PMID- 37156800 OWN - NLM STAT- MEDLINE DCOM- 20230510 LR - 20230601 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 13 IP - 1 DP - 2023 May 8 TI - Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK. PG - 7478 LID - 10.1038/s41598-023-32641-1 [doi] LID - 7478 AB - Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise. CI - (c) 2023. The Author(s). FAU - Lim, Jamie L AU - Lim JL AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Augustinus, Roy AU - Augustinus R AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Plomp, Jaap J AU - Plomp JJ AD - Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Roya-Kouchaki, Kasra AU - Roya-Kouchaki K AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Vergoossen, Dana L E AU - Vergoossen DLE AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Fillie-Grijpma, Yvonne AU - Fillie-Grijpma Y AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Struijk, Josephine AU - Struijk J AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Thomas, Rachel AU - Thomas R AD - Department PDC-Pathologie, Leiden University Medical Center, Leiden, The Netherlands. FAU - Salvatori, Daniela AU - Salvatori D AD - Veterinary Faculty, Department Clinical Sciences, Universiteit Utrecht, Utrecht, The Netherlands. FAU - Steyaert, Christophe AU - Steyaert C AD - argenx BV, Zwijnaarde, Belgium. FAU - Blanchetot, Christophe AU - Blanchetot C AD - argenx BV, Zwijnaarde, Belgium. FAU - Vanhauwaert, Roeland AU - Vanhauwaert R AD - argenx BV, Zwijnaarde, Belgium. FAU - Silence, Karen AU - Silence K AD - argenx BV, Zwijnaarde, Belgium. FAU - van der Maarel, Silvere M AU - van der Maarel SM AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. FAU - Verschuuren, Jan J AU - Verschuuren JJ AD - Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Huijbers, Maartje G AU - Huijbers MG AD - Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. m.g.m.huijbers@lumc.nl. AD - Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. m.g.m.huijbers@lumc.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230508 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - 0 (Receptors, Cholinergic) RN - 0 (Autoantibodies) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - Male MH - Animals MH - Mice MH - Mice, SCID MH - *Receptor Protein-Tyrosine Kinases/metabolism MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - *Myasthenia Gravis/metabolism MH - Receptors, Cholinergic/metabolism MH - Autoantibodies MH - Muscle Weakness MH - Acetylcholine PMC - PMC10167245 COIS- M.G.H., J.J.P., S.M.M. and J.J.V. are co-inventors on two patent applications on MuSK-related research. LUMC, M.G.H., J.J.P., S.M.M. and J.J.V. receive license income from these patents. LUMC receives royalties for a diagnostic MuSK ELISA. C.S., C.B., R.V., and K.S., are (former) employees/consultants of argenx BV and some are holders of employee equity in argenx SE. Argenx exclusively owns two patent families which have been filed by applicant 'Academisch Ziekenhuis Leiden (h.o.d.n. LUMC)'. The two patent families WO2020/055241 and WO2020/055240 are directed to respectively agonistic and antagonistic antibodies binding to Ig-like 1 domain of MuSK. 'argenx IIP BV' and 'Academisch Ziekenhuis Leiden' are co-applicants on a patent family (WO2021/180676) directed to antibodies binding to Ig-like 1 domain of MuSK, and therapeutic uses thereof. No other authors have conflicts of interest. EDAT- 2023/05/09 00:42 MHDA- 2023/05/10 06:42 PMCR- 2023/05/08 CRDT- 2023/05/08 23:17 PHST- 2023/01/20 00:00 [received] PHST- 2023/03/30 00:00 [accepted] PHST- 2023/05/10 06:42 [medline] PHST- 2023/05/09 00:42 [pubmed] PHST- 2023/05/08 23:17 [entrez] PHST- 2023/05/08 00:00 [pmc-release] AID - 10.1038/s41598-023-32641-1 [pii] AID - 32641 [pii] AID - 10.1038/s41598-023-32641-1 [doi] PST - epublish SO - Sci Rep. 2023 May 8;13(1):7478. doi: 10.1038/s41598-023-32641-1.