Structural determinants of IgG1-FcγRIIIa interaction: A comprehensive computational study

Monoclonal antibodies (mAbs) have revolutionized therapeutic strategies in recent decades, with IgG1s being the major class. Their function depends not only on antigen binding but also on effector functions modulated by their interactions with immune receptors, such as FcγRIIIa. This computational study investigates the structural impact of two key elements on IgG1::FcγRIIIa interactions: fucosylation at the conserved N-glycosylation site on Asn297, and the light chain (LC) isotype. As case study, adalimumab and avelumab in afucosylated and fucosylated states were chosen to compare κ and λ commercial antibodies, respectively. Molecular dynamics (MD) simulations revealed differences in the stability and interaction patterns of these mAb::FcγRIIIa complexes. Notably, novel residues involved in FcγRIIIa binding, which had not been previously reported, have been identified, expanding the knowledge of the structural determinants of this interaction. These findings, together with an energetic evaluation of the complexes, demonstrate that while known FcγRIIIa binding residues are essential for receptor recognition, they are not sufficient alone to stabilize the mAb::receptor complex. Importantly, the absence of fucose and the κ-LC isotype contribute to increased binding stability, while the λ-LC isotype and fucosylation introduce structural constraints that reduce the complex stability. These insights reveal that both glycosylation and LC isotype are pivotal in regulating mAbs Fc effector functions, paving the way to new strategies for their design and optimization with a particular attention to antibody-dependent cellular cytotoxicity (ADCC) and with significant implications for drug development and efficacy in antibody-based therapies.