Matching of trastuzumab (Herceptin®) epitope mimics onto the surface of Her-2/neu - a new method of epitope definition

As seen with the proto-oncogene Her-2/neu, antibodies targeting different parts of a receptor can have opposing effects. Depending on epitope specificity, in this case, tumor growth can be inhibited - but also enhanced. Therefore, the definition of molecular binding sites is of increasing importance in modern medicine. We here introduce a novel approach for binding site localization, utilizing information obtained by the phage display technique. This is a high throughput screening method for identification of peptide mimics, so called mimotopes, of any binding structure of interest. All target molecules whose structure is available in the RCSB Protein Data Bank can be scanned for mimotope matches on their surface. In this study, we present the matching results of five mimotopes defined for the epitope recognized by trastuzumab (Herceptin®), a humanized monoclonal antibody inhibiting tumor growth, on Her-2/neu. The localization thus obtained corresponds to the known trastuzumab epitope. We therefore suggest the algorithm as a novel way of binding site definition, circumventing co-crystallization experiments.