Human monoclonal antibodies to epidermal growth factor receptor

Abstract

In accordance with the present invention, there are provided fully human monoclonal antibodies against human epidermal growth factor receptor (EGF-r). Nucelotide sequences encoding and amino acid sequences comprising heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences from CDR1 through CDR3, are provided. Hybridomas expressing such immunoglobulin molecules and monoclonal antibodies are also provided. Also provided in accordance with the invention are antibodies that possess one or more of the following functional characteristics: (i) inhibit tyrosine phosphorylation of EGF-r, (ii) do not inhibit EGF-r internalization, (ii) inhibit EGF-r degradation, (iii) inhibition of EGF induced EGF-r degradation, (iv) protect threonine phosphorylation of EGF-r, (v) protect threonine phosphorylation of other molecules, particularly a 62 KD molecule identified by immunoprecipitation, and (vi) inhibit vascular endothelial cell growth factor signal by tumor cells by greater than 50% and endothelial cells by greater than 40% relative to control.

1 . An isolated human antibody that binds to human epidermal growth factor receptor (EGF-r), wherein said antibody: 
 inhibits tyrosine phosphorylation of EGF-r;    is internalized with EGF-r;    inhibits the degradation of EGF-r; and    inhibits the EGF induced degradation of EGF-r.    
     
     
         2 . An isolated human antibody that binds to human epidermal growth factor receptor, wherein said antibody protects threonine phosphorylation of EGF-r.  
     
     
         3 . An isolated human antibody that binds to human epidermal growth factor receptor, wherein said antibody protects threonine phosphorylation of a 63 KD protein.  
     
     
         4 . An isolated human antibody that binds to human epidermal growth factor receptor, wherein said antibody: 
 inhibits VEGF production by tumor cells by greater than 50%; and    inhibits VEGF production by endothelial cells by greater than 40%.    
     
     
         5 . The antibody of  claim 4 , wherein the tumor cells are A431 cells.  
     
     
         6 . The antibody of  claim 4 , wherein the endothelial cells are ECV304 cells.  
     
     
         7 . An isolated human antibody that binds to human epidermal growth factor receptor, wherein said antibody: 
 inhibits tyrosine phosphorylation of EGF-r;    is internalized with EGF-r;    inhibits the degradation of EGF-r;    inhibits the EGF induced degradation of EGF-r;    protects threonine phosphorylation of EGF-r;    protects threonine phosphorylation of a 63 KD protein;    inhibits VEGF production by tumor cells by greater than 50%; and    inhibits VEGF production by endothelial cells by greater than 40%.