TNFR2 Agonism: Basic Science and Promising Treatment for Multiple Sclerosis and Related Diseases

The three pathological hallmarks of multiple sclerosis (MS) are inflammation, demyelination, and progressive neurodegeneration. None of the approved disease-modifying therapies for MS counters all three pathologies, and, more specifically, none is approved for neuroprotection. Axonal loss is the most significant contributor to chronic and irreversible disability in MS. A tantalizing molecular target has emerged to uniquely counter all three MS pathologies: tumor necrosis factor receptor 2 (TNFR2). Agonism or activation of TNFR2 has been shown in MS models to induce immunosuppression, oligodendrocyte precursor differentiation, and neuroprotection. Further, in basic science studies stemming from the past 15 years, TNFR2 agonism is known to be a strong inducer of T-regulatory cells (Tregs). Treg cells, and especially those expressing TNFR2, are known to confer the strongest suppression per cell type. TNFR2 is even more attractive as a therapeutic target because of its restricted expression by only a handful of CNS and immune cell subsets, thereby minimizing the likelihood of systemic and other adverse effects. Recent antibody design work suggests many of the hurdles of Treg agonism may have been overcome. This review covers the current treatment landscape for MS, the basic science of TNFR2, the rationale for and evidence behind TNFR2 agonism to treat multiple sclerosis, the design of potent TNFR2 agonist antibodies, and the treatment applications for other neurological, autoimmune, or inflammatory diseases.