Genetically modified tumor-targeted bacteria with reduced virulence

• US 20070009489A1
• Filed: 04/28/2005
• Published: 01/11/2007
• Est. Priority Date: 09/10/1997
• Status: Active Grant

• Current Assignee: Vion Pharmaceuticals, Inc., Yale University
• Original Assignee: Vion Pharmaceuticals, Inc., Yale University
• Inventors: Bermudes, David, Low, Kenneth
• Granted Patent: US 7,514,089 B2
• Time in Patent Office: Days
• US Class Current: 424/93.400
• CPC Class Codes: A61K 2039/523 expressing foreign proteins
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• 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 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0275 Salmonella
• 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: C07K 14/255 Salmonella (G)
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10S 435/879 Salmonella

Abstract

The present invention is directed to mutant Salmonella sp. having a genetically modified msbB gene in which the mutant Salmonella is capable of targeting solid tumors. The present invention further relates to the therapeutic use of the mutant Salmonella for growth inhibition and/or reduction in volume of solid tumors.

Claims

1. A mutant Salmonella sp. comprising genetically modified msbB gene in which the mutant Salmonella is capable of targeting a solid tumor when administered in vivo.

2. The mutant Salmonella of claim 1 which is designated YS1629 and having ATCC Accession No. 202025 or is designated YS1170 and having ATCC Accession No. 202024 or is designated YS8211 and having ATCC Accession No. 202026.

3. The mutant Salmonella of claim 1 which is selected from the group consisting of Salmonella typhi, Salmonella choleraesuis, and Salmonella enteritidis.

4. The mutant Salmonella of claim 1 which expresses an altered lipid A molecule.

5. The mutant Salmonella of claim 1 which induces TNFα

expression at about 5 percent to about 40 percent of that induced by a wild type Salmonella sp.

6. The mutant Salmonella of claim 1 which induces TNFα

expression at about 10 percent to about 35 percent of that induced by a wild type Salmonella sp.

7. Lipopolysaccharide purified from the mutant Salmonella of claim 1 which induces TNFα

expression at less than or equal to 0.001 percent of that induced by a wild type Salmonella sp.

8. The mutant Salmonella of claim 1 in which a chelating agent inhibits growth by about 90 percent compared to the growth of a wild type Salmonella sp.

9. The mutant Salmonella of claim 1 in which a chelating agent inhibits growth by about 99 percent compared to the growth of a wild type Salmonella sp.

10. The mutant Salmonella of claim 1 in which a chelating agent inhibits growth greater than 99 percent compared to the growth of a wild type Salmonella sp.

12. The mutant Salmonella of claim 1 which survives in macrophages at about 50 percent to about 30 percent of the level of survival of a wild type Salmonella sp.

13. The mutant Salmonella of claim 1 which survives in macrophages at about 30 percent to about 10 percent of the level of survival of a wild type Salmonella sp.

14. The mutant Salmonella of claim 1 which survives in macrophages at about 10 percent to about 1 percent of the level of survival of a wild type Salmonella sp.

15. A method of inhibiting growth or reducing volume of a solid tumor cancer, comprising administering an effective amount of the mutant Salmonella sp. of claim 1 to a patient having a solid tumor cancer.

16. The method according to claim 15 in which the mutant Salmonella is selected from the group consisting of Salmonella typhi, Salmonella choleraesuis, and Salmonella enteritidis.

17. The method according to claim 15 in which the mutant Salmonella expresses an altered lipid A molecule.

18. The method according to claim 15 in which the mutant Salmonella induces TNFα

expression at about 5 percent to about 40 percent of that induced by a wild-type Salmonella sp.

19. The method according to claim 15 in which the mutant Salmonella induces TNFα

expression at about 10 percent to about 35 percent of that induced by a wild-type Salmonella sp.

20. The method according to claim 15 in which lipopolysaccharide purified from the mutant Salmonella induces TNFα

expression at less than or equal to 0.001 percent of that induced by a wild type Salmonella sp.

21. The method according to claim 15 in which a chelating agent inhibits growth of the mutant Salmonella by about 90 percent compared to the growth of a wild-type Salmonella sp.

11. (canceled)

22-31. -31. (canceled)