# US 2013/0280217 A1 · Methods for Use of a Specific Anti-Angiogenic Adenoviral Agent

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- Number: US 2013/0280217 A1
- Document ID: US20130280217A1
- Status: Published application
- Kind: A1
- Application number: 13/797,160
- Filed: 2013-03-12
- Published: 2013-10-24
- Earliest claimed: 2010-01-05
- Applicants: Vascular Biogenics Ltd.
- Inventors: YAEL COHEN; NAAMIT SHER; EREZ FEIGE; LIVNAT BANGIO; EYAL BREITBART
- Web page: https://patentgrep.com/patent/US20130280217A1

## CPC

- C12N 15/86: Viral vectors
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61K 48/0083: {characterised by an aspect of the administration regime}
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/04: Immunostimulants
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 14/7151: {for tumor necrosis factor [TNF], for lymphotoxin [LT]}
- C12N 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C07K 2319/00: Fusion polypeptide
- C12N 2799/022: where the vector is derived from an adenovirus
- C12N 2830/008: cell type or tissue specific enhancer/promoter combination
- C12N 2830/85: mammalian
- 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

Anti-angiogenic adenovirus vectors, and therapeutic use thereof are provided, and more particularly, but not exclusively, clinical protocols for treatment of solid tumors in patients with an Ad5-PPE-1-3X-fas-chimera adenovirus vector.

## Claims

### Claim 1

A method of treating a solid tumor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a non-replicating adenovirus vector, wherein said vector comprises a polynucleotide which comprises a fas-chimera transgene transcriptionally linked to a murine pre-proendothelin promoter, wherein said therapeutically effective amount is at least 1×108 virus particles.

### Claim 2 (depends on 1)

The method of claim 1, wherein said therapeutically effective amount is at least about 1×109 to about 1×1016 virus particles or at least about 1×1011 to about 1×1013 virus particles.

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The method of claim 1, wherein said therapeutically effective amount is at least about 3×1012 virus particles or at least about 1×1013 virus particles.

### Claim 5

(canceled)

### Claim 6 (depends on 1)

The method of claim 1, wherein said fas-chimera transgene comprises the sequence as set forth in SEQ ID NO: 2.

### Claim 7 (depends on 1)

The method of claim 1, wherein said fas-chimera transgene comprises the sequence as set forth in SEQ ID NO: 3.

### Claim 8 (depends on 1)

The method of claim 1, wherein said fas-chimera transgene comprises the sequence as set forth in SEQ ID NO: 4.

### Claim 9 (depends on 1)

The method of claim 1, wherein said murine pre-pro endothelin promoter comprises an enhancer comprising the sequence as set forth in SEQ ID NO: 6 or the complements sequence thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein said murine pre-pro endothelin promoter comprises an enhancer comprising the sequence as set forth in SEQ ID NO: 8 or the complementary sequence thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein said murine pre-pro endothelin promoter comprises an enhancer comprising the sequence as set forth in SEQ ID NO: 7 or a complementary sequence thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein said murine pre-pro endothelin promoter comprises the sequence as set forth in SEQ ID NO: 13.

### Claim 13 (depends on 1)

The method of claim 1, wherein said murine prepro-endothelin promoter comprises the sequence as set forth in SEQ ID NO: 12.

### Claim 14

(canceled)

### Claim 15 (depends on 1)

The method of claim 1, wherein said non-replicating adenovirus vector is an adenovirus 5 vector.

### Claim 16 (depends on 1)

The method of claim 1, wherein said adenovirus vector comprises the polynucleotide sequence as set forth in SEQ ID NO: 9 or 10.

### Claim 17 (depends on 1)

The method of claim 1, wherein said solid tumor is a cancer.

### Claim 18 (depends on 1)

The method of claim 1, wherein said solid tumor is a primary tumor or a metastatic tumor.

### Claim 19

(canceled)

### Claim 20 (depends on 1)

The method of claim 1, wherein said adenovirus vector is administered systemically.

### Claim 21 (depends on 20)

The method of claim 20, wherein said vector is administered systemically by a route selected from the group consisting of intra-articular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, infusion, oral administration, rectal administration, nasal administration and inhalation.

### Claim 22 (depends on 1)

The method of claim 1, comprising administering said adenovirus vector in at least two separate systemic doses.

### Claim 23 (depends on 1)

The method of claim 1, wherein said adenovirus is detected in the blood of said subject at least about 4 days post administration.

### Claim 24 (depends on 1)

The method of claim 1, wherein an amount of serum anti-adenovirus antibodies is increased following said administering, and said adenovirus is detected in the blood of said subject at least about 21 days post administration.

### Claim at position 25

25-37. (canceled)

### Claim 38 (depends on 1)

The method of claim 1, wherein said non-replicating adenovirus vector is administered to said subject, in at least two separate doses, and wherein said administration does not induce a dose-dependent increase in antibodies against said adenovirus vector in said subject.

### Claim at position 27

39-65. (canceled)

### Claim 66 (depends on 1)

The method of claim 1, wherein said administering inhibits angiogenesis of said tumor or inhibits growth of said tumor.

### Claim 67

(canceled)

### Claim 68

(canceled)

### Claim 69 (depends on 1)

The method of claim 1, wherein said solid tumor is a thyroid cancer.

### Claim 70 (depends on 69)

The method of claim 69, wherein said therapeutically effective amount is at least about 1×1013 virus particles.

### Claim 71 (depends on 1)

The method of claim 1, wherein said solid tumor is a neuroendocrine cancer.

### Claim 72 (depends on 71)

The method of claim 71, wherein said therapeutically effective amount is at least about 1×1013 virus particles.

### Claim 73

A kit for treating a solid tumor in a subject in need thereof, comprising a unit dosage of virus particles of a non-replicating adenovirus vector comprising the polynucleotide sequence as set forth in SEQ ID NO: 9 or 10 wherein said non-replicating adenovirus vector is formulated for intravenous administration, and instructions for administration of said adenovirus.

### Claim 74

(canceled)

### Claim 75

(canceled)

### Claim 76

A method for administering a therapeutic composition comprising an adenoviral vector to a subject, comprising administering a therapeutically effective amount of the composition to the subject at least twice, wherein the administering does not induce a dose-dependent increase in anti-adenovirus antibodies against said adenoviral vector in the subject.

### Claim at position 39

77-82. (canceled)

### Claim 83 (depends on 1)

The method of claim 1, wherein said subject is further receiving a chemotherapeutic agent.

### Claim 84 (depends on 83)

The method of claim 83, wherein said chemotherapeutic agent is administered prior to treatment with said virus particles, concomitantly with treatment with said virus particles, or following treatment with said virus particles.

### Claim 85

(canceled)

### Claim 86

(canceled)

### Claim 87 (depends on 83)

The method of claim 83, wherein said chemotherapeutic agent is sunitinib.

### Claim 88

An adenovirus vector comprising the polynucleotide sequence as set forth in SEQ ID NO:9.

### Claim 89

An adenovirus vector comprising the polynucleotide sequence as set forth in SEQ ID NO: 10.