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

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 t...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430546/
https://www.ncbi.nlm.nih.gov/pubmed/28428630
http://dx.doi.org/10.1038/s41598-017-01019-5
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author 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.
author_facet 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.
author_sort Losen, Mario
collection PubMed
description 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.
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spelling pubmed-54305462017-05-15 Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys 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. Sci Rep Article 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. Nature Publishing Group UK 2017-04-20 /pmc/articles/PMC5430546/ /pubmed/28428630 http://dx.doi.org/10.1038/s41598-017-01019-5 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
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.
Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430546/
https://www.ncbi.nlm.nih.gov/pubmed/28428630
http://dx.doi.org/10.1038/s41598-017-01019-5
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