Neonatal fragment crystallizable receptor explained

Fc fragment of IgG, receptor, transporter, alpha
Hgncid:3621
Symbol:FCGRT
Entrezgene:2217
Omim:601437
Refseq:NM_004107
Uniprot:P55899
Chromosome:19
Arm:q
Band:13.3

The neonatal fragment crystallizable (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.[8] FcRn has also been shown to play a role in regulating IgG and serum albumin turnover.[9] [10] [11] Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF, and down-regulated by IFN-γ.

Interactions of FcRn with IgG and serum albumin

In addition to binding to IgG, FCGRT has been shown to interact with human serum albumin.[12] [13] 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.[14] 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.[15] [16]

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[17] and bone-marrow derived cells.[18] [19] [20] The clearance rate of IgG and albumin is abnormally short in mice that lack functional FcRn. 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.[21] In this way, IgG and serum albumin are salvaged to avoid lysosomal degradation.[22] [23] [24] This cellular mechanism provides an explanation for the prolonged in vivo half-lives of IgG and serum albumin and transport of these ligands across cellular barriers.[25] 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.

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.[26] In the kidneys, FcRn is expressed on epithelial cells called podocytes to prevent IgG and albumin from clogging the glomerular filtration barrier.[27] [28] 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.[29] [30] Studies have also shown that FcRn-mediated transcytosis is involved with the trafficking of the HIV-1 virus across genital tract epithelium.[31]

Half-life extension of therapeutic proteins

The identification of FcRn as a central regulator of IgG levels led to the engineering of IgG-FcRn interactions to increase in vivo persistence of IgG.[32] [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). Enbrel (etanercept) was the first successful IgG Fc-linked soluble receptor therapeutic and works by binding and neutralizing the pro-inflammatory cytokine, TNF-α.[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. 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.[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] [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 was recently approved (as 'Vyvgart') for the treatment of generalized myasthenia gravis in December 2021.[56]

Further reading

Notes and References

  1. Story CM, Mikulska JE, Simister NE . 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 . 7964511 . 2191771 . 10.1084/jem.180.6.2377 .
  2. Kandil E, Egashira M, Miyoshi O, Niikawa N, Ishibashi T, Kasahara M, Miyosi O . 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 . 8646894 . 10.1159/000134316 .
  3. Web site: Entrez Gene: FCGRT Fc fragment of IgG, receptor, transporter, alpha.
  4. Simister NE, Mostov KE. Keith E. Mostov . 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 . 2534798 . 10.1101/sqb.1989.054.01.068 .
  5. Kuo TT, Aveson VG . Neonatal Fc receptor and IgG-based therapeutics . mAbs . 3 . 5 . 422–430 . 2011-01-01 . 22048693 . 3225846 . 10.4161/mabs.3.5.16983 .
  6. Rodewald R, Kraehenbuhl JP . Receptor-mediated transport of IgG . The Journal of Cell Biology . 99 . 1 Pt 2 . 159s–164s . July 1984 . 6235233 . 2275593 . 10.1083/jcb.99.1.159s .
  7. Simister NE, Rees AR . Isolation and characterization of an Fc receptor from neonatal rat small intestine . European Journal of Immunology . 15 . 7 . 733–738 . July 1985 . 2988974 . 10.1002/eji.1830150718 . 42396197 .
  8. Firan M, Bawdon R, Radu C, Ober RJ, Eaken D, Antohe F, Ghetie V, Ward ES . 6 . 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 . 11470769 . 10.1093/intimm/13.8.993 . free .
  9. Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES . Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice . European Journal of Immunology . 26 . 3 . 690–696 . March 1996 . 8605939 . 10.1002/eji.1830260327 . 85730132 . free .
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  11. Book: Ward ES, Ober RJ . Chapter 4: Multitasking by exploitation of intracellular transport functions the many faces of FcRn . Advances in Immunology . 103 . 77–115 . 2009 . 19755184 . 4485553 . 10.1016/S0065-2776(09)03004-1 . 978-0-12-374832-4 .
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  13. Andersen JT, Dee Qian J, Sandlie I . 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 . 17048273 . 10.1002/eji.200636556 . 22024929 .
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  15. Kim JK, Tsen MF, Ghetie V, Ward ES . 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 . 7925571 . 10.1002/eji.1830241025 . 43499403 .
  16. Martin WL, West AP, Gan L, Bjorkman PJ . 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 . 11336709 . 10.1016/s1097-2765(01)00230-1 . free .
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  18. Akilesh S, Christianson GJ, Roopenian DC, Shaw AS . Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism . Journal of Immunology . 179 . 7 . 4580–4588 . October 2007 . 17878355 . 10.4049/jimmunol.179.7.4580 . free .
  19. Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E, Roopenian DC, Lencer WI, Blumberg RS . 6 . 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 . 18599440 . 2453734 . 10.1073/pnas.0801717105 . free . 2008PNAS..105.9337Q .
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  21. Prabhat P, Gan Z, Chao J, Ram S, Vaccaro C, Gibbons S, Ober RJ, Ward ES . 6 . 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 . 17384151 . 1851587 . 10.1073/pnas.0700337104 . free . 2007PNAS..104.5889P .
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  24. Larsen MT, Rawsthorne H, Schelde KK, Dagnæs-Hansen F, Cameron J, Howard KA . 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 . 30016735 . 10.1016/j.jconrel.2018.07.023 . 51677989 .
  25. Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI . 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 . 12163559 . 2193935 . 10.1084/jem.20020400 .
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  56. Web site: 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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