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Characterizing epidermal growth factor receptor trafficking in the presence of antibody-based therapeutics

Due to its common overexpression in epithelial-based cancers and the extensive characterization of its role in tumor growth, the epidermal growth factor receptor (EGFR) has been an attractive target for anti-cancer therapies. Numerous anti-EGFR antibodies are in development and several have been clinically approved. While many monoclonal antibodies (mAbs) against EGFR target the ligand-binding domain to competitively inhibit signaling, the recently-discovered mAb 806 binds to a transitional form of EGFR that is only found in a small percentage of wild-type (wt) receptors but commonly found in the constutively active mutant EGFRvIII. It has thus been proposed that mAb 806 can act synergistically with mAbs targeting the EGFR ligand-binding domain to downregulate EGFR from the cell surface, perhaps via enhanced internalization due to crosslinking. Through trafficking experiments combining mAb 806 with the competitive ligand inhibitor mAb 225, the efficacy and underlying mechanisms of combination antibody treatment will be explored. Coupled with the development of a computational model for receptor crosslinking in the presence of multiple drugs, the trafficking experiments will identify successful strategies for downregulation of wtEGFR and EGFRvIII and will inform the development of the next generation of anti-EGFR antibody-based therapeutics.