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 | pmc = | 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| accessdate = }}</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>{{cite journal | vauthors = Simister NE, Mostov KE|author2-link=Keith E. Mostov | title = Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog | 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 }}</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> FurtherIn studiesrodents, revealedFcRn awas similaroriginally identified as the receptor inthat humanstransports maternal immunoglobulin G (IgG) from mother to neonatal offspring via [[mother's milk]], leading to theits namingname as athe neonatal Fc receptor.<ref Inname=":2">{{cite humansjournal | vauthors = Rodewald R, howeverKraehenbuhl JP | title = Receptor-mediated transport of IgG | journal = The Journal of Cell Biology | volume = 99 | issue = 1 Pt 2 | pages = 159s–164s | date = July 1984 | pmid = 6235233 | pmc = 2275593 | doi = 10.1083/jcb.99.1.159s }}</ref><ref name=":3">{{cite journal | vauthors = Simister NE, itRees AR | title = Isolation and characterization of an Fc receptor from neonatal rat small intestine | journal = European Journal of Immunology | volume = 15 | issue = 7 | pages = 733–738 | date = July 1985 | pmid = 2988974 | doi = 10.1002/eji.1830150718 | s2cid = 42396197 }}</ref> In humans, FcRn is foundpresent in the placenta towhere helpit facilitate transport oftransports mother's IgG to the growing fetus.<ref Itname="pmid7964511" /><ref name=":15">{{cite journal | vauthors = Firan M, Bawdon R, Radu C, Ober RJ, Eaken D, Antohe F, Ghetie V, Ward ES | display-authors = 6 | title = The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans | journal = International Immunology | volume = 13 | issue = 8 | pages = 993–1002 | date = August 2001 | pmid = 11470769 | doi = 10.1093/intimm/13.8.993 | doi-access = free }}</ref> FcRn has also been shown to play a role in monitoringregulating IgG and [[serum albumin]] turnover.<ref name=":06">{{cite journal | vauthors = Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES | title = Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice | journal = European Journal of Immunology | volume = 26 | issue = 3 | pages = 690–696 | date = March 1996 | pmid = 8605939 | doi = 10.1002/eji.1830260327 | s2cid = 85730132 | doi-access = free }}</ref><ref name="pmid12566415" /><ref name=":11" /><ref name=":7">{{cite journal | vauthors = Roopenian DC, Akilesh S | title = FcRn: the neonatal Fc receptor comes of age | language = En | journal = Nature Reviews. Immunology | volume = 7 | issue = 9 | pages = 715–25715–725 | date = September 2007 | pmid = 17703228 | doi = 10.1038/nri2155 | s2cid = 6980400 }}</ref><ref name=":5">{{cite book | vauthors = Ward ES, Ober RJ | title = Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn | series = Advances in Immunology | volume = 103 | pages = 77–115 | date = 2009 | pmid = 19755184 | pmc = 4485553 | doi = 10.1016/S0065-2776(09)03004-1 | isbn = 978-0-12-374832-4 }}</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>{{cite journal | vauthors = Andersen JT, Dee Qian J, Sandlie I | title = The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin | journal = European Journal of Immunology | volume = 36 | issue = 11 | pages = 3044–3051 | date = November 2006 | pmid = 17048273 | doi = 10.1002/eji.200636556 | 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">{{cite journal | vauthors = Dickinson ThereforeBL, Badizadegan K, Wu Z, Ahouse JC, Zhu X, Simister NE, Blumberg RS, Lencer WI | display-authors = 6 | title = Bidirectional FcRn-dependent canIgG bindtransport in a polarized human intestinal epithelial cell line | journal = The Journal of Clinical Investigation | volume = 104 | issue = 7 | pages = 903–911 | date = October 1999 | pmid = 10510331 | pmc = 408555 | doi = 10.1172/JCI6968 }}</ref> The binding site for 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:02" 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>{{cite journal | vauthors = RoopenianWard DCES, AkileshZhou SJ, Ghetie V, Ober RJ | title = FcRn:Evidence theto neonatalsupport Fcthe receptorcellular comesmechanism ofinvolved agein |serum languageIgG =homeostasis in Enhumans | journal = Nature Reviews.International Immunology | volume = 715 | issue = 92 | pages = 715–25187–195 | date = SeptemberFebruary 20072003 | pmid = 1770322812578848 | doi = 10.10381093/nri2155intimm/dxg018 | doi-access = 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>{{cite journal | vauthors = Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E, Roopenian DC, Lencer WI, Blumberg RS | display-authors = 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 | doi-access = free | bibcode = 2008PNAS..105.9337Q }}</ref><ref>{{cite journal | vauthors = Montoyo HP, Vaccaro C, Hafner M, Ober RJ, Mueller W, Ward ES | 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 | doi-access = free | bibcode = 2009PNAS..106.2788M }}</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. TheFollowing 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 bloodthe extracellular environment.<ref name=":8" /><ref name=":9" /><ref>{{cite journal | vauthors = Prabhat P, Gan Z, Chao J, Ram S, Vaccaro C, Gibbons S, Ober RJ, Ward ES | display-authors = 6 | title = Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy | 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 | doi-access = free | bibcode = 2007PNAS..104.5889P }}</ref> In this way, IgG and serum albumin avoidsare salvaged to avoid lysosomal degradation.<ref Thisname=":8">{{cite mechanismjournal provides| anvauthors explanation= forOber RJ, Martinez C, Vaccaro C, Zhou J, Ward ES | title = Visualizing the greatersite serumand circulationdynamics halfof IgG salvage by the MHC class I-liferelated receptor, FcRn | journal = Journal of IgGImmunology and| serumvolume albumin= 172 | issue = 4 | pages = 2021–2029 | date = February 2004 | pmid = 14764666 | doi = 10.4049/jimmunol.172.4.2021 | s2cid = 30526875 | doi-access = free }}</ref><ref name="pmid18843053:9">{{cite journal | vauthors = GoeblOber NARJ, BabbeyMartinez CMC, Datta-MannanLai AX, WitcherZhou DRJ, WroblewskiWard VJ, Dunn KWES | title = NeonatalExocytosis Fcof receptorIgG mediatesas internalizationmediated ofby Fcthe inreceptor, transfectedFcRn: humanan endothelialanalysis cellsat the single-molecule level | journal = MolecularProceedings Biologyof the National Academy of Sciences of the CellUnited States of America | volume = 19101 | issue = 1230 | pages = 5490–50511076–11081 | date = DecemberJuly 20082004 | pmid = 1884305315258288 | pmc = 2592658503743 | doi = 10.10911073/mbcpnas.E070402970101 | doi-02-0101access = free | bibcode = 2004PNAS..10111076O }}</ref><ref>{{cite journal | vauthors = RoopenianLarsen DCMT, AkileshRawsthorne SH, Schelde KK, Dagnæs-Hansen F, Cameron J, Howard KA | title = FcRn:Cellular therecycling-driven in vivo half-life extension using recombinant albumin fusions tuned for neonatal Fc receptor comes(FcRn) engagement | journal = Journal of ageControlled Release | languagevolume = En287 | journalpages = Nature132–141 Reviews| date = October 2018 | pmid = 30016735 | doi = 10.1016/j.jconrel.2018.07.023 Immunology| 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 = 7196 | issue = 93 | pages = 715–25303–310 | date = SeptemberAugust 20072002 | pmid = 1770322812163559 | pmc = 2193935 | doi = 10.10381084/nri2155jem.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 | urldoi-access = http://www.jimmunol.org/content/179/7/4580.longfree }}</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>{{cite journal | vauthors = Pyzik M, Rath T, Kuo TT, Win S, Baker K, Hubbard JJ, Grenha R, Gandhi A, Krämer TD, Mezo AR, Taylor 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 | display-authors = 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 | 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 = PLoSPLOS 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.<ref name=":11">{{cite journal | vauthors = Ghetie V, Popov S, Borvak J, Radu C, Matesoi D, Medesan C, Ober RJ, Ward ES | display-authors = 6 | title = Increasing the serum persistence of an IgG fragment by random mutagenesis | journal = Nature Biotechnology | volume = 15 | issue = 7 | pages = 637–640 | date = July 1997 | pmid = 9219265 | doi = 10.1038/nbt0797-637 | s2cid = 39836528 }}</ref><ref name=":10">{{cite journal | vauthors = Ward ES, Ober RJ | 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 }}</ref> For example, the half-life extended complement C5-specific antibody, Ultomiris (ravulizumab), has been approved for the treatment of autoimmunity<ref>{{Cite web|title=Ultomiris® (ravulizumab-cwvz) {{!}} Alexion|url=https://alexion.com/|access-date=2021-10-03 |language=en}}</ref> and a half-life extended antibody cocktail (Evusheld) with 'YTE' mutations<ref>{{cite journal | vauthors = Dall'Acqua WF, Woods RM, Ward ES, Palaszynski SR, Patel NK, Brewah YA, Wu H, Kiener PA, Langermann S | display-authors = 6 | title = Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences | journal = Journal of Immunology | volume = 169 | issue = 9 | pages = 5171–5180 | date = November 2002 | pmid = 12391234 | doi = 10.4049/jimmunol.169.9.5171 | s2cid = 29398244 | doi-access = free }}</ref> is used for the prophylaxis of 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>{{cite journal | vauthors = Andersen JT, Dalhus B, Viuff D, Ravn BT, Gunnarsen KS, Plumridge A, Bunting K, Antunes F, Williamson R, Athwal S, Allan E, Evans L, Bjørås M, Kjærulff S, Sleep D, Sandlie I, Cameron J | display-authors = 6 | title = Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding | 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 | doi-access = free }}</ref> It has also been shown that conjugation of some drugs to the Fc domainregion 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">{{cite journal | vauthors = Strohl WR | title = Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters | journal = BioDrugs | volume = 29 | issue = 4 | pages = 215–239 | date = August 2015 | pmid = 26177629 | pmc = 4562006 | doi = 10.1007/s40259-015-0133-6 }}</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 {{citation needed|datename=March":12" 2016}}./> 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>{{cite journal | vauthors = HuangGoldenberg CMM | title = Receptor-FcEtanercept, fusiona therapeutics,novel trapsdrug for the treatment of patients with severe, andactive MIMETIBODYrheumatoid technologyarthritis | journal = CurrentClinical Opinion in BiotechnologyTherapeutics | volume = 2021 | issue = 61 | pages = 692–975–87; discussion 1–2 | date = DecemberJanuary 20091999 | pmid = 1988953010090426 | doi = 10.1016/j.copbio.2009.10.010S0149-2918(00)88269-7 | doi-access = free }}</ref>

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