Internalizing ErbB2 Antibodies

Abstract

This invention provides novel erbB2-binding internalizing antibodies. The antibodies, designated F5 and C1, specifically bind to c-erbB2 antigen and, upon binding, are readily internalizing into the cell bearing the c-erbB2 marker. Chimeric molecules comprising the F5 and/or C1 antibodies attached to one or more effector molecules are also provided.

What is claimed is: 
     
         1 . An internalizing antibody that specifically binds to an ErbB2 epitope bound by a C1 antibody comprising the amino acid sequence set forth in SEQ ID NO: 2, which internalizing antibody binds to ErbB2 with an affinity of 10 −5 M to 10 −12 M and shares at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. 
     
     
         2 . The internalizing antibody of  claim 1 , wherein the antibody binds to ErbB2 with an affinity of about 100 nM or better. 
     
     
         3 . The internalizing antibody of  claim 1 , wherein the internalizing antibody comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 by no more than 30 residues. 
     
     
         4 . The internalizing antibody of  claim 2 , wherein the antibody comprises a C-terminal cysteine residue. 
     
     
         5 . The internalizing antibody of  claim 4 , wherein the internalizing antibody is coupled to a liposome. 
     
     
         6 . The liposome-coupled antibody of  claim 5 , wherein the liposome bears an external hydrophilic polymer. 
     
     
         7 . The liposome-coupled antibody of  claim 6 , wherein the external hydrophilic polymer is a polyethylene glycol (PEG). 
     
     
         8 . The liposome-coupled antibody of  claim 7 , wherein the antibody is coupled to the liposome through the external hydrophilic polymer. 
     
     
         9 . The liposome-coupled antibody of  claim 8 , wherein the antibody is coupled to the liposome through the polyethylene glycol. 
     
     
         10 . The liposome-coupled antibody of  claim 9 , wherein the liposome is a doxorubicin containing liposome. 
     
     
         11 . The liposome-coupled antibody of  claim 10 , wherein the liposome is taken up by SKBR3 cells in vitro. 
     
     
         12 . A pharmaceutical composition comprising the liposome-coupled antibody of  claim 9  in a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating a HER2 positive carcinoma, the method comprising administering the composition of  claim 12  to a patient suffering from a HER2 positive carcinoma in therapeutically effective dose. 
     
     
         14 . The method of  claim 13 , wherein the composition is administered by single or multiple administrations. 
     
     
         15 . The method of  claim 14 , wherein the composition is administered intravenously. 
     
     
         16 . An internalizing antibody comprising the six CDRs of a C1 antibody comprising the amino acid sequence set forth in SEQ ID NO: 2. 
     
     
         17 . The internalizing antibody of  claim 16 , wherein the antibody is a human antibody.