

26. 26. The isolated antibody of any one of claims 23 to 25, comprising the same heavy chain complementarity determining region and / or the same light chain complementarity determining region as Delta 1-39.

27. 27. The isolated antibody of claim 26, comprising the same heavy chain variable region and the same light chain variable region as an antibody selected from the group consisting of Delta 1-39.

28. 28. Cross-reacting with human delta-1 chain and non-human mammalian delta-1 chain, claims 1 to 27 10. An isolated antibody according to any one of claims 1 to 9.

29. 29. The isolated antibody of claim 28, wherein said non-human mammalian delta-1 chain is a non-human primate delta-1 chain.

30. 30. The isolated antibody of claim 29, wherein the non-human primate delta-1 chain is a cynomolgus monkey delta-1 chain.

31. 31. The isolated antibody of any of claims 1-30, capable of binding to a γδ1 TCR containing multiple gamma chains.

32. 32. The isolated antibody of any one of claims 1 to 31, which is a full length antibody or an antigen-binding fragment thereof.

33. Fab, (Fab') ２ 33. The isolated antibody of claim 32, which is a single chain antibody or a single chain antibody.

34. 33. The isolated antibody of any one of claims 1 to 32, which is a human antibody or a humanized antibody.

35. The isolated antibody of claims 1-32 and 34, wherein the antibody is a full length antibody, and the full length antibody is an IgG molecule.

36. 36. The isolated antibody of claim 35, which is an IgG1 or IgG4 molecule.

37. 37. The isolated antibody of claim 36, which is an IgG1 molecule.

38. 38. The isolated antibody of claim 36 or claim 37, wherein the IgG1 has one or more mutations selected from: (1) an E333A mutation, (2) an S239D / A330L / I332E mutation, (3) a K326W / E333S mutation, or (4) an S239D / I332E / G236A mutation.

39. A pharmaceutical composition comprising any one of the antibodies of claims 1 to 38 and a pharma- ceutically acceptable carrier.

40. 2. The isolated antibody of claim 1, comprising a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:

57.

41. 41. The isolated antibody of claim 40, which cross-reacts with human delta-1 chain and with a non-human mammalian delta-1 chain.

42. 42. The isolated antibody of claim 41, wherein said non-human mammalian delta-1 chain is a non-human primate delta-1 chain.

43. 43. The isolated antibody of claim 42, wherein said non-human primate delta-1 chain is a cynomolgus monkey delta-1 chain.

44. 31. The isolated antibody of any one of claims 1 to 30, capable of binding to a γδ1 TCR containing multiple gamma chains.

45. 45. The isolated antibody of any one of claims 40 to 44, which is a full length antibody or an antigen-binding fragment thereof.

46. 46. ​​The isolated antibody of any one of claims 40 to 45, which is a human antibody or a humanized antibody.

47. 46. ​​The isolated antibody of any of claims 40-45, which is a Fab, (Fab')2, or single chain antibody.

48. 46. ​​The isolated antibody of any one of claims 40 to 45, which is an IgG molecule.

49. 49. The isolated antibody of claims 40-46 and 48, which is an IgG1 or IgG4 molecule.

50. 50. The isolated antibody of claim 49, which is an IgG1 molecule.

51. 51. The isolated antibody of claim 49 or claim 50, wherein the antibody is an IgG1 molecule, and the IgG1 has one or more mutations selected from: (1) an E333A mutation; (2) an S239D / A330L / I332E mutation; (3) a K326W / E333S mutation; or (4) an S239D / I332E / G236A mutation.

52. 51. The isolated antibody of claim 50, comprising a heavy chain constant region set forth as SEQ ID NO:31 and / or a light chain constant region set forth as SEQ ID NO:

73.

53. 53. An isolated antibody according to claim 40 or claim 52, having a VL CDR1 set forth as SEQ ID NO:55, a VL CDR2 set forth as SEQ ID NO:56, a VL CDR3 set forth as SEQ ID NO:57, a VH CDR1 set forth as SEQ ID NO:56, a VH CDR2 set forth as SEQ ID NO:53, a VH CDR3 set forth as SEQ ID NO:54, and having a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as SEQ ID NO:

73.

54. 54. The isolated antibody of any one of claims 40-46, 48-50, 52-53, comprising a heavy chain set forth as SEQ ID NO:79 and / or a light chain set forth as SEQ ID NO:

78.

55. 55. The isolated antibody of any one of claims 40 to 54, comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:

9.

56. 56. The isolated antibody of claim 55, which is a full-length antibody or an antigen-binding fragment thereof.

57. 57. The isolated antibody of claim 55 or claim 56, which is a human antibody or a humanized antibody.

58. 58. The isolated antibody of claim 57 which is a single chain antibody.

59. 58. The isolated antibody of any one of claims 55 to 57, which is an IgG molecule.

60. 60. The isolated antibody of claim 59, which is an IgG1 or IgG4 molecule.

61. 61. The isolated antibody of claim 60, which is an IgG1 molecule.

62. 62. The isolated antibody of claim 61, wherein the antibody is an IgG1 molecule, and the IgG1 has one or more mutations selected from: (1) an E333A mutation; (2) an S239D / A330L / I332E mutation; (3) a K326W / E333S mutation; or (4) an S239D / I332E / G236A mutation.

63. 62. The isolated antibody of any one of claims 55 to 61, comprising a heavy chain constant region set forth as SEQ ID NO:31 and / or a light chain constant region set forth as SEQ ID NO:

73.

64. 64. The isolated antibody of claim 63, comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:9, and having a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as SEQ ID NO:

73.

65. 65. The isolated antibody of claim 64, comprising a heavy chain set forth as SEQ ID NO:79 and a light chain set forth as SEQ ID NO:

78.

66. 66. The isolated antibody of claim 65, which is Delta 1-39.

67. 67. The isolated antibody of any one of claims 55 to 66, which cross-reacts with human delta-1 chain and with a non-human mammalian delta-1 chain.

68. 68. The isolated antibody of claim 67, wherein said non-human mammalian delta-1 chain is a non-human primate delta-1 chain.

69. 69. The isolated antibody of claim 68, wherein said non-human primate delta-1 chain is a cynomolgus monkey delta-1 chain.

70. 70. The isolated antibody of any of claims 1-69, capable of binding to a γδ1 TCR containing multiple gamma chains.

71. 7. The isolated antibody of claim 70, 70A or 70B, comprising a heavy chain set forth as SEQ ID NO:79 and a light chain set forth as SEQ ID NO:

78.

72. A pharmaceutical composition comprising any one of the antibodies of claims 1 to 71 and a pharma- ceutically acceptable carrier.

73. A pharmaceutical composition comprising the antibody of claim 1 and a pharma- ceutically acceptable carrier.

74. 41. A pharmaceutical composition comprising the antibody of claim 40 and a pharma- ceutically acceptable carrier.

75. 56. A pharmaceutical composition comprising the antibody of claim 53 or 55 and a pharma- ceutically acceptable carrier.

76. 72. A pharmaceutical composition comprising the antibody of claim 71 and a pharma- ceutically acceptable carrier.

77. The heavy chain variable region (VH) and / or light chain variable region (VL) of the antibody according to any one of claims 1 to 71 An isolated nucleic acid molecule comprising one or more nucleic acid sequences encoding a chain variable region (VL).

78. 78. The isolated nucleic acid molecule of claim 77, comprising one or more nucleic acid sequences encoding the heavy chain variable region (VH) of an antibody of any one of claims 1 to 62.

79. 78. The isolated nucleic acid molecule of claim 77, comprising one or more nucleic acid sequences encoding the light chain variable region (VL) of an antibody of any one of claims 1 to 62.

80. 78. The isolated nucleic acid molecule of claim 77, comprising one or more nucleic acid sequences encoding the heavy chain variable region (VH) and light chain variable region (VL) of an antibody of any one of claims 1 to 71.

81. 81. The isolated nucleic acid molecule of any one of claims 77 to 80, wherein said one or more nucleic acid sequences encode an antibody VH and / or VL comprising a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:

57.

82. 82. The isolated nucleic acid molecule of any one of claims 77 to 81, comprising one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising the VH set forth as SEQ ID NO:24 and / or the VL set forth as SEQ ID NO:

9.

83. The isolated nucleic acid molecule of any one of claims 77 to 82, wherein the one or more nucleic acid sequences encode the VH and / or VL of an antibody comprising a HC constant region set forth as SEQ ID NO:31 and / or a light chain constant region set forth as SEQ ID NO:

73.

84. 84. The isolated nucleic acid molecule of claim 83, wherein said one or more nucleic acid sequences encode the VH and / or VL of G9.2-17.

85. An isolated nucleic acid molecule comprising one or more nucleic acid sequences encoding the heavy chain (HC) and / or light chain (LC) of an antibody according to any one of claims 1 to 71.

86. 86. The isolated nucleic acid molecule of claim 85, comprising one or more nucleic acid sequences encoding an antibody heavy chain (HC) and / or light chain (LC), wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:

57.

87. 87. The isolated nucleic acid molecule of claim 86, comprising one or more nucleic acid sequences encoding the VH set forth as SEQ ID NO:24 and / or the VL set forth as SEQ ID NO:

3.

88. The isolated nucleic acid molecule of any one of claims 86 to 87, wherein the one or more nucleic acid sequences encode the HC and / or LC of an antibody comprising a HC constant region set forth as SEQ ID NO:31 and / or a light chain constant region set forth as SEQ ID NO:

73.

89. The isolated nucleic acid molecule of claim 88, wherein the one or more nucleic acid sequences encode an antibody HC and / or LC comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:9, as well as a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as SEQ ID NO:

73.

90. 90. The isolated nucleic acid molecule of claim 89, wherein the one or more nucleic acid sequences encode the HC and / or LC of an antibody comprising a heavy chain set forth as SEQ ID NO:79 and a light chain set forth as SEQ ID NO:

78.

91. 91. The isolated nucleic acid molecule of claim 90, wherein the one or more nucleic acid sequences encode the HC and / or LC of G9.2-17.

92. A vector comprising the isolated nucleic acid molecule of any one of claims 77 to 91.

93. 92. The vector of claim 91 which is an expression vector.

94. 94. The vector of claim 92 or claim 93, wherein the isolated nucleic acid comprises the VH.

95. 94. The vector of claim 92 or claim 93, wherein the isolated nucleic acid comprises the VL.

96. 94. The vector of claim 92 or claim 93, wherein the isolated nucleic acid comprises the VL and the VH.

97. 94. The vector of claim 92 or claim 93, wherein the isolated nucleic acid comprises the heavy chain.

98. 94. The vector of claim 92 or claim 93, wherein the isolated nucleic acid comprises the light chain.

99. 94. The vector of claim 92 or claim 93, wherein the isolated nucleic acid comprises the light chain and the heavy chain.

100. The vector of any one of claims 92 to 99, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising the HC constant region set forth as SEQ ID NO:31 and / or the light chain constant region set forth as SEQ ID NO:

73.

101. 101. The vector of any one of claims 92 to 100, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody, wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:

57.

102. The vector of any one of claims 92 to 101, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:9, and a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as SEQ ID NO:

73.

103. The vector according to any one of claims 92 to 102, wherein said nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of an antibody comprising a heavy chain set forth as SEQ ID NO:79 and a light chain set forth as SEQ ID NO:

78.

104. The vector of claim 102 or claim 103, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the VH and / or VL of G9.2-17.

105. The vector of any one of claims 92 to 104, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the HC and / or LC of an antibody comprising the HC constant region set forth as SEQ ID NO:31 and / or the light chain constant region set forth as SEQ ID NO:

73.

106. The vector of claim 104 or claim 105, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the heavy chain (HC) and / or light chain (LC) of an antibody, wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:68, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:53, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:54, and / or a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:55, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:56, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:

57.

107. The vector of any one of claims 104 to 106, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the HC and / or LC of an antibody comprising a VH set forth as SEQ ID NO:24 and a VL set forth as SEQ ID NO:9, and a heavy chain constant region set forth as SEQ ID NO:31 and a light chain constant region set forth as SEQ ID NO:

73.

108. The vector of any one of claims 104 to 107, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the HC and / or LC of an antibody comprising a heavy chain set forth as SEQ ID NO:79 and a light chain set forth as SEQ ID NO:

78.

109. The vector of any one of claims 104 to 108, wherein the nucleic acid molecule comprises one or more nucleic acid sequences encoding the HC and / or LC of G9.2-17.

110. A composition comprising the vector according to any one of claims 92 to 109.

111. A host cell comprising the vector according to any one of claims 92 to 109.

112. 112. The host cell of claim 111, selected from the group consisting of an E. coli cell, a simian COS cell, a Chinese hamster ovary (CHO) cell, or a myeloma cell.

113. 80. A method of inhibiting γδ T cell activation in a subject, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of claims 62-77.

114. 80. A method of inhibiting γδ T cell activation in a subject, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of claims 74-76.

115. A method of inhibiting γδ T cell activation in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Delta 1-39.

116. 110. A method for inhibiting γδ T cell activation in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the isolated nucleic acid and / or vector of any one of claims 77-109.

117. 117. The method of any one of claims 113-116, wherein the subject in need thereof is a human patient having, suspected of having, or at risk of having a solid cancer.

118. The method of claim 117, wherein the subject is a human patient having a solid tumor selected from the group consisting of pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, upper and lower gastrointestinal malignancies, squamous cell head and neck cancer, genitourinary cancer, ovarian cancer, and sarcoma.

119. 119. The method of any one of claims 113-118, further comprising administering to the subject an inhibitor of a checkpoint molecule, an activator of a costimulatory receptor, an inhibitor of an innate immune cell target, a chemotherapeutic agent, or an antihypertensive agent.

120. 120. The method of claim 119, wherein 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.

121. 120. The method of claim 119, wherein the costimulatory receptor is selected from the group consisting of OX40, GITR, CD137, CD40, CD27, and ICOS.

122. 120. The method of claim 119, wherein the innate immune cell target is selected from the group consisting of KIR, NKG2A, CD96, TLR, IDO, and Galectin-9.

123. The method of any one of claims 113-122, wherein said effective amount of said pharmaceutical composition is sufficient to block activation of γδ T cells in said subject.

124. 121. The method of claim 120, wherein the checkpoint molecule is PD-1 and the human patient has skin cancer.

125. 125. The method of claim 124, wherein the skin cancer is melanoma.

126. The method of claim 120, wherein the checkpoint molecule is CTLA-4 and the human patient has lung cancer.

127. 1. A method for producing an antibody specific for the delta-1 chain of a T cell receptor, comprising the steps of: (i) culturing the host cell of claim 111 or claim 112 under conditions that allow expression of the antibody; and (ii) recovering the antibody so produced from the cell culture. A method comprising:

128. A method for depleting and / or eliminating gd T cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to any one of claims 62 to 77.

129. A method for depleting and / or eliminating gd T cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to any one of claims 74 to 76. and

130. A method for depleting and / or eliminating gd T cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Delta 1-39.

131. A method for depleting and / or eliminating gd T cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the isolated nucleic acid and / or vector of any one of claims 77 to 109.

132. The method of claim 131 , wherein the subject in need thereof is a human patient having, suspected of having, or at risk of having a solid cancer.

133. The method of claim 132, wherein the subject is a human patient having a solid tumor selected from the group consisting of pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, upper and lower gastrointestinal malignancies, squamous cell head and neck cancer, genitourinary cancer, ovarian cancer, and sarcoma.

134. 134. The method of any one of claims 131-133, further comprising administering to the subject an inhibitor of a checkpoint molecule, an activator of a costimulatory receptor, an inhibitor of an innate immune cell target, a chemotherapeutic agent, or an antihypertensive agent.

135. 135. The method of claim 134, wherein 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.

136. 136. The method of claim 135, wherein the costimulatory receptor is selected from the group consisting of OX40, GITR, CD137, CD40, CD27, and ICOS.

137. 136. The method of claim 135, wherein the innate immune cell target is selected from the group consisting of KIR, NKG2A, CD96, TLR, IDO, and Galectin-9.

138. The method of any one of claims 128-137, wherein said effective amount of said pharmaceutical composition is sufficient to deplete and / or eliminate γδ T cells in said subject.

139. The method of claim 135, wherein the checkpoint molecule is PD-1 and the human patient has skin cancer.

140. 140. The method of claim 139, wherein the skin cancer is melanoma.

141. The method of claim 135, wherein said checkpoint molecule is CTLA-4 and said human patient has lung cancer.

142. 1. A method of identifying or selecting, and optionally treating, a cancer patient, comprising: (i) preparing a blood sample from a subject in need thereof; (ii) measuring the level of Delta 1 in said blood sample; and (iii) identifying the subject as having or at risk for cancer based on the level of Delta 1 in the blood sample, wherein an elevated level of Delta 1 in the blood sample of the subject compared to a control indicates that the subject has the cancer or is at risk for the cancer. Identifying, indicative of a risk of cancer A method comprising:

143. 143. The method of claim 142, wherein the control comprises a blood sample from a subject without cancer.

144. 143. The method of claim 142, wherein the control comprises a predetermined reference value.

145. The method of claim 142 or claim 143, wherein the blood sample is a serum sample or a plasma sample.

146. The method of any one of claims 142 to 145, wherein the subject is a human subject.

147. 147. The method of any one of claims 142-146, wherein the cancer is selected from the group consisting of pancreatic cancer, non-small cell lung cancer (NSCLC), and colorectal cancer.

148. The method of any one of claims 142 to 147, wherein the level of Delta 1 is measured by immunoassay.

149. The method of any one of claims 142 to 147, wherein the immunoassay is flow cytometry.

150. The method according to any one of claims 142 to 149, wherein said immunoassay uses any of the antibodies according to claims 1 to 71.

151. The method of any one of claims 142 to 150, wherein the immunoassay is flow cytometry and uses Delta 1-39.

152. 152. The method of any one of claims 142-151, further comprising performing one or more additional diagnostic assays to confirm the presence of said cancer.

153. 153. The method of any one of claims 142-152, further comprising administering to the subject an anti-cancer therapy to treat the cancer.

154. The method of claim 153, wherein the anti-cancer therapy comprises administering to the subject an effective amount of an anti-Delta 1 antibody.

155. The method of claim 154, wherein the anti-cancer therapy comprises administering to the subject an effective amount of an anti-Delta 1 antibody of any one of claims 1 to 71.

156. 156. The method of claim 155, wherein the anti-cancer therapy comprises administering to the subject an effective amount of Delta 1-39.

157. 32. The isolated antibody of claim 31 , which binds to one or more gamma chains selected from 3, 4, 5, 8, or 9.

158. An isolated antibody described in claim 31 or claim 31A that binds to gamma chains 3, 4, 5, 8, and 9.

159. 45. The isolated antibody of claim 44, which binds to one or more gamma chains selected from 3, 4, 5, 8, or 9.

160. 45. The isolated antibody of claim 44, which binds to gamma chains 3, 4, 5, 8, and 9.

161. 71. The isolated antibody of claim 70, which binds to one or more gamma chains selected from 3, 4, 5, 8, or 9.

162. 7. The isolated antibody of claim 70 or 70A, which binds to gamma chains 3, 4, 5, 8, and 9.

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