Anti-TROP2 antibody-drug conjugate

Patent metadata

Field	Value
Publication number	US-9850312-B2
Application number	US-201615187179-A
Country	US
Kind code	B2
Filing date	Jun 20, 2016
Priority date	Dec 25, 2013
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

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: -L 1 -L 2 -L P -NH—(CH 2 )n 1 -L a -(CH 2 )n 2 -C(═O)— wherein the anti-TROP2 antibody is connected to the terminal of L 1 , and the antitumor compound is connected to the carbonyl group of the —(CH 2 )n 2 -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, wherein a linker and an antitumor compound represented by the following formula and anti-TROP2 antibody are connected: -(Succinimid-3-yl-N)—CH 2 CH 2 CH 2 CH 2 CH 2 —C(═O)-GGFG-NH—CH 2 —O—CH 2 —C(═O)—(NH-DX)
wherein
-(Succinimid-3-yl-N)— has a structure represented by the following formula:

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 a group represented by the following formula:

wherein the nitrogen atom of the amino group at position 1 is the connecting position, wherein the anti-TROP2 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 23, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 24 and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 25 in its heavy chain variable region and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 26, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 27 and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 28 in its light chain variable region.

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.

9. The antibody-drug conjugate according to claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain and a light chain selected from the group consisting of;
a heavy chain variable region consisting of the amino acid sequence of positions 20 to 140 of SEQ ID NO: 12 and a light chain variable region consisting of the amino acid sequence of positions 21 to 129 of SEQ ID NO: 18,
a heavy chain variable region consisting of the amino acid sequence of positions 20 to 140 of SEQ ID NO: 14 and a light chain variable region consisting of the amino acid sequence of positions 21 to 129 SEQ ID NO: 18,
a heavy chain variable region consisting of the amino acid sequence of positions of 20 to 140 of SEQ ID NO: 14 and a light chain variable region consisting of the amino acid sequence of positions 21 to 129 of SEQ ID NO: 20, and
a heavy chain variable region consisting of the amino acid sequence of positions 20 to 140 of SEQ ID NO: 16 and a light chain variable region consisting of the amino acid sequence of positions 21 to 129 of SEQ ID NO: 22.

10. The antibody-drug conjugate according to claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain and a light chain selected from the group consisting of;
a heavy chain consisting of the amino acid sequence of positions 20 to 470 of SEQ ID NO: 12 and a light chain consisting of the amino acid sequence of positions 21 to 234 of SEQ ID NO: 18,
a heavy chain consisting of the amino acid sequence of positions 20 to 470 of SEQ ID NO: 14 and a light chain consisting of the amino acid sequence of positions 21 to 234 of SEQ ID NO: 18,
a heavy chain consisting of the amino acid sequence of positions 20 to 470 of SEQ ID NO: 14 and a light chain consisting of the amino acid sequence of positions 21 to 234 of SEQ ID NO: 20, and
a heavy chain consisting of the amino acid sequence of positions 20 to 470 of SEQ ID NO: 16 and a light chain consisting of the amino acid sequence of positions 21 to 234 of SEQ ID NO: 22.

11. The antibody-drug conjugate according to claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain variable region consisting of the amino acid sequence of positions 20 to 140 of SEQ ID NO: 12 and a light chain variable region consisting of the amino acid sequence of positions 21 to 129 of SEQ ID NO: 18.

12. The antibody-drug conjugate according to claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain consisting of the amino acid sequence of positions 20 to 470 of SEQ ID NO: 12 and a light chain consisting of the amino acid sequence of positions 21 to 234 of SEQ ID NO: 18.

13. The antibody-drug conjugate according to claim 10 , wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

14. The antibody-drug conjugate according to claim 12 , wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

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

• A61K47/6863

  the tumour determinant being from stomach or intestines cancer cell · CPC title

• C07K16/303

  Liver or Pancreas · 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

• C07K16/30 Primary

  from tumour cells · CPC title