Methods for treating hematologic cancers

Patent metadata

Field	Value
Publication number	US-2016222121-A1
Application number	US-201415024396-A
Country	US
Kind code	A1
Filing date	Sep 25, 2014
Priority date	Sep 26, 2013
Publication date	Aug 4, 2016
Grant date	—

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 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.

Assignees

• Costim Pharmaceuticals Inc
• Medical College Wisconsin Inc

Inventors

• Johnson Bryon Duane
• Millman Robert

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K2039/507

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

• A61K47/6849

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