Anti-mesothelin immunoconjugates and uses therefor

Abstract

The present invention provides immunoconjugates composed of antibodies, e.g., monoclonal antibodies, or antibody fragments that bind to mesothelin, that are conjugated to cytotoxic agents, e.g., maytansine, or derivatives thereof, and/or co-administered or formulated with one or more additional anti-cancer agents. The immunoconjugates of the invention can be used in the methods of the invention to treat and/or diagnose and/or monitor cancers, e.g. solid tumors. recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for the membrane-anchored, 40 kDa mesothelin polypeptide, which is overexpressed in several tumors, such as pancreatic and ovarian tumors, mesothelioma and lung cancer cells

1 . An immunoconjugate comprising a cytotoxic agent and an isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for Mesothelin (SEQ ID NO:370), wherein said antibody or functional fragment thereof recognize an epitope of mesothelin that is not masked by another extracellular antigen, such as cancer antigen 125 (CA125). 
     
     
         2 . An immunoconjugate comprising a cytotoxic agent and an isolated antigen-binding region of an antibody according to  claim 1  or a functional fragment thereof. 
     
     
         3 . An immunoconjugate comprising a cytotoxic agent and an isolated antigen-binding region of an antibody according to  claim 2 , wherein said isolated antigen-binding region comprises a CDR region as depicted in Table 7. 
     
     
         4 . An immunoconjugate comprising a cytotoxic agent and an isolated antigen-binding region according to  claim 2 , which comprises a heavy chain or light chain amino acid sequence selected from the group consisting of the
 (i) SEQ ID NO's depicted in table 7; and   (ii) a sequence having at least 60 percent sequence identity in the CDR regions with the CDR regions depicted in SEQ ID NO's depicted in table 7.   
     
     
         5 . An immunoconjugate comprising a cytotoxic agent and an isolated antibody to according to  claim 1 , which is an IgG. 
     
     
         6 . An immunoconjugate comprising a cytotoxic agent and an isolated antigen-binding region according to  claim 2 , comprising one or more of the Sequences as depicted in table 7. 
     
     
         7 . An immunoconjugate comprising a cytotoxic agent and an isolated functional fragment according to  claim 2 , which is a Fab or scFv antibody fragment. 
     
     
         8 . An isolated nucleic acid sequence that encodes an antigen-binding region of a human antibody according to  claim 1  or functional fragment thereof. 
     
     
         9 . A nucleic acid sequence encoding a variable heavy chain of an isolated antibody or functional fragment thereof, which comprises (i) a sequence selected from the group consisting of SEQ ID NOS as depicted in table 7 or (ii) a nucleic acid sequence that hybridizes under high stringency conditions to the complementary strand of SEQ ID NO as depicted in table 7, wherein said antibody or functional fragment thereof is specific for an epitope of Mesothelin. 
     
     
         10 . A vector comprising a nucleic acid sequence according to  claim 9 . 
     
     
         11 . An isolated cell comprising a vector according to  claim 10 . 
     
     
         12 . An isolated cell according to  claim 11 , wherein said cell is bacterial or a mammalian cell. 
     
     
         13 . A pharmaceutical composition comprising an immunoconjugate according to  claim 1 , and a pharmaceutically acceptable carrier or excipient therefore. 
     
     
         14 . A pharmaceutical composition according to  claim 13  for treatment of undesired presence of mesothelin. 
     
     
         15 . An immunoconjugate according to  claim 1 , wherein the cytotoxic agent is maytansinoid or a derivative thereof and wherein the antibody and the cytotoxic agent are linked via a cleavable linker.