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

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 Mane-Damas, Peter C. Molenaar, Pilar Martinez-Martinez, Eline van der Esch, Janine Schuurman, Marc H. de Baets, Paul W. H. I. Parren

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

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.

Original languageEnglish
Article number992
Number of pages11
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 20 Apr 2017

Keywords

  • FAB-ARM EXCHANGE
  • MAIN IMMUNOGENIC REGION
  • FC-GAMMA-RIIA
  • 3-DIMENSIONAL STRUCTURE
  • INTERACTION STRENGTH
  • MONOCLONAL-ANTIBODY
  • NERVE-STIMULATION
  • PASSIVE TRANSFER
  • REFERENCE VALUES
  • IMMUNOGLOBULIN

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