Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis

• Published in: Experimental neurology Vol. 317; pp. 133 - 143
• Main Authors: Huijbers, Maartje G., Plomp, Jaap J., van Es, Inge E., Fillié-Grijpma, Yvonne E., Kamar-Al Majidi, Samar, Ulrichts, Peter, de Haard, Hans, Hofman, Erik, van der Maarel, Silvère M., Verschuuren, Jan J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2019
• Subjects: Action Potentials; Animals; Electromyography; Humans; Immunoglobulin Fc Fragments - metabolism; Immunoglobulin G - blood; In Vitro Techniques; Mice; Mice, Inbred NOD; Mice, SCID; Motor Endplate - drug effects; Muscle Contraction; Muscle Weakness - drug therapy; Muscle Weakness - etiology; Muscle Weakness - genetics; MuSK; Myasthenia gravis; Myasthenia Gravis, Autoimmune, Experimental - complications; Myasthenia Gravis, Autoimmune, Experimental - drug therapy; Myasthenia Gravis, Autoimmune, Experimental - genetics; Neonatal Fc receptor; Neuroimmunology; Neuromuscular diseases; Neuromuscular junction; Receptor Protein-Tyrosine Kinases - genetics; Receptors, Fc - antagonists & inhibitors; MuSK; EPP; FDB; CMAP; IVIg; Neuromuscular junction; Lrp4; α-BTx; AChR; dTC; Myasthenia gravis; OD; MG; Neonatal Fc receptor; Neuroimmunology; PBS; Neuromuscular diseases; i.p; NMJ; i.v; n.s; LAL; SEM; MEPP; ELISA
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.03.001

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. •Efgartigimod, a new FcRn blocker, improves murine MuSK myasthenia gravis.•Treatment lowers serum level of injected human MuSK IgG4 autoantibodies ~8-fold.•Subtle neuromuscular synapse recovery underlies substantial in vivo improvement.