Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
08 05 2023
08 05 2023
Historique:
received:
20
01
2023
accepted:
30
03
2023
medline:
10
5
2023
pubmed:
9
5
2023
entrez:
8
5
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37156800
doi: 10.1038/s41598-023-32641-1
pii: 10.1038/s41598-023-32641-1
pmc: PMC10167245
doi:
Substances chimiques
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Receptors, Cholinergic
0
Autoantibodies
0
Acetylcholine
N9YNS0M02X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7478Informations de copyright
© 2023. The Author(s).
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