Combination therapy involving antibodies against claudin 18.2 for treatment of cancer

Patent metadata

Field	Value
Publication number	US-2020390887-A1
Application number	US-202017008316-A
Country	US
Kind code	A1
Filing date	Aug 31, 2020
Priority date	May 23, 2012
Publication date	Dec 17, 2020
Grant date	—

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.

First claim

1 . A method of treating or preventing a cancer disease comprising administering to a patient an antibody having the ability of binding to CLDN18.2 in combination with an agent stimulating γδ T cells.

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

3 . The method of claim 1 or 2 , wherein the agent stimulating γδ T cells is a bisphosphonate.

4 . The method of any one of claims 1 to 3 , wherein the agent stimulating γδ T cells is a nitrogen-containing bisphosphonate (aminobisphosphonate).

5 . The method of any one of claims 1 to 4 , wherein the agent stimulating γδ T cells 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.

6 . The method of any one of claims 1 to 5 , wherein the agent stimulating γδ T cells is administered in combination with interleukin-2.

7 . The method of any one of claims 1 to 6 , wherein the method further comprises administering an agent stabilizing or increasing expression of CLDN18.2.

8 . The method of claim 7 , wherein expression of CLDN18.2 is at the cell surface of a cancer cell.

9 . The method of claim 7 or 8 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises an agent which induces a cell cycle arrest or an accumulation of cells in one or more phases of the cell cycle, preferably in one or more phases of the cell cycle other than the G1-phase, more preferably in the G2-phase and/or the S-phase.

10 . The method of any one of claims 7 to 9 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises an agent selected from the group consisting of anthracyclines, platinum compounds, nucleoside analogs, taxanes, and camptothecin analogs, or prodrugs thereof, and combinations thereof.

11 . The method of any one of claims 7 to 10 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises an agent selected from the group consisting of epirubicin, oxaliplatin, cisplatin, 5-fluorouracil or prodrugs thereof, docetaxel, irinotecan, and combinations thereof.

12 . The method of any one of claims 7 to 11 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises a combination of oxaliplatin and 5-fluorouracil or prodrugs thereof, a combination of cisplatin and 5-fluorouracil or prodrugs thereof, a combination of at least one anthracycline and oxaliplatin, a combination of at least one anthracycline and cisplatin, a combination of at least one anthracycline and 5-fluorouracil or prodrugs thereof, a combination of at least one taxane and oxaliplatin, a combination of at least one taxane and cisplatin, a combination of at least one taxane and 5-fluorouracil or prodrugs thereof, or a combination of at least one camptothecin analog and 5-fluorouracil or prodrugs thereof.

13 . The method of any one of claims 7 to 12 , wherein the agent stabilizing or increasing expression of CLDN18.2 is an agent inducing immunogenic cell death.

14 . The method of claim 13 , wherein the agent inducing immunogenic cell death comprises an agent selected from the group consisting of anthracyclines, oxaliplatin and combinations thereof.

15 . The method of any one of claims 7 to 14 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises a combination of epirubicin and oxaliplatin.

16 . The method of any one of claims 7 to 15 , wherein the method comprises administering at least one anthracycline, at least one platinum compound and at least one of 5-fluorouracil and prodrugs thereof.

17 . The method of any one of claims 10 to 16 , wherein the anthracycline is selected from the group consisting of epirubicin, doxorubicin, daunorubicin, idarubicin and vairubicin, and preferably is epirubicin.

18 . The method of any one of claims 10 to 17 , wherein the platinum compound is selected from the group consisting of oxaliplatin and cisplatin.

19 . The method of any one of claims 10 to 18 , wherein the nucleoside analog is selected from the group consisting of 5-fluorouracil and prodrugs thereof.

20 . The method of any one of claims 10 to 19 , wherein the taxane is selected from the group consisting of docetaxel and paclitaxel.

21 . The method of any one of claims 10 to 20 , wherein the camptothecin analog is selected from the group consisting of irinotecan and topotecan.

22 . The method of any one of claims 7 to 21 , wherein the method comprises administering (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.

23 . The method of any one of claims 1 to 22 , wherein the antibody having the ability of binding to CLDN18.2 binds to the first extracellular loop of CLDN18.2.

24 . The method of any one of claims 1 to 23 , 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.

25 . The method of any one of claims 1 to 24 , 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).

26 . The method of any one of claims 1 to 25 , wherein the method comprises administering the antibody having the ability of binding to CLDN18.2 at a dose of up to 1000 mg/m 2 .

27 . The method of any one of claims 1 to 26 , wherein the method comprises administering the antibody having the ability of binding to CLDN18.2 repeatedly at a dose of 300 to 600 mg/m 2 .

28 . The method of any one of claims 1 to 27 , wherein the cancer is CLDN18.2 positive.

29 . The method of any one of claims 1 to 28 , wherein the cancer is an adenocarcinoma, in particular an advanced adenocarcinoma.

30 . The method of any one of claims 1 to 29 , 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.

31 . The method of any one of claims 1 to 30 , wherein the patient is a HER2/neu negative patient or a patient with HER2/neu positive status but not eligible to trastuzumab therapy.

32 . The method of any one of claims 1 to 31 , wherein CLDN18.2 has the amino acid sequence according to SEQ ID NO: 1.

33 . A medical preparation compris

Assignees

• Astellas Pharma Inc
• Tron Translationale Onkologie An Der Univ Der Johannes Gutenberg Univ Mainz

Inventors

• Sahin Ugur
• Tureci Ozlem
• Mitnacht-Kraus Rita
• Jacobs Stefan Denis
• Utsch Magdalena Jadwiga
• Heinz Cornelia Adriana Maria
• Stadler Christiane Regina

Classifications

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title