B cell-specific mAb–siRNA conjugates improve experimental myasthenia

Naazneen Ibtehaj, Afrin Bahauddin, Maxim Ivannikov, Erik Rytting, Mohammad Jamaluddin, Yuejin Liang, Jiaren Sun, Sherry Haller, Xiaorong Wu, Ruksana Huda

Research output: Contribution to journalArticlepeer-review

Abstract

Myasthenia gravis (MG) is a debilitating autoimmune disease characterized by muscle fatigue and weakness caused by autoantibody- and complement-mediated damage to the neuromuscular junction. This study sought to compare the efficacy of unique sets of monoclonal antibody–siRNA conjugates, individually (mono) or in combination (duo), against the crucial receptors predominantly or solely expressed on two subsets of B cells—plasma B cells and their precursor (transitional mature B) cells in a mouse model of MG. At the optimized doses, the conjugates, likely due to the combined activities of mAb and siRNA, substantially decreased the expression levels of CD268 (B cell-activating factor receptor) in mature B cells and CD269 (B-cell maturation antigen) in plasma cells concomitantly with reducing the levels of acetylcholine receptor (AChR)-specific autoantibodies. PEGylation, but not pretreatment with an antibody against type 1 interferon receptor, further improved duoconjugate-induced reduction in the autoantibody levels. Our results show that the duoconjugate treatment significantly improved the clinical symptoms of MG, consistent with the preservation of bungarotoxin-bound functional AChRs. In the future, developing similar target-specific combination molecules can potentially turn into a new and effective therapeutic approach for MG.

Original languageEnglish (US)
Article number102983
JournalJournal of Autoimmunity
Volume135
DOIs
StatePublished - Feb 2023

Keywords

  • Acetylcholine receptor
  • Autoantibody
  • Autoimmunity
  • Myasthenia gravis
  • mAb–siRNA conjugate

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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