Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates

Immunoglobulin G (IgG) antibodies coordinate immune effector responses by interacting with effector cells via fragment crystallizable g (Fcg) receptors. The IgG Fc domain directs effector responses through subclass and glycosylation variation. Although each Fc variant has been extensively characterized in isolation, during immune responses, IgG is almost always produced in Fc mixtures. How this influences effector responses has not been examined. Here, we measure Fcg receptor binding to mixed Fc immune complexes. Binding of these mixtures falls along a continuum between pure cases and quantitatively matches a mechanistic model, except for several low-affinity interactions mostly involving IgG2. We find that the binding model provides refined estimates of their affinities. Finally, we demonstrate that the model predicts effector cell-elicited platelet depletion in humanized mice. Contrary to previous views, IgG2 exhibits appreciable binding through avidity, though it is insufficient to induce effector responses. Overall, this work demonstrates a quantitative framework for modeling mixed IgG Fc-effector cell regulation.

Automated summary

In this study, the binding of mixed Fc immune complexes to receptors was measured and found to match a mechanistic model, providing refined estimates of the affinities of Fc variants. Additionally, the model was shown to predict effector cell-elicited platelet depletion in humanized mice. Overall, this work demonstrates a quantitative framework for modeling mixed IgG Fc-effector cell regulation.