CD20 monoclonal antibodies for the treatment of multiple sclerosis: up-to-date

ABSTRACT

Introduction: Featuring demyelination and axonal degeneration, multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system representing a prominent cause of disability in young adults. The recently established therapeutic targeting of B cells in MS patients using CD20 monoclonal antibodies (CD20-mAbs) not only profoundly suppresses inflammatory disease activity but also materializes as the first treatment approach against disability accumulation in a subset of patients with primary progressive MS.

Areas covered: We will review current concepts regarding the immunopathology of B cells as well as results of clinical trials with CD20-mAbs in MS, from the murine-human chimeras rituximab and ublituximab to their increasingly humanized counterparts ocrelizumab and ofatumumab. We conducted a literature search using PubMed, clinicaltrials.gov, and clinicaltrialsregister.eu. We will focus on studies emphasizing the effectiveness of these mAbs in reducing MS disease activity and progression, long-term safety, optimal dosage and maintenance regimens. Lastly, we will turn to outstanding questions regarding anti-CD20 therapy in MS.

Expert opinion: CD20-mAbs could become first-line drugs in selected patients with highly active MS and already constitute an option for PPMS. Future studies could evaluate whether administration regimens currently in use can be optimized, while registry data could shed light on risk versus benefits on the long run, considering immunosenescence and a potentially increased risk of malignancies and infections in an aging population.

Trial registration: ClinicalTrials.gov identifier: NCT02980042.

Trial registration: ClinicalTrials.gov identifier: NCT03315923.

Trial registration: ClinicalTrials.gov identifier: NCT02746744.

Trial registration: ClinicalTrials.gov identifier: NCT03193866.

Trial registration: ClinicalTrials.gov identifier: NCT03535298.

Trial registration: ClinicalTrials.gov identifier: NCT03599245.

Trial registration: ClinicalTrials.gov identifier: NCT03562975.

Trial registration: ClinicalTrials.gov identifier: NCT03523858.

Trial registration: ClinicalTrials.gov identifier: NCT02688985.

Trial registration: ClinicalTrials.gov identifier: NCT03535298.

Trial registration: ClinicalTrials.gov identifier: NCT03500328.

Trial registration: ClinicalTrials.gov identifier: NCT03085810.

Trial registration: ClinicalTrials.gov identifier: NCT02792218.

Trial registration: ClinicalTrials.gov identifier: NCT02792231.

Trial registration: ClinicalTrials.gov identifier: NCT03249714.

Trial registration: ClinicalTrials.gov identifier: NCT03560739.

Trial registration: ClinicalTrials.gov identifier: NCT03277261.

Trial registration: ClinicalTrials.gov identifier: NCT03277248.

KEYWORDS:

• CD20 monoclonal antibody
• B-cell therapy
• multiple sclerosis
• ofatumumab
• ocrelizumab
• rituximab
• ublituximab

Article highlights

• The pivotal role of B cells in the pathogenesis of MS is undisputable, as underlined by the therapeutic effect of CD20-monoclonal antibodies (CD20-mAbs)

• CD20-mAbs elicit prompt and sustained decreases in MS disease activity, underpinning antibody-independent roles of B cell in MS

• Rituximab (RTX), the first CD20-mAb deployed in MS, has provided compelling proof of effectivity in relapsing MS and the longest follow-up on adverse effects, but has to be prescribed off-label

• Ocrelizumab (OCR) is the first CD20-mAb approved for use both in relapsing and progressive disease, yet incurs significantly higher therapy costs

• Experience with newer generation CD20-mAbs is limited, but ofatumumab (OFA) could represent an interesting alternative due to its s.c. formulation, while ublituximab (UTX) could promise shorter infusion times

This box summarizes key points contained in the article.

Declaration of interest

A Berthele reports personal fees, non-financial support, and compensations paid to his institution from Alexion, Bayer Healthcare, Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and Teva, all outside the submitted work. B Hemmer has served since 2016 on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare and TG therapeutics; he has received a speaker honorarium from Desitin; holds part of two patents; one for detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are funded by the Bundesministerium für Bildung und Forschung (01GI1601D) and the Deutsche Forschungsgemeinschaft (01GI1601D, 390857198).