Linkers for conjugation of cell-binding molecules

Patent metadata

Field	Value
Publication number	US-10975112-B2
Application number	US-201514740403-A
Country	US
Kind code	B2
Filing date	Jun 16, 2015
Priority date	Jun 16, 2015
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.

First claim

What is claimed is:

1. A hydrophilic linker compound of Formula (I)

wherein:
Y represents a functional group that is capable of reacting with a cell-binding agent;
Q and T are either —X 1 —P(═O)(OM)-, or —X 1 —S(O 2 )—, or —X 1 —S(O)—, or —X 1 —P(═O)(OM)-X 2 —, or —X 1 —P(═O)[X 2 —R 4 —Z]—X 3 —, or —X 1 —P(═O)[X 2 —R 1 —Y]—X 3 —, or —X 1 —S(O 2 )—X 2 —, or —X 1 —S(O)—X 2 —, wherein X 1 , X 2 and X 3 are independently N(R 7 ), O, CH 2 or S provided that at least one X 1 is either N(R 7 ) or S;
m and n are integer from 0 to 5, but not 0 at the same time;
Z represents a functional group that enables linkage of the hydrophilic linker compound to a cytotoxic drug via an alkyl, alkenyl, alkynyl, aromatic, heteroalkyl, disulfide, thioether, thioester, hydrazone, ether, ester, carbamate, carbonate, secondary, tertiary, or quartary amine, imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond;
R 5 , R 6 , and R 7 are the same or different and are H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof;
each of R 1 , R 2 , R 3 and R 4 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof, or a chain of atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects to a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug or each other; and
M is H, or Na, or K, or N + R 1 R 2 R 3 or a pharmaceutical salt.

2. A cell-binding agent-drug conjugate compound of Formula (II)

wherein:
Cb represents a cell-binding agent;
Drug represents a drug;
Q and T are either —X 1 —P(═O)(OM)-, or —X 1 —S(O 2 )—, or —X 1 —S(O)—, or —X 1 —P(═O)(OM)-X 2 —, or —X 1 —P(═O)[X 2 —R 4 -Drug]-X 3 —, or —X 1 —P(═O)[X 2 —R 1 —Cb]—X 3 —, or —X 1 —S(O 2 )—X 2 —, or —X 1 —S(O)—X 2 —;
X 1 , X 2 and X 3 are independently N(R 7 ), O, CH 2 or S provided that at least one X 1 is either N(R 7 ) or S;
m and n are integer from 0 to 5, but not 0 at the same time;
q is 1 to 30;
R 5 , R 6 , and R 7 are the same or different and are H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof;
each of R 1 , R 2 , R 3 and R 4 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof, or a chain of atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects to a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug or each other; and
M is H, or Na, or K, or N + R 1 R 2 R 3 or a pharmaceutical salt,
wherein the cell binding agent is an antibody, a single chain antibody, an antibody fragment that binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that binds the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment that binds to the target cell, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment that binds to the target cell.

3. A compound of Formula (III):

wherein:
Cb represents a cell-binding agent;
m and n are integer from 0 to 5, but not 0 at the same time;
q is 1 to 30;
Z represents a functional group that is capable of reacting with a cytotoxic drug via an alkyl, alkenyl, alkynyl, aromatic, heteroalkyl, disulfide, thioether, thioester, hydrazone, ether, ester, carbamate, carbonate, secondary, tertiary, or quartary amine, imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond;
each of R 1 , R 2 , R 3 and R 4 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof, or a chain of atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects to a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug or each other;
R 5 , and R 6 are the same or different and are H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof;
Q and T are either —X 1 —P(═O)(OM)-, or —X 1 —S(O 2 )—, or —X 1 —S(O)—, or —X 1 —P(═O)(OM)-X 2 —, or —X 1 —P(═O)[X 2 —R 4 —Z]—X 3 —, or —X 1 —P(═O)[X 2 —R 1 —Cb]—X 3 —, or —X 1 —S(O 2 )—X 2 —, or —X 1 —S(O)—X 2 —;
X 1 , X 2 and X 3 are independently N(R 7 ), O, CH 2 or S provided that at least one X 1 is either N(R 7 ) or S,
wherein the cell binding agent is an antibody, a single chain antibody, an antibody fragment that binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that binds the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment that binds to the target cell, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment that binds to the target cell.

4. A compound of Formula (IV):

wherein:
Y represents a functional group that is capable of reacting with a cell-binding agent;
Drug represents a drug;
m and n are integer from 0 to 5, but not 0 at the same time;
q is 1 to 30;
each of R 1 , R 2 , R 3 and R 4 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether, or amide having 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 0 to about 1000, or combination thereof, or a cha

Assignees

• Suzhou M Conj Biotech Co Ltd
• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert Yongxin

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/68033

  the drug being a maytansine · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6803

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

• C07F9/6584

  having one phosphorus atom as ring hetero atom · CPC title