# US 10,946,069 B2 · Combination therapy involving antibodies against claudin 18.2 for treatment of pancreatic cancer

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- Number: US 10,946,069 B2
- Document ID: US10946069B2
- Status: Granted
- Kind: B2
- Application number: 16/401,931
- Filed: 2019-05-02
- Published: 2019-10-03
- Granted: 2021-03-16
- Earliest claimed: 2013-02-20
- Assignees: Astellas Pharma Inc.; TRON—Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz
- Applicants: Astellas Pharma Inc.; TRON-Translationale Onkologie an der Universitatsmedizin der Johannes Gutenberg-Universitat Mainz gemeinnutzige GmbH
- Inventors: Ugur Sahin; Ozlem Tureci; Rita Mitnacht-Kraus; Stefan Woll; Stefan Jacobs; Cornelia Heinz
- Web page: https://patentgrep.com/patent/US10946069B2

## CPC

- A61K 38/2013: {IL-2}
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- 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 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/30: from tumour cells
- C07K 16/303: {Liver or Pancreas}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- 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 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/74: Inducing cell proliferation
- 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 pancreatic cancer and metastases thereof.

## Claims

### Claim 1

A method of treating pancreatic cancer in a patient in need thereof, wherein the pancreatic cancer is characterized by cells expressing claudin 18 splice variant 2 (CLDN18.2), the method comprising:
administering an anti-CLDN18.2 antibody to the patient, wherein the antibody comprises a heavy chain variable region (VH) having an amino acid sequence represented by SEQ ID NO: 32 and a light chain variable region (VL) having an amino acid sequence represented by SEQ ID NO: 39, and wherein the antibody has the ability of binding to CLDN18.2 and mediates killing of cells expressing CLDN18.2;
administering gemcitabine to the patient to increase susceptibility of the cells to killing by the anti-CLDN18.2 antibody; and
administering a taxane to the patient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the taxane is paclitaxel.

### Claim 3 (depends on 1)

The method of claim 1, wherein the taxane is albumin-bound paclitaxel.

### Claim 4 (depends on 3)

The method of claim 3, wherein the pancreatic cancer is primary pancreatic carcinoma or metastatic pancreatic carcinoma.

### Claim 5 (depends on 3)

The method of claim 3, wherein the pancreatic cancer is metastatic pancreatic carcinoma.

### Claim 6 (depends on 3)

The method of claim 3, wherein the antibody is administered at a dose of up to 1000 mg/m2.

### Claim 7 (depends on 1)

The method of claim 1, wherein gemcitabine is administered intravenously.

### Claim 8 (depends on 7)

The method of claim 7, wherein gemcitabine is administered at a dose of 0.8 to 1.5 g/m2 of body surface area.

### Claim 9 (depends on 7)

The method of claim 7, wherein gemcitabine is administered repeatedly according to a gemcitabine dosing regimen, wherein the gemcitabine dosing regimen comprises once weekly administration for 3 of 4 weeks.

### Claim 10 (depends on 9)

The method of claim 9, wherein gemcitabine is administered at a dose of 1000 mg/m2 of body surface area.

### Claim 11 (depends on 10)

The method of claim 10, wherein the pancreatic cancer is primary pancreatic carcinoma or metastatic pancreatic carcinoma.

### Claim 12 (depends on 10)

The method of claim 10, wherein the pancreatic cancer is metastatic pancreatic carcinoma.

### Claim 13 (depends on 10)

The method of claim 10, wherein the antibody is administered repeatedly according to an antibody dosing regimen, wherein the antibody dosing regimen comprises an initial dose of up to 1000 mg/m2 followed by repeated doses of 300 to 600 mg/m2.

### Claim 14

A method of treating metastatic pancreatic carcinoma in a patient in need thereof, wherein the pancreatic carcinoma is characterized by cells expressing claudin 18 splice variant 2 (CLDN18.2), the method comprising:
administering an anti-CLDN18.2 antibody to the patient, wherein the antibody comprises a heavy chain variable region (VH) having an amino acid sequence represented by SEQ ID NO: 32 and a light chain variable region (VL) having an amino acid sequence represented by SEQ ID NO: 39, and wherein the antibody has the ability of binding to CLDN18.2 and mediates killing of cells expressing CLDN18.2; and
administering a combination of chemotherapeutic agents to the patient, wherein the combination comprises gemcitabine and a taxane and wherein the combination stabilizes or increases expression of CLD18.2.

### Claim 15 (depends on 14)

The method of claim 14, wherein the taxane is albumin-bound paclitaxel.

### Claim 16 (depends on 15)

The method of claim 15, wherein the combination is administered repeatedly according to a combination dosing regimen, wherein the combination dosing regimen comprises once weekly administration for 3 of 4 weeks.

### Claim 17 (depends on 16)

The method of claim 16, wherein the antibody is administered repeatedly according to antibody dosing regimen, wherein the antibody dosing regimen comprises an initial dose of up to 1000 mg/m2 followed by repeated doses of 300 to 600 mg/m2.

### Claim 18 (depends on 17)

The method of claim 17, wherein the antibody is a chimeric antibody comprising a human kappa light chain constant region and a human IgG1 heavy chain constant region.

### Claim 19 (depends on 18)

The method of claim 18, wherein the human kappa light chain constant region is allotype Km(3) and the human IgG1 heavy chain constant region is allotype G1m(3).

### Claim 20 (depends on 17)

The method of claim 17, wherein the anti-CLDN18.2 antibody comprises a heavy chain having an amino acid sequence represented by SEQ ID NO: 17 and a light chain having an amino acid represented by SEQ ID NO: 24.