B7H4-Targeting Antibody-Drug Conjugates and Methods of Use Thereof

Abstract

The present disclosure relates generally to antibody-drug conjugates comprising monoclonal antibodies that specifically bind to human B7-H4 in either soluble form or membrane-bound (i.e., when expressed on the cell surface), and methods of using these conjugates as therapeutic and / or diagnostic agents. TIFF2024501894000420.tif208165

Claims

1. A variable heavy chain complementarity determining region 1 (CDRH1) containing the amino acid sequence GFIVSRNY (SEQ ID NO:2), a variable heavy chain complementarity determining region 2 (CDRH2) containing the amino acid sequence IYGSGRT (SEQ ID NO:3), and an amino acid sequence or amino acid sequence a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence QSVSSSY (SEQ ID NO:53), a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO:53), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO:54), and Variable light chain complementarity determining region 3 (CDRL3) containing 2. An isolated antibody that specifically binds to B7-H4, comprising:

2. 2. The isolated antibody of claim 1, comprising a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:44 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:

50.

3. A heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:44 and an amino acid sequence and a heavy chain comprising a heavy chain constant region comprising a light chain comprising a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:50 and a light chain constant region comprising the amino acid sequence of SEQ ID NO:

51.

3. The isolated antibody of claim 1 or 2, comprising:

4. A heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:22 and an amino acid sequence and a heavy chain comprising a heavy chain constant region comprising a light chain comprising a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:50 and a light chain constant region comprising the amino acid sequence of SEQ ID NO:

51.

2. The isolated antibody of claim 1, comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:45 and a light chain comprising the amino acid sequence of SEQ ID NO:52; (ii) a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:50; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:23 and a light chain comprising the amino acid sequence of SEQ ID NO:

52.

2. The isolated antibody of claim 1, comprising:

6. The isolated antibody of any one of claims 1 to 5, which is a monoclonal antibody.

7. The isolated antibody of any one of claims 1 to 6, which is a rabbit monoclonal antibody, a mouse monoclonal antibody, a chimeric monoclonal antibody, a humanized monoclonal antibody, or a fully human monoclonal antibody.

8. The isolated antibody of any one of claims 1 to 7, which is an IgG isotype antibody or an IgG1 isotype antibody.

9. 9. The isolated antibody of any one of claims 1 to 8, which competes for specific binding to human B7-H4 with an isolated antibody comprising a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:44 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:50, or with an isolated antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:45 and a light chain comprising the amino acid sequence of SEQ ID NO:

52.

10. A B7-H4 antibody-drug conjugate comprising an isolated antibody according to any one of claims 1 to 9.

11. A method for treating a pulmonary arthritis with a pulmonary arthritis comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis drug comprising administering to said ... Each linker-drug moiety is a multifunctional linker that connects the antibody to one or more drug units (e.g., one or more therapeutic agents (D)) via a releasable assembly unit for each drug unit and connects a hydrophilic group to the drug unit of each linker-drug moiety; Including, The releasable assembly unit is capable of releasing free drug in the vicinity of a target site targeted by the antibody; and the multifunctional linker comprises a peptide moiety between the targeting moiety and the hydrophilic group, the peptide moiety comprising at least two amino acids; The B7-H4 antibody-drug conjugate of claim 10.

12. 11. The B7-H4 antibody-drug conjugate of claim 10, selected from any one of the conjugates of Table A1, Table A2, Table B1, or Table B2.

13. The B7-H4 antibody-drug conjugate of any one of claims 10 to 12, comprising formula (XXXVII): During the ceremony, d 13 is approximately 2, the drug is attached to the antibody heavy chain via a linker moiety at the asparagine residue at position 297 as numbered according to EU numbering; and ■ is GlcNAc, △ is Fuc, and □ is GalNAc.

14. The B7-H4 antibody-drug conjugate of any one of claims 10 to 12, comprising formula (XXXVIII): During the ceremony, d 13 is approximately 2, the drug is attached to the antibody heavy chain via a linker moiety at the asparagine residue at position 297 as numbered according to EU numbering; and ■ is GlcNAc, △ is Fuc, and □ is GalNAc.

15. 13. The B7-H4 antibody-drug conjugate of any one of claims 10 to 12, comprising: Or a pharma- ceutically acceptable salt or isomer thereof.

16. A B7-H4 antibody-drug conjugate comprising the formula (XXXVII): During the ceremony, ANTIBODYs bind to B7-H4 and comprise a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO:2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO:3), and a variable heavy chain complementarity determining region 3 (CDRH4) comprising the amino acid sequence IYGSGRT (SEQ ID NO:4). a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence QSVSSSY (SEQ ID NO:53); a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence GAS (SEQ ID NO:54); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO:55); and a variable light chain complementarity determining region 3 (CDRL3) comprising: d 13 is approximately 2; the drug is attached to the antibody heavy chain via a linker moiety at an asparagine residue at position 297 as numbered according to EU numbering; ■ is GlcNAc, △ is Fuc, and □ is GalNAc.

17. The B7-H4 antibody-drug conjugate of claim 16, wherein the ANTIBODY comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:44 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

50.

18. A B7-H4 antibody-drug conjugate comprising the formula (XXXVII): During the ceremony, The ANTIBODY binds to B7-H4 and has a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:44 and the amino acid sequence and a heavy chain comprising a heavy chain constant region comprising a light chain comprising a light chain variable sequence comprising the amino acid sequence of SEQ ID NO:50 and a light chain constant region comprising the amino acid sequence of SEQ ID NO:51; d 13 is approximately 2; The drug is attached to the heavy chain of the antibody via a linker moiety at the asparagine residue at position 296 according to SEQ ID NO:45; and ■ is GlcNAc, △ is Fuc, and □ is GalNAc.

19. A pharmaceutical composition comprising the antibody-drug conjugate described in any one of claims 10 to 18 and a pharma- ceutically acceptable excipient.

20. A pharmaceutical composition comprising an isolated antibody according to any one of claims 1 to 9 and a pharma- ceutically acceptable excipient.

21. A pharmaceutical composition for treating or preventing a disease or disorder in a subject in need thereof, comprising an antibody-drug conjugate described in any one of claims 10 to 18, a pharmaceutical composition described in claim 19 or 20, or an isolated antibody described in any one of claims 1 to 9.

22. Use of an antibody-drug conjugate according to any one of claims 10 to 18, a pharmaceutical composition according to claim 19 or 20, or an isolated antibody according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

23. 23. The pharmaceutical composition of claim 21 or the use of claim 22, wherein the conjugate releases one or more therapeutic agents upon biodegradation.

24. 23. The pharmaceutical composition of claim 21 or the use of claim 22, wherein the disease or disorder is cancer.

25. 25. The pharmaceutical composition or use of claim 24, wherein the cancer is a B7-H4 positive cancer.

26. The pharmaceutical composition or use of claim 24, wherein the cancer is bile duct carcinoma, breast cancer, endometrial cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, uterine cancer, thyroid cancer, renal cancer, head and neck cancer, gastric cancer, melanoma, cholangial carcinoma, pancreatic cancer, colon cancer, or bladder cancer.

27. The pharmaceutical composition or use of claim 25, wherein the B7-H4 positive cancer is breast cancer, endometrial cancer, ovarian cancer, or cholangial carcinoma.

28. The pharmaceutical composition or use according to any one of claims 21 to 27, wherein the subject is a human.

29. A pharmaceutical composition or use according to any one of claims 21 to 28, used in combination with a therapeutic agent.

30. The isolated antibody of claim 1, which is a cysteine ​​engineered antibody.

31. A nucleic acid molecule comprising a sequence encoding the light chain variable sequence, the heavy chain variable sequence, or both the light chain variable sequence and the heavy chain variable sequence of an antibody described in any one of claims 1 to 9.

32. A sequence encoding SEQ ID NO:44; a sequence encoding SEQ ID NO:50; a sequence encoding both SEQ ID NO:44 and SEQ ID NO:50; a sequence encoding SEQ ID NO:44 and a sequence encoding SEQ ID NO:52; or a sequence encoding SEQ ID NO:44, and a sequence encoding SEQ ID NO:52 A nucleic acid molecule comprising:

33. A cell comprising a nucleic acid molecule described in claim 31 or 32.

34. Use of a nucleic acid molecule according to claim 31 or 32, or a cell according to claim 33, in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

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