Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Neurology. 2011 Nov 22;77(21):1877-86. doi: 10.1212/WNL.0b013e318239f7ef. Epub 2011 Nov 9.
We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon-β and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system.
Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF.
The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56(bright) NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood.
Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment.
The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period.
我们之前曾报道，抗 CD25 人源化单克隆抗体达利珠单抗可减少干扰素-β应答不理想的多发性硬化（MS）患者的对比增强病变（CEL），且这种应答与 CD56（bright）NK 细胞的扩增相关。这些数据已在安慰剂对照的多中心试验（CHOICE 研究）中得到重现。本研究旨在探究达利珠单抗单药治疗是否可减少未经治疗的复发缓解型多发性硬化（RRMS）患者的 CEL，以及达利珠单抗对鞘内免疫系统的影响。
16 例高炎症活性 RRMS 患者入组一项开放标签、基线与治疗期对照的、为期 54 周的达利珠单抗单药治疗 II 期研究，并在后续进行了连续的临床和 MRI 检查，以及全血和 CSF 中的免疫生物标志物检测。
该试验达到了预设的结局。脑 CEL 减少了 87.7%（主要终点），并改善了多发性硬化功能综合评分（次要终点）、斯克里普斯神经功能评定量表和扩展残疾状态量表（三级终点）的评分。外周血和 CSF 中 CD56（bright）NK 细胞显著扩增，导致 T 细胞/NK 细胞和 B 细胞/NK 细胞比值以及 CSF 中的 IL-12p40 下降。令人惊讶的是，CSF 和外周血中的免疫细胞上的 CD25 Tac 表位均被同等阻断。
达利珠单抗单药治疗可抑制 RRMS 患者 MS 斑块的形成，免疫调节性 NK 细胞可能直接在中枢神经系统中抑制致病性免疫反应的激活。
本研究提供了 III 级证据，表明达利珠单抗可在 54 周内减少未经治疗的 RRMS 患者的 CEL 数量。
