# US 7,608,269 B2 · Compositions and methods for treating cancer by modulating HER-2 and EGF receptors

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- Number: US 7,608,269 B2
- Document ID: US7608269B2
- Status: Granted
- Kind: B2
- Application number: 10/344,470
- Filed: 2001-08-14
- Published: 2004-03-18
- Granted: 2009-10-27
- Earliest claimed: 2000-08-14
- Assignees: Oregon Health & Science University
- Inventors: Gail M. Clinton
- Web page: https://patentgrep.com/patent/US7608269B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/71: for growth factors; for growth regulators
- C07K 16/32: against translation products of oncogenes
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- 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)
- G01N 2333/71: for growth factors; for growth regulators
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

An alternative HER-2/neu product, herstatin, consists of subdomains I and II from the ectodomain of p185HER-2 and a unique 79 amino acid C-terminus encoded by intron 8. Recombinant herstatin added to cells was found to bind to and inhibit p185HER-2. The effects of ectopic expression of herstatin in combination with either p185HER-2 or with its homolog, the EGF receptor, in several cell lines was studied. Cotransfection of herstatin with HER-2 inhibited p185HER-2 levels and caused an approximate 8-fold reduction in p185 tyrosine phosphorylation. Inhibition of p185HER-2 tyrosine phosphorylation corresponded to a dramatic decline in colony formation by cells that coexpressed p185HER-2 and herstatin. Herstatin also interferred with EGF activation of the EGF receptor in cotransfected cells as demonstrated by impaired receptor tyrosine phosphorylation, reduced receptor down-regulation, and growth suppression. For both p185HER-2 and the EGF receptor, the extent of inhibition was affected by the expression levels of herstatin relative to the receptor. Herstatin is an autoinhibitor of p185HER-2 and expands its inhibitory activity to another member of the group I family of receptor tyrosine kinases, the EGF receptor. Herstatin blocked the activated Akt-mediated EGF survival signal, as well as transforming growth factor alpha (TGFα)-mediated EGF receptor activation, survival signal and proliferation signal. Purified recombinant herstatin specifically inhibited human carcinoma cells that over-express HER-2, and was effectively absorbed into the blood of intraperitoneally injected mice, where it was not proteolytically degraded and was present for between one and three hours.

## Claims

### Claim 1

A method for targeting a therapeutic agent to solid tumor tissue, wherein the solid tumor tissue is characterized by expression of EGF receptor, comprising attaching the therapeutic agent to an isolated polypeptide having from about 50 to 79 contiguous amino acid residues of SEQ ID NO: 1, wherein the polypeptide binds to the extracellular domain of EGF receptor with an affinity binding constant of at least 108M−1; and administering the attached therapeutic agent to a subject in need thereof determined to have a tumor characterized by expression of EGF receptor.

### Claim 2 (depends on 1)

The method for targeting a therapeutic agent to solid tumor tissue of claim 1, wherein the isolated polypeptide is from about 69 to 79 contiguous amino acid Residues of SEQ ID NO:1.

### Claim 3

A method for targeting a therapeutic agent to solid tumor tissue, wherein the solid tumor tissue is characterized by expression of EGF receptor, comprising attaching the therapeutic agent to an isolated polypeptide having from about 50 to 79 contiguous amino acid residues of a sequence selected from the group consisting of SEQ ID NOS: 11, 15 and 17-26, wherein the polypeptide binds to the extracellular domain of EGF receptor with an affinity binding constant of at least 10 8M31 1; and administering the attached therapeutic agent to a subject in need thereof determined to have a tumor characterized by expression of EGF receptor.

### Claim 4 (depends on 3)

The method of claim 3, wherein the isolated polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:11, 15 and 17-26.

### Claim 5 (depends on 3)

The method of claim 3, wherein the isolated polypeptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOS:11, 15 and 17-26.

### Claim 6 (depends on 3)

The method of claim 3, wherein the isolated polypeptide comprises the amino acid sequence of SEQ ID NO:11.

### Claim 7 (depends on 3)

The method of claim 3, wherein the isolated polypeptide consists of the amino acid sequence of SEQ ID NO:11.

### Claim 8 (depends on 3)

The method of claim 3, wherein the solid tumor that expresses EGF receptor is at least one selected from the group consisting of squamous cell carcinoma, lung carcinoma, colon carcinoma, and glial cell tumors.