# US 2014/0193414 A1 · Anti-her antibodies

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- Number: US 2014/0193414 A1
- Document ID: US20140193414A1
- Status: Published application
- Kind: A1
- Application number: 14/100,211
- Filed: 2013-12-09
- Published: 2014-07-10
- Earliest claimed: 2009-03-20
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Germaine Fuh; Lauric Haber; Gabriele Schaefer; Mark X. Sliwkowski
- Web page: https://patentgrep.com/patent/US20140193414A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61P 35/04: specific for metastasis
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/31: multispecific
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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)
- 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)

## Abstract

The invention provides anti-HER antibodies, including multispecific anti-HER antibodies, compositions comprising and methods of using these antibodies. Also provided herein are EGFR/HER3 multispecific antibodies that are less toxic than traditional EGFR antagonists.

## Claims

### Claim 1

A multispecific antibody comprising an antigen-binding domain that specifically binds to EGFR and HER3, wherein the toxicity of the antibody is less than the toxicity of an EGFR antagonist.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the toxicity is dermatological toxicity.

### Claim 3 (depends on 1)

The antibody of claim 1, wherein the EGFR antagonist is cetuximab.

### Claim 4 (depends on 1)

The antibody of claim 1, wherein the antibody inhibits a biological activity of at least one of EGFR and HER3

### Claim 5 (depends on 2)

The antibody of claim 2, wherein the antibody inhibits EGF binding to EGFR.

### Claim 6 (depends on 2)

The antibody of claim 2, wherein the antibody inhibits TGF-α induced EGFR phosphorylation.

### Claim 7 (depends on 1)

The antibody of claim 1, wherein the antibody inhibits tumor cell growth.

### Claim 8 (depends on 1)

The antibody of claim 1, wherein the antibody binds to domain III of EGFR.

### Claim 9 (depends on 1)

The antibody of claim 1, wherein the antibody binds to EGFR and HER3 with a Kd of less than 10−6 M.

### Claim 10 (depends on 9)

The antibody of claim 9, wherein the antibody binds to EGFR with a Kd of less than 10−6 M and binds to HER3 with a Kd of less than 10−7 M.

### Claim 11 (depends on 1)

The antibody of claim 1, wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of LSGDWIH (SEQ ID NO: 48);
(b) HVR-H2 comprising the amino acid sequence of VGEISAAGGYTD (SEQ ID NO: 51); and
(c) HVR-H3 comprising the amino acid sequence of ARESRVSFEAAMDY (SEQ ID NO: 53); and
(d) HVR-L1 comprising the amino acid sequence of NIATDVA (SEQ ID NO: 55);
(e) HVR-L2 comprising the amino acid sequence of SASF (SEQ ID NO: 56); and
(f) HVR-L3 comprising the amino acid sequence of SEPEPYT (SEQ ID NO: 57).

### Claim 12 (depends on 1)

The antibody of claim 1, comprising
(a) a heavy chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 30;
(b) a light chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 29; or
(c) a heavy chain variable domain as in (a) and a light chain variable domain as in (b).

### Claim 13 (depends on 12)

The antibody of claim 12, comprising a heavy chain variable domain of SEQ ID NO: 30.

### Claim 14 (depends on 12)

The antibody of claim 12, comprising a light chain variable domain sequence of SEQ ID NO: 29.

### Claim 15

A multispecific antibody comprising a heavy chain variable domain sequence of SEQ ID NO: 30 and a light chain variable domain sequence of SEQ ID NO: 29.

### Claim 16 (depends on 1)

The antibody of claim 1, wherein the antibody is a full length IgG1 antibody.

### Claim 17 (depends on 1)

Isolated nucleic acid encoding the antibody of claim 1.

### Claim 18 (depends on 17)

A host cell comprising the nucleic acid of claim 17.

### Claim 19

A multispecific antibody comprising an antigen-binding domain that specifically binds to EGFR and HER3, wherein the antibody comprises
(a) HVR-H1 comprising the amino acid sequence of LSGDWIH (SEQ ID NO: 48);
(b) HVR-H2 comprising the amino acid sequence of VGEISAAGGYTD (SEQ ID NO: 51); and
(c) HVR-H3 comprising the amino acid sequence of ARESRVSFEAAMDY (SEQ ID NO: 53); and
(d) HVR-L1 comprising the amino acid sequence of NIATDVA (SEQ ID NO: 55);
(e) HVR-L2 comprising the amino acid sequence of SASF (SEQ ID NO: 56); and
(f) HVR-L3 comprising the amino acid sequence of SEPEPYT (SEQ ID NO: 57).

### Claim 20

A multispecific antibody comprising an antigen-binding domain that specifically binds to EGFR and HER3, wherein the antibody comprises
(a) a heavy chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 30;
(b) a light chain variable domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 29; or
(c) a heavy chain variable domain as in (a) and a light chain variable domain as in (b).

### Claim 21 (depends on 20)

The antibody of claim 20 comprising a heavy chain variable domain of SEQ ID NO: 30.

### Claim 22 (depends on 20)

The antibody of claim 20, comprising a light chain variable domain sequence of SEQ ID NO: 29.

### Claim 23 (depends on 18)

A method of producing an antibody comprising culturing the host cell of claim 18 so that the antibody is produced.

### Claim 24 (depends on 1)

An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

### Claim 25 (depends on 1)

A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 1)

A method of treating an individual having cancer comprising administering to the individual an effective amount of the antibody of claim 1.

### Claim 27 (depends on 26)

The antibody of claim 26, wherein the cancer comprises cells that express EGFR and HER3.

### Claim 28 (depends on 26)

The antibody of claim 26, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, and non-small lung cell cancer.

### Claim 29 (depends on 1)

A method of inhibiting a biological activity of a HER receptor in an individual comprising administering to the individual an effective amount of the antibody of claim 1 to inhibit a biological activity of a HER receptor.