1057-OR: Fcµ Fragment of IgM: A Novel Tolerance-Restoring Therapeutic for Autoimmune Type 1 Diabetes

Introduction and Objective: Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β-cells. We discovered a previously unrecognized immunomodulatory role for immunoglobulin M (IgM) in maintaining beta cell-specific immune tolerance. Our goal was to optimize polyclonal IgM, generate its derivative with maximal tolerogenic activity, and define the mechanism of action. Methods: Purified IgM was enzymatically cleaved to produce Fab and Fcµ fragments. The immunomodulatory properties of IgM and its fragments were tested in a) NOD mice for diabetes prevention or reversal and immune modulation, and in b) IgM-knockout mice for diabetes reversal following islet transplantation. The minimal effective dose, shelf life, and optimal delivery route were determined. Pharmacokinetics of human IgM in BL/6 mouse was assessed post intraperitoneal (IP) injection. IgM glycosylation via lectin profiling and IgM apoptotic cell binding were compared across healthy and diabetic donors. Results: Fcµ retained full immunomodulatory capacity, preventing T1D in NOD mice. IgM and Fcµ expanded Tregs (GARP+Helios+) and RORγ+ and T-bet+ CD4+ T cells, and restored B-cell homeostasis. In transplant recipients, only intact IgM and Fcµ restored long-term normoglycemia. Pharmacokinetics revealed human IgM detectable within 30 min post-injection but cleared by 24 h. Shelf-life testing showed a 50% reduction in potency after 12 months. IV administration most effectively halted disease progression compared to subcutaneous and IP. Healthy IgM bound apoptotic B and T cells efficiently, while diabetic IgM showed impaired clearance. Lectin profiling revealed reduced α2,6-sialylation in T1D IgM, implicating defective glycosylation in loss of immunomodulatory activity. Conclusion: IgM and Fcµ actively restore immune tolerance, prevent and reverse diabetes, promote islet engraftment, and enhance regulatory immune pathways. Defective glycosylation may underlie IgM dysfunction in T1D. These results support Fcµ as a novel tolerance-restoring biologic for autoimmune T1D. Disclosure P. Chhabra: None. M. Ma: Other - Co-founder of the IsletRegen, LLC; Current; IsletRegen, LLC. J. Cook: None. K. Brayman: Other - Cofounder and Chief Medical Officer; Current; IsletRegen, LLC.