METHODS FOR TREATING HEMATOLOGIC CANCERS

• US 20160222121A1
• Filed: 09/25/2014
• Published: 08/04/2016
• Est. Priority Date: 09/26/2013
• Status: Active Grant

• Current Assignee: Medical College of Wisconsin Incorporated, Novartis Ag
• Original Assignee: Medical College of Wisconsin Incorporated, CoStim Pharmaceuticals Inc. (Novartis Ag)
• Inventors: Johnson, Bryon Duane, Millman, Robert
• Granted Patent: US 10,570,204 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 51/1096 radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/626 Diabody or triabody
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention relates to methods of treating hematologic cancers using a combination of inhibitors of PD-1 or PD-L1 and TIM-3, LAG-3 or CTLA-4. In one embodiment, an inhibitor of PD-1 or PD-L1 is administered in combination with an inhibitor of TIM-3. In another embodiment, an inhibitor of PD-1 or PD-L1 is administered in combination with an inhibitor of LAG-3. In yet another embodiment, an inhibitor of PD-1 or PD-L1 is administered in combination with an inhibitor of CTLA-4.

Claims

1. A method of treating a subject afflicted with a hematologic cancer comprising administering to the subject a therapeutically effective amount of an inhibitor of PD-L1 or PD-1 and an inhibitor of TIM-3, LAG-3 or CTLA4.

2. The method of claim 1 wherein an inhibitor of PD-L1 is administered in combination with an inhibitor of TIM-3.

3. The method of claim 1 wherein an inhibitor of PD-1 is administered in combination with an inhibitor of TIM-3.

4. The method of claim 1 wherein an inhibitor of PD-L1 is administered in combination with an inhibitor of LAG-3.

5. The method of claim 1 wherein an inhibitor of PD-1 is administered in combination with an inhibitor of LAG-3.

6. The method of claim 1 wherein an inhibitor of PD-L1 is administered in combination with an inhibitor of CTLA-4.

7. The method of claim 1 wherein an inhibitor of PD-1 is administered in combination with an inhibitor of CTLA-4.

8. The method of any of claims 1-7, wherein the inhibitor is chosen from an inhibitory nucleic acid, a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to one or more of PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

9. The method of any of claims 1-7, wherein the inhibitor is a bispecific or multispecific antibody, or antigen binding fragment thereof, selective for PD-1 or PD-L1 and TIM-3, LAG-3 or CTLA4.

10. The method of any of claims 1-7, wherein a combination of inhibitors comprising a first inhibitor that selectively inhibits or blocks PD-1 or PD-L1 and a second inhibitor that selectively inhibits or blocks TIM-3, LAG-3 or CTLA4 are administered.

11. The method of any of claims 1-7, wherein the inhibitor is a soluble ligand of PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

12. The method of claim 10, wherein the first inhibitor, second inhibitor, or both inhibitors, is an antibody or an antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4.

13. The method of claim 12, wherein said antibody, or antigen binding fragment thereof, is murine, chimeric, humanized, composite, or human.

14. The method of claim 12, wherein said antibody, or antigen binding fragment thereof, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or is selected from the group consisting of Fv, Fav, F(ab′

)2), Fab′

, dsFv, scFv, sc(Fv)2, and diabodies fragments.

15. The method of claim 12, wherein said antibody, or antigen binding fragment thereof, is conjugated to a cytotoxic agent.

16. The method of claim 15, wherein said cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope.

17. The method of claim 8, wherein said inhibitory nucleic acid comprises an RNA interfering agent which inhibits expression of PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

18. The method of claim 17, wherein said RNA interfering agent is a small interfering RNA (siRNA), small hairpin RNA (shRNA), or a microRNA (miRNA).

19. The method of claim 8, wherein said inhibitory nucleic acid comprises an antisense oligonucleotide complementary to PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

20. The method of any of claims 1-7, wherein said inhibitor comprises a peptide or peptidomimetic that inhibits or blocks PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

21. The method of any of claims 1-7, wherein said inhibitor comprises a small molecule that inhibits or blocks PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

22. The method of any of claims 1-7, wherein said inhibitor comprises an aptamer that inhibits or blocks PD-1, PD-L1, TIM-3, LAG-3 or CTLA-4.

23. The method of any of claims 1-7, wherein said inhibitor is administered in a pharmaceutically acceptable formulation.

24. The method of any of claims 1-7, further comprising administering to the subject a therapeutic agent for treating the hematologic cancer.

25. The method of any of claims 1-7, further comprising a step of transient or complete lymphodepletion.

26. The method of claim 25, wherein sublethal whole body irradiation is used for transient lymphodepletion.

27. The method of claim 25, wherein lethal whole body irradiation is used for complete lymphodepletion.

28. The method of claim 25, wherein the step of lymphodepletion occurs before, concurrently with, or after the step of agent administration.

29. The method of any of claims 1-7, wherein the hematologic cancer is selected from the group consisting of multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin'"'"'s lymphoma, Hodgkin'"'"'s lymphoma, mantle cell lymphoma, follicular lymphoma, Waldenstrom'"'"'s macroglobulinemia, B-cell lymphoma and diffuse large B-cell lymphoma, precursor B-lymphoblastic leukemia/lymphoma, B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma (with or without villous lymphocytes), hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of the MALT type, nodal marginal zone B-cell lymphoma (with or without monocytoid B cells), Burkitt'"'"'s lymphoma;

precursor T-lymphoblastic lymphoma/leukemia, T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell lymphoma/leukemia (HTLV 1-positive), nasal-type extranodal NK/T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic γ

-δ

T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides/Sezary syndrome, anaplastic large cell lymphoma (T/null cell, primary cutaneous type), anaplastic large cell lymphoma (T-/null-cell, primary systemic type), peripheral T-cell lymphoma not otherwise characterized, angioimmunoblastic T-cell lymphoma, polycythemia vera (PV), myelodysplastic syndrome (MDS), indolent Non-Hodgkin'"'"'s Lymphoma (iNHL) and aggressive Non-Hodgkin'"'"'s Lymphoma (aNHL).

30. The method of any of claims 1-7, wherein the hematologic cancer is selected from the group consisting of B-cell lymphoma, myeloid leukemia and multiple myeloma.

31. The method of any of claims 1-7, wherein the hematologic cancer is multiple myeloma.

32. The method of any of claims 1-7, wherein the subject is a human.

33. A kit for treating a subject afflicted with a hematologic cancer comprising one or more agents, wherein at least one agent selectively inhibits or blocks PD-1 or PD-L1 and TIM-3, LAG-3 or CTLA4.

34. The kit of claim 33, wherein the agent is a bispecific or multispecific antibody, or antigen binding fragment thereof, selective for PD-1 or PD-L1 and TIM-3, LAG-3 or CTLA4.

35. A kit for treating a subject afflicted with a hematologic cancer comprising a first agent that selectively inhibits or blocks PD-1 or PD-L1 and a second agent that selectively inhibits or blocks TIM-3, LAG-3 or CTLA4.

36. The kit of claim 35, wherein said first agent and/or second agent is an antibody, or an antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 protein and/or TIM-3, LAG-3 or CTLA4 protein.

37. The kit of claim 35 or 36, wherein said antibody, or antigen binding fragment thereof, is murine, chimeric, humanized, composite, or human.

38. The kit of claim 35 or 36, wherein said antibody, or antigen binding fragment thereof, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or is selected from the group consisting of Fv, Fav, F(ab′

)2), Fab′

, dsFv, scFv, sc(Fv)2, and diabodies fragments.

39. The kit of claim 35 or 36, wherein said antibody, or antigen binding fragment thereof, is conjugated to a cytotoxic agent.

40. The kit of claim 39, wherein said cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope.

41. The kit of claim 35 or 36, wherein said agent is selected from the group consisting of a) an RNA interfering agent which inhibits expression of PD-L1 or PD-1 and TIM-3, LAG-3 or CTLA4, optionally wherein said RNA interfering agent is an small interfering RNA (siRNA), small hairpin RNA (shRNA), or a microRNA (miRNA);

b) an antisense oligonucleotide complementary to PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4;

c) a peptide or peptidomimetics that inhibits or blocks PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4;

d) a small molecule that inhibits or blocks PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4, optionally wherein said small molecule inhibits a protein-protein interaction between PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4 and a receptor; and

e) an aptamer that inhibits or blocks PD-1 or PD-L1 and/or TIM-3, LAG-3 or CTLA4.