Combination of Anti-PD-1 Antibodies and Anti-CD20/Anti-CD3 Antibodies to Treat Cancer

• US 20170174779A1
• Filed: 12/21/2016
• Published: 06/22/2017
• Est. Priority Date: 12/22/2015
• Status: Abandoned Application

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: THURSTON, Gavin, VARGHESE, Bindu, BROWNSTEIN, Carrie, LOWY, Israel
• Application Number:
  US15/386,453
• Publication Number:
  US 20170174779A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3061 Blood cells
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]

Abstract

The present invention provides methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin'"'"'s lymphoma or acute lymphoblastic leukemia). The methods of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3.

Claims

1. A method of treating or inhibiting the growth of a tumor comprising administering to a subject in need thereof a therapeutically effective amount each of (a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);

and (b) a bispecific antibody comprising a first antigen-binding arm that specifically binds CD20 and a second antigen-binding arm that specifically binds CD3.

2. The method of claim 1, wherein the anti-PD-1 antibody comprises between 0.1-20 mg/kg of the subject'"'"'s body weight.

3. The method of claim 2, wherein the anti-PD-1 antibody comprises 0.3, 1, 3 or 10 mg/kg of the subject'"'"'s body weight.

4. The method of claim 1, wherein the bispecific antibody comprises between 0.1-10 mg/kg of the subject'"'"'s body weight.

5. The method of claim 1, wherein the bispecific antibody comprises 10-8000 micrograms.

6. The method of claim 1, wherein the anti-PD-1 antibody is administered prior to, concurrent with or after the bispecific antibody.

7. The method of claim 6, wherein the anti-PD-1 antibody is administered prior to the bispecific antibody.

8. The method of claim 7, wherein the anti-PD-1 antibody is administered 1 week prior to the bispecific antibody.

9. The method of claim 1, wherein one or more doses of the anti-PD-1 antibody are administered in combination with one or more doses of the bispecific antibody.

10. The method of claim 9, wherein each dose of the anti-PD-1 antibody comprises between 0.1-20 mg/kg of the subject'"'"'s body weight.

11. The method of claim 10, wherein each dose of the anti-PD-1 antibody comprises 0.3, 1, 3, or 10 mg/kg of the subject'"'"'s body weight.

12. The method of claim 9, wherein each dose of the bispecific antibody comprises between 0.1-10 mg/kg of the subject'"'"'s body weight.

13. The method of claim 10, wherein each dose of the bispecific antibody comprises between 10-8000 micrograms.

14. The method of claim 13, wherein each dose of the anti-PD-1 antibody comprises 1, 3 or 10 mg/kg and each dose of the bispecific antibody comprises 30, 100, 300, 1000 or 2000 micrograms.

15. The method of claim 9, wherein each dose of the anti-PD-1 antibody is administered 0.5-12 weeks after the immediately preceding dose.

16. The method of claim 15, wherein each dose of the bispecific antibody is administered 0.5-12 weeks after the immediately preceding dose.

17. The method of claim 16, wherein each dose of the anti-PD-1 antibody is administered once in two weeks and each dose of the bispecific antibody is administered once a week.

18. The method of claim 9, wherein each dose of the bispecific antibody is split into 2-5 fractions within a dosing period.

19. The method of claim 9, wherein the anti-PD-1 antibody is administered prior to, concurrent with or after the bispecific antibody.

20. The method of claim 19, wherein the anti-PD-1 antibody is administered prior to the bispecific antibody.

21. The method of claim 20, wherein the anti-PD-1 antibody is administered 1 week prior to the bispecific antibody.

22. The method of claim 9, wherein the antibodies are administered intravenously, subcutaneously, or intraperitoneally.

23. The method of claim 9, wherein the tumor comprises a B-cell cancer.

24. The method of claim 23, wherein the B-cell cancer is selected from the group consisting of Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, follicular lymphoma, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, marginal zone lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, B-cell lymphomas, lymphomatoid granulomatosis, Burkitt'"'"'s lymphoma, acute lymphoblastic leukemia, hairy cell leukemia, and B cell chronic lymphocytic leukemia.

25. The method of claim 1, wherein the subject is resistant or inadequately responsive to, or relapsed after prior therapy.

26. The method of claim 1, wherein the treatment produces a therapeutic effect selected from the group consisting of delay in tumor growth, reduction in tumor cell number, tumor regression, increase in survival, partial response, and complete response.

27. The method of claim 26, wherein tumor growth is delayed by at least 10 days as compared to an untreated subject.

28. The method of claim 1, wherein the tumor growth is inhibited by at least 50% as compared to an untreated subject.

29. The method of claim 9, wherein the tumor growth is inhibited by at least 50% as compared to a subject administered with either antibody as monotherapy.

30. The method of claim 20, wherein the tumor growth is inhibited by at least 50% as compared to a subject administered a bispecific anti-CD20/anti-CD3 antibody prior to an anti-PD-1 antibody.

31. The method of claim 9 further comprising administering to the subject a third therapeutic agent or therapy, wherein the third therapeutic agent or therapy is selected from the group consisting of radiation, surgery, a chemotherapeutic agent, a cancer vaccine, a PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFβ

) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-21, IL-15, an antibody-drug conjugate, an anti-inflammatory drug, and a dietary supplement.

32. The method of claim 9, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:

1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

2.

33. The method of claim 32, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:

3;

HCDR2 comprises the amino acid sequence of SEQ ID NO;

4;

HCDR3 comprises the amino acid sequence of SEQ ID NO;

5;

LCDR1 comprises the amino acid sequence of SEQ ID NO;

6;

LCDR2 comprises the amino acid sequence of SEQ ID NO;

7; and

LCDR3 comprises the amino acid sequence of SEQ ID NO;

8.

34. The method of claim 33, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:

1 and the LCVR comprises the amino acid sequence of SEQ ID NO;

2.

35. The method of claim 34, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

9 and a light chain comprising the amino acid sequence of SEQ ID NO;

10.

36. The method of claim 9, wherein the first antigen-binding arm of the bispecific antibody comprises three heavy chain CDRs (A-HCDR1, A-HCDR2 and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO:

11 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

12.

37. The method of claim 36, wherein A-HCDR1 comprises the amino acid sequence of SEQ ID NO:

14;

A-HCDR2 comprises the amino acid sequence of SEQ ID NO;

15;

A-HCDR3 comprises the amino acid sequence of SEQ ID NO;

16;

LCDR1 comprises the amino acid sequence of SEQ ID NO;

17;

LCDR2 comprises the amino acid sequence of SEQ ID NO;

18; and

LCDR3 comprises the amino acid sequence of SEQ ID NO;

19.

38. The method of claim 37, wherein the A-HCVR comprises the amino acid sequence of SEQ ID NO:

11 and the LCVR comprises the amino acid sequence of SEQ ID NO;

12.

39. The method of claim 9, wherein the second antigen-binding arm of the bispecific antibody comprises three heavy chain CDRs (B-HCDR1, B-HCDR2 and B-HCDR3) of a heavy chain variable region (B-HCVR) comprising the amino acid sequence of SEQ ID NO:

13 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

12.

40. The method of claim 39, wherein B-HCDR1 comprises the amino acid sequence of SEQ ID NO:

20;

B-HCDR2 comprises the amino acid sequence of SEQ ID NO;

21;

B-HCDR3 comprises the amino acid sequence of SEQ ID NO;

22;

LCDR1 comprises the amino acid sequence of SEQ ID NO;

17;

LCDR2 comprises the amino acid sequence of SEQ ID NO;

18; and

LCDR3 comprises the amino acid sequence of SEQ ID NO;

19.

41. The method of claim 40, wherein the B-HCVR comprises the amino acid sequence of SEQ ID NO:

13 and the LCVR comprises the amino acid sequence of SEQ ID NO;

12.