Avirulent oncolytic herpes simplex virus strains engineered to counter the innate host response

• US 20060039894A1
• Filed: 06/24/2005
• Published: 02/23/2006
• Est. Priority Date: 06/24/2004
• Status: Active Grant

• Current Assignee: New York University
• Original Assignee: New York University
• Inventors: Mohr, Ian, Mulvey, Matthew
• Granted Patent: US 7,731,952 B2
• Time in Patent Office: Days
• US Class Current: 424/93.600
• CPC Class Codes: A61K 2039/5254 avirulent or attenuated
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 35/763 Herpes virus
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 2710/16643 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/16661 Methods of inactivation or attenuation
• CPC Class Codes: C12N 2710/16662 by genetic engineering
• 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 an avirulent, oncolytic herpes simplex virus modified from a wild-type herpes simplex virus so that both γ₁34.5 genes of the virus have been deleted and each replaced with an interferon-resistance gene that is expressed as an immediate-early gene. The present invention also relates to a pharmaceutical composition that includes the modified herpes simplex virus of the present invention and a pharmaceutically acceptable vehicle for in situ administration to tumor cells. Also provided in the present invention are methods for killing tumor cells in a subject and for immunizing a subject against an infectious disease, cancer, or an autoimmune disease that involve administering to a subject the modified avirulent, oncolytic herpes simplex virus of the present invention.

Claims

1. An avirulent, oncolytic herpes simplex virus modified from a wild-type herpes simplex virus so that both γ

₁34.5 genes of the virus have been deleted and each replaced with an interferon-resistance gene that is expressed as an immediate-early gene.

2. The oncolytic modified virus according to claim 1, wherein the interferon resistance gene is a herpes simplex virus Us11 gene.

3. The oncolytic modified virus according to claim 1, wherein the interferon-resistance gene is under the control of a herpes simplex virus immediate-early promoter.

4. The oncolytic modified virus according to claim 3, wherein the promoter is the Δ

27 IE promoter.

5. The oncolytic modified virus according to claim 1, wherein the modified virus further comprises an intact herpes simplex virus Us12 gene.

6. The oncolytic modified herpes simplex virus according to claim 1 further comprising an ICP 6-inactivating mutation.

7. The oncolytic modified virus according to claim 1, wherein the wild-type herpes simplex virus is herpes simplex virus type 1 (HSV-1).

8. The oncolytic modified virus according to claim 7, wherein the HSV-1 is a strain selected from the group consisting of HSV-1 strain 17, strain KOS, strain F, and any clinical isolate.

9. The oncolytic modified virus according to claim 1, wherein the wild-type herpes simplex virus is herpes simplex virus type 2 (HSV-2).

10. The oncolytic modified virus according to claim 9, wherein the HSV-2 is a strain selected from the group consisting of HSV-2 strain G, strain HG52, and any clinical isolate.

11. A pharmaceutical composition comprising:

the avirulent, oncolytic modified herpes simplex virus according to claim 1, and

a pharmaceutically acceptable vehicle for in situ administration to tumor cells.

12. The pharmaceutical composition according to claim 11, wherein the wild-type herpes simplex virus is herpes simplex virus type 1.

13. The pharmaceutical composition according to claim 11, wherein the wild-type herpes simplex virus is herpes simplex virus type 2.

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

administering to a subject the avirulent, oncolytic modified herpes simplex virus according to claim 1 under conditions effective to kill tumor cells in the subject.

15. The method according to claim 14, wherein the tumor cells are selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, and medulloblastoma, melanoma cells, pancreatic cancer cells, prostate carcinoma cells, breast cancer cells, lung cancer cells, colon cancer cells, lymphoma cells, hepatoma cells, mesothelioma, and epidermoid carcinoma cells.

16. The method according to claim 14, wherein the administering is carried out by injection, infusion, instillation, or inhalation.

17. The method according to claim 14, wherein the subject is a mammal.

18. The method according to claim 17, wherein the mammal is a human.

19. A method of immunizing a subject against an infectious disease, cancer, or an autoimmune disease, said method comprising:

administering to a subject the avirulent, oncolytic modified herpes simplex virus according to claim 1 under conditions effective to immunize the subject against an infectious disease, cancer, or an autoimmune disease.