# US 7,608,255 B2 · Replication-competent anti-cancer vectors

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- Number: US 7,608,255 B2
- Document ID: US7608255B2
- Status: Granted
- Kind: B2
- Application number: 11/249,873
- Filed: 2005-10-13
- Published: 2006-02-09
- Granted: 2009-10-27
- Earliest claimed: 1999-07-12
- Assignees: Saint Louis University
- Inventors: William S. M. Wold; Karoly Toth; Konstantin Doronin; Ann E. Tollefson
- Web page: https://patentgrep.com/patent/US7608255B2

## CPC

- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 35/761: Adenovirus
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/005: from viruses
- C12N 15/86: Viral vectors
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C12N 2710/10322: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2710/10332: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2710/10343: viral genome or elements thereof as genetic vector
- C12N 2830/001: controllable enhancer/promoter combination
- C12N 2830/008: cell type or tissue specific enhancer/promoter combination
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

Novel vectors which are replication competent in neoplastic cells and which overexpress an adenovirus death protein are disclosed. Some of the disclosed vectors are replication-restricted to neoplastic cells or to neoplastic alveolar type II cells. Compositions and methods for promoting the death of neoplastic cells using these replication-competent vectors are also disclosed.

## Claims

### Claim 1

A method for treating cancer in an animal having a tumor comprising administering to the tumor an adenovirus vector wherein said adenovirus vector is replication-competent in a normal cell and a tumor cell and overexpresses an adenovirus death protein (ADP), wherein overexpression is defined as overexpression relative to dl309.

### Claim 2 (depends on 1)

The method of claim 1, wherein overexpression relative to dl309 is detectable by western blot, cell lysis, virus release or by a cell spreading assay.

### Claim 3 (depends on 2)

The method of claim 2, wherein the overexpression relative to dl309 is detectable by western blot.

### Claim 4 (depends on 2)

The method of claim 2, wherein the overexpression relative to dl309 is detectable by cell lysis.

### Claim 5 (depends on 2)

The method of claim 2, wherein the overexpression relative to dl309 is detectable by virus release.

### Claim 6 (depends on 2)

The method of claim 2, wherein the overexpression relative to dl309 is detectable by a cell spreading assay.

### Claim 7 (depends on 1)

The method of claim 1, wherein the adenovirus vector comprises SEQ ID NO:3 or SEQ ID NO:4.

### Claim 8 (depends on 1)

The method of claim 1, wherein the adenovirus death protein comprises SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11 or SEQ ID NO:12.

### Claim 9 (depends on 1)

The method of claim 1, further comprising the step of passively immunizing the animal against the adenovirus vector.

### Claim 10 (depends on 1)

The method of claim 1, further comprising treating the tumor with radiation.

### Claim 11 (depends on 10)

The method of claim 10, further comprising administering a recombinant adenovirus that is replication-defective to the tumor and treating the tumor with radiation.

### Claim 12 (depends on 1)

The method of claim 1, further comprising treating the tumor with chemotherapy.

### Claim 13 (depends on 1)

The method of claim 1, further comprising administering to the tumor one or more replication-defective adenoviruses, wherein each replication-defective adenovirus expresses an anti-cancer gene product, and wherein the adenovirus vector facilitates the spread of the replication-defective adenovirus in the tumor.

### Claim 14 (depends on 1)

The method of claim 1, wherein the adenovirus vector lacks expression of at least one E3 protein selected from the group consisting of gp19K, RIDα, RIDβ and 14.7K.

### Claim 15 (depends on 14)

The method of claim 14, wherein the adenovirus vector lacks expression of the gp19K protein.

### Claim 16 (depends on 14)

The method of claim 14, wherein the adenovirus vector lacks expression of the RIDα protein.

### Claim 17 (depends on 14)

The method of claim 14, wherein the adenovirus vector lacks expression of the RIDβ protein.

### Claim 18 (depends on 14)

The method of claim 14, wherein the adenovirus vector lacks expression of the 14.7K protein.

### Claim 19 (depends on 14)

The method of claim 14, wherein the adenovirus vector lacks expression of the gp19K, RIDα, RIDβ and 14.7K proteins.

### Claim 20 (depends on 1)

The method of claim 1, wherein the adenovirus vector comprises a deletion in the E3 region that removes a splice site for any of the E3 mRNAs.

### Claim 21 (depends on 1)

The method of claim 1, wherein the adenovirus vector comprises at least one deletion in the E3 region, wherein the at least one deletion comprises a sequence that encodes at least one E3 protein, wherein the protein is selected from the group consisting of gp19K, RIDα, RIDβ, and 14.7K.

### Claim 22 (depends on 21)

The method of claim 21, wherein the at least one deletion comprises a sequence that encodes the gp19K, RIDα, RIDβ and 14.7K proteins.

### Claim 23 (depends on 22)

The method of claim 22, wherein the at least one deletion further comprises a sequence that encodes the 6.7K protein.

### Claim 24 (depends on 22)

The method of claim 22, wherein the at least one deletion further comprises a sequence that encodes the 12.5K protein.

### Claim 25 (depends on 22)

The method of claim 22, wherein the at least one deletion further comprises a sequence that encodes the 6.7K and 12.5K proteins.

### Claim 26 (depends on 1)

The method of claim 1, wherein the animal is a human.

### Claim 27 (depends on 1)

The method of claim 1, wherein:
a) the ADP is expressed from an ADP coding sequence positioned under the control of a promoter other than the endogenous promoters for ADP;
b) the adenovirus vector comprises a deletion in the E3 region that removes a splice site for an E3 mRNA;
c) the ADP is expressed from an ADP coding sequence flanked by a pre-mRNA splicing and cleavage/polyadenylation signal other than the pre-mRNA splicing and cleavage/polyadenylation signal normally associated with the ADP gene, or
d) the ADP is expressed from an ADP coding sequence that is positioned downstream of the coding sequence for another adenovirus mRNA, together with a sequence on the 5′ side of the ADP coding sequence that allows for internal initiation of translation of ADP.

### Claim 28 (depends on 1)

The method of claim 1, wherein the ADP is expressed from an ADP coding sequence positioned under the control of promoter other than the endogenous promoters for ADP.

### Claim 29 (depends on 28)

The method of claim 28, wherein the ADP coding sequence is positioned under the control of a promoter that is exogenous to adenovirus.

### Claim 30 (depends on 27)

The method of claim 27, wherein the animal is a human.

### Claim 31 (depends on 1)

The method of claim 1, wherein the ADP coding sequence is positioned behind a coding sequence for another adenovirus mRNA together with a sequence on the 5′ side of the ADP coding sequence that allows for internal initiation of translation of ADP.

### Claim 32 (depends on 31)

The method of claim 31, wherein the sequence on the 5′ side of the ADP coding sequence that allows for internal initiation of translation of ADP is an Ad tripartite leader or a viral internal ribosome initiation sequence.

### Claim 33 (depends on 19)

The method of claim 19, wherein the adenovirus vector additionally lacks expression of the E3 6.7K and 12.5K proteins.

### Claim 34 (depends on 1)

The method of claim 1, wherein the adenovirus vector is an Ad1, Ad2, Ad5 or Ad6 vector.

### Claim 35 (depends on 1)

The method of claim 1, wherein the adenovirus vector is administered to the tumor by injection of vector intravenously or intrathecally.

### Claim 36 (depends on 1)

The method of claim 1, wherein the adenovirus vector is administered to the tumor by direct injection of the tumor.

### Claim 37 (depends on 27)

The method of claim 27, wherein the animal is passively immunized against the recombinant adenovirus.