VACCINIA VIRUS FOR GENE-DIRECTED ENZYME PRODRUG THERAPY

• US 20160130564A1
• Filed: 06/18/2014
• Published: 05/12/2016
• Est. Priority Date: 06/19/2013
• Status: Abandoned Application

• Current Assignee: Institute of Cancer Research Royal Cancer Hospital (University of London)
• Original Assignee: Institute of Cancer Research Royal Cancer Hospital (University of London)
• Inventors: Springer, Caroline, Tommasini, Serena, Marais, Richard
• Application Number:
  US14/898,284
• Publication Number:
  US 20160130564A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/136 having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 38/48 acting on peptide bonds (3.4)
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• 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 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
• CPC Class Codes: C12N 9/485 Exopeptidases (3.4.11-3.4.19)
• CPC Class Codes: C12Y 304/16 Serine-type carboxypeptidases (3.4.16)
• CPC Class Codes: C12Y 304/17021 Glutamate carboxypeptidase II (3.4.17.21)

Abstract

Methods of making vaccinia viruses for gene-directed prodrug therapy are disclosed and their use in the treatment of disease is provided. In particular, the anti-tumor effects of vaccinia viruses that are modified to express a prodrug-activating enzyme are disclosed.

Claims

1-21. -21. (canceled)

22. A vaccinia virus which is capable of expressing a glutamate carboxypeptidase within a cell.

23. The vaccinia virus according to claim 22, wherein the glutamate carboxypeptidase is CPG2 or a mutant, variant or homologue thereof.

24. The vaccinia virus according to claim 23, wherein the glutamate carboxypeptidase comprises an amino acid sequence which has at least 80% identity to SEQ ID NO:

2.

25. The vaccinia virus according to claim 23, wherein the vaccinia virus comprises a CPG2 expression cassette insert in a vaccinia virus virulence gene.

26. The vaccinia virus according to claim 25, wherein the vaccinia virus virulence gene is vaccinia thymidine kinase (vTK).

27. A two component system for gene directed enzyme prodrug therapy which comprises:

(a) a vaccinia virus according to claim 22; and

(b) a prodrug which can be converted into an active drug by a glutamate carboxypeptidase.

28. The two component system according to claim 27, wherein the prodrug comprises;

a glutamic acid group or a glutamic acid analogue group,

wherein the glutamic acid group or the glutamic acid analogue is connected via N to a linker which is connected to a cytotoxic agent.

29. The two component system according to claim 28, wherein the linker comprises a functional group selected from:

carbonyl, carbamate, urea, and equivalents.

30. The two component system according to claim 28, wherein the cytotoxic agent comprises a nitrogen mustard or a nitrogen mustard analogue.

31. The two component system according to claim 30, wherein the prodrug is N-(4-[bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid or a salt thereof.

32. A method of killing a neoplastic cell, the method comprising treating the neoplastic cell with:

a vaccinia virus according to claim 22 and a prodrug which is capable of being converted into an active form by a glutamate carboxypeptidase.

33. The method of killing a neoplastic cell according to claim 32, wherein the prodrug comprises a glutamic acid group or a glutamic acid analogue group, wherein the glutamic acid group or the glutamic acid analogue is connected via N to a linker which is connected to a cytotoxic agent.

34. The method of killing a neoplastic cell according to claim 33, wherein the linker comprises a functional group selected from:

carbonyl, carbamate, urea, and equivalents.

35. The method of killing a neoplastic cell according to claim 33, wherein the cytotoxic agent comprises a nitrogen mustard or a nitrogen mustard analogue.

36. The method of killing a neoplastic cell according to claim 35, wherein the prodrug is N-(4-[bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid or a salt thereof.

45. The method of claim 23, wherein the CPG2 comprises an amino acid sequence which has at least 80% identity to SEQ ID NO:

2.

37. A method of treating a tumour in a patient in need of treatment, the method comprising administering to the patient:

a vaccinia virus which is capable of expressing a glutamate carboxypeptidase in a cell; and

, a prodrug which is capable of being converted into an active form by the glutamate carboxypeptidase.

38. The method of claim 37, wherein the vaccinia virus is genetically modified to have enhanced tumour selectivity.

39. The method of claim 37, wherein the vaccinia virus has one or more inactivated virulence genes.

40. The method of claim 39, wherein the one or more inactivated virulence genes include vaccinia thymidine kinase (vTK).

41. The method of claim 40, wherein the inactivated vTK gene comprises a CPG2 expression cassette insert.

42. The method of claim 40, wherein the inactivated vTK gene comprises a luciferase expression cassette insert.

43. The method of claim 39, wherein the one or more inactivated virulence genes include vaccinia growth factor (VGF).

44. The method of claim 37, wherein the glutamate carboxypeptidase is CPG2 or a mutant, variant or homologue thereof.

46. The method of claim 37, wherein the tumor is a solid tumor.

47. The method of claim 37, wherein the tumor is selected from head and neck cancer, colorectal cancer, lung cancer, melanoma, or breast cancer, cervix cancer, CNS cancer, ovarian cancer, kidney cancer, leukemia, brain tumor, or prostate cancer.