In brief

Early attempts to treat multiple sclerosis (MS) by blocking the cytokine TNF-alpha failed, and in some cases made the disease worse. This review explains why: TNF signals through two receptors with opposite effects, and blocking both indiscriminately removes a protective pathway. It then follows the story forward to atrosab, an antibody that blocks only the harmful receptor (TNFR1) while sparing the protective one (TNFR2), and the early promise this receptor-selective strategy has shown in animal models of MS.

Abstract

Multiple sclerosis (MS) is the most common disabling disease of the central nervous system (CNS), with a progressive neurodegenerative pattern. It is characterized by demyelination of white matter in the CNS and apoptosis of oligodendrocytes. Tumor necrosis factor (TNF) alpha is a major cytokine in the pathogenesis of MS. However, the failure of TNF-alpha inhibitors in preclinical and clinical trials disapproved of their use in MS patients. Nevertheless, failures and misses sometimes open avenues for new hits. In later years it was discovered that TNF signaling is mediated via two different receptors, TNFR1 and TNFR2, both of which have paradoxical effects: TNFR1 mediates demyelination and apoptosis, while TNFR2 promotes remyelination and neuroprotection. This explained the failure of non-selective TNF-alpha blockers in MS, and suggested that repurposing them using a receptor-selective approach could yield novel biologic agents with a broader spectrum of indications and better safety profiles. This review focuses on a novel premier TNFR1 blocker, atrosab, which was tested in the experimental autoimmune encephalomyelitis (EAE) animal model of MS and demonstrated a reduction in symptom severity. The early promise shown by atrosab in preclinical studies gives hope for another revolutionary drug for MS in the future. Clinical trials that will finally decide whether this drug can be used as a better therapeutic agent for MS are still ongoing, and currently there is no approved evidence regarding the efficacy of these agents in treating MS.

Key takeaways

Why non-selective anti-TNF failed: blocking TNF broadly worsened MS and became a contraindication in demyelinating disease, because it also removed a protective signal.
Two receptors, opposite jobs: TNFR1 drives inflammation, apoptosis, and demyelination; TNFR2 supports immune modulation, remyelination, and neuroprotection.
The selective idea: block only TNFR1 (or activate TNFR2) to keep the protective arm intact, a more precise strategy than shutting down all TNF signaling.
Atrosab: a humanized anti-TNFR1 antibody that reduced symptom severity and demyelination in EAE animal models; engineered derivatives improved its affinity and pharmacokinetics.
Where it stands: promising preclinical evidence only, with human clinical trials ongoing and no approved efficacy in MS yet. The approach may also extend to psoriasis, IBD, and rheumatoid arthritis, where non-selective anti-TNF is limited by demyelinating side effects.

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Citation

Zahid M, Busmail A, Penumetcha SS, Ahluwalia S, Irfan R, Khan SA, Rohit Reddy S, Vasquez Lopez ME, Mohammed L. Tumor Necrosis Factor Alpha Blockade and Multiple Sclerosis: Exploring New Avenues. Cureus. 2021;13(10):e18847. doi:10.7759/cureus.18847.

Dr. Saher Ahluwalia is a co-author of this review.