Genetically modified tumor-targeted bacteria with reduced virulence

• US 7,354,592 B2
• Filed: 02/23/2005
• Issued: 04/08/2008
• Est. Priority Date: 09/10/1997
• Status: Expired due to Fees

• Current Assignee: Vion Pharmaceuticals, Inc., Yale University
• Original Assignee: Vion Pharmaceuticals, Inc., Yale University
• Inventors: Bermudes, David, Low, Kenneth Brooks
• Primary Examiner(s): Bui; Phuong T
• Application Number:
  US11/064,533
• Publication Number:
  US 20050255088A1
• Time in Patent Office: 1,140 Days
• Field of Search: 424/235.1, 424/258.1, 424/93.2, 424/93.4, 435/252.3, 435/252.8
• US Class Current: 424/235.1
• 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 39/0275 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/255 Salmonella (G)
• CPC Class Codes: C12N 9/1029 transferring groups other than amino-acyl groups (2.3.1)
• CPC Class Codes: C12P 19/44 Preparation of O-glycosides, e.g. glucosides polysaccharides and not substituted disaccharides C12P19/04, C12P19/12
• 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 invention is also directed to Salmonella sp. containing a genetically modified msbB gene as well as an genetic modification in a biosynthetic pathway gene such as the purl gene. 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 method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering an effective amount of a mutant Salmonella sp. to a patient having a solid tumor cancer, wherein said mutant Salmonella sp. comprises a disrupted msbB gene and is capable of targeting a solid tumor cancer when administered in vivo.

2. The method of claim 1, wherein the mutant Salmonella sp. is Salmonella typhi, Salmonella choleraesuis, or Salmonella enteritidis.

3. The method of claim 1, wherein the mutant Salmonella sp. expresses an altered lipid A molecule.

4. The method of claim 1, wherein the mutant Salmonella sp. induces TNFα

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

5. The method of claim 1, wherein the mutant Salmonella sp. induces TNFα

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

6. The method of claim 1, wherein a chelating agent inhibits the growth of the mutant Salmonella sp. by about 90 percent compared to the growth of a wild-type Salmonella sp.

7. The method of claim 1, wherein a chelating agent inhibits the growth of the mutant Salmonella sp. by about 99 percent compared to the growth of a wild-type Salmonella sp.

8. The method of claim 1, wherein a chelating agent inhibits the growth of the mutant Salmonella sp. by greater than 99 percent compared to the growth of a wild-type Salmonella sp.

9. The method of claim 6, wherein the chelating agent is Ethylenediaminetetraacetic Acid (EDTA), Ethylene Glycol-bis(β

-aminoethyl Ether) N,N,N′

,N′

,-Tetraacetic Acid (EGTA), or sodium citrate.

10. The method of claim 1, wherein the mutant Salmonella sp. survives in macrophages at about 50 percent to about 30 percent of the level of survival of a wild-type Salmonella sp.

11. The method of claim 1, wherein the mutant Salmonella sp. survives in macrophages at about 30 percent to about 10 percent of the level of survival of a wild-type Salmonella sp.

12. The method of claim 1, wherein the mutant Salmonella sp. survives in macrophages at about 10 percent to about 1 percent of the level of survival of a wild-type Salmonella sp.

13. The method of claim 1, wherein the solid tumor cancer is melanoma, colon carcinoma, lung cancer, liver cancer, kidney cancer, prostate cancer, or breast cancer.