Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys
Abstract 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 po...
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2017
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oai:doaj.org-article:24f5b6bf021946909f7c67a223ec548b2021-12-02T11:40:13ZHinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys10.1038/s41598-017-01019-52045-2322https://doaj.org/article/24f5b6bf021946909f7c67a223ec548b2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01019-5https://doaj.org/toc/2045-2322Abstract 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.Mario LosenAran F. LabrijnVivianne H. van Kranen-MastenbroekMaarten L. JanmaatKrista G. HaanstraFrank J. BeurskensTom VinkMargreet JonkerBert A. ‘t HartMarina Mané-DamasPeter C. MolenaarPilar Martinez-MartinezEline van der EschJanine SchuurmanMarc H. de BaetsPaul W. H. I. ParrenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Mario Losen Aran F. Labrijn Vivianne H. van Kranen-Mastenbroek Maarten L. Janmaat Krista G. Haanstra Frank J. Beurskens Tom Vink Margreet Jonker Bert A. ‘t Hart Marina Mané-Damas Peter C. Molenaar Pilar Martinez-Martinez Eline van der Esch Janine Schuurman Marc H. de Baets Paul W. H. I. Parren Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| description |
Abstract 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. |
| format |
article |
| author |
Mario Losen Aran F. Labrijn Vivianne H. van Kranen-Mastenbroek Maarten L. Janmaat Krista G. Haanstra Frank J. Beurskens Tom Vink Margreet Jonker Bert A. ‘t Hart Marina Mané-Damas Peter C. Molenaar Pilar Martinez-Martinez Eline van der Esch Janine Schuurman Marc H. de Baets Paul W. H. I. Parren |
| author_facet |
Mario Losen Aran F. Labrijn Vivianne H. van Kranen-Mastenbroek Maarten L. Janmaat Krista G. Haanstra Frank J. Beurskens Tom Vink Margreet Jonker Bert A. ‘t Hart Marina Mané-Damas Peter C. Molenaar Pilar Martinez-Martinez Eline van der Esch Janine Schuurman Marc H. de Baets Paul W. H. I. Parren |
| author_sort |
Mario Losen |
| title |
Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| title_short |
Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| title_full |
Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| title_fullStr |
Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| title_full_unstemmed |
Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| title_sort |
hinge-deleted igg4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/24f5b6bf021946909f7c67a223ec548b |
| work_keys_str_mv |
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