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Cited by 427Monoclonal and Polyclonal Antibodies ResearchImmunodeficiency and Autoimmune DisordersSystemic Lupus Erythematosus Research

Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans

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Ulrichts, Peter, Guglietta, Antonio, Dreier, Torsten, van Bragt, Tonke, Hanssens, Valérie, Hofman, Erik, Vankerckhoven, Bernhardt, Verheesen, Peter +8 more·2018·Journal of Clinical Investigation
DOI 10.1172/jci97911PMC PMC6159959
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Abstract

BACKGROUND: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs. METHODS: A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys. RESULTS: Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed. CONCLUSION: Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT03457649. FUNDING: argenx BVBA.

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  • MST-HN IgG Fc is an analog of efgartigimod, a competitive antagonist with weaker affinity and pH-dependent binding to FcRn.

    “Another anti-FcRn therapeutic, the Fc fragment MST-HN IgG Fc (an analog of efgartigimod), a competitive antagonist with weaker affinity and pH-dependent binding to FcRn, was included for comparison.”

    From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [18]

    The Introduction (page unavailable) identifies efgartigimod as an IgG1-derived Fc fragment with pH-dependent FcRn binding, and the discussion describes how it outcompetes IgG for FcRn. Our copy does not identify MST-HN IgG Fc or establish that it is an efgartigimod analog with weaker affinity; searches for MST-HN and the affinity comparison found no such passage. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • In vitro studies have shown that blocking FcRn function leads to a decrease in the salvage of IgG, which instead gets routed into lysosomal compartments for degradation.

    “in vitro studies have shown that blocking FcRn function leads to a decrease in the salvage of IgG, which instead gets routed into lysosomal compartments for degradation [17,18].”

    From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [18]

    The Introduction explains that FcRn salvages IgG through recycling and says blocking the FcRn–IgG interaction is expected to cause IgG degradation and faster clearance. Its in vitro microscopy shows an anti-FcRn antibody in lysosomes, but does not show that blocked IgG itself was routed there for degradation. The claim presents that specific outcome as demonstrated in vitro rather than expected. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Treatment with both rozanolixizumab and MST-HN IgG Fc generally leads to a sustained reduction of IgG levels by 60-80% from baseline levels in humans.

    “Despite these different molecular properties, treatment with both agents generally leads to a sustained reduction of IgG levels by 60–80% from baseline levels in humans [18,22].”

    From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [18]

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Research works printed but not linked: 53

  1. Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of autoimmune dis- eases: improved prevalence estimates and under- standing of clustering of diseases. J Autoimmun. 2009;33(3-4):197-207. · DOI
  2. Sinha AA, Lopez MT, McDevitt HO. Autoimmune diseases: the failure of self tolerance. Science. 1990;248(4961):1380-1388. · DOI
  3. Sesarman A, Vidarsson G, Sitaru C. The neo- natal Fc receptor as therapeutic target in IgG- mediated autoimmune diseases. Cell Mol Life Sci. 2010;67(15):2533-2550. · DOI
  4. Bambauer R, Latza R, Burgard D, Schiel R. Ther- apeutic apheresis in hematologic, autoimmune and dermatologic diseases with immunologic origin. Ther Apher Dial. 2016;20(5):433-452. · DOI
  5. Perez EE, et al. Update on the use of immuno- globulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1-S46.
  6. Low SC, Mezo AR. Inhibitors of the FcRn:IgG protein-protein interaction. AAPS J. 2009;11(3):432-434. · DOI
  7. Brambell FW. The transmission of immunity from mother to young and the catabolism of immuno- globulins. Lancet. 1966;2(7473):1087-1093.
  8. Challa DK, Velmurugan R, Ober RJ, Sally Ward E. FcRn: from molecular interactions to regulation of IgG pharmacokinetics and functions. Curr Top Microbiol Immunol. 2014;382:249-272.
  9. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715-725. · DOI · Paper page
  10. Ober RJ, Martinez C, Lai X, Zhou J, Ward ES. Exo- cytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level. Proc Natl Acad Sci U S A. 2004;101(30):11076-11081. · DOI · Paper page
  11. Ober RJ, Martinez C, Vaccaro C, Zhou J, Ward ES. Visualizing the site and dynamics of IgG salvage by the MHC class I-related receptor, FcRn. J Immunol. 2004;172(4):2021-2029. · DOI · Paper page
  12. 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. Eur J Immunol. 1996;26(3):690-696. · DOI
  13. Roopenian DC, et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol. 2003;170(7):3528-3533. · DOI
  14. Sand KM, Bern M, Nilsen J, Noordzij HT, Sand- lie I, Andersen JT. Unraveling the interaction between FcRn and albumin: opportunities for design of albumin-based therapeutics. Front Immunol. 2014;5:682.
  15. Vaccaro C, Zhou J, Ober RJ, Ward ES. Engi- neering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 2005;23(10):1283-1288. · DOI · Paper page
  16. Challa DK, et al. Autoantibody depletion amelio- rates disease in murine experimental autoimmune encephalomyelitis. MAbs. 2013;5(5):655-659. · DOI
  17. Patel DA, Puig-Canto A, Challa DK, Perez Montoyo H, Ober RJ, Ward ES. Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. J Immunol. 2011;187(2):1015-1022. · DOI
  18. Nixon AE, et al. Fully human monoclonal anti- body inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates. Front Immunol. 2015;6:176.
  19. Ward ES, Martinez C, Vaccaro C, Zhou J, Tang Q, Ober RJ. From sorting endosomes to exocytosis: association of Rab4 and Rab11 GTPases with the Fc receptor, FcRn, during recycling. Mol Biol Cell. 2005;16(4):2028-2038. · DOI · Paper page
  20. Abdiche YN, et al. The neonatal Fc receptor (FcRn) binds independently to both sites of the IgG homodimer with identical affinity. MAbs. 2015;7(2):331-343. · DOI · Paper page
  21. Clynes R. Protective mechanisms of IVIG. Curr Opin Immunol. 2007;19(6):646-651. · DOI
  22. Dirks NL, Meibohm B. Population pharmacoki- netics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633-659. · DOI · Paper page
  23. Martins JP, Kennedy PJ, Santos HA, Barrias C, Sarmento B. A comprehensive review of the neonatal Fc receptor and its application in drug delivery. Pharmacol Ther. 2016;161:22-39. · DOI
  24. Dall'Acqua WF, et al. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol. 2002;169(9):5171-5180. · DOI
  25. Borrok MJ, et al. pH-dependent binding engineering reveals an FcRn affinity thresh- old that governs IgG recycling. J Biol Chem. 2015;290(7):4282-4290. · DOI
  26. Vaccaro C, Bawdon R, Wanjie S, Ober RJ, Ward ES. Divergent activities of an engineered anti- body in murine and human systems have impli- cations for therapeutic antibodies. Proc Natl Acad Sci U S A. 2006;103(49):18709-18714. · DOI
  27. Waldmann TA, Terry WD. Familial hypercatabol- ic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin. J Clin Invest. 1990;86(6):2093-2098. · DOI
  28. Wani MA, et al. Familial hypercatabolic hypo- proteinemia caused by deficiency of the neo- natal Fc receptor, FcRn, due to a mutant beta2- microglobulin gene. Proc Natl Acad Sci U S A. 2006;103(13):5084-5089. · DOI
  29. Derksen RH, Schuurman HJ, Gmelig Meyling FH, Struyvenberg A, Kater L. Rebound and overshoot after plasma exchange in humans. J Lab Clin Med. 1984;104(1):35-43.
  30. Neuber T, et al. Characterization and screening of IgG binding to the neonatal Fc receptor. MAbs. 2014;6(4):928-942. · DOI
  31. West AP, Bjorkman PJ. Crystal structure and immu- noglobulin G binding properties of the human major histocompatibility complex-related Fc recep- tor. Biochemistry. 2000;39(32):9698-9708. · DOI
  32. Weflen AW, et al. Multivalent immune com- plexes divert FcRn to lysosomes by exclusion from recycling sorting tubules. Mol Biol Cell. 2013;24(15):2398-2405. · DOI · Paper page
  33. Baker K, et al. Neonatal Fc receptor expres- sion in dendritic cells mediates protective immunity against colorectal cancer. Immunity. 2013;39(6):1095-1107. · DOI
  34. Liu JF, et al. Comparing the autoantibody lev- els and clinical efficacy of double filtration plasmapheresis, immunoadsorption, and intra- venous immunoglobulin for the treatment of late-onset myasthenia gravis. Ther Apher Dial. 2010;14(2):153-160. · DOI
  35. Schmidt E, et al. Protein A immunoadsorp- tion: a novel and effective adjuvant treat- ment of severe pemphigus. Br J Dermatol. 2003;148(6):1222-1229. · DOI
  36. Snyder HW, Bertram JH, Channel M, Ernst NR, Balint JP, Jones FR. Reduction in platelet-binding immunoglobulins and improvement in platelet counts in patients with HIV-associated idiopathic thrombocytopenia purpura (ITP) following extracorporeal immunoadsorption of plasma over staphylococcal protein A-silica. Artif Organs. 1989;13(1):71-77. · DOI
  37. Grevys A, et al. Fc Engineering of human IgG1 for altered binding to the neonatal Fc recep- tor affects Fc effector functions. J Immunol. 2015;194(11):5497-5508. · DOI
  38. Furst DE. Serum immunoglobulins and risk of infection: how low can you go? Semin Arthritis Rheum. 2009;39(1):18-29. · DOI
  39. Jacob S, Rajabally YA. Current proposed mecha- nisms of action of intravenous immunoglobulins in inflammatory neuropathies. Curr Neurophar- macol. 2009;7(4):337-342. · DOI
  40. Finkel AG, Howard JF, Mann JD. Successful treatment of headache related to intravenous immunoglobulin with antimigraine medications. Headache. 1998;38(4):317-321. · DOI
  41. Kobrynski L. Subcutaneous immunoglobulin therapy: a new option for patients with pri- mary immunodeficiency diseases. Biologics. 2012;6:277-287.
  42. Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev. 2013;27(3):171-178. · DOI
  43. Oshima H, et al. Characterization of murine CD70 by molecular cloning and mAb. Int Immu- nol. 1998;10(4):517-526. · DOI
  44. Foote J, Winter G. Antibody framework residues affecting the conformation of the hypervariable loops. J Mol Biol. 1992;224(2):487-499. · DOI
  45. Popov S, Hubbard JG, Kim J, Ober B, Ghetie V, Ward ES. The stoichiometry and affinity of the interaction of murine Fc fragments with the MHC class I-related receptor, FcRn. Mol Immu- nol. 1996;33(6):521-530. · DOI
  46. Firan M, et al. The MHC class I-related receptor, FcRn, plays an essential role in the materno fetal transfer of gamma-globulin in humans. Int Immunol. 2001;13(8):993-1002. · DOI · Paper page
  47. Ober RJ, Caves J, Ward ES. Analysis of exponen- tial data using a noniterative technique: applica- tion to surface plasmon experiments. Anal Biochem. 2003;312(1):57-65. · DOI
  48. Zhou J, Mateos F, Ober RJ, Ward ES. Conferring the binding properties of the mouse MHC class I-related receptor, FcRn, onto the human ortho- log by sequential rounds of site-directed muta- genesis. J Mol Biol. 2005;345(5):1071-1081. · DOI
  49. Chao J, Ward ES, Ober RJ. A software frame- work for the analysis of complex microscopy image data. IEEE Trans Inf Technol Biomed. 2010;14(4):1075-1087. · DOI
  50. van Dongen JJ, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26(9):1908-1975. · DOI
  51. Gough K, et al. Assessment of dose proportionality: report from the statisticians in the Pharmaceuti- cal Industry/Pharmacokinetics UK Joint Working Party. Drug Inf J. 1995;29(3):1039-1048. · DOI
  52. Deisenhofer J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9-and 2.8-A resolu- tion. Biochemistry. 1981;20(9):2361-2370. · DOI
  53. Kim JK, Firan M, Radu CG, Kim CH, Ghetie V, Ward ES. Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn. Eur J Immunol. 1999;29(9):2819-2825. · DOI

Cited by

Sorted by citations

Authors
Ulrichts, P., Guglietta, A., Dreier, T., van Bragt, T., Hanssens, V., Hofman, E., Vankerckhoven, B., Verheesen, P., Ongenae, N., Lykhopiy, V., Enriquez, F. J., Cho, J., Ober, R. J., Ward, E. S., de Haard, H., & Leupin, N.
Affiliations
  • Argenx (Belgium) (BE)
  • Texas A&M Health Science Center (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2018-07-24
Volume
128
Issue
10
Pages
4372-4386
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci97911
PMC
PMC6159959
OpenAlex
W2883123810
Cited by
427
References
0
Citations by year
2026: 110 · 2025: 93 · 2024: 74 · 2023: 35 · 2022: 36 · 2021: 28 · 2020: 26 · 2019: 23 · 2018: 2
FWCI
13.65
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • Lirias (submittedVersion)
Funders
argenx bvba (not applicable)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords
efgartigimod, neonatal Fc receptor, IgG clearance, autoimmune disease, pharmacokinetics, pharmacodynamics, immunogenicity, first-in-human safety, healthy volunteers
MeSH terms
Adult, Animals, Autoantibodies, Autoimmune Diseases, Cricetulus, Double-Blind Method, Female, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Macaca fascicularis, Male, Receptors, Fc, Histocompatibility Antigens Class I, CHO Cells

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