Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

• Published in: Scientific reports Vol. 7; no. 1; pp. 992 - 11
• Main Authors: Losen, Mario, Labrijn, Aran F., van Kranen-Mastenbroek, Vivianne H., Janmaat, Maarten L., Haanstra, Krista G., Beurskens, Frank J., Vink, Tom, Jonker, Margreet, ‘t Hart, Bert A., Mané-Damas, Marina, Molenaar, Peter C., Martinez-Martinez, Pilar, van der Esch, Eline, Schuurman, Janine, de Baets, Marc H., Parren, Paul W. H. I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 14/63; 631/250/38; 631/378/371; Antigens; Autoantibodies; Autoimmune diseases; Dysphagia; Electromyography; Epitopes; Humanities and Social Sciences; Immunoglobulin G; Ion channels; Monoclonal antibodies; multidisciplinary; Myasthenia gravis; Neuromuscular junctions; Neurosciences; Science; Science (multidisciplinary); Synaptic transmission
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01019-5

Autoantibodies against ion channels are the cause of numerous neurologic autoimmune disorders. Frequently, such pathogenic autoantibodies have a restricted epitope-specificity. In such cases, competing antibody formats devoid of pathogenic effector functions (blocker antibodies) have the potential to treat disease by displacing autoantibodies from their target. Here, we have used a model of the neuromuscular autoimmune disease myasthenia gravis in rhesus monkeys ( Macaca mulatta ) to test the therapeutic potential of a new blocker antibody: MG was induced by passive transfer of pathogenic acetylcholine receptor-specific monoclonal antibody IgG1-637. The effect of the blocker antibody (IgG4Δhinge-637, the hinge-deleted IgG4 version of IgG1-637) was assessed using decrement measurements and single-fiber electromyography. Three daily doses of 1.7 mg/kg IgG1-637 (cumulative dose 5 mg/kg) induced impairment of neuromuscular transmission, as demonstrated by significantly increased jitter, synaptic transmission failures (blockings) and a decrease in the amplitude of the compound muscle action potentials during repeated stimulations (decrement), without showing overt symptoms of muscle weakness. Treatment with three daily doses of 10 mg/kg IgG4Δhinge-637 significantly reduced the IgG1-637-induced increase in jitter, blockings and decrement. Together, these results represent proof-of principle data for therapy of acetylcholine receptor-myasthenia gravis with a monovalent antibody format that blocks binding of pathogenic autoantibodies.