Neonatal fragment crystallizable receptor
Fc fragment of IgG, receptor, transporter, alpha | |||||||
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Identifiers | |||||||
Symbol | FCGRT | ||||||
Chr. 19 q13.3 | |||||||
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The neonatal fragment crystallizable (Fc) receptor (also FcRn, IgG receptor FcRn large subunit p51, or
Interactions of FcRn with IgG and serum albumin
In addition to binding to IgG, FCGRT has been shown to
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
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.[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 (
Targeting FcRn to treat autoimmune disease
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
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- ^ "Ultomiris® (ravulizumab-cwvz) | Alexion". Retrieved 2021-10-03.
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- ^ "Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals". U.S. Food and Drug Administration. 8 December 2021.
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- ^ "argenx Announces U.S. Food and Drug Administration (FDA) Approval of VYVGART™ (efgartigimod alfa-fcab) in Generalized Myasthenia Gravis". Argenx. 17 December 2021.
Further reading
- Dürrbaum-Landmann I, Kaltenhäuser E, Flad HD, Ernst M (April 1994). "HIV-1 envelope protein gp120 affects phenotype and function of monocytes in vitro". Journal of Leukocyte Biology. 55 (4): 545–551. S2CID 44412688.
- Leach JL, Sedmak DD, Osborne JM, Rahill B, Lairmore MD, Anderson CL (October 1996). "Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport". Journal of Immunology. 157 (8): 3317–3322. S2CID 10701519.
- Kivelä J, Parkkila S, Waheed A, Parkkila AK, Sly WS, Rajaniemi H (December 1997). "Secretory carbonic anhydrase isoenzyme (CA VI) in human serum". Clinical Chemistry. 43 (12): 2318–2322. PMID 9439449.
- Vaughn DE, Bjorkman PJ (January 1998). "Structural basis of pH-dependent antibody binding by the neonatal Fc receptor". Structure. 6 (1): 63–73. PMID 9493268.
- West AP, Bjorkman PJ (August 2000). "Crystal structure and immunoglobulin G binding properties of the human major histocompatibility complex-related Fc receptor(,)". Biochemistry. 39 (32): 9698–9708. PMID 10933786.
- Mikulska JE, Pablo L, Canel J, Simister NE (August 2000). "Cloning and analysis of the gene encoding the human neonatal Fc receptor". European Journal of Immunogenetics. 27 (4): 231–240. PMID 10998088.
- Zhu X, Meng G, Dickinson BL, Li X, Mizoguchi E, Miao L, et al. (March 2001). "MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells". Journal of Immunology. 166 (5): 3266–3276. PMID 11207281.
- Ober RJ, Radu CG, Ghetie V, Ward ES (December 2001). "Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies". International Immunology. 13 (12): 1551–1559. PMID 11717196.
- Praetor A, Hunziker W (June 2002). "beta(2)-Microglobulin is important for cell surface expression and pH-dependent IgG binding of human FcRn". Journal of Cell Science. 115 (Pt 11): 2389–2397. PMID 12006623.
- Claypool SM, Dickinson BL, Yoshida M, Lencer WI, Blumberg RS (August 2002). "Functional reconstitution of human FcRn in Madin-Darby canine kidney cells requires co-expressed human beta 2-microglobulin". The Journal of Biological Chemistry. 277 (31): 28038–28050. PMID 12023961.
- Praetor A, Jones RM, Wong WL, Hunziker W (August 2002). "Membrane-anchored human FcRn can oligomerize in the absence of IgG". Journal of Molecular Biology. 321 (2): 277–284. PMID 12144784.
- Shah U, Dickinson BL, Blumberg RS, Simister NE, Lencer WI, Walker WA (February 2003). "Distribution of the IgG Fc receptor, FcRn, in the human fetal intestine". Pediatric Research. 53 (2): 295–301. PMID 12538789.
- Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL (February 2003). "The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan". The Journal of Experimental Medicine. 197 (3): 315–322. PMID 12566415.
- Schilling R, Ijaz S, Davidoff M, Lee JY, Locarnini S, Williams R, Naoumov NV (August 2003). "Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions". Journal of Virology. 77 (16): 8882–8892. PMID 12885906.
- Zhou J, Johnson JE, Ghetie V, Ober RJ, Ward ES (September 2003). "Generation of mutated variants of the human form of the MHC class I-related receptor, FcRn, with increased affinity for mouse immunoglobulin G". Journal of Molecular Biology. 332 (4): 901–913. PMID 12972260.
- Cianga P, Cianga C, Cozma L, Ward ES, Carasevici E (December 2003). "The MHC class I related Fc receptor, FcRn, is expressed in the epithelial cells of the human mammary gland". Human Immunology. 64 (12): 1152–1159. PMID 14630397.
- Ober RJ, Martinez C, Vaccaro C, Zhou J, Ward ES (February 2004). "Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn". Journal of Immunology. 172 (4): 2021–2029. PMID 14764666.
External links
- neonatal+Fc+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)