Impact of Immune Complex Size and Glycosylation on IgG Binding to Human FcγRs

IgG molecules are widely used as therapeutic agents either in the form of intact Abs or as Fc fusion proteins. Although efficient binding of the IgG Fc fragment to cellular Fc gamma Rs may be essential to achieve a high cytolytic activity, it may be advantageous for other applications to limit or abolish this interaction. Genetic or biochemical approaches have been used to generate these non-Fc gamma R-binding IgG variants. By using soluble versions of Fc gamma Rs and monomeric versions of these altered IgG molecules, it was demonstrated that these IgG variants no longer bind to Fc gamma Rs. Importantly, however, these assays do not reflect the physiologic interaction of IgG with low-affinity cellular Fc gamma Rs occurring in the form of multimeric immune complexes. In this study, we investigated how the size of an immune complex can affect the interaction of normal and various versions of potentially non-Fc gamma R-binding IgG variants with cellular Fc gamma Rs. We show that neither the D265A mutation nor EndoS treatment resulting in IgG molecules with only one N-acetylglucosamine and a fucose residue was fully able to abolish the interaction of all IgG subclasses with cellular Fc gamma Rs, suggesting that IgG subclass-specific strategies are essential to fully interfere with human Fc gamma R binding. The Journal of Immunology, 2013, 190: 4315-4323.