ANTIBODIES AGAINST MSLN AND METHODS OF THEIR USE

Claims

1. An antibody that binds to MSLN, comprising a single-domain antibody that comprises a heavy chain variable region that includes: a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, b) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 6, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 8, c) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 13, d) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 18, e) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 23, f) CDR1 of the variable heavy chain comprising the amino acid sequence of SEQ ID NO: 26, CDR2 of the variable heavy chain comprising the amino acid sequence of SEQ ID NO: 27, and CDR3 of the variable heavy chain comprising the amino acid sequence of SEQ ID NO: 28, g) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or h) CDR1 of the variable region of the heavy chain, comprising the amino acid sequence of SEQ ID NO: 36, CDR2 of the variable region of the heavy chain, comprising the amino acid sequence of SEQ ID NO: 37, and CDR3 of the variable region of the heavy chain, comprising the amino acid sequence of SEQ ID NO:

38.

2. The antibody of claim 1, wherein the single-domain antibody comprises CDR1 of the variable region of the heavy chain, comprising the amino acid sequence of SEQ ID NO: 31, CDR2 of the variable region of the heavy chain, comprising the amino acid sequence of SEQ ID NO: 32, and CDR3 of the variable region of the heavy chain, comprising the amino acid sequence of SEQ ID NO:

33.

3. The antibody according to claim 1 or 2, wherein the single-domain antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 9, 14, 19, 24, 29, 34 and 39.

4. The antibody of any one of claims 1-3, wherein the single-domain antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

34.

5. The antibody of any one of claims 1-4, wherein the antibody comprises an Fc region.

6. The antibody of claim 5, wherein the Fc region comprises an Fc region selected from the group consisting of the Fc regions of IgG1, IgG2, IgG3, and IgG4.

7. The antibody of claim 5 or 6, wherein the Fc region comprises an IgG1 Fc region.

8. The antibody of claim 7, wherein the Fc region of IgG1 contains one or more mutations that enhance antibody-dependent cellular cytotoxicity (ADCC).

9. The antibody according to claim 7 or 8, wherein the Fc region of IgG1 comprises the mutations L235V, F243L, R292P and Y300L, the mutations S239D, A330L and I332E, or the mutations L235V, F243L, R292P, Y300L and P396L.

10. An immunoconjugate comprising an antibody according to any one of claims 1-9 linked to a therapeutic agent or label.

11. The immunoconjugate of claim 10, wherein the therapeutic agent is a cytotoxin or a radioactive isotope.

12. The immunoconjugate of claim 10, wherein the label is selected from the group consisting of a radioisotope, a fluorescent dye, or an enzyme.

13. An antigen recognition receptor comprising an extracellular antigen binding domain that comprises an antibody according to any one of claims 1-9.

14. The antigen recognition receptor of claim 13, which is a chimeric antigen receptor (CAR) or a recombinant T cell receptor.

15. The antigen recognition receptor according to claim 13 or 14, which is a CAR.

16. An antigen recognition receptor according to any one of claims 13-15, wherein the antibody comprises a VHH.

17. An immunoreactive cell comprising an antigen-recognizing receptor according to any one of claims 13-16.

18. The immunoreactive cell of claim 17, wherein the immunoreactive cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a natural killer T (NKT) cell, and a myeloid cell.

19. The immunoreactive cell of claim 18, wherein the immunoreactive cell is a T cell.

20. A pharmaceutical composition comprising a) an antibody according to any one of claims 1-9, an immunoconjugate according to any one of claims 10-12, or an immunoreactive cell according to any one of claims 17-19, and b) a pharmaceutically acceptable carrier.

21. One or more nucleic acids encoding an antibody according to any one of claims 1-9.

22. One or more vectors containing the nucleic acid of claim 21.

23. A host cell containing the nucleic acid of claim 21 or the vector of claim 22.

24. A method for producing an antibody according to any one of claims 1-9, comprising expressing the antibody in a host cell according to claim 23 and isolating the antibody from the host cell.

25. A method for reducing tumor burden in a subject, comprising administering to the subject an effective amount of an antibody according to any one of claims 1-9, an immunoconjugate according to any one of claims 10-12, an immunoreactive cell according to any one of claims 17-19, or a pharmaceutical composition according to claim 20.

26. A method for treating and / or preventing cancer, comprising administering to a subject an effective amount of an antibody according to any one of claims 1-9, an immunoconjugate according to any one of claims 10-12, an immunoreactive cell according to any one of claims 17-19, or a pharmaceutical composition according to claim 20.

27. A method for increasing the survival of a subject suffering from cancer, comprising administering to the subject an effective amount of an antibody according to any one of claims 1-9, an immunoconjugate according to any one of claims 10-12, an immunoreactive cell according to any one of claims 17-19, or a pharmaceutical composition according to claim 20.

28. The method according to any one of claims 25-27, wherein the tumor or cancer exhibits high microsatellite instability (MSI).

29. The method of any one of claims 25-28, wherein the tumor or cancer is selected from the group consisting of mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymus carcinoma, endometrial carcinoma, gastric tumor, cholangiocarcinoma, head and neck cancer, blood cancer, and combinations thereof.

30. An antibody according to any one of claims 1-9, intended for use as a medicinal product.

31. An antibody according to any one of claims 1 to 9, intended for the treatment of cancer.

32. A pharmaceutical composition according to claim 20, intended for use as a medicinal product.

33. A pharmaceutical composition according to claim 20, intended for the treatment of cancer.

34. The antibody of claim 31 or the pharmaceutical composition of claim 33, wherein the cancer exhibits high microsatellite instability (MSI).

35. The antibody of claim 31 or the pharmaceutical composition of claim 33, wherein the cancer is selected from the group consisting of mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymus carcinoma, endometrial carcinoma, gastric tumor, cholangiocarcinoma, head and neck cancer, blood cancer, and combinations thereof.

36. A kit comprising an antibody according to any one of claims 1-9, an immunoconjugate according to any one of claims 10-12, a pharmaceutical composition according to claim 20, a nucleic acid according to claim 21, a vector according to claim 22, or an immunoreactive cell according to any one of claims 17-19.

37. The kit according to item 36, additionally containing written instructions for the treatment and / or prevention of neoplasm.