# US 2006/0154333 A1 · Pan-HER antagonists and methods of use

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2006/0154333 A1
- Document ID: US20060154333A1
- Status: Published application
- Kind: A1
- Application number: 11/172,611
- Filed: 2005-06-30
- Published: 2006-07-13
- Earliest claimed: 2005-01-11
- Assignees: Molecular Logix, Inc.
- Inventors: Philip Pienkos; Daniel Monticello
- Web page: https://patentgrep.com/patent/US20060154333A1

## CPC

- C07K 14/475: Growth factors; Growth regulators
- A61K 38/1808: {Epidermal growth factor [EGF] urogastrone}
- A61P 17/06: Antipsoriatics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/4756: {Neuregulins, i.e. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor}
- C07K 14/485: Epidermal growth factor [EGF], i.e. urogastrone
- C07K 14/495: Transforming growth factor [TGF]
- 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 present invention features human epidermal receptor (HER) antagonists. These antagonists are polypeptide variants of ligands of HER. The HER ligand polypeptide variants of the invention possess Pan-HER antagonistic properties and can inhibit at least one HER-mediated biological activity of one or more HER subtypes, such as inhibition of the receptor's kinase activation activity and subsequently, cell proliferation. Such polypeptide variants, and nucleic acids encoding these polypeptide variants can be used therapeutically in situations in which inhibition of HER activity is indicated.

## Claims

### Claim 1

A human epidermal receptor (HER)-ligand polypeptide variant comprising a HER ligand polypeptide in which the amino acid position that corresponds to amino acid Gly 39 of human wild-type epidermal growth factor (EGF) is substituted with another amino acid, wherein the HER ligand polypeptide further comprises at least one substituted domain, and wherein the variant has at least one Pan-HER antagonist activity.

### Claim 2 (depends on 1)

The variant of claim 1 wherein the HER ligand polypeptide is EGF.

### Claim 3 (depends on 1)

The variant of claim 1, wherein the amino acid substitution is selected from the group consisting of: phenylalanine, leucine, aspartic acid, and isoleucine.

### Claim 4 (depends on 1)

The variant of claim 1, wherein the amino acid substitution is leucine.

### Claim 5 (depends on 1)

The variant of claim 1 wherein the substituted domain is the amino terminus of EGF.

### Claim 6 (depends on 1)

The variant of claim 1 wherein the HER ligand polypeptide is EGF and the substituted domain is amino acids 1-5 of mature EGF corresponding to amino acids NSDSE.

### Claim 7 (depends on 6)

The variant of claim 6 wherein the substituted domain of EGF is replaced with homologous amino acids of HRGβ1 corresponding to amino acids SHLVK.

### Claim 8 (depends on 1)

The variant of claim 1 wherein the HER ligand polypeptide is BiRegulin (BiR).

### Claim 9 (depends on 8)

The variant of claim 8 wherein amino acid Gly 39 is replaced with the amino acid, leucine.

### Claim 10 (depends on 1)

The variant of claim 1 comprising at least one additional amino acid substitution at a position other than the amino acid position corresponding Gly 39 of wild-type human EGF.

### Claim 11 (depends on 10)

The variant of claim 10, wherein the additional amino acid substitution is selected from at least one amino acid substitution at a position corresponding to G18, V35, and R41 of wild-type human EGF or any combination thereof.

### Claim 12 (depends on 8)

The variant of claim 8 comprising an additional amino acid substitution at amino acid position V35.

### Claim 13 (depends on 12)

The variant of claim 12 wherein the valine at amino acid position 35 is replaced with glutamic acid.

### Claim 14 (depends on 1)

The variant of claim 1 comprising BiRV35EG39L.

### Claim 15 (depends on 1)

The variant of claim 1 wherein the variant has at least one antagonistic activity against each of HER1, HER3 and HER4.

### Claim 16 (depends on 15)

A pharmaceutical composition comprising the HER ligand polypeptide variant of claim 15 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 16)

A method of treating a patient with a disease characterized by overexpression of HER comprising, administering to the patient, a therapeutically effective amount of a pharmaceutical composition of claim 16.

### Claim 18 (depends on 17)

The method of claim 17, wherein the disease is cancer.

### Claim 19 (depends on 18)

The method of claim 18, wherein the cancer is selected from the group consisting of gliomas, squamous cell carcinomas, breast carcinomas, melanomas, invasive bladder carcinomas, colorectal carcinomas and esophageal cancers.

### Claim 20 (depends on 17)

The method of claim 17, wherein the disease is psoriasis.

### Claim 21 (depends on 1)

The variant of claim 1, wherein the HER ligand polypeptide is selected from the group consisting of: human epidermal growth factor (EGF), transforming growth factor-α (TGFα), betacellulin, heparin-binding EGF-like growth factor (HB-EGF), neuregulins, heregulin, amphiregulin (AR) and epiregulin.

### Claim 22 (depends on 1)

The variant of claim 1, wherein the substituted domain is the B-loop domain.

### Claim 23 (depends on 1)

A HER ligand polypeptide variant of claim 1 comprising EGF G39L having a B-loop domain that has been substituted with a corresponding B-loop domain from another HER ligand polypeptide selected from the group consisting of: human epidermal growth factor (EGF), transforming growth factor-α (TGFα), betacellulin, heparin-binding EGF-like growth factor (HB-EGF), neuregulins, heregulin, amphiregulin (AR) and epiregulin, and wherein the variant has at least one Pan-HER antagonistic activity.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising the HER ligand polypeptide variant of claim 1 and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 23)

A pharmaceutical composition comprising the HER ligand polypeptide variant of claim 23 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 24)

A method of treating a patient with a disease characterized by overexpression of HER comprising, administering to the patient, a therapeutically effective amount of a pharmaceutical composition of claim 24.

### Claim 27 (depends on 26)

The method of claim 26, wherein the disease is cancer.

### Claim 28 (depends on 27)

The method of claim 27, wherein the cancer is selected from the group consisting of gliomas, squamous cell carcinomas, breast carcinomas, melanomas, invasive bladder carcinomas, colorectal carcinomas and esophageal cancers.

### Claim 29 (depends on 26)

The method of claim 26, wherein the disease is psoriasis.

### Claim 30

A human epidermal receptor (HER)-ligand polypeptide variant having at least one Pan-HER antagonist activity wherein the variant comprises a mutation that disrupts binding via Domain I and/or III.

### Claim 31 (depends on 30)

A variant of claim 30 wherein the variant comprises a mutation that disrupts binding via Domain I.

### Claim 32 (depends on 31)

A variant of claim 31 wherein the variant further comprises a mutation that enhances the binding affinity via Domain III.

### Claim 33 (depends on 30)

A variant of claim 30 wherein the variant comprises a mutation that disrupts binding via Domain III and a mutation that enhances binding affinity via Domain I.

### Claim 34 (depends on 30)

A variant of claim 30 further comprising a mutation that modifies receptor binding specificity.

### Claim 35 (depends on 1)

A nucleic acid encoding a variant of claim 1.

### Claim 36 (depends on 14)

A nucleic acid encoding a variant of claim 14.

### Claim 37 (depends on 23)

A nucleic acid encoding a variant of claim 23.

### Claim 38 (depends on 30)

A nucleic acid encoding a variant of claim 30.