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

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.

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

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

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).