Synthetic oncolytic LNP-replicon RNA and uses for cancer immunotherapy

Patent metadata

Field	Value
Publication number	US-11717548-B2
Application number	US-202016739407-A
Country	US
Kind code	B2
Filing date	Jan 10, 2020
Priority date	Mar 8, 2019
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

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 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 RNA comprising a sequence that encodes an interleukin (IL)-12 molecule;
and
wherein the IL-12 molecule is expressed by the self-amplifying replicon RNA.

2. The synthetic oncolytic virus of claim 1 , wherein the lipid nanoparticle further comprises one or more types of lipid, where the one or more types of lipid comprises a cationic lipid.

3. The synthetic oncolytic virus of claim 1 , wherein the lipid nanoparticle further comprises 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), cholesterol, and C14-PEG2000.

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

5. The synthetic oncolytic virus of claim 4 , wherein the alphavirus is Venezuela Equine Encephalitis virus, Semliki Forest virus, or Sindbis virus.

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

7. The synthetic oncolytic virus 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.

8. The synthetic oncolytic virus of claim 7 , wherein the self-amplifying replicon RNA comprises a point mutation of G3936C and/or A4758G of SEQ ID NO: 1.

9. The synthetic oncolytic virus of claim 1 , wherein the self-amplifying replicon RNA further comprises a serum albumin coding sequence.

10. The synthetic oncolytic virus of claim 1 , wherein the self-amplifying replicon RNA further comprises a lumican coding sequence.

11. The synthetic oncolytic virus of claim 1 , wherein the IL-12 molecule is IL-12, an IL-12 subunit, or a mutant IL-12 molecule that retains the immunomodulatory function.

12. The synthetic oncolytic virus of claim 11 , wherein the IL-12 molecule comprises IL-12α and/or IL-12β subunits.

13. The synthetic oncolytic virus of claim 1 , wherein the lipid nanoparticle has a diameter of about 100-120 nm.

14. The synthetic oncolytic virus of claim 1 , wherein the lipid nanoparticle has a zeta potential of about 3-6 mv.

15. The synthetic oncolytic virus of claim 1 , wherein the lipid nanoparticle and the self-amplifying replicon RNA have a mass ratio of about 1:1.

16. A pharmaceutical composition, comprising the synthetic oncolytic virus of claim 1 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is formulated for intratumoral injection.

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

19. The pharmaceutical composition of claim 16 , wherein the lipid nanoparticle further comprises 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and cholesterol.

20. The pharmaceutical composition of claim 19 , further comprising C14-PEG2000.

21. 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; and
(ii) a self-amplifying replicon RNA comprising a sequence that encodes an interleukin (IL)-12 molecule;
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;
wherein the lipid nanoparticle is capable of triggering immunogenic cell death;
wherein the IL-12 molecule is expressed by the self-amplifying replicon RNA; and
wherein the pharmaceutical composition further comprises C14-PEG2000.

22. The synthetic oncolytic virus of claim 1 , wherein the lipid nanoparticle is capable of triggering immunogenic cell death.

Assignees

• Massachusetts Inst Technology
• Ohio State Innovation Foundation

Inventors

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

Classifications

• A61K35/768 Primary

  Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766 · 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

• C07K14/5434

  IL-12 · 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