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

Abstract

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.

Keywords: FcRn; antibody engineering; monoclonal antibody; recycling; transcytosis.

Figure 1

Three-dimensional view of IgG Fc–FcRn interaction and IgG Fc mutations in mAbs. IgG Fc, FcRn α-chain and β2-microglobulin are shown in dark blue, grey, and dark grey, respectively. IgG Fc–FcRn interaction is shown in red (IgG Fc), yellow (FcRn) and pink (β2-m) spheres. IgG Fc mutations in mAbs are shown as green (YTE), orange (LS) and purple (LA). The figures were made using PyMOL Molecular Graphics System Version 2.5.3 Copyright^© (Schrödinger) and the crystal structure data of IgG–Fc in complex with human FcRn (4N0U). mAbs: monoclonal antibody.

Figure 2

mAb mutations in Fc or Fab IgG. In Fc IgG, mutations can increase binding to FcRn at pH6 only (blue) or at pH6 and pH7 (pink) to increase mAb half-life and biodistribution or endogenous IgG degradation, respectively. FcRn inhibitors (green) can also increase endogenous IgG degradation. In Fab IgG (yellow), mutations can decrease IgG binding at pH6 and can be coupled to Fc IgG mutations (recycling or sweeping mAb) to increase Ag clearance. mAb: monoclonal antibody.