Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability

Abstract

Currently, there are four monoclonal antibodies (mAbs) that target the cluster of differentiation (CD) 20 receptor available to treat multiple sclerosis (MS): rituximab, ocrelizumab, ofatumumab, and ublituximab. B-cell depletion therapy has changed the therapeutic landscape of MS through robust efficacy on clinical manifestations and MRI lesion activity, and the currently available anti-CD20 mAb therapies for use in MS are a cornerstone of highly effective disease-modifying treatment. Ocrelizumab is currently the only therapy with regulatory approval for primary progressive MS. There are currently few data regarding the relative efficacy of these therapies, though several clinical trials are ongoing. Safety concerns applicable to this class of therapeutics relate primarily to immunogenicity and mechanism of action, and include infusion-related or injection-related reactions, development of hypogammaglobulinemia (leading to increased infection and malignancy risk), and decreased vaccine response. Exploration of alternative dose/dosing schedules might be an effective strategy for mitigating these risks. Future development of biosimilar medications might make these therapies more readily available. Although anti-CD20 mAb therapies have led to significant improvements in disease outcomes, CNS-penetrant therapies are still needed to more effectively address the compartmentalized inflammation thought to play an important role in disability progression.

Fig. 1

B-cell targets in CNS and periphery [4]. B-cell populations in the periphery, which contain tolerance defects, escape suppression by Treg and CD8+ T cells and enter germinal centers, where they differentiate into pathogenic memory B cells through interactions with follicular Th cells. Subsets of these pathogenic memory B cells, which express chemokine receptors CXCR3 and CCR6, proinflammatory cytokines, and adhesion molecule VLA-4, then infiltrate CNS through the blood-brain barrier, where they encounter T cells in follicle-like structures, leading to clonal expansion. Once inside the CNS, memory B cells may become plasmablasts, which secrete antibodies. Pathogenic B cells also secrete pro-inflammatory cytokines, which leads to activation of astrocytes and microglia, failure of effector T-cell inhibition, and activation of CD4+ T cells. CD cluster of differentiation, CNS central nervous system, GM-CSF granulocyte-macrophage colony-stimulating factor, IL interleukin, Th T helper, TNF tumor necrosis factor, Treg T regulatory

Fig. 2

B-cell maturation. B cells originate from common lymphoid progenitor (stem) cells in bone marrow. They first develop into pro-B cells, then differentiate into pre-B cells (at which point CD20 is expressed) and immature B cells through a process of rearrangements at the immunoglobulin locus which lead to surface expression of the pre-B cell receptor, and later a mature B-cell receptor capable of binding antigen. Immature B cells undergo a selection process to prevent development of self-reactivity. They then migrate out of the bone marrow into the periphery (lymph nodes and spleen), where they become mature naïve B cells. Binding to cognate antigen triggers development of antigen-specific mature activated B cells, which become either plasmablasts and antibody-secreting plasma cells (CD20-) or remain memory B cells (CD20+). CD cluster of differentiation, CSF cerebrospinal fluid, HLA human leukocyte antigen, Ig immunoglobulin

Fig. 3

Anti-CD20 monoclonal antibody target epitopes (minor variability exists in published data). Ofatumumab binds to discontinuous sequences of the small (residues 74–80) and large extracellular loops (residues 145–161) of CD20 [137]. Rituximab binds to amino acid residues 165-182 on large extracellular loop of CD20 while ocrelizumab binds to amino acid residues 165–180 on large extracellular loop of CD20 [137]. Ublituximab binds to residues 158–159 and 168–171 on large extracellular loop of CD20 [138]. CD cluster of differentiation