Microorganisms for therapy

• US 7,588,767 B2
• Filed: 06/18/2004
• Issued: 09/15/2009
• Est. Priority Date: 06/18/2003
• Status: Active Grant

• Current Assignee: Genelux Corporation
• Original Assignee: Genelux Corporation
• Inventors: Szalay, Aladar A., Zhang, Qian, Yu, Yong A., Timiryasova, Tatyana
• Primary Examiner(s): Campell; Bruce
• Assistant Examiner(s): Blumel; Benjamin P
• Application Number:
  US10/872,156
• Publication Number:
  US 20050031643A1
• Time in Patent Office: 1,915 Days
• Field of Search: None
• US Class Current: 424/199.1
• CPC Class Codes: A61K 2039/5254 avirulent or attenuated
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/744 Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/285 Vaccinia virus or variola virus
• 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 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/24132 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/24134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2710/24143 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2710/24161 : Methods of inactivation or attenuation
• 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: C12P 19/34 : Polynucleotides, e.g. nucleic acids, oligoribonucleotides
• CPC Class Codes: C12P 21/02 : having a known sequence of two or more amino acids, e.g. glutathione

Abstract

Therapeutic methods and microorganisms therefore are provided. The microorganisms are designed to accumulate in immunoprivileged tissues and cells, such as in tumors and other proliferating tissue and in inflamed tissues, compared to other tissues, cells and organs, so that they exhibit relatively low toxicity to host organisms. The microorganisms also are designed or modified to result in leaky cell membranes of cells in which they accumulate, resulting in production of antibodies reactive against proteins and other cellular products and also permitting exploitation of proliferating tissues, particularly tumors, to produce selected proteins and other products. Methods for making tumor specific antibodies and also methods of making gene products encoded by the microorganism as well as antibodies reactive therewith are provided.

Claims

1. A recombinant vaccinia virus, comprising a modified thymidine kinase (TK) gene, a modified hemagglutinin (HA) gene, and a modified F3 gene or locus, wherein each of said gene or locus is inactivated, wherein the vaccinia virus is a Lister strain.

3. The recombinant vaccinia virus of claim 1, wherein at least the F3 gene is inactivated by insertion of heterologous nucleic acid therein.

5. The recombinant virus of claim 1, where the strain is the LIVP strain.

6. The recombinant vaccinia virus of claim 1, wherein the modification of the F3 gene is at the NotI site within the F3 gene or a corresponding locus.

7. The recombinant vaccinia virus of claim 6, wherein the modification is at position 35 of the F3 gene or at position 1475 inside of the HindIII-F fragment of vaccinia virus DNA strain LIVP.

8. The recombinant vaccinia virus of claim 1, wherein the TK, HA and F3 gene comprises an insertion of heterologous nucleic acid that encodes a protein.

9. The recombinant vaccinia virus of claim 8, wherein the heterologous nucleic acid comprises a regulatory sequence operatively linked to the nucleic acid encoding the protein.

10. The recombinant vaccinia virus of claim 1, wherein the virus comprises heterologous nucleic acid inserted under the control of a vaccinia virus promoter.

11. The recombinant vaccinia virus of claim 10, wherein the promoter comprises an early/late vaccinia pE/L promoter.

12. The recombinant vaccinia virus of claim 8, wherein the heterologous nucleic acid encodes a detectable protein or a protein capable of inducing a detectable signal.

13. An isolated host cell containing a recombinant vaccinia virus of claim 1.

14. An isolated tumor cell, comprising a recombinant vaccinia virus of claim 1.

15. A pharmaceutical composition containing a recombinant vaccinia virus of claim 1 in a pharmaceutically acceptable vehicle.

16. The pharmaceutical composition of claim 15 that is formulated for systemic administration.

17. The pharmaceutical composition of claim 15 that is formulated for intravenous administration or is formulated in a delivery vehicle.

18. The virus of claim 1 that comprises nucleic acid encoding a therapeutic product.

19. A combination, comprising at least two microorganisms formulated for administration to an animal for elimination of immunoprivileged cells or tissues, wherein one of the microorganisms is a virus of claim 1.

20. The combination of claim 19, wherein the immunoprivileged cells or tissues comprises tumor cells.

21. The combination of claim 19, wherein the microorganisms are formulated in separate compositions.

22. A kit comprising the combination of claim 19, wherein each composition is formulated and packaged for single dosage administration.

23. The recombinant vaccinia virus of claim 10, wherein the heterologous nucleic acid encodes a detectable protein or a protein capable of inducing a detectable signal.

2. A recombinant vaccinia virus, comprising a modified thymidine kinase (TK) gene, a modified hemagglutinin (HA) gene, and a modified F3 gene or locus, wherein each of the F3 gene or locus, the TK gene and HA gene is modified by insertion of heterologous nucleic acid, wherein the vaccinia virus is a Lister strain.

4. The recombinant vaccinia virus of claim 2, wherein the F3 gene and the TK gene are inactivated by insertion of heterologous nucleic acid.

24. The recombinant virus of claim 2, where the strain is the LIVP strain.

25. The recombinant vaccinia virus of claim 2, wherein each of the HA, TK and the F3 gene or locus is inactivated by insertion of the heterologous nucleic acid therein.