Therapeutic antitumor combination of a TLR4 ligand with other treatments

Patent metadata

Field	Value
Publication number	US-11266746-B2
Application number	US-201716313454-A
Country	US
Kind code	B2
Filing date	Feb 24, 2017
Priority date	Jun 27, 2016
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

Methods of treating cancer or reducing the incidence of relapse of a cancer in a subject comprising co-administration of Toll-like receptor (TLR) 4 ligand, such as an HMGN1 protein, and a TLR 7 or 8 ligand, and optionally an immune checkpoint inhibitor, to the subject in need of such therapy. The TLR4-mediated immune-stimulating effect is synergistically enhanced by ligands of TLR7 or 8, and the immune checkpoint inhibitor. Also described here is a nanoparticle delivery platform for the co-administration of the TLR 4 ligand and the TLR 7 or 8 ligand.

First claim

The invention claimed is:

1. A method of treating cancer or reducing the incidence of relapse of a cancer in a subject comprising:
co-administering a) a Toll-like receptor (TLR) 4 ligand, b) a TLR7 or 8 ligand, and c) a checkpoint inhibitor to the subject, thereby treating the cancer or reducing the incidence of relapse of the cancer, wherein the TLR4 ligand is HMGN1 protein.

2. The method of claim 1 , wherein the HMGN1 protein, TLR7 or TLR8 ligand and immune checkpoint inhibitor are administered in the absence of a tumor antigen.

3. The method of claim 1 , wherein the TLR7 or TLR8 ligand is resiquimod, imiquimod, an imidazoquinoline derivative, 852A, VTX1463, AZD8848, ANA773, or a combination thereof.

4. The method of claim 1 , wherein the immune checkpoint inhibitor is
i) cyclophosphamide,
ii) an anti-CTLA4, anti-PD1, anti-PDL1, anti-PDL2, anti-LAG-3, anti-BTLA, anti-B7H3, anti-B7H4, anti-TIM3, or an anti-A2aR antibody, or
iii) combinations of i) and ii).

5. The method of claim 1 , comprising co-administration of the HMGN1 protein, resiquimod and cyclophosphamide.

6. The method of claim 5 , wherein the cyclophosphamide is administered to the patient at a dose of about 100 mg/kg or less.

7. The method of claim 1 , comprising co-administration of the HMGN1 protein, resiquimod and an anti-CTLA antibody.

8. The method of claim 1 , wherein the cancer is a solid tumor, a thymoma, colon cancer, kidney cancer, or liver cancer.

9. The method of claim 1 , wherein the co-administration comprises intratumoral, intraperitoneal, intravenous, or intramuscular injection of at least the HMGN1 protein.

10. The method of claim 1 , wherein HMGN1 protein is administered by intratumoral injection.

11. The method of claim 1 , wherein the HMGN1 protein and the TLR7 or TLR8 ligand is administered sequentially or simultaneously.

12. The method of claim 1 , wherein the HMGN1 protein and the TLR7 or TLR8 ligand are administered in the absence of a tumor antigen.

13. The method of claim 1 , comprising administering a composition comprising a nanoparticle adsorbed with the HMGN1 protein and the TLR 7 or 8 ligand.

14. The method of claim 13 wherein the nanoparticle is a gold nanoparticle.

15. The method of claim 14 , wherein the nanoparticle is PEGylated.

16. The method of claim 15 , wherein the nanoparticle has an average diameter of between about 10 nm and about 100 nm.

17. The method of claim 15 , wherein the nanoparticle has an average zeta potential between about −40 mV and about +40 mV.

18. The method of claim 14 , wherein the composition comprises between about 70% and about 96% gold.

19. The method of claim 15 , wherein the composition comprises between about 2% and about 22% polyethylene glycol (PEG).

20. The method of claim 13 , wherein the composition comprises between about 0.5% and about 10% HMGN1.

21. The method of claim 13 , wherein the composition comprises between about 0.5% and about 10% TLR 7 or 8 ligand.

22. The method of claim 13 , wherein the TLR7 or TLR8 ligand is resiquimod, imiquimod, an imidazoquinoline derivative, 852A, VTX1463, AZD8848, or a combination thereof.

23. A composition comprising an HMGN1 protein, a Toll-like receptor (TLR) 7 or 8 ligand adsorbed to a nanoparticle, and an immune checkpoint inhibitor, and wherein the immune checkpoint inhibitor comprises:
i) cyclophosphamide,
ii) an antibody, wherein that antibody is an anti-CTLA4, anti-PD1, anti-PDL1, anti-PDL2, anti-LAG-3, anti-BTLA, anti-B7H3, anti-B7H4, anti-TIM3, or an anti-A2aR antibody, and
iii) combinations of i) and ii).

24. The composition of claim 23 , wherein the nanoparticle is a gold nanoparticle.

Assignees

• Us Health
• The United Slates Of America As Represented By The Sec Dep Of Health And Human Services

Inventors

• Oppenheim Joost J
• Yang De
• Han Zhen
• Barchi Jr Joseph John
• Bustin Michael

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K47/6923

  the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title