Neonatal fragment crystallizable receptor
The neonatal fragment crystallizable (Fc) receptor is a protein that is encoded by the FCGRT gene.
It is an IgG Fc receptor which is similar in structure to the MHC class I molecule.
FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother’s milk, leading to its name as the neonatal Fc receptor.
In humans, FcRn is present in the placenta where it transports mother’s IgG to the growing fetus.
FcRn has also been shown to play a role in regulating IgG and serum albumin turnover.
Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF, and down-regulated by IFN-γ.
FCGRT has been shown to interact with human serum albumin.
FcRn-mediated transcytosis of IgG across epithelial cells is possible because FcRn binds IgG at acidic pH (<6.5) but not at neutral or higher pH.
The binding site for FcRn on involves in the interaction of relatively well conserved histidine residues on IgG
FcRn-mediated recycling and transcytosis of IgG and serum albumin FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation of these proteins in endothelial cells and bone-marrow derived cells.
FcRn antagonists reduce the half-life of circulating IgG by blocking IgG physiological recycling, subjecting circulating IgG auto antibodies to lysosomal destruction
Diverse roles for FcRn in various organs: FcRn is expressed on antigen-presenting leukocytes such as dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.
In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.
Current studies are investigating FcRn in the liver because there are relatively low concentrations of both IgG and albumin in liver bile despite high concentrations in the blood.
FcRn antagonists have been approved for generalized myasthenia gravis and are under investigation for multiple indications in immuno hematology, including ITP.
FcRn is as a central regulator of IgG levels led to the engineering of IgG-FcRn interactions to increase in vivo persistence of IgG.
The half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has been approved for the treatment of autoimmunity and a half-life extended antibody cocktail (Evusheld) is used for the prophylaxis of SARS-CoV2.
Several drugs on the market that have Fc portions fused to the effector proteins in order to increase their half-lives through FcRn-mediated recycling: Amevive (alefacept), Arcalyst (rilonacept), Enbrel (etanercept), Nplate (romiplostim), Orencia (abatacept) and Nulojix (belatacept).
Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.
Multiple autoimmune disorders are caused by the binding of IgG to self antigens.
Since FcRn extends IgG half-life in the circulation, it can also confer long half-lives on these pathogenic antibodies and promote autoimmune disease.
Therapies seek to disrupt the IgG-FcRn interaction to increase the clearance of disease-causing IgG autoantibodies from the body.
The infusion of intravenous immunoglobulin (IVIg) to saturate FcRn’s IgG recycling capacity and proportionately reduce the levels of disease-causing IgG autoantibody binding to FcRn, thereby increasing disease-causing IgG autoantibody removal.
Another strategy is the blocking the binding of IgG to FcRn by delivering antibodies that bind with high affinity to this receptor through their Fc region or variable regions.
These engineered Fc fragments or antibodies are being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and skin blistering diseases (pemphigus), and the Fc-based inhibitor, efgartigimod, for the treatment of generalized myasthenia gravis.