Neonatal fragment crystallizable receptor: Difference between revisions

The '''neonatal fragment crystallizable (Fc) receptor''' (also '''FcRn''', '''IgG receptor FcRn large subunit p51''', or [[Francis Brambell|Brambell]] receptor) is a [[protein]] that in humans is encoded by the ''FCGRT'' [[gene]].<ref name="pmid7964511">{{cite journal | vauthors = Story CM, Mikulska JE, Simister NE | title = A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus | journal = J.The Exp.Journal Med.of Experimental Medicine | volume = 180 | issue = 6 | pages = 2377–81 2377–2381 | date = December 1994 | pmid = 7964511 | pmc = 2191771 | doi = 10.1084/jem.180.6.2377 }}</ref><ref name="pmid8646894">{{cite journal | vauthors = Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O | title = The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3 | journal = Cytogenet.Cytogenetics and Cell Genet.Genetics | volume = 73 | issue = 1–2 | pages = 97–8 97–98 | date = July 1996 | pmid = 8646894 | doi = 10.1159/000134316 }}</ref><ref>{{cite web | title = Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2217}}</ref> It is an [[Fc receptor|IgG Fc receptor]] which is similar in structure to the [[MHC class I]] molecule and also associates with [[Beta-2 microglobulin|beta-2-microglobulin]].<ref>{{Citecite journal |last1 vauthors = Simister|first1= NE|last2=, Mostov|first2= KE|dateauthor2-link=1989Keith E. Mostov | title = Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog |url=https://pubmed.ncbi.nlm.nih.gov/2534798/| journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 54 | issue = Pt 1 | pages = 571–580 | date = 1989 | pmid = 2534798 | doi = 10.1101/sqb.1989.054.01.068|issn=0091-7451|pmid=2534798 }}</ref><ref name=":0">{{cite journal | vauthors = Kuo TT, Aveson VG | title = Neonatal Fc receptor and IgG-based therapeutics | journal = mAbs | volume = 3 | issue = 5 | pages = 422–30422–430 | date = 2011-01-01 | pmid = 22048693 | pmc = 3225846 | doi = 10.4161/mabs.3.5.16983 }}</ref> In rodents, 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.<ref name=":2">{{Citecite journal |last1 vauthors = Rodewald|first1= R|last2=, Kraehenbuhl|first2= JP |date=1984| title = Receptor-mediated transport of IgG | journal = The Journal of Cell Biology | volume = 99 (1 Pt 2)| issue = 1 Pt 2 | pages =159s–64s 159s–164s | date = July 1984 | pmid = 6235233 | pmc = 2275593 | doi = 10.1083/jcb.99.1.159s|pmid=6235233|pmc=2275593 }}</ref><ref name=":3">{{Citecite journal |last1 vauthors = Simister|first1= NE|last2=, Rees|first2= AR |date=1985| title = Isolation and characterization of an Fc receptor from neonatal rat small intestine | journal = European Journal of Immunology | volume = 15 | issue = 7 | pages =733–8 733–738 | date = July 1985 | pmid = 2988974 | doi = 10.1002/eji.1830150718 |pmid=2988974| s2cid = 42396197 }}</ref> In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus.<ref name="pmid7964511" /><ref name=":15">{{Citecite journal |last1 vauthors = Firan|first1= M.|last2=, Bawdon|first2= R.|last3=, Radu|first3= C.|last4=, Ober|first4=R. J.|last5=RJ, Eaken|first5= D.|last6=, Antohe|first6= F.|last7=, Ghetie|first7= V.|last8=, Ward ES |first8 display-authors =E. S.|date=20016 | title = The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans |url=https://pubmed.ncbi.nlm.nih.gov/11470769/| journal = International Immunology | volume = 13 | issue = 8 | pages = 993–1002 | date = August 2001 | pmid = 11470769 | doi = 10.1093/intimm/13.8.993 |issn=0953 doi-8178|pmidaccess =11470769 free }}</ref> FcRn has also been shown to play a role in regulating IgG and [[serum albumin]] turnover.<ref name=":6">{{Citecite journal |last1 vauthors = Ghetie|first1= V.|last2=, Hubbard|first2= JG|last3=, Kim|first3= JK|last4=, Tsen|first4= MF|last5=, Lee|first5= Y|last6=, Ward|first6= ES |date=1996| title = Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice |url=https://pubmed.ncbi.nlm.nih.gov/8605939/| journal = European Journal of Immunology | volume = 26 | issue = 3 | pages = 690–696 | date = March 1996 | pmid = 8605939 | doi = 10.1002/eji.1830260327 |issn=0014-2980|pmid=8605939| s2cid = 85730132 | doi-access = free }}</ref><ref name="pmid12566415" /><ref name=":11" /><ref name=":7">{{cite journal | vauthors = Roopenian DC, Akilesh S|date=September 2007| title = FcRn: the neonatal Fc receptor comes of age | language = En | journal = Nature Reviews. Immunology |language=En| volume = 7 | issue = 9 | pages =715–25 715–725 | date = September 2007 | pmid = 17703228 | doi = 10.1038/nri2155 |pmid=17703228| s2cid = 6980400 }}</ref><ref name=":5">{{Citecite book journal|last1 vauthors = Ward|first1= ES|last2=, Ober|first2= RJ |date=2009| title = Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn |journal series = Advances in Immunology | volume = 103 | pages = 77–115 | date = 2009 | pmid = 19755184 | pmc = 4485553 | doi = 10.1016/S0065-2776(09)03004-1 |issn isbn =1557 978-8445|pmc=4485553|pmid=197551840-12-374832-4 }}</ref> Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, [[Tumor necrosis factor alpha|TNF-α]], and down-regulated by [[Interferon gamma|IFN-γ]].<ref name=":02" />

== Interactions of FcRn with IgG and serum albumin ==

In addition to binding to IgG, FCGRT has been shown to [[Protein-protein interaction|interact]] with [[Humanhuman serum albumin]].<ref name=pmid12566415>{{cite journal | vauthors = Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL | title = The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan | journal = J.The Exp.Journal Med.of Experimental Medicine | volume = 197 | issue = 3 | pages = 315–22 315–322 | date = February 2003 | pmid = 12566415 | pmc = 2193842 | doi = 10.1084/jem.20021829 }}</ref><ref>{{Citecite journal |last1 vauthors = Andersen|first1= JT|last2=, Dee Qian|first2= J|last3=, Sandlie|first3= I |date=2006| title = The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin |url=https://pubmed.ncbi.nlm.nih.gov/17048273/| journal = European Journal of Immunology | volume = 36 | issue = 11 | pages = 3044–3051 | date = November 2006 | pmid = 17048273 | doi = 10.1002/eji.200636556 |issn=0014-2980|pmid=17048273| s2cid = 22024929 }}</ref> 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.<ref name=":2" /><ref name=":3" /><ref name=":4">{{Citecite journal |last1 vauthors = Dickinson|first1= BL|last2=, Badizadegan|first2= K|last3=, Wu|first3= Z|last4=, Ahouse|first4= JC|last5=, Zhu|first5= X|last6=, Simister|first6= NE|last7=, Blumberg|first7= RS|last8=, Lencer|first8= WI |date display-authors =1999 6 | title = Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line | journal = The Journal of Clinical Investigation | volume = 104 | issue = 7 | pages = 903–911 |doi date =10.1172/JCI6968|issn=0021-9738 October 1999 | pmid = 10510331 | pmc = 408555 | doi = 10.1172/JCI6968 }}</ref> Therefore,The FcRnbinding cansite bindfor FcRn on IgG fromhas been mapped using functional and structural studies, and involves in the slightlyinteraction of relatively well conserved histidine residues on IgG with acidic [[Lumenresidues on FcRn.<ref>{{cite journal (anatomy)|intestinal lumen]]vauthors and= ensureKim efficientJK, unidirectionalTsen transportMF, toGhetie theV, basolateralWard sideES where| title = Localization of the pHsite of the murine IgG1 molecule that is neutralinvolved in binding to slightlythe basicmurine intestinal Fc receptor | journal = European Journal of Immunology | volume = 24 | issue = 10 | pages = 2429–2434 | date = October 1994 | pmid = 7925571 | doi = 10.1002/eji.1830241025 | s2cid = 43499403 }}</ref> <ref>{{cite journal | vauthors name=" Martin WL, West AP, Gan L, Bjorkman PJ | title = Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding | journal = Molecular Cell | volume = 7 | issue = 4" | pages = 867–877 | date = April 2001 | pmid = 11336709 | doi = 10.1016/s1097-2765(01)00230-1 | doi-access = free }}</ref>

== RecyclingFcRn-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]]<ref>{{Citecite journal |last1 vauthors = Ward|first1= ES|last2=, Zhou|first2= J|last3=, Ghetie|first3= V|last4=, Ober|first4= RJ |date=2003| title = Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans |url=https://pubmed.ncbi.nlm.nih.gov/12578848/| journal = International Immunology | volume = 15 | issue = 2 | pages = 187–195 | date = February 2003 | pmid = 12578848 | doi = 10.1093/intimm/dxg018 |issn=0953 doi-8178|pmidaccess =12578848 free }}</ref> and bone-marrow derived cells.<ref>{{cite journal | vauthors = Akilesh S, Christianson GJ, Roopenian DC, Shaw AS | title = Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism | journal = Journal of Immunology | volume = 179 | issue = 7 | pages = 4580–84580–4588 | date = October 2007 | pmid = 17878355 | doi = 10.4049/jimmunol.179.7.4580 | doi-access = free }}</ref><ref>{{Citecite journal |last1 vauthors = Qiao|first1= SW|last2=, Kobayashi|first2= K|last3=, Johansen|first3=F-E|last4= FE, Sollid|first4= LM|last5=, Andersen|first5= JT|last6=, Milford|first6= E|last7=, Roopenian|first7= DC|last8=, Lencer|first8= WI|last9=, Blumberg|first9= RS |date display-authors =2008 6 | title = Dependence of antibody-mediated presentation of antigen on FcRn | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 27 | pages = 9337–9342 | date = July 2008 | pmid = 18599440 | pmc = 2453734 | doi = 10.1073/pnas.0801717105 |issn=1091 doi-6490|pmcaccess =2453734|pmid=18599440 free | bibcode = 2008PNAS..105.9337Q|doi-access=free }}</ref><ref>{{Citecite journal |last1 vauthors = Montoyo|first1= HP|last2=, Vaccaro|first2= C|last3=, Hafner|first3= M|last4=, Ober|first4= RJ|last5=, Mueller|first5= W|last6=, Ward|first6= ES |date=2009| title = Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 8 | pages = 2788–2793 | date = February 2009 | pmid = 19188594 | pmc = 2650344 | doi = 10.1073/pnas.0810796106 |issn=1091 doi-6490|pmcaccess =2650344|pmid=19188594 free | bibcode = 2009PNAS..106.2788M|doi-access=free }}</ref> The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn.<ref name=":6" /><ref name="pmid12566415" /> IgG, serum albumin and other serum proteins are continuously internalized into cells through [[pinocytosis]]. Generally, internalized serum proteins are transported from theearly [[endosomes]] to the [[lysosome|lysosomes]], where they are degraded. Following entry into cells, the two most abundant serum proteins, IgG and serum albumin, are bound by FcRn at the slightly acidic pH (<6.5) within early (sorting) endosomes, sorted and recycled to the cell surface where they are released at the neutral pH (>7.0) of the extracellular environment.<ref name=":8" /><ref name=":9" /><ref>{{Citecite journal |last vauthors = Prabhat|first= P|last2=, Gan|first2= Z|last3=, Chao|first3= J|last4=, Ram|first4= S|last5=, Vaccaro|first5= C|last6=, Gibbons|first6= S|last7=, Ober|first7= RJ|last8=, Ward|first8= ES |date display-authors =2007-04-03 6 | title = Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy |url=https://pubmed.ncbi.nlm.nih.gov/17384151| journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 14 | pages = 5889–5894 | date = April 2007 | pmid = 17384151 | pmc = 1851587 | doi = 10.1073/pnas.0700337104 |issn=0027 doi-8424|pmcaccess =1851587 free |pmid bibcode =17384151 2007PNAS..104.5889P }}</ref> In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation.<ref name=":8">{{Citecite journal |last1 vauthors = Ober|first1= RJ|last2=, Martinez|first2= C|last3=, Vaccaro|first3= C|last4=, Zhou|first4= J|last5=, Ward|first5= ES |date=2004| title = Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn |url=https://pubmed.ncbi.nlm.nih.gov/14764666/| journal = Journal of Immunology | volume = 172 | issue = 4 | pages = 2021–2029 | date = February 2004 | pmid = 14764666 | doi = 10.4049/jimmunol.172.4.2021 |issn=0022-1767|pmid=14764666| s2cid = 30526875 | doi-access = free }}</ref><ref name=":9">{{Citecite journal |last1 vauthors = Ober|first1= RJ|last2=, Martinez|first2= C|last3=, Lai|first3= X|last4=, Zhou|first4= J|last5=, Ward|first5= ES |date=2004| title = Exocytosis of IgG as mediated by the receptor, FcRn: Anan analysis at the single-molecule level | journal = Proceedings of the National Academy of Sciences of the United States of America |language=en| volume = 101 | issue = 30 | pages = 11076–11081 |doi date =10.1073/pnas.0402970101|issn=0027-8424 July 2004 | pmid = 15258288 | pmc = 503743 |bibcode doi =2004PNAS 10.1073/pnas.10111076O0402970101 | doi-access = free | bibcode = 2004PNAS..10111076O }}</ref><ref>{{Citecite journal |last1 vauthors = Larsen|first1= MT|last2=, Rawsthorne|first2= H|last3=, Schelde|first3= KK|last4=, Dagnæs-Hansen|first4= F|last5=, Cameron|first5= J|last6=, Howard|first6= KA |date=2018| title = Cellular recycling-driven in vivo half-life extension using recombinant albumin fusions tuned for neonatal Fc receptor (FcRn) engagement |url=https://pubmed.ncbi.nlm.nih.gov/30016735/| journal = Journal of Controlled Release | volume = 287 | pages = 132–141 | date = October 2018 | pmid = 30016735 | doi = 10.1016/j.jconrel.2018.07.023 |issn=1873-4995|pmid=30016735| s2cid = 51677989 }}</ref> This cellular mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin.<ref name=":7" /><ref name=":5" /><ref name=":8" /> and transport of these ligands across cellular barriers.<ref name=":15" /><ref name=":4" /><ref>{{cite journal | vauthors = Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI | title = Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung | journal = The Journal of Experimental Medicine | volume = 196 | issue = 3 | pages = 303–310 | date = August 2002 | pmid = 12163559 | pmc = 2193935 | doi = 10.1084/jem.20020400 }}</ref> In addition, for cell types bathed in an acidic environment such as the slightly acidic [[Lumen (anatomy)|intestinal lumen]], cell surface FcRn can bind to IgG, transport bound ligand across intestinal epithelial cells followed by release at the near neutral pH at the basolateral surface.<ref name=":2" /><ref name=":3" /><ref name=":4" />

== RoleDiverse roles for FcRn in various organs ==

FcRn is expressed on antigen-presenting leukocytes likesuch as dendritic cells and is also expressed in neutrophils to help clear opsonized bacteria.<ref name=":02">{{cite journal | vauthors = Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, Blumberg RS | title = Neonatal Fc receptor: from immunity to therapeutics | journal = Journal of Clinical Immunology | volume = 30 | issue = 6 | pages = 777–89777–789 | date = November 2010 | pmid = 20886282 | pmc = 2970823 | doi = 10.1007/s10875-010-9468-4 }}</ref> In the kidneys, FcRn is expressed on epithelial cells called [[podocyte]]s to prevent IgG and albumin from clogging the glomerular filtration barrier.<ref>{{cite journal | vauthors = Akilesh S, Huber TB, Wu H, Wang G, Hartleben B, Kopp JB, Miner JH, Roopenian DC, Unanue ER, Shaw AS | display-authors = 6 | title = Podocytes use FcRn to clear IgG from the glomerular basement membrane | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 3 | pages = 967–72967–972 | date = January 2008 | pmid = 18198272 | pmc = 2242706 | doi = 10.1073/pnas.0711515105 | url = http://www.jimmunol.org/content/179/7/4580.long | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT | title = The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery | journal = Journal of Controlled Release | volume = 211 | pages = 144–62144–162 | date = August 2015 | pmid = 26055641 | doi = 10.1016/j.jconrel.2015.06.006 | s2cid = 205878058 }}</ref> 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.<ref>{{cite journal | vauthors = Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT | title = Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics | journal = Frontiers in Immunology | volume = 5 | pages = 682 | date = 2015-01-26 | pmid = 25674083 | pmc = 4306297 | doi = 10.3389/fimmu.2014.00682 | doi-access = free }}</ref><ref>{{Citecite journal |last1 vauthors = Pyzik|first1= M|last2=, Rath|first2= T|last3=, Kuo|first3= TT|last4=, Win|first4= S|last5=, Baker|first5= K|last6=, Hubbard|first6= JJ|last7=, Grenha|first7= R|last8=, Gandhi|first8= A|last9=, Krämer|first9= TD|last10=, Mezo|first10= AR|last11=, Taylor|first11= ZS, McDonnell K, Nienaber V, Andersen JT, Mizoguchi A, Blumberg L, Purohit S, Jones SD, Christianson G, Lencer WI, Sandlie I, Kaplowitz N, Roopenian DC, Blumberg RS |date display-authors =2017 6 | title = Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 14 | pages = E2862–E2871 | date = April 2017 | pmid = 28330995 | pmc = 5389309 | doi = 10.1073/pnas.1618291114 |issn=1091-6490|pmc=5389309|pmid=28330995| doi-access = free | bibcode = 2017PNAS..114E2862P }}</ref> Studies have also shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.<ref>{{cite journal | vauthors = Gupta S, Gach JS, Becerra JC, Phan TB, Pudney J, Moldoveanu Z, Joseph SB, Landucci G, Supnet MJ, Ping LH, Corti D, Moldt B, Hel Z, Lanzavecchia A, Ruprecht RM, Burton DR, Mestecky J, Anderson DJ, Forthal DN | display-authors = 6 | title = The Neonatal Fc receptor (FcRn) enhances human immunodeficiency virus type 1 (HIV-1) transcytosis across epithelial cells | journal = PLOS Pathogens | volume = 9 | issue = 11 | pages = e1003776 | date = 2013-11-01 | pmid = 24278022 | pmc = 3836734 | doi = 10.1371/journal.ppat.1003776 | doi-access = free }}</ref>

The identification of FcRn as a central regulator of IgG levels<ref name=":6" /> led to the engineering of IgG-FcRn interactions to increase in vivo persistence of IgG has been demonstrated.<ref name=":11">{{Citecite journal |last1 vauthors = Ghetie|first1= V.|last2=, Popov|first2= S.|last3=, Borvak|first3= J.|last4=, Radu|first4= C.|last5=, Matesoi|first5= D.|last6=, Medesan|first6= C.|last7=, Ober|first7=R. J.|last8=RJ, Ward ES |first8 display-authors =E. S.|date=19976 | title = Increasing the serum persistence of an IgG fragment by random mutagenesis |url=https://pubmed.ncbi.nlm.nih.gov/9219265/| journal = Nature Biotechnology | volume = 15 | issue = 7 | pages = 637–640 | date = July 1997 | pmid = 9219265 | doi = 10.1038/nbt0797-637 |issn=1087-0156|pmid=9219265| s2cid = 39836528 }}</ref><ref name=":10">{{Citecite journal |last1 vauthors = Ward|first1= ES|last2=, Ober|first2= RJ |date=2018| title = Targeting FcRn to Generate Antibody-Based Therapeutics | journal = Trends in Pharmacological Sciences | volume = 39 | issue = 10 | pages = 892–904 | date = October 2018 | pmid = 30143244 | pmc = 6169532 | doi = 10.1016/j.tips.2018.07.007|issn=1873-3735|pmc=6169532|pmid=30143244 }}</ref> For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has recently been approved for the treatment of autoimmunity<ref>{{Cite web|title=Ultomiris® (ravulizumab-cwvz) {{!}} Alexion|url=https://alexion.com/|access-date=2021-10-03|website=https://alexion.com |language=en}}</ref> and a half-life extended antibody cocktailscocktail (Evusheld) with 'YTE' mutations<ref>{{Citecite journal |last vauthors = Dall'Acqua|first= WF|last2=, Woods|first2= RM|last3=, Ward|first3= ES|last4=, Palaszynski|first4= SR|last5=, Patel|first5= NK|last6=, Brewah|first6= YA|last7=, Wu|first7= H|last8=, Kiener|first8= PA|last9=, Langermann|first9= S |date=2002 display-11-01authors = 6 | title = Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences |url=https://pubmed.ncbi.nlm.nih.gov/12391234| journal = Journal of Immunology (Baltimore,| Md.:volume 1950)|volume= 169 | issue = 9 | pages = 5171–5180 | date = November 2002 | pmid = 12391234 | doi = 10.4049/jimmunol.169.9.5171 |issn s2cid =0022-1767 29398244 |pmid doi-access =12391234 free }}</ref> areis inused latefor stagethe clinicalprophylaxis trials to treatof SARS-CoV2.<ref>{{cite web | title = Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals | date = 8 December 2021 | publisher = U.S. Food and Drug Administration | url = https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-long-acting-monoclonal-antibodies-pre-exposure}}</ref> Engineering of albumin-FcRn interactions has also generated albumin variants with increased in vivo half-lives.<ref>{{Citecite journal |last vauthors = Andersen|first= JT|last2=, Dalhus|first2= B|last3=, Viuff|first3= D|last4=, Ravn|first4= BT|last5=, Gunnarsen|first5= KS|last6=, Plumridge|first6= A|last7=, Bunting|first7= K|last8=, Antunes|first8= F|last9=, Williamson|first9= R|last10=, Athwal|first10= S|last11=, Allan|first11= E, Evans L, Bjørås M, Kjærulff S, Sleep D, Sandlie I, Cameron J |date=2014 display-05-09authors = 6 | title = Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding |url=https://pubmed.ncbi.nlm.nih.gov/24652290| journal = The Journal of Biological Chemistry | volume = 289 | issue = 19 | pages = 13492–13502 | date = May 2014 | pmid = 24652290 | pmc = 4036356 | doi = 10.1074/jbc.M114.549832 |issn=1083 doi-351X|pmcaccess =4036356|pmid=24652290 free }}</ref> 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.<ref name="pmid18316573">{{cite journal | vauthors = Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, Gillies SD, Folkman J, Javaherian K | display-authors = 6 | title = Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy | journal = Clinical Cancer Research | volume = 14 | issue = 5 | pages = 1487–931487–1493 | date = March 2008 | pmid = 18316573 | doi = 10.1158/1078-0432.CCR-07-1530 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Poznansky MJ, Halford J, Taylor D | title = Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance | journal = FEBS Letters | volume = 239 | issue = 1 | pages = 18–22 | date = October 1988 | pmid = 3181423 | doi = 10.1016/0014-5793(88)80537-4 | s2cid = 38592689 | doi-access = free }}</ref><ref name=":12">{{Citecite journal |last vauthors = Strohl|first= WR |date=2015| title = Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters | journal = BioDrugs: Clinical| Immunotherapeutics,volume Biopharmaceuticals= and29 Gene Therapy|volume=29| issue = 4 | pages = 215–239 | date = August 2015 | pmid = 26177629 | pmc = 4562006 | doi = 10.1007/s40259-015-0133-6|issn=1179-190X|pmc=4562006|pmid=26177629 }}</ref>

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 ([[alefacept]]), Arcalyst ([[rilonacept]]), Enbrel ([[etanercept]]), Nplate ([[romiplostim]]), Orencia ([[abatacept]]) and Nulojix ([[belatacept]]).<ref name=":12" /> Enbrel ([[etanercept]]) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, [[Tumor necrosis factor alpha|TNF-α.]]<ref name=":12" /><ref>{{Citecite journal |last vauthors = Goldenberg|first= MM|date=January 1999| title = Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis |url=https://pubmed.ncbi.nlm.nih.gov/10090426| journal = Clinical Therapeutics | volume = 21 | issue = 1 | pages = 75–87; discussion 1–2 | date = January 1999 | pmid = 10090426 | doi = 10.1016/S0149-2918(00)88269-7 |issn=0149 doi-2918|pmidaccess =10090426 free }}</ref>

SeveralMultiple 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.<ref>{{cite journal | vauthors = Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D | title = The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease | journal = The Journal of Clinical Investigation | volume = 113 | issue = 9 | pages = 1328–331328–1333 | date = May 2004 | pmid = 15124024 | pmc = 398424 | doi = 10.1172/JCI18838 }}</ref><ref name=":13">{{Citecite journal |last vauthors = Hansen|first= RJ|last2=, Balthasar|first2= JP|date=June 2003| title = Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia |url=https://pubmed.ncbi.nlm.nih.gov/12761810| journal = Journal of Pharmaceutical Sciences | volume = 92 | issue = 6 | pages = 1206–1215 | date = June 2003 | pmid = 12761810 | doi = 10.1002/jps.10364|issn=0022-3549|pmid=12761810 }}</ref><ref name=":14">{{Citecite journal |last vauthors = Patel|first= DA|last2=Cantó|first2=AP|last3=, Puig-Canto A, Challa|first3= DK|last4=, Perez Montoyo|first4=HP|last5= H, Ober|first5= RJ|last6=, Ward|first6= ES |date=2011-07-15| title =FcRn Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157913/| journal = Journal of immunologyImmunology (Baltimore, Md. : 1950)| volume = 187 | issue = 2 | pages = 1015–1022 |doi date =10.4049/jimmunol.1003780 July 2011 |issn pmid =0022-1767 21690327 | pmc = 3157913 |pmid doi =21690327 10.4049/jimmunol.1003780 }}</ref> Therapies seek to disrupt the IgG-FcRn interaction to increase the clearance of disease-causing IgG autoantibodies from the body.<ref name=":10" /> 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.<ref name=":13" /><ref name=":1">{{cite journal | vauthors = Sockolosky JT, Szoka FC | title = The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy | journal = Advanced Drug Delivery Reviews | volume = 91 | pages = 109–24109–124 | date = August 2015 | pmid = 25703189 | pmc = 4544678 | doi = 10.1016/j.addr.2015.02.005 | series = Editor's Collection 2015 }}</ref><ref>{{cite journal | vauthors = Nimmerjahn F, Ravetch JV |date=2008-01-01| title = Anti-inflammatory actions of intravenous immunoglobulin | journal = Annual Review of Immunology | volume = 26 | issue = 1 | pages =513–33 513–533 | date = 2008-01-01 | pmid = 18370923 | doi = 10.1146/annurev.immunol.26.021607.090232|pmid=18370923 }}</ref> More recent approaches involve the strategy of blocking the binding of IgG to FcRn by injectingdelivering antibodies that bind with high affinity to this receptor through their Fc region<ref name=":16">{{Citecite journal |last1 vauthors = Vaccaro|first1= C|last2=, Zhou|first2= J|last3=, Ober|first3= RJ|last4=, Ward|first4= ES |date=2005| title = Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels |url=https://pubmed.ncbi.nlm.nih.gov/16186811/| journal = Nature Biotechnology | volume = 23 | issue = 10 | pages = 1283–1288 | date = October 2005 | pmid = 16186811 | doi = 10.1038/nbt1143 |issn=1087-0156|pmid=16186811| s2cid = 13526188 }}</ref><ref name=":14" /><ref>{{Citecite journal |last vauthors = Ulrichts|first= P|last2=, Guglietta|first2= A|last3=, Dreier|first3= T|last4=, van Bragt|first4= T|last5=, Hanssens|first5= V|last6=, Hofman|first6= E|last7=, Vankerckhoven|first7= B|last8=, Verheesen|first8= P|last9=, Ongenae|first9= N|last10=, Lykhopiy|first10= V|last11=, Enriquez FJ, Cho J, Ober RJ, Ward ES, de Haard H, Leupin N |first11 display-authors =F|date=2018-10-01 6 | title = Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans |url=https://pubmed.ncbi.nlm.nih.gov/30040076| journal = The Journal of Clinical Investigation | volume = 128 | issue = 10 | pages = 4372–4386 |doi date =10.1172/JCI97911 October 2018 |issn pmid =1558-8238 30040076 | pmc = 6159959 |pmid doi =30040076 10.1172/JCI97911 }}</ref> or variable regions.<ref>{{Citecite journal |last1 vauthors = Nixon|first1= AE|last2=, Chen|first2= J|last3=, Sexton|first3= DJ|last4=, Muruganandam|first4= A|last5=, Bitonti|first5= AJ|last6=, Dumont|first6= J|last7=, Viswanathan|first7= M|last8=, Martik|first8= D|last9=, Wassaf|first9= D|last10=, Mezo|first10= A|last11=, Wood|first11= CR, Biedenkapp JC, TenHoor C |date display-authors =2015 6 | title = Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates | journal = Frontiers in Immunology | volume = 6 | pages = 176 | date = 2015 | pmid = 25954273 | pmc = 4407741 | doi = 10.3389/fimmu.2015.00176 |issn=1664-3224|pmc=4407741|pmid=25954273| doi-access = free }}</ref><ref>{{Citecite journal |last1 vauthors = Kiessling|first1= P|last2=, Lledo-Garcia|first2= R|last3=, Watanabe|first3= S|last4=, Langdon|first4= G|last5=, Tran|first5= D|last6=, Bari|first6= M|last7=, Christodoulou|first7= L|last8=, Jones|first8= E|last9=, Price|first9= G|last10=, Smith|first10= B|last11=, Brennan|first11= F, White I, Jolles S |date display-authors =2017 6 | title = The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study |url=https://pubmed.ncbi.nlm.nih.gov/29093180/| journal = Science Translational Medicine | volume = 9 | issue = 414 | pages = eaan1208 | date = November 2017 | pmid = 29093180 | doi = 10.1126/scitranslmed.aan1208 |issn=1946-6242|pmid=29093180| s2cid = 206694327 | doi-access = free }}</ref><ref>{{Citecite journal |last1 vauthors = Blumberg|first1= LJ|last2=, Humphries|first2= JE|last3=, Jones|first3= SD|last4=, Pearce|first4= LB|last5=, Holgate|first5= R|last6=, Hearn|first6= A|last7=, Cheung|first7= J|last8=, Mahmood|first8= A|last9=, Del Tito|first9= B|last10=, Graydon|first10= JS|last11=, Stolz|first11= LE, Bitonti A, Purohit S, de Graaf D, Kacena K, Andersen JT, Christianson GJ, Roopenian DC, Hubbard JJ, Gandhi AK, Lasseter K, Pyzik M, Blumberg RS |date display-authors =2019 6 | title = Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses | journal = Science Advances | volume = 5 | issue = 12 | pages = eaax9586 | date = December 2019 | pmid = 31897428 | pmc = 6920022 | doi = 10.1126/sciadv.aax9586 |issn=2375-2548|pmc=6920022|pmid=31897428| bibcode = 2019SciA....5.9586B }}</ref> These engineered Fc fragments or antibodies are currently being used in clinical trials as treatments for antibody-mediated autoimmune diseases such as primary immune thrombocytopenia and myastheniaskin gravis.blistering diseases (pemphigus),<ref>{{Citecite journal |last1 vauthors = Newland|first1= AC|last2=, Sánchez-González|first2= B|last3=, Rejtő|first3= L|last4=, Egyed|first4= M|last5=, Romanyuk|first5= N|last6=, Godar|first6= M|last7=, Verschueren|first7= K|last8=, Gandini|first8= D|last9=, Ulrichts|first9= P|last10=, Beauchamp|first10= J|last11=, Dreier|first11= T, Ward ES, Michel M, Liebman HA, de Haard H, Leupin N, Kuter DJ |date display-authors =2020 6 | title = Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia | journal = American Journal of Hematology | volume = 95 | issue = 2 | pages = 178–187 |doi date =10.1002/ajh.25680 February 2020 |issn pmid =1096-8652 31821591 | pmc = 7004056 |pmid doi =31821591 10.1002/ajh.25680 }}</ref><ref>{{Citecite journal |last1 vauthors = Robak|first1= T|last2=, Kaźmierczak|first2= M|last3=, Jarque|first3= I|last4=, Musteata|first4= V|last5=, Treliński|first5= J|last6=, Cooper|first6= N|last7=, Kiessling|first7= P|last8=, Massow|first8= U|last9=, Woltering|first9= F|last10=, Snipes|first10= R|last11=, Ke|first11= J, Langdon G, Bussel JB, Jolles S |date display-authors =2020 6 | title = Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia | journal = Blood Advances | volume = 4 | issue = 17 | pages = 4136–4146 |doi date =10.1182/bloodadvances.2020002003 September 2020 |issn pmid =2473-9537 32886753 | pmc = 7479959 |pmid doi =32886753 10.1182/bloodadvances.2020002003 }}</ref><ref>{{Citecite journal |last1 vauthors =Wolfe Werth VP, Culton DA, Concha JS, Graydon JS, Blumberg LJ, Okawa J, Pyzik M, Blumberg RS, Hall RP |first1 display-authors =GI 6 |last2 title =Ward Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus |first2 journal =ES The Journal of Investigative Dermatology |last3 volume =de Haard141 |first3 issue =H 12 |last4 pages =Ulrichts 2858–2865.e4 |first4 date =P December 2021 |last5 pmid =Mozaffar 34126109 |first5 doi =T 10.1016/j.jid.2021.04.031 |last6 s2cid =Pasnoor 235439165 |first6 doi-access =M free }}</ref><ref>{{cite journal |last7 vauthors =Vidarsson Goebeler M, Bata-Csörgő Z, De Simone C, Didona B, Remenyik E, Reznichenko N, Stoevesandt J, Ward ES, Parys W, de Haard H, Dupuy P, Verheesen P, Schmidt E, Joly P |first7 display-authors =G|date=2021 6 | title =IgG regulationTreatment throughof FcRnpemphigus blocking:vulgaris Aand novelfoliaceus mechanismwith forefgartigimod, thea treatmentneonatal ofFc myastheniareceptor gravis|url=httpsinhibitor://pubmed.ncbi.nlm.nih.gov/34563918/ a phase II multicentre, open-label feasibility trial | journal = The British Journal of theDermatology Neurological| date = October 2021 Sciences| volume =430 186 | issue = 3 | pages =118074 429–439 | pmid = 34608631 | doi = 10.10161111/jbjd.jns.2021.11807420782 |issn s2cid =1878 238355823 | doi-5883access = free |pmid hdl =34563918 2437/328911 |s2cid hdl-access =237488156 free }}</ref> FDAand approvalthe isFc-based anticipatedinhibitor, efgartigimod, based on the 'Abdeg' technology<ref name=":16" /> was recently approved (as 'Vyvgart') for the treatment of generalized myasthenia gravis in lateDecember 2021.<ref>{{cite web | title = argenx Announces U.S. Food and Drug Administration (FDA) Approval of VYVGART™ (efgartigimod alfa-fcab) in Generalized Myasthenia Gravis | work = Argenx | date = 17 December 2021 | url = https://www.argenx.com/news/argenx-announces-us-food-and-drug-administration-fda-approval-vyvgarttm-efgartigimod-alfa-fcab }}</ref>

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