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KR-20260062933-A - Anti-γδ TCR Antibody and Its Uses

KR20260062933AKR 20260062933 AKR20260062933 AKR 20260062933AKR-20260062933-A

Abstract

The present application provides a molecule comprising an antibody that binds to a T cell receptor (TCR). In particular, the present application provides an antibody that binds to a human γδ TCR, wherein such human γδ T cells can be activated and regulated. The present application also provides a bispecific tumor-targeted immunomodulator that simultaneously binds to a tumor-associated antigen and a γδ T cell receptor to enhance cell-mediated immune responses in cancer treatment. The present application also provides a method for producing such an antibody and a method for killing cancer cells using such an antibody.

Inventors

  • 양, 슈아이
  • 우, 슈
  • 투, 샤오지에
  • 왕,수주안
  • 종, 솅웨이
  • 슈, 첸유
  • 젱, 웬웬
  • 리, 슈
  • 가오, 퀴
  • 장, 야펭

Assignees

  • 레전드 바이오테크 유에스에이, 인크.
  • 레전드 바이오테크 아일랜드 리미티드

Dates

Publication Date
20260507
Application Date
20240827
Priority Date
20230831

Claims (20)

  1. As V H H binding to γδ TCR, The above V H H comprises a CDR1 having the amino acid sequence SEQ ID NO: 15, 19, 23, 27, 31, 35, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 85, 89, 93, 121, 125, 140, 150, 154, 158, 162, 178, 182, or 186; SEQ ID NO: CDR2 containing the amino acid sequence of 16, 20, 24, 28, 32, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 82, 86, 90, 94, 122, 126, 137, 141, 151, 155, 159, 179, 183, or 187; V H H, comprising a CDR3 containing the amino acid sequence of SEQ ID NO: 17, 21, 25, 29, 33, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 83, 87, 91, 95, 123, 127, 138, 142, 152, 156, 160, 163, 180, 184, or 188 .
  2. In paragraph 1, The above V H H each includes CDR1, CDR2, and CDR3 comprising the following amino acid sequences: (1) SEQ ID NO: 15, 16 and 17; or (2) SEQ ID NO: 19, 20 and 21; or (3) SEQ ID NO: 23, 24 and 25; or (4) SEQ ID NO: 27, 28 and 29; or (5) SEQ ID NO: 31, 32 and 33; or (6) SEQ ID NO: 35, 24 and 36; or (7) SEQ ID NO: 38, 39 and 40; or (8) SEQ ID NO: 42, 43 and 44; or (9) SEQ ID NO: 46, 47 and 48; or (10) SEQ ID NO: 50, 51 and 52; or (11) SEQ ID NO: 54, 55 and 56; or (12) SEQ ID NO: 58, 59 and 60; or (13) SEQ ID NO: 62, 63 and 64; or (14) SEQ ID NO: 66, 67 and 68; or (15) SEQ ID NO: 70, 71 and 72; or (16) SEQ ID NO: 74, 75 and 76; or (17) SEQ ID NO: 78, 79 and 80; or (18) SEQ ID NO: 46, 82 and 83; or (19) SEQ ID NO: 85, 86 and 87; or (20) SEQ ID NO: 89, 90 and 91; or (21) SEQ ID NO: 93, 94 and 95; or (22) SEQ ID NO: 121, 122 and 123; or (23) SEQ ID NO: 125, 126 and 127; or (24) SEQ ID NO: 54, 137 and 138; or (25) SEQ ID NO: 140, 141 and 142; or (26) SEQ ID NO: 150, 151 and 152; or (27) SEQ ID NO: 154, 155 and 156; or (28) SEQ ID NO: 158, 159 and 160; or (29) SEQ ID NO: 162, 59 and 163; or (30) SEQ ID NO: 178, 179 and 180; or (31) SEQ ID NO: 182, 183 and 184; or (32) SEQ ID NO: 186, 187 and 188.
  3. In paragraph 1 or 2, The above V H H comprises the amino acid sequence of SEQ ID NO: 14, 18, 22, 26, 30, 34, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 84, 88, 92, 120, 124, 136, 139, 149, 153, 157, 161, 177, 181, or 185, or an amino acid sequence having at least 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99 % sequence identity therewith.
  4. In any one of paragraphs 1 through 3, The above V H H is a humanized, V H H.
  5. In paragraph 4, The above V H H comprises the amino acid sequence of SEQ ID NO: 199, 200, 201, 202, 203, or 204, or an amino acid sequence having at least 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to this .
  6. As a polypeptide structure that binds to γδ TCR, The above polypeptide structure is a polypeptide structure comprising a V H H and an immunoglobulin Fc region according to any one of claims 1 to 5.
  7. In paragraph 6, The above immunoglobulin Fc region is a polypeptide structure in which the above immunoglobulin Fc region is an IgG Fc region such as an IgG1, IgG2, IgG3, or IgG4 Fc region.
  8. As an antibody binding to γδ TCR or an antigen-binding fragment thereof, The above antibody or its antigen-binding fragment is, a) Heavy chain variable region (VH) including the following: i) HCDR1 containing the sequence SEQ ID NO: 97, 105, 113, 129, 144, 165, 171, 190, or 209; ii) HCDR2 comprising the sequence SEQ ID NO: 98, 106, 114, 130, 145, 166, 172, 206, 191 or 210; and iii) HCDR3 containing the sequence SEQ ID NO: 99, 107, 115, 131, 146, 167, 173, 192 or 211; and/or b) Light chain variable region (VL) including the following: i) LCDR1 containing the sequence SEQ ID NO: 101, 109, 117, 133, 175, 194 or 213; ii) LCDR2 comprising the sequence SEQ ID NO: 102, 110, 118, 134, or 214; and iii) An antibody or its antigen-binding fragment comprising LCDR3 having the sequence SEQ ID NO: 103, 111, 119, 135, 148, 169, 176, 195 or 215.
  9. In paragraph 8, The above antibody or its antigen-binding fragment is, (1) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 97, 98, and 99; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 101, 102, and 103; (2) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 105, 106, and 107; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 109, 110, and 111; (3) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 113, 114, and 115; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 117, 118, and 119; (4) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 129, 130, and 131; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 133, 134, and 135; (5) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 144, 145, and 146; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 109, 110, and 148; (6) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 165, 166, and 167; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 109, 110, and 169; (7) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 171, 172, and 173; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 175, 118, and 176; (8) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 171, 206, and 173; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 175, 118, and 176; (9) HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 190, 191, and 192; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 194, 110, and 195; or (10) an antibody or its antigen-binding fragment comprising HCDR1, HCDR2, and HCDR3 each having amino acid sequences of SEQ ID NO: 209, 210, and 211; and/or LCDR1, LCDR2, and LCDR3 each having amino acid sequences of SEQ ID NO: 213, 214, and 215.
  10. In Article 8 or 9, The above antibody or its antigen-binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 96, 104, 112, 128, 143, 164, 170, 189, 205, or 208, or an amino acid sequence having at least 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to this; An antibody or its antigen-binding fragment comprising a VL comprising an amino acid sequence of SEQ ID NO: 100, 108, 116, 132, 147, 168, 174, 193, 207 or 212, or an amino acid sequence having at least 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with respect to this.
  11. In any one of paragraphs 8 through 10, The above antibody or its antigen-binding fragment is, (1) VH comprising the amino acid sequence of SEQ ID NO: 96 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 100 or an amino acid sequence having at least 80% sequence identity with it; (2) VH comprising the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 108 or an amino acid sequence having at least 80% sequence identity with it; (3) VH comprising the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 116 or an amino acid sequence having at least 80% sequence identity with it; (4) VH comprising the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 132 or an amino acid sequence having at least 80% sequence identity with it; (5) VH comprising the amino acid sequence of SEQ ID NO: 143 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 147 or an amino acid sequence having at least 80% sequence identity with it; (6) VH comprising the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 168 or an amino acid sequence having at least 80% sequence identity with it; (7) VH comprising the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 174 or an amino acid sequence having at least 80% sequence identity with it; (8) VH comprising the amino acid sequence of SEQ ID NO: 189 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 193 or an amino acid sequence having at least 80% sequence identity with it; (9) VH comprising the amino acid sequence of SEQ ID NO: 208 or an amino acid sequence having at least 80% sequence identity with it; and/or VL comprising the sequence of SEQ ID NO: 212 or an amino acid sequence having at least 80% sequence identity with it; or (10) An antibody or its antigen-binding fragment comprising a VH having the sequence of SEQ ID NO: 205 or an amino acid sequence having at least 80% sequence identity with it; and/or a VL having the sequence of SEQ ID NO: 207 or an amino acid sequence having at least 80% sequence identity with it.
  12. In any one of paragraphs 8 through 11, The above antibody or its antigen-binding fragment further comprises a heavy chain constant region (CH) comprising an amino acid sequence derived from the heavy chain constant region of human immunoglobulin; Preferably, the heavy chain invariant region is an IgG heavy chain invariant region such as an IgG1, IgG2, IgG3, or IgG4 heavy chain invariant region; Preferably, the antibody or the antigen-binding fragment thereof further comprises a light chain-constant region (CL), such as a κ light chain-constant region comprising an amino acid sequence derived from a light chain-constant region of human immunoglobulin.
  13. In any one of paragraphs 8 through 12, The above antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment selected from scFv, Fab, Fab', (Fab') 2 , Fv fragment, bispecific antibody, bispecific antibody, multispecific antibody, chimeric antibody or humanized antibody.
  14. As a multispecific molecule, The above-mentioned multispecific molecule comprises a γδ TCR binding domain and an additional binding domain, wherein the γδ TCR binding domain comprises V H H according to any one of claims 1 to 5, and the additional binding domain binds to a target other than the γδ TCR; preferably, the multispecific molecule is a bispecific antibody.
  15. As a multispecific molecule, The above-mentioned multispecific molecule comprises a γδ TCR binding domain and an additional binding domain, wherein the γδ TCR binding domain comprises VH and VL regions according to any one of claims 8 to 13, and the additional binding domain binds to a target other than the γδ TCR; preferably, the multispecific molecule is a bispecific antibody.
  16. In paragraph 15, The above γδ TCR binding domain is a multispecific molecule, such as a scFv containing a VL-linker-VH or VH-linker-VL structure.
  17. In any one of paragraphs 14 through 16, A multispecific molecule in which a target other than the above γδ TCR is a cancer antigen such as a tumor-specific antigen or a tumor-associated antigen.
  18. In Paragraph 17, The above cancer antigen is an antigen of a blood cancer, and the above blood cancer is, for example, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma, a multispecific molecule.
  19. In Paragraph 17, The above cancer antigen is an antigen of a solid tumor, and the above solid tumor is a multispecific molecule that is, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell lung cancer or non-small cell lung cancer), colon cancer, prostate cancer, cervical cancer, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma (liver cancer), renal cell carcinoma (kidney cancer), head and neck cancer, mesothelioma, melanoma, sarcoma, or brain tumor (for example, a glioma such as glioblastoma).
  20. In any one of paragraphs 17 through 19, The above cancer antigen is a multispecific molecule selected from CD33, CD19, CD20, CD22, CD30, CD70, CLL-1, BCMA, DLL-3, Claudin 6, Claudin 18.2, GPC3, GPC2, GPRC5D, CD229, FcRH5, GUCY2C, mesothelin, HER2, PSMA, or PSCA.

Description

Anti-γδ TCR Antibody and Its Uses Cross-reference of related applications This application claims priority to international application number PCT/CN2023/116291 filed on August 31, 2023 and international application number PCT/CN2023/123953 filed on October 11, 2023, the entirety of which is incorporated herein by reference. Rank declaration The contents submitted below as an XML file are incorporated herein by reference in their entirety. A sequence list in computer-readable format (CRF) (file name: IEC240451PCT_SEQUENCE LISTING.xml, date of entry: August 26, 2024, size: 239,106 bytes). Technology field The present disclosure relates to a molecule comprising an antibody that binds to a T cell receptor (TCR). In particular, the present disclosure relates to an antibody that binds to a human γδ TCR, wherein human γδ T cells can be activated and regulated. The present disclosure also relates to a bispecific tumor-targeted immunomodulator, wherein such immunomodulators simultaneously bind to tumor-associated antigens and γδ T cell receptors to enhance cell-mediated immune responses in cancer treatment. Furthermore, the present disclosure provides a method for producing such an antibody and a method for killing cancer cells using such an antibody. Human γδ T cells are a distinct subgroup of immune cells, accounting for 0.5% to 5% of peripheral blood lymphocytes. Unlike αβ T cells, the T cell receptor (TCR) expressed by γδ T cells consists of γ and δ chains and recognizes antigens that do not rely on MHC restriction. Generally, based on the TCR δ chain, human γδ T cells can be divided into four major groups: Vδ1, Vδ2, Vδ3, and Vδ5 γδ T cells. Vδ1 can co-express with various Vγ chains (Vγ2, Vγ3, Vγ4, Vγ5, Vγ8, and Vγ10) to form distinct Vδ1 γδ T cell subgroups, which are primarily distributed in the skin, small intestine, and other mucosal tissues. Small amounts of Vδ1 γδ T cells have also been found in the liver and spleen. Vδ2 is co-expressed almost exclusively with Vγ9 to form Vγ9Vδ2 T cells, which are the major γδ T cells in blood circulation. Vδ3 γδ T cells are mainly found in the liver and small intestinal epithelium. Vδ5 γδ T cells are mainly found in peripheral blood (Liu and Zhang, Cells (2020) 9(5):1206). γδ T cells recognize tumor cells via the γδ TCR and natural killer receptor (NKR). Vγ9Vδ2 TCR recognition relies on non-peptide phosphate antigens (e.g., isopentenyl pyrophosphate, IPP) of butyrophyllin 3A1 (BTN3A1) and butyrophyllin 2A1 (BTN2A1). In addition, Vγ9Vδ2 T cells also recognize tumor cells via NKG2D and DNAM-1 (conjugated to their ligands (MICA/B, ULBP, Nectin-2, and PVR)) (Liu and Zhang, Cells (2020) 9(5):1206). Vδ1 T cells recognize lipid antigens presented by CD1d via the Vδ1 TCR. NKG2D and natural cytotoxic receptors (NCR, NKp30, NKp44, NKp46) and their ligands are involved in the recognition of tumor cells by Vδ1 T cells. Under sustained stimulation by TCR agonists, in the presence of IL-15 or IL-2, Vδ1 T cells can express NCR (Mikulak et al., JCI Insight (2019) 19; 4(24):e125884, Almeida et al., Clin. Cancer Res (2016) 22:5795-5804), and these cells exhibit potent antitumor activity against tumor cells and demonstrate very high IFNγ secretion capabilities. Studies on Vδ3 and Vδ5 TCR ligands are very limited, and little is known about the antitumor mechanisms of these cells. Currently, most clinical trials have focused on autologous γδ T cells due to the unique characteristics of γδ T cells (e.g., MHC restriction and lack of risk of graft-versus-host disease (GVHD)). Additionally, adoptive transfer of autologous Vγ9Vδ2 T cells has been demonstrated to be well-tolerated and capable of inducing anti-tumor immunity. Most strategies currently under evaluation incorporate tumor targeting mechanisms, such as chimeric antigen receptors (CARs) or bispecific T cell conjugates (bsTCEs), which can play a key role in achieving more stable and consistent clinical responses. Preliminary results from these targeting methods (co-cell and antibody-based) have shown high potential and demonstrated the safety of Vγ9Vδ2 and Vδ1 T cell-based strategies. However, cell-based products face challenges not present in antibody-based therapies, such as high costs, production difficulties or the need for specialized facilities, and the need for preliminary lymphocyte-removal chemotherapy. Accordingly, the present disclosure relates to the development of antibodies capable of effectively activating and engaging γδ T cells. The present specification provides a V H H that binds to a γδ TCR, wherein the V H H comprises a CDR1 having the amino acid sequence of SEQ ID NO: 15, 19, 23, 27, 31, 35, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 85, 89, 93, 121, 125, 140, 150, 154, 158, 162, 178, 182, or 186; SEQ ID NO: CDR2 containing the amino acid sequence of 16, 20, 24, 28, 32, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 82, 86, 90, 94, 122, 126, 137, 141, 151, 155, 159, 179, 183, or 187; and includes a CDR3 containing the