Overcoming Synthetic Challenges and Evaluating in Vivo Efficacy of the MOG-Fc-Bifunctional Peptide Inhibitor for EAE in Mice

Multiple sclerosis (MS) is an autoimmune disease that causes neural degeneration as a result of the immune system launching an attack on the myelin sheath surrounding neurons. MS has multiple disease states; each one has been associated with a different onset pathway and requires a separate treatment. Primary progressive MS (PPMS) is a rare form of MS that affects 10-15% of MS patients, and Ocrelizumab is currently the only FDA-approved treatment on the market. While it can be effective in managing PPMS, Ocrelizumab can only delay the onset of the disease. In this study, MOG-Fc-BPI was designed as a potential therapeutic agent to suppress experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner, altering immune cells from an inflammatory to a regulatory phenotype. Here, MOG-Fc-BPI was successfully synthesized by conjugating the MOG-R₅ peptide using sortase A enzyme to the C-terminus of the Fc-domain with LABL peptide at the N-terminus. Purified MOG-Fc-BPI was formulated to reach a concentration of 15 mg/mL for the in vivo study. MOG-stimulated EAE in C57BL/6 mice (a model for PPMS) that were treated with MOG-Fc-BPI on days 4 and 7 at 35 nmol/dose showed complete disease suppression on day 19 (score = 0; without symptoms) compared to PBS. The MOG-Fc-BPI-treated mice showed increased body weights throughout the study, while PBS-treated mice lost around 10% bodyweight during the peak of the disease without recovery up to the end of the study. Overall, this study provided a proof-of-concept that MOG-Fc-BPI has the potential to suppress PPMS.