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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/25457

Title: Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys
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.
Mane-Damas, Marina
Molenaar, Peter C.
Martinez-Martinez, Pilar
van der Esch, Eline
Schuurman, Janine
de Baets, Marc H.
Parren, Paul W. H. I.
Issue Date: 2017
Citation: SCIENTIFIC REPORTS, 7, p. 1-11 (Art N° 992)
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 (IgG4 Delta hinge-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 IgG4 Delta hinge-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.
Notes: [Losen, Mario; Mane-Damas, Marina; Molenaar, Peter C.; Martinez-Martinez, Pilar; van der Esch, Eline; de Baets, Marc H.] Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands. [Labrijn, Aran F.; Janmaat, Maarten L.; Beurskens, Frank J.; Vink, Tom; Schuurman, Janine; Parren, Paul W. H. I.] Genmab, Utrecht, Netherlands. [van Kranen-Mastenbroek, Vivianne H.] Maastricht Univ, Med Ctr, Dept Clin Neurophysiol, Rijswijk, Netherlands. [Haanstra, Krista G.; Jonker, Margreet; 't Hart, Bert A.] Biomed Primate Res Ctr, Rijswijk, Netherlands. [Jonker, Margreet; Parren, Paul W. H. I.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands. ['t Hart, Bert A.] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, Groningen, Netherlands. [de Baets, Marc H.] Hasselt Univ, Biomed Res Inst BIOMED, Neuroimmunol Grp, Diepenbeek, Belgium.
URI: http://hdl.handle.net/1942/25457
DOI: 10.1038/s41598-017-01019-5
ISI #: 000412940300001
ISSN: 2045-2322
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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