HYDROPHILIC ANTIBODY-DRUG CONJUGATES
Hydrophilic Linkers, Drug-Linker compounds, Drug-Ligand Conjugate compounds and Ligand-Linkers and methods of making and using the same are provided.
1 - 21 . (canceled)
22 . A method of treating a patient in need thereof, comprising administering to the patient a Drug-Ligand Conjugate Compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
L is a Ligand that specifically binds to a target;
L A is a Ligand attachment component;
L H is an optionally branched hydrophilic linker, each branch of L H 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 to which it is attached;
R L1 is optional and is 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 absent;
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 absent; 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 about 4 to about 20;
the subscript p′ is an integer of from 1 to 4;
and
each D E is an auristatin 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; and
wherein the Drug-Ligand Conjugate has a hydrophilicity index of less than two,
wherein the patient has cancer, an autoimmune disease or an infectious disease and wherein the Ligand of the Drug-Ligand Conjugate Compound specifically binds to a target cell associated with the cancer, autoimmune disease or infectious disease.
23 . The method of claim 22 , wherein the Drug-Ligand Conjugate Compound is administered at a dose of from 0.1 to 10 mg/kg.
24 . The method of claim 22 , wherein:
(a) p is at least 8 and the dose of the Drug-Ligand Conjugate compound administered to the patient is the same or less than that of a two loaded conjugate having the same drug linker; or
(b) p is at least 8 and the dose of the Drug-Ligand Conjugate compound administered to the patient is the same or less than that of a four loaded conjugate having the same drug linker;
wherein the Drug-Ligand Conjugate compound and the two or four loaded conjugate are administered on a comparable schedule.
25 . The method of claim 22 , wherein the patient is human.
26 . (canceled)
27 . A pharmaceutical composition comprising an effective amount of the Drug-Ligand Conjugate Compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein
(a) the Drug-Ligand Conjugate Compound is formulated in a unit dosage injectable form; or
(b) the amount of Drug-Ligand Conjugate Compound administered to a patient is in the range of about 0.1 to about 10 mg/kg of the patient's weight; or
(c) the Drug-Ligand Conjugate Compound is administered intravenously,
wherein the Drug-Ligand Conjugate Compound of formula (I) is:
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
L is a Ligand that specifically binds to a target;
L A is a Ligand attachment component;
L H is an optionally branched hydrophilic linker, each branch of L H 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 to which it is attached;
R L1 is optional and is 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 absent;
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 absent; 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 about 4 to about 20;
the subscript p′ is an integer of from 1 to 4;
and
each D E is an auristatin 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; and
wherein the Drug-Ligand Conjugate has a hydrophilicity index of less than two.
28 . The method of claim 22 , wherein L H comprises a modified peptide, wherein at least one 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.
29 . The method of claim 22 , wherein R 12 is the side chain of L-threonine; or a pharmaceutically acceptable salt or solvate thereof.
30 . The method of claim 22 , wherein p of the Compound is at least 8; or a pharmaceutically acceptable salt or solvate thereof.
31 . The method of claim 22 , wherein p of the Compound is at least 10; or a pharmaceutically acceptable salt or solvate thereof.
32 . The method of claim 22 , wherein p of the Compound is at least 16; or a pharmaceutically acceptable salt or solvate thereof.
33 . The method of claim 22 , wherein L A is a succinimide or hydrolyzed succinimide; or a pharmaceutically acceptable salt or solvate thereof.
34 . The method of claim 22 , wherein L A is succinimide or succinamido diaminopropionic acid, each of which may be hydrolyzed; or a pharmaceutically acceptable salt or solvate thereof.
35 . The method of claim 22 , wherein the p′ of the Compound is 1, and wherein the -L A -L H of the Compound have the formula:
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 the D E and the Ligand unit (L), respectively; and the sulfur atom is from the Ligand unit.
36 . The method of claim 22 , wherein the Compound has a formula selected from the group consisting of:
and pharmaceutically acceptable salts and solvates thereof, wherein S is a sulfur atom from the Ligand unit.
37 . The method of claim 22 , wherein the Ligand unit (L) of the Compound is a protein, polypeptide, or peptide.
38 . The method of claim 22 , wherein the Ligand unit (L) of the Compound is an antibody.
39 . The method of claim 22 , wherein the p′ of the Compound is 1; or a pharmaceutically acceptable salt or solvate thereof.
40 . The method of claim 39 , wherein L H comprises a modified peptide, wherein at least one 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.
41 . The method of claim 39 , wherein R 12 is the side chain of L-threonine; or a pharmaceutically acceptable salt or solvate thereof.
42 . The method of claim 39 , wherein p of the Compound is at least 8; or a pharmaceutically acceptable salt or solvate thereof.
43 . The method of claim 39 , wherein L A is a succinimide or a hydrolyzed succinimide; or a pharmaceutically acceptable salt or solvate thereof.
44 . The method of claim 39 , or a pharmaceutically acceptable salt or solvate thereof, wherein the Ligand unit (L) of the Compound is an antibody.
45 . The method of claim 39 , wherein L A is a succinimide or a hydrolyzed succinimide; or a pharmaceutically acceptable salt or solvate thereof.
46 . The method of claim 39 , or a pharmaceutically acceptable salt or solvate thereof, wherein L A is succinamide or succinamido diaminopropionic acid, each of which may be hydrolyzed.