Use of sting agonists to treat hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-9642830-B2
Application number	US-201415028813-A
Country	US
Kind code	B2
Filing date	Oct 21, 2014
Priority date	Oct 21, 2013
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

The invention includes methods of treating a subject having hepatitis B viral (HBV) infection. In certain embodiments, the method of the invention comprises stimulating the innate cytokine response in macrophages, dendritic cells and/or liver non-parenchymal cells with small molecular STING agonists, thus suppressing HBV replication in hepatocytes. In other embodiments, the method of the invention can be used to treat chronic HBV infections. The invention further provides methods of identifying compounds useful in treating HBV infection in a subject.

First claim

What is claimed:

1. A method of treating a hepatitis B viral (HBV) infection in a subject, the method comprising administering a pharmaceutically effective amount of a STING agonist to the subject, wherein the STING agonist comprises at least one selected from the group consisting of 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), methoxyvone, 6,4′-dimethoxyflavone, 4′-methoxyflavone, 3′,6′-dihydroxyflavone, 7,2′-dihydroxyflavone, daidzein, formononetin, retusin 7-methyl ether, and any combinations thereof.

2. The method of claim 1 , wherein the STING agonist stimulates an innate cytokine response in at least one cell from the subject, wherein the cell is selected from the group consisting of macrophage, dendritic cell, liver non-parenchymal cell, and any combinations thereof.

3. The method of claim 2 , wherein the innate cytokine response is mediated through cytokines in the subject.

4. The method of claim 3 , wherein the innate cytokine response is mediated through type 1 interferon in the subject.

5. The method of claim 1 , wherein the STING agonist comprises DMXAA.

6. The method of claim 1 , wherein the STING agonist suppresses hepatitis B virus replication in infected hepatocytes in the subject.

7. The method of claim 6 , wherein the STING agonist reduces hepatitis B virus capsid levels in the subject.

8. A method of identifying a compound useful in treating hepatitis B virus (HBV) infection, the method comprising:
treating at least one cell selected from the group consisting of liver resident dendritic cell, macrophage, nonparenchymal cell, and any combination thereof with a test compound, thereby generating a treated cell;
incubating the treated cell in a conditioned medium;
separating the conditioned medium or a portion thereof from the treated cell; and
incubating a HBV-infected hepatocyte with the conditioned medium or portion thereof, wherein, if the conditioned medium or portion thereof suppresses HBV replication in the HBV-infected hepatocyte, the test compound is identified as a compound useful in treating HBV infection.

9. The method of claim 8 , further comprising measuring hepatitis B virus replication in the HBV-infected hepatocyte incubated with the conditioned medium or portion thereof.

10. The method of claim 8 , wherein the treating step stimulates an innate cytokine immune response within the at least one cell with release of cytokines into the conditioned medium.

11. The method of claim 10 , wherein the cytokine comprises a Type I interferon.

12. A method of treating a subject having a hepatitis B virus (HBV) infection in a subject, the method comprising:
treating at least one cell selected from the group consisting of liver resident dendritic cell, macrophage, nonparenchymal cell, and any combinations thereof, with a compound, thus generating a treated cell;
incubating the treated cell in a conditioned medium;
separating the conditioned medium or a portion thereof from the treated cell; and
administering the conditioned medium or portion thereof to the subject.

13. The method of claim 12 , wherein the compound comprises at least one STING agonist.

14. The method of claim 13 , wherein the at least one STING agonist comprises a flavonoid.

15. The method of claim 14 , wherein the flavonoid comprises at least one selected from the group consisting of 10-(carboxymethyl) 9(10H)acridone (CMA), 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), methoxyvone, 6,4′-dimethoxyflavone, 4′-methoxyflavone, 3′,6′-dihydroxyflavone, 7,2′-dihydroxyflavone, daidzein, formononetin, retusin 7-methyl ether, xanthone, and any combinations thereof.

16. The method of claim 14 , wherein the flavonoid comprises DMXAA.

17. The method of claim 12 , wherein the at least one cell is human.

18. The method of claim 12 , wherein the at least one cell is modified to express a mutant STING.

19. The method of claim 18 , wherein at least one cell is transfected or transformed with a mutant STING prior to the treating step.

20. The method of claim 18 , wherein the mutant STING is STING S162A.

21. The method of claim 12 , wherein the at least one cell is autologous to the subject.

22. A method of treating a hepatitis B viral (HBV) infection in a subject, the method comprising administering a pharmaceutically effective amount of a STING agonist to the subject, wherein the STING agonist is the only therapeutically effective agent administered to the subject.

23. The method of claim 22 , wherein the STING agonist stimulates an innate cytokine response in at least one cell in the subject, wherein the cell is selected from the group consisting of macrophage, dendritic cell, liver non-parenchymal cell, and any combinations thereof.

24. The method of claim 22 , wherein the STING agonist is a flavonoid.

25. The method of claim 24 , wherein the flavonoid comprises at least one selected from the group consisting of 10-(carboxymethyl) 9(10H)acridone (CMA), 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), methoxyvone, 6,4′-dimethoxyflavone, 4′-methoxyflavone, 3′,6′-dihydroxyflavone, 7,2′-dihydroxyflavone, daidzein, formononetin, retusin 7-methyl ether, xanthone and any combinations thereof.

26. The method of claim 22 , wherein the STING agonist suppresses hepatitis B virus replication in infected hepatocytes in the subject.

27. The method of claim 22 , wherein the STING agonist reduces hepatitis B virus capsid levels in the subject.

Assignees

• Univ Drexel

Inventors

• Chang Jinhong
• Guo Fang
• Block Timothy M
• Guo Ju-Tao

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61K31/473

  ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title