Anti-CD28 x anti-PSMA antibodies

Patent metadata

Field	Value
Publication number	US-12378326-B2
Application number	US-202418440860-A
Country	US
Kind code	B2
Filing date	Feb 13, 2024
Priority date	Feb 23, 2022
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

Provided herein are novel anti-CD28×anti-PSMA antibodies and methods of using such antibodies for the treatment of PSMA-associated cancers. Subject anti-CD28×anti-PSMA antibodies are capable of agonistically binding to CD28 costimulatory molecules on T cells and PSMA on tumor cells. Thus, such antibodies selectively enhance anti-tumor activity at tumor sites while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful in combination with other anti-cancer therapies (e.g., anti-CD3×anti-PSMA antibodies) for the treatment of prostate cancers.

First claim

What is claimed is:

1. A bispecific antibody comprising a first antigen binding domain (ABD) that binds PSMA and a second ABD that binds CD28, wherein the first ABD that binds PSMA comprises a VH of SEQ ID NO: 214 and a VL of SEQ ID NO: 218, and the second ABD that binds CD28 comprises a VH of SEQ ID NO: 396 and a VL of SEQ ID NO: 400.

2. The bispecific antibody of claim 1 , wherein the first ABD or second ABD is an scFv.

3. The bispecific antibody of claim 2 , wherein the scFv comprises an scFv linker selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 456), and GGGSGGSGGCPPCGGSGG (SEQ ID NO: 457).

4. The bispecific antibody of claim 3 , wherein the second ABD is the scFv, and the scFv linker is SEQ ID NO:457.

5. The bispecific antibody of claim 1 , wherein the bispecific antibody further comprises a first Fc domain and a second Fc domain.

6. The bispecific antibody of claim 5 , wherein the first Fc domain and the second Fc domain are each variant human IgG1, IgG2, or IgG4 Fc domains.

7. The bispecific antibody of claim 6 , wherein one of the first and second Fc domains comprises heterodimerization variant T366W, and the other of the first and second Fc domains comprises heterodimerization variants T366S/L368A/Y407V, wherein numbering is according to EU numbering.

8. The bispecific antibody of claim 6 , wherein the first and the second Fc domains each comprise ablation variants L234A/L235A/D265S, wherein numbering is according to EU numbering.

9. The bispecific antibody of claim 6 , wherein the first or the second Fc domain comprises purification variants H435R/Y436F, wherein numbering is according to EU numbering.

10. The bispecific antibody of claim 6 , wherein the first Fc domain comprises amino acid substitutions L234A/L235A/D265S/T366W, and the second Fc domain comprises amino acid substitutions L234A/L235A/D265S/T366S/L368A/Y407V/H435R/Y436F, wherein numbering is according to EU numbering.

11. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a first monomer that is at least 95% identical to SEQ ID NO: 342, a second monomer that is at least 95% identical to SEQ ID NO: 343, and a light chain that is at least 95% identical to SEQ ID NO: 344.

12. A pharmaceutical composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier.

13. A composition comprising one or more nucleic acids encoding the bispecific antibody of claim 1 .

14. A composition comprising one or more expression vectors, wherein each of the one or more expression vectors comprises a nucleic acid of the one or more nucleic acids of claim 13 .

15. A host cell comprising the composition of claim 14 .

16. A method of making a bispecific antibody comprising culturing the host cell of claim 15 under conditions wherein the bispecific antibody is expressed and recovering the bispecific antibody.

17. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient the bispecific antibody of claim 1 .

18. The method of claim 17 , wherein the prostate cancer is castration-resistant prostate cancer.

19. A method of enhancing T cell proliferation in the presence of PSMA-expressing cells, comprising contacting the cells with the bispecific antibody of claim 1 .

20. A method of inhibiting the growth or proliferation of PSMA-expressing cells, comprising contacting the cells with the bispecific antibody of claim 1 .

21. A bispecific anti-PSMA×anti-CD28 antibody comprising:
a) a first monomer having an amino acid sequence of SEQ ID NO: 342;
b) a second monomer having an amino acid sequence of SEQ ID NO: 343; and
c) a light chain having an amino acid sequence of SEQ ID NO: 344.

22. A pharmaceutical composition comprising the bispecific antibody of claim 21 and a pharmaceutically acceptable carrier.

23. A nucleic acid composition comprising:
a) a first nucleic acid encoding a first monomer;
b) a second nucleic acid encoding a second monomer; and
c) a third nucleic acid encoding a light chain,
wherein the first monomer, second monomer, and light chain are the first monomer, second monomer, and light chain of claim 21 , respectively.

24. An expression vector composition comprising:
a) a first expression vector comprising a first nucleic acid encoding a first monomer;
b) a second expression vector comprising a second nucleic acid encoding a second monomer; and
c) a third expression vector comprising a third nucleic acid encoding a light chain,
wherein the first monomer, second monomer, and light chain are the first monomer, second monomer, and light chain of claim 21 , respectively.

25. A host cell comprising the expression vector composition of claim 24 .

26. A method of making a bispecific antibody comprising culturing the host cell of claim 25 under conditions wherein the bispecific antibody is expressed and recovering the bispecific antibody.

27. A method of treating prostate cancer in a patient in need thereof, comprising administering to the patient the bispecific antibody of claim 21 .

28. The method of claim 27 , wherein the prostate cancer is castration-resistant prostate cancer.

29. A method of enhancing T cell proliferation in the presence of PSMA-expressing cells, comprising contacting the cells with the bispecific antibody of claim 21 .

30. A method of inhibiting the growth or proliferation of PSMA-expressing cells, comprising contacting the cells with the bispecific antibody of claim 21 .

Assignees

• Xencor Inc
• Janssen Biotech Inc

Inventors

• Desjarlais John R
• Moore Gregory
• Hedvat Michael
• Diaz Juan
• Gusti Zeng Veronica
• Dragovich Matthew Adam
• Erhardt Joseph
• Mcdevitt Theresa
• Moussa Fouad
• Seth Pankaj
• Shen Fei
• Zwolak Adam

Classifications

• C07K16/3069

  Reproductive system, e.g. ovaria, uterus, testes, prostate · CPC title

• C07K16/2818 Primary

  against CD28 or CD152 · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/31

  multispecific · CPC title