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  • Review Article
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Modulation of IL-2Rα with daclizumab for treatment of multiple sclerosis

Nature Reviews Neurology volume 9, pages 394–404 (2013)Cite this article

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Abstract

Multiple sclerosis (MS) is a debilitating neurological disorder involving autoimmune destruction of myelin. Although the pathogenic mechanisms underlying MS are not fully understood, T cells are thought to have a key role in orchestrating the aberrant CNS-directed adaptive immune response in the early and relapsing–remitting phase of disease. New therapeutic interventions with improved efficacy over existing drugs and good tolerability are needed. A promising therapy under investigation is daclizumab—a humanized monoclonal antibody directed against the IL-2 receptor α chain (CD25). Clinical trials have shown that daclizumab strongly inhibits disease activity and slows disease progression in MS. Novel and intriguing mechanisms of action of daclizumab have been identified that might explain its clinical efficacy—namely, expansion and enhancement of the immune regulatory function of CD56bright natural killer cells, reduction of early T-cell activation through blockade of IL-2 cross-presentation by dendritic cells, and reduction of lymphoid tissue inducer cells—thereby enhancing endogenous mechanisms of immune tolerance. This Review discusses the efficacy and safety of daclizumab in patients with MS and provides a detailed insight into the multifunctional mechanisms of action of this drug.

Key Points

  • Daclizumab is an immune-modulating humanized IgG1 monoclonal antibody directed against the IL-2 receptor α chain (IL-2Rα, also known as CD25) that is under investigation for treatment of multiple sclerosis (MS)

  • Binding of daclizumab to IL-2Rα prevents assembly and signalling of the high-affinity IL-2R, which is involved in immune system activation

  • In clinical trials, daclizumab strongly inhibited disease activity and slowed disease progression in patients with MS, with a fairly good tolerability and safety profile

  • Novel mechanisms of action whereby daclizumab modulates the immune system in MS have been identified

  • These mechanisms involve expansion and stimulation of immune regulatory CD56bright natural killer cells, reduction of early T-cell activation, and reduction in the number of proinflammatory lymphoid tissue inducer cells

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Figure 1: Imbalances in immune regulatory networks lead to autoimmunity underlying multiple sclerosis.
Figure 2: Component subunits of the intermediate-affinity IL-2 receptor and high-affinity IL-2 receptor.
Figure 3: Putative mechanisms of action of daclizumab.

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Acknowledgements

H. Wiendl is supported by the German Research Foundation (individual research grant “The role of NK cells in the immune regulation of MS” and centre grants CRC128 “Multiple sclerosis” and SFB1009 “Breaking barriers”), the German Competence Network of MS (KKNMS) founded by the German Federal Ministry of Education and Research (BMBF), the European Union (BEST-MS), the Interdisciplinary Clinical Research Centre Münster (IZKF) and the Interdisciplinary Centre for Clinical Research Münster (IMF). C. C. Gross is supported by the German Research Foundation (individual research grant “The role of NK cells in the immune regulation of MS”). We thank A. Fitton and P. Lane of UBC Scientific Solutions, a company that has received support from Biogen Idec, for assistance with searching of the literature, drafting of the figures, and editing of the manuscript for language prior to submission.

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  1. Department of Neurology, University of Münster, Albert Schweitzer Campus 1, Münster, 48149, Germany

    Heinz Wiendl & Catharina C. Gross

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H. Wiendl has received honoraria for lecturing, and travel expenses for attending meetings from Bayer Health Care, Biogen Idec/Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Sanofi Aventis, and TEVA Neuroscience; has served or serves as a consultant for Biogen Idec, Merck Serono, Novartis Pharma, Sanofi-Aventis; and receives research support from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Merck Serono, Novartis, Novo Nordisk, Sanofi-Aventis. C. C. Gross has received travel expenses for attending meetings from Novartis Pharma.

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Wiendl, H., Gross, C. Modulation of IL-2Rα with daclizumab for treatment of multiple sclerosis. Nat Rev Neurol 9, 394–404 (2013). https://doi.org/10.1038/nrneurol.2013.95

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