Design of an Fc Mutation to Abrogate Fcγ Receptor Binding Based on Residue Interaction Network Analysis

Immunoglobulins mediate their immune responses through interactions with Fc γ-receptors (FcγRs) on immune cells, triggering crucial responses such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). While enhancing these interactions can be beneficial, in certain therapeutic scenarios, such as cytokine or receptor blockade therapies, it is critical to reduce FcγR binding to avoid adverse immune reactions. This study aims to design negative mutations in the Fc region to reduce Fcγ receptor binding based on the residue interaction network analysis. The mutation sites of Fc were targeted through betweenness centrality analysis, and mutations were designed by focusing on hydrophobic to hydrophilic residue changes. The negative effect of the designed mutants on binding affinity was verified by previous reports and binding experiments. From this study, we identified a new Fc variant candidate (V263(B)D) that lacks a binding affinity for Fcγ receptors. This research highlights a strategic approach for designing Fc mutations that effectively reduce immune activation, which may be valuable in therapeutic contexts, where immune response moderation is crucial.