Listeria-based adjuvants

Patent metadata

Field	Value
Publication number	US-10064898-B2
Application number	US-201615220641-A
Country	US
Kind code	B2
Filing date	Jul 27, 2016
Priority date	Mar 11, 2011
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

This invention provides methods and compositions for using Listeria monocytogenes as an adjuvant for enhancing immune responses in a subject.

First claim

What is claimed is:

1. A method of reconstituting an immune response in a subject in an antigen-independent manner, the method comprising administering a live attenuated recombinant Listeria strain to said subject, wherein said Listeria strain comprises a mutation or a deletion of a genomic internalin C (inlC) gene and ActA gene, and wherein said administration reconstitutes said immune response in the subject in an antigen-independent manner.

2. The method of claim 1 , wherein said Listeria strain comprises a nucleic acid molecule, wherein said nucleic acid molecule comprises a first open reading frame encoding a non-hemolytic LLO protein or immunogenic fragment thereof, an N-terminal ActA fragment or a truncated ActA, or a PEST amino acid sequence selected from the group consisting of SEQ ID NO: 8-19.

3. The method of claim 1 , wherein said Listeria over expresses and secretes said non-hemolytic LLO protein or immunogenic fragment thereof, said N-terminal ActA fragment or a truncated ActA, or said PEST amino acid sequence selected from the group consisting of SEQ ID NO: 8-19.

4. The method of claim 1 , wherein said recombinant Listeria further comprises a mutation or a deletion of a genomic PlcA gene, PrfA gene or a PlcB gene.

5. The method of claim 2 , wherein said nucleic acid molecule further comprises a second open reading frame encoding a metabolic enzyme, wherein said metabolic enzyme complements an endogenous gene that is lacking in the chromosome of said recombinant Listeria strain.

6. The method of claim 5 , wherein said metabolic enzyme encoded by said second open reading frame is an alanine racemase enzyme or a D-amino acid transferase enzyme.

7. The method of claim 2 , wherein said nucleic acid molecule is integrated into the Listeria genome.

8. The method of claim 2 , wherein said nucleic acid molecule is in a plasmid that is stably maintained in said recombinant Listeria strain in the absence of antibiotic selection.

9. The method of claim 1 , wherein said subject is an adult human, a child or a non-human mammal.

10. The method of claim 1 , wherein the Listeria strain is used alone or is combined with an additional adjuvant.

11. The method of claim 10 , wherein said additional adjuvant is a non-nucleic acid adjuvant including aluminum adjuvant, Freund's adjuvant, MPL, emulsion, GM-CSF, QS21, SBAS2, CpG-containing oligonucleotide, a nucleotide molecule encoding an immune-stimulating cytokine, comprises a bacterial mitogen, or a bacterial toxin.

12. The method of claim 1 , wherein said method allows the treatment of said disease.

13. The method of claim 12 , wherein said disease is a tumor or a cancer, or an infectious disease.

14. The method of claim 13 , wherein said method increases the ratio of CD8+/T regulatory cells in said tumor.

Assignees

• Advaxis Inc
• Univ Pennsylvania
• Univ Georgia

Inventors

• Rothman John
• Wallecha Anu
• Singh Reshma
• Harn Jr Donald A
• Paterson Yvonne

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K2039/523

  expressing foreign proteins · CPC title

• C12N7/00

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title