PMID- 30851266 OWN - NLM STAT- MEDLINE DCOM- 20200226 LR - 20200226 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 317 DP - 2019 Jul TI - Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis. PG - 133-143 LID - S0014-4886(18)30575-2 [pii] LID - 10.1016/j.expneurol.2019.03.001 [doi] AB - Myasthenia gravis is hallmarked by fatigable muscle weakness resulting from neuromuscular synapse dysfunction caused by IgG autoantibodies. The variant with muscle-specific kinase (MuSK) autoantibodies is characterized by prominent cranial and bulbar weakness and a high frequency of respiratory crises. The majority of MuSK MG patients requires long-term immunosuppressive treatment, but the result of these treatments is considered less satisfactory than in MG with acetylcholine receptor antibodies. Emergency treatments are more frequently needed, and many patients develop permanent facial weakness and nasal speech. Therefore, new treatment options would be welcome. The neonatal Fc receptor protects IgG from lysosomal breakdown, thus prolonging IgG serum half-life. Neonatal Fc receptor antagonism lowers serum IgG levels and thus may act therapeutically in autoantibody-mediated disorders. In MuSK MG, IgG4 anti-MuSK titres closely correlate with disease severity. We therefore tested efgartigimod (ARGX-113), a new neonatal Fc receptor blocker, in a mouse model for MuSK myasthenia gravis. This model involves 11 daily injections of purified IgG4 from MuSK myasthenia gravis patients, resulting in overt myasthenic muscle weakness and, consequently, body weight loss. Daily treatment with 0.5 mg efgartigimod, starting at the fifth passive transfer day, reduced the human IgG4 titres about 8-fold, despite continued daily injection. In muscle strength and fatigability tests, efgartigimod-treated myasthenic mice outperformed control myasthenic mice. Electromyography in calf muscles at endpoint demonstrated less myasthenic decrement of compound muscle action potentials in efgartigimod-treated mice. These substantial in vivo improvements of efgartigimod-treated MuSK MG mice following a limited drug exposure period were paralleled by a tendency of recovery at neuromuscular synaptic level (in various muscles), as demonstrated by ex vivo functional studies. These synaptic improvements may well become more explicit upon longer drug exposure. In conclusion, our study shows that efgartigimod has clear therapeutic potential in MuSK myasthenia gravis and forms an exciting candidate drug for many autoantibody-mediated neurological and other disorders. CI - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Huijbers, Maartje G AU - Huijbers MG AD - Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address: M.G.M.Huijbers@lumc.nl. FAU - Plomp, Jaap J AU - Plomp JJ AD - Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands. FAU - van Es, Inge E AU - van Es IE AD - Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands. FAU - Fillie-Grijpma, Yvonne E AU - Fillie-Grijpma YE AD - Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands. FAU - Kamar-Al Majidi, Samar AU - Kamar-Al Majidi S AD - Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands. FAU - Ulrichts, Peter AU - Ulrichts P AD - argenx BVBA, Industriepark Zwijnaarde 7, 9052, Zwijnaarde, Gent, Belgium. FAU - de Haard, Hans AU - de Haard H AD - argenx BVBA, Industriepark Zwijnaarde 7, 9052, Zwijnaarde, Gent, Belgium. FAU - Hofman, Erik AU - Hofman E AD - argenx BVBA, Industriepark Zwijnaarde 7, 9052, Zwijnaarde, Gent, Belgium. FAU - van der Maarel, Silvere M AU - van der Maarel SM AD - Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands. FAU - Verschuuren, Jan J AU - Verschuuren JJ AD - Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190306 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Immunoglobulin G) RN - 0 (Receptors, Fc) RN - EC 2.7.10.1 (MuSK protein, mouse) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Action Potentials MH - Animals MH - Electromyography MH - Humans MH - Immunoglobulin Fc Fragments/metabolism MH - Immunoglobulin G/blood MH - In Vitro Techniques MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Motor Endplate/drug effects MH - Muscle Contraction MH - Muscle Weakness/*drug therapy/etiology/*genetics MH - Myasthenia Gravis, Autoimmune, Experimental/complications/*drug therapy/*genetics MH - Receptor Protein-Tyrosine Kinases/*genetics MH - Receptors, Fc/antagonists & inhibitors OTO - NOTNLM OT - MuSK OT - Myasthenia gravis OT - Neonatal Fc receptor OT - Neuroimmunology OT - Neuromuscular diseases OT - Neuromuscular junction EDAT- 2019/03/10 06:00 MHDA- 2020/02/27 06:00 CRDT- 2019/03/10 06:00 PHST- 2018/10/11 00:00 [received] PHST- 2019/01/24 00:00 [revised] PHST- 2019/03/04 00:00 [accepted] PHST- 2019/03/10 06:00 [pubmed] PHST- 2020/02/27 06:00 [medline] PHST- 2019/03/10 06:00 [entrez] AID - S0014-4886(18)30575-2 [pii] AID - 10.1016/j.expneurol.2019.03.001 [doi] PST - ppublish SO - Exp Neurol. 2019 Jul;317:133-143. doi: 10.1016/j.expneurol.2019.03.001. Epub 2019 Mar 6.