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 terminal group of Formula (I): 
       
         
           
           
               
               
           
         
       
       conjugated to said therapeutic agent in a pharmaceutically acceptable carrier, diluent or excipient, wherein said therapeutic agent is linked to Formula I via a linker that undergoes cleavage in vivo and releases said therapeutic agent in an active form at a tumor which expresses CAIX. 
     
     
         34 . The targeted therapeutic agent of  claim 33 , wherein the linker comprises a peptide that is cleavable by a protease that is present in the extracellular matrix of a tumor or that is released after tumor cell death. 
     
     
         35 . The targeted therapeutic agent of  claim 34  wherein said protease is selected from the group consisting of MMP-1, MMP-2, MMP-3, Cathepsin A, Cathepsin B, and Cathepsin C. 
     
     
         36 . The targeted therapeutic agent of  claim 35 , wherein the linker comprises valine-citrulline and is cleavable by Cathepsin B. 
     
     
         37 . The targeted therapeutic agent of  claim 33 , wherein the linker further comprises a self-immolating spacer. 
     
     
         38 . The targeted therapeutic agent of  claim 33 , wherein therapeutic agent is a chemotherapeutic agent selected from an auristatin, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a lexitropsin, a duocarmycin, a topoisomerase inhibitor, a taxane, a puromycin, a dolastatin, a maytansinoid and a vinca alkaloid or a combination of two or more thereof. 
     
     
         39 . The targeted therapeutic agent of  claim 33 , wherein therapeutic agent is a chemotherapeutic agent selected from Erlotinib (TARCEVA®), Bortezomib (VELCADE®), Fulvestrant (FASLODEX®), Sutent (SU11248), Letrozole (FEMARA®), Imatinib mesylate (GLEEVEC®), PTK787/ZK 222584, Oxaliplatin (Eloxatin®), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®), Lapatinib (GSK572016), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006), and Gefitinib (IRESSA®), AG1478, AG1571 (SU 5271; Sugen) or a combination of two or more thereof. 
     
     
         40 . The targeted therapeutic agent of  claim 33 , wherein therapeutic agent is a DNA intercalating agent selected from one or more of acridines, actinomycins, anthracyclines, benzothiopyranoindazoles, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin, actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cis-platin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan and topotecan and pharmaceutically acceptable salts, acids, derivatives or combinations of two or more of any of the above. 
     
     
         41 . A targeted small drug conjugate of Formula II, comprising a terminal group of Formula I, and a linker to a cytotoxic payload, having the structure of Formula II, 
       
         
           
           
               
               
           
         
       
       in a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         42 . The targeted pharmaceutical composition of  claim 41 , wherein said cytotoxic payload remains attached to said binding moiety while in circulation but is released from said SMDC at a tumor site. 
     
     
         43 . The targeted pharmaceutical composition of  claim 41  which causes shrinkage of solid tumors expressing CAIX, selected from glioblastoma, head and neck cancer, lung cancer, cervical cancer, colorectal cancer, breast cancer, and renal cell carcinoma. 
     
     
         44 . The targeted pharmaceutical composition of  claim 41 , wherein solid tumor is a renal carcinoma. 
     
     
         45 . The targeted pharmaceutical composition of  claim 41 , wherein said conjugate is substantially stable to hydrolysis in phosphate buffered saline (PBS) at 37° C. 
     
     
         46 . The targeted pharmaceutical composition of  claim 41 , wherein the linker comprises a peptide that is cleavable by a protease that is present in the extracellular matrix of a tumor or that is released after tumor cell death. 
     
     
         47 . The targeted pharmaceutical composition of  claim 41 , which diffuses out of blood vessels in seconds following administration. 
     
     
         48 . A method for treating a CAIX expressing tumor in a subject in need thereof, comprising administration of an effective amount of the pharmaceutical composition of  claim 33 , said administration causing regression or shrinkage of said tumor. 
     
     
         49 . A method for treating a CAIX expressing tumor in a subject in need thereof, comprising administration of an effective amount of the pharmaceutical composition of  claim 41  said administration causing regression or shrinkage of said tumor. 
     
     
         50 . The method of  claim 49 , wherein said CAIX expressing tumor is selected from glioblastoma, head and neck cancer, lung cancer, cervical cancer, colorectal cancer, breast cancer, and renal cell carcinoma. 
     
     
         51 . The method of  claim 50 , wherein said CAIX expressing tumor is a renal carcinoma.