Anti-TROP2 antibody-drug conjugate

Patent metadata

Field	Value
Publication number	US-11008398-B2
Application number	US-201916256715-A
Country	US
Kind code	B2
Filing date	Jan 24, 2019
Priority date	Dec 25, 2013
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

It is intended to provide an antitumor drug having an excellent therapeutic effect, which is excellent in terms of antitumor effect and safety. There is provided an antibody-drug conjugate in which an antitumor compound represented by the following formula is conjugated to an anti-TROP2 antibody via a linker having a structure represented by the following formula: -L1-L2-LP-NH—(CH2)n1-La-(CH2)n2-C(═O)— wherein the anti-TROP2 antibody is connected to the terminal of L1, and the antitumor compound is connected to the carbonyl group of the —(CH2)n2-C(═O)— moiety with the nitrogen atom of the amino group at position 1 as a connecting position.

First claim

The invention claimed is:

1. An antibody-drug conjugate, comprising an anti-TROP2 antibody and an antitumor compound connected by a linker, the anti-TROP2 antibody comprising a heavy chain variable region comprising a CDRH1 consisting of SEQ ID NO: 23, a CDRH2 consisting of SEQ ID NO: 24, and a CDRH3 consisting of SEQ ID NO: 25, and a light chain variable region comprising a CDRL1 consisting of SEQ ID NO: 26, a CDRL2 consisting of SEQ ID NO: 27, and a CDRL3 consisting of SEQ ID NO: 28; wherein the linker and the antitumor compound are represented by any one of the following:
-(Succinimid-3-yl-N)—CH 2 CH 2 —C(═O)-GGFG-NH-CH 2 CH 2 —C(═O)-(NH-DX),
-(Succinimid-3-yl-N)—CH 2 CH 2 —C(═O)-GGFG-NH—CH 2 CH 2 CH 2 —C(═O)-(NH-DX),
-(Succinimid-3-yl-N)—CH 2 CH 2 CH 2 CH 2 CH 2 —C(═O)-GGFG-NH-CH 2 CH 2 —C(═O)-(NH-DX),
-(Succinimid-3-yl-N)—CH 2 CH 2 CH 2 CH 2 CH 2 —C(═O)-GGFG-NH-CH 2 CH 2 CH 2 —C(═O)-(NH-DX),
-(Succinimid-3-yl-N)—CH 2 CH 2 CH 2 CH 2 CH 2 —C(═O)-GGFG-NH-CH 2 CH 2 CH 2 CH 2 CH 2 -C(═O)-(NH-DX),
-(Succinimid-3-yl-N)—CH 2 CH 2 —C(═O)—NH—CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —C(═O)-GGFG-NH—CH 2 CH 2 —C(═O)-(NH-DX),
-(Succinimid-3-yl-N)—CH 2 CH 2 —C(═O)—NH—CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 -O—CH 2 CH 2 —C(═O)-GGFG-NH-CH 2 CH 2 —C(═O)-(NH-DX), or
-(Succinimid-3-yl-N)—CH 2 CH 2 —C(═O)—NH—CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 -O—CH 2 CH 2 —C(═O)-GGFG-NH—CH 2 CH 2 CH 2 —C(═O)-(NH-DX)
wherein
-(Succinimid-3-yl-N)- has a structure of:

which is connected to the antibody at position 3 thereof and is connected to a methylene group in the linker structure containing this structure on the nitrogen atom at position 1, and
(NH-DX) represents:

wherein the nitrogen atom of the amino group at position 1 is the connecting position.

2. The antibody-drug conjugate according to claim 1 , wherein an average number of units of the selected one drug-linker structure conjugated per antibody is in a range of from 2 to 8.

3. The antibody-drug conjugate according to claim 1 , wherein an average number of units of the selected one drug-linker structure conjugated per antibody is in a range of from 3 to 8.

4. A drug containing the antibody-drug conjugate according to claim 1 or a salt thereof.

5. An antitumor drug and/or anticancer drug containing the antibody-drug conjugate according to claim 1 or a salt thereof.

6. A method of treating cancer in an individual comprising administering to an individual with cancer the drug according to claim 5 , wherein the cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, cervical cancer, head and neck cancer, or esophageal cancer.

7. A pharmaceutical composition containing the antibody-drug conjugate according to claim 1 or a salt thereof as an active component, and a pharmaceutically acceptable formulation component.

8. A method of treating cancer in an individual comprising administering to an individual with cancer the pharmaceutical composition according to claim 7 , wherein the cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, cervical cancer, head and neck cancer, or esophageal cancer.

Assignees

• Daiichi Sankyo Co Ltd
• Univ Sapporo Medical

Inventors

• Agatsuma Toshinori
• Takahashi Shu
• Hasegawa Jun
• Okajima Daisuke
• Hamada Hirofumi
• Yamaguchi Miki

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/68037

  the drug being a camptothecin [CPT] or derivatives · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title