B cell-specific mAb–siRNA conjugates improve experimental myasthenia

• Published in: Journal of autoimmunity 2023-02, Vol.135, p.102983, Article 102983
• Main Authors: Ibtehaj, Naazneen, Bahauddin, Afrin, Ivannikov, Maxim, Rytting, Erik, Jamaluddin, Mohammad, Liang, Yuejin, Sun, Jiaren, Haller, Sherry L., Wu, Xiaorong, Huda, Ruksana
• Format: Article
• Language: English
• Subjects: Acetylcholine receptor; Animals; Antibodies, Monoclonal; Autoantibodies; Autoantibody; Autoimmunity; mAb–siRNA conjugate; Mice; Myasthenia gravis; Myasthenia Gravis, Autoimmune, Experimental; Receptors, Cholinergic; RNA, Small Interfering
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2022.102983

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. •B cell-targeting monoclonal antibody and siRNA conjugates were tested for therapeutic potential in a mouse model of myasthenia gravis (MG).•Both mono and duo conjugates substantially reduced critical receptors of B cells.•B cell targeting mAb-siRNA conjugates reduced AChR-specific autoantibody levels.•PEGylation further influenced conjugate induced target receptor suppression and autoantibody reduction.•Improvement of clinical symptoms were moderately affected by the duoconjugate treatment.