cyrillustan/fcgr-binding

A Multivalent Binding Model for FcgRs

Dissecting FcγR Regulation Through a Multivalent Binding Model

Many immune receptors transduce activation across the plasma membrane through their clustering. With Fcγ receptors, this clustering is driven by binding to antibodies of differing affinity 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, the contribution of differing affinities to multiple FcγRs 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-FcγR 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 rationally designed IgG effector function, or deconvolution of function, in both a forward and reverse manner.

Some key findings

• Avidity most prominently modulates low-affinity FcγR-immune complex binding
• A multivalent binding model can quantitatively predict FcγR-immune complex binding
• Immune complex avidity has an outsized contribution to FcγR multimerization as compared to binding
• A binding model deconvoles and predicts the influence of interventions modulating in vivo FcγR-driven effector function