Pyrrolobenzodiazepine-antibody conjugates

Abstract

The present invention relates to pyrrolobenzodiazepines (PBDs) having a labile protecting group in the form of a linker to an antibody.

1 - 138 . (canceled) 
     
     
         139 . A conjugate of formula (I):
   Ab-(DL) p   (I)
   wherein:   Ab is an antibody that binds to KAAG1 or Mesothelin;   DL is   
       
         
           
           
               
               
           
         
         wherein: 
         X is selected from the group comprising: a single bond, —CH 2 — and —C 2 H 4 —; 
         n is from 1 to 8; 
         m is 0 or 1; 
         R 7  is either methyl or phenyl; 
         when there is a double bond between C2 and C3, R 2  is selected the group consisting of: 
         (ia) C 5-10  aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, alkoxy, carboxy, C 1-7  alkyl, C 3-7  heterocyclyl, bis-oxy-C 1-3  alkylene, and —C(═O)OR, wherein R is a C 1-7  alkyl group, a C 3-20  heterocyclyl group, or a C 5-20  aryl group; 
         (ib) C 1-5  saturated aliphatic alkyl; 
         (ic) C 3-6  saturated cycloalkyl; 
         (id) 
       
       
         
           
           
               
               
           
         
       
       wherein each of R 21 , R 22  and R 23  are independently selected from H, C 1-3  saturated alkyl, C 2-3  alkenyl, C 2-3  alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2  group is no more than 5;
 (ie) 
 
       
         
           
           
               
               
           
         
       
       wherein one of R 25a  and R 25b  is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
 (if) 
 
       
         
           
           
               
               
           
         
       
       where R 24  is selected from: H; C 1-3  saturated alkyl; C 2-3  alkenyl; C 2-3  alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
 when there is a single bond between C2 and C3, R 2  is 
 
       
         
           
           
               
               
           
         
         where R 26a  and R 26b  are independently selected from H, F, C 1-4  saturated alkyl, C 2-3  alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4  alkyl amido and C 1-4  alkyl ester; or, when one of R 26a  and R 26b  is H, the other is selected from nitrile and a C 1-4  alkyl ester; 
         when there is a double bond between C2′ and C3′, R 12  is selected the group consisting of: 
         (iia) C 5-10  aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, alkoxy, carboxy, C 1-7  alkyl, C 3-7  heterocyclyl, bis-oxy-C 1-3  alkylene, and —C(═O)OR, wherein R is a C 1-7  alkyl group, a C 3-20  heterocyclyl group, or a C 5-20  aryl group; 
         (iib) C 1-5  saturated aliphatic alkyl; 
         (iic) C 3-6  saturated cycloalkyl; 
         (iid) 
       
       
         
           
           
               
               
           
         
       
       wherein each of R 31 , R 32  and R 33  are independently selected from H, C 1-3  saturated alkyl, C 2-3  alkenyl, C 2-3  alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12  group is no more than 5;
 (iie) 
 
       
         
           
           
               
               
           
         
       
       wherein one of R 35a  and R 35b  is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
 (iif) 
 
       
         
           
           
               
               
           
         
       
       where R 34  is selected from: H; C 1-3  saturated alkyl; C 2-3  alkenyl; C 2-3  alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
 when there is a single bond between C2′ and C3′, R 12  is 
 
       
         
           
           
               
               
           
         
       
       where R 36a  and R 36b  are independently selected from H, F, C 1-4  saturated alkyl, C 2-3  alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4  alkyl amido and C 1-4  alkyl ester; or, when one of R 36a  and R 36b  is H, the other is selected from nitrile and a C 1-4  alkyl ester;
 and p is from 1 to 8. 
 
     
     
         140 . The conjugate according to  claim 139 , wherein X is —CH 2 —. 
     
     
         141 . The conjugate according to  claim 139 , wherein n is:
 i) 1 to 4; or   ii) 2.   
     
     
         142 . The conjugate according to  claim 139 , wherein there is a double bond between C2 and C3, and R 2  is a C 1-5  saturated aliphatic alkyl group. 
     
     
         143 . The conjugate according to  claim 142 , wherein R 2  is methyl, ethyl or propyl. 
     
     
         144 . The conjugate according to  claim 139 , wherein there is a double bond between C2 and C3, and R 2  is:
 (a) phenyl, which bears one to three substituent groups, wherein the substituents may be selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or   (b) cyclopropyl; or   (c) a group of formula:   
       
         
           
           
               
               
           
         
         wherein the total number of carbon atoms in the R 2  group is no more than 3; or 
         (d) the group: 
       
       
         
           
           
               
               
           
         
       
       or
 (e) a group of formula: 
 
       
         
           
           
               
               
           
         
         wherein R 24  is selected from H and methyl. 
       
     
     
         145 . The conjugate according to  claim 139 , wherein there is a single bond between C2 and C3, R 2  is 
       
         
           
           
               
               
           
         
       
       and
 (a) R 26a  and R 26b  are both H; or 
 (b) R 26a  and R 26b  are both methyl; or 
 (c) one of R 26a  and R 26b  is H, and the other is selected from C 1-4  saturated alkyl, C 2-3  alkenyl, which alkyl and alkenyl groups are optionally substituted. 
 
     
     
         146 . The conjugate according to  claim 139 , wherein there is a double bond between C2′ and C3′, and R 12  is a C 1-5  saturated aliphatic alkyl group. 
     
     
         147 . The conjugate according to  claim 146 , wherein R 12  is methyl, ethyl or propyl. 
     
     
         148 . The conjugate according to  claim 139 , wherein there is a double bond between C2′ and C3′, and R 12  is:
 (a) phenyl, which bears one to three substituent groups, wherein the substituents are selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or 
 (b) cyclopropyl; or 
 (c) a group of formula: 
 
       
         
           
           
               
               
           
         
         wherein the total number of carbon atoms in the R 12  group is no more than 3; or 
         (d) the group: 
       
       
         
           
           
               
               
           
         
       
       or
 (e) a group of formula: 
 
       
         
           
           
               
               
           
         
         wherein R 34  is selected from H and methyl. 
       
     
     
         149 . The conjugate according to  claim 139 , wherein there is a single bond between C2′ and C3′, R 12  is 
       
         
           
           
               
               
           
         
       
       and
 (a) R 36a  and R 36b  are both H; or 
 (b) R 36a  and R 36b  are both methyl; or 
 (c) one of R 36a  and R 36b  is H, and the other is selected from C 1-4  saturated alkyl, C 2-3  alkenyl, which alkyl and alkenyl groups are optionally substituted. 
 
     
     
         150 . The conjugate according to  claim 139 , wherein DL is: 
       
         
           
           
               
               
           
         
       
     
     
         151 . The conjugate according to  claim 139  wherein, when the antibody binds to KAAG1:
 i) the antibody comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO:107, a VH CDR2 with the amino acid sequence of SEQ ID NO:106, and a VH CDR1 with the amino acid sequence of SEQ ID NO:105; 
 ii) the antibody comprises a VH domain having the sequence of SEQ ID NO:101; 
 iii) the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO:110, a VL CDR2 with the amino acid sequence of SEQ ID NO:109, and a VL CDR1 with the amino acid sequence of SEQ ID NO:108; 
 iv) the antibody comprises a VL domain having the sequence of SEQ ID NO: 102; 
 v) the antibody comprises a VL domain having the sequence of SEQ ID NO: 113; 
 vi) the antibody comprises a VL domain having the sequence of SEQ ID NO: 115; 
 vii) the antibody in an intact antibody; 
 viii) the antibody comprises a heavy chain having the sequence of SEQ ID NO:103, or a heavy chain having the sequence of SEQ ID NO:111; 
 ix) the antibody comprises a light chain having the sequence of SEQ ID NO: 104; 
 x) the antibody comprises a light chain having the sequence of SEQ ID NO: 114; or 
 xi) the antibody comprises a light chain having the sequence of SEQ ID NO: 116. 
 
     
     
         152 . The conjugate according to  claim 139 , wherein, when the antibody binds to Mesothelin:
 i) the antibody comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO:207, a VH CDR2 with the amino acid sequence of SEQ ID NO:206, and a VH CDR1 with the amino acid sequence of SEQ ID NO:205;   ii) the antibody comprises a VH domain having the sequence of SEQ ID NO:201;   iii) the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO:210, a VL CDR2 with the amino acid sequence of SEQ ID NO:209, and a VL CDR1 with the amino acid sequence of SEQ ID NO:208;   iv) the antibody comprises a VL domain having the sequence of SEQ ID NO:202;   v) the antibody comprises a heavy chain having the sequence of SEQ ID NO:203, or a heavy chain having the sequence of SEQ ID NO:211;   vi) the antibody comprises a light chain having the sequence of SEQ ID NO:204;   vii) the antibody comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO:218, a VH CDR2 with the amino acid sequence of SEQ ID NO:217, and a VH CDR1 with the amino acid sequence of SEQ ID NO:216;   viii) the antibody comprises a VH domain having the sequence of SEQ ID NO:212;   ix) the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO:221, a VL CDR2 with the amino acid sequence of SEQ ID NO:220, and a VL CDR1 with the amino acid sequence of SEQ ID NO:219;   x) the antibody comprises a VL domain having the sequence of SEQ ID NO:213;   xi) the antibody in an intact antibody;   xii) the antibody comprises a heavy chain having the sequence of SEQ ID NO:214, or a heavy chain having the sequence of SEQ ID NO:222; or   xiii) the antibody comprises a light chain having the sequence of SEQ ID NO:215.   
     
     
         153 . The conjugate according to  claim 139 , wherein, when the antibody binds to Mesothelin:
 i) the antibody comprises a VH domain having a VH CDR3 with the amino acid sequence of SEQ ID NO:229, a VH CDR2 with the amino acid sequence of SEQ ID NO:228, and a VH CDR1 with the amino acid sequence of SEQ ID NO:227;   ii) the antibody comprises a VH domain having the sequence of SEQ ID NO:223;   iii) the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO:232, a VL CDR2 with the amino acid sequence of SEQ ID NO:231, and a VL CDR1 with the amino acid sequence of SEQ ID NO:230;   iv) the antibody comprises a VL domain having the sequence of SEQ ID NO: 224;   v) the antibody comprises a heavy chain having the sequence of SEQ ID NO:225, or a heavy chain having the sequence of SEQ ID NO:233;   vi) the antibody comprises a light chain having the sequence of SEQ ID NO:226;   vii) the antibody comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO:240, a VH CDR2 with the amino acid sequence of SEQ ID NO:239, and a VH CDR1 with the amino acid sequence of SEQ ID NO:238;   viii) the antibody comprises a VH domain having the sequence of SEQ ID NO:234;   ix) the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO:243, a VL CDR2 with the amino acid sequence of SEQ ID NO:242, and a VL CDR1 with the amino acid sequence of SEQ ID NO:241;   x) the antibody comprises a VL domain having the sequence of SEQ ID NO:235;   xi) the antibody in an intact antibody;   xii) the antibody comprises a heavy chain having the sequence of SEQ ID NO:236, or a heavy chain having the sequence of SEQ ID NO:244; or   xiii) the antibody comprises a light chain having the sequence of SEQ ID NO:237.   
     
     
         154 . A composition comprising a mixture of the conjugates as defined in  claim 139  wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is 1 to 4. 
     
     
         155 . The conjugate according to  claim 139 , for use in therapy. 
     
     
         156 . The conjugate according to  claim 139 , for use in the treatment of a proliferative disease in a subject. 
     
     
         157 . The conjugate for use according to  claim 156 , wherein the disease is cancer. 
     
     
         158 . The conjugate for use according to  claim 157 , wherein, when the antibody binds to KAAG1, the cancer is a cancer selected from the group consisting of: ovarian, breast, prostate and renal cancer. 
     
     
         159 . The conjugate for use according to  claim 157 , wherein, when the antibody binds to Mesothelin, the cancer is a cancer selected from the group consisting of: mesothelioma, lung cancer, ovarian cancer and pancreatic cancer. 
     
     
         160 . A pharmaceutical composition comprising the conjugate of  claim 139 , and a pharmaceutically acceptable diluent, carrier or excipient, optionally wherein the pharmaceutical composition further comprises a therapeutically effective amount of a chemotherapeutic agent.