# US 9,518,118 B2 · Anti-HER2 antibodies and immunoconjugates

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- Number: US 9,518,118 B2
- Document ID: US9518118B2
- Status: Granted
- Kind: B2
- Application number: 14/851,001
- Filed: 2015-09-11
- Published: 2016-04-07
- Granted: 2016-12-13
- Earliest claimed: 2014-09-12
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Xiaocheng Chen; Mark Dennis; Jagath Reddy Junutula; Gail Lewis Phillips; Thomas Harden Pillow; Mark X. Sliwkowski
- Web page: https://patentgrep.com/patent/US9518118B2

## CPC

- C07K 16/32: against translation products of oncogenes
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 47/68: the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6863: {the tumour determinant being from stomach or intestines cancer cell}
- A61K 49/00: Preparations for testing in vivo
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- 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}
- C07K 16/3015: {Breast}
- G01N 33/57515: of the breast
- G01N 33/5753: of the stomach or small intestine
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- 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 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- G01N 2333/82: Translation products from oncogenes
- 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
- 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

The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

## Claims

### Claim 1

An isolated antibody that binds to HER2, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:16; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:13; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:14.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10.

### Claim 3 (depends on 1)

The antibody of claim 1, which is a monoclonal antibody.

### Claim 4 (depends on 1)

The antibody of claim 1, which is a humanized or chimeric antibody.

### Claim 5 (depends on 1)

The antibody of claim 1, which is an antibody fragment that binds HER2.

### Claim 6 (depends on 1)

The antibody of claim 1, wherein HER2 is human HER2 comprising amino acids 23 to 1255 of SEQ ID NO: 1.

### Claim 7 (depends on 1)

The antibody of claim 1, wherein the antibody binds to extracellular domain I of HER2.

### Claim 8 (depends on 7)

The antibody of claim 7, wherein extracellular domain I of HER2 has the sequence of SEQ ID NO: 35.

### Claim 9 (depends on 1)

The antibody of claim 1, which is an IgG1, IgG2a or IgG2b antibody.

### Claim 10 (depends on 1)

The antibody of claim 1, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

### Claim 11 (depends on 1)

The antibody of claim 1, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

### Claim 12 (depends on 1)

The antibody of claim 1, wherein the antibody comprises:
a) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 18; or
b) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23; or
c) a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18.

### Claim 13 (depends on 1)

The antibody of claim 1, wherein the antibody comprises the heavy chain constant region of SEQ ID NO: 28.

### Claim 14 (depends on 1)

The antibody of claim 1, wherein the antibody comprises the light chain constant region of SEQ ID NO: 25.

### Claim 15

An isolated antibody that binds to HER2, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23.

### Claim 16

An isolated antibody that binds to HER2, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

The antibody of claim 1 conjugated to a label.

### Claim 19 (depends on 18)

The antibody of claim 18, wherein the label is a positron emitter.

### Claim 20 (depends on 19)

The antibody of claim 19, wherein the positron emitter is 89Zr.

### Claim 21 (depends on 1)

The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising a sequence at least 95% identical to the sequence of SEQ ID NO: 11 and a light chain variable region comprising a sequence at least 95% identical to the sequence of SEQ ID NO: 10.

### Claim 22 (depends on 2)

The antibody of claim 2, which is an IgG1, IgG2a or IgG2b antibody.

### Claim 23 (depends on 22)

The antibody of claim 22, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

### Claim 24 (depends on 22)

The antibody of claim 22, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

### Claim 25 (depends on 22)

The antibody of claim 22, wherein the antibody comprises a K149C mutation in the light chain constant region.

### Claim 26 (depends on 21)

The antibody of claim 21, which is an IgG1, IgG2a or IgG2b antibody.

### Claim 27 (depends on 26)

The antibody of claim 26, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

### Claim 28 (depends on 26)

The antibody of claim 26, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

### Claim 29 (depends on 26)

The antibody of claim 26, wherein the antibody comprises a K149C mutation in the light chain constant region.