# US 11,439,678 B2 · Oncolytic adenoviruses armed with heterologous genes

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- Number: US 11,439,678 B2
- Document ID: US11439678B2
- Status: Granted
- Kind: B2
- Application number: 15/967,093
- Filed: 2018-04-30
- Published: 2018-11-01
- Granted: 2022-09-13
- Earliest claimed: 2013-10-25
- Assignees: Psioxus Therapeutics Limited
- Applicants: Psioxus Therapeutics Limited
- Inventors: Brian Robert Champion; Alice Claire Noel Brown; Kerry David Fisher; Tamara Nicolson
- Web page: https://patentgrep.com/patent/US11439678B2

## CPC

- A61K 35/761: Adenovirus
- A61K 39/0011: {Cancer antigens}
- A61P 35/00: Antineoplastic agents
- 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 2039/5256: {expressing foreign proteins}
- 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
- 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

The present disclosure relates to a group B adenovirus comprising a sequence of formula (I): 5′ITR-B1-BA-B2-BX-BB-BY-B3-3′ITR wherein: B1 is bond or comprises: E1A, E1B or E1A-E1B; BA comprises-E2B-L1-L2-L3-E2A-L4; B2 is a bond or comprises: E3; BX is a bond or a DNA sequence comprising: a restriction site, one or more transgenes or both; BB comprises L5; BY is a bond or a DNA sequence comprising: a restriction site, one or more transgenes or both; B3 is a bond or comprises: E4; wherein at least one of BX or BY is not a bond, pharmaceutical compositions comprising the same and use of the viruses and compositions in treatment, particularly in the treatment of cancer. The disclosure also extends to plasmids and processes employed to prepare the said viruses.

## Claims

### Claim 1

A replication competent group B oncolytic adenovirus comprising a sequence of formula (I):
5′ITR-B1-BA-B2-BX-BB-BY-B3-3′ITR
wherein:
B1 comprises: E1A, E1B or E1A-E1B;
BA comprises: E2B-L1-L2-L3-E2A-L4;
B2 is a bond or comprises: E3;
BX is a bond or a DNA sequence comprising: a restriction site, one or more transgenes under the control of an exogenous promoter or both;
BB comprises L5;
BY comprises a transgene cassette comprising a transgene and a splice acceptor sequence; and
B3 is a bond or comprises: E4;
wherein the transgene cassette is under the control of an endogenous major late promoter.

### Claim 2 (depends on 1)

A replication competent adenovirus according to claim 1, wherein BY also comprises the sequence shown in SEQ ID NO: 11 or a DNA sequence that hybridizes thereto under stringent conditions.

### Claim 3 (depends on 1)

A replication competent adenovirus according to claim 1, wherein the splice acceptor is selected from CAGG, SEQ ID NO: 17 and SEQ ID NO: 18.

### Claim 4 (depends on 1)

A replication competent adenovirus according to claim 1, wherein the transgene cassette further comprises an internal ribosome entry sequence or a high self-cleavage efficiency 2A peptide.

### Claim 5 (depends on 4)

A replication competent adenovirus according to claim 4, wherein the transgene cassette encodes a high self-cleavage efficiency 2A peptide.

### Claim 6 (depends on 1)

A replication competent adenovirus according to claim 1, wherein the transgene cassette further comprises a Kozak sequence.

### Claim 7 (depends on 6)

An adenovirus according to claim 6, wherein the transgene cassette comprises a Kozak sequence at the start of a protein coding sequence.

### Claim 8 (depends on 1)

An adenovirus according to claim 1, wherein the transgene cassette further comprises a polyadenylation sequence.

### Claim 9 (depends on 1)

An adenovirus according to claim 1, wherein the transgene cassette further comprises a restriction site at the 3′ end of the DNA sequence and/or at the 5′ end of the DNA sequence.

### Claim 10 (depends on 1)

An adenovirus according to claim 1, wherein at least one transgene cassette encodes a monocistronic mRNA.

### Claim 11 (depends on 1)

An adenovirus according to claim 1, wherein at least one transgene cassette encodes a polycistronic mRNA.

### Claim 12 (depends on 1)

An adenovirus according to claim 1, wherein the transgene cassette encodes a reporter gene.

### Claim 13 (depends on 1)

An adenovirus according to claim 1, wherein the adenovirus is Ad11.

### Claim 14 (depends on 1)

An adenovirus according to claim 1, wherein the adenovirus is chimeric Enadenotucirev (EnAd).

### Claim 15 (depends on 1)

An adenovirus according to claim 1, wherein the virus comprises the sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 69, or SEQ ID NO: 73.

### Claim 16 (depends on 1)

A composition comprising an adenovirus according to claim 1.

### Claim 17 (depends on 1)

A method of treating a patient comprising administering a therapeutically effective amount of an adenovirus of claim 1.

### Claim 18 (depends on 16)

A method of treating a patient comprising administering a therapeutically effective amount of a composition according to claim 16.

### Claim 19 (depends on 1)

An adenovirus according to claim 1 wherein BX comprises the sequence of SEQ ID NO: 10, or a DNA sequence that hybridizes thereto under stringent conditions.

### Claim 20 (depends on 1)

An adenovirus according to claim 1, wherein BX is a bond.

### Claim 21 (depends on 1)

An adenovirus according to claim 1, wherein the transgene cassette encodes an RNAi sequence, a peptide or a protein.

### Claim 22 (depends on 21)

An adenovirus according to claim 21, wherein the encoded protein is an antibody or binding fragment thereof.

### Claim 23 (depends on 1)

An adenovirus according to claim 1, wherein the transgene cassette encodes a protein independently selected from the group consisting of sodium iodide symporter, an intracellular metalloproteins, HSV1-tk, GFP, luciferase and oestrogen receptor.

### Claim 24 (depends on 21)

An adenovirus according to claim 21, wherein the encoded protein is a cytokine or chemokine.

### Claim 25 (depends on 22)

An adenovirus according to claim 22, wherein the antibody or binding fragment thereof is specific to an antigen independently selected from the group consisting of OX40, OX40 ligand, CD27, CD28, CD30, CD40, CD40 ligand, CD70, CD137, GITR, 4-1BB, ICOS, ICOS ligand, CTLA-4, PD-1, PD-L1, PD-L2, VISTA, B7-H3, B7-H4, HVEM, ILT-2, ILT-3, ILT-4, TIM-3, LAG-3, BTLA, LIGHT, and CD160.

### Claim 26 (depends on 24)

An adenovirus according to claim 24, wherein the cytokine is independently selected from the group consisting of IL-1α, IL-1β, IL-6, IL-9, IL-12, IL-13, IL-17, IL-18, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-33, IL-35, IL-2, IL-4, IL-5, IL-7, IL-10, IL-15, IL-21, IL-25, IL-1RA, IFNα, IFNβ, IFNγ, TNFα, TGFβ, lymphotoxin α (LTA) and GM-CSF.

### Claim 27 (depends on 21)

An adenovirus according to claim 21, wherein the encoded protein is a chemokine independently selected from the group comprising IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21, CXCR2, CCR2, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR3, CXCR4, CXCR5, CRTH2 or a receptor thereof.