Engineering FcRn binding kinetics dramatically extends antibody serum half-life and enhances therapeutic potential

BACKGROUND: Optimizing the IgG Fc domain for neonatal Fc receptor (FcRn) binding is crucial for enhancing antibody pharmacokinetics. The prolonged serum half-life of IgG antibody is governed by its pH-dependent interaction with FcRn, enabling efficient binding at acidic endosomal pH, intracellular trafficking, and release at neutral serum pH. However, a critical yet previously unrecognized challenge in Fc engineering for extending the serum half-life of therapeutic antibodies is the intense competition with endogenous IgG for FcRn binding during intracellular trafficking, which limits FcRn-mediated transport and reduces the serum persistence of therapeutic antibodies. To address this, we developed an Fc variant that precisely modulates pH-dependent FcRn binding kinetics, accelerates FcRn association at acidic pH, and promotes rapid dissociation at neutral pH, thereby enhancing FcRn-drive…