Dissecting FcγR Regulation Through a Multivalent Binding Model

Abstract

Many immune receptors transduce activation across the plasma membrane through their clustering. With Fc{gamma} receptors, this clustering is driven by binding to antibodies of differing affinities that are in turn bound to multivalent antigen. As a consequence of this activation mechanism, accounting for and rationally manipulating IgG effector function is complicated by, among other factors, differing affinities between Fc{gamma}R species and changes in the valency of antigen binding. In this study, we show that a model of multivalent receptor-ligand binding can effectively account for the contribution of IgG-Fc{gamma}R affinity and immune complex valency. This model in turn enables us to make specific predictions about the effect of immune complexes of defined composition. In total, these results enable both rational immune complex design for a desired IgG effector function and the deconvolution of effector function by immune complexes.\n\nSummary pointsO_LIAvidity most prominently modulates low-affinity Fc{gamma}R-immune complex binding\nC_LIO_LIA multivalent binding model can quantitatively predict Fc{gamma}R-immune complex binding\nC_LIO_LIImmune complex avidity has an outsized contribution to Fc{gamma}R multimerizationas compared to binding\nC_LIO_LIA binding model deconvoles and predicts the influence of interventions modulating in vivo Fc{gamma}R-driven effector function\nC_LI