# US 8,771,695 B2 · Antibodies directed to HER-3 and uses thereof

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- Number: US 8,771,695 B2
- Document ID: US8771695B2
- Status: Granted
- Kind: B2
- Application number: 12/761,370
- Filed: 2010-04-15
- Published: 2012-03-08
- Granted: 2014-07-08
- Earliest claimed: 2005-12-30
- Assignees: U3 Pharma GmbH; Amgen Inc.
- Applicants: Mike Rothe; Martin Treder; Susanne Hartmann; Daniel J. Freeman; Robert Radinsky; Eric Borges
- Inventors: Mike Rothe; Martin Treder; Susanne Hartmann; Daniel J. Freeman; Robert Radinsky; Eric Borges
- Web page: https://patentgrep.com/patent/US8771695B2

## CPC

- C07K 16/32: against translation products of oncogenes
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- G01N 33/575: for cancer
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12N 15/00: Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor (mutants or genetically engineered microorganisms, per se C12N1/00, C12N5/00, C12N7/00; new plants per se A01H; plant reproduction by tissue culture techniques A01H4/00; new animals per se A01K67/00; use of medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases, gene therapy A61K48/00)
- C12N 15/09: Recombinant DNA-technology
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N 2800/00: Nucleic acids vectors
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- 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)
- 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 invention relates to binding proteins that bind to HER-3 and polynucleotides encoding the same. Expression vectors and host cells comprising the same for the production of the binding protein of the invention are also provided. In addition, the invention provides compositions and methods for diagnosing and treating diseases associated with HER-3 mediated signal transduction and/or its ligand heregulin.

## Claims

### Claim 1

A method for treating a HER-3 expressing cancer in a patient, comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3 wherein said isolated binding protein comprises:
(a) a heavy, chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO:236, a CDRH2 having the sequence of SEQ ID NO:258, and a CDRH3 having the sequence of SEQ ID NO:283; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID NO:320, a CDRL2 having the sequence of SEQ ID NO:343, and a CDRL3 having the sequence of SEQ ID NO:360;
(b) a heavy, chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO:236, a CDRH2 having the sequence of SEQ ID NO:258, and a CDRH3 having the sequence of SEQ ID NO:285; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID NO:320, a CDRL2 having the sequence of SEQ ID NO:343, and a CDRL3 having the sequence of SEQ ID NO:360;
(c) a heavy, chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO:251, a CDRH2 having the sequence of SEQ ID NO:278, and a CDRH3 having the sequence of SEQ ID NO:309; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID NO:334, a CDRL2 having the sequence of SEQ ID NO:356, and a CDRL3 having the sequence of SEQ ID NO:381;
(d) a heavy, chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO:252, a CDRH2 having the sequence of SEQ ID NO:280, and a CDRH3 having the sequence of SEQ ID NO:313; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID NO:337, a CDRL2 having the sequence of SEQ ID NO:351, and a CDRL3 having the sequence of SEQ ID NO:385; or
(e) a heavy, chain amino acid sequence that comprises a CDRH1 having the sequence of SEQ ID NO:256, a CDRH2 having the sequence of SEQ ID NO:282, and a CDRH3 having the sequence of SEQ ID NO:315; and a light chain amino acid sequence that comprises a CDRL1 having the sequence of SEQ ID NO:340, a CDRL2 having the sequence of SEQ ID NO:344, and a CDRL3 having the sequence of SEQ ID NO:387.

### Claim 2 (depends on 1)

The method of claim 1, wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, testis cancer, soft tissue sarcoma and head and neck cancer.

### Claim 3 (depends on 1)

The method of claim 1, wherein said cancer exhibits increased HER-3 phosphorylation, increased HER-2/HER-3 heterodimerization or an increased activity of PI3-kinase, c-jun-terminal kinase, AKT, ERK2 and/or PYK2.

### Claim 4

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises a light chain and a heavy chain, wherein the heavy chain amino acid sequence is selected from the group consisting of SEQ ID NOS: 42, 54, 70, 92, and 96.

### Claim 5

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises a heavy chain and a light chain, wherein the light chain amino acid sequence is selected from the group consisting of SEQ ID NOS: 44, 56, 72, 94, and 98.

### Claim 6

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises the heavy chain amino acid sequence of SEQ ID NO: 92 and the light chain amino acid sequence of SEQ ID NO: 94.

### Claim 7 (depends on 6)

The method of claim 6, wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, testis cancer, soft tissue sarcoma and head and neck cancer.

### Claim 8 (depends on 6)

The method of claim 6, wherein said cancer exhibits increased HER-3 phosphorylation, increased HER-2/HER-3 heterodimerization or an increased activity of PI3-kinase, c-jun-terminal kinase, AKT, ERK2 and/or PYK2.

### Claim 9

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises the heavy chain amino acid sequence of SEQ ID NO: 42 and the light chain amino acid sequence of SEQ ID NO: 44.

### Claim 10 (depends on 9)

The method of claim 9, wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, testis cancer, soft tissue sarcoma and head and neck cancer.

### Claim 11 (depends on 9)

The method of claim 9, wherein said cancer exhibits increased HER-3 phosphorylation, increased HER-2/HER-3 heterodimerization or an increased activity of PI3-kinase, c-jun-terminal kinase, AKT, ERK2 and/or PYK2.

### Claim 12

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises the heavy chain amino acid sequence of SEQ ID NO: 54 and the light chain amino acid sequence of SEQ ID NO: 56.

### Claim 13 (depends on 12)

The method of claim 12, wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, testis cancer, soft tissue sarcoma and head and neck cancer.

### Claim 14 (depends on 12)

The method of claim 12, wherein said cancer exhibits increased HER-3 phosphorylation, increased HER-2/HER-3 heterodimerization or an increased activity of PI3-kinase, c-jun-terminal kinase, AKT, ERK2 and/or PYK2.

### Claim 15

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises the heavy chain amino acid sequence of SEQ ID NO: 70 and the light chain amino acid sequence of SEQ ID NO: 72.

### Claim 16 (depends on 15)

The method of claim 15, wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, testis cancer, soft tissue sarcoma and head and neck cancer.

### Claim 17 (depends on 15)

The method of claim 15, wherein said cancer exhibits increased HER-3 phosphorylation, increased HER-2/HER-3 heterodimerization or an increased activity of PI3-kinase, c-jun-terminal kinase, AKT, ERK2 and/or PYK2.

### Claim 18

A method for treating a HER-3 expressing cancer in a patient comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising as an active ingredient an isolated binding protein that binds to HER-3, wherein said binding protein comprises the heavy chain amino acid sequence of SEQ ID NO: 96 and the light chain amino acid sequence of SEQ ID NO: 98.

### Claim 19 (depends on 18)

The method of claim 18, wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, testis cancer, soft tissue sarcoma and head and neck cancer.

### Claim 20 (depends on 18)

The method of claim 18, wherein said cancer exhibits increased HER-3 phosphorylation, increased HER-2/HER-3 heterodimerization or an increased activity of PI3-kinase, c-jun-terminal kinase, AKT, ERK2 and/or PYK2.