Neonatal Fc receptor (FcRn): a novel target for therapeutic antibodies and antibody engineering

Abstract

The biomedical applications of antibodies as prophylactics, therapeutics and diagnostics are developing rapidly. Neonatal Fc receptor (FcRn) is a major IgG Fc receptor capable of facilitating the translocation of IgG. FcRn can protect IgG from intracellular catabolism, thereby increasing its half-life. In recent decade, the interaction between FcRn and the Fc region has been reported with the focuses on either prolonging the plasma half-life of therapeutic IgG or shortening the half-life of pathogenic IgG. The FcRn-IgG interaction can be altered by modifying the Fc region to change their affinity (increase or decrease), and/or by reducing the Fc fragments of IgG to enhance its penetration into tissues or cells. By over expression of FcRn, the exogenous catabolism can be reduced, meanwhile the circulating IgG level could be enhanced. It has been confirmed in different FcRn over-expressed transgenic mice models, substantial humoral responses against antigens with weak immunogenicity can be mounted. In addition, designing inhibitors for FcRn-IgG interaction is another application prospect for treating IgG-mediated autoimmune diseases. Recent research advancements strengthen the understanding that FcRn is a key and promising drugable target in IgG intervention in the field of antibody engineering.

A comprehensive review of the neonatal Fc receptor and its application in drug delivery

“…(Leach et al, 1996;Palmeira et al, 2012) Lung IgG transport. (Hand and Cantey, 1974;Kuo et al, 2010;Wang et al, 2014) …”

“…In rats, it can be detected in alveoli, but not in humans . Additionally, FcRn can be detected at high levels in tracheal epithelial cells (Wang et al, 2014).…”

Enhanced FcRn-dependent transepithelial delivery of IgG by Fc-engineering and polymerization

“…Therefore, in this study, we established a protocol for an in vitro transcytosis assay based on the human epithelial cell line T84 [12] to compare FcRn-mediated transcellular transport of unlabelled IgG variants under non-inflammatory conditions. We present data showing that Fcpolymerization and the presence of an acidic luminal environment act synergistically with IgG Fc-engineering for improved FcRn binding [46][47][48] to enhance transcellular transport. Such knowledge is fundamental as it will guide the design of novel IgG-based drugs and vaccines tailored for optimal mucosal delivery.…”

Engineered Fc based antibody domains and fragments as novel scaffolds

“…The interactions of the Fc region with FcRn significantly contribute to the exceptionally long serum half-life of IgG1 (about three weeks) compared to that of small-molecule drugs (minutes to hours) [35]. However, due to the unique pH-dependent association of the Fc with FcRn, in which Fc binds with FcRn at the endosomal pH but is released back to circulation at a physiological pH, enhanced affinity does not immediately equate to improved half-life in vivo [36].…”