The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

被引:28
作者
Milo, Ron [1 ]
机构
[1] Ben Gurion Univ Negev, Barzilai Med Ctr, Dept Neurol, IL-78278 Ashqelon, Israel
关键词
CD25; CD56(bright) NK cells; clinical trial; daclizumab; IL-2; receptor; multiple sclerosis; T cell; MONOCLONAL-ANTIBODY THERAPY; PLACEBO-CONTROLLED PHASE-3; REGULATORY T-CELLS; ORAL BG-12; ALEMTUZUMAB; ANTAGONISTS; ACTIVATION; TRIAL;
D O I
10.1177/1756285613504021
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the alpha-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Based on the assumption that it would block the activation and expansion of autoreactive T cells that are central to the immune pathogenesis of multiple sclerosis (MS), daclizumab was tested in several small open-label clinical trials in MS and demonstrated a profound inhibition of inflammatory disease activity. Surprisingly, accompanying mechanistic studies revealed that the most important biological effect of daclizumab was rather a dramatic expansion and activation of immunoregulatory CD56(bright) natural-killer (NK) cells that correlated with treatment response, while there was no or only minor effect on peripheral T-cell activation and function. These CD56(bright) NK cells were able to gain access to the central nervous system in MS and kill autologous activated T cells. Additional and relatively large phase IIb clinical trials showed that daclizumab, as add-on or monotherapy in relapsing-remitting (RR) MS, was highly effective in reducing relapse rate, disability progression, and the number and volume of gadolinium-enhancing, T1 and T2 lesions on brain magnetic resonance imaging (MRI), and reproduced the expansion of CD56(bright) NK cells as a biomarker for daclizumab activity. Daclizumab is generally very well tolerated and has shown a favorable adverse event (AE) profile in transplant recipients. However, several potentially serious and newly emerging AEs (mainly infections, skin reactions, elevated liver function tests and autoimmune phenomena in several body organs) may require strict safety monitoring programs in future clinical practice and place daclizumab together with other new and highly effective MS drugs as a second-line therapy. Ongoing phase III clinical trials in RRMS are expected to provide definite information on the efficacy and safety of daclizumab and to determine its place in the fast-growing armamentarium of MS therapies.
引用
收藏
页码:7 / 21
页数:15
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