Computational Engineering of a Therapeutic Antibody to Inhibit Multiple Mutants of HER2 Without Compromising Inhibition of the Canonical HER2

Abstract

AbstractGenomic germline and somatic variations may impact drug binding and even lead to resistance. However, designing a different drug for each mutant may not be feasible. In this study, we identified the most common cancer somatic mutations from the Catalogue of Somatic Mutations in Cancer (COSMIC) that occur in structurally characterized binding sites of approved therapeutic antibodies. We found two HER2 mutations, S310Y and S310F, that substantially compromise binding of Pertuzumab, a widely used therapeutics, and lead to drug resistance. To address these mutations, we designed a multi-specific version of Pertuzumab, that retains original function while also bindings these HER2 variants. This new antibody is stable and inhibits HER3 phosphorylation in a cell-based assay for all three variants, suggesting it can inhibit HER2-HER3 dimerization in patients with any of the variants. This study demonstrates how a small number of carefully selected mutations can add new specificities to an existing antibody without compromising its original function, creating a single drug that targets multiple common variants, making a drug that is not personalized yet its activity may be.