Hydrophilic antibody-drug conjugates

Patent metadata

Field	Value
Publication number	US-12257281-B2
Application number	US-202318361558-A
Country	US
Kind code	B2
Filing date	Jul 28, 2023
Priority date	Feb 17, 2014
Publication date	Mar 25, 2025
Grant date	Mar 25, 2025

Abstract

Hydrophilic Linkers, Drug-Linker compounds, Drug-Ligand Conjugate compounds and Ligand-Linkers and methods of making and using the same are provided.

First claim

What is claimed is:

1. A Compound having the formula:
(a) (L H ) p′ -L A
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L H is an optionally branched hydrophilic linker, each branch of L H having the formula:
-AA 1 —R L1 —R L2 —R L3 —;

L A is a Ligand Attachment component; and
p′ is an integer from 1 to 4; and
wherein the left and right lines of L H indicate attachment sites for a D E unit and L A , respectively; or
(b) ([L H ] p′ -L A ) p -L
or a pharmaceutically acceptable salt or solvate thereof; wherein:
L is a Ligand that specifically binds to a target;
L H is an optionally branched hydrophilic linker, each branch of L H having the formula:
-AA 1 —R L1 —R L2 —R L3 —;

L A is a Ligand Attachment component;
the subscript p is an integer from about 4 to 20; and
the subscript p′ is an integer from 1 to 4;
wherein the left and right lines of L H indicate attachment sites to the D E Unit and L A , respectively;
wherein in (a) or (b):
AA 1 is a hydrophilic amino acid that can form a cleavable bond with a D E unit when it is attached;
R L1 is a hydrophilic amino acid or an optionally substituted alkylene, which may share an atom with L A when R L2 and R L3 are not present;
R L2 is optional and is selected from a hydrophilic amino acid and an optionally substituted alkylene, which may share an atom with L A when R L2 is present and R L3 is not present; and

R L3 is optional and is selected from a hydrophilic amino acid and an optionally substituted alkylene, which may share an atom with L A when R L3 is present,
wherein at least one of R L1 , R L2 , and R L3 is an amino acid that is covalently linked by a reactive group in its side chain to an adjacent group.

2. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
(a) AA 1 is a hydrophilic amino acid selected from the group consisting of Glycine and L forms of Aspartate, Glutamate, Asparagine, Glutamine, Histidine, Lysine, Arginine, Serine and Alanine;
(b) when R L1 is present, it is selected from the group consisting of:
Glycine; L or D forms of Aspartate, Glutamate, Asparagine, Glutamine,
Histidine, Lysine, Arginine, Serine and Alanine; —NH—CH(R a )—C(O)—; and —NH—CH(COOH)—R b —; wherein R a is selected
from —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CO 2 H, and —CH 2 CH 2 CH 2 CH 2 CO 2 H; and R b is selected
from —CH 2 NH—, —CH 2 CH 2 NH—, —CH 2 CH 2 CH 2 NH—, —CH 2 CH 2 CH 2 CH 2 NH—, —CH 2 CH 2 C(O)—, —CH 2 CH 2 CH 2 C(O)—
and —CH 2 CH 2 CH 2 CH 2 C(O)—; and
a C 1 -C 6 alkylene, optionally substituted with 1-4 substituents selected from —NH—, —C(O)—, —COOH, —N(C 1 -C 3 alkyl), —NH 2 or —NH(C 1 -C 3 alkyl);

(c) when R L2 is present, it is selected from the group consisting of:
Glycine; L or D forms of Aspartate, Glutamate, Asparagine, Glutamine,
Histidine, Lysine, Arginine, Serine and Alanine; —NH—CH(R a )—C(O)—; and —NH—CH(COOH)—R b —; wherein R a is selected
from —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CO 2 H, and —CH 2 CH 2 CH 2 CH 2 CO 2 H; and R b is selected
from —CH 2 NH—, —CH 2 CH 2 NH—, —CH 2 CH 2 CH 2 NH—, —CH 2 CH 2 CH 2 CH 2 NH—, —CH 2 CH 2 C(O)—, —CH 2 CH 2 CH 2 C(O)—
and —CH 2 CH 2 CH 2 CH 2 C(O)—; and
a C 1 -C 6 alkylene, optionally substituted with 1-4 substituents selected from —NH—, —C(O)—, —COOH, —N(C 1 -C 3 alkyl), —NH 2 or —NH (C 1 -C 3 alkyl); and

(d) when R L3 is present, it is selected from the group consisting of:
Glycine; L or D forms of Aspartate, Glutamate, Asparagine, Glutamine,
Histidine, Lysine, Arginine, Serine and Alanine; —NH—CH(R a )—C(O)—; and —NH—CH(COOH)—R b —; wherein R a is selected
from —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 CO 2 H,
and —CH 2 CH 2 CH 2 CH 2 CO 2 H; and R b is selected
from —CH 2 NH—, —CH 2 CH 2 NH—, —CH 2 CH 2 CH 2 NH—, —CH 2 CH 2 CH 2 CH 2 NH—, —CH 2 CH 2 C(O)—, —CH 2 CH 2 CH 2 C(O)—
and —CH 2 CH 2 CH 2 CH 2 C(O)—; and
and C 1 -C 6 alkylene, optionally substituted with 1-4 substituents selected from —NH—, —C(O)—, —COOH, —N(C 1 -C 3 alkyl), —NH 2 or —NH(C 1 -C 3 alkyl).

3. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
(a) AA 1 is present and R L1 , R L2 and R L3 are absent;
(b) AA 1 is present, R L1 is present and R L2 and R L3 are absent;
(c) AA 1 is present, R L1 is present, R L2 is present and R L3 is absent;
(d) AA 1 is present, R L1 is present, R L2 is present and R L3 is present;
(e) AA 1 is present and at least one of R L1 , R L2 and R L3 is present and is an optionally substituted alkylene;
(f) AA 1 is Glutamate and at least one of R L1 , R L2 and R L3 is present and is an optionally substituted alkylene;
(g) AA 1 is Glutamate, R L1 is a hydrophilic amino acid and at least one of R L2 and R L3 is present and is an optionally substituted alkylene;
(h) AA 1 and R L1 are hydrophilic amino acids and at least one of R L2 and R L3 is present and is an optionally substituted alkylene;
(i) AA 1 is a hydrophilic amino acid and R L1 and optionally R L2 are an optionally substituted alkylene;
(j) AA 1 is present and at least one of R L1 , R L2 and R L3 is present and is an optionally substituted alkylene selected from the group consisting of ethylenediamine, —NH—CH(COOH)—CH 2 —NH—and —CO—CH(CH 2 NH 2 )—;
(k) AA 1 is Glutamate, R L1 is a hydrophilic amino acid and at least one of R L2 and R L3 is present and is an optionally substituted alkylene selected from the group consisting of ethylenediamine, —NH—CH(COOH)—CH 2 —NH—and —CO—CH(CH 2 NH 2 )—;
(l) AA 1 and R L1 are hydrophilic amino acids and at least one of R L2 and R L3 is present and is an optionally substituted alkylene selected from the group consisting of ethylenediamine, —NH—CH(COOH)—CH 2 —NH—and —CO—CH(CH 2 NH 2 )—; or
(m) AA 1 is a hydrophilic amino acid and R L1 and optionally R L2 are an optionally substituted alkylene selected from the group consisting of ethylenediamine, —NH—CH(COOH)—CH 2 —NH—and —CO—CH(CH 2 NH 2 )—.

4. The Compound of claim 1 , wherein —L H — has the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 21 is selected from the group consisting of —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH — CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH, —C H 2 CH 2 OH —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CH 2 CO 2 H, and —CH 2 CH 2 CH 2 CH 2 CO 2 H; and
R 22 is selected from the group consisting of —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH; and
the left and right wavy lines indicate attachment to D E , H or a protecting group, and L A , respectively.

5. The Compound of claim 1 , wherein —L H — has the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein
R 22 is selected from —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH, and —CH 2 CH 2 OH; and
the left and right wavy lines indicate attachments to D E , H or a protecting group, and L A , respectively.

6. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein —L H — has the formula selected from the group consisting of:

wh

Assignees

• Seagen Inc

Inventors

• Doronina Svetlana
• Lyon Robert
• Senter Peter

Classifications

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title

• A61K47/6861

  the tumour determinant being from kidney or bladder cancer cell · 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