Granted Patent B2

US 12,226,439 · App. 17/934,166 · Granted Feb 18, 2025

Inventors: Christopher D. Thanos (Tiburon, CA); Laura Hix Glickman (Oakland, CA); Justin Skoble (Berkeley, CA); Alexandre Charles Michel Iannello (Oakland, CA)

Assignee: Actym Therapeutics, Inc.

A61K35/74A61K39/0275A61K39/4611A61K39/4614A61K39/4622A61K39/4644A61K39/464832A61P35/00C07K14/521C07K16/248C07K16/2818C07K16/2827C12N1/205C12N15/74A61K45/06A61K2239/50C12R2001/42

Abstract

Claims (56)

1. A method of treatment of cancer, comprising administering an immunostimulatory bacterium, wherein:

the immunostimulatory bacterium comprises a plasmid that encodes an anti-cancer therapeutic product;

the genome of the immunostimulatory bacterium is modified so that the bacterium is taken up by phagocytic cells and does not infect epithelial cells; and

the bacterium without the modifications does infect epithelial cells.

2. A method of treatment of cancer in a subject, comprising administering an immunostimulatory bacterium, wherein:

the immunostimulatory bacterium comprises a plasmid that encodes a therapeutic product;

nucleic acid encoding the therapeutic product is under control of a eukaryotic promoter; and

the immunostimulatory bacterium comprises genome modifications, whereby the bacterium is pagP - /msbB - .

3. The method of claim 1 , wherein the immunostimulatory bacterium comprises a genome modification or modifications whereby the bacterium lacks flagella, wherein the wild-type bacterium comprises flagella.

4. The method of claim 2 , wherein the immunostimulatory bacterium comprises a genome modification or modifications whereby the bacterium lacks flagella, wherein the wild-type bacterium comprises flagella.

5. The method of claim 1 , wherein the immunostimulatory bacterium is an adenosine auxotroph.

6. The method of claim 1 , wherein the therapeutic product is a protein or a nucleic acid.

7. The method of claim 1 , wherein the therapeutic product is an immunostimulatory protein that, when expressed in a mammalian subject, confers, or contributes to anti-tumor immunity in the tumor microenvironment.

8. The method of claim 4 , wherein the therapeutic product is an immunostimulatory protein that, when expressed in a mammalian subject, confers, or contributes to anti-tumor immunity in the tumor microenvironment.

9. The method of claim 2 , wherein the therapeutic product is an immunostimulatory protein that confers or contributes to an anti-tumor immune response in the tumor microenvironment.

10. The method of claim 1 , wherein the therapeutic product is a cytokine.

11. The method of claim 1 , wherein the therapeutic product is selected from among one or more of: IL-2, IL-7, IL-12p70 (IL-12p40+IL-12p35), IL-15, IL-36 gamma, IL-2 that has attenuated binding to IL-2Ra, IL-15/IL-15R alpha chain complex, IL-18, IL-21, IL-23, IL-2 modified so that it does not bind to IL-2Ra, CXCL9, CXCL10, CXCL11, interferon-α, interferon-β, interferon-γ, CCL3, CCL4, CCL5, proteins that are involved in or that effect or potentiate recruitment/persistence of T cells, CD40, CD40 ligand, CD28, OX40, OX40 ligand, 4-1BB, 4-1BB ligand, members of the B7-CD28 family, CD47 antagonists, TGF-beta polypeptide antagonists, and members of the tumor necrosis factor receptor (TNFR) superfamily.

12. The method of claim 1 , wherein the therapeutic product is an antibody or antigen-binding fragment thereof.

13. The method of claim 1 , wherein the therapeutic product is an interferon.

14. The method of claim 4 , wherein the therapeutic product is an interferon.

15. The method of claim 14 , wherein the interferon is selected from among one or more of interferon-α, interferon-β, and interferon-γ.

16. The method of claim 12 , wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof or is a human antibody or antigen-binding fragment thereof.

17. The method of claim 12 , wherein the antibody or antigen-binding fragment thereof is an antagonist of PD-1, PD-L1, CTLA-4, VEGF, VEGFR2, or IL-6.

18. The method of claim 1 , wherein the therapeutic product is a cytotoxin.

19. The method of claim 1 , wherein the therapeutic product is a tumor antigen or a tumor neoantigen.

20. The method of claim 1 , wherein nucleic acid encoding the therapeutic product is operatively linked to nucleic acid encoding a secretory signal, whereby, upon expression, the therapeutic product is secreted.

21. The method of claim 2 , wherein nucleic acid encoding the therapeutic product is operatively linked to nucleic acid encoding a secretory signal, whereby, upon expression, the therapeutic product is secreted into the tumor microenvironment.

22. The method of claim 4 , wherein nucleic acid encoding the therapeutic product is operatively linked to nucleic acid encoding a secretory signal, whereby, upon expression, the therapeutic product is secreted into the tumor microenvironment.

23. The method of claim 1 , wherein the cancer comprises a solid tumor or a hematological malignancy.

24. A method of treatment of cancer in a subject, comprising administering an immunostimulatory bacterium to the subject, wherein:

the immunostimulatory bacterium comprises a plasmid that encodes a therapeutic product;

the immunostimulatory bacterium comprises genome modifications, whereby the bacterium is pagP - /msbB - ;

the bacterium accumulates in a tumor in the subject; and

the cancer comprises a solid tumor or a hematological malignancy.

25. The method of claim 1 , wherein the cancer is selected from among leukemia, lymphoma, gastric cancer, and cancer of the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head and neck, colorectum, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testicles, cervix, and liver.

26. The method of claim 4 , wherein the cancer is selected from among leukemia, lymphoma, gastric cancer, and cancer of the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head and neck, colorectum, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testicles, cervix, and liver.

27. The method of claim 1 , wherein the bacterium is formulated for systemic administration.

28. The method of claim 1 , wherein the immunostimulatory bacterium is a Salmonella species.

29. The method of claim 1 , wherein the immunostimulatory bacterium is a Salmonella typhimurium strain.

30. The method of claim 29 , wherein the Salmonella typhimurium strain is derived from a wild-type Salmonella typhimurium strain having all of the identifying characteristics of the strain deposited under ATCC accession no. 14028, or is the strain deposited under ATCC accession no. 14028.

31. The method of claim 1 , wherein the genome of the immunostimulatory bacterium is modified, whereby the bacterium does not express functional endogenous aspartate-semialdehyde dehydrogenase (asd).

32. The method of claim 31 , wherein the plasmid encodes asd.

33. The method of claim 1 , wherein the immunostimulatory bacterium is a strain of Salmonella, Shigella, Escherichia coli, Bifidobacterium, Rickettsia, Vibrio, Listeria, Klebsiella, Bordetella, Neisseria, Aeromonas, Francisella, Cholera, Corynebacterium, Citrobacter, Chlamydia, Haemophilus, Brucella, Mycobacterium, Mycoplasma, Legionella, Rhodococcus, Pseudomonas, Helicobacter, Bacillus , or Erysipelothrix, or an attenuated strain thereof or a modified strain thereof of any of the preceding list of bacterial strains.

34. The method of claim 1 , wherein the immunostimulatory bacterium is a strain of Salmonella, Escherichia coli , or Listeria.

35. The method of claim 4 , wherein the immunostimulatory bacterium is a strain of Salmonella, Escherichia coli , or Listeria.

36. The method of claim 2 , wherein the bacterium is a Salmonella typhimurium strain.

37. A method of treatment of cancer, comprising administering a cell comprising an immunostimulatory bacterium to a subject with a cancer that comprises a solid tumor or a hematological malignancy, wherein:

the immunostimulatory bacterium comprises a plasmid that encodes a therapeutic product;

the immunostimulatory bacterium comprises one or more genome modification(s), whereby the bacterium is pagP/msbB and lacks flagella; and

the wild-type bacterium comprises flagella.

38. The method of claim 37 , wherein the cell is a T-cell, or a hematopoietic cell.

39. The method of claim 4 , wherein the immunostimulatory bacterium comprises genome modifications whereby the bacterium is csgD − .

40. A method of treatment of cancer in a subject, comprising administering an immunostimulatory bacterium, wherein:

the immunostimulatory bacterium comprises a plasmid that encodes a therapeutic product; and

the immunostimulatory bacterium comprises genome modification(s), whereby the bacterium is msbB − /pagP − and is csgD − .

41. The method of claim 40 , wherein the immunostimulatory bacterium is a strain of Salmonella.

Assignments (1)

Continuity (13)

References Cited (400)