Combination therapy to enhance NK cell mediated cytotoxicity

Patent metadata

Field	Value
Publication number	US-9415104-B2
Application number	US-201414198845-A
Country	US
Kind code	B2
Filing date	Mar 6, 2014
Priority date	Dec 5, 2008
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

The function of natural killer (NK) cells is regulated by inhibitory and activating signals delivered by cell surface receptors, 1-7F9 is a fully human monoclonal antibody (mAb) directed against KIR2DL1 and K1R2DL2/3 receptors that blocks its interaction with its HLA-C ligands breaking NK cell tolerance to autologous tumor ceils. Lεnalidomide has been shown to increase NK cell cytotoxicity in vitro. The combination of lenalidomide and 1-7F9 enhanced NK cell mediated cytotoxicity against U266 cells beyond that observed with each agent alone. Lenalidomide also increased the expression of NKG2D, DNAM-I and TRAIL ligands including: MICA, ULB P2, CD1 12 and DR 4 on U266 cells. In in vitro cytotoxicity assays, lenalidomide enhanced the susceptibility of myeloma cell lines to NK ceil. The NK ceil signaling pathways was also explored after lenalidomide treatment and the results show that lenalidomide may upregulate the phospho-SHIP1 (Tyr1020) and has no effect on phospho-p44/42 (ERK 1/2) (Thr202/Tyr204) in NK cells. These results provide pre clinical rationale for clinical investigation of 1-7F9 anti-KIR mAb and lenalidomide in MM.

First claim

I claim:

1. A method of treating a patient having a cancer, comprising administering to the patient a combination of a therapeutically effective amount of (a) 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof, and (b) an antibody or an antigen-binding fragment thereof that (i) cross-reacts with KIR2DL1 and KIR2DL2/3, and (ii) enhances NK cell cytotoxicity.

2. The method according to claim 1 , wherein the patient is a human.

3. The method according to claim 1 , wherein the therapeutically effective amount of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof is between about 1 mg to about 50 mg per day.

4. The method according to claim 1 , wherein the therapeutically effective amount of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof is between about 5 mg to about 50 mg per day.

5. The method according to claim 1 , wherein the therapeutically effective amount of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof is between about 1 mg to about 25 mg per day.

6. The method according to claim 1 , wherein the therapeutically effective amount of said antibody or antigen-binding fragment thereof is between about 1 mg/kg to about 3 mg/kg per month.

7. The method according to claim 1 , wherein the cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and a myelodysplastic syndrome (MDS).

8. The method according to claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2.

9. The method according to claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:3.

10. A method of treating a patient having a cancer, consisting essentially of administering to the patient a combination of a therapeutically effective amount of (a) 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof and (b) an antibody or an antigen-binding fragment thereof that (i) cross-reacts with KIR2DL1 and KIR2DL2/3, and (ii) enhances NK cell cytotoxicity.

11. The method according to claim 10 , wherein the cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and a myelodysplastic syndrome (MDS).

12. The method according to claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2.

13. The method according to claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:3.

14. The method according to claim 1 , wherein the combination elicits a synergistic or additive effect on NK cell-mediated killing of cancer cells.

15. The method according to claim 10 , wherein the combination elicits a synergistic or additive effect on NK cell-mediated killing of cancer cells.

16. A kit for inducing death of cancer cells, comprising:
a biologically active amount of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof; and
a biologically active amount of an antibody or an antigen-binding fragment thereof that (i) cross-reacts with KIR2DL1 and KIR2DL2/3, and (ii) enhances NK cell cytotoxicity.

17. A kit for treating a cancer, comprising:
at least one therapeutically effective dose of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)piperidine-2,6-dione or a pharmaceutically acceptable salt thereof; and
at least one therapeutically effective dose of an antibody or an antigen-binding fragment thereof that (i) cross-reacts with KIR2DL1 and KIR2DL2/3, and (ii) enhances NK cell cytotoxicity.

18. The kit according to claim 16 , wherein the cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and a myelodysplastic syndrome (MDS).

19. The kit according to claim 17 , wherein the cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and a myelodysplastic syndrome (MDS).

20. The kit according to claim 16 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2.

21. The kit according to claim 17 , wherein said antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:2.

22. The kit according to claim 16 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:3.

23. The kit according to claim 17 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:1 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:3.

Assignees

• Novo Nordisk As

Inventors

• Farag Sherif S

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61K39/3955 Primary

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title