Functional Dissection of the Epidermal Growth Factor Receptor Epitopes Targeted by Panitumumab and Cetuximab

摘要: Cetuximab and panitumumab, two antibodies targeting the extracellular domain of epidermal growth factor receptor (EGFR), are major clinical importance particularly in treatment metastatic colorectal cancer. As patients may acquire resistance-mediating mutations within EGFR domain, functional dissection exact binding sites help predict responses. We therefore assessed epitope recognition panitumumab by screening phage-displayed random cyclic 7mer linear 12mer peptide libraries on this antibody. Phage screenings revealed strong, potentially epitope-mimicking consensus motifs targeted panitumumab. A computational approach was used to map sequences back potential region III EGFR. The presumed regions (386)WPEXRT(391) a biochemically similar though discontinuous P349-F352-D355 neighboring loop could be confirmed as part functionally relevant site site-directed mutational analysis. To more accurately differentiate from previously characterized cetuximab epitope, studies were performed broad range additional mutants. Taken together, analysis large, partially overlapping epitopes consisting 17 critical amino acid positions. Four these positions selectively (I467, S468, Q408, H409), whereas another four recognized (W386, E388, R390, T391). In view significance mutations, our data guide decisions selected receiving EGFR-targeted therapies.