Drug conjugate containing an antibody against Claudin 18.2

Abstract

The present invention generally provides therapies for effectively treating and / or preventing cancers associated with cells expressing CLDN18.2, including, for example, gastric cancer, esophageal cancer, pancreatic cancer, lung cancer such as non-small cell lung cancer (NSCLC), ovarian cancer, colorectal cancer, liver cancer, head and neck cancer, and gallbladder cancer, as well as metastases thereof, particularly gastric cancer metastasis, e.g., Krukenberg tumor, peritoneal metastasis, and lymph node metastasis. Particularly preferred cancer diseases are adenocarcinomas of the stomach, esophagus, pancreatic duct, bile duct, lung, and ovary. [Solution] The present invention provides anti-CLDN18.2 antibody-drug conjugates that are effective in treating and / or preventing cancer diseases associated with cells that express CLDN18.2, including gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, liver cancer, head and neck cancer, and gallbladder cancer, as well as metastases thereof.

Claims

1. The use of an antibody conjugate comprising an antibody capable of binding to CLDN18.2 covalently attached to a therapeutic portion for the manufacture of a pharmaceutical product for treating or preventing CLDN18.2-expressing cancer in cancer patients, The aforementioned antibody is (a) An antibody that binds to CLDN18.2, comprising an antibody heavy chain sequence containing the amino acid sequence represented by SEQ ID NO: 32 and an antibody light chain sequence containing the amino acid sequence represented by SEQ ID NO: 39; (b) An antibody that binds to CLDN18.2, comprising an antibody heavy chain sequence containing the amino acid sequence represented by SEQ ID NO: 30 and an antibody light chain sequence containing the amino acid sequence represented by SEQ ID NO: 35; and (c) A variant of the antibody of (a) or (b) comprising up to two amino acid substitutions in the variable region of the antibody heavy chain sequence or the antibody light chain sequence excluding the CDR. Selected from the group consisting of, The antibody in (a) comprises an antibody heavy chain containing the amino acid sequence of SEQ ID NO: 17 or 51 and an antibody light chain containing the amino acid sequence of SEQ ID NO:

24. The antibody in (b) comprises an antibody heavy chain containing the amino acid sequence of SEQ ID NO: 15 and an antibody light chain containing the amino acid sequence of SEQ ID NO:

20. The antibody variant of (a) comprises an antibody heavy chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 32, and an antibody light chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 39, The antibody variant of (b) comprises an antibody heavy chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 30, and an antibody light chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 35, Antibody conjugates are used for internal translocation into cells.

2. The use according to claim 1, wherein the antibody having the ability to bind to CLDN18.2 specifically binds to CLDN18.

2.

3. The use according to claim 1 or 2, wherein the antibody capable of binding to CLDN18.2 is a monoclonal antibody or its antigen-binding fragment, a bispecific antibody, a humanized or chimeric antibody.

4. The use according to any one of claims 1 to 3, wherein an antibody having the ability to bind to CLDN18.2 binds to the extracellular domain of CLDN18.

2.

5. The use according to any one of claims 1 to 4, wherein an antibody having the ability to bind to CLDN18.2 binds to the first extracellular loop of CLDN18.

2.

6. The use according to any one of claims 1 to 4, wherein the treatment area is permeable to the cell membrane.

7. The use according to any one of claims 1 to 6, wherein the therapeutic portion is a cytotoxic agent or a cell proliferation inhibitor.

8. The use according to any one of claims 1 to 7, wherein the therapeutic portion is meitansinoid or auristatin.

9. The use according to claim 8, wherein the maytansinoid is selected from the group consisting of DM1 and DM4.

10. The use according to claim 8, wherein auristatin is selected from the group consisting of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).

11. The use according to any one of claims 1 to 10, wherein an antibody capable of binding to CLDN18.2 is covalently attached to the therapeutic portion by a linker.

12. The use according to claim 11, wherein the linker is a severable linker.

13. The use according to claim 11 or 12, wherein the linker is cleavable under intracellular conditions.

14. The use according to any one of claims 11 to 13, wherein the linker is hydrolyzable at a pH of less than 5.

5.

15. The use according to any one of claims 11 to 14, wherein the linker is cleavable by an intracellular protease.

16. The use according to any one of claims 11 to 15, wherein the linker is a cathepsin-cleavable linker.

17. The use according to any one of claims 11 to 16, wherein the linker comprises a dipeptide.

18. The use according to claim 17, wherein the dipeptide is val-cit or phe-lys.

19. The use according to any one of claims 1 to 18, wherein the antibody conjugate is administered in an amount effective for the treatment or prevention of CLDN18.2-expressing cancer.

20. The use according to any one of claims 1 to 19, wherein the antibody conjugate is administered in a dose between 3 and 30 mg / kg of body weight.

21. The antibody conjugate is administered at a dose of 9-90 mg per 1 m² of the human patient's body surface. 2 The use according to any one of claims 1 to 19, administered in a dose between [a certain value].

22. The use according to any one of claims 1 to 21, wherein a single dose of antibody conjugate or two or more doses of antibody conjugate are administered.

23. The use according to any one of claims 1 to 22, wherein the antibody conjugate is administered by intravenous injection.

24. The use according to any one of claims 1 to 23, wherein the pharmaceutical is formulated for further administration of surgery, chemotherapy, and / or radiotherapy.

25. The use according to any one of claims 1 to 24, wherein the cancer is adenocarcinoma, in particular advanced adenocarcinoma.

26. The use according to any one of claims 1 to 25, wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer, pancreatic cancer, lung cancer such as non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, colorectal cancer, liver cancer, head and neck cancer, gallbladder cancer, and metastases thereof, Krukenberg tumor, peritoneal metastases, and / or lymph node metastases.

27. The use according to any one of claims 1 to 26, wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer, particularly lower esophageal cancer, esophagogastric junction cancer, and gastroesophageal cancer.

28. The use according to any one of claims 1 to 27, wherein the patient is HER2 / neu-negative or has a HER2 / neu-positive condition but is not eligible for trastuzumab therapy.

29. The use according to any one of claims 1 to 28, wherein CLDN18.2 has the amino acid sequence according to SEQ ID NO:

1.

30. An antibody conjugate comprising an antibody having the ability to bind to CLDN18.2 covalently attached to the treatment site, The aforementioned antibody is (a) An antibody that binds to CLDN18.2, comprising an antibody heavy chain sequence containing the amino acid sequence represented by SEQ ID NO: 32 and an antibody light chain sequence containing the amino acid sequence represented by SEQ ID NO: 39; (b) An antibody that binds to CLDN18.2, comprising an antibody heavy chain sequence containing the amino acid sequence represented by SEQ ID NO: 30 and an antibody light chain sequence containing the amino acid sequence represented by SEQ ID NO: 35; and (c) A variant of the antibody of (a) or (b) comprising up to two amino acid substitutions in the variable region of the antibody heavy chain sequence or the antibody light chain sequence excluding the CDR. Selected from the group consisting of, The antibody in (a) comprises an antibody heavy chain containing the amino acid sequence of SEQ ID NO: 17 or 51 and an antibody light chain containing the amino acid sequence of SEQ ID NO:

24. The antibody in (b) comprises an antibody heavy chain containing the amino acid sequence of SEQ ID NO: 15 and an antibody light chain containing the amino acid sequence of SEQ ID NO:

20. The antibody variant of (a) comprises an antibody heavy chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 32, and an antibody light chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 39, The antibody variant of (b) comprises an antibody heavy chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 30, and an antibody light chain sequence having at least 98% sequence identity with the sequence represented by SEQ ID NO: 35, Antibody conjugates are antibodies that are translocated internally into cells.

31. The antibody conjugate according to claim 30, wherein an antibody having the ability to bind to CLDN18.2 specifically binds to CLDN18.

2.

32. The antibody conjugate according to claim 30 or 31, wherein the antibody capable of binding to CLDN18.2 is a monoclonal antibody or its antigen-binding fragment, a bispecific antibody, a humanized or chimeric antibody.

33. The antibody conjugate according to any one of claims 30 to 32, wherein an antibody having the ability to bind to CLDN18.2 binds to the extracellular domain of CLDN18.

2.

34. The antibody conjugate according to any one of claims 30 to 33, wherein an antibody having the ability to bind to CLDN18.2 binds to the first extracellular loop of CLDN18.

2.

35. The antibody conjugate according to any one of claims 30 to 34, wherein the therapeutic portion is permeable to the cell membrane.

36. The antibody conjugate according to any one of claims 30 to 35, wherein the therapeutic portion is a cytotoxic agent or a cell proliferation inhibitor.

37. The antibody conjugate according to any one of claims 30 to 36, wherein the therapeutic portion is a meitansinoid or auristatin.

38. The antibody conjugate according to claim 37, wherein the maytansinoid is selected from the group consisting of DM1 and DM4.

39. The antibody conjugate according to claim 37, wherein the auristatin is selected from the group consisting of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).

40. The antibody conjugate according to any one of claims 30 to 39, wherein an antibody having the ability to bind to CLDN18.2 is covalently attached to the therapeutic portion by a linker.

41. The antibody conjugate according to claim 40, wherein the linker is a cleavable linker.

42. The antibody conjugate according to claim 40 or 41, wherein the linker is cleavable under intracellular conditions.

43. The antibody conjugate according to any one of claims 40 to 42, wherein the linker is hydrolyzable at a pH of less than 5.

5.

44. The antibody conjugate according to any one of claims 40 to 43, wherein the linker is cleavable by an intracellular protease.

45. The antibody conjugate according to any one of claims 40 to 44, wherein the linker is a cathepsin-cleavable linker.

46. The antibody conjugate according to any one of claims 40 to 45, wherein the linker comprises a dipeptide.

47. The antibody conjugate according to claim 46, wherein the dipeptide is val-cit or phe-lys.

48. A pharmaceutical formulation comprising an antibody conjugate according to any one of claims 30 to 47, and a pharmaceutically acceptable diluent, carrier, or excipient.

49. A pharmaceutical preparation comprising an antibody conjugate according to any one of claims 30 to 47.

50. The pharmaceutical preparation according to claim 49, which exists in the form of a kit including a container containing an antibody conjugate.

51. Use of an antibody conjugate according to any one of claims 30 to 47, a pharmaceutical formulation according to claim 48, or a pharmaceutical preparation according to claim 49 or 50 for the manufacture of a pharmaceutical for use in the treatment or prevention of CLDN18.2-expressing cancer.

52. The use according to claim 51, wherein the pharmaceutical preparation further comprises printed instructions for the use of the formulation in the treatment or prevention of CLDN18.2-expressing cancer.

53. The use according to claim 51 or 52, wherein the pharmaceutical preparation is formulated to treat or prevent cancer.

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