METHODS AND COMPOSITIONS FOR MODULATING TUMOR CELL ACTIVITY
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.