Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation

Antibodies can mediate immune recruitment or clearance of immune complexes through the interaction of their Fc domain with cellular Fc receptors. Clustering of antibodies is a key step in generating sufficient avidity for efficacious receptor recognition. However, Fc receptors may be saturated with prevailing, endogenous serum immunoglobulin and this raises the threshold by which cellular receptors can be productively engaged. Here, we review the factors controlling serum IgG levels in both healthy and disease states, and discuss how the presence of endogenous IgG is encoded into the functional activation thresholds for low- and high-affinity Fc receptors. We discuss the circumstances where antibody engineering can help overcome these physiological limitations of therapeutic antibodies. Finally, we discuss how the pharmacological control of Fc receptor saturation by endogenous IgG is emerging as a feasible mechanism for the enhancement of antibody therapeutics. •Antibody effector functions can be mediated through the interaction of their Fc domain with cellular Fc receptors.•Fc receptors may be saturated with prevailing, endogenous serum immunoglobulin raising the threshold for immune activation.•Antibody engineering can help overcome these physiological limitations of therapeutic antibodies.•Pharmacological control of Fc receptor saturation by endogenous IgG is a feasible mechanism for the enhancement of antibody therapeutics.