Monoclonal Antibody Engineering and Design to Modulate FcRn Activities: A Comprehensive Review

Area of Science:

• Immunology
• Pharmacology
• Biochemistry

Background:

• The neonatal Fc receptor (FcRn) plays a crucial role in regulating immunoglobulin G (IgG) homeostasis.
• Understanding FcRn binding mechanisms is vital for developing IgG-based therapeutics like monoclonal antibodies (mAbs) and Fc-fusion proteins.
• FcRn interactions influence drug pharmacokinetics, including half-life and biodistribution.

Purpose of the Study:

• To review the biological mechanisms of pH-dependent FcRn binding.
• To explore how modifying FcRn binding affinity impacts IgG pharmacokinetics and therapeutic outcomes.
• To discuss the applications of targeting FcRn interactions in human therapeutics.

Main Methods:

• Review of literature on FcRn binding, mAb mutations, and anti-FcRn antibodies.
• Analysis of studies investigating the effects of FcRn modulation on IgG half-life and degradation.
• Discussion of pH-dependent modulation of antigen binding in relation to FcRn interactions.

Main Results:

• Mutations near or within the FcRn binding site can enhance FcRn affinity at acidic pH, increasing mAb half-life and improving biodistribution.
• Mutations that increase FcRn affinity at both acidic and neutral pH can block FcRn binding, leading to endogenous IgG degradation.
• Anti-FcRn antibodies are emerging as a strategy for targeted IgG depletion.

Conclusions:

• Targeting IgG-FcRn interactions offers significant potential for therapeutic applications.
• Modulating FcRn binding can be used to enhance the efficacy of IgG-based drugs or induce IgG depletion.
• Further research into FcRn modulation holds promise for advancing human therapeutics.