Neonatal Fc receptor and IgG-based therapeutics

Abstract

The majority of potent new biologics today are IgG-based molecules that have demonstrated tissue-targeting specificity with favorable clinical response. Several factors determine the efficacy of these products, including target specificity, serum half-life and effector functions via complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity or drug conjugates. In this review, we will focus on the interaction between therapeutic antibody and neonatal Fc receptor (FcRn), which is one of the critical factors in determining the circulating antibody half-life. Specifically, we will review the fundamental biology of FcRn, FcRn functions in various organs, Fc mutations designed to modulate binding to FcRn, IgG-based therapeutics that directly exploit FcRn functions and tools and strategies used to study FcRn-IgG interactions. Comprehensive understanding of FcRn-IgG interactions not only allows for development of effective therapeutics, but also avoidance of potential adverse effects.

Figure 1

FcRn mediates bidirectional transport and membrane recycling of IgG in epithelial cells. IgG is believed to enter the cell by fluid phase pintocytosis (assuming neutral pH condition) and does not bind to FcRn until the endosome is acidified. However, in the duodenum, the acidic luminal environment may allow IgG to bind to FcRn at the apical membrane surface before endocytosis. Two FcRn bind to a single IgG molecule. IgG may be transcytosed to the opposite membrane surface or recycled back to the same membrane surface. The exact intracellular pathway is believed to differ between cells. IgG is dissociated from FcRn at the membrane surface at neutral pH.

Figure 2

Mutations in amino acid residues in the Fc region to enhance FcRn affinity. Diagram of the Fc portion of human IgG1 (protein data bank (PDB) ID: 1DN2) was generated using RasMol (OpenRasMol). FcRn binds at the CH2–CH3 hinge region of Fc at I253, H310, H430, and to a lesser extent H433 and Y436.– Amino acid residues near the Fc hinge region mutated to increase binding to FcRn are grouped in colors according to the various combination listed in Table 1.