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

Area of Science:

• Biochemistry
• Immunology
• Protein Engineering

Background:

• Optimizing neonatal Fc receptor (FcRn) binding in the IgG Fc domain is key for antibody pharmacokinetics.
• Therapeutic antibody serum persistence relies on pH-dependent FcRn interaction, but endogenous IgG competition hinders this.
• A novel Fc variant was developed to overcome competition and enhance FcRn-mediated transport.

Purpose of the Study:

• To engineer an Fc variant with precisely modulated FcRn binding kinetics.
• To enhance FcRn-driven intracellular transport and outcompete endogenous IgG.
• To achieve significant improvements in therapeutic antibody serum half-life.

Main Methods:

• Comprehensive site-directed saturation mutagenesis and functional screening of Fc variants.
• Identification and characterization of Fc variants YML and EML with distinct FcRn binding kinetics.
• In vivo validation using human FcRn transgenic mice to assess serum half-life extension.

Main Results:

• The YML Fc variant demonstrated superior FcRn association at acidic pH and rapid dissociation at neutral pH.
• YML extended the serum half-life of trastuzumab by 6.1-fold in human FcRn transgenic mice.
• YML outperformed previously reported Fc-engineered variants in prolonging serum persistence and maintained potent effector functions.

Conclusions:

• A rational Fc engineering framework was established to optimize FcRn binding kinetics, addressing endogenous IgG competition.
• Precise control over pH-dependent FcRn association and dissociation rates is critical for Fc engineering.
• The YML Fc variant represents a next-generation platform for developing biologics with superior pharmacokinetics and therapeutic efficacy.