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.
Highlights
Myasthenia gravis (MG) is one of the best-understood autoimmune disorders and is characterized by muscle weakness as a result of impaired neuromuscular transmission
More than half of acetylcholine receptor (AChR)-specific autoantibodies in MG patients is directed to the main immunogenic region (MIR) on the AChR alpha subunits[6], as exemplified by the human monoclonal antibody IgG1-6377, 8
The MIR is important for expression and assembly of the AChR, MIR-specific autoantibodies do not interfere with AChR function, such as recognition of acetylcholine released from nerve terminals and opening of the receptor channel[8]
Summary
Myasthenia gravis (MG) is one of the best-understood autoimmune disorders and is characterized by muscle weakness as a result of impaired neuromuscular transmission. An IgG4 version of the same antibody, IgG4-637, did not induce PTMG, and prevented IgG1-637-mediated muscle weakness[11] This protective effect was explained by the inability of IgG4-637 to activate rhesus monkey complement, and the intrinsic ability of human IgG4 molecules to engage in Fab-arm exchange leading to functional monovalency; preventing antigenic modulation through cross-linking[11, 13, 14]. During Fab-arm exchange, bispecific antibodies will be generated with unknown partner-specificities, which may result in unpredictable pharmacodynamics Taken together, these considerations suggest that for immunotherapy of MG an alternative antibody format with superior non-activating (no complement activation or Fcγ-receptor interaction) and non-cross-linking properties, compared to IgG4, is desired for clinical implementation
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