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

Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc-FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG-FcRn interactions and their application in human therapeutics.

Automated summary

This review discusses the mutations that regulate FcRn binding and the application of anti-FcRn monoclonal antibodies. Mutations near and outside the FcRn binding site can enhance affinity for FcRn, leading to prolonged half-life and improved biodistribution of monoclonal antibodies. Blocking FcRn binding can result in degradation of endogenous IgG. Anti-FcRn monoclonal antibodies have the potential to deplete endogenous IgG and show promising biological and clinical applications.