Pharmacological Targeting of Fc Receptor and FcRn Pathways: Therapeutic Antibody Engineering in Immune-Mediated Disorders.

The Fc domain of therapeutic antibodies is a major pharmacological determinant of efficacy, safety, and disposition because it governs interactions with Fc receptors and the neonatal Fc receptor (FcRn). Advances in Fc engineering have enabled the rational modulation of antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, complement activation, and IgG recycling, thereby improving the pharmacodynamic and pharmacokinetic profiles of antibody-based biologics. In this review, we discuss the structural basis of Fc-mediated signaling and summarize how FcγR- and FcRn-directed engineering strategies are being applied across cancer, autoimmune disease, allergy, and selected chronic inflammatory conditions. Particular emphasis is placed on the pharmacological consequences of Fc glycoengineering, Fc silencing or enhancement, and FcRn antagonism, as well as on clinically advanced agents that illustrate these principles in practice. We also address translational challenges, including receptor polymorphism, tissue-specific response variability, immunogenicity, and developability. Overall, Fc engineering has emerged as a central pharmacological strategy for optimizing next-generation antibody therapeutics.