Milo Ron
Department of Neurology, Barzilai Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, 2 Hahistadrut St, Ashkelon 78278, Israel.
Ther Adv Neurol Disord. 2014 Jan;7(1):7-21. doi: 10.1177/1756285613504021.
Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the α-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.
达利珠单抗是一种免疫球蛋白G1（IgG1）同型的人源化单克隆抗体，它能与活化T细胞和CD4+CD25+FoxP3+调节性T细胞上表达的高亲和力白细胞介素-2（IL-2）受体的α亚基（CD25）结合。基于其能阻断自身反应性T细胞的激活和扩增这一假设（自身反应性T细胞在多发性硬化症（MS）的免疫发病机制中起核心作用），达利珠单抗在多项MS的小型开放标签临床试验中进行了测试，并显示出对炎症性疾病活动有显著抑制作用。令人惊讶的是，伴随的机制研究表明，达利珠单抗最重要的生物学效应是免疫调节性CD56（明亮型）自然杀伤（NK）细胞的显著扩增和激活，这与治疗反应相关，而对外周T细胞的激活和功能没有或只有轻微影响。这些CD56（明亮型）NK细胞能够进入MS患者的中枢神经系统并杀死自体活化T细胞。另外相对较大规模的IIb期临床试验表明，达利珠单抗作为复发缓解型（RR）MS的附加治疗或单一疗法，在降低复发率、残疾进展以及脑磁共振成像（MRI）上钆增强、T1和T2病变的数量和体积方面非常有效，并再次出现CD56（明亮型）NK细胞的扩增，作为达利珠单抗活性的生物标志物。达利珠单抗一般耐受性良好，在移植受者中显示出良好的不良事件（AE）谱。然而，一些潜在的严重且新出现的AE（主要是感染、皮肤反应、肝功能检查升高以及多个身体器官的自身免疫现象）可能需要在未来临床实践中实施严格的安全监测方案，并将达利珠单抗与其他新型高效MS药物一起列为二线治疗药物。RRMS正在进行的III期临床试验预计将提供关于达利珠单抗疗效和安全性的确切信息，并确定其在快速增长的MS治疗药物库中的地位。
