# US 9,433,675 B2 · Combination therapy involving antibodies against claudin 18.2 for treatment of cancer

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,433,675 B2
- Document ID: US9433675B2
- Status: Granted
- Kind: B2
- Application number: 14/401,557
- Filed: 2013-05-21
- Published: 2015-06-11
- Granted: 2016-09-06
- Earliest claimed: 2012-05-23
- Assignees: Ganymed Pharmaceuticals AG; TRON—Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz gemeinnützige GmbH
- Applicants: Ganymed Pharmaceuticals AG; TRON—Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz gemeinnützige GmbH
- Inventors: Ugur Sahin; Özlem Türeci; Rita Mitnacht-Kraus; Stefan Denis Jacobs; Magdalena Jadwiga Utsch; Cornelia Adriana Maria Heinz; Christiane Regina Stadler
- Web page: https://patentgrep.com/patent/US9433675B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 31/282: Platinum compounds
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- 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 33/243: Platinum; Compounds thereof
- A61K 38/2013: {IL-2}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/30: from tumour cells
- C07K 16/3046: {Stomach, Intestines}
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- 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]
- 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 a combination therapy for effectively treating and/or preventing diseases associated with cells expressing CLDN18.2, including cancer 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 and metastases thereof.

## Claims

### Claim 1

A method of treating a cancer characterized by cells expressing claudin 18 splice variant 2, comprising:
administering to a patient an antibody having the ability of binding to claudin 18 splice variant 2 (CLDN18.2) in combination with an agent stimulating γδ T cells and an agent stabilizing or increasing expression of CLDN18.2, wherein the agent stimulating γδ T cells is a bisphosphonate and the agent stabilizing or increasing expression of CLDN18.2 comprises at least one anthracycline, at least one platinum compound and at least one of 5-fluorouracil and prodrugs thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the agent stabilizing or increasing expression of CLDN18.2 comprises (i) epirubicin, oxaliplatin and 5-fluorouracil, (ii) epirubicin, oxaliplatin and capecitabine, (iii) epirubicin, cisplatin and 5-fluorouracil, (iv) epirubicin, cisplatin and capecitabine, or (v) folinic acid, oxaliplatin and 5-fluorouracil.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody having the ability of binding to CLDN18.2 binds to the first extracellular loop of CLDN18.2.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody having the ability of binding to CLDN18.2 mediates cell killing by one or more of complement dependent cytotoxicity (CDC) mediated lysis, antibody dependent cellular cytotoxicity (ADCC) mediated lysis, induction of apoptosis and inhibition of proliferation.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody having the ability of binding to CLDN18.2 is an antibody selected from the group consisting of (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2737, DSM ACC2738, DSM ACC2739, DSM ACC2740, DSM ACC2741, DSM ACC2742, DSM ACC2743, DSM ACC2745, DSM ACC2746, DSM ACC2747, DSM ACC2748, DSM ACC2808, DSM ACC2809, or DSM ACC2810, (ii) an antibody which is a chimerized or humanized form of the antibody under (i), (iii) an antibody having the specificity of the antibody under (i) and (iv) an antibody comprising the antigen binding portion or antigen binding site, in particular the variable region, of the antibody under (i) and preferably having the specificity of the antibody under (i).

### Claim 6 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of cancer of the stomach, cancer of the esophagus, in particular the lower esophagus, cancer of the eso-gastric junction and gastroesophageal cancer.

### Claim 7 (depends on 1)

The method of claim 1, wherein the bisphosphonate is administered to the patient in combination with interleukin-2.

### Claim 8 (depends on 1)

The method of claim 1, wherein the γδ T cells are Vγ9Vδ2 T cells.

### Claim 9 (depends on 1)

The method of claim 1, wherein the bisphosphonate is a nitrogen-containing bisphosphonate (aminobisphosphonate).

### Claim 10 (depends on 1)

The method of claim 1, wherein the bisphosphonate is selected from the group consisting of zoledronic acid, clodronic acid, ibandronic acid, pamidronic acid, risedronic acid, minodronic acid, olpadronic acid, alendronic acid, incadronic acid, and salts thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the bisphosphonate is zoledronic acid.

### Claim 12 (depends on 1)

The method of claim 1, wherein the at least one anthracycline is selected from the group consisting of epirubicin, doxorubicin, daunorubicin, idarubicin and valrubicin.

### Claim 13 (depends on 1)

The method of claim 1, wherein the at least one anthracycline is epirubicin.

### Claim 14 (depends on 1)

The method of claim 1, wherein the at least one platinum compound is selected from the group consisting of oxaliplatin and cisplatin.

### Claim 15 (depends on 1)

The method of claim 1, wherein the cancer is gastric cancer.

### Claim 16 (depends on 1)

The method of claim 1, wherein the cancer is metastatic gastric cancer.

### Claim 17 (depends on 1)

The method of claim 1, wherein the cancer is an esophageal adenocarcinoma, a pancreatic adenocarcinoma, or a lung adenocarcinoma.

### Claim 18 (depends on 1)

The method of claim 1, wherein the antibody has a heavy chain variable region comprising an amino acid sequence represented by SEQ ID NO: 32.

### Claim 19 (depends on 1)

The method of claim 1, wherein the antibody has a light chain variable region comprising an amino acid sequence represented by SEQ ID NO: 39.

### Claim 20 (depends on 1)

The method of claim 1, wherein the antibody has a heavy chain variable region comprising an amino acid sequence represented by SEQ ID NO: 32 and a light chain variable region comprising an amino acid sequence represented by SEQ ID NO: 39.

### Claim 21 (depends on 20)

The method of claim 20, further comprising administering interleukin-2.

### Claim 22 (depends on 20)

The method of claim 20, wherein the bisphosphonate is zoledronic acid.

### Claim 23 (depends on 20)

The method of claim 20, wherein the at least one anthracycline is epirubicin, the at least one platinum compound is oxaliplatin, and the at least one of 5-fluorouracil and prodrugs thereof is 5-fluorouracil or capecitabine.