Therapeutic IgG-and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology

• 成果类型: Article
• 署名作者: Bayer, Alexandra C.; Sanmarco, Liliana M.; Pellerin, Alex; Masi, Gianvito; Plasencia, Agustin; Anderson, Jordan M.; Nowak, Richard J.; Damato, Valentina; Massacesi, Luca; Pham, Minh C.; Khani-Habibabadi, Fatemeh; Vital, Heather; Higginson-Scott, Nathan; Otipoby, Kevin L.; Xing, Yi; Mascanfroni, Ivan D.; O'connor, Kevin C.
• 署名单位: Yale University; Yale University; University of Florence
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2505984122
• 发表日期: 2025-10-21
• 页码: e2505984122
• 关键词: autoimmune disease; myasthenia gravis; immunoglobulins (Ig)-proteases; pathogenic IgM; complement; MOTOR END-PLATE; GENERALIZED MYASTHENIA; DOUBLE-BLIND; STREPTOCOCCAL ENDOPEPTIDASE; monoclonal-antibodies; CYSTEINE PROTEINASE; STRICT SPECIFICITY; effector functions; COMPLEMENT-SYSTEM; b-cells

摘要

Myasthenia gravis (MG) is an autoimmune disorder caused mainly by autoantibodies against the acetylcholine receptor (AChR), leading to muscle weakness. While treatments targeting AChR autoantibodies benefit many, some patients remain refractory, highlighting the need for personalized therapies. This study evaluates the therapeutic potential of S-1117, a pan-IgG-specific protease, in AChR autoantibody-mediated pathology. Using live cell-based assays, we examined AChR-specific monoclonal IgG autoantibodies (mAbs) and patient-derived serum samples for their effects on receptor binding, blockade, internalization, and complement activation, before and after treatment with S-1117. S-1117 effectively removed the crystallizable fragment (Fc)gamma from both mAbs and serum IgG, impairing Fc gamma- mediated complement activation in both soluble and antigen-bound forms. In cases with partial complement reduction, AChR-specific IgM contributed to complement deposition. AChR-IgM acted in concert with IgG in some patients to enhance complement deposition, while acting as main complement driver in others. An IgM-specific protease completely suppressed the pathogenic effects of AChR-IgM in two independent patient cohorts. These findings highlight the therapeutic potential of S-1117 in neutralizing AChR-IgG Fc gamma- mediated effector functions and reveal an MG subset driven by IgM pathology. Our study shows that targeting both IgG-and IgM-mediated mechanisms with therapeutic proteases provides an approach to MG treatment and establishes a framework for patient stratification based on disease mechanisms, advancing precision medicine in MG.