Biology:Neonatal Fc receptor

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Short description: Mammalian protein found in Homo sapiens
Fc fragment of IgG, receptor, transporter, alpha
Identifiers
SymbolFCGRT
NCBI gene2217
HGNC3621
OMIM601437
RefSeqNM_004107
UniProtP55899
Other data
LocusChr. 19 q13.3

The neonatal Fc receptor (also FcRn, IgG receptor FcRn large subunit p51, or Brambell receptor) is a protein that in humans is encoded by the FCGRT gene.[1][2][3] It is an IgG Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin.[4][5] 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.[6][7] In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus.[1][8] FcRn has also been shown to play a role in regulating IgG and serum albumin turnover.[9][10][11][12][13] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.[14]

Interactions of FcRn with IgG and serum albumin

In addition to binding to IgG, FCGRT has been shown to interact with human serum albumin.[10][15] 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.[6][7][16] The binding site for FcRn on IgG has been mapped using functional and structural studies, and involves in the interaction of relatively well conserved histidine residues on IgG with acidic residues on FcRn.[17] [18]

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[19] and bone-marrow derived cells.[20][21][22] The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn.[9][10] IgG, serum albumin and other serum proteins are continuously internalized into cells through pinocytosis. Generally, internalized serum proteins are transported from early endosomes to 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.[23][24][25] In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation.[23][24][26] This cellular mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin[12][13][23] and transport of these ligands across cellular barriers.[8][16][27] In addition, for cell types bathed in an acidic environment such as the slightly acidic 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.[6][7][16]

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 (alefacept), Arcalyst (rilonacept), Enbrel (etanercept), Nplate (romiplostim), Orencia (abatacept) and Nulojix (belatacept).[40] Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.[40][41]

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

  1. ↑ 1.0 1.1 "A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus". The Journal of Experimental Medicine 180 (6): 2377–2381. December 1994. doi:10.1084/jem.180.6.2377. PMID 7964511. 
  2. ↑ "The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3". Cytogenetics and Cell Genetics 73 (1–2): 97–98. July 1996. doi:10.1159/000134316. PMID 8646894. 
  3. ↑ "Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2217. 
  4. ↑ "Cloning and expression of the neonatal rat intestinal Fc receptor, a major histocompatibility complex class I antigen homolog". Cold Spring Harbor Symposia on Quantitative Biology 54 (Pt 1): 571–580. 1989. doi:10.1101/sqb.1989.054.01.068. PMID 2534798. 
  5. ↑ "Neonatal Fc receptor and IgG-based therapeutics". mAbs 3 (5): 422–430. 2011-01-01. doi:10.4161/mabs.3.5.16983. PMID 22048693. 
  6. ↑ 6.0 6.1 6.2 "Receptor-mediated transport of IgG". The Journal of Cell Biology 99 (1 Pt 2): 159s–164s. July 1984. doi:10.1083/jcb.99.1.159s. PMID 6235233. 
  7. ↑ 7.0 7.1 7.2 "Isolation and characterization of an Fc receptor from neonatal rat small intestine". European Journal of Immunology 15 (7): 733–738. July 1985. doi:10.1002/eji.1830150718. PMID 2988974. 
  8. ↑ 8.0 8.1 "The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans". International Immunology 13 (8): 993–1002. August 2001. doi:10.1093/intimm/13.8.993. PMID 11470769. 
  9. ↑ 9.0 9.1 9.2 "Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice". European Journal of Immunology 26 (3): 690–696. March 1996. doi:10.1002/eji.1830260327. PMID 8605939. 
  10. ↑ 10.0 10.1 10.2 "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. February 2003. doi:10.1084/jem.20021829. PMID 12566415. 
  11. ↑ 11.0 11.1 "Increasing the serum persistence of an IgG fragment by random mutagenesis". Nature Biotechnology 15 (7): 637–640. July 1997. doi:10.1038/nbt0797-637. PMID 9219265. 
  12. ↑ 12.0 12.1 "FcRn: the neonatal Fc receptor comes of age" (in En). Nature Reviews. Immunology 7 (9): 715–725. September 2007. doi:10.1038/nri2155. PMID 17703228. 
  13. ↑ 13.0 13.1 "Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn". Advances in Immunology 103: 77–115. 2009. doi:10.1016/S0065-2776(09)03004-1. PMID 19755184. 
  14. ↑ 14.0 14.1 "Neonatal Fc receptor: from immunity to therapeutics". Journal of Clinical Immunology 30 (6): 777–789. November 2010. doi:10.1007/s10875-010-9468-4. PMID 20886282. 
  15. ↑ "The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin". European Journal of Immunology 36 (11): 3044–3051. November 2006. doi:10.1002/eji.200636556. PMID 17048273. 
  16. ↑ 16.0 16.1 16.2 "Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line". The Journal of Clinical Investigation 104 (7): 903–911. October 1999. doi:10.1172/JCI6968. PMID 10510331. 
  17. ↑ "Localization of the site of the murine IgG1 molecule that is involved in binding to the murine intestinal Fc receptor". European Journal of Immunology 24 (10): 2429–2434. October 1994. doi:10.1002/eji.1830241025. PMID 7925571. 
  18. ↑ "Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding". Molecular Cell 7 (4): 867–877. April 2001. doi:10.1016/s1097-2765(01)00230-1. PMID 11336709. 
  19. ↑ "Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans". International Immunology 15 (2): 187–195. February 2003. doi:10.1093/intimm/dxg018. PMID 12578848. 
  20. ↑ "Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism". Journal of Immunology 179 (7): 4580–4588. October 2007. doi:10.4049/jimmunol.179.7.4580. PMID 17878355. 
  21. ↑ "Dependence of antibody-mediated presentation of antigen on FcRn". Proceedings of the National Academy of Sciences of the United States of America 105 (27): 9337–9342. July 2008. doi:10.1073/pnas.0801717105. PMID 18599440. Bibcode: 2008PNAS..105.9337Q. 
  22. ↑ "Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice". Proceedings of the National Academy of Sciences of the United States of America 106 (8): 2788–2793. February 2009. doi:10.1073/pnas.0810796106. PMID 19188594. Bibcode: 2009PNAS..106.2788M. 
  23. ↑ 23.0 23.1 23.2 "Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn". Journal of Immunology 172 (4): 2021–2029. February 2004. doi:10.4049/jimmunol.172.4.2021. PMID 14764666. 
  24. ↑ 24.0 24.1 "Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level". Proceedings of the National Academy of Sciences of the United States of America 101 (30): 11076–11081. July 2004. doi:10.1073/pnas.0402970101. PMID 15258288. Bibcode: 2004PNAS..10111076O. 
  25. ↑ "Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy". Proceedings of the National Academy of Sciences of the United States of America 104 (14): 5889–5894. April 2007. doi:10.1073/pnas.0700337104. PMID 17384151. 
  26. ↑ "Cellular recycling-driven in vivo half-life extension using recombinant albumin fusions tuned for neonatal Fc receptor (FcRn) engagement". Journal of Controlled Release 287: 132–141. October 2018. doi:10.1016/j.jconrel.2018.07.023. PMID 30016735. 
  27. ↑ "Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung". The Journal of Experimental Medicine 196 (3): 303–310. August 2002. doi:10.1084/jem.20020400. PMID 12163559. 
  28. ↑ "Podocytes use FcRn to clear IgG from the glomerular basement membrane". Proceedings of the National Academy of Sciences of the United States of America 105 (3): 967–972. January 2008. doi:10.1073/pnas.0711515105. PMID 18198272. 
  29. ↑ "The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery". Journal of Controlled Release 211: 144–162. August 2015. doi:10.1016/j.jconrel.2015.06.006. PMID 26055641. 
  30. ↑ "Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics". Frontiers in Immunology 5: 682. 2015-01-26. doi:10.3389/fimmu.2014.00682. PMID 25674083. 
  31. ↑ "Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury". Proceedings of the National Academy of Sciences of the United States of America 114 (14): E2862–E2871. April 2017. doi:10.1073/pnas.1618291114. PMID 28330995. 
  32. ↑ "The Neonatal Fc receptor (FcRn) enhances human immunodeficiency virus type 1 (HIV-1) transcytosis across epithelial cells". PLOS Pathogens 9 (11): e1003776. 2013-11-01. doi:10.1371/journal.ppat.1003776. PMID 24278022. 
  33. ↑ 33.0 33.1 "Targeting FcRn to Generate Antibody-Based Therapeutics". Trends in Pharmacological Sciences 39 (10): 892–904. October 2018. doi:10.1016/j.tips.2018.07.007. PMID 30143244. 
  34. ↑ "Ultomiris® (ravulizumab-cwvz) | Alexion" (in en). https://alexion.com/. 
  35. ↑ "Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences". Journal of Immunology 169 (9): 5171–5180. November 2002. doi:10.4049/jimmunol.169.9.5171. PMID 12391234. 
  36. ↑ "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. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-long-acting-monoclonal-antibodies-pre-exposure. 
  37. ↑ "Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding". The Journal of Biological Chemistry 289 (19): 13492–13502. May 2014. doi:10.1074/jbc.M114.549832. PMID 24652290. 
  38. ↑ "Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy". Clinical Cancer Research 14 (5): 1487–1493. March 2008. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573. 
  39. ↑ "Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance". FEBS Letters 239 (1): 18–22. October 1988. doi:10.1016/0014-5793(88)80537-4. PMID 3181423. 
  40. ↑ 40.0 40.1 40.2 "Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters". BioDrugs 29 (4): 215–239. August 2015. doi:10.1007/s40259-015-0133-6. PMID 26177629. 
  41. ↑ "Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis". Clinical Therapeutics 21 (1): 75–87; discussion 1–2. January 1999. doi:10.1016/S0149-2918(00)88269-7. PMID 10090426. 
  42. ↑ "The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease". The Journal of Clinical Investigation 113 (9): 1328–1333. May 2004. doi:10.1172/JCI18838. PMID 15124024. 
  43. ↑ 43.0 43.1 "Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia". Journal of Pharmaceutical Sciences 92 (6): 1206–1215. June 2003. doi:10.1002/jps.10364. PMID 12761810. 
  44. ↑ 44.0 44.1 "Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model". Journal of Immunology 187 (2): 1015–1022. July 2011. doi:10.4049/jimmunol.1003780. PMID 21690327. 
  45. ↑ "The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy". Advanced Drug Delivery Reviews. Editor's Collection 2015 91: 109–124. August 2015. doi:10.1016/j.addr.2015.02.005. PMID 25703189. 
  46. ↑ "Anti-inflammatory actions of intravenous immunoglobulin". Annual Review of Immunology 26 (1): 513–533. 2008-01-01. doi:10.1146/annurev.immunol.26.021607.090232. PMID 18370923. 
  47. ↑ 47.0 47.1 "Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels". Nature Biotechnology 23 (10): 1283–1288. October 2005. doi:10.1038/nbt1143. PMID 16186811. 
  48. ↑ "Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans". The Journal of Clinical Investigation 128 (10): 4372–4386. October 2018. doi:10.1172/JCI97911. PMID 30040076. 
  49. ↑ "Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates". Frontiers in Immunology 6: 176. 2015. doi:10.3389/fimmu.2015.00176. PMID 25954273. 
  50. ↑ "The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study". Science Translational Medicine 9 (414): eaan1208. November 2017. doi:10.1126/scitranslmed.aan1208. PMID 29093180. 
  51. ↑ "Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses". Science Advances 5 (12): eaax9586. December 2019. doi:10.1126/sciadv.aax9586. PMID 31897428. Bibcode: 2019SciA....5.9586B. 
  52. ↑ "Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia". American Journal of Hematology 95 (2): 178–187. February 2020. doi:10.1002/ajh.25680. PMID 31821591. 
  53. ↑ "Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia". Blood Advances 4 (17): 4136–4146. September 2020. doi:10.1182/bloodadvances.2020002003. PMID 32886753. 
  54. ↑ "Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus". The Journal of Investigative Dermatology 141 (12): 2858–2865.e4. December 2021. doi:10.1016/j.jid.2021.04.031. PMID 34126109. 
  55. ↑ "Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial". The British Journal of Dermatology 186 (3): 429–439. October 2021. doi:10.1111/bjd.20782. PMID 34608631. 
  56. ↑ "argenx Announces U.S. Food and Drug Administration (FDA) Approval of VYVGART™ (efgartigimod alfa-fcab) in Generalized Myasthenia Gravis". Argenx. 17 December 2021. https://www.argenx.com/news/argenx-announces-us-food-and-drug-administration-fda-approval-vyvgarttm-efgartigimod-alfa-fcab. 

Further reading

External links




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