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IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis

IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis
IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis
The neonatal Fc receptor (FcRn) is an MHC class I–like molecule that is widely distributed in mammalian organs, tissues, and cells. FcRn is critical to maintaining immunoglobulin G (IgG) and albumin levels through rescuing these molecules from lysosomal degradation. IgG autoantibodies are associated with many autoimmune diseases, including myasthenia gravis (MG), a rare neuromuscular autoimmune disease that causes debilitating and, in its generalized form (gMG), potentially life-threatening muscle weakness. IgG autoantibodies are directly pathogenic in MG and target neuromuscular junction proteins, causing neuromuscular transmission failure. Treatment approaches that reduce autoantibody levels, such as therapeutic plasma exchange and intravenous immunoglobulin, have been shown to be effective for gMG patients but are not indicated as ongoing maintenance therapies and can be associated with burdensome side effects. Agents that block FcRn-mediated recycling of IgG represent a rational and promising approach for the treatment of gMG. Blocking FcRn allows targeted reduction of all IgG subtypes without decreasing concentrations of other Ig isotypes; therefore, FcRn blocking could be a safe and effective treatment strategy for a broad population of gMG patients. Several FcRn-blocking antibodies
and one antibody Fc fragment have been developed and are currently in various stages of clinical development. This article describes the mechanism of FcRn blockade as a novel approach for IgG-mediated disease therapy and reviews promising clinical data using such FcRn blockers for the treatment of gMG.
Autoimmune disease, Clinical neurology, Clinical trials, Myasthenia, Neuromuscular disease
0022-510X
Wolfe, Gil I.
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Ward, E. Sally
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de Haard, Hans
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Ulrichts, Peter
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Mozattar, Tahseen
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Pasnoor, Mamatha
f35a3929-966e-4b55-b36a-4bcd2223a77b
Vidarsson, Gastur
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Wolfe, Gil I.
8d7257b7-b3c7-40cf-a9b0-5b006c07cee0
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
de Haard, Hans
8f6dc3d7-f74e-4091-8495-77fb4c4121e0
Ulrichts, Peter
f87fa2f0-a33d-4584-bdde-13b2eb76e68d
Mozattar, Tahseen
23d24ffa-d634-4eaf-bd1d-a329a7d4326e
Pasnoor, Mamatha
f35a3929-966e-4b55-b36a-4bcd2223a77b
Vidarsson, Gastur
c752da88-f664-4a5d-ac5f-c5a5534aa51c

Wolfe, Gil I., Ward, E. Sally, de Haard, Hans, Ulrichts, Peter, Mozattar, Tahseen, Pasnoor, Mamatha and Vidarsson, Gastur (2021) IgG regulation through FcRn blocking: A novel mechanism for the treatment of myasthenia gravis. Journal of the Neurological Sciences, 430, [118074]. (doi:10.1016/j.jns.2021.118074).

Record type: Review

Abstract

The neonatal Fc receptor (FcRn) is an MHC class I–like molecule that is widely distributed in mammalian organs, tissues, and cells. FcRn is critical to maintaining immunoglobulin G (IgG) and albumin levels through rescuing these molecules from lysosomal degradation. IgG autoantibodies are associated with many autoimmune diseases, including myasthenia gravis (MG), a rare neuromuscular autoimmune disease that causes debilitating and, in its generalized form (gMG), potentially life-threatening muscle weakness. IgG autoantibodies are directly pathogenic in MG and target neuromuscular junction proteins, causing neuromuscular transmission failure. Treatment approaches that reduce autoantibody levels, such as therapeutic plasma exchange and intravenous immunoglobulin, have been shown to be effective for gMG patients but are not indicated as ongoing maintenance therapies and can be associated with burdensome side effects. Agents that block FcRn-mediated recycling of IgG represent a rational and promising approach for the treatment of gMG. Blocking FcRn allows targeted reduction of all IgG subtypes without decreasing concentrations of other Ig isotypes; therefore, FcRn blocking could be a safe and effective treatment strategy for a broad population of gMG patients. Several FcRn-blocking antibodies
and one antibody Fc fragment have been developed and are currently in various stages of clinical development. This article describes the mechanism of FcRn blockade as a novel approach for IgG-mediated disease therapy and reviews promising clinical data using such FcRn blockers for the treatment of gMG.

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wolfe et al 2021 - Version of Record
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Accepted/In Press date: 8 September 2021
e-pub ahead of print date: 13 September 2021
Published date: 15 November 2021
Additional Information: Funding Information: Medical writing support was provided by Elizabeth Meucci, PhD, of MedErgy, and was funded by argenx, Zwijnaarde, Belgium. Publisher Copyright: © 2021
Keywords: Autoimmune disease, Clinical neurology, Clinical trials, Myasthenia, Neuromuscular disease

Identifiers

Local EPrints ID: 453395
URI: http://eprints.soton.ac.uk/id/eprint/453395
ISSN: 0022-510X
PURE UUID: 06405962-4948-4697-8e67-beaac115158d
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

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Date deposited: 13 Jan 2022 18:21
Last modified: 17 Mar 2024 03:53

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Contributors

Author: Gil I. Wolfe
Author: E. Sally Ward ORCID iD
Author: Hans de Haard
Author: Peter Ulrichts
Author: Tahseen Mozattar
Author: Mamatha Pasnoor
Author: Gastur Vidarsson

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