Restoring function of tumour acidified T cells

• US 10,640,806 B2
• Filed: 09/22/2017
• Issued: 05/05/2020
• 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
• Primary Examiner(s): Gamett, Daniel C
• Application Number:
  US15/712,802
• Publication Number:
  US 20180087088A1
• Time in Patent Office: 956 Days
• Field of Search: None
• 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, wherein the urease is conjugated to an antibody specific for CEACAM6.

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 are in an environment of 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 antibody is an AFAIKL2 antibody or a 2A3 antibody.

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

10. 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 and combinations thereof.

11. The method of claim 10, wherein the cytokine is IL-2.

12. The method of claim 1, in conjunction with immunotherapy.

13. The method of claim 12, wherein the immunotherapy is adoptive T cell therapy.

14. 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.

15. The method of claim 14, wherein the urease is administered in an amount sufficient to decrease PD-1 expression on the T cells.

16. The method of claim 14, wherein the pH is increased to 7.2.

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, wherein the urease is conjugated to an antibody specific for CEACAM6.

19. A method of inhibiting lactate-induced T cell tolerance to tumor cells, the method comprising administering urease to the T cells, wherein the urease is conjugated to an antibody specific for CEACAM6.

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, wherein the urease is conjugated to an antibody specific for CEACAM6.

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 conjugated to an antibody specific for CEACAM6 and 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.