Antibody drug conjugates

Abstract

The present disclosure provides antibody drug conjugates comprising STING modulators. Also provided are compositions comprising the antibody drug conjugates. The compounds and compositions are useful for stimulating an immune response in a subject in need thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 a is an integer from 1 to 20; 
 Ab is an anti-CCR2 antibody, anti-CCR2 antibody fragment, or an anti-CCR2 antigen-binding fragment; 
 D is a modulator of STING activity comprising an amino group on a guanine base, a guanine base derivative, an adenine base, or an adenine base derivative; and 
 L is a linker that, is covalently bonded to Ab; and is also covalently bonded to said amino group on D. 
 
     
     
         2 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein D-L is represented by the formula (Ia): 
       
         
           
           
               
               
           
         
       
       wherein:
    denotes the point of attachment to Ab; 
 b is an integer from 1 to 20; 
 m is 0, 1, 2, 3, or 4; 
 n is 0 or 1; 
 each R 1  is independently selected from C 1 -C 4 alkyl, O—C 1 -C 4 alkyl, and halogen; 
 R 2  is selected from C 1 -C 4 alkyl and —(CH 2 CH 2 O) s —CH 3 ; wherein s is an integer from 1 to 10; 
 R 3  and R 3′  are each independently selected from hydrogen and C 1 -C 3 alkyl; and 
 L 1  is a cleavable linker fragment. 
 
     
     
         3 . (canceled) 
     
     
         4 . A compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
 m is 0;   n is 0; and   R 3  and R 3′  are each hydrogen.   
     
     
         5 . A compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein L 1  is 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment to the nitrogen atom of formula (Ia); 
    is the point of attachment to Ab; 
 t is an integer from 1 and 10; 
 W is absent or a self-immolative group; 
 Z is absent or a peptide of 2 to 5 amino acids; 
 U and U′ are independently absent or a spacer; and 
 Q is a heterobifunctional group; 
 
       provided that W and Z are not both absent. 
     
     
         6 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein W is a self-immolative group selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment to the carbonyl group; and 
    is the point of attachment to Z. 
 
     
     
         7 . (canceled) 
     
     
         8 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein W is 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment to the carbonyl group, and 
    is the point of attachment to Z. 
 
     
     
         9 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Z is a peptide capable of being enzymatically cleaved. 
     
     
         10 .- 11 . (canceled) 
     
     
         12 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Z is Ala-Val or Val-Ala. 
     
     
         13 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein U′ is absent and U is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment to Z; 
    is the point of attachment to Q; 
 p is an integer from 1 to 6; 
 q is an integer from 1 to 20; 
 X is O or —CH 2 —; and 
 each r is independently 0 or 1. 
 
     
     
         14 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein U′ is absent and U is: 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment to Z; 
    is the point of attachment to Q; 
 p is an integer from 1 to 6; 
 q is an integer from 1 to 20. 
 
     
     
         15 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Q is a heterobifunctional group which is attached to U′ or, when U′ is absent, is attached to Ab through chemical or enzyme-mediated conjugation. 
     
     
         16 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Q is selected from 
       
         
           
           
               
               
           
         
       
       wherein
    is the point of attachment to U or, when U is absent, the point of attachment to Z; and 
    is the point of attachment to U′, or, when U′ is absent, the point of attachment to Ab. 
 
     
     
         17 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein Q is: 
       
         
           
           
               
               
           
         
       
       wherein:
    is the point of attachment to U or, when U is absent, the point of attachment to Z; and
    is the point of attachment to U′, or, when U′ is absent, the point of attachment to Ab. 
 
 
     
     
         18 . A compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein t is 1. 
     
     
         19 . A compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2  is —CH 3 , and R 3  and R 3′  are each hydrogen. 
     
     
         20 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein a is from 2 to 6. 
     
     
         21 . A compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein b is 1. 
     
     
         22 .- 23 . (canceled) 
     
     
         24 . A compound of  claim 1 , wherein D is a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 X 10  is SH or OH; 
 X 20  is SH or OH; 
 Y c  is O, S, or CH 2 ; 
 Y d  is O, S, or CH 2 ; 
 B 100  is a group represented by formula (B 1 -A) or formula (B 1 -B): 
 
       
         
           
           
               
               
           
         
         R 13 , R 14 , R 15 , R 16  and R 17  are each independently a hydrogen atom or a substituent; 
         R 1000  is hydrogen or a bond to the carbonyl group of formula (I); 
         Y 11 , Y 12 , Y 13 , Y 14 , Y 15  and Y 16  are each independently N or CR 1a , wherein R 1a  is hydrogen or a substituent; 
         Z 11 , Z 12 , Z 13 , Z 14 , Z 15  and Z 16  are each independently N or C; 
         R 105  is a hydrogen atom or a substituent; 
         B 200  is a group represented by formula (B 2 -A) or formula (B 2 -B): 
       
       
         
           
           
               
               
           
         
         R 23 , R 24 , R 25 , R 26  and R 27  are each independently a hydrogen atom or a substituent; 
         R 100′  is hydrogen or a bond to the carbonyl group of formula (I); 
         Y 21 , Y 22 , Y 23 , Y 24 , Y 25  and Y 26  are each independently N or CR 2a , wherein R 2a  is hydrogen or a substituent; 
         Z 21 , Z 22 , Z 23 , Z 24 , Z 25  and Z 26  are each independently N or C; and 
         R 205  is a hydrogen atom or a substituent; wherein R 105  and R 205  are each independently attached to 2- or 3-position of the 5-membered ring they are attached to respectively; 
         provided that: 
         one of B 100  or B 200  is attached to ‘L’ in formula (I) through the amino group. 
       
     
     
         25 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is a compound of formula (IIIa): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
       B 100  is a group represented by formula (B 1 -A) or formula (B 1 -B): 
       
         
           
           
               
               
           
         
       
       R 13 , R 14 , R 15 , R 16  and R 17  are each independently a hydrogen atom or a substituent; 
       R 1000  is hydrogen or a bond to the carbonyl group of formula (I); 
       Y 11 , Y 12 , Y 13 , Y 14 , Y 15  and Y 16  are each independently N or CR 1a , wherein R 1a  is hydrogen or a substituent; 
       Z 11 , Z 12 , Z 13 , Z 14 , Z 15  and Z 16  are each independently N or C; 
       R 105  is a hydrogen atom or a substituent; 
       B 200  is a group represented by formula (B 2 -A) or formula (B 2 -B): 
       
         
           
           
               
               
           
         
       
       R 23 , R 24 , R 25 , R 26  and R 27  are each independently a hydrogen atom or a substituent; 
       R 100′  is hydrogen or a bond to the carbonyl group of formula (I); 
       Y 21 , Y 22 , Y 23 , Y 24 , Y 25  and Y 26  are each independently N or CR 2a , wherein R 2a  is hydrogen or a substituent; 
       Z 21 , Z 22 , Z 23 , Z 24 , Z 25  and Z 26  are each independently N or C; and 
       R 205  is a hydrogen atom or a substituent; wherein R 105  and R 205  are each independently attached to 2- or 3-position of the 5-membered ring they are attached to respectively; 
       provided that: 
       one of B 100  or B 200  is: 
       
         
           
           
               
               
           
         
       
       wherein: 
       R 18  is hydrogen or C 1-6  alkyl; and 
       R 19  is a halogen atom; 
       and the other is attached to the ‘L’ group in formula (I) through an —NH— group. 
     
     
         26 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is a compound of formula of formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       R 1  and R 2  are each independently a hydroxy group or a halogen atom; 
       B 1  is: 
       
         
           
           
               
               
           
         
       
       R 18  is hydrogen or C 1-6  alkyl; 
       R 19  is a halogen atom; 
       B 2  is: 
       
         
           
           
               
               
           
         
       
       and 
       Q 2  and Q 4  are each independently an oxygen atom or a sulfur atom. 
     
     
         27 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein   is the point of attachment to L. 
     
     
         28 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, of formula (VI): 
       
         
           
           
               
               
           
         
       
       wherein a is an integer from 1 to 6 
     
     
         29 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody or fragment thereof that binds human CCR2 or a portion thereof, and is capable of blocking binding of a chemokine to CCR2 and inhibiting a function of CCR2. 
     
     
         30 . A compound of  claim 29 , or a pharmaceutically acceptable salt thereof, wherein the antibody is selected from the group consisting of monoclonal antibody 1D9 or an antibody which can compete with 1D9 for binding to human CCR2 or a portion of CCR2; MC-21; STI-B020X; UniTI-101; and 4.40A68G. 
     
     
         31 . A compound of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody is monoclonal antibody 1D9 or an antibody which can compete with 1D9 for binding to human CCR2 or a portion of CCR2. 
     
     
         32 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab is a chimeric antibody, a humanized antibody, a human antibody, a mouse antibody, a rat antibody, a goat antibody, or a rabbit antibody. 
     
     
         33 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a light chain CDR1 comprising amino acids 24-39 of SEQ ID NO: 1; a light chain CDR2 comprising amino acids 55-61 of SEQ ID NO: 1; a light chain CDR3 comprising amino acids 94-102 of SEQ ID NO: 1; a heavy chain CDR1 comprising amino acids 31-35 of SEQ ID NO:2; a heavy chain CDR2 comprising amino acids 50-68 of SEQ ID NO:2; and a heavy chain CDR3 comprising amino acids 101-106 of SEQ ID NO:2. 
     
     
         34 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         35 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1. 
     
     
         36 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 2. 
     
     
         37 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1. 
     
     
         38 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1. 
     
     
         39 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab further comprises a heavy chain constant region selected from human immunoglobulins IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2  heavy chain constant regions. 
     
     
         40 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a light chain constant region selected from the group consisting of human immunoglobulins IgGκ and IgGλ light chain constant regions. 
     
     
         41 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab binds to the same epitope as an antibody comprising a variable heavy chain region of SEQ ID NO: 2 and a variable light chain region of SEQ ID NO: 1. 
     
     
         42 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a heavy chain region of SEQ ID NO: 3. 
     
     
         43 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a light chain region of SEQ ID NO: 4. 
     
     
         44 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ab comprises a heavy chain region of SEQ ID NO: 3 and a light chain region of SEQ ID NO: 4. 
     
     
         45 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         46 .- 49 . (canceled) 
     
     
         50 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a compound of  claim 1 . 
     
     
         51 . A method for stimulating an immune response in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a compound of  claim 1 . 
     
     
         52 .- 60 . (canceled)