Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and Stabilization of Disease Progression in Multiple Sclerosis

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Abstract
Multiple sclerosis (MS) is an immune-mediated disorder of the brain and spinal cord in which at least part of the inflammatory process can be objectively measured by contrast-enhancing lesions (CELs) on brain magnetic resonance (MR) imaging. When used as an add-on therapy to interferon beta, daclizumab significantly inhibits CELs in MS.1-3 Studies from our laboratory revealed an unexpected mechanism of action of daclizumab in MS—it increases the quantity and function of immunoregulatory CD56bright natural killer (NK) cells, which downregulate adaptive T-cell responses.4 Although overall NK cell quantity or function has been described as diminished in patients with MS,5 the quantity of immunoregulatory CD56bright NK cells has not been systematically studied. Studies from our laboratory first identified expansion of these cells by daclizumab based on their combined phenotype as CD8αdim lymphocytes that are CD3−, CD4−, and CD19−.4 Recently, an unbiased large-scale immunophenotyping approach identified a diminished quantity of CD8dim cells as a biomarker that distinguishes patients with MS and patients with clinically isolated syndrome from healthy control subjects.6 Furthermore, numbers of CD56bright NK cells are increased by several other effective immunomodulatory therapies in MS such as interferon beta7 and rituximab.8 These data suggest that CD56bright NK cells may be relevant immunoregulatory cells in MS. Because type 1 interferons are known to enhance NK cell function9 and, conversely, because NK cells induce interferon beta during viral infection,10 the following important question emerged: Is synergism between interferon beta and daclizumab required for therapeutic efficacy in MS? In addition, although intravenous daclizumab (1 mg/kg) administered every 4 weeks blocks more than 95% of CD25 on T cells in the blood,4 it is unclear whether CD25 saturation is also achieved in tissues and whether a higher dosage of daclizumab may be more efficacious. This article reports the MR imaging and clinical and immunologic results of a second open-label baseline vs treatment phase II clinical trial of daclizumab in patients with MS that was performed at the Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, and that addresses these new and important questions. In addition, the article describes pilot biomarkers that potentially allow the early identification of patients who may not respond optimally to daclizumab monotherapy at the standard dosage. Instead, these patients may need a higher dosage of daclizumab or combination with interferon beta to achieve full therapeutic benefit.