Hydrophilic antibody-drug conjugates

Abstract

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.