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Review
. 2020 Sep;146(3):479-491.e5.
doi: 10.1016/j.jaci.2020.07.016.

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations

Hans-Hartmut Peter  1 , Hans D Ochs  2 , Charlotte Cunningham-Rundles  3 , Donald C Vinh  4 , Peter Kiessling  5 , Bernhard Greve  5 , Stephen Jolles  6
Affiliations
Review

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations

Hans-Hartmut Peter et al. J Allergy Clin Immunol. 2020 Sep.

Abstract

The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.

Keywords: FcRn; FcRn inhibitors; IgG; albumin; antibody-mediated autoimmunity; autoantibody; hypogammaglobulinemia; immunoglobulin; infection risk; neonatal Fc receptor.

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Figures

Fig 1
Fig 1
Distribution and function of immunoglobulin isotypes. PIgR, Polymeric immunoglobulin receptor.
Fig E1
Fig E1
Impact of selected primary and secondary antibody deficiencies on IgG., , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , APRIL, A proliferation-inducing ligand; BAFF, B-cell activating factor; BLyS, B-lymphocyte stimulator; DMARD, disease-modifying antirheumatic drug; JAK, Janus kinase.
See this image and copyright information in PMC

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