Poxviral oncolytic vectors

• US 8,778,328 B2
• Filed: 11/17/2008
• Issued: 07/15/2014
• Est. Priority Date: 11/19/2007
• Status: Active Grant

• Current Assignee: Transgene S.A. (Compagnie Merieux Alliance SAS)
• Original Assignee: Transgene S.A. (Compagnie Merieux Alliance SAS)
• Inventors: Erbs, Philippe, Foloppe, Johann
• Primary Examiner(s): MOSHER, MARY
• Application Number:
  US12/743,407
• Publication Number:
  US 20110059049A1
• Time in Patent Office: 2,066 Days
• Field of Search: None
• US Class Current: 424/93.2
• 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 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 35/76 Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 38/45 Transferases (2)
• CPC Class Codes: A61K 38/50 acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/24122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2710/24132 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/24143 viral genome or elements thereof as genetic vector
• 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

A poxvirus other than NYVAC but comprising a defective F4L and/or I4L gene and compositions comprising such poxvirus are useful for therapeutic purposes, and more particularly for the treatment of cancer.

Claims

1. An oncolytic poxvirus comprising a defective I4L and/or F4L gene and a defective J2R gene, wherein the poxvirus further comprises a suicide gene with the proviso that said poxvirus is not NYVAC.

2. The poxvirus as defined by claim 1, wherein said poxvirus further comprises a defective F2L gene.

3. The poxvirus as defined by claim 2, wherein said poxvirus belongs to the Chordopoxvirinae subfamily.

4. The poxvirus as defined by claim 3, wherein said poxvirus belongs to the Vaccinia virus species.

5. The poxvirus as defined by claim 4, wherein said poxvirus is a Vaccinia virus strain Copenhagen.

6. The poxvirus as defined by claim 1, wherein said suicide gene codes a protein having at least a cytosine deaminase activity.

7. The poxvirus as defined by claim 6, wherein said suicide gene is FCY1, FCA1 or CodA or an analogue thereof.

8. The poxvirus as defined by claim 6, wherein said protein having at least a cytosine deaminase activity is the FCU1-8 polypeptide represented in the sequence identifier SEQ ID NO:

2 and analogues thereof.

9. The poxvirus as defined by claim 6, wherein said suicide gene codes a protein having at least one cytosine deaminase and one uracil phosphoribosyl transferase activity.

10. The poxvirus as defined by claim 9, wherein said suicide gene codes a polypeptide comprising an amino acid sequence substantially as represented in the sequence identifier SEQ ID NO:

3 (coda;

;

upp), SEQ ID NO;

1 (FCU1) or the amino acid sequence of FCY1;

;

FUR1.

11. The poxvirus as defined by claim 6, wherein said poxvirus further comprises a nucleic acid sequence comprising a gene coding a permease.

12. The poxvirus as defined by claim 11, wherein permease is a purine or a cytosine permease of S. Cerevisiae.

13. The poxvirus as defined by claim 12, wherein said permease is selected from the group consisting of FCY2 and Fur4 and analogues thereof.

14. The poxvirus as defined by claim 11, wherein said gene coding a permease is placed under the elements necessary for its expression.

15. A process for preparing a poxvirus, in which process:

(i) a poxvirus as defined by claim 1, is introduced into a cell;

(ii) said cell is cultured under conditions which are appropriate for enabling said poxvirus to be produced, and;

(iii) said poxvirus is recovered from the cell culture.

16. A composition which comprises a poxvirus as defined by claim 1, in combination with a pharmaceutically acceptable excipient.

17. The composition as defined by claim 16, further comprising one or more substances which potentiate the cytotoxic effect of 5-Fluorocytosine.

18. The composition as defined by claim 17, wherein said substances which potentiate the cytotoxic effect of 5-Fluorocytosine are drugs which inhibit the enzymes of the pathway for the de novo biosynthesis of the pyrimidines.

19. The composition as defined by claim 17, wherein said substance which potentiates the cytotoxic effect of 5-Fluorocytosine is methotrexate.

20. A medicament comprising a poxvirus as defined by claim 1.

21. A method for treating a disease state, wherein a poxvirus as defined by claim 1 or 2 is administered to an host organism or cell which is in need of such treatment.

22. The method as defined by claim 21, wherein said poxvirus is administered via the systemic route.

23. The method as defined by claim 21, further comprising an additional step in which pharmaceutically acceptable quantities of a prodrug are administered to said host organism or cell.

24. The method as defined by claim 23, wherein the administration of said prodrug takes place at least 3 days after the administration of said poxvirus.

25. The method as defined by claim 24, wherein the administration of said prodrug takes place 7 days after the administration of said poxvirus.

26. A method for the treatment of cancer, comprising administering to a host organism or cell in need of such treatment, for such period of time as required to elicit the desired effect, a thus effective amount of a poxvirus as defined by claim 1 or 2.

27. The composition as defined by claim 18, wherein said drugs which inhibit the enzymes of the pathway for the de novo biosynthesis of the pyrimidines are selected from the group consisting of PALA, Leflunomide, and A771726.

28. The method as defined by claim 23, wherein said prodrug is an analogue of cytosine.

29. The method as defined by claim 28, wherein said analogue of cytosine is 5-Fluorocytosine.