ONCOLYTIC HERPES SIMPLEX VIRUS AND THERAPEUTIC USES THEREOF

• US 20150110822A1
• Filed: 09/07/2012
• Published: 04/23/2015
• Est. Priority Date: 09/08/2011
• Status: Active Grant

• Current Assignee: Benevir Biopharm, Inc. (Johnson & Johnson), New York University
• Original Assignee: Benevir Biopharm, Inc. (Johnson & Johnson), New York University
• Inventors: Mulvey, Matthew C., Mohr, Ian J.
• Granted Patent: US 9,623,059 B2
• Time in Patent Office: Days
• US Class Current: 424/186.1
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 35/763 Herpes virus
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/16632 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• 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

Abstract

The present invention relates to variants of herpes simplex virus (HSV) that selectively infect and replicate in cancer cells, including HSV strains that selectively infect and replicate in bladder cancer cells. Preferred HSV of the invention have intact endogenous Us11 and Us12 genes and have genes encoding ICP34.5 replaced with a gene encoding Us11 fused to an HSV immediate early (IE) promoter. The variant HSV of the invention also comprise one or more additional heterologous genes encoding immunomodulatory polypeptides. Methods and compositions using these variant HSV, e.g., for treating cancer in a subject, are also provided.

Claims

1. A variant herpes simplex virus (HSV) having an intact endogenous Us12 encoding gene and an intact endogenous Us11 encoding gene, lacking functional ICP34.5 encoding genes,

wherein each ICP34.5 encoding gene is replaced by a polynucleotide cassette comprising:

(a) a Us11 encoding gene operably associated with an immediate early (IE) promoter; and

(b) at least one heterologous gene encoding a polypeptide capable of enhancing an anti-tumor response.

3. The variant HSV according to claim 1, in which said heterologous gene encodes an immunomodulatory polypeptide is selected from the group consisting of a TAP 1/2 (“

TAP”

) inhibitor, granulocyte macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha and CD40 ligand (CD40L) and a prodrug converting enzyme.

4. The variant HSV according to claim 3, in which said at least one immunomodulatory polypeptide is GM-CSF.

6. The variant HSV according to claim 1, comprising at least two (2) heterologous genes encoding a polypeptide capable of enhancing an anti-tumor response.

7. The variant HSV according to claim 6, wherein said one of said two heterologous genes encodes a TAP inhibitor and the other encodes a mammalian GM-CSF.

8. The variant HSV according to claim 7, in which the TAP inhibitor inhibits a non-human TAP.

9. The variant HSV according to claim 8, in which the TAP inhibitor inhibits a murine TAP.

10. The variant HSV according to claim 9, in which the TAP inhibitor is the UL49.5 polypeptide from bovine herpesvirus.

11. The variant HSV according to claim 6, wherein one of said two heterologous genes encodes a TAP inhibitor and the other encodes a prodrug converting enzyme.

16. The variant HSV according to claim 1, in which the IE promoter is an α

27 IE promoter.

17. The variant HSV according to claim 1, in which the heterologous gene is operably associated with a promoter selected from the group consisting of a CMV promoter and an EFla promoter.

21. A pharmaceutical formulation comprising:

the variant HSV according to claim 1, and a pharmaceutically acceptable carrier for administration to tumor cells.

24. A method for killing tumor cells in a subject comprising:

administering to a subject in need thereof the pharmaceutical formulation according to claim 21 under conditions effective to kill tumor cells in the subject.

30. A method for treating cancer, wherein said method comprises administering to an individual in need of treatment, a therapeutically effective amount of the pharmaceutical formulation according to claim 24.

2. (canceled)

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19. A variant herpes simplex virus (HSV) having an intact endogenous Us12 encoding gene and an intact endogenous Us11 encoding gene, lacking functional ICP34.5 encoding genes, wherein each ICP34.5 encoding gene is replaced with a polynucleotide cassette comprising a nucleic acid sequence set forth in one of SEQ ID NO:

21, SEQ ID NO;

22,;

SEQ ID NO;

23, SEQ ID NO;

24 and SEQ ID NO;

25.

20. A variant herpes simplex virus (HSV) having a genome sequence set forth in SEQ ID NO:

26, SEQ ID NO;

27, SEQ ID NO;

28, SEQ ID NO;

29, or SEQ ID NO;

30.

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