Hydrophilic antibody-drug conjugates

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 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 )—.

7. 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 OH, —CH 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 and L A , respectively.

8. 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 and L A , respectively.

9. 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:

wherein the left and right wavy lines indicate attachments to D E and L A , respectively.

10. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein

the Compound comprises the formula:

wherein each R 31 is independently selected from the group consisting of —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH, —CH 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 each of the bars indicates attachment to a D E unit.

11. The Compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the Compound comprises the formula:

wherein each of the bars indicates attachment to a D E unit.