# US 8,273,568 B2 · Replication-competent herpes simplex virus mediates destruction of neoplastic cells

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- Number: US 8,273,568 B2
- Document ID: US8273568B2
- Status: Granted
- Kind: B2
- Application number: 10/788,410
- Filed: 2004-03-01
- Published: 2004-11-18
- Granted: 2012-09-25
- Earliest claimed: 1994-06-23
- Assignees: Georgetown University
- Inventors: Robert L. Martuza; Samuel D. Rabkin; Toshihiro Mineta
- Web page: https://patentgrep.com/patent/US8273568B2

## CPC

- C12N 15/86: Viral vectors
- A01K 67/0271: Chimeric vertebrates, e.g. comprising exogenous cells
- A61K 35/763: Herpes virus
- C07K 14/005: from viruses
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/8509: {for producing genetically modified animals, e.g. transgenic}
- A01K 2217/05: Animals comprising random inserted nucleic acids (transgenic)
- A01K 2267/0331: Animal model for proliferative diseases
- 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)
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 2039/525: {Virus}
- A61K 2121/00: Preparations for use in therapy
- C12N 2710/16622: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2710/16632: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2710/16643: viral genome or elements thereof as genetic vector
- C12N 2830/00: Vector systems having a special element relevant for transcription
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

A method for killing malignant brain tumor cells in vivo entails providing replication competent herpes simplex virus vectors to tumor cells. A replication competent herpes simplex virus vector, with defective expression of the γ34.5 gene and the ribonucleotide reductase gene, specifically destroys tumor cells, is hypersensitive to anti-viral agents, and yet is not neurovirulent.

## Claims

### Claim 1

A herpes simplex virus with a genome that comprises (i) an expressible non-herpes simplex virus nucleotide sequence encoding a cytokine capable of eliciting an immune response against a tumor cell, and (ii) an alteration in the γ34.5 gene such that no functional γ34.5 gene product is made, wherein the neurovirulence of said herpes simplex virus is attenuated.

### Claim 2 (depends on 1)

The herpes simplex virus of claim 1, further comprising at least one further gene alteration.

### Claim 3 (depends on 2)

The herpes simplex virus of claim 2, wherein said at least one further gene alteration is in the ribonucleotide reductase gene, such that no functional ribonucleotide reductase is made.

### Claim 4 (depends on 3)

The herpes simplex virus of claim 3, wherein said herpes simplex virus is G207 expressing the cytokine.

### Claim 5 (depends on 1)

The herpes simplex virus of claim 1, wherein an essential viral gene product of said virus is under the control of a tumor cell-specific promoter rather than its own viral promoter.

### Claim 6 (depends on 1)

A composition comprising the herpes simplex virus of claim 1 and a pharmaceutically acceptable vehicle for said virus.

### Claim 7 (depends on 5)

The herpes simplex virus of claim 5, wherein said tumor cell-specific promoter is nestin promoter.

### Claim 8 (depends on 5)

The herpes simplex virus of claim 5, wherein said tumor cell-specific promoter is basic fibroblast growth factor promoter.

### Claim 9 (depends on 5)

The herpes simplex virus of claim 5, wherein said tumor cell-specific promoter is epidermal growth factor promoter.