Anti-PSMA antibodies, bispecific antigen-binding molecules that bind PSMA and CD3, and uses thereof

Patent metadata

Field	Value
Publication number	US-12344677-B2
Application number	US-202117476856-A
Country	US
Kind code	B2
Filing date	Sep 16, 2021
Priority date	Jul 31, 2015
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The present invention provides antibodies that bind to prostate-specific membrane antigen (PSMA), bispecific antibodies that bind to PSMA and CD3, and methods of using the same. According to certain embodiments, the antibodies of the invention bind human PSMA with high affinity and bind CD3 to induce human T cell proliferation. The invention includes antibodies that bind PSMA and CD3 and induce T cell-mediated killing of PSMA-expressing tumor cells. According to certain embodiments, the present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human PSMA. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of prostate tumors expressing PSMA. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and/or therapeutically beneficial. For example, the antibodies of the invention are useful for the treatment of various cancers.

First claim

What is claimed is:

1. A method for treating a human prostate specific membrane antigen (PSMA)-expressing cancer in a human subject, the method comprising administering a bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human PSMA,
wherein the first antigen-binding domain that specifically binds human CD3 comprises heavy chain complementarity determining regions A1-HCDR1, A1-HCDR2 and A1-HCDR3 contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1514, or SEQ ID NO: 1618, and light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1386, and
wherein the second antigen-binding domain that specifically binds human PSMA comprises heavy chain complementarity determining regions A2-HCDR1, A2-HCDR2 and A2-HCDR3 contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 66, and light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1386.

2. The method of claim 1 , wherein A1-HCDR1, A1-HCDR2 and A1-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1516, 1518 and 1520.

3. The method of claim 1 , wherein A1-HCDR1, A1-HCDR2 and A1-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1620, 1622 and 1624.

4. The method of claim 1 , wherein A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOS: 68, 70 and 72.

5. The method of claim 2 , wherein A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 68, 70 and 72.

6. The method of claim 3 , wherein A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 68, 70 and 72.

7. The method of claim 1 , wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

8. The method of claim 2 , wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

9. The method of claim 3 , wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

10. The method of claim 4 , wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

11. The method of claim 5 , wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

12. The method of claim 6 , wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

13. The method of claim 1 , wherein the first antigen-binding domain that specifically binds human CD3 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1514 or SEQ ID NO: 1618, and a LCVR comprising the amino acid sequence of SEQ ID NO: 1386, and wherein the second antigen-binding domain that specifically binds human PSMA comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 66, and a LCVR comprising the amino acid sequence of SEQ ID NO: 1386.

14. The method of claim 13 , wherein the first antigen-binding domain that specifically binds human CD3 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1514.

15. The method of claim 13 , wherein the first antigen-binding domain that specifically binds human CD3 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1618.

16. A method for treating a human prostate specific membrane antigen (PSMA)-expressing cancer in a human subject, the method comprising administering an isolated bispecific antibody comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human PSMA,
wherein the first antigen-binding domain that specifically binds human CD3 comprises heavy chain complementarity determining regions A1-HCDR1, A1-HCDR2 and A1-HCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 1516, 1518 and 1520, and light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392, and
wherein the second antigen-binding domain that specifically binds human PSMA comprises heavy chain complementarity determining regions A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 68, 70 and 72, and light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

17. The method of claim 16 , wherein the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1514 and a LCVR comprising the amino acid sequence of SEQ ID NO: 1386, and the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 66 and a LCVR comprising the amino acid sequence of SEQ ID NO: 1386.

18. The method of claim 16 , wherein the cancer is selected from the group consisting of prostate cancer, kidney cancer, bladder cancer, colorectal cancer, and gastric cancer.

19. The method of claim 18 , wherein the cancer is prostate cancer.

20. The method of claim 19 , wherein the prostate cancer is castrate-resistant prostate cancer.

21. A method for treating a human prostate specific membrane antigen (PSMA)-expressing cancer in a human subject, the method comprising administering an isolated bispecific antibody comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human PSMA,
wherein the first antigen-binding domain that specifically binds human CD3 comprises heavy chain complementarity determining regions A1-HCDR1, A1-HCDR2 and A1-HCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 1620, 1622 and 1624, and light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392, and
wherein the second antigen-binding domain that specifically binds human PSMA comprises heavy chain complementarity determining regions A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 68, 70 and 72, and light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs: 1388, 1390 and 1392.

22. The method of claim 21 , wherein the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1618 and a LCVR comprising the amino acid sequence of SEQ ID NO: 1386, and the second antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 66 and a LCVR comprising the amino acid sequence of SEQ ID NO: 1386.

23. The method of claim 21 , wherein the cancer is selected from the group consisting of prostate cancer, kidney cancer, bladder cancer, colorectal cancer, and gastric cancer.

24. The method of claim 23 , wherein the cancer is prostate cancer.

25. The method of claim 24 , wherein the prostate cancer is castrate-resistant

Assignees

• Regeneron Pharma

Inventors

• Kirshner Jessica R
• Crawford Alison
• Thurston Gavin
• Smith Eric
• Haber Lauric
• Dudgeon Drew
• Rafique Ashique

Classifications

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/734

  Complement-dependent cytotoxicity [CDC] · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title