pH-dependent binding engineering reveals an FcRn affinity threshold that governs IgG recycling

Area of Science:

• Immunology
• Pharmacology
• Biochemistry

Background:

• The neonatal Fc receptor (FcRn) plays a crucial role in IgG homeostasis and pharmacokinetics.
• Modulating the pH-dependent IgG/FcRn interaction is a key strategy for extending antibody half-life.
• Previous studies have generated diverse antibody variants with varied pharmacokinetic profiles.

Purpose of the Study:

• To investigate the impact of varying FcRn binding affinities at neutral pH on IgG pharmacokinetics.
• To identify the critical affinity threshold for FcRn binding at neutral pH that dictates IgG recycling efficiency.
• To understand how FcRn-mediated half-life extension is limited by specific binding parameters.

Main Methods:

• Generation of novel Fc variants with high affinity at acidic pH and varied affinities at neutral pH (pH 7.4).
• Assessment of pharmacokinetic outcomes in human FcRn transgenic mice and cynomolgus monkeys.
• Analysis of IgG recycling efficiency based on FcRn binding affinities at different pH levels.

Main Results:

• Multiple Fc variants with enhanced FcRn affinity at acidic pH demonstrated extended serum half-lives.
• An underappreciated affinity threshold for FcRn binding at neutral pH was identified, crucial for efficient IgG recycling.
• Variants with neutral pH FcRn affinities below this threshold showed efficient recycling and increased serum persistence.
• Increasing neutral pH FcRn affinity beyond the threshold diminished serum persistence.
• Ultra-high FcRn affinity at both acidic and neutral pH resulted in rapid serum clearance.

Conclusions:

• IgG pharmacokinetics are significantly influenced by FcRn binding affinity at both acidic and neutral pH.
• Efficient IgG recycling and extended serum half-life depend on FcRn binding affinities below a specific neutral pH threshold.
• Optimizing FcRn interactions requires a balance between acidic and neutral pH binding affinities to achieve desired pharmacokinetic profiles.