ONCOLYTIC VIRUS FOR EXPRESSION OF IMMUNE CHECKPOINT MODULATORS

• US 20170157188A1
• Filed: 07/16/2015
• Published: 06/08/2017
• Est. Priority Date: 07/16/2014
• Status: Active Grant

• Current Assignee: Transgene S.A. (Compagnie Merieux Alliance SAS)
• Original Assignee: Transgene S.A. (Compagnie Merieux Alliance SAS)
• Inventors: Rittner, Karola, Geist, Michel, Thioudellet, Christine, Silvestre, Nathalie, Marchand, Jean-Baptiste
• Granted Patent: US 10,555,981 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 35/761 Adenovirus
• CPC Class Codes: A61K 35/763 Herpes virus
• CPC Class Codes: A61K 35/765 Reovirus; Rotavirus
• CPC Class Codes: A61K 35/766 Rhabdovirus, e.g. vesicular stomatitis virus
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0019 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 Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/535 Granulocyte CSF; Granulocyte-macrophage CSF
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 : Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 15/8636 : Vaccina virus vectors
• CPC Class Codes: C12N 2710/24121 : Viruses as such, e.g. new isolates, mutants or their genomic sequences
• CPC Class Codes: C12N 2710/24132 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2799/023 : where the vector is derived from a poxvirus
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: C12N 9/1077 : Pentosyltransferases (2.4.2)
• CPC Class Codes: C12N 9/80 : acting on amide bonds in linear amides (3.5.1)
• CPC Class Codes: C12Y 204/02009 : Uracil phosphoribosyltransferase (2.4.2.9)
• CPC Class Codes: C12Y 305/01023 : Ceramidase (3.5.1.23)
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides an oncolytic virus comprising nucleotide sequence(s) encoding one or more immune checkpoint modulator(s). It also concerns a pharmaceutical composition comprising effective amount of said oncolytic virus and, eventually, a pharmaceutically acceptable vehicle and its use for treating proliferative diseases such as cancers.

Claims

1. An oncolytic virus comprising inserted in its genome a nucleic acid molecule encoding one or more immune checkpoint modulator(s).

2. The oncolytic virus of claim 1, wherein said oncolytic viruses is selected from the group consisting of reovirus, Seneca Valley virus (SVV), vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), herpes simplex virus (HSV), morbillivirus virus, retrovirus, influenza virus, Sinbis virus, poxvirus, and adenovirus.

3. The oncolytic virus of claim 2, wherein said poxvirus is a vaccinia virus.

4. The oncolytic virus of claim 3, wherein said oncolytic virus is a vaccinia virus defective for thymidine kinase (TK) resulting from inactivating mutations in the J2R viral gene.

5. The oncolytic virus of claim 3, wherein said virus is a vaccinia virus defective for Ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral I4L and/or F4L gene(s).

6. The oncolytic virus of claim 1, wherein said oncolytic virus further comprises at least one therapeutic gene inserted in the viral genome.

7. The oncolytic virus of claim 6, wherein said therapeutic gene is selected from the group consisting of genes encoding suicide gene products and genes encoding immunostimulatory proteins.

8. The oncolytic virus of claim 7, wherein said suicide gene is selected from the group consisting of genes coding protein having a cytosine deaminase (CDase) activity, a thymidine kinase activity, an uracil phosphoribosyl transferase (UPRTase) activity, a purine nucleoside phosphorylase activity and a thymidylate kinase activity.

9. The oncolytic virus of claim 8, wherein said suicide gene product has CDase and UPRTase activities.

10. The oncolytic virus of claim 9, wherein said oncolytic virus is a vaccinia virus defective for both TK and RR activities and comprising inserted into its genome the therapeutic FCU1 suicide gene.

11. The oncolytic virus of claim 7, wherein said imunostimulatory protein is an interleukin or a colony-stimulating factor.

12. The oncolytic virus of claim 11, wherein said oncolytic virus is a vaccinia virus defective for TK activity and comprising inserted into its genome the therapeutic human GM-CSF.

13. The oncolytic virus of claim 1, wherein said one or more immune checkpoint modulator(s) is selected from the group consisting of peptide ligands, soluble domains of natural receptors, RNAi, antisense molecules, antibodies and protein scaffolds.

14. The oncolytic virus of claim 13, wherein said one or more immune checkpoint modulator(s) antagonizes at least partially the activity of inhibitory immune checkpoint(s) mediated by any of the following PD-1, PD-L1, PD-L2, LAG3, Tim3, BTLA and CTLA4.

15. The oncolytic virus of claim 14, wherein said one or more immune checkpoint modulator(s) comprises an antibody that specifically binds to human PD-1 selected from the group consisting of Nivolumab, Pembrolizumab and pidilizumab.

16. The oncolytic virus of claim 14, wherein said one or more immune checkpoint modulator(s) comprises an antibody that specifically binds to human PD-L1 selected from the group consisting of MPDL3280A and BMS-936559.

17. The oncolytic virus of claim 14, wherein said one or more immune checkpoint modulator(s) comprises an antibody that specifically binds to human CTLA-4 selected from the group consisting of ipilimumab, tremelimumab and single chain anti-CTLA4 antibodies.

18. A pharmaceutical composition comprising an effective amount of an oncolytic virus comprising inserted in its genome a nucleic acid molecule encoding one or more immune checkpoint modulator(s) and a pharmaceutical acceptable vehicle.

19. The pharmaceutical composition of claim 18 comprising from approximately 10⁷ pfu to approximately 5×

10⁹ pfu of said oncolytic virus.

20. The pharmaceutical composition of claim 18 which is formulated for parenteral administration.

21. A method for treating a proliferative disease, comprising administering an oncolytic virus comprising inserted in its genome a nucleic acid molecule encoding one or more immune checkpoint modulator(s) or a pharmaceutical composition comprising an effective amount of said oncolytic virus and a pharmaceutical acceptable vehicle.

22. The method according to claim 21, wherein said proliferative disease is a cancer.

23. The method according to claim 21, wherein said oncolytic virus is administered by intravenous or intratumoral route.

24. The method according to claim 23, which comprises from 2 to 5 intravenous or intratumoral administrations of 10⁸ or 10⁹ pfu of oncolytic vaccinia virus at approximately 1 or 2 weeks interval.

25. The method according to claim 21, which further comprises administration of a prodrug and/or a substance effective in anticancer therapy.