Bispecific binding proteins and uses thereof

Patent metadata

Field	Value
Publication number	US-RE49908-E
Application number	US-202117364539-A
Country	US
Kind code	E1
Filing date	Jun 30, 2021
Priority date	May 6, 2016
Publication date	Apr 9, 2024
Grant date	Apr 9, 2024

Abstract

The disclosure generally provides proteins that bind two epitopes (e.g., a first and a second epitope) and that are bivalent for binding to each of the first and second epitopes. The disclosure also provides for specific binding proteins, including antibodies, which bind to a target protein. The disclosure also provides compositions comprising such proteins, nucleic acid molecules encoding such proteins and methods of making such proteins. The disclosure provides methods of inducing an immune response in a subject as well as methods for treating or preventing cancer in a subject by administering the proteins, nucleic acid molecules and/or compositions to the subject.

First claim

What is claimed is:

1. A bispecific binding protein that binds to PD-1 and CTLA-4 comprising a first heavy chain comprising the amino acid sequence of SEQ ID NO: 9, a first light chain comprising the amino acid sequence of SEQ ID NO: 7, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 12, and a second light chain comprising the amino acid sequence of SEQ ID NO: 4.

2. The protein of claim 1 comprising an Fc region, wherein the Fc region is aglycosylated.

3. The protein of claim 1 comprising an Fc region, wherein the Fc region is deglycosylated.

4. The protein of claim 1 comprising an Fc region, wherein the Fc region has reduced fucosylation or is afucosylated.

5. A composition comprising the protein of claim 1 and a pharmaceutically acceptable carrier.

6. A nucleic acid molecule comprising a nucleotide sequence encoding a protein of claim 1 .

7. A vector comprising the nucleic acid molecule of claim 6 .

8. An isolated host cell comprising the vector of claim 7 .

9. A method of treating or preventing cancer in a subject, the method comprising administering the protein of claim 1 to the subject.

10. The method of claim 9 , wherein the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

11. A method of enhancing an immune response in a subject, the method comprising administering the protein of claim 1 to the subject.

12. The nucleic acid molecule of claim 6 , wherein the nucleotide encoding the protein of claim 1 comprises a nucleotide sequence encoding a first heavy chain, comprising the nucleotide sequence of SEQ ID NO: 10; a nucleotide sequence encoding a first light chain, comprising the nucleotide sequence of SEQ ID NO: 8; a nucleotide sequence encoding a second heavy chain, comprising the nucleotide sequence of SEQ ID NO: 13; and a nucleotide sequence encoding a second light chain, comprising the nucleotide sequence of SEQ ID NO: 11.

13. A bispecific binding protein that binds to PD-1 and CTLA-4 comprising:
(i) a first heavy chain comprising a VH1-CDR1, VH1-CDR2 and VH1-CDR3, wherein VH1-CDR1 comprises the amino acid sequence of residues 26-35 of SEQ ID NO: 9, wherein VH1-CDR2 comprises the amino acid sequence of residues 50-66 of SEQ ID NO: 9, and wherein VH1-CDR3 comprises the amino acid sequence of residues 99-111 of SEQ ID NO: 9; (ii) a first light chain comprising a VL1-CDR1, VL1-CDR2, VL1-CDR3, wherein VL1-CDR1 comprises the amino acid sequence of residues 24-41 of SEQ ID NO: 7, wherein VL1-CDR2 comprises the amino acid sequence of residues 55-61 of SEQ ID NO: 7, and wherein VL1-CDR3 comprises the amino acid sequence of residues 94-100 of SEQ ID NO: 7; (iii) a second heavy chain comprising a VH2-CDR1, VH2-CDR2 and VH2-CDR3, wherein VH2-CDR1 comprises the amino acid sequence of residues 26-35 of SEQ ID NO: 12, wherein VH2-CDR2 comprises the amino acid sequence of residues 50-66 of SEQ ID NO: 12, and wherein VH2-CDR3 comprises the amino acid sequence of residues 99-114 of SEQ ID NO: 12; and (iv) a second light chain comprising a VL2-CDR1, VL2-CDR2 and VL2-CDR3, wherein VL2-CDR1 comprises the amino acid sequence of residues 24-34 of SEQ ID NO: 4, wherein VL2-CDR2 comprises the amino acid sequence of residues 50-56 of SEQ ID NO: 4, and wherein VL2-CDR3 comprises the amino acid sequence of residues 89-95 of SEQ ID NO: 4.

14. The protein of claim 13 comprising an Fc region, wherein the Fc region is aglycosylated.

15. The protein of claim 13 comprising an Fc region, wherein the Fc region is deglycosylated.

16. The protein of claim 13 comprising an Fc region, wherein the Fc region has reduced fucosylation or is afucosylated.

17. A composition comprising the protein of claim 13 and a pharmaceutically acceptable carrier.

18. A nucleic acid molecule comprising a nucleotide sequence encoding a protein of claim 13.

19. A vector comprising the nucleic acid molecule of claim 18.

20. An isolated host cell comprising the vector of claim 19.

21. A method of treating cancer in a subject, the method comprising administering the protein of claim 13 to the subject.

22. The method of claim 21, wherein the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

23. A method of enhancing an immune response in a subject, the method comprising administering the protein of claim 13 to the subject.

24. A bispecific binding protein that binds to PD-1 and CTLA-4 comprising a first heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51, a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 49, a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52, and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 54.

25. The protein of claim 24 comprising an Fc region, wherein the Fc region is aglycosylated.

26. The protein of claim 24 comprising an Fc region, wherein the Fc region is deglycosylated.

27. The protein of claim 24 comprising an Fc region, wherein the Fc region has reduced fucosylation or is afucosylated.

28. A composition comprising the protein of claim 24 and a pharmaceutically acceptable carrier.

29. A nucleic acid molecule comprising a nucleotide sequence encoding a protein of claim 24.

30. A vector comprising the nucleic acid molecule of claim 29.

31. An isolated host cell comprising the vector of claim 30.

32. A method of treating cancer in a subject, the method comprising administering the protein of claim 24 to the subject.

33. The method of claim 32, wherein the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

34. A method of enhancing an immune response in a subject, the method comprising administering the protein of claim 24 to the subject.

35. The method of claim 10, wherein the cancer is melanoma.

36. The method of claim 10, wherein the cancer is renal cell carcinoma.

37. The method of claim 10, wherein the cancer is lung cancer.

38. The method of claim 22, wherein the cancer is melanoma.

39. The method of claim 22, wherein the cancer is renal cell carcinoma.

40. The method of claim 22, wherein the cancer is lung cancer.

41. The method of claim 33, wherein the cancer is melanoma.

42. The method of claim 33, wherein the cancer is renal cell carcinoma.

43. The method of claim 33, wherein the cancer is lung cancer.

Assignees

• Medimmune Llc

Inventors

• Kasturirangan Srinath
• Gao Changshou
• Rainey Godfrey
• Morrow Michelle
• Dobson Claire Louise
• Drabic Stacey
• Schofield Darren
• Carlesso Gianluca
• Pollizzi Kristen
• Mazor Yariv
• Oberst Michael
• Hammond Scott A
• Lobo Brian
• Manikwar Prakash
• Seaman Jonathan
• Dovedi Simon
• Herbst Ronald

Classifications

• C12N15/63

  Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C12N5/10

  Cells modified by introduction of foreign genetic material · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title