Targeting the epidermal growth factor receptor using IgM antibodies: towards next generation cancer immunotherapy

Antibodies are subdivided into five immunoglobulin (Ig) isotypes. To date, the most widely used isotype for immunotherapy is IgG. However, IgM, which has up to twelve antigen binding sites, could have higher avidity and therefore could be an attractive candidate for next-generation therapeutic agents. This study investigates the conformational dynamics and interactions of IgM antibodies, particularly Cetuximab and Matuzumab, with the epidermal growth factor receptor (EGFR), a crucial target in cancer therapy. Employing integrative modelling and multiscale molecular dynamics (MD) simulation approaches, we show that the IgM antibodies maintain structural stability with a rigid Fc domain, which is stabilised by glycans, alongside highly dynamic Fab domains. Importantly, our IgM models demonstrate the potential for multivalent binding to multiple EGFRs, surpassing the binding capabilities of equivalent IgG constructs. Rigorous free-energy calculations reveal higher overall binding affinities of IgM antibodies compared to their IgG counterparts. Indeed, IgMs interact more with EGFR due to the higher number of Fab domains. These multivalent interactions, coupled with higher binding affinities and slower dissociation rates, suggest that IgM antibodies can provide prolonged engagement with cancer antigens, potentially enhancing antitumor responses. Collectively, our study supports the potential use of IgM antibodies as more effective therapeutic agents in cancer treatment, offering a promising alternative to overcome the limitations of current antibody therapies.