B-cell targeting strategies for the treatment of multiple sclerosis: from non-cellular therapies to CAR-engineered cell therapies.

backgroundAccumulating evidence indicates that B-cell lineages play a central role in the pathogenesis of multiple sclerosis (MS). This understanding has reshaped the therapeutic landscape of MS, particularly following the success of anti-CD20 monoclonal antibodies (mAbs), which have become a cornerstone of MS treatment. Despite their efficacy in reducing relapse rates and slowing disability accumulation, current B-cell-depleting therapies have important limitations, including incomplete control of compartmentalized immune responses within the central nervous system (CNS).

methodsThis review summarizes the progress and limitations of current and emerging B-cell-targeting strategies for MS. We discuss established non-cellular approaches, including monoclonal antibodies, Bruton's tyrosine kinase (BTK) inhibitors, and B-cell activating factor (BAFF) inhibitors, and examine the rationale, potential advantages, and challenges of emerging chimeric antigen receptor (CAR)-engineered cell therapies.

resultsAnti-CD20 mAbs have demonstrated significant clinical efficacy; however, their limited CNS penetration and broad depletion of B-cell populations highlight the need for more targeted approaches. BTK inhibitors represent an emerging strategy to modulate B-cell and myeloid-cell signaling, while BAFF-targeting therapies have provided important insights into the complex role of B-cell survival pathways in MS. CAR-engineered cell therapies have emerged as a promising cellular approach capable of inducing profound and potentially durable depletion of pathogenic B-cell populations, including CNS-resident B-cell subsets.

conclusionsB-cell-targeting therapies continue to expand the therapeutic landscape of MS. Although current non-cellular approaches have improved disease control, their limitations emphasize the need for next-generation strategies. CAR-engineered cell therapies represent a promising frontier with the potential to achieve more sustained immune modulation and address some unmet therapeutic challenges in MS.