Neonatal Fc receptor

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Fc fragment of IgG, receptor, transporter, alpha
NCBI gene2217
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LocusChr. 19 q13.3
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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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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]


  1. ^ a b Story CM, Mikulska JE, Simister NE (December 1994). "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. doi:10.1084/jem.180.6.2377. PMC 2191771. PMID 7964511.
  2. ^ Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O (July 1996). "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. doi:10.1159/000134316. PMID 8646894.
  3. ^ "Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha".
  4. ^ Simister NE, Mostov KE (1989). "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. doi:10.1101/sqb.1989.054.01.068. PMID 2534798.
  5. ^ Kuo TT, Aveson VG (2011-01-01). "Neonatal Fc receptor and IgG-based therapeutics". mAbs. 3 (5): 422–430. doi:10.4161/mabs.3.5.16983. PMC 3225846. PMID 22048693.
  6. ^ a b c Rodewald R, Kraehenbuhl JP (July 1984). "Receptor-mediated transport of IgG". The Journal of Cell Biology. 99 (1 Pt 2): 159s–164s. doi:10.1083/jcb.99.1.159s. PMC 2275593. PMID 6235233.
  7. ^ a b c Simister NE, Rees AR (July 1985). "Isolation and characterization of an Fc receptor from neonatal rat small intestine". European Journal of Immunology. 15 (7): 733–738. doi:10.1002/eji.1830150718. PMID 2988974. S2CID 42396197.
  8. ^ a b Firan M, Bawdon R, Radu C, Ober RJ, Eaken D, Antohe F, et al. (August 2001). "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. doi:10.1093/intimm/13.8.993. PMID 11470769.
  9. ^ a b c Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES (March 1996). "Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice". European Journal of Immunology. 26 (3): 690–696. doi:10.1002/eji.1830260327. PMID 8605939. S2CID 85730132.
  10. ^ a b c 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. doi:10.1084/jem.20021829. PMC 2193842. PMID 12566415.
  11. ^ a b Ghetie V, Popov S, Borvak J, Radu C, Matesoi D, Medesan C, et al. (July 1997). "Increasing the serum persistence of an IgG fragment by random mutagenesis". Nature Biotechnology. 15 (7): 637–640. doi:10.1038/nbt0797-637. PMID 9219265. S2CID 39836528.
  12. ^ a b Roopenian DC, Akilesh S (September 2007). "FcRn: the neonatal Fc receptor comes of age". Nature Reviews. Immunology. 7 (9): 715–725. doi:10.1038/nri2155. PMID 17703228. S2CID 6980400.
  13. ^ a b Ward ES, Ober RJ (2009). "Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn". Advances in Immunology. 103: 77–115. doi:10.1016/S0065-2776(09)03004-1. PMC 4485553. PMID 19755184.
  14. ^ a b Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, Blumberg RS (November 2010). "Neonatal Fc receptor: from immunity to therapeutics". Journal of Clinical Immunology. 30 (6): 777–789. doi:10.1007/s10875-010-9468-4. PMC 2970823. PMID 20886282.
  15. ^ Andersen JT, Dee Qian J, Sandlie I (November 2006). "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. doi:10.1002/eji.200636556. PMID 17048273. S2CID 22024929.
  16. ^ a b c Dickinson BL, Badizadegan K, Wu Z, Ahouse JC, Zhu X, Simister NE, et al. (October 1999). "Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line". The Journal of Clinical Investigation. 104 (7): 903–911. doi:10.1172/JCI6968. PMC 408555. PMID 10510331.
  17. ^ Kim JK, Tsen MF, Ghetie V, Ward ES (October 1994). "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. doi:10.1002/eji.1830241025. PMID 7925571. S2CID 43499403.
  18. ^ Martin WL, West AP, Gan L, Bjorkman PJ (April 2001). "Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding". Molecular Cell. 7 (4): 867–877. doi:10.1016/s1097-2765(01)00230-1. PMID 11336709.
  19. ^ Ward ES, Zhou J, Ghetie V, Ober RJ (February 2003). "Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans". International Immunology. 15 (2): 187–195. doi:10.1093/intimm/dxg018. PMID 12578848.
  20. ^ Akilesh S, Christianson GJ, Roopenian DC, Shaw AS (October 2007). "Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism". Journal of Immunology. 179 (7): 4580–4588. doi:10.4049/jimmunol.179.7.4580. PMID 17878355.
  21. ^ Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E, et al. (July 2008). "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. Bibcode:2008PNAS..105.9337Q. doi:10.1073/pnas.0801717105. PMC 2453734. PMID 18599440.
  22. ^ Montoyo HP, Vaccaro C, Hafner M, Ober RJ, Mueller W, Ward ES (February 2009). "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. Bibcode:2009PNAS..106.2788M. doi:10.1073/pnas.0810796106. PMC 2650344. PMID 19188594.
  23. ^ a b c 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. doi:10.4049/jimmunol.172.4.2021. PMID 14764666. S2CID 30526875.
  24. ^ a b Ober RJ, Martinez C, Lai X, Zhou J, Ward ES (July 2004). "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. Bibcode:2004PNAS..10111076O. doi:10.1073/pnas.0402970101. PMC 503743. PMID 15258288.
  25. ^ Prabhat P, Gan Z, Chao J, Ram S, Vaccaro C, Gibbons S, et al. (April 2007). "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. doi:10.1073/pnas.0700337104. PMC 1851587. PMID 17384151.
  26. ^ Larsen MT, Rawsthorne H, Schelde KK, Dagnæs-Hansen F, Cameron J, Howard KA (October 2018). "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. doi:10.1016/j.jconrel.2018.07.023. PMID 30016735. S2CID 51677989.
  27. ^ Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI (August 2002). "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. doi:10.1084/jem.20020400. PMC 2193935. PMID 12163559.
  28. ^ Akilesh S, Huber TB, Wu H, Wang G, Hartleben B, Kopp JB, et al. (January 2008). "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. doi:10.1073/pnas.0711515105. PMC 2242706. PMID 18198272.
  29. ^ Bern M, Sand KM, Nilsen J, Sandlie I, Andersen JT (August 2015). "The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery". Journal of Controlled Release. 211: 144–162. doi:10.1016/j.jconrel.2015.06.006. PMID 26055641.
  30. ^ Sand KM, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT (2015-01-26). "Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics". Frontiers in Immunology. 5: 682. doi:10.3389/fimmu.2014.00682. PMC 4306297. PMID 25674083.
  31. ^ Pyzik M, Rath T, Kuo TT, Win S, Baker K, Hubbard JJ, et al. (April 2017). "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. doi:10.1073/pnas.1618291114. PMC 5389309. PMID 28330995.
  32. ^ Gupta S, Gach JS, Becerra JC, Phan TB, Pudney J, Moldoveanu Z, et al. (2013-11-01). "The Neonatal Fc receptor (FcRn) enhances human immunodeficiency virus type 1 (HIV-1) transcytosis across epithelial cells". PLOS Pathogens. 9 (11): e1003776. doi:10.1371/journal.ppat.1003776. PMC 3836734. PMID 24278022.
  33. ^ a b Ward ES, Ober RJ (October 2018). "Targeting FcRn to Generate Antibody-Based Therapeutics". Trends in Pharmacological Sciences. 39 (10): 892–904. doi:10.1016/ PMC 6169532. PMID 30143244.
  34. ^ "Ultomiris® (ravulizumab-cwvz) | Alexion". Retrieved 2021-10-03.
  35. ^ Dall'Acqua WF, Woods RM, Ward ES, Palaszynski SR, Patel NK, Brewah YA, et al. (November 2002). "Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences". Journal of Immunology. 169 (9): 5171–5180. doi:10.4049/jimmunol.169.9.5171. PMID 12391234. S2CID 29398244.
  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.
  37. ^ Andersen JT, Dalhus B, Viuff D, Ravn BT, Gunnarsen KS, Plumridge A, et al. (May 2014). "Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding". The Journal of Biological Chemistry. 289 (19): 13492–13502. doi:10.1074/jbc.M114.549832. PMC 4036356. PMID 24652290.
  38. ^ Lee TY, Tjin Tham Sjin RM, Movahedi S, Ahmed B, Pravda EA, Lo KM, et al. (March 2008). "Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy". Clinical Cancer Research. 14 (5): 1487–1493. doi:10.1158/1078-0432.CCR-07-1530. PMID 18316573.
  39. ^ Poznansky MJ, Halford J, Taylor D (October 1988). "Growth hormone-albumin conjugates. Reduced renal toxicity and altered plasma clearance". FEBS Letters. 239 (1): 18–22. doi:10.1016/0014-5793(88)80537-4. PMID 3181423. S2CID 38592689.
  40. ^ a b c Strohl WR (August 2015). "Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters". BioDrugs. 29 (4): 215–239. doi:10.1007/s40259-015-0133-6. PMC 4562006. PMID 26177629.
  41. ^ Goldenberg MM (January 1999). "Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis". Clinical Therapeutics. 21 (1): 75–87, discussion 1–2. doi:10.1016/S0149-2918(00)88269-7. PMID 10090426.
  42. ^ Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D (May 2004). "The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease". The Journal of Clinical Investigation. 113 (9): 1328–1333. doi:10.1172/JCI18838. PMC 398424. PMID 15124024.
  43. ^ a b Hansen RJ, Balthasar JP (June 2003). "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. doi:10.1002/jps.10364. PMID 12761810.
  44. ^ a b Patel DA, Puig-Canto A, Challa DK, Perez Montoyo H, Ober RJ, Ward ES (July 2011). "Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model". Journal of Immunology. 187 (2): 1015–1022. doi:10.4049/jimmunol.1003780. PMC 3157913. PMID 21690327.
  45. ^ Sockolosky JT, Szoka FC (August 2015). "The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy". Advanced Drug Delivery Reviews. Editor's Collection 2015. 91: 109–124. doi:10.1016/j.addr.2015.02.005. PMC 4544678. PMID 25703189.
  46. ^ Nimmerjahn F, Ravetch JV (2008-01-01). "Anti-inflammatory actions of intravenous immunoglobulin". Annual Review of Immunology. 26 (1): 513–533. doi:10.1146/annurev.immunol.26.021607.090232. PMID 18370923.
  47. ^ a b Vaccaro C, Zhou J, Ober RJ, Ward ES (October 2005). "Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels". Nature Biotechnology. 23 (10): 1283–1288. doi:10.1038/nbt1143. PMID 16186811. S2CID 13526188.
  48. ^ Ulrichts P, Guglietta A, Dreier T, van Bragt T, Hanssens V, Hofman E, et al. (October 2018). "Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans". The Journal of Clinical Investigation. 128 (10): 4372–4386. doi:10.1172/JCI97911. PMC 6159959. PMID 30040076.
  49. ^ Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, Dumont J, et al. (2015). "Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates". Frontiers in Immunology. 6: 176. doi:10.3389/fimmu.2015.00176. PMC 4407741. PMID 25954273.
  50. ^ Kiessling P, Lledo-Garcia R, Watanabe S, Langdon G, Tran D, Bari M, et al. (November 2017). "The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study". Science Translational Medicine. 9 (414): eaan1208. doi:10.1126/scitranslmed.aan1208. PMID 29093180. S2CID 206694327.
  51. ^ Blumberg LJ, Humphries JE, Jones SD, Pearce LB, Holgate R, Hearn A, et al. (December 2019). "Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses". Science Advances. 5 (12): eaax9586. Bibcode:2019SciA....5.9586B. doi:10.1126/sciadv.aax9586. PMC 6920022. PMID 31897428.
  52. ^ Newland AC, Sánchez-González B, Rejtő L, Egyed M, Romanyuk N, Godar M, et al. (February 2020). "Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia". American Journal of Hematology. 95 (2): 178–187. doi:10.1002/ajh.25680. PMC 7004056. PMID 31821591.
  53. ^ Robak T, Kaźmierczak M, Jarque I, Musteata V, Treliński J, Cooper N, et al. (September 2020). "Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia". Blood Advances. 4 (17): 4136–4146. doi:10.1182/bloodadvances.2020002003. PMC 7479959. PMID 32886753.
  54. ^ Werth VP, Culton DA, Concha JS, Graydon JS, Blumberg LJ, Okawa J, et al. (December 2021). "Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus". The Journal of Investigative Dermatology. 141 (12): 2858–2865.e4. doi:10.1016/j.jid.2021.04.031. PMID 34126109. S2CID 235439165.
  55. ^ Goebeler M, Bata-Csörgő Z, De Simone C, Didona B, Remenyik E, Reznichenko N, et al. (October 2021). "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. doi:10.1111/bjd.20782. PMID 34608631. S2CID 238355823.
  56. ^ "argenx Announces U.S. Food and Drug Administration (FDA) Approval of VYVGART™ (efgartigimod alfa-fcab) in Generalized Myasthenia Gravis". Argenx. 17 December 2021.

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