Methods of treating a tumor by administering a claudin-6 (CLDN6) or CLDN9 antibody-pyrrolobenzodiazepine derivative conjugate

Patent metadata

Field	Value
Publication number	US-12350344-B2
Application number	US-202217714032-A
Country	US
Kind code	B2
Filing date	Apr 5, 2022
Priority date	Sep 29, 2017
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

Abstract

The present invention provides a novel antibody-pyrrolodiazepine derivative and a novel antibody-pyrrolodiazepine derivative conjugate using the same, and a novel CLDN6 and/or CLDN9 antibody.

First claim

The invention claimed is:

1. A method for treating a tumor, comprising administering to a patient in need thereof an antibody-drug conjugate selected from the following group:

wherein, in each structural formula shown above,
m 2 represents an integer of 1 or 2;
Ab represents an antibody or a functional fragment of the antibody, wherein the antibody is an antibody which binds to CLDN6 and/or CLDN9;
the N297 glycan of Ab represents any one of N297-(Fuc)MSG1, N297-(Fuc)MSG2, and a mixture thereof, and N297-(Fuc)SG, with N297-(Fuc)MSG1, N297-(Fuc)MSG2, and N297-(Fuc)SG having structures represented by the following formulas:

wherein
each wavy line represents bonding to Asn297 of the antibody,
L(PEG) represents —NH—CH 2 CH 2 —(O—CH 2 CH 2 ) 3 —*, wherein the amino group at the left end is bound via an amide bond to carboxylic acid at the 2-position of a sialic acid at the non-reducing terminal in each or either one of the 1-3 and 1-6 branched chains of β-Man in the N297 glycan, and each asterisk represents bonding to a nitrogen atom at the 1- or 3-position of the triazole ring in the corresponding structural formula.

2. The method according to claim 1 , wherein the tumor expresses CLDN6, CLDN9, or a combination thereof.

3. The method according to claim 1 , wherein the tumor is ovarian cancer, lung cancer, gastric cancer, endometrial cancer, testicular cancer, uterine cervix cancer, placental choriocarcinoma, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, brain tumor, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, or esophageal cancer.

4. The method according to claim 1 , wherein the antibody comprises a heavy chain comprising CDRH1, CDRH2, and CDRH3 and a light chain comprising CDRL1, CDRL2, and CDRL3 as described in any one of the following:
(a) CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 9, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 10, and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 11, and CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 5, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 6, and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 7 or an amino acid sequence having one or two amino acid substitutions in the amino acid sequence represented by SEQ ID NO: 7;
(b) CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 15, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 16, and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 17, and CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 12, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 13, and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 14;
(c) CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 9, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 10, and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 11, and CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 5, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 6, and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 7 or an amino acid sequence represented by SEQ ID NO: 8.

5. The method according to claim 1 , wherein the antibody comprises a heavy chain variable region and a light chain variable region as described in any one of the following (a) and (b):
(a) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 21 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 19; and
(b) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 25 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 23.

6. The method according to claim 1 , wherein the antibody comprises a heavy chain variable region consisting of an amino acid sequence selected from the group consisting of the following (a) to (e) and a light chain variable region consisting of an amino acid sequence selected from the group consisting of the following (f) to (k):
(a) an amino acid sequence represented by SEQ ID NO: 54;
(b) an amino acid sequence represented by SEQ ID NO: 58;
(c) an amino acid sequence represented by SEQ ID NO: 62;
(d) an amino acid sequence with a homology of at least 95% or higher to a sequence of a framework region excluding CDR sequences in any of the sequences (a) to (c);
(e) an amino acid sequence having one to several amino acid deletions, substitutions, or additions in a sequence of a framework region excluding CDR sequences in any of the sequences (a) to (c);
(f) an amino acid sequence represented by SEQ ID NO: 38;
(g) an amino acid sequence represented by SEQ ID NO: 42;
(h) an amino acid sequence represented by SEQ ID NO: 46;
(i) an amino acid sequence represented by SEQ ID NO: 50;
(j) an amino acid sequence with a homology of at least 95% or higher to a sequence of a framework region excluding CDR sequences in any of the sequences (f) to (i); and
(k) an amino acid sequence having one to several amino acid deletions, substitutions, or additions in a sequence of a framework region excluding CDR sequences in any of the sequences (f) to (i).

7. The method according to claim 6 , the antibody comprising a heavy chain variable region and a light chain variable region selected from the group consisting of the following (a) to (e):
(a) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 54 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 38;
(b) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 58 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 42;
(c) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 54 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 46;
(d) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 58 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 50; and
(e) a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 62 and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 46.

8. The method according to claim 1 , the antibody comprising a heavy chain and a light chain selected from the group consisting of the following (a) to (e):
(a) a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 52 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 36 (H1L1);
(b) a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 56 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 40 (H2L2);
(c) a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 471 of SEQ ID NO: 52 and a light chain consisting of an amino acid sequence consisting of amino acid residues

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Toda Narihiro
• Ota Yusuke
• Doi Fuminao
• Meguro Masaki
• Hayakawa Ichiro
• Ashida Shinji
• Masuda Takeshi
• Nakada Takashi
• Iwamoto Mitsuhiro
• Harada Naoya
• Terauchi Tomoko
• Okajima Daisuke
• Nakamura Kensuke
• Uchida Hiroaki
• Hamada Hirofumi

Classifications

• A61K35/00 Primary

  Medicinal preparations containing materials or reaction products thereof with undetermined constitution · CPC title

• A61K47/6803 Primary

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

• A61K47/68035 Primary

  the drug being a pyrrolobenzodiazepine · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title