Modified vaccinia virus strains for use in diagnostic and therapeutic methods

• US 8,052,968 B2
• Filed: 10/16/2007
• Issued: 11/08/2011
• Est. Priority Date: 10/16/2006
• Status: Active Grant

• Current Assignee: Genelux Corporation
• Original Assignee: Genelux Corporation
• Inventors: Szalay, Aladar A., Zhang, Qian, Yu, Yong A., Frentzen, Alexa, Chen, Nanhai
• Primary Examiner(s): PENG, BO
• Application Number:
  US11/975,090
• Publication Number:
  US 20090053244A1
• Time in Patent Office: 1,484 Days
• Field of Search: 435/320.1, 424/135.1
• US Class Current: 424/93.21
• CPC Class Codes: A61K 2039/523 expressing foreign proteins
• CPC Class Codes: A61K 2039/5254 avirulent or attenuated
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 33/241 Lead; Compounds thereof
• CPC Class Codes: A61K 33/242 Gold; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 33/244 Lanthanides; Compounds thereof medicinal preparations containing radioactive lanthanides for use in therapy or testing in vivo A61K51/00
• CPC Class Codes: A61K 35/76 Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/204 IL-6
• CPC Class Codes: A61K 38/36 Blood coagulation or fibrinolysis factors
• CPC Class Codes: A61K 38/484 Plasmin (3.4.21.7)
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/285 Vaccinia virus or variola virus
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 : Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/0058 : Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
• 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 49/0045 : the fluorescent agent being a peptide or protein used for imaging or diagnosis in vivo
• CPC Class Codes: A61K 49/0047 : Green fluorescent protein [GFP]
• CPC Class Codes: A61K 49/0097 : Cells, viruses, ghosts, red blood cells, viral vectors, used for imaging or diagnosis in vivo
• CPC Class Codes: A61K 49/14 : Peptides, e.g. proteins
• CPC Class Codes: A61K 49/1896 : not provided for elsewhere, e.g. cells, viruses, ghosts, red blood cells, virus capsides
• CPC Class Codes: A61K 51/00 : Preparations containing radioactive substances for use in therapy or testing in vivo
• 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: C07K 14/005 : from viruses
• CPC Class Codes: C07K 14/47 : from mammals
• CPC Class Codes: C07K 14/54 : Interleukins [IL]
• CPC Class Codes: C07K 14/5412 : IL-6
• CPC Class Codes: C07K 14/7155 : for interleukins [IL]
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/20 : containing a tag with affinity for a non-protein ligand
• CPC Class Codes: C07K 2319/60 : containing spectroscopic/fluorescent detection, e.g. green fluorescent protein [GFP]
• CPC Class Codes: C07K 2319/61 : containing an enzyme fusion for detection (lacZ, luciferase)
• CPC Class Codes: C07K 2319/74 : containing a fusion for binding to a cell surface receptor
• CPC Class Codes: C12N 15/86 : Viral vectors
• CPC Class Codes: C12N 2710/14171 : Demonstrated in vivo effect
• CPC Class Codes: C12N 2710/24121 : Viruses as such, e.g. new isolates, mutants or their genomic sequences
• 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 2710/24141 : Use of virus, viral particle or viral elements as a vector
• CPC Class Codes: C12N 2710/24143 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/24162 : 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
• CPC Class Codes: C12Q 1/04 : Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor C12Q1/6897 takes precedence
• CPC Class Codes: G01N 33/574 : for cancer
• CPC Class Codes: G01N 33/585 : with a particulate label, e.g. coloured latex

Abstract

Modified viruses and methods for preparing the modified viruses are provided. Vaccines that contain the viruses are provided. The viruses can be used in methods of treatment of diseases, such as proliferative and inflammatory disorders, including as anti-tumor agents. The viruses also can be used in diagnostic methods.

Claims

1. A recombinant replication competent Lister strain vaccinia virus that encodes a diagnostic or therapeutic protein that comprises an anti-vascular endothelial (VEGF) single chain antibody, and that comprises an inactivated hemagglutinin (HA) gene, thymidine kinase (TK) gene or F14.5L gene.

2. A recombinant Lister strain vaccinia virus of claim 1, comprising, an inactivated hemagglutinin (HA) gene, thymidine kinase (TK) gene, and F14.5L gene or locus, wherein

the Lister strain vaccinia virus is an LIVP strain of virus;

and

the DNA encoding the protein comprising an anti-VEGF single chain antibody is inserted into one or more of a gene locus selected from among the HA gene locus, TK gene locus and the F14.5L gene locus in the Lister strain vaccinia virus.

3. The recombinant Lister strain vaccinia virus of claim 1 selected from among GLV-1h107, GLV-1h108 and GLV-1h109.

4. A recombinant Lister strain vaccinia virus of claim 1 that comprises replacement of the A34R gene with the A34R gene from another vaccinia virus strain.

5. The recombinant Lister strain vaccinia virus of claim 4, wherein the A34R gene is replaced by the A34R gene from vaccinia IHD-J strain.

6. The recombinant Lister strain vaccinia virus of claim 4, wherein the replacement increases the extracellular enveloped virus (EEV) form of vaccinia virus and/or increases the resistance of the virus to virus neutralizing antibodies.

7. A recombinant Lister strain vaccinia virus of claim 1 that comprises deletion of the A35R gene.

8. The recombinant Lister stain vaccinia virus of claim 1 that is an LIVP strain.

9. A recombinant Lister strain virus of claim 1, further comprising one or more heterologous nucleic acid molecules that encode(s) a diagnostic protein and/or another therapeutic gene product.

10. The recombinant Lister strain virus of claim 9, further comprising a nucleic acid molecule that encodes a diagnostic protein that is a detectable protein or a protein that induces a detectable signal.

11. The recombinant Lister strain virus of claim 10, wherein the diagnostic protein is selected from among a luciferase, a fluorescent protein, an iron storage molecule, an iron transporter, an iron receptor or a protein that binds a contrasting agent, chromophore or a compound or detectable ligand that can be detected.

12. The recombinant Lister strain virus of claim 9, wherein the therapeutic gene product is selected from among a cytokine, a chemokine, an immunomodulatory molecule, an antigen, a single chain antibody, antisense RNA, prodrug converting enzyme, siRNA, angiogenesis inhibitor, a toxin, an antitumor oligopeptide, a mitosis inhibitor protein, an antimitotic oligopeptide, an anti-cancer polypeptide antibiotic and tissue factor.

13. A combination, comprising a recombinant Lister strain vaccinia virus of claim 1 and an anticancer compound.

14. The combination of claim 13, wherein the anti-cancer compound is selected from among a cytokine, a chemokine, a growth factor, a photosensitizing agent, a toxin, an anti-cancer antibiotic, a chemotherapeutic compound, a radionuclide, an angiogenesis inhibitor, a signaling modulator, an anti-metabolite, an anti-cancer vaccine, an anti-cancer oligopeptide, a mitosis inhibitor protein, an antimitotic oligopeptide, an anti-cancer antibody, an anti-cancer antibiotic, an immunotherapeutic agent, a bacterium and a combination of any of the preceding thereof.

15. The combination of claim 13, wherein the anti-cancer compound is selected from among cisplatin, carboplatin, gemcitabine, irinotecan, an anti-EGFR antibody and an anti-VEGF antibody.

16. The combination of claim 13, wherein the anti-cancer compound and virus are formulated as a single composition or separately in two compositions.

17. A kit, comprising the combination of claim 13;

and optional instructions for administration of the composition(s).

18. A pharmaceutical composition comprising a recombinant Lister strain vaccinia virus of claim 1 in a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18 that is formulated for local or systemic administration.

20. The pharmaceutical composition of claim 18, comprising two or more viruses.

21. A combination, comprising:

a recombinant Lister strain vaccinia virus of claim 1; and

an anticancer compound selected from among cisplatin, carboplatin, gemcitabine, irinotecan, an anti-EGFR antibody and an anti-VEGF antibody.

22. The combination of claim 21, wherein the Lister strain vaccinia virus is an LIVP strain vaccinia virus.

23. The combination of claim 22, wherein the Lister strain vaccinia virus is selected from among GLV-1h107, GLV-1h108 and GLV-1h109.

24. The combination of claim 21, wherein the Lister strain vaccinia virus and the anti-cancer compound are formulated as a single composition or separately in two compositions.

25. The combination of claim 21, further comprising a pharmaceutically acceptable carrier.

26. An isolated cell containing a recombinant Lister strain vaccinia virus of claim 1.

27. An isolated tumor cell containing a recombinant Lister strain vaccinia virus of claim 1.

28. The combination of claim 13, wherein the anti-cancer compound is selected from among dacarbazine, vincristine and mitomycin.

29. The recombinant Lister strain vaccinia virus of claim 2, wherein the LIVP strain prior to insertion of the heterologous nucleic acid is GLV-1h68.

30. The recombinant Lister strain vaccinia virus of claim 1, wherein the anti-VEGF single chain antibody is antibody G6.

31. The recombinant Lister strain vaccinia virus of claim 1, wherein the anti-VEGF single chain antibody is encoded as a FLAG fusion protein.

32. The recombinant Lister strain vaccinia virus of claim 1, wherein expression of the protein comprising an anti-VEGF single chain antibody is under the control of a vaccinia early promoter, vaccinia early/late promoter or vaccinia late promoter.

33. A recombinant Lister strain vaccinia virus of claim 1, comprising an inactivated hemagglutinin (HA) gene, thymidine kinase (TK) gene, and F14.5L gene or locus.

34. A recombinant oncolytic vaccinia virus, comprising, an inactivated hemagglutinin (HA) gene, thymidine kinase (TK) gene, and F14.5L gene or locus, wherein the virus encodes a protein comprising an anti-VEGF single chain antibody.