ANTIBODIES SPECIFIC TO DELTA 1 CHAIN OF T CELL RECEPTOR
Disclosed herein are antibodies specific to a delta1 chain of a γδ T cell receptor and methods of using such for modulating γδ T cell bioactivity. Such anti-Delta1 antibodies may also be used to treat diseases associated with γδ T cell activation, such as solid tumors, or for detecting presence of γδ1 T cells.
1 . An isolated antibody that binds a delta 1 chain of a T cell receptor, wherein the antibody comprises a light chain variable domain (V L ) comprising a light chain complementarity determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein the LC CDR1 comprises SEQ ID NO: 46, the HC CDR2 comprises SEQ ID NO: 47, and the HC CDR3 comprises sequence selected from any of SEQ ID NOs: 48, 52, 56, 59, 63, 67, 70, 74 and 78.
2 . The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable domain (V H ) comprising a heavy chain CDR1 (HC CDR1), a heavy chain CDR2 (HC CDR2), and a heavy chain CDR3 (HC CDR3), wherein the HC CDR1 comprises sequence selected from any of SEQ ID NOs: 43, 49, 53, 60, and 64, the HC CDR2 comprises sequence selected from any of SEQ ID NOs: 44, 50, 54, 57, 61, 65, 68, and 72, and the HC CDR3 comprises sequence selected from any of SEQ ID NOs: 45, 51, 55, 58, 62, 66, 69, 71, 73, 75, 76, and 77.
3 . The isolated antibody of claim 1 , wherein the wherein the LC CDR1 comprises SEQ ID NO: 46, the HC CDR2 comprises SEQ ID NO: 47, and the HC CDR3 comprises SEQ ID NO: 78.
4 . The isolated antibody of claim 2 , wherein the wherein the LC CDR1 comprises SEQ ID NO: 46, the HC CDR2 comprises SEQ ID NO: 47, and the HC CDR3 comprises SEQ ID NO: 78.
5 . The isolated antibody of claim 4 , wherein the HC CDR1 comprises SEQ ID NO: 43, the HC CDR2 comprises SEQ ID NO: 57, and the HC CDR3 comprises SEQ ID NO: 77.
6 . The isolated antibody of claim 5 , wherein the V H comprises SEQ ID NO:23 and the V L comprises SEQ ID NO:24.
7 . The isolated antibody of claim 5 , wherein the antibody is Delta 1-17.
8 . An isolated antibody that binds a delta 1 chain of a T cell receptor, wherein the antibody comprises (i) a heavy chain variable domain (V H ), which comprises the same heavy chain complementary determining regions (HC CDRs) as reference antibody Delta1-17, and (ii) a light chain variable domain (V L ), which comprises the same light chain complementary determining regions (LC CDRs) as reference antibody Delta1-17, wherein antibody Delta1-17 comprises a V H set forth as SEQ ID NO:23 and a V L set forth as SEQ ID NO:24.
9 . The isolated antibody of claim 8 , wherein the antibody comprises the V H that is at least 85% identical to SEQ ID NO:23, and/or the V L that is at least 85% identical to SEQ ID NO:24.
10 . The isolated antibody of claim 6 , wherein the antibody is a full-length antibody or an antigen-binding fragment thereof.
11 . The isolated antibody of claim 10 , wherein antibody is a full-length antibody, which is an IgG molecule.
12 . The isolated antibody of claim 10 , wherein the antibody is a Fab, a (Fab′) 2 , or a single-chain antibody.
13 . The isolated antibody of claim 6 , wherein the antibody is a human antibody or a humanized antibody.
14 . A pharmaceutical composition, comprising the antibody of claim 6 and a pharmaceutically acceptable carrier.
15 . A method of inhibiting the activation of immunosuppressive γδ T cell in a subject, the method comprising administering to a subject in need thereof an effective amount of an pharmaceutical composition of claim 14 .
16 . The method of claim 15 , wherein the subject in need thereof is a human patient having, suspected of having, or at risk for, a solid cancer.
17 . The method of claim 16 , 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, glioblastoma, upper and lower gastrointestinal malignancies, squamous cell head and neck cancer, genitourinary cancer, carcinoid tumors, endometrial cancer, renal cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer, adrenocortical cancer, and sarcomas.
18 . A method of treating a solid tumor, comprising administering to a human subject in need thereof any effective amount of the pharmaceutical composition of claim 14 .
19 . The method of claim 18 , wherein the solid tumor is selected from the group consisting of pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, glioblastoma, upper and lower gastrointestinal malignancies, carcinoid tumors, squamous cell head and neck cancer, genitourinary cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, ovarian cancer, neuroendocrine cancer, adrenocortical cancer, and sarcomas.
20 . The method of claim 17 , further comprising administering to the subject an agent selected from the group consisting of: an inhibitor of a checkpoint molecule, an activator of a co-stimulatory receptor, an inhibitor of an innate immune cell target, a chemotherapeutic agent, an anti-hypertension agent, and a combination of any agents thereof.