Methods for treating hematologic cancers

Patent metadata

Field	Value
Publication number	US-10570204-B2
Application number	US-201415024396-A
Country	US
Kind code	B2
Filing date	Sep 25, 2014
Priority date	Sep 26, 2013
Publication date	Feb 25, 2020
Grant date	Feb 25, 2020

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.

First claim

What is claimed is:

1. A method of treating a subject afflicted with a hematologic cancer, comprising administering to the subject a therapeutically effective amount of a bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3.

2. The method of claim 1 , wherein said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is murine, chimeric, humanized, composite, or human.

3. The method of claim 1 , wherein said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or comprises an Fv, Fav, F(ab′)2, Fab′, dsFv, scFv, sc(Fv)2, and diabody fragment.

4. The method of claim 1 , wherein said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is conjugated to a therapeutic moiety selected from the group consisting of a lymphokine, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), a cytokine, and a growth factor.

5. The method of claim 1 , wherein said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is administered in a pharmaceutically acceptable formulation.

6. The method of claim 1 , further comprising administering to the subject a therapeutic agent for treating the hematologic cancer.

7. The method of claim 1 , further comprising administering to the subject a treatment that causes transient lymphodepletion.

8. The method of claim 7 , wherein the treatment that causes transient lymphodepletion comprises sublethal whole body irradiation, a myeloablative agent, an immunosuppressive agent, or a combination thereof.

9. The method of claim 7 , wherein the treatment that causes transient lymphodepletion is administered occurs before, concurrently with, or after the bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is administered.

10. The method of claim 1 , 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).

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

12. The method of claim 1 , wherein the hematologic cancer is multiple myeloma.

13. The method of claim 1 , wherein the subject is a human.

14. A method of treating a subject afflicted with a multiple myeloma, comprising administering to the subject a therapeutically effective amount of an inhibitor of PD-L1 and an inhibitor of TIM-3, comprising (a) an antibody, or antigen-binding fragment thereof, that binds to PD-L1, and an antibody, or antigen-binding fragment thereof, that binds to TIM-3; or (b) a bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3.

15. The method of claim 14 , wherein said antibody, or antigen binding fragment thereof, that binds to PD-L1, said antibody, or antigen-binding fragment thereof, that binds to TIM-3, or said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is murine, chimeric, humanized, composite, or human.

16. The method of claim 14 , comprising administering to the subject a therapeutically effective amount of an inhibitor of PD-L1 and an inhibitor of TIM-3, comprising an antibody, or antigen-binding fragment thereof, that binds to PD-L1, and an antibody, or antigen-binding fragment thereof, that binds to TIM 3.

17. The method of claim 14 , wherein said antibody, or antigen binding fragment thereof, that binds to PD-L1, said antibody, or antigen-binding fragment thereof, that binds to TIM-3, or said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or comprises an Fv, Fav, F(ab′)2, Fab′, dsFv, scFv, sc(Fv)2, or diabody fragment.

18. The method of claim 14 , wherein said antibody, or antigen binding fragment thereof, that binds to PD-L1, said antibody, or antigen-binding fragment thereof, that binds to TIM-3, or said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is conjugated to a therapeutic moiety selected from the group consisting of a lymphokine, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), a cytokine, and a growth factor.

19. The method of claim 14 , wherein said antibody, or antigen binding-fragment thereof, that binds to PD-L1, said antibody, or antigen-binding fragment thereof, that binds to TIM-3, or said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is administered in a pharmaceutically acceptable formulation.

20. The method of claim 14 , further comprising administering to the subject a therapeutic agent for treating the multiple myeloma.

21. The method of claim 14 , further comprising administering to the subject a treatment that causes transient lymphodepletion.

22. The method of claim 21 , wherein the treatment that causes transient lymphodepletion comprises sublethal whole body irradiation, a myeloablative agent, an immunosuppressive agent, or a combination thereof.

23. The method of claim 21 , wherein the treatment that causes transient lymphodepletion is administered before, concurrently with, or after the said antibody, or antigen binding fragment thereof, that binds to PD-L1, said antibody, or antigen-binding fragment thereof, that binds to TIM-3, or said bispecific or multispecific antibody, or antigen-binding fragment thereof, selective for PD-L1 and TIM-3, is administered.

Assignees

• Novartis Ag
• Medical College Wisconsin Inc

Inventors

• Johnson Bryon Duane
• Millman Robert

Classifications

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title