Synthetic oncolytic LNP-replicon RNA and uses for cancer immunotherapy

Patent metadata

Field	Value
Publication number	US-12383589-B2
Application number	US-202318334449-A
Country	US
Kind code	B2
Filing date	Jun 14, 2023
Priority date	Mar 8, 2019
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present disclosure relates to synthetic oncolytic viruses comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an immunomodulatory molecule.

First claim

What is claimed is:

1. A method for treating cancer in a subject in need thereof, comprising:
administering to the subject an effective amount of a synthetic oncolytic virus, comprising:
(i) a lipid nanoparticle comprising N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3); and
(ii) a self-amplifying replicon ribonucleic acid (RNA) comprising a sequence that encodes an interleukin (IL)-12 molecule, wherein the IL-12 molecule is expressed by the self-amplifying replicon RNA.

2. The method of claim 1 , wherein the subject is a human patient having or suspected of having a cancer.

3. The method of claim 2 , wherein the human patient has a cancer selected from the group consisting of melanoma, breast cancer and colon cancer.

4. The method of claim 1 , wherein the synthetic oncolytic virus is administered to the subject in a single dose.

5. The method of claim 1 , wherein the synthetic oncolytic virus is administered to the subject by intratumoral injection, intramuscular injection, subcutaneous injection, or intravenous injection.

6. The method of claim 1 , wherein the lipid nanoparticle further comprises 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and cholesterol.

7. The method of claim 6 , wherein the lipid nanoparticle further comprises 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (C14-PEG2000).

8. The method of claim 1 , wherein the self-amplifying replicon RNA is derived from an alphavirus or a hepatitis C virus.

9. The method of claim 8 , wherein the alphavirus is Venezuela Equine Encephalitis virus, Semliki Forest virus, or Sindbis virus.

10. The method of claim 1 , wherein the sequence that encodes the IL-12 molecule is located in a subgenomic region of the self-amplifying replicon RNA.

11. The method of claim 1 , wherein the self-amplifying replicon RNA comprises a nucleotide sequence that has at least 90% sequence identity to the sequence set forth in SEQ ID NO: 1.

12. The method of claim 11 , wherein the self-amplifying replicon RNA comprises a point mutation of G3936C and/or A4758G relative to SEQ ID NO: 1.

13. The method of claim 1 , wherein the IL-12 molecule is IL-12, an IL-12 subunit, or a mutant IL-12 molecule that retains immunomodulatory function of IL-12.

14. The method of claim 13 , wherein the IL-12 molecule comprises IL-12α and/or IL-12β subunits.

15. The method of claim 1 , wherein the lipid nanoparticle has a diameter of about 100-120 nm.

16. The method of claim 1 , wherein the lipid nanoparticle has a zeta potential of about 3-6 mv.

17. The method of claim 1 , wherein the lipid nanoparticle and the self-amplifying replicon RNA have a mass ratio of about 1:1.

18. The method of claim 1 , wherein the lipid nanoparticle is capable of triggering immunogenic cell death.

19. A method for treating cancer in a subject in need thereof, comprising:
administering to the subject a pharmaceutical composition comprising a synthetic oncolytic virus and a pharmaceutically acceptable carrier;
wherein the synthetic oncolytic virus comprises:
(i) a lipid nanoparticle comprising TT3, 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and cholesterol; wherein the lipid nanoparticle is capable of triggering immunogenic cell death; and
(ii) a self-amplifying replicon ribonucleic acid (RNA) comprising a sequence that encodes an interleukin (IL)-12 molecule;
wherein the self-amplifying replicon RNA comprises the nucleotide sequence set forth in SEQ ID NO: 1, and wherein the IL-12 molecule is expressed by the self-amplifying replicon RNA; and

wherein the pharmaceutical composition further comprises 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (C14-PEG2000).

Assignees

• Massachusetts Inst Technology
• Ohio State Innovation Foundation

Inventors

• Irvine Darrell J
• Wittrup Karl Dane
• Weiss Ron
• Li Yingzhong
• Momin Noor
• Dong Yizhou

Classifications

• C12N2770/36132

  Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent · CPC title

• C12N7/00 Primary

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• C07K14/5434

  IL-12 · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title