Selective depletion of autoreactive plasma cells as a novel strategy to treat acetylcholine receptor antibody-positive myasthenia gravis

Myasthenia gravis (MG) is a chronic autoimmune disease mediated by autoantibodies targeting the neuromuscular junction and leading to muscle weakness. Although there are autoantibodies of different specificities, most MG patients have autoantibodies directed against the nicotinic acetylcholine receptor (AChR), in particular against the extracellular domain of the α1 subunit (αECD), containing the main immunogenic region (MIR). Here, we demonstrate an original approach to selectively deplete plasma cells secreting autoantibodies targeting αECD. An antibody-mediated cytotoxicity-engager (ACE) consisting of an anti-hCD38-antibody conjugated to hAChR αECD (αECD) was used to deplete hAChR αECD-specific cells selectively in vivo. The reduction of pathogenic cells was accompanied by lower antibody titers, a reduction of MG disease score, protection of grip strength, and maintenance of body weight. Notably, antibody-secreting cells that are nonspecific for hAChR αECD were not affected. The resulting amelioration of MG pathology in ACE-treated animals highlights the decisive role of αECD-antibodies in the pathogenesis of MG and the clinical relevance of the novel therapeutic strategy.