| Autor: |
Vanhauwaert, Roeland, Oury, Julien, Vankerckhoven, Bernhardt, Steyaert, Christophe, Jensen, Stine Marie, Vergoossen, Dana L. E., Kneip, Christa, Santana, Leah, Lim, Jamie L., Plomp, Jaap J., Augustinus, Roy, Koide, Shohei, Blanchetot, Christophe, Ulrichts, Peter, Huijbers, Maartje G., Silence, Karen, Burden, Steven J. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 9/18/2024, Vol. 16 Issue 765, p1-16, 16p |
| Abstrakt: |
Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development. Editor's summary: Muscle-specific kinase (MuSK) is required for the formation and maintenance of neuromuscular junctions, the synaptic connections between motor neurons and muscle fibers. Impairments in MuSK signaling cause certain forms of neuromuscular disease such as congenital myasthenic syndrome and myasthenia gravis. Here, Vanhauwaert et al. present the development of ARGX-119, an agonist antibody for MuSK. ARGX-119 activated MuSK in vitro across different species, including humans, and showed no off-target binding. ARGX-119 was safe in healthy mice and rescued motor function, prolonged survival, and reversed disease relapse in a mouse model of congenital myasthenia. These data support further development of ARGX-119 for neuromuscular diseases. —Daniela Neuhofer [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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