# US 11,077,156 B2 · Oncolytic adenovirus compositions

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- Number: US 11,077,156 B2
- Document ID: US11077156B2
- Status: Granted
- Kind: B2
- Application number: 14/852,981
- Filed: 2015-09-14
- Published: 2015-12-31
- Granted: 2021-08-03
- Earliest claimed: 2013-03-14
- Assignees: The Salk Institute for Biological Studies
- Applicants: Salk Institute for Biological Studies
- Inventors: Clodagh O'Shea; Shigeki Miyake-Stoner
- Web page: https://patentgrep.com/patent/US11077156B2

## CPC

- A61K 35/761: Adenovirus
- A61K 35/768: Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- 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 15/86: Viral vectors
- C12N 2710/10021: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2710/10032: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2710/10043: viral genome or elements thereof as genetic vector
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

An adenovirus comprising an E1A polypeptide comprising one or more modifications and comprising an E4orf6/7 polypeptide comprising one or more modifications is described. Compositions and kits comprising the modified adenoviruses are also described. Further described is a method of treating a proliferative disorder in a subject comprising administering to the subject an adenovirus comprising the E1A polypeptide comprising one or more modifications and comprising the E4orf6/7 polypeptide comprising one or more modifications.

## Claims

### Claim 1

A recombinant adenovirus comprising:
a modified genome comprising:
(i) an adenovirus E1A promoter operably linked to a nucleic acid sequence encoding an E1A protein comprising a modification in a first Rb-binding site; and
(ii) an adenovirus E4 promoter operably linked to an E4orf6/7 gene product coding sequence having a deletion or a modification of only one of the two E4orf6/7 exons, wherein the deletion of the modification impairs E4orf6/7 gene product activity and/or expression; wherein the recombinant adenovirus selectively replicates in Rb-deficient cells.

### Claim 2 (depends on 1)

The recombinant adenovirus of claim 1, wherein the
E1A protein further comprises a modification in a second Rb-binding site.

### Claim 3 (depends on 1)

The recombinant adenovirus of claim 1, wherein the E1A protein modification is selected from:
a deletion of the LXCXE motif;
a deletion of amino acid residues 122-126;
a deletion of amino acid residues 2-11;
a substitution at residue Y47;
a substitution at residue C124; and any combination of the above.

### Claim 4 (depends on 3)

The recombinant adenovirus of claim 3, wherein the modification in the E1A protein is at least one of the substitution at residue Y47, wherein the substitution is a Y47H substitution, and the substitution at residue C124, wherein the substitution is a C124G substitution.

### Claim 5 (depends on 1)

The recombinant adenovirus of claim 1, the modified genome further comprising: a nucleic acid sequence encoding an E4orf1 protein comprising one or more modifications.

### Claim 6 (depends on 5)

The recombinant adenovirus of claim 5, wherein the one or more modifications of the E4orf1 protein are selected from:
a deletion in the C-terminal region;
a deletion of the last four amino acids in the C-terminal region; and
a deletion of residues 125-128.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the recombinant adenovirus of claim 1 and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

The recombinant adenovirus of claim 1, wherein the deletion or the modification of the only one of the two E4orf6/7 exons is a deletion or a modification of the second E4orf6/7 exon.

### Claim 9 (depends on 1)

The recombinant adenovirus of claim 1, the modified genome further comprising a nucleic acid sequence encoding an E4orf6 protein.

### Claim 10 (depends on 1)

The recombinant adenovirus of claim 1, wherein the modification of the E1A protein comprises a deletion of the LXCXE motif within the first Rb-binding site of said E1A protein.

### Claim 11 (depends on 10)

The recombinant adenovirus of claim 10, wherein the deletion or the modification of the only one of the two E4orf6/7 exons is a deletion of the second E4orf6/7 exon.

### Claim 12 (depends on 11)

The recombinant adenovirus of claim 11, the modified genome further comprising a nucleic acid sequence encoding an E4orf6 protein.

### Claim 13 (depends on 12)

The recombinant adenovirus of claim 12, wherein the adenovirus is serotype 5.

### Claim 14 (depends on 13)

A pharmaceutical composition comprising the recombinant adenovirus of claim 13 and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 10)

The recombinant adenovirus of claim 10, wherein the deletion or the modification of only the one of the two E4orf6/7 exons is a modification of the second E4orf6/7 exon.

### Claim 16 (depends on 15)

The recombinant adenovirus of claim 15, the modified genome further comprising a nucleic acid sequence encoding an E4orf6 protein.

### Claim 17 (depends on 16)

The recombinant adenovirus of claim 16, wherein the adenovirus is serotype 5.

### Claim 18 (depends on 17)

A pharmaceutical composition comprising the recombinant adenovirus of claim 17 and a pharmaceutically acceptable carrier.

### Claim 19

A recombinant adenovirus comprising:
(i) an adenovirus E1A promoter operably linked to a nucleic acid sequence encoding an E1A protein comprising a modification in a first Rb-binding site; and
(ii) an adenovirus E4 promoter operably linked to an E4orf6/7 gene product coding sequence having a deletion or a modification of only one of the two E4orf6/7 exons, wherein the deletion or the modification impairs E4orf6/7 gene product activity and/or expression; and
(ii) a nucleic acid sequence encoding an E4orf1 protein comprising one or more modifications; or a deletion of all of the E4orf1 coding sequence;
wherein the recombinant adenovirus selectively replicates in Rb-deficient cells.

### Claim 20 (depends on 19)

The recombinant adenovirus of claim 19, wherein the E1A protein further comprises a modification in a second Rb-binding site.

### Claim 21 (depends on 19)

The recombinant adenovirus of claim 19, wherein the E1A protein modification is selected from:
a deletion of the LXCXE motif; a deletion of amino acid residues 122-126;
a deletion of amino acid residues 2-11;
a substitution at residue Y47;
a substitution at residue C124; and any combination of the above.

### Claim 22 (depends on 21)

The recombinant adenovirus of claim 21, wherein the modification in the E1A protein is at least one of the substitution at residue Y47, wherein the substitution is a Y47H substitution, and the substitution at residue C124, wherein the substitution is a C124G substitution.

### Claim 23 (depends on 19)

The recombinant adenovirus of claim 19, wherein the deletion or the modification of the only one of the two E4orf6/7 exons is a deletion or a modification of the second E4orf6/7 exon.

### Claim 24 (depends on 19)

The recombinant adenovirus of claim 19, wherein the one or more modifications of the E4orf1 protein are selected from:
a deletion in the C-terminal region;
a deletion of the last four amino acids in the C-terminal region; and
a deletion of residues 125-128.

### Claim 25 (depends on 19)

A pharmaceutical composition comprising the recombinant adenovirus of claim 19 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 19)

The recombinant adenovirus of claim 19, the modified genome further comprising a nucleic acid sequence encoding an E4orf6 protein.