Efficacy and Safety of Existing and Emerging Monoclonal Antibody Therapies for Multiple Sclerosis

European Neurological Review, 2016;11(2):96–100 DOI: https://doi.org/10.17925/ENR.2016.11.02.96


The introduction of monoclonal antibodies for multiple sclerosis (MS) has provided a molecular targeted approach to modify the course of disease. A major advantage of monoclonal antibodies in the treatment of MS is that they are designed to be specific to their target and have very few off-target effects. Monoclonal antibodies have distinct structural characteristics and different targets, and their various mechanisms of action include cross-linking, blocking interactions, induction of signal transduction via receptor binding, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. Monoclonal antibodies should not therefore be considered a single class of treatments. Natalizumab and alemtuzumab are highly efficacious treatments approved for treating MS, though they tend to be reserved for patients with more active disease. Other monoclonal antibodies in advanced development include ocrelizumab, ofatumumab, daclizumab and opicinumab (anti-LINGO-1). Screening and monitoring is required to enable the optimal utilisation of all monoclonal antibodies and the benefit–risk profile of each monoclonal antibody needs to be fully considered before use. At present, patients have variable access to effective MS treatments, and this issue is likely to become even more important to address as new therapies become available.
Keywords: Monoclonal antibodies, multiple sclerosis (MS), alemtuzumab, daclizumab, natalizumab, ocrelizumab, ofatumumab, opicinumab
Disclosure: Gavin Giovannoni has received compensation for serving as a consultant or speaker for, or has received research support from: AbbVie, Bayer Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck- Serono, Novartis, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals.
Acknowledgments: Medical writing assistance was provided by Catherine Amey at Touch Medical Media, funded by Roche.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: May 31, 2016 Accepted August 05, 2016
Correspondence: Gavin Giovannoni, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, 4 Newark Street, London E1 2AT, UK; Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK. E: g.giovannoni@qmul.ac.uk
Support: The publication of this article was supported by an independent, educational grant provided by Roche. Roche had no influence on the development or content of the article except in reviewing the accuracy of the medical data presented.

The options available for treating multiple sclerosis (MS) have increased substantially over the last two decades. Initial first-line disease-modifying therapies (DMTs), included intramuscular (IM) interferon (IFN) β-1a (Avonex®, Biogen, Cambridge, Massachusetts, US), subcutaneous (SC) IFN β-1a (Rebif®, EMD Serono, Rockland, Massachusetts, US), SC IFN β-1b (Betaferon®, Bayer, Leverkusen, Germany; Extavia®, Novartis, Basel, Switzerland [2007]) and SC glatiramer acetate [GA] (Copaxone®, Teva Neuroscience, Petah Tikva, Israel). Mitoxantrone and later natalizumab, both high efficacy treatments, were generally used second-line.1–7 Although moderately efficacious, patient adherence to IFNs and GA was and remains an important challenge despite innovations in the formulation and delivery of these DMTs.8,9 Further, some patients with MS develop neutralising antibodies (NAbs) when treated with IFN-β, which abrogates the therapeutic efficacy.10 Poor adherence to these DMTs has been shown to result in a reduction in efficacy and in worse patient outcomes.11

It is common practice in some countries for physicians to prescribe several first-line therapies such as IFN β-1a or GA before switching to monoclonal antibodies.12 However, there is growing evidence that, in addition to the early initiation of treatment after diagnosis,13 early treatment optimisation after insufficient response to initial treatment is important to achieve a favourable outcome.14 Recently, a new strategy has emerged, ‘treating to target,’ where the aim is to achieve no evidence of disease activity (NEDA). This composite measure is defined as no relapse activity, no Expanded Disability Status Scale (EDSS) disability progression, and no new magnetic resonance imaging (MRI) lesions (T1 Gd+ and/or active T2 lesions).15–17 Confirming NEDA necessitates regular monitoring of relapses, disability and for subclinical activity on MRI.18 There is a report from a study of 152 patients indicating that the monoclonal antibody, natalizumab, is associated with a higher proportion of patients achieving NEDA status compared with those reported previously for injectable treatments.19

Monoclonal antibodies are used therapeutically in a variety of medical disciplines including oncology, rheumatology, gastroenterology, dermatology and prevention of transplant rejection. Three monoclonal antibody treatments are currently approved for treating MS, (natalizumab,20–24 alemtuzumab25–30 and daclizumab31). These are high efficacy treatments but tend to be reserved for more active patients, in particular in patients with rapidly-evolving severe MS (Table 1). Other humanised monoclonal antibodies are currently in advanced development (Phase II and III) mainly in the treatment of patients with relapsing-remitting MS (RRMS). These include ocrelizumab,32,33 ofatumumab (both anti-CD20)34,35 and opicinumab (anti-LINGO-1).36

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Keywords: Monoclonal antibodies, multiple sclerosis (MS), alemtuzumab, daclizumab, natalizumab, ocrelizumab, ofatumumab, opicinumab