Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis.
Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis.
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DOI：
10.1001/archneurol.2009.50
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发表时间：
2009-04
影响因子：
--
通讯作者：
Martin, Roland
中科院分区：
文献类型：
--
作者：
Bielekova, Bibiana;Howard, Thomas;Packer, Amy N.;Richert, Nancy;Blevins, Gregg;Ohayon, Joan;Waldmann, Thomas A.;McFarland, Henry F.;Martin, Roland
回答三个与Daclizumab治疗多发性硬化症(MS)相关的重要问题：1.Daclizumab的疗效是否依赖于联合干扰素-β？2.大剂量的Daclizumab对持续疾病活动的患者是否更有效？3.生物标志物能预测Daclizumab的全部或部分治疗反应吗？Daclizumab在干扰素-β反应不足的MS患者中的开放标签基线对照治疗II期试验。干扰素-β基线治疗3个月后，干扰素-β与达利珠单抗联合治疗5.5个月。如果患者在5.5个月时脑部MRI上的对比增强病变(CEL)与基线相比至少减少了75%，Daclizumab继续作为单一疗法治疗10个月。否则，Daclizumab的剂量将增加一倍。马里兰州贝塞斯达国家神经疾病和中风研究所神经免疫学分会。15例接受干扰素-β标准制剂的MS患者，他们在过去12个月内有1次以上复发或残疾持续增加，并在3个月的基线脑磁共振检查中至少有2次CEL。达利珠单抗1 mg/kg静脉滴注，每4周1次，联合干扰素-β(0~5.5月)和单用(6.5月~15.5月)。主要结果是干扰素-β单独治疗、联合治疗和达利珠单抗治疗之间的细胞毒性降低。次要结果包括临床残疾和免疫生物标志物的变化。总体而言，33%的患者经历了一些治疗的副作用。两名患者出现全身副作用，达利珠单抗停用。13例MS患者中有9例单用达克利珠单抗治疗有效，4例患者需要联合应用达利珠单抗和干扰素-β来稳定疾病活动性。总体而言，Daclizumab治疗导致了72%的CEL抑制，并显著改善了临床残疾。先导生物标志物(CD56bright NK细胞的扩张和CD8+T细胞的收缩)被识别出来，可以区分完全和部分Daclizumab应答者。Daclizumab单抗治疗对干扰素-β治疗的大多数持续性疾病活动性患者是有效的。Daclizumab联合干扰素-β或更大剂量的Daclizumab可能是在所有患者中实现最佳治疗反应所必需的。生物标志物可能能够识别对Daclizumab单一治疗反应不佳的患者。只有大量患者长期服用达克利珠单抗，才能充分确定其作为治疗高炎症性MS的安全性和远期疗效。
To answer three important questions related to the efficacy of daclizumab in multiple sclerosis (MS): 1. Is the therapeutic effect of daclizumab dependent on combination with IFN-β? 2. Is a higher dose of daclizumab more efficacious in patients with persistent disease activity? 3. Can biomarkers predict full- versus partial therapeutic response to daclizumab? An open label baseline-versus-treatment phase II trial of daclizumab in MS patients with inadequate response to IFN-β. The 3 months of IFN-β baseline was followed by 5.5 months of combination therapy of IFN-β with daclizumab. If patients experienced at least a 75% reduction of contrast enhancing lesions (CEL) on brain MRI at month 5.5 as compared to baseline, daclizumab was continued as monotherapy for 10 months. Otherwise, the dose of daclizumab was doubled. Neuroimmunology Branch (NIB) of the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. 15 MS patients receiving standard preparations of IFN-β, who experienced more than 1 relapse or sustained increase in disability in preceding 12 months, and had at least 2 CEL during 3 monthly baseline brain MRIs. Daclizumab 1 mg/kg intravenous (IV) infusion every 4 weeks in combination with IFN-β (months 0 to 5.5) and as monotherapy (months 6.5–15.5). The primary outcome was the reduction of CEL between IFN-β monotherapy, combination therapy and daclizumab monotherapy. The secondary outcomes included changes in clinical disability and immunological biomarkers. Overall 33% of patients experienced some side effects of therapy. Two patients developed systemic side effects and daclizumab was discontinued. While daclizumab monotherapy was efficacious in nine out of thirteen MS patients, the combined daclizumab and IFN-β treatment was necessary to stabilize disease activity in four. Overall, daclizumab therapy led to 72% inhibition of CEL and to a significant improvement in clinical disability. Pilot biomarkers (expansion of CD56bright NK cells and contraction of CD8+ T cells) were identified that can differentiate between full- and partial daclizumab responders. Daclizumab monotherapy is an effective treatment in the majority of patients with persistent disease activity on IFN-β therapy. Either combination of daclizumab with IFN-β or higher doses of daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may be able to identify patients with suboptimal response to daclizumab monotherapy. Only long-term administration to a large number of patients can fully define the safety and long-term efficacy of daclizumab as treatment for high-inflammatory MS.
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影响因子：
4.4
作者：
Iversen, AC;Norris, PS;Benedict, CA
通讯作者：
Benedict, CA
影响因子：
3.3
作者：
Saraste, M.;Irjala, H.;Airas, L.
通讯作者：
Airas, L.
DOI：
10.1073/pnas.0601335103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Bielekova, B;Catalfamo, M;Martin, R
通讯作者：
Martin, R
DOI：
10.1073/pnas.0402653101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Bielekova, B;Richert, N;Martin, R
通讯作者：
Martin, R
影响因子：
5.8
作者：
Fischer, JS;Rudick, RA;Reingold, SC
通讯作者：
Reingold, SC