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Review
. 2023 Mar 23:14:1004795.
doi: 10.3389/fimmu.2023.1004795. eCollection 2023.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic

Jérôme de Sèze  1   2 , Elisabeth Maillart  3   4 , Antoine Gueguen  5 , David A Laplaud  6 , Laure Michel  7   8   9 , Eric Thouvenot  10   11 , Hélène Zephir  12 , Luc Zimmer  13 , Damien Biotti  14 , Roland Liblau  15   16
Affiliations
Review

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic

Jérôme de Sèze et al. Front Immunol. .

Abstract

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

Keywords: anti-CD20; multiple sclerosis; ocrelizumab; ofatumumab; rituximab; ublituximab.

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Conflict of interest statement

JS has received fees for serving on scientific advisory boards andconsulting, and research support from Novartis and Roche. EM has received research support from Fondation ARSEP and Biogen Idec, travel funding and/or consulting fees from Alexion, Biogen Idec, BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. AG has received personal compensation for consulting, lecturing and congress participation from Novartis, Alexon, AEI/Roche andNovartis. DL has received fees for board membership and consultancy and grants from Alexion, Actelion, BMS, Biogen,Merck, Novartis, Roche, Sanofi and Teva. LM has received consulting fees from Biogen, Novartis Pharma, Teva, BMS, Roche,Sanofi-Genzyme and Janssen Cilag. ET has received honoraria, travel grants, or research grants from the following pharmaceutical companies: Actelion, Biogen, Bristol Myers Squibb/Celgene, Merck, Novartis, Roche, Teva. HZ has received personal fees from Novartisrelated to this work and consulting fees from Biogen, Roche,Alexion, Roche, BMS, Novartis and Merck, unrelated to this work. DB has received personal compensation for consulting,serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Celgene-BMS and Alexion. RL has received consultancy and speaker honoraria from Biogen, Sanofi-Genzyme, Merck-Serono,Novartis, Orion and GSK, and research grants from GSK, Population Bio and Roche. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Involvement of B cells in multiple sclerosis pathophysiology. (A) Distribution of B cells in the central nervous system areas involved in MS pathology. CSF: cerebrospinal fluid. (B) Representation of an active MS lesion with a central inflamed vein, a demyelinated core, and a rim of active demyelination, and distribution of immune cell subpopulations (, , , –20) (C) Representation of a meningeal follicle-like structure (, , –25).
Figure 2
Figure 2
Anti-CD20 mAbs structure, epitope binding and mechanisms of action. (A) Structure of rituximab, ocrelizumab, ofatumumab and ublituximab antibodies (B) Binding epitopes of rituximab, ocrelizumab, ofatumumab and ublituximab on CD20. Adapted from Fox, 2021 (46) (C) Schematic representation of different mechanisms of action involved upon anti-CD20 mAbs binding and their relative contribution (D). CDC, complement dependent cytotoxicity; ADCC, antibody-dependent cellular cytotoxicity; RTX, rituximab; OCR, ocrelizumab; OFA, ofatumumab; UTX, ublituximab.
Figure 3
Figure 3
Anti-CD20 mediated changes in subtypes and their functions. CD20+ B cell depletion leads to an increase in CD40 expression (n.s: non-significant) and MHC II expression in myeloid cells (79); a decrease in CD4+ and CD8+ effector function (79), proinflammatory Th1 and Th17 responses (82), and numbers of terminally differentiated T cells, and an increase in CD4+ effector memory cells (85). Secretion of cytokines are changed upon B cell deletion (79, 85). CD20+ T cell depletion induces a decrease in myelin-specific CD20+ CD8+ cells (84), in both CD20+ CD4+ and CD8+ cells (86), in CD20+ T cell migration (85) and a decrease in pro-inflammatory cytokines (49, 87).
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