Neonatal fragment crystallizable receptor

The neonatal fragment crystallizable (Fc) receptor (also FcRn, IgG receptor FcRn large subunit p51, or

FcRn is expressed on antigen-presenting leukocytes such as dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.[14] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.^[28][29] 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.^[30][31] Studies have also shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.^[32]

Half-life extension of therapeutic proteins

The identification of FcRn as a central regulator of IgG levels^[9] led to the engineering of IgG-FcRn interactions to increase in vivo persistence of IgG.^[11][33] For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has been approved for the treatment of autoimmunity^[34] and a half-life extended antibody cocktail (Evusheld) with 'YTE' mutations^[35] is used for the prophylaxis of SARS-CoV2.^[36] Engineering of albumin-FcRn interactions has also generated albumin variants with increased in vivo half-lives.^[37] It has also been shown that conjugation of some drugs to the Fc region of IgG or serum albumin to generate fusion proteins significantly increases their half-life.^[38][39][40]

There are 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. They include: Amevive (

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.[42]^[43][44] Therapies seek to disrupt the IgG-FcRn interaction to increase the clearance of disease-causing IgG autoantibodies from the body.^[33] One such therapy is 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.^[43][45][46] More recent approaches involve the strategy of blocking the binding of IgG to FcRn by delivering antibodies that bind with high affinity to this receptor through their Fc region^[47][44][48] or variable regions.^[49][50][51] 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),^{[52][53][54][55]} and the Fc-based inhibitor, efgartigimod, based on the 'Abdeg' technology^[47] was recently approved (as 'Vyvgart') for the treatment of generalized myasthenia gravis in December 2021.^[56]

References