Methods and compositions for modulating tumor cell activity

Abstract

Antibodies which target clusterin, a protein involved in the epithelial-to-mesenchymal transition of carcinoma cells, are identified and characterized. The antibodies may be used to modulate tumour cell activity through binding the clusterin.

1 - 30 . (canceled) 
     
     
         31 . A monoclonal antibody or antigen binding fragment capable of specific binding to a β-subunit of human clusterin, wherein said monoclonal antibody binds to an epitope including amino acids 421-443 of the β-subunit of human clusterin more efficiently than a second monoclonal antibody raised against a synthetic peptide including or comprised within said epitope. 
     
     
         32 . The monoclonal antibody or antigen binding fragment of  claim 31 , wherein said monoclonal antibody does not bind significantly to a synthetic peptide including or comprised within said epitope. 
     
     
         33 . The monoclonal antibody or antigen binding fragment of  claim 31 , wherein the monoclonal antibody inhibits migration of cells in an ink clearance assay better than the second antibody. 
     
     
         34 . The monoclonal antibody or antigen binding fragment of  claim 31 , wherein the monoclonal antibody or antigen binding fragment is capable of inhibiting epithelial-to-mesenchymal transitions in carcinoma cells. 
     
     
         35 . A monoclonal antibody or an antigen binding fragment capable of specific binding to a β-subunit of human clusterin, wherein said monoclonal antibody binds to an epitope including amino acids 421-443 of the β-subunit of human clusterin and comprises a) a light chain variable region; and b) a heavy chain variable region comprising a CDR1 as set forth in SEQ ID NO.:6 and a CDR2 as set forth in SEQ ID NO.:7. 
     
     
         36 . The monoclonal antibody or antigen binding fragment of  claim 35 , wherein the antibody or antigen binding fragment comprises a light chain variable region having complementary determining regions identical to those of SEQ ID NO.:8 or SEQ ID NO.:9 and a heavy chain variable having a CDR1 as set forth in SEQ ID NO.:6, a CDR2 as set forth in SEQ ID NO.:7 and a CDR3 as set forth in SEQ ID NO.165. 
     
     
         37 . The monoclonal antibody or antigen binding fragment of  claim 36 , wherein the CDR1 is as set forth in SEQ ID NO.: 85. 
     
     
         38 . The monoclonal antibody or antigen binding fragment of  claim 36 , wherein the CDR2 is as set forth in SEQ ID NO.:119. 
     
     
         39 . The monoclonal antibody or antigen binding fragment of  claim 35 , wherein the antibody or antigen binding fragment comprises a light chain variable region having complementary determining regions identical to those of SEQ ID NO.:10 and a heavy chain variable having a CDR1 as set forth in SEQ ID NO.:6, a CDR2 as set forth in SEQ ID NO.:7 and a CDR3 as set forth in SEQ ID NO.166. 
     
     
         40 . The monoclonal antibody or antigen binding fragment of  claim 39 , wherein the CDR1 is as set forth in SEQ ID NO.:86. 
     
     
         41 . The monoclonal antibody or antigen binding fragment of  claim 39 , wherein the CDR2 is as set forth in SEQ ID NO.:120. 
     
     
         42 . The monoclonal antibody or antigen binding fragment of  claim 35 , wherein the antibody or antigen binding fragment comprises a light chain variable region having complementary determining regions identical to those of SEQ ID NO.:11 and a heavy chain variable having a CDR1 as set forth in SEQ ID NO.:6, a CDR2 as set forth in SEQ ID NO.:7 and a CDR3 as set forth in SEQ ID NO.167. 
     
     
         43 . The monoclonal antibody or antigen binding fragment of  claim 42 , wherein the CDR1 is as set forth in SEQ ID NO.:87. 
     
     
         44 . The monoclonal antibody or antigen binding fragment of  claim 42 , wherein the CDR2 is as set forth in SEQ NO.:121. 
     
     
         45 . A conjugate comprising a) an antibody or antigen binding fragment capable of specific binding to a β-subunit of human clusterin, wherein said monoclonal antibody binds to an epitope including amino acids 421-443 of the β-subunit of human clusterin and b) an agent having anti-tumor activity or a contrast agent. 
     
     
         46 . The conjugate of  claim 45 , wherein the agent having anti-tumor activity is a toxin. 
     
     
         47 . A pharmaceutical composition comprising the antibody or antigen binding fragment of  claim 31 . 
     
     
         48 . A pharmaceutical composition comprising the antibody or antigen binding fragment of  claim 35 . 
     
     
         49 . A pharmaceutical composition comprising the conjugate of  claim 45 . 
     
     
         50 . The pharmaceutical composition, wherein the agent having anti-tumor activity is a toxin.