Format

Send to

Choose Destination
Sci Rep. 2017 Apr 20;7(1):992. doi: 10.1038/s41598-017-01019-5.

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

Author information

1
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. m.losen@maastrichtuniversity.nl.
2
Genmab, Utrecht, The Netherlands. a.labrijn@genmab.com.
3
Department of Clinical Neurophysiology, Maastricht University Medical Center, Rijswijk, The Netherlands.
4
Genmab, Utrecht, The Netherlands.
5
Biomedical Primate Research Centre, Rijswijk, The Netherlands.
6
Department of immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
7
University of Groningen, University Medical Center, Department of Neuroscience, Groningen, The Netherlands.
8
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
9
Neuroimmunology Group, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.

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.

PMID:
28428630
PMCID:
PMC5430546
DOI:
10.1038/s41598-017-01019-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center