Small Molecule Drug Conjugates

Abstract

A binding moiety (B) for Carbonic Anhydrase IX (CAIX), the binding moiety comprising:The binding moiety is univalent, bivalent, or multivalent. A targeted therapeutic agent may comprise the binding moiety. The invention also includes a method for treating a disease expressing elevated levels of CAIX by administering the targeted therapeutic agent.

1 - 32 . (canceled) 
     
     
         33 . A pharmaceutical composition comprising a targeted therapeutic agent comprising a compound of formula (I):
   B-L-D  (I),
   
       wherein:
 B is a low molecular weight binding moiety for Carbonic Anhydrase IX (CAIX), wherein said binding moiety comprises a terminal group of formula (T2): 
 
       
         
           
           
               
               
           
         
         D is a drug moiety; and 
         L is a linker group that undergoes cleavage in vivo for releasing said drug moiety in an active form, wherein said linker L comprises a 1,2,3-triazole ring, wherein said drug moiety and binder moiety are linked to 1 and 4 positions of the triazole ring and the 5 position of the triazole ring is also optionally substituted. 
       
     
     
         34 . The pharmaceutical composition according to  claim 33 , wherein said compound is substantially stable to hydrolysis in phosphate buffered saline (PBS) at 37° C. 
     
     
         35 . The pharmaceutical composition according to  claim 33 , wherein said compound has a half-life in mouse serum at 37° C. as determined by HPLC of from about 1 hour to about 50 hours. 
     
     
         36 . The pharmaceutical composition according to  claim 33 , wherein the triazole is substituted at the 4 position by a group R selected from H, halogen, halomethyl, or C1-C7 alkyl or heteroalkyl. 
     
     
         37 . The pharmaceutical composition according to  claim 33 , wherein the binding moiety-linker moiety comprises a terminal group of formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The pharmaceutical composition according to  claim 37 , wherein said linker comprises a polar or charged moiety for improving water solubility of the conjugate. 
     
     
         39 . The pharmaceutical composition according to  claim 38 , wherein said polar or charged moiety is an oligomer comprising from 2 to 10 monomers selected from natural and non-natural amino acids, saccharides, (meth)acrylic acid and salts thereof, hydroxyethyl (meth)acrylate, and ethylene glycol. 
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein said polar or charged moiety is a Cys-Asp-Arg-Asp amino acid oligomer. 
     
     
         41 . The pharmaceutical composition according to  claim 33 , wherein said drug in active form is an antineoplastic chemical compound. 
     
     
         42 . The pharmaceutical composition according to  claim 41 , wherein said drug is a tubulin disruptor. 
     
     
         43 . A pharmaceutical composition comprising a targeted therapeutic agent comprising Formula (II): 
       
         
           
           
               
               
           
         
         wherein MMAE is a drug group of formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         44 . A method for treating a solid tumor expressing Carbonic Anhydrase IX, for example glioblastoma, head and neck cancer, lung cancer, cervical cancer, colorectal cancer or breast cancer, in particular renal cell carcinoma, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to  claim 33 . 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . A method for treating a solid tumor expressing Carbonic Anhydrase IX, for example glioblastoma, head and neck cancer, lung cancer, cervical cancer, colorectal cancer or breast cancer, in particular renal cell carcinoma, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to  claim 43 . 
     
     
         48 . The pharmaceutical composition according to  claim 33  wherein said compound has a half-life in mouse serum at 37° C. as determined by HPLC from about 10 hours to about 50 hours. 
     
     
         49 . (canceled) 
     
     
         50 . The pharmaceutical composition according to  claim 33 , wherein the triazole is substituted at the 4 position by a group R selected from H, methyl or ethyl. 
     
     
         51 . The pharmaceutical composition according to  claim 50 , wherein R is H.