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EP-4010378-B1 - ANTI-CCR8 MONOCLONAL ANTIBODIES AND USES THEREOF

EP4010378B1EP 4010378 B1EP4010378 B1EP 4010378B1EP-4010378-B1

Inventors

  • LI, Runsheng
  • HUANG, WENTAO

Dates

Publication Date
20260506
Application Date
20211011

Claims (12)

  1. An antibody or fragment thereof having binding specificity to a human chemokine (C-C motif) receptor 8 (CCR8) protein, wherein the antibody or fragment thereof comprises a heavy chain variable region comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3 and a light chain variable region light chain comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein: the CDRH1 comprises the amino acid sequence of SEQ ID NO: 35, the CDRH2 comprises the amino acid sequence of SEQ ID NO: 36, the CDRH3 comprises the amino acid sequence of SEQ ID NO: 37, the CDRL1 comprises the amino acid sequence of SEQ ID NO: 25 or 28, the CDRL2 comprises the amino acid sequence of SEQ ID NO: 26, and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 27.
  2. The antibody or fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 38-40, and the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 32-34 and 41-43.
  3. The antibody or fragment thereof of claim 1, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:40, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:42.
  4. The antibody or fragment thereof of any one of claims 1-3, which is humanized.
  5. The antibody or fragment of any one of claims 1-4, which is capable of mediating antibody-dependent cellular cytotoxicity (ADCC).
  6. The antibody or fragment of claim 5, which is not afucosylated.
  7. The antibody or fragment thereof of any one of claims 1-6, which further has a binding specificity to a second target protein.
  8. A composition comprising the antibody or fragment thereof of any one of claims 1-7 and a pharmaceutically acceptable carrier.
  9. The composition of claim 8, further comprising a second antibody having specificity to a tumor antigen.
  10. The antibody or fragment thereof of any one of claims 1-7 for use in a method of treating cancer in a patient in need thereof.
  11. Use of the antibody or fragment thereof of any one of claims 1-7 for the preparation of a medicament for treating cancer.
  12. The antibody or fragment thereof for use of claim 10 or the use of claim 11, wherein the cancer is selected from the group consisting of bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urethral cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, oesophageal cancer, ovarian cancer, renal cancer, melanoma, prostate cancer and thyroid cancer.

Description

BACKGROUND Chemokine (C-C motif) receptor 8 (CCR8) is a member of the beta chemokine receptor family, and is a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptors are important for the migration of various cell types into the inflammatory sites. This receptor protein preferentially expresses in the thymus. The ligand of the CCR8 is CCL1. CCL8 also functions as a CCR8 agonist. CCR8 is expressed principally on regulatory T cells (Treg) and is important for CCR8+ Treg-mediated immunosuppression. Recent studies have demonstrated that CCR8 is uniquely upregulated in human tumor-resident Tregs of cancer patients. It was also demonstrated that CCR8+ myeloid cells were expanded in patients with cancer. Antibodies targeting CCR8 have been shown to significantly suppress tumor growth and improve long-term survival in animal models. This antitumor activity correlated with increased tumor specific T cells, and enhanced infiltration of CD4+ and CD8+ T cells. Treatment with the antibodies prevented induction and suppressive function of Tregs without affecting CD8+ T cells. Targeting CCR8, therefore, is a promising cancer immunotherapy approach. WO 2020 / 138489 A1 and CA 3 124 332 A1 disclose a monoclonal antibody or an antibody fragment thereof that binds to CCR8, which recognizes tyrosine at position 17 in the amino acid sequence SEQ ID No. 1 of the disclosures. US 2020 / 222463 A1 discloses a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody against CCR8. Anonymous: "Purified anti-mouse CD198 (CCR8) Antibody", Biolegend - Product sheet, 16 December 2015, pages 1 to 2, XP055768629 discloses the purified anti-mouse CD198 (CCR8) antibody SA214G2. WO 2007 / 044756 A2 discloses inter alia a monoclonal antibody 414B that binds human CCR8 protein. SUMMARY Anti-CCR8 antibodies are discovered herein that have high binding affinity to the human CCR8 protein, and are efficient in mediating antibody-dependent cellular cytotoxicity (ADCC). The invention is set out in the appended set of claims. According to the invention, an antibody or fragment thereof is provided, having binding specificity to a human chemokine (C-C motif) receptor 8 (CCR8) protein. The antibody or fragment thereof comprises a heavy chain variable region comprising heavy chain complementarity determining regions CDRH1, CDRH2, and CDRH3 and a light chain variable region light chain comprising complementarity determining regions CDRL1, CDRL2, and CDRL3. Disclosed not according to the invention is that the CDRH1 comprises the amino acid sequence of SEQ ID NO: 22, the CDRH2 comprises the amino acid sequence of SEQ ID NO: 23, the CDRH3 comprises the amino acid sequence of SEQ ID NO: 24, the CDRL1 comprises the amino acid sequence of SEQ ID NO: 25 or 28, the CDRL2 comprises the amino acid sequence of SEQ ID NO: 26, and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 27. According to the invention, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 35, the CDRH2 comprises the amino acid sequence of SEQ ID NO: 36, the CDRH3 comprises the amino acid sequence of SEQ ID NO: 37, the CDRL1 comprises the amino acid sequence of SEQ ID NO: 25 or 28, the CDRL2 comprises the amino acid sequence of SEQ ID NO: 26, and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 27. Also provided, according to the invention, are compositions comprising the antibody or fragment thereof of the invention and a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises a second antibody having specificity to a tumor antigen. In some embodiments, the second antibody is a tumor-opsonizing antibody. Methods and uses for the treatment of diseases and conditions are also provided. Also disclosed not according to the invention is a method of treating cancer in a patient in need thereof, comprising administering to the patient the antibody or fragment thereof of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the CCR8-binding affinity of the chimeric antibodies with murine VH/VL.FIG. 2 shows the ADCC activity of three of the chimeric antibodies.FIG. 3 shows that humanized 88D2C6 antibodies have high affinities.FIG. 4 shows that humanized 137D1H10 antibodies have high affinities.FIG. 5 shows that, compared to the chimeric antibodies, the humanized antibodies have significantly higher ADCC activities.FIG. 6 shows the results of cell-based binding of LM-108 and reference antibody to human CCR8 by flow cytometry. Upper panel: FACS binding of LM-108 on human CCR8 expressing HEK293. Lower panel: FACS binding of LM-108 on HEK293 cells.FIG. 7 shows cell-based binding of LM-108 to human CCR8 high expressing U2OS cells by flow cytometry.FIG. 8 shows cell-based binding of LM-108 to human CCR8 low expressing Jurkat cells by flow cytometry.FIG. 9 shows the r