Drug conjugates comprising antibodies against claudin 18.2

Patent metadata

Field	Value
Publication number	US-11541127-B2
Application number	US-201615565848-A
Country	US
Kind code	B2
Filing date	Apr 13, 2016
Priority date	Apr 15, 2015
Publication date	Jan 3, 2023
Grant date	Jan 3, 2023

Abstract

The present invention provides anti-CLDN18.2 antibody-drug conjugates which are effective for treating and/or preventing cancer diseases associated with cells expressing CLDN18.2, including 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

The invention claimed is:

1. A method of treating a cancer expressing a human CLDN18.2 polypeptide by administering an antibody-drug conjugate to a human patient, said antibody-drug conjugate comprising an antibody having the ability of binding to a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 covalently attached to at least one toxin drug moiety,
wherein the antibody-drug conjugate, upon binding to cells expressing the human CLDN18.2 polypeptide, is internalized into the cells and wherein the antibody-drug conjugate mediates killing of the cells through toxin-mediated cytotoxicity, complement dependent cytotoxicity (CDC) mediated lysis, and antibody dependent cellular cytotoxicity (ADCC) mediated lysis;
wherein the antibody having the ability of binding to the polypeptide comprising the amino acid sequence of SEQ ID NO: 1 recognizes the same epitope as a CLDN18.2-binding antibody comprising an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39;
wherein the antibody having the ability of binding to the polypeptide comprising the amino acid sequence of SEQ ID NO: 1 comprises a heavy chain variable region (V H ) comprising a V H CDR1 of positions 45-52 of SEQ ID NO: 17, a V H CDR2 of positions 70-77 of SEQ ID NO: 17, and a V H CDR3 of positions 116-126 of SEQ ID NO: 17 and a light chain variable region (V L ) comprising a V L CDR1 of positions 47-58 of SEQ ID NO: 24, a V L CDR2 of positions 76-78 of SEQ ID NO: 24, and a V L CDR3 of positions 115-123 of SEQ ID NO: 24;
wherein the antibody having the ability of binding to the polypeptide comprising the amino acid sequence of SEQ ID NO: 1 comprises a human heavy chain constant region selected from the group consisting of IgG1 and IgG3;
wherein (a) the toxin drug moiety is a maytansinoid or an auristatin; and (b) the antibody is covalently attached to the toxin drug moiety by a cleavable linker.

2. The method of claim 1 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39.

3. The method of claim 1 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 17 or 51 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 24.

4. The method of claim 1 , wherein the maytansinoid is selected from the group consisting of DM1 and DM4.

5. The method of claim 1 , wherein the auristatin is selected from the group consisting of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).

6. The method of claim 1 , wherein the linker is cleavable by an intracellular protease.

7. The method of claim 1 , wherein the linker is a cathepsin-cleavable linker.

8. The method of claim 1 , wherein the linker comprises a dipeptide.

9. The method of claim 8 , wherein the dipeptide is val-cit or phe-lys.

10. The method of claim 1 , which further comprises administering surgery, chemotherapy and/or radiation therapy.

11. The method of claim 1 , wherein the cancer is an adeno-carcinoma.

12. The method of claim 1 , wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, cancer of the gallbladder and the metastasis thereof, a Krukenberg tumor, peritoneal metastasis, and lymph node metastasis.

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

14. The method of claim 1 , wherein the human CLDN18.2 polypeptide comprises the amino acid sequence SEQ ID NO: 1.

15. The method of claim 1 , wherein the cancer is an advanced adenocarcinoma.

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

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

18. The method of claim 1 , wherein the toxin drug moiety is selected from the group consisting of DM4 and monomethyl auristatin E (MMAE).

19. A method of treating a gastric, esophageal, or pancreatic cancer expressing a human CLDN18.2 polypeptide by administering an antibody-drug conjugate to a human patient, said antibody-drug conjugate comprising an antibody having the ability of binding to a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 covalently attached to at least one toxin drug moiety via a cleavable linker,
wherein the antibody-drug conjugate, upon binding to cells expressing the human CLDN18.2 polypeptide, is internalized into the cells and wherein the antibody-drug conjugate mediates killing of the cells through toxin-mediated cytotoxicity, complement dependent cytotoxicity (CDC) mediated lysis, and antibody dependent cellular cytotoxicity (ADCC) mediated lysis;
wherein the antibody having the ability of binding to the polypeptide comprising the amino acid sequence of SEQ ID NO: 1 comprises a heavy chain variable region (V H ) comprising a V H CDR1 of positions 45-52 of SEQ ID NO: 17, a V H CDR2 of positions 70-77 of SEQ ID NO: 17, and a V H CDR3 of positions 116-126 of SEQ ID NO: 17 and a light chain variable region (V L ) comprising a V L CDR1 of positions 47-58 of SEQ ID NO: 24, a V L CDR2 of positions 76-78 of SEQ ID NO: 24, and a V L CDR3 of positions 115-123 of SEQ ID NO: 24;
wherein the antibody having the ability of binding to the polypeptide comprising the amino acid sequence of SEQ ID NO: 1 (a) recognizes the same epitope as a CLDN18.2-binding antibody comprising an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39 or (b) comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39;
wherein the toxin drug moiety is selected from the group consisting of DM4 and monomethyl auristatin E (MMAE).

20. The method of claim 19 , wherein the cleavable linker is an N-succinimidyl-4-(2-pyridyldithio)butyrate linker.

21. The method of claim 19 , wherein the cleavable linker is a valine-citrulline linker.

22. The method of claim 19 , wherein the toxin drug moiety is DM4 and the cleavable linker is an N-succinimidyl-4-(2-pyridyldithio)butyrate linker.

23. The method of claim 22 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39.

24. The method of claim 22 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 17 or 51 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 24.

25. The method of claim 19 , wherein the toxin drug moiety is MMAE and the cleavable linker is a valine-citrulline linker.

26. The method of claim 25 , wherein the antibody comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 39.

27. The method of cl

Assignees

• Ganymed Pharmaceuticals Gmbh
• Tron—Translationale Onkologie An Der Univ Der Johannes Gutenberg Univ Mainz Ggmbh
• Astellas Pharma Inc
• Tron—Translationale Onkologie An Der Univ Der Johannes Gutenberg Univ Mainz Gemeinnuetzige Gm

Inventors

• Sahin Ugur
• Tureci Ozlem
• Walter Korden
• Kreuzberg Maria
• Mitnacht-Kraus Rita
• Le Gall Fabrice
• Jacobs Stefan

Classifications

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• A61K47/6859 Primary

  the tumour determinant being from liver or pancreas cancer cell · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/303

  Liver or Pancreas · CPC title

• A61P35/00

  Antineoplastic agents · CPC title