Clinical trial of a humanized anti-IL-2/IL-15 receptor β chain in HAM/TSP
Clinical trial of a humanized anti-IL-2/IL-15 receptor β chain in HAM/TSP
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DOI：
10.1002/acn3.50820
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发表时间：
2019-07-05
影响因子：
5.3
通讯作者：
Jacobson, Steven
中科院分区：
文献类型：
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作者：
Enose-Akahata, Yoshimi;Oh, Unsong;Jacobson, Steven
目的人T细胞嗜淋巴病毒1 （HTLV-1）相关脊髓病/热带痉挛性截瘫（HAM/TSP）是一种慢性进行性神经系统疾病。在HAM/TSP患者中，CD8(+) T细胞的慢性活化，如自发淋巴细胞增殖和htlv -1特异性细胞毒性T细胞的增加所证明。由于IL-2和IL-15刺激记忆性CD8(+) T细胞活性，这些细胞因子与HAM/TSP的免疫发病机制有关。在这项I期试验中，我们评估了Hu-Mik β 1的安全性、药代动力学和能力，Hu-Mik β 1是一种针对IL-2/IL-15受体β链（IL-2/IL-15R β: CD122）的人源化单克隆抗体，通过抑制IL-15的作用来饱和CD122并调节HAM/TSP患者的异常免疫反应。方法对9例HAM/TSP患者分别以0.5 mg/kg、1.0 mg/kg、1.5 mg/kg的剂量静脉给予Hu-Mik β 1。每隔3周给药5剂虎奶β 1。采用标准化量表评估临床反应。研究人员检测了HAM/TSP患者的病毒和免疫结果，包括HTLV-1前病毒载量、T细胞表型分析和自发淋巴细胞增殖。结果在HAM/TSP患者中，hu - milk β 1给药无明显毒性。9例HAM/TSP患者中有5例实现了Hu-Mik β 1对CD122的饱和。Hu-Mik β 1与异常CD8(+) T细胞功能的抑制有关，包括自发淋巴细胞增殖和脱颗粒以及ifn - γ的表达，特别是在达到CD122饱和的HAM/TSP患者中。解释沪乳β 1治疗对HAM/TSP患者有许多免疫作用，但未观察到临床疗效。我们也没有发现任何剂量相关的毒性。
Objective Human T cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8(+) T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV-1-specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL-2 and IL-15 stimulate memory CD8(+) T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu-Mik beta 1, a humanized monoclonal antibody directed toward the IL-2/IL-15 receptor beta-chain (IL-2/IL-15R beta: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL-15 action. Methods Hu-Mik beta 1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu-Mik beta 1 were administered at 3-week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV-1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. Results There was no significant toxicity associated with Hu-Mik beta 1 administration in HAM/TSP patients. Saturation of CD122 by Hu-Mik beta 1 was achieved in five out of nine HAM/TSP patients. Administration of Hu-Mik beta 1 was associated with inhibition of aberrant CD8(+) T cell function including spontaneous lymphoproliferation and degranulation and IFN-gamma expression, especially in HAM/TSP patients that achieved CD122 saturation. Interpretation The treatment with Hu-Mik beta 1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose-related toxicity.