# US 9,751,934 B2 · Monoclonal antibodies against claudin-18 for treatment of cancer

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- Number: US 9,751,934 B2
- Document ID: US9751934B2
- Status: Granted
- Kind: B2
- Application number: 14/661,882
- Filed: 2015-03-18
- Published: 2015-09-10
- Granted: 2017-09-05
- Earliest claimed: 2005-11-24
- Assignees: Ganymed Pharmaceuticals AG; Johannes Gutenberg-Universitat Mainz
- Applicants: Ganymed Pharmaceuticals AG
- Inventors: Ugur Sahin; Özlem Türeci; Dirk Usener; Stefan Fritz; Christoph Uherek; Gunda Brandenburg; Harald-Gerhard Geppert; Anja Kristina Schröder; Phillippe Thiel
- Web page: https://patentgrep.com/patent/US9751934B2

## CPC

- A61K 51/1063: {the tumor cell being from stomach or intestines}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin}
- A61K 47/6813: {the drug being a peptidic cytokine, e.g. an interleukin or interferon}
- A61K 47/6821: {Plant heterodimeric toxins, e.g. abrin or modeccin}
- A61K 47/6823: {Double chain ricin}
- A61K 47/6829: {Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6859: {the tumour determinant being from liver or pancreas cancer cell}
- A61K 47/6863: {the tumour determinant being from stomach or intestines cancer cell}
- A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate}
- 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 16/18: against material from animals or humans
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/3046: {Stomach, Intestines}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)

## Abstract

The present invention provides antibodies useful as therapeutics for treating and/or preventing diseases associated with cells expressing CLD18, including tumor-related diseases such as gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder.

## Claims

### Claim 1

An antibody that specifically binds CLD18A2, comprising:
a heavy chain variable region (VH) having
a VH CDR1 of positions 45-52 of SEQ ID NO: 118,
a VH CDR2 of positions 70-77 of SEQ ID NO: 118, and
a VH CDR3 of positions 116-126 of SEQ ID NO: 118; and
a light chain variable region (VL) having
a VL CDR1 of positions 47-58 of SEQ ID NO: 125,
a VL CDR2 of positions 76-78 of SEQ ID NO: 125, and
a VL CDR3 of positions 115-123 of SEQ ID NO: 125.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the antibody is selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, a secretory IgA, an IgD, and an IgE antibody.

### Claim 3 (depends on 1)

The antibody of claim 1, wherein the antibody is a chimeric antibody.

### Claim 4 (depends on 1)

The antibody of claim 1, wherein the antibody comprises a human IgG1 constant region.

### Claim 5 (depends on 1)

The antibody of claim 1, wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 135.

### Claim 6 (depends on 1)

The antibody of claim 1, wherein the VL comprises an amino acid sequence represented by SEQ ID NO: 142.

### Claim 7 (depends on 1)

The antibody of claim 1, wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 135 and the VL comprises an amino acid sequence represented by SEQ ID NO: 142.

### Claim 8 (depends on 7)

The antibody of claim 7, wherein the antibody is selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, a secretory IgA, an IgD, and an IgE antibody.

### Claim 9 (depends on 7)

The antibody of claim 7, wherein the antibody is a chimeric antibody.

### Claim 10 (depends on 7)

The antibody of claim 7, wherein the antibody comprises a human IgG1 constant region.

### Claim 11

An antibody that specifically binds CLD18A2, comprising:
a heavy chain of SEQ ID NO: 118 and a light chain of SEQ ID NO: 125.

### Claim 12 (depends on 1)

A method of treating a tumor-related disease selected from the group consisting of gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder, comprising:
administering to a subject the antibody of claim 1.

### Claim 13 (depends on 12)

The method of claim 12, wherein the tumor-related disease is gastric cancer.

### Claim 14 (depends on 12)

The method of claim 12, wherein the tumor-related disease is pancreatic cancer.

### Claim 15 (depends on 12)

The method of claim 12, wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 135 and the VL comprises an amino acid sequence represented by SEQ ID NO: 142.

### Claim 16 (depends on 12)

The method of claim 12, wherein the antibody comprises a heavy chain of SEQ ID NO: 118 and a light chain of SEQ ID NO: 125.

### Claim 17 (depends on 16)

The method of claim 16, further comprising administering to the subject a chemotherapeutic agent.

### Claim 18 (depends on 17)

The method of claim 17, wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin, cisplatin, taxotere, 5-fluoruracil, methotrexate, gemcitabine and cyclophosphamide.

### Claim 19 (depends on 16)

The method of claim 16, wherein the tumor-related disease is gastric cancer.

### Claim 20 (depends on 16)

The method of claim 16, wherein the tumor-related disease is pancreatic cancer.