Meditopia: Meditope‐Enabled Bonds and their Affinity with Cetuximab

A meditope is a peptide found in the fragment antigen-binding (Fab) region of an antibody, and can be used to bind substances, such as monoclonal antibodies (mAbs) and pharmaceuticals. We centered on four mutations that can increase the affinity between the meditope and the mAb, allowing for a stronger bond. Our focus was on the anti-epidermal growth factor receptor mAb cetuximab, which tracks the overexpression of the epidermal growth factor receptor (EGFR) by cancer cells. Utilizing a meditope, cetuximab can be linked to chemotherapy, creating a more effective treatment that only attacks cancer cells, significantly reducing possible long-term side effects. In this study, yeast display and deep mutational scanning tracked, enhanced, and joined four mutations within the meditope, increasing affinity, or bond strength, for cetuximab 10-fold, from Kd 130 nm to 15 nm. Those mutations led to heightened cetuximab recruitment to EGFR-overexpressing cancer cells, and therefore more efficient targeting of cancer. The methods used in this study can develop other effective meditope-linked monoclonal antibodies and chemotherapy treatments. The Mahtomedi MSOE Center for BioMolecular Modeling MAPS Team will use 3-D modeling and printing technology to examine structure-function relationships of meditope-mAb binding within cetuximab. The visual model will be a valuable tool in developing our story.