Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management

Abstract

Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]₄[Formula: see text]₁ integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

Keywords: Alemtuzumab; Disease-modifying therapy; Monoclonal antibodies; Multiple sclerosis; Natalizumab; Ocrelizumab; Ofatumumab; Rituximab; Ublituximab.

Fig. 1

Mechanism of action of mAb in the treatment of multiple sclerosis. Rituximab, ocrelizumab, ofatumumab, and ublituximab target CD20 expressing lymphocytes B causing ADCC and CDC of circulating lymphocytes B. Alemtuzumab targets CD52 expressing lymphocytes, eosinophils, monocytes/macrophages, and dendritic cells, resulting in their rapid depletion. Natalizumab binds to $\alpha$4$\beta$1 integrin receptor on endothelial cells, preventing interaction between $\alpha$4$\beta$1 integrin and VCAM-1 and, therefore, inhibiting migration of leukocytes through the BBB into the CNS parenchyma. Created with BioRender.com. ADCC antibody-dependent cell-mediated cytolysis, APC antigen-presenting cell, CD cluster of differentiation, CDC complement-dependent cytolysis, IL interleukin, TGF-$\beta$ transforming growth factor $\beta$, TNF-$\alpha$ tumor necrosis factor $\alpha$, VCAM-1 vascular cell adhesion molecule 1