# US 11,028,127 B2 · Peptides capable of reactivating p53 mutants

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- Number: US 11,028,127 B2
- Document ID: US11028127B2
- Status: Granted
- Kind: B2
- Application number: 16/704,010
- Filed: 2019-12-05
- Published: 2020-03-26
- Granted: 2021-06-08
- Earliest claimed: 2013-08-07
- Assignees: Yeda Research and Development Co. Ltd.
- Applicants: Yeda Research and Development Co. Ltd.
- Inventors: Moshe Oren; Varda Rotter; Perry Tal
- Web page: https://patentgrep.com/patent/US11028127B2

## CPC

- C07K 7/06: having 5 to 11 amino acids
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/00: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K 14/4746: {p53}
- 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)
- 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)
- 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

## Abstract

The invention provides peptides that can reactivate p53 mutants efficiently and specifically, as well as methods that allow the identification, selection and isolation of such peptides, in a precise, cost and time effective manner. In particular, there are provided mutant p53 reactivating peptides that can restore the native wild type p53 folding, and hence the tumor suppressor activity, to the mutant p53 protein. Such peptides are useful for treating various conditions and diseases in which p53 is mutated.

## Claims

### Claim 1

A recombinant or synthetic peptide comprising the amino-acid sequence selected from the group consisting of SEQ ID NO: 139, 140, 203, 216 and 227, wherein said peptide at least partially reactivates a mutant p53 protein; and wherein said peptide is up to 15 amino-acids in length.

### Claim 2 (depends on 1)

The peptide of claim 1, conjugated to at least one cell permeation moiety.

### Claim 3 (depends on 1)

The peptide of claim 1, wherein said peptide at least partially changes the conformation of said mutant p53 protein to a conformation of a wild-type (WT) p53 protein.

### Claim 4 (depends on 1)

The peptide of claim 1, wherein said peptide at least partially changes the conformation of said mutant p53 protein such that said mutant p53 protein is recognized by a monoclonal antibody directed against a WT p53 protein.

### Claim 5 (depends on 1)

The peptide of claim 1, wherein said mutant p53 protein is not recognized by a monoclonal antibody directed against a WT p53 protein.

### Claim 6 (depends on 1)

The peptide of claim 1, wherein said mutant p53 protein, upon binding to said peptide, is recognized by an antibody directed against a WT p53 protein.

### Claim 7 (depends on 6)

The peptide of claim 6, wherein said antibody is Ab1620.

### Claim 8 (depends on 1)

The peptide of claim 1, wherein said peptide at least partially restores the activity of said mutant p53 protein to the activity of a WT p53 protein.

### Claim 9 (depends on 8)

The peptide of claim 8, wherein said activity is reducing viability of cells expressing said mutant p53 protein.

### Claim 10 (depends on 8)

The peptide of claim 8, wherein said activity is promoting apoptosis of cells expressing said mutant p53 protein.

### Claim 11 (depends on 8)

The peptide of claim 8, wherein said activity is binding to a p53 consensus DNA binding element in cells expressing said mutant p53 protein.

### Claim 12 (depends on 11)

The peptide of claim 11, wherein said binding results in at least partial activation of an endogenous p53 target gene.

### Claim 13 (depends on 12)

The peptide of claim 12, wherein said endogenous target gene is selected from the group consisting of p21, MDM2 and PUMA.

### Claim 14 (depends on 1)

The peptide of claim 1, wherein said mutant p53 protein is of a different conformation than a WT p53 protein.

### Claim 15 (depends on 1)

The peptide of claim 1, wherein said mutant p53 protein is at least partly inactive compared to a WT p53 protein.

### Claim 16 (depends on 1)

The peptide of claim 1 attached to a cell penetrating moiety.

### Claim 17

A recombinant or synthetic peptide comprising the amino-acid sequence set forth in any one of SEQ ID NOs: 139, 140, 203, 216 and 227, wherein said peptide is up to 15 amino-acids in length.

### Claim 18 (depends on 1)

A method of treating a disorder associated with mutant p53 protein, lessening a severity of a disease associated with a mutant p53 protein or ameliorating symptoms associated with a disease associated with a mutant p53, comprising the step of administering a therapeutically effective amount of the peptide of claim 1 to a subject in need thereof, thereby treating said disorder associated with mutant p53 protein, lessening the severity of said disease associated with a mutant p53 protein or ameliorating symptoms associated with said disease associated with said mutant p53.

### Claim 19 (depends on 18)

The method of claim 18, wherein said disease is cancer.

### Claim 20 (depends on 16)

A method of treating a disorder associated with mutant p53 protein, lessening a severity of a disease associated with a mutant p53 protein or ameliorating symptoms associated with a disease associated with a mutant p53, comprising the step of administering a therapeutically effective amount of the peptide of claim 16 to a subject in need thereof, thereby treating said disorder associated with mutant p53 protein, lessening the severity of said disease associated with a mutant p53 protein or ameliorating symptoms associated with said disease associated with said mutant p53.

### Claim 21

A recombinant or synthetic peptide comprising the amino-acid sequence set forth in any one of SEQ ID NOs: 244 and 263, wherein said peptide is up to 30 amino-acids in length.

### Claim 22 (depends on 17)

A method of treating a disorder associated with mutant p53 protein, lessening a severity of a disease associated with a mutant p53 protein or ameliorating symptoms associated with a disease associated with a mutant p53, comprising the step of administering a therapeutically effective amount of the peptide of claim 17 to a subject in need thereof, thereby treating said disorder associated with mutant p53 protein, lessening the severity of said disease associated with a mutant p53 protein or ameliorating symptoms associated with said disease associated with said mutant p53.

### Claim 23 (depends on 22)

The method of claim 22, wherein said disease is cancer.