Antibody drug conjugates (adcs) having enzymatically cleavable groups

Abstract

The invention relates to novel binder-drug conjugates (ADCs) having improved properties, to active metabolites of these ADCs and to processes for their preparation. The present invention furthermore relates to the use of these conjugates for the treatment and/or prevention of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases.

1 - 24 . (canceled) 
     
     
         25 . An antibody-drug conjugate of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         AK is an antibody or an antigen-binding antibody fragment thereof; 
         n is a number from 1 to 50; 
         X 1  is N, 
         X 2  is N and 
         X 3  is C; 
       
       or
 X 1  is N, 
 X 2  is C and 
 X 3  is N; 
 
       or
 X 1  is CH or CF, 
 X 2  is C and 
 X 3  is N; 
 
       or
 X 1  is NH, 
 X 2  is C and 
 X 3  is C; 
 
       or
 X 1  is CH, 
 X 2  is N and 
 X 3  is C; 
 R 1  is methyl; 
 R 2  is methyl, ethyl, —CH 2 —CH(CH 3 ) 2 , —CH 2 —C(═O)OH or isopropyl; 
 R 3  is methyl, ethyl, —CH 2 —CH(CH 3 ) 2  or —CH 2 —C(═O)—NH 2 ; and 
 M is the group
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)—COOH, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —W, 
 #—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)—COOH, 
 #—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH, 
 #—C(═O)—CH 2 —W, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 2-8 —C(═O)—###, 
 #—C(═O)—(CH 2 ) 3 —C(═O)—###, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 )—##, or 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 —CH 2 —O) 1-8 —(CH 2 ) 2 —NH—C(═O)—CH 2 —##; 
 wherein: 
 # represents the bond to —NR 1 —; 
 W is the group: 
 
 
       
         
           
           
               
               
           
         
         
           ## represents the bond to a sulfur atom of a cysteine side-chain of the antibody or antigen-binding antibody fragment thereof, and 
           ### represents the bond to a nitrogen atom of a lysine side-chain of the antibody or antigen-binding antibody fragment thereof, 
         
         wherein the antibody or antigen-binding antibody fragment binds to CXCR5. 
       
     
     
         26 . The antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof,
 wherein:   X 1  is CH,   X 2  is C,   X 3  is N;   R 1  is methyl;   R 2  is methyl, —CH 2 —CH(CH 3 ) 2 , —CH 2 —C(═O)OH or isopropyl;   R 3  is methyl, —CH 2 —CH(CH 3 ) 2  or —CH 2 —C(═O)—NH 2 ; and   M is the group:
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)—COOH, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —W, 
 #—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)—COOH, 
 #—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH, 
 #—C(═O)—CH 2 —W, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)—###, 
 #—C(═O)—(CH 2 ) 3 —C(═O)—###, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 )—##, or 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 —CH 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —##. 
   
     
     
         27 . The antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is methyl;   R 3  is methyl, —CH 2 —CH(CH 3 ) 2 , or —CH 2 —C(═O)—NH 2 ;   M is the group
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)—COOH, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)—###; 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W, 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 )—##, or 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 —CH 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 —##. 
   
     
     
         28 . The antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is methyl;   R 3  is —CH 2 —C(═O)—NH 2 ;   M is the group:
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)—###; or 
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W. 
   
     
     
         29 . The antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein:
 n is a number from 1 to 20;   R 2  is methyl;   R 3  is —CH 2 —C(═O)—NH 2 ;   M is the group
 #—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)—###. 
   
     
     
         30 . The antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         AK1 is the antibody or antigen-binding fragment thereof, which is attached via a sulfur atom of a cysteine side-chain; 
         AK2 is the antibody or antigen-binding fragment thereof, which is attached via a nitrogen atom of a lysine side-chain; 
         wherein the antibody or antigen-binding antibody fragment binds to CXCR5; and 
         n is a number from 1 to 50. 
       
     
     
         31 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein n is a number from 1 to 20. 
     
     
         32 . The antibody-drug conjugate of  claim 31 , or a pharmaceutically acceptable salt thereof, wherein n is a number from 1 to 8. 
     
     
         33 . The antibody-drug conjugate of  claim 32 , or a pharmaceutically acceptable salt thereof, wherein n is a number from 4 to 8. 
     
     
         34 . The antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof, wherein the antibody or the antigen-binding antibody fragment thereof, after binding to CXCR5, is internalized by the target cell through the binding. 
     
     
         35 . A pharmaceutical composition comprising at least one antibody-drug conjugate of  claim 25 , or a pharmaceutically acceptable salt thereof, in combination with an inert, non-toxic, pharmaceutically suitable auxiliary. 
     
     
         36 . The antibody-drug conjugate of  claim 25 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         37 . The antibody-drug conjugate of  claim 36 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         38 . The antibody-drug conjugate of  claim 36 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         39 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The antibody-drug conjugate of  claim 39 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         41 . The antibody-drug conjugate of  claim 40 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         42 . The antibody-drug conjugate of  claim 40 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         43 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The antibody-drug conjugate of  claim 43 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         45 . The antibody-drug conjugate of  claim 44 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         46 . The antibody-drug conjugate of  claim 44 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         47 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         48 . The antibody-drug conjugate of  claim 47 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         49 . The antibody-drug conjugate of  claim 48 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         50 . The antibody-drug conjugate of  claim 48 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         51 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         52 . The antibody-drug conjugate of  claim 51 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         53 . The antibody-drug conjugate of  claim 52 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         54 . The antibody-drug conjugate of  claim 52 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         55 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         56 . The antibody-drug conjugate of  claim 55 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         57 . The antibody-drug conjugate of  claim 56 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         58 . The antibody-drug conjugate of  claim 56 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         59 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         60 . The antibody-drug conjugate of  claim 59 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         61 . The antibody-drug conjugate of  claim 60 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         62 . The antibody-drug conjugate of  claim 60 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         63 . The antibody-drug conjugate of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         64 . The antibody-drug conjugate of  claim 63 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 93, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 94; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 96, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 97, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 98. 
     
     
         65 . The antibody-drug conjugate of  claim 64 , wherein the variable heavy chain comprises SEQ ID NO: 91 and the variable light chain comprises SEQ ID NO: 95. 
     
     
         66 . The antibody-drug conjugate of  claim 64 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 99 and a light chain comprising SEQ ID NO: 100. 
     
     
         67 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 30 . 
     
     
         68 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 39 . 
     
     
         69 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 43 . 
     
     
         70 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 47 . 
     
     
         71 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 51 . 
     
     
         72 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 55 . 
     
     
         73 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 59 . 
     
     
         74 . A method for treatment of a disease associated with CXCR5 expression, comprising administering to a subject in need thereof an effective amount of the antibody-drug conjugate of  claim 63 .