SYSTEMIC TREATMENT OF METASTATIC AND/OR SYSTEMICALLY-DISSEMINATED CANCERS USING GM-CSF-EXPRESSING POXVIRUSES

• US 20070065411A1
• Filed: 09/07/2006
• Published: 03/22/2007
• Est. Priority Date: 09/07/2005
• Status: Active Grant

• Current Assignee: Sillajen Biotherapeutics Incorporated (SillaJen, Inc.)
• Original Assignee: Sillajen Biotherapeutics Incorporated (SillaJen, Inc.)
• Inventors: Kirn, David
• Granted Patent: US 9,180,149 B2
• Time in Patent Office: Days
• US Class Current: 424/93.200
• CPC Class Codes: A01K 2207/20 Animals treated with compounds which are neither proteins nor nucleic acids
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 2267/0393 Animal model comprising a reporter system for screening tests
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• 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 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 14/535 Granulocyte CSF; Granulocyte-macrophage CSF
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/24111 Orthopoxvirus, e.g. vaccinia virus, variola
• 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

The present invention concerns methods and compositions for the treatment of cancer and cancer cells using intravascular administration of a vaccinia virus. In some embodiments, methods and compositions involve a replicative vaccinia virus that encodes GM-CSF.

Claims

1. A method of killing a cancer cell in a subject comprising administering to the subject an effective amount of a replicative vaccinia virus having an expression region with a promoter directing expression of a nucleic acid encoding granulocyte-macrophage colony stimulating factor (GM-CSF), wherein the administration is intravascular.

2. The method of claim 1, wherein the vaccinia virus is administered intravenously.

3. The method of claim 1, wherein the vaccinia virus is administered intraarterially.

4. The method of claim 1, wherein the vaccinia virus is in a pharmaceutically acceptable formulation.

5. The method of claim 1, wherein the vaccinia virus has a deletion in its genome.

6. The method of claim 5, wherein the vaccinia virus has a mutation in one or more genes.

7. The method of claim 6, wherein the mutation is a deletion.

8. The method of claim 6, wherein at least the thymidine kinase gene has been deleted.

9. The method of claim 6, wherein the vaccinia virus has a mutation in a gene encoding:

a) vaccinia virus growth factor;

b) a functional interferon-modulating polypeptide, wherein the interferon-modulating polypeptide directly binds interferon;

c) a complement control polypeptide, wherein the mutation results in the virus lacking at least one functional complement control polypeptide;

d) a TNF-modulating polypeptide, wherein the mutation results in the virus lacking at least one functional TNF-modulating polypeptide;

e) a serine protease inhibitor, wherein the mutation results in the virus lacking at least one functional serine protease inhibitor;

f) an IL-1β

modulator polypeptide, wherein the mutation results in the virus lacking at least one functional IL-1β

modulator polypeptide;

g) a functional A4IL, B7R, NIL or vCKBP chemokine binding polypeptide or C11R EGF-like polypeptide, wherein the mutation results in the virus lacking at least one function of A41L, B7R, NIL, vCKBP, or C11R;

or h) a polypeptide, wherein the mutation results in an increase in infectious EEV form of vaccinia virus.

10. The method of claim 8, further comprising a mutation in a vaccinia virus growth factor.

11. The method of claim 1, wherein the vaccinia virus is the Wyeth or Western Reserve (WR) strain.

12. The method of claim 11, wherein the vaccinia virus is the WR strain.

13. The method of claim 1, wherein the promoter is a vaccinia virus promoter.

14. The method of claim 13, wherein the promoter is a synthetic promoter.

15. The method of claim 13, wherein the promoter directs transcription during at least the early phase of infection.

16. The method of claim 13, wherein the promoter directs transcription during at least the late phase of infection.

17. The method of claim 1, wherein the subject is administered the vaccinia virus multiple times.

18. The method of claim 17, wherein a second treatment occurs within 3 weeks of a first treatment.

19. The method of claim 18, wherein the second treatment occurs within 2 weeks of the first treatment.

20. The method of claim 17, wherein the same dose is administered.

21. The method of claim 1, wherein the subject is administered between about 1 o⁵ and about 10¹³ pfu of virus.

22. The method of claim 1, wherein the subject is administered between about 107 and about 10¹⁰ pfu of virus.

23. The method of claim 1, wherein the administration occurs intravascularly by injection.

24. The method of claim 1, wherein the administration occurs intravascularly using intravenous drip or bolus.

25. The method of claim 1, wherein the administration occurs intravascularly using a pump.

26. The method of claim 1, wherein the cancer cell is a metastasized cancer cell.

27. The method of claim 1, wherein the subject has lung cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, hepatocellular cancer, leukemia, lymphoma, myeloma, or melanoma.

28. A method for treating cancer in a subject comprising administering to the subject an effective amount of a replicative vaccinia virus having an expression region with a promoter directing expression of a nucleic acid encoding granulocyte-macrophage colony stimulating factor (GM-CSF), wherein the administration is intravascular.

29. A method for treating one or more metastases in a subject comprising administering to the subject an effective amount of a replicative vaccinia having an expression region with a promoter directing expression of a nucleic acid encoding granulocyte-macrophage colony stimulating factor (GM-CSF), wherein the administration is intravascular.