iNKT cell modulators and methods of using the same

Patent metadata

Field	Value
Publication number	US-9365496-B2
Application number	US-201214361434-A
Country	US
Kind code	B2
Filing date	Nov 30, 2012
Priority date	Nov 30, 2011
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Disclosed herein are α-galactosylceramide (α-GalCer) analogs and compositions thereof, methods of activating invariant Natural Killer T (iNKT) cells using said analogs, methods of treating diseases by activating iNKT cells using said analogs, and combination therapy of said analogs.

First claim

What is claimed is:

1. A compound having a structure:

wherein n is 1, 2, or 3;
or a salt thereof.

2. The compound or salt of claim 1 , wherein n is 1.

3. The compound or salt of claim 1 , wherein n is 2 or 3.

4. A composition comprising the compound or salt of claim 1 and a pharmaceutically acceptable carrier.

5. A composition of claim 4 further comprising a second therapeutic selected from the group consisting of a chemotherapeutic agent, a biological response modifying agent, and an immunotherapeutic agent.

6. A method of activating a natural killer T (NKT) cell comprising contacting the cell with the compound or salt of claim 1 in an amount effective to activate the NKT cell.

7. The method of claim 6 , wherein the contacting comprises administering compound or salt of claim 1 to a subject in need of NKT cell activation.

8. The method of claim 7 , wherein the subject suffers from cancer.

9. The method of claim 8 , wherein the subject suffers from melanoma.

10. The method of claim 7 , further comprising administering to the subject a second therapeutic selected from the group consisting of a chemotherapeutic agent, a biological response modifying agent, and an immunotherapeutic agent.

11. The method of claim 10 , wherein the second therapeutic comprises an immunotherapeutic that comprises a cancer vaccine.

12. The method of claim 10 , wherein the second therapeutic agent comprises an immunotherapeutic that comprises a cancer antigen or a polynucleotide comprising a nucleotide sequence encoding a cancer antigen.

13. The method of claim 10 , wherein the second therapeutic comprises an immunotherapeutic agent that comprises at least one antibody selected from the group consisting of an anti-Her2/neu receptor antibody, an anti-CD52 antibody, an anti-CD33 antibody, an anti-CD20 antibody, an anti-TNFα antibody, an anti-CD25 IL-2 receptor antibody, an anti-CD40/CD40L antibody, an anti-CTLA-4 antibody, an anti-PD-1 (anti-CD279) antibody, an anti-PDL-1 antibody, an anti-GITR antibody, and an anti-OX-40 (anti-CD 134) antibody.

14. The method of claim 13 , wherein the antibody is selected from the group consisting of an anti-CTLA4 antibody, an anti-PD1 antibody, an anti-PDL1 antibody, an anti-OX40 antibody and an anti-GITR antibody.

15. The method of claim 13 , wherein the antibody is a monoclonal antibody, a humanized antibody, a human antibody or a chimeric antibody.

16. The method of claim 10 , wherein the second therapeutic and the compound or salt thereof are administered simultaneously.

17. The method of claim 10 , wherein the second therapeutic and the compound or salt thereof are administered sequentially.

18. A method of treating a subject suffering from cancer comprising administering to the subject the compound or salt of claim 1 in an amount effective to treat the cancer.

19. The method of claim 18 , wherein the subject is human.

20. The method of claim 18 , wherein the cancer is melanoma.

21. The method of claim 18 , further comprising administering an immunotherapeutic agent to the subject.

22. The method of claim 21 , wherein the immunotherapeutic agent comprises at least one antibody selected from the group consisting of an anti-Her2/neu receptor antibody, an anti-CD52 antibody, an anti-CD33 antibody, an anti-CD20 antibody, an anti-TNFα antibody, an anti-CD25 IL-2 receptor antibody, an anti-CD40/CD40L antibody, an anti-CTLA-4 antibody, an anti-PD-1 (anti-CD279) antibody, an anti-PDL-1 antibody, an anti-GITR antibody, and an anti-OX-40 (anti-CD 134) antibody.

23. A kit comprising (a) the compound or salt of claim 1 and (b) an immunotherapeutic agent, packaged together but not in admixture.

24. The kit of claim 23 , wherein the immunotherapeutic agent is an antibody.

25. A compound having the structure:

wherein
R 1 is C 5 -C 25 alkyl, C 5 -C 25 alkenyl, C 5 -C 25 alkynyl, C 5 -C 25 heteroalkyl, C 5 -C 25 heteroalkenyl, or C 5 -C 25 heteroalkynyl;
R 2 and R 3 are each independently selected from OH, SH, amino or substituted amino;
R 4 is C 5 -C 20 alkyl, C 5 -C 20 alkenyl, C 5 -C 20 alkynyl, C 5 -C 20 heteroalkyl, C 5 -C 20 heteroalkenyl, or C 5 -C 20 heteroalkynyl;
X is O, S, SO 2 , SO(NH), SO(N(alkyl)), NH, N(alkyl), or CH 2 ;
Y is O, NH, N(alkyl), or S;

or a salt thereof.

26. A compound having the structure:

wherein
R 1 is C 5 -C 25 alkyl, C 5 -C 25 alkenyl, C 5 -C 25 alkynyl, C 5 -C 25 heteroalkyl, C 5 -C 25 heteroalkenyl, or C 5 -C 25 heteroalkynyl;
R 2 and R 3 are each independently selected from OH, SH, amino or substituted amino;
R 4 is C 5 -C 20 alkyl, C 5 -C 20 alkenyl, C 5 -C 20 alkynyl, C 5 -C 20 heteroalkyl, C 5 -C 20 heteroalkenyl, or C 5 -C 20 heteroalkynyl;
X is O, S, SO 2 , SO(NH), SO(N(alkyl)), NH, N(alkyl), or CH 2 ;
Y is O, NH, N(alkyl), or S;

or a salt thereof.

27. The composition of claim 5 , wherein the second therapeutic comprises an immunotherapeutic that comprises a cancer vaccine.

28. The composition of claim 5 , wherein the second therapeutic agent comprises an immunotherapeutic that comprises a cancer antigen.

29. The method of claim 10 , wherein the second therapeutic comprises an immunotherapeutic that comprises a polynucleotide that comprises a nucleotide sequence encoding a cancer antigen.

Assignees

• Univ Oxford
• Univ Birmingham
• Ludwig Inst Cancer Res

Inventors

• Cerundolo Vincenzo
• Besra Gurdyal S
• Cox Liam

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C2601/18

  with a ring being at least seven-membered · CPC title