Neonatal Fc Receptor: From Immunity to Therapeutics

The neonatal Fc receptor (FcRn), also known as the Brambell receptor and encoded by Fcgrt, is a MHC class I like molecule that functions to protect IgG and albumin from catabolism, mediates transport of IgG across epithelial cells, and is involved in antigen presentation by professional antigen presenting cells. Its function is evident in early life in the transport of IgG from mother to fetus and neonate for passive immunity and later in the development of adaptive immunity and other functions throughout life. The unique ability of this receptor to prolong the half-life of IgG and albumin has guided engineering of novel therapeutics. Here, we aim to summarize the basic understanding of FcRn biology, its functions in various organs, and the therapeutic design of antibody- and albumin-based therapeutics in light of their interactions with FcRn

Expression of placental alkaline phosphatase does not correlate with IgG binding, internalization and transcytosis.

The human homologue of FcRn, an IgG Fc receptor expressed in rat villous syncytiotrophoblasts, might be involved in IgG transfer from the maternal to the fetal circulation. However, because the receptor does not bind IgG at the physiological pH of the maternal blood (pH 7.4), FcRn is probably not involved in the initial uptake of IgG. A role in IgG internalization has been suggested for placental alkaline phosphatase (PLAP), which is highly expressed on the apical surface of syncytiotrophoblasts. To determine whether PLAP does indeed have a role in IgG uptake, we analysed the ability of PLAP to bind, internalize and transcytose IgG in BeWo choriocarcinoma cells endogenously expressing the protein, or in Madin-Darby canine kidney (MDCK) cells transfected with the PLAP cDNA. Although PLAP expression in MDCK cells resulted in increased IgG binding to intact cells, binding was not correlated with the level of PLAP expressed in the different cell lines. Furthermore our findings do not support a role for PLAP in IgG endocytosis or transcytosis

N-Glycan Moieties in Neonatal Fc Receptor Determine Steady-state Membrane Distribution and Directional Transport of IgG*S⃞

The neonatal Fc receptor (FcRn) is a major histocompatibility complex class I-related molecule known to protect IgG and albumin from catabolism and transport IgG across polarized epithelial cells in a bidirectional manner. Previous studies have shown species-specific differences in ligand binding, IgG transport direction, and steady-state membrane distribution when expressed in polarized epithelial cells. We hypothesized that these differences may be due to the additional N-glycans expressed on the rat FcRn, because N-glycans have been proposed to function as apical targeting signals, and that two of the N-glycan moieties have been shown to contribute to the IgG binding of rat FcRn. A panel of mutant human FcRn variants was generated to resemble the N-glycan expression of rat FcRn in various combinations and subsequently transfected into Madin-Darby canine kidney II cells together with human β2-microglobulin. Mutant human FcRn clones that contained additional N-glycan side-chain modifications, including that which was fully rodentized, still exhibited specificity for human IgG and failed to bind to mouse IgG. At steady state, the mutant human FcRn with additional N-glycans redistributed to the apical cell surface similar to that of rat FcRn. Furthermore, the rodentized human FcRn exhibited a reversal of IgG transport with predominant transcytosis from an apical-to-basolateral direction, which resembled that of the rat FcRn isoform. These studies show that the N-glycans in FcRn contribute significantly to the steady-state membrane distribution and direction of IgG transport in polarized epithelia