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|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.
't Hart, Bert A.
Molenaar, Peter C.
van der Esch, Eline
de Baets, Marc H.
Parren, Paul W. H. I.
|Issue Date: ||2017|
|Publisher: ||NATURE PUBLISHING GROUP|
|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.|
|ISI #: ||000412940300001|
|Type: ||Journal Contribution|
|Validation: ||ecoom, 2018|
|Appears in Collections: ||Research publications|
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