Agonist antibody to MuSK protects mice from MuSK myasthenia gravis.

Autor:	Oury J; Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Medical School, New York, NY 10016., Gamallo-Lana B; Department of Neuroscience and Physiology, Neuroscience Institute, New York University School of Medicine, New York, NY 10016., Santana L; Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Medical School, New York, NY 10016., Steyaert C; argenx, Zwijnaarde 9052, Belgium., Vergoossen DLE; Department of Human Genetics, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands.; Department of Neurology, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands., Mar AC; Department of Neuroscience and Physiology, Neuroscience Institute, New York University School of Medicine, New York, NY 10016., Vankerckhoven B; argenx, Zwijnaarde 9052, Belgium., Silence K; argenx, Zwijnaarde 9052, Belgium., Vanhauwaert R; argenx, Zwijnaarde 9052, Belgium., Huijbers MG; Department of Human Genetics, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands.; Department of Neurology, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands., Burden SJ; Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Medical School, New York, NY 10016.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Sep 24; Vol. 121 (39), pp. e2408324121. Date of Electronic Publication: 2024 Sep 17.
DOI:	10.1073/pnas.2408324121
Abstrakt:	Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism. Competing Interests: Competing interests statement:C.S., B.V., K.S., and R.V. are employees of and have equity ownership in argenx BV. Issued patents: S.J.B., NYU Medical School, US9329182 S.J.B., Wei Zhang, Maartje Huijbers, Johannes J. Verschuuren, and Silvere M. van der Maarel; NYU Medical School and LUMC; US20150125442A1 S.J.B. et al., NYU Medical School and argenx; US11492401 Patent applications: M.G.H. et al., LUMC, WO2020/055241 M.G.H. et al., LUMC and argenx, WO2021/180676 R.V. et al.; argenx, Université de Montréal and NYU Medical School; WO2023/147489 R.V. et al.; argenx and NYU Medical School; WO2023/218099. S.J.B. is grateful for financial support for research from argenx.
Databáze:	MEDLINE
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