Treatment Effect of CD40 Inhibition in Combination with Duoconjugates in a Mouse Model of Myasthenia Gravis 2306252

Abstract Introduction Muscle weakness and fatigue in autoimmune myasthenia gravis (MG) result from neuromuscular junction damage caused by autoantibody- and complement-mediated destruction of the acetylcholine receptor (AChR). In our ongoing efforts to develop a new and effective treatment for MG, we evaluated the effect of CD40 inhibition combined with duoconjugate treatments (BAFF receptor and B-cell maturation antigen-specific) in a mouse model of MG. Methods Conjugates consisted of target-specific siRNA linked to monoclonal antibodies that target pathogenic plasma cells and mature B cells. We evaluated this treatment using a Torpedo AChR/Complete Freund’s Adjuvant-immunized mouse model of MG. Results Our research shows that conjugate treatment disrupts pathogenic B cells, reducing autoantibody levels and improving clinical outcomes. Additionally, combining CD40 with duoconjugates boosts treatment effectiveness, but only with specific combinations, not when used alone. Conclusion Our results suggest that CD40 inhibition, whether alone or in combination with other treatments, may not be effective for treating myasthenia gravis or other antibody-mediated autoimmune disorders. Funding Source AFM Telethon Topic Categories Therapeutic Approaches to Autoimmunity (THER)