Hydrophilic antibody-drug conjugates

Patent metadata

Field	Value
Publication number	US-11510959-B2
Application number	US-202117160225-A
Country	US
Kind code	B2
Filing date	Jan 27, 2021
Priority date	Feb 17, 2014
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

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 Drug-Linker Compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
L A is a Ligand attachment component;
L H is an optionally branched hydrophilic linker having the formula:
-AA 1 -R L1 —R L2 —R L3 —

wherein:
AA 1 is a hydrophilic amino acid that forms a cleavable bond with the D E unit to which it is attached;
R L1 is optional and is selected from a hydrophilic amino acid or an optionally substituted alkylene, which may share an atom with L A when R L1 is present and 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;
the subscript p′ is an integer of from 1 to 4; and
each D E is an auristatin (Aur) having the formula:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:
R 1 and R 2 each are independently selected from the group consisting of hydrogen (H) and optionally substituted —C 1 -C 8 alkyl; with the proviso that both R 1 and R 2 are not H, unless both of R 3 and R 3′ are not H;
R 3 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
R 3′ is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl, and at least one of R 3 and R 3′ is not H;
R 4 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
R 5 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n —, wherein R a and R b are independently selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
R 7 is selected from the group consisting of H and optionally substituted —C 1 -C 8 alkyl;
each R 8 is independently selected from the group consisting of H, —OH, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —O—(C 1 -C 8 alkyl);
R 12 is selected from the side chains of the group consisting of threonine, serine, asparagine, aspartic acid, glutamine, glutamic acid, homoserine, hydroxyvaline, furyl alanine, threonine(PO 3 H 2 ), pyrazolyl alanine, triazolyl alanine and thiazolyl alanine; or a pharmaceutically acceptable salt or solvate thereof;
wherein the left and right lines of L H indicate covalent attachments to the D E unit and L A , respectively.

2. The Compound of claim 1 , wherein L H comprises a modified peptide, wherein at least one of R L1 , R L2 and R L3 is an amino acid that is covalently linked by a reactive group on its side chain to an adjacent group; or a pharmaceutically acceptable salt or solvate thereof.

3. The Compound of claim 1 , wherein R 12 is the side chain of L-threonine; or a pharmaceutically acceptable salt or solvate thereof.

4. The Compound of claim 1 , wherein L A comprises a maleimide; or a pharmaceutically acceptable salt or solvate thereof.

5. 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 )—CO—; 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, —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 CO—, —CH 2 CH 2 CH 2 CO—, —CH 2 CH 2 CH 2 CO— and —CH 2 CH 2 CH 2 CH 2 CO—; 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 )—CO—; 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, —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 CO—, —CH 2 CH 2 CH 2 CO—, —CH 2 CH 2 CH 2 CO— and —CH 2 CH 2 CH 2 CH 2 CO—; 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 )—CO—; 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, —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 CO—, —CH 2 CH 2 CH 2 CO—, —CH 2 CH 2 CH 2 CO— and —CH 2 CH 2 CH 2 CH 2 CO—; and

an 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).

6. 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 o

Assignees

• Seagen Inc

Inventors

• Doronina Svetlana
• Lyon Robert
• Senter Peter

Classifications

• A61K38/05 Primary

  Dipeptides · CPC title

• A61P37/02

  Immunomodulators · CPC title

• 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

• A61K47/6889 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

• A61P35/00

  Antineoplastic agents · CPC title