RESTORING FUNCTION OF TUMOUR ACIDIFIED T CELLS

• US 20180087088A1
• Filed: 09/22/2017
• Published: 03/29/2018
• Est. Priority Date: 09/24/2016
• Status: Active Grant

• Current Assignee: Helix Biopharma Corp
• Original Assignee: Helix Biopharma Corp
• Inventors: Wong, Wah Yau, Tian, Baomin, Gaspar, Kim, Uger, Marni Diane, Rohmann, Sven, Chao, Heman Lap Man
• Granted Patent: US 10,640,806 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/55533 IL-2
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 39/001129 Molecules with a "CD" designation not provided for elsewhere
• CPC Class Codes: A61K 47/6815 Enzymes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C12N 9/00 Enzymes; Proenzymes; Compositions thereof preparations containing enzymes for cleaning teeth A61K8/66, A61Q11/00; medicinal preparations containing enzymes or proenzymes A61K38/43; enzyme containing detergent compositions C11D; enzymes with nucleic acid structure, e.g. ribozymes, C12N15/113; Processes for preparing, activating, inhibiting, separating or purifying enzymes preparation of malt C12C1/00
• CPC Class Codes: C12Q 1/58 involving urea or urease

Abstract

Methods and compositions to restore function to acidified T cells are provided. The methods comprise administering urease to the T cells. Compositions comprise urease.

Claims

1. A method for restoring function to acidified T cells, the method comprising administering urease to the T cells.

2. The method of claim 1, wherein restoring function comprises increasing production of cytokines.

3. The method of claim 2, wherein the cytokines comprise IL-2.

4. The method of claim 1, wherein the T cells are acidified relative to physiological pH such that the T cells have a pH of less than about 7.2, less than about 7.1, less than about 7.0, less than about 6.9, or less than about 6.8.

5. The method of claim 4, wherein the T cells are acidified with lactate produced by a solid tumor.

6. The method of claim 1, wherein the T cells are in the presence of urea, either native or administered.

7. The method of claim 1, wherein the T cells express PD-1, optionally at higher than normal levels compared to a non-acidified T cell and wherein the urease inhibits PD-1 expression and/or activation.

8. The method of claim 1, wherein the urease is conjugated to a targeting moiety.

9. The method of claim 8, wherein the targeting moiety is an antibody specific for a tumor-associated antigen.

10. The method of claim 8, wherein the tumor-associated antigen is CEACAM6.

11. The method of claim 10, wherein the antibody is an AFAIKL2 antibody or a 2A3 antibody.

12. The method of claim 1, wherein the urease inhibits PD-L1 expression on acid sensitive cancer cells.

13. The method of claim 1, further comprising administering to said acidified T cells an active agent selected from a PD-1 inhibitor, a chemotherapeutic agent, radiation, a hormone, a cytokine such as IL-2 and combinations thereof.

14. The method of claim 1, in conjunction with immunotherapy, such as adoptive T cell therapy.

15. The method of claim 1, wherein the urease is administered in an amount sufficient to increase the pH in the vicinity of the acidified T cells to physiological levels, such as 7.2.

16. The method of claim 15, wherein the urease is administered in an amount sufficient to decrease PD-1 expression on the T cells.

17. The method of claim 1, wherein the urease is administered in an amount that does not cause significant T cell death or harm.

18. A method of normalizing IL-2 production by T cells subjected to acidified conditions, the method comprising administering urease to the T cells.

19. A method of inhibiting lactate-induced T cell tolerance to tumor cells, the method comprising administering urease to the T cells.

20. A method for increasing an immune response to a CEACAM6+ and/or PD-L1+ cancer by reactivating acidified T cells, the method comprising administering urease to a subject having a CEACAM6+ and/or PD-L1+ cancer.

21. The method of claim 20, wherein said urease increases T cell infiltration into said cancer, said cancer being a solid tumor.

22. A composition comprising or consisting of urease and optionally a PD-1 inhibitor and/or a PDL-1 inhibitor for restoring T cell function.

23. The composition of claim 22, wherein said composition increases IL-2 production by T cells.