Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans
Peter Ulrichts, … , Hans de Haard, Nicolas Leupin
Peter Ulrichts, … , Hans de Haard, Nicolas Leupin
Published July 24, 2018
Citation Information: J Clin Invest. 2018;128(10):4372-4386. https://doi.org/10.1172/JCI97911.
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Clinical Research and Public Health Autoimmunity

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

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.

Authors

Peter Ulrichts, Antonio Guglietta, Torsten Dreier, Tonke van Bragt, Valérie Hanssens, Erik Hofman, Bernhardt Vankerckhoven, Peter Verheesen, Nicolas Ongenae, Valentina Lykhopiy, F. Javier Enriquez, JunHaeng Cho, Raimund J. Ober, E. Sally Ward, Hans de Haard, Nicolas Leupin

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Figure 2

Differences in subcellular trafficking behavior between efgartigimod and anti-FcRn Ab.

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Differences in subcellular trafficking behavior between efgartigimod and...
(A) HMEC-1 cells expressing hFcRn-GFP were pulse-chased with Alexa Fluor 647–labeled efgartigimod, isotype control (HEL-specific hIgG1), or anti-FcRn Ab at concentrations of 25, 200, and 75 μg/ml, respectively, for 30 minutes and chased for 0, 30, and 120 minutes. Levels of cell-associated Alexa Fluor 647 were determined using flow cytometry. Representative histogram plots for 2 independent experiments are shown. (B) Cell-associated fluorescence levels for analyses carried out as in panel A, displayed as the percentage of fluorescence remaining at different chase times relative to the pulse-only samples. For chase times of 30 and 120 minutes, means of 4 samples (2 samples per experiment, 2 experiments) are shown. Error bars indicate SEM, and statistical significance of the difference between efgartigimod and hIgG1 following a 30-minute chase is indicated. *P < 0.05, 1-way ANOVA. (C) HMEC-1 cells expressing human FcRn-GFP were pulse-chased with 500 μg/ml Alexa Fluor 555–labeled dextran and then pulse-chased (30-minute pulse, 0- or 16-hour chase) with Alexa Fluor 647–labeled efgartigimod (25 μg/ml) or anti-FcRn Ab (75 μg/ml). Images of representative cells are shown, with arrowheads in the anti-FcRn panel (16 hours) indicating Ab that is localized in dextran-positive compartments. Data for Alexa Fluor 647–labeled efgartigimod or Alexa Fluor 647–labeled anti-FcRn and FcRn-GFP are displayed as acquired. The lysosomes in boxed regions (labeled 1 and 2 for each inhibitor) are cropped and expanded (lower panels), and pixel intensities along the dotted lines are shown. Intensities are normalized against the highest pixel value in each 16-hour image (Alexa Fluor 555) or for both 16-hour images (Alexa Fluor 647). GFP, Alexa Fluor 555, and Alexa Fluor 647 are pseudocolored blue, red, and green, respectively. Scale bars: 3 μm (upper panels); 1 μm (cropped lysosomes). Microscopy data are representative of at least 2 independent experiments.