Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-a][1,4]diazepines

Patent metadata

Field	Value
Publication number	US-12246196-B2
Application number	US-202217849688-A
Country	US
Kind code	B2
Filing date	Jun 26, 2022
Priority date	Sep 29, 2017
Publication date	Mar 11, 2025
Grant date	Mar 11, 2025

Abstract

Provided are novel antibody-pyrrolodiazepine derivative and novel antibody-pyrrolodiazepine derivative conjugates, as well as methods of using the same, and a novel CLDN6 and/or CLDN9 antibody. The disclosed compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics, and include substituted benzo[e]pyrrolo[1,2-α][1,4]diazepine.

First claim

The invention claimed is:

1. An antibody-drug conjugate represented by [Formula 1]:
Ab-[-L-D] m 1   [Formula 1]

wherein:
Ab represents an immunoglobulin G (IgG) antibody or a functional fragment of the immunoglobulin G (IgG) antibody;
wherein the immunoglobulin G (IgG) antibody optionally has a remodeled glycan; and
wherein the immunoglobulin G (IgG) antibody may bond to L directly via its amino acid residue, via a glycan, or via a remodeled glycan;

L represents the following formula:
-Lb-La-Lp-NH—B—CH 2 —OC(O)—*

wherein:
Lb represents a spacer bonding La and a glycan or remodeled glycan of Ab represented by the following [Formula 5], [Formula 6], [Formula 7], or [Formula 67]:

wherein:
represents bonding to a glycan or remodeled glycan of Ab; and
* represents bonding to La;

La represents —C(O)—(CH 2 CH 2 ) n 2 —C(O)—, —C(O)—(CH 2 CH 2 ) n 2 —C(O)—NH—(CH 2 CH 2 ) n 3 —C(O)—, —C(O)—(CH 2 CH 2 ) n 2 —C(O)—NH—(CH 2 CH 2 O) n 3 —CH 2 —C(O)—, —C(O)—(CH 2 CH 2 ) n 2 —NH—C(O)—(CH 2 CH 2 O) n 3 —CH 2 CH 2 —C(O)—, —(CH 2 ) n 4 —O—C(O)—, —(CH 2 ) n 9 —C(O)—, or —(CH 2 CH 2 ) n 10 —C(O)—NH—(CH 2 CH 2 O) n 11 —CH 2 CH 2 —C(O)—;
n 2 represents 1, 2, or 3;
n 3 represents 1, 2, 3, 4, or 5;
n 4 represents 0, 1, or 2;
n 9 represents 2,3,4,5,6,or 7;
n 1 ° represents 1, 2, or 3;
n″ represents 6, 7, 8, 9, or 10;
Lp represents an amino acid residue consisting of two, three, four, five, six, or seven amino acids selected from the group consisting of alanine (A), arginine (R), asparagine (N), aspartic add (D), citrulline (Cit), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), selenocysteine (U), serine (S), threonine (T), tryptophan (W), tyrosine (Y), and valine (V);
B represents phenylene or heteroarylene; and
* represents bonding to D;
D represents a drug represented by the following [Formula 2]:

wherein:
X represents —NH—, —O—, or —S—;
Y represents —NH—, —O—, or —S—;
R 1 represents H, halogen, C is alkyl, NR′R″, OH, OC is alkyl, SH, or SC is alkyl;
R 2 represents H, halogen, C is alkyl, NR′R″, OH, OC is alkyl, SH, or SC is alkyl;

(i) R 3 represents H; and
R ° and R 3 , taken together with the carbon atom to which they are bound, form ═CH 2 or a saturated 3- to 5-membered spirocyclyl; or

(ii) R 3 and R ° , taken together with the carbon atoms to which they are bound, form —CR 5 ═CH; and
R 5 represents C 1-6 alkyl, aryl, or heteroaryl;
wherein the Cis alkyl Is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, and OC 1-6 alkyl;
wherein the aryl or heteroaryl Is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C(NR′)NR″R″, NR′R″, NHC(NR′)NR″R″, NHC(O)R′, OH, OC 1-6 alkyl, SC is alkyl, and C 3-5 cycloalkoxy;
wherein each Cis alkyl substituent is optionally and Independently substituted with one, two, or three substituents Independently selected from the group consisting of halogen, C(NR′)NR″R″, NR′R″, NHC(NR′)NR″R″, OH, and OC(O)R′; and
wherein each OC is alkyl substituent Is optionally and independently substituted with one, two, or three independently selected halogen substituents; or

(iii) R 3 , W, and R 3 , taken together with the carbon atoms to which they are bound, form a 1,2-phenylene or 6-membered heterocyclylene;
wherein the 1,2-phenylene or 6-membered heterocyclylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Cis alkyl, and OC is alkyl; and
wherein each C 1-4 alkyl and OC 1-4 alkyl substituent Is optionally and independently substituted with one, two, or three Independently selected halogen substituents;

each R′ independently represents H or Cis alkyl;
each R″ independently represents H or Cis alkyl;
each R″ independently represents H or Cis alkyl;
R 6 represents H;
R 7 represents H; or
R 6 and R′, taken together with the carbon atom and nitrogen atom to which they are bound, form —CH═N—;
R 8 represents OH or OC 1-3 alkyl;
ring A represents a saturated 3- to 5-membered spirocyclyl, wherein the 3- to 5-membered spirocyclyl is optionally substituted with one, two, three, or four independently selected halogen substituents;
n 1 represents 2, 3, 4, 5, 6, 7, or 8;
* represents bonding to L; and
m 1 represents 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The antibody-drug conjugate according to claim 1 , wherein the immunoglobulin G (IgG) antibody is immunoglobulin G1 (IgG 1), immunoglobulin G2 (IgG2), or immunoglobulin G4 (IgG4).

3. The antibody-drug conjugate according to claim 1 , wherein the immunoglobulin G (IgG) antibody bonds to L via a glycan bonding to Asn297 of the N297 glycan of the immunoglobulin G (IgG) antibody.

4. The antibody-drug conjugate according to claim 3 , wherein the N297 glycan of the immunoglobulin G (IgG) antibody is a remodeled glycan.

5. The antibody-drug conjugate according to claim 3 , wherein the N297 glycan of Ab represents:
(i) N297-(Fuc)MSG1 of [Formula 29], N297-(Fuc)MSG2 of [Formula 30], or N297-(Fuc)SG of [Formula 31]:

wherein: IDC-261,C1
L(PEG) represents —NH—CH 2 CH 2 —(OCH 2 CH 2 ) n 5 —*;
wherein the —NH— at the left end is bound via an amide bond to the carboxylic acid at the 2-position of a sialic acid at the non-reducing terminal in one or both of the 1-3 and 1-6 branched chains of the b-Man in the N297 glycan; and
wherein each * represents bonding to L;

n 5 represents 2,3,4,5,6,7,8,9,or 10; and
each represents bonding to Asn297 of the immunoglobulin G (IgG) antibody; or

(ii) a mixture of N297-(Fuc)MSG1 of the [Formula 29] and N297-(Fuc)MSG2 of the [Formula 30] above.

6. The antibody-drug conjugate according to claim 5 , wherein n 3 represents 2, 3, 4, or 5.

7. The antibody-drug conjugate according to claim 3 , wherein the antibody-drug conjugate is represented by the following [Formula 19]:

wherein:
Ab represents an immunoglobulin G (IgG) antibody or a functional fragment of the immunoglobulin G (IgG) antibody;
the N297 glycan of Ab represents:

(i) N297-(Fuc)MSG1 of [Formula 29], N297-(Fuc)MSG2 of [Formula 30], or N297-(Fuc)SG of [Formula 31]:

wherein:
L(PEG) represents —NH—CH 2 CH 2 —(OCH 2 CH 2 ) n 3 —*;
wherein the —NH— at the left end is bound via an amide bond to the carboxylic acid at the 2-position of a sialic acid at the non-reducing terminal in one or both of the 1-3 and 1-6 branched chains of the β-Man in the N297 glycan; and
wherein each * represents bonding to a nitrogen atom at the 1-position or 3-position of the triazole ring of Z 1 in L;

n 5 represents 2, 3, 4, or 5; and
each represents bonding to Asn297 of the immunoglobulin G (IgG) antibody; or

(ii) a mixture of N297-(Fuc)MSG1 of the [Formula 29] and

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

  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 Primary

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title