The human FcgammaRs interact with antigen-complexed IgG ligands to both activate and modulate a powerful network of inflammatory host-protective effector functions that are key to the normal physiology of immune resistance to pathogens. More than 100 therapeutic monoclonal antibodies (mAbs) are approved or in late stage clinical trials, many of which harness the potent FcgammaR-mediated effector systems to varying degrees. This is most evident for antibodies targeting cancer cells inducing antibody-dependent killing or phagocytosis but is also true to some degree for the mAbs that neutralise or remove small macromolecules such as cytokines or other immunoglobulins. The use of mAb therapeutics has also revealed a “scaffolding” role for FcgammaR which, in different contexts, may either underpin the therapeutic mAb action such as immune agonism or may trigger catastrophic adverse effects. The still unmet therapeutic need in many cancers, inflammatory diseases or emerging infections such as SARS-CoV-2, requires increased effort on the development of improved and novel mAbs. A more mature appreciation of the immunobiology of individual FcgammaR function and the complexity of the relationships between FcgammaRs and antibodies is fuelling efforts to develop more potent “next-gen” therapeutic antibodies. Such development strategies now include focused glycan or protein engineering of the Fc to increase affinity and/or tailor specificity for selective engagement of individual activating FcgammaRs or the inhibitory FcgammaRIIb or alternatively, for the ablation of FcgammaR interaction altogether. This review touches on recent aspects FcgammaR and IgG immunobiology and its relationship to the present and future actions of therapeutic mAbs.
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We thank Halina Trist for assistance with the manuscript. NHMRC, Janina and Bill Amiet Trust, Margaret Walkom Trust and Nancy E. Pendergast Trust, Genmab, for their support.