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- W1844667028 abstract "14536 Background: Panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), has anti- tumor activity as monotherapy in both preclinical models and clinical trials. The objective of this study was to identify the epitope on EGFR for panitumumab and compare it to that of cetuximab, a chimeric anti-EGFR Ab. Methods: The extracellular domain of EGFR (amino acids 1–618) and domains I, II, III, IV individually were expressed to determine the domain on EGFR that was necessary for panitumumab binding. Chromatography was used to compare the binding affinity of panitumumab vs cetuximab. By flow cytometry and amino acid replacement scanning, the critical residues involved in panitumumab and cetuximab binding for EGFR were determined. Using diffraction data from the panitumumab Fab’2 and published data for cetuximab, crystal structure models of EGFR and the residues determined to be critical for panitumumab or cetuximab binding were built. To evaluate in vitro activity, A549 NSCLC cells were treated with 20μg/ml of panitumumab or cetuximab for 1 hour prior to a 15-minute stimulation with known EGFR ligands (TGF-α, amphiregulin, epiregulin, HB-EGF, betacellulin, and EGF). Inhibition of ligand-induced phosphorylation of EGFR was determined using a specific anti-pEGFR (pY1068) antibody. Results: Truncation analysis by flow cytometry narrowed the binding epitopes of panitumumab and cetuximab to domain III of EGFR. Point mutations revealed that amino acids 349, 355, 412, and 438 were critical for panitumumab and cetuximab binding. A 2.9 Angstrom crystal structure of the panitumumab Fab’2 was solved. Models of the panitumumab-EGFR and cetuximab-EGFR complexes were generated and predicted that the CDRs for both light and heavy chains would be proximal to domain III of EGFR. From in vitro studies, panitumumab and cetuximab can inhibit receptor activation of all known EGFR ligands in A549 NSCLC tumor cells. Conclusion: Panitumumab and cetuximab bind to comparable surface exposed amino acids in domain III of EGFR and inhibit all known EGFR ligands, resulting in inhibition of receptor activation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen Inc." @default.
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- W1844667028 date "2008-05-20" @default.
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- W1844667028 title "Panitumumab and cetuximab epitope mapping and in vitro activity" @default.
- W1844667028 doi "https://doi.org/10.1200/jco.2008.26.15_suppl.14536" @default.
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