ONCOLYTIC RHABDOVIRUS

• US 20120275999A1
• Filed: 12/10/2010
• Published: 11/01/2012
• Est. Priority Date: 12/10/2009
• Status: Active Grant

• Current Assignee: Turnstone Limited Partnership
• Original Assignee: Children's Hospital of Eastern Ontario Research Institute, Ottawa Hospital Research Institute (Ottawa Hospital)
• Inventors: Bell, John C., Stojdl, David F.
• Granted Patent: US 9,045,729 B2
• Time in Patent Office: Days
• US Class Current: 424/1.11
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2760/20021 Viruses as such, e.g. new isolates, mutants or their genomic sequences
• CPC Class Codes: C12N 2760/20032 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2760/20062 by genetic engineering
• CPC Class Codes: C12N 2760/20071 Demonstrated in vivo effect
• 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: 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

Embodiments of the invention include compositions and methods related to Maraba virus and their use as anti-cancer therapeutics. Such rhabdoviruses possess tumor cell killing properties in vitro and in vivo.

Claims

1. An attenuated rhabdovirus comprising a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:

5 and an amino acid substitution at position 242 of SEQ ID NO;

5, or a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4, or a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

5 and an amino acid substitution at position 242 of SEQ ID NO;

5 and a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4.

2. The rhabdovirus of claim 1, wherein the genetic mutation is a arginine substitution for the glutamine at position 242 of SEQ ID NO:

5, or a tryptophan substitution for the leucine at position 123 of SEQ ID NO;

4.

3. A method of killing a hyperproliferative cell comprising contacting the cell with an isolated oncolytic rhabdovirus encoding a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:

5 and an amino acid substitution at position 242 of SEQ ID NO;

5, or a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4, or a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

5 and an amino acid substitution at position 242 of SEQ ID NO;

5 and a M protein having an aminoS acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4.

4. The method of claim 3, wherein the cell is comprised in a patient.

5. The method of claim 4, wherein the cell is a cancer cell.

6. The method of claim 5, wherein the cancer cell is a metastatic cancer cell.

7. The method of claim 4, wherein the oncolytic rhabdovirus is administered to the patient.

8. The method of claim 7, wherein the oncolytic rhabdovirus is administered by intraperitoneal, intravenous, intra-arterial, intramuscular, intradermal, intratumoral subcutaneous, or intranasal administration.

9. The method of claim 3, further comprising administering a second anti-cancer therapy.

10. The method of claim 9, wherein the second anti-cancer therapy is a second oncolytic virus.

11. The method of claim 10, wherein the second oncolytic virus is a vaccinia, herpes, measles, Newcastle disease, adenovirus, alphavirus, parvovirus, or rhabdovirus.

12. The method of claim 11, wherein the second anti-cancer agent is a second oncolytic rhabdovirus.

13. The method of claim 12, wherein the second oncolytic rhabdovirus is vesicular stomatitis virus (VSV), Carajas virus, Chandripura virus, Cocal virus, Isfahan virus, Piry virus, Vesicular stomatitis Alagoas virus, BeAn 157575 virus, Boteke virus, Calchaqui virus, Eel virus American, Gray Lodge virus, Jurona virus, Klamath virus, Kwatta virus, La Joya virus, Malpais Spring virus, Mount Elgon bat virus, Perinet virus, Tupaia virus, Farmington, Bahia Grande virus, Muir Springs virus, Reed Ranch virus, Hart Park virus, Flanders virus, Kamese virus, Mosqueiro virus, Mossuril virus, Barur virus, Fukuoka virus, Kern Canyon virus, Nkolbisson virus, Le Dantec virus, Keuraliba virus, Connecticut virus, New Minto virus, Sawgrass virus, Chaco virus, Sena Madureira virus, Timbo virus, Almpiwar virus, Aruac virus, Bangoran virus, Bimbo virus, Bivens Arm virus, Blue crab virus, Charleville virus, Coastal Plains virus, DakArK 7292 virus, Entamoeba virus, Garba virus, Gossas virus, Humpty Doo virus, Joinjakaka virus, Kannamangalam virus, Kolongo virus, Koolpinyah virus, Kotonkon virus, Landjia virus, Manitoba virus, Marco virus, Nasoule virus, Navarro virus, Ngaingan virus, Oak-Vale virus, Obodhiang virus, Oita virus, Ouango virus, Parry Creek virus, Rio Grande cichlid virus, Sandjimba virus, Sigma virus, Sripur virus, Sweetwater Branch virus, Tibrogargan virus, Xiburema virus, Yata virus, Rhode Island, Adelaide River virus, Berrimah virus, Kimberley virus, or Bovine ephemeral fever virus.

14. The method of claim 9, wherein the second cancer therapy is chemotherapeutic, radiotherapeutic, or immunotherapeutic.

15. A method for treating a cancer patient comprising administering an effective amount of an isolated oncolytic rhabdovirus encoding a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:

5 and an amino acid substitution at position 242 of SEQ ID NO;

5, or a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4, or a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

5 and an amino acid substitution at position 242 of SEQ ID NO;

5 and a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4.

16. The method of claim 15, wherein the oncolytic rhabdovirus is administered intraperitoneal, intravenous, intra-arterial, intramuscular, intradermal, intratumoral, subcutaneous, or intranasal administration.

17. The method of claim 15, further comprising administering a second cancer therapy.

18. The method of claim 17, wherein the second anti-cancer therapy comprises a second oncolytic virus.

19. The method of claim 18, wherein the second oncolytic virus is a vaccinia, herpes, measles, Newcastle disease, adenovirus, or rhabdovirus.

20. The method of claim 19, wherein the second anti-cancer therapy comprises a second oncolytic rhabdovirus.

21. The method of claim 20, wherein the second rhabdovirus is vesicular stomatitis virus (VSV), Carajas virus, Chandripura virus, Cocal virus, Isfahan virus, Maraba virus, Piry virus, Vesicular stomatitis Alagoas virus, BeAn 157575 virus, Boteke virus, Calchaqui virus, Eel virus American, Gray Lodge virus, Jurona virus, Klamath virus, Kwatta virus, La Joya virus, Malpais Spring virus, Mount Elgon bat virus, Perinet virus, Tupaia virus, Farmington, Bahia Grande virus, Muir Springs virus, Reed Ranch virus, Hart Park virus, Flanders virus, Kamese virus, Mosqueiro virus, Mossuril virus, Barur virus, Fukuoka virus, Kern Canyon virus, Nkolbisson virus, Le Dantec virus, Keuraliba virus, Connecticut virus, New Minto virus, Sawgrass virus, Chaco virus, Sena Madureira virus, Timbo virus, Almpiwar virus, Aruac virus, Bangoran virus, Bimbo virus, Bivens Arm virus, Blue crab virus, Charleville virus, Coastal Plains virus, DakArK 7292 virus, Entamoeba virus, Garba virus, Gossas virus, Humpty Doo virus, Joinjakaka virus, Kannamangalam virus, Kolongo virus, Koolpinyah virus, Kotonkon virus, Landjia virus, Manitoba virus, Marco virus, Nasoule virus, Navarro virus, Ngaingan virus, Oak-Vale virus, Obodhiang virus, Oita virus, Ouango virus, Parry Creek virus, Rio Grande cichlid virus, Sandjimba virus, Sigma virus, Sripur virus, Sweetwater Branch virus, Tibrogargan virus, Xiburema virus, Yata virus, Rhode Island, Adelaide River virus, Berrimah virus, Kimberley virus, or Bovine ephemeral fever virus.

22. The method of claim 17, wherein the second cancer therapy is chemotherapy, radiotherapy, immunotherapy, or surgery.

23. A composition comprising an isolated oncolytic rhabdovirus having a nucleic acid segment encoding a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:

5 and an amino acid substitution at position 242 of SEQ ID NO;

5, or a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4, or a G protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

5 and an amino acid substitution at position 242 of SEQ ID NO;

5 and a M protein having an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO;

4 and an amino acid substitution at position 123 of SEQ ID NO;

4.

24. The composition of claim 23, further comprising a second oncolytic virus.

25. The composition of claim 24, wherein the second oncolytic virus is vaccinia virus, herpes virus, measles virus, Newcastle disease virus, adenovirus, or rhabdovirus.

26. The composition of claim 25 wherein the second oncolytic virus is a rhabdovirus.

27. The composition of claim 26, wherein the second rhabdovirus is Carajas virus, Chandripura virus, Cocal virus, Isfahan virus, Maraba virus, Piry virus, Vesicular stomatitis Alagoas virus, BeAn 157575 virus, Boteke virus, Calchaqui virus, Eel virus American, Gray Lodge virus, Jurona virus, Klamath virus, Kwatta virus, La Joya virus, Malpais Spring virus, Mount Elgon bat virus, Perinet virus, Tupaia virus, Farmington, Bahia Grande virus, Muir Springs virus, Reed Ranch virus, Hart Park virus, Flanders virus, Kamese virus, Mosqueiro virus, Mossuril virus, Barur virus, Fukuoka virus, Kern Canyon virus, Nkolbisson virus, Le Dantec virus, Keuraliba virus, Connecticut virus, New Minto virus, Sawgrass virus, Chaco virus, Sena Madureira virus, Timbo virus, Almpiwar virus, Aruac virus, Bangoran virus, Bimbo virus, Bivens Arm virus, Blue crab virus, Charleville virus, Coastal Plains virus, DakArK 7292 virus, Entamoeba virus, Garba virus, Gossas virus, Humpty Doo virus, Joinjakaka virus, Kannamangalam virus, Kolongo virus, Koolpinyah virus, Kotonkon virus, Landjia virus, Manitoba virus, Marco virus, Nasoule virus, Navarro virus, Ngaingan virus, Oak-Vale virus, Obodhiang virus, Oita virus, Ouango virus, Parry Creek virus, Rio Grande cichlid virus, Sandjimba virus, Sigma virus, Sripur virus, Sweetwater Branch virus, Tibrogargan virus, Xiburema virus, Yata virus, Rhode Island, Adelaide River virus, Berrimah virus, Kimberley virus, or Bovine ephemeral fever virus.

28. The composition of claim 23, wherein the composition is a pharmaceutically acceptable composition.

29. The composition of claim 28, further comprising a second anti-cancer agent.

30. The composition of claim 29, wherein the second anti-cancer agent is a chemotherapeutic, radiotherapeutic, or immunotherapeutic.