The Rise of Precision Monoclonal Antibodies in Treating MS

The realm of multiple sclerosis (MS) and other autoimmune diseases is undergoing a significant evolution, driven by advancements in B-cell–depleting therapies. A recent comprehensive review, published in CNS Drugs, highlighted how sophisticated molecular engineering of anti-CD20 and anti-CD19 monoclonal antibodies (mAbs) is leading to more effective, safer, and better-tolerated treatments for patients, with profound implications for the biosimilar industry and the US health care system.¹

B-cell depletion has proven an exceptionally effective strategy in MS, neuromyelitis optica spectrum disorder (NMOSD), and various hematologic malignancies. | Image credit: chartphoto - stock.adobe.com

B-cell depletion has proven an exceptionally effective strategy in MS, neuromyelitis optica spectrum disorder (NMOSD), and various hematologic malignancies.² Early successes with rituximab, an anti-CD20 mAb, opened the door for subsequent developments like ocrelizumab, ofatumumab, and ublituximab (all anti-CD20), as well as inebilizumab (an anti-CD19 mAb).^2,3 While these therapies share the goal of B-cell elimination, the review underscored that their underlying structural differences translate into distinct mechanisms of action, impacting the sustainability of B-cell depletion, safety profiles, and patient tolerability.

The researchers conducted the review because of the growing need to improve upon earlier therapies. Despite rituximab's powerful impact on MS, challenges such as high rates of infusion-related reactions (IRRs) and intravenous administration spurred the pursuit of more refined solutions. The study aimed to dissect the nuances between chimeric, humanized, and fully human mAbs; the role of glycoengineering; and how different mechanisms of action—specifically antibody-dependent cell-mediated cytotoxicity (ADCC) vs complement-dependent cytotoxicity (CDC)—influence clinical outcomes.

The narrative review, informed by literature, examined the molecular characteristics and clinical performance of both existing and emerging B-cell–targeting agents. The research emphasized how specific molecular engineering choices directly translate into tangible benefits for patient care.

Key findings of the review that could shape future biosimilar development and clinical practice included the following.

• Enhanced tolerability via engineering: The review found that the specific "humanness" of an antibody scaffold has less impact on IRRs than its primary mechanism of action. mAbs predominantly utilizing ADCC, such as ocrelizumab and ublituximab, tend to exhibit superior tolerability profiles compared with those where CDC plays a more dominant role (eg, rituximab). The introduction of a subcutaneous formulation for ofatumumab further showed how the administration route can boost patient convenience and access.
• Overcoming genetic variability: A critical discovery highlighted was the role of glycoengineering in enhancing ADCC activity. This modification, by reducing fucose content in the antibody's Fc region, proves vital in mitigating the effects of FcγRIIIa polymorphisms. These genetic variations can otherwise lead to suboptimal B-cell depletion and reduced treatment efficacy in some individuals. This breakthrough offers a pathway to more consistently effective therapies, as demonstrated by inebilizumab in NMOSD and ublituximab in MS, by ensuring robust B-cell depletion across diverse patient genotypes.
• Targeted mechanisms for improved outcomes: Understanding that different mAbs engage distinct B-cell lysis pathways (ADCC, CDC, antibody-dependent cell phagocytosis [ADCP]) enables more precise therapy design. For instance, inebilizumab, an anti-CD19 mAb, depletes B cells solely through ADCC and ADCP without complement activation, potentially contributing to its favorable IRR profile.
• Broad immunomodulatory effects: Beyond direct B-cell depletion, anti-CD20 mAbs exert widespread immunomodulatory effects, influencing T-cell populations and fostering immune tolerance. Deeper insight into their impact on the adaptive immune system opens avenues for identifying novel biomarkers relevant to disease progression and treatment efficacy.

The implications for the biosimilar industry and the US health care system are substantial. As patents on original biologic therapies expire, the development of biosimilars becomes increasingly important for managing health care costs and expanding patient access. The insights from this review will empower biosimilar manufacturers to develop next-generation B-cell therapies that not only meet efficacy standards but also offer enhanced safety and convenience.

The continuous development of novel B-cell targeting strategies, including brain shuttle antibodies, bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapies, and antibody-drug conjugates, underscores a dynamic future for the management of MS and other B-cell–mediated autoimmune diseases. These advancements promise to continually refine treatment approaches, leading to even more precise and effective therapies for patients.

The authors concluded, “The role of genetic polymorphisms and pharmacogenetics is a new concept in MS and could open the door to potentially more personalized approaches as novel treatment options become available. Further elucidation of the characteristics that drive therapeutic success for anti-CD20 mAbs could pave the way for the development of new treatments, including bispecific antibodies and CAR T-cell therapies, and improve the overall quality of life for people living with MS.”

References

1. Cree BA, Berger JR, Greenberg B. The evolution of anti-CD20 treatment for multiple sclerosis: optimization of antibody characteristics and function. CNS Drugs. 2025;39(6):545-564. doi:10.1007/s40263-025-01182-8

2. de Seze J, Maillart E, Gueguen A, et al. Anti-CD20 therapies in multiple sclerosis: from pathology to the clinic. Front Immunol. 2023;14:1004795. doi:10.3389/fimmu.2023.1004795

3. Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol. 2008;65(11):1443-1448. doi:10.1001/archneur.65.11.noc80069