Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.
Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.
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DOI：
10.1212/nxi.0000000000001096
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Kasper LH
中科院分区：
文献类型：
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作者：
Fadul CE;Mao-Draayer Y;Ryan KA;Noelle RJ;Wishart HA;Channon JY;Kasper IR;Oliver B;Mielcarz DW;Kasper LH
CD 40及其配体CD 40 L（CD 154）的共刺激对于T细胞的功能分化是重要的。临床前研究已经认识到这种共刺激相互作用在多发性硬化（MS）实验模型发病机制中的重要性。确定抗CD 40配体人源化单克隆抗体（mAb）（托拉珠单抗/IDEC-131）在复发缓解型MS（RRMS）患者中的安全性、药代动力学和免疫效应。这项单机构开放标签剂量递增研究（I期）入组了12例RRMS患者，每隔一周接受4次1、5、10或15 mg/kg人源化α CD 40 L（托拉珠单抗）IV输注。患者每年随访18周，最后随访5年。除安全性和药代动力学外，其他次要和探索性指标包括免疫效应、临床、MRI、实验室和神经心理学评价。认为15起不良事件（均为轻度至中度）与治疗可能相关或相关性未知。在18周规定的研究期间，未发生严重不良事件，包括血栓栓塞事件。5年的年度和长期随访显示无迟发性毒性。5和10 mg/kg剂量组之间的药代动力学呈非线性。两个剂量组之间toralizumab的血清半衰期一致，平均值为15.3天（SD = 1.9）。流式细胞术显示淋巴细胞亚群无耗竭。治疗后观察到CD 25 +/CD 3+和CD 25 +/CD 4+比值增加，并向抗炎细胞因子反应转变。我们的研究表明，阻断CD 40 L在RRMS患者中是安全的，耐受性良好，同时增加CD 25 + T细胞和抗炎细胞因子谱。这些发现支持进一步的研究，以评估阻断CD 40 L作为RRMS潜在治疗方法的疗效。本研究提供了关于抗CD 40 L mAb在RRMS患者中的安全性、药代动力学和免疫效应的IV级证据。
Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS). This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations. Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment. Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 + T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS. This study provides Class IV evidence on the safety, pharmacokinetics, and immune effects of an mAb to CD40L in patients with RRMS.