Both cladribine and alemtuzumab may effect MS via B-cell depletion.
Both cladribine and alemtuzumab may effect MS via B-cell depletion.
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DOI：
10.1212/nxi.0000000000000360
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发表时间：
2017-07
期刊：
影响因子：
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通讯作者：
Schmierer K
中科院分区：
文献类型：
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作者：
Baker D;Herrod SS;Alvarez-Gonzalez C;Zalewski L;Albor C;Schmierer K
通过对在Cladriine和Alemtuzumab诱导治疗的关键III期试验中收集的但未见报道的淋巴细胞亚群的分析，了解Cladriine(CLAD)治疗MS的疗效。口服治疗多发性硬化症(Clarity)(NCT00213135)cladriine和Alemtuzumab和Rebif在多发性硬化症中的疗效比较研究一(CARE-MS I)(NCT00530348)Alemtuzumab试验的监管提交通过信息自由请求从欧洲医学会获得。提取数据并进行统计分析。在透明状态下测试的两种剂量(3.5毫克/千克；5.25毫克/千克)都将96周的年化复发率降低到0.16-0.18，两种剂量在降低MRI损害和残疾方面同样有效。然而，令人惊讶的是，T细胞的消耗相当温和。Cladriine 3.5 mg/kg使CD4+细胞减少40%-45%，CD8+细胞减少15%-30%，而阿仑珠单抗对CD4+细胞和CD8+细胞的抑制分别为70%-95%和47%-55%。然而，两种剂量的Cladriine均可导致70%-90%的CD19+B细胞耗竭，与阿仑珠单抗(90%)相似。CD19+细胞缓慢再生至基线的15%-25%。然而，Alemtuzumab在注射后6-12个月诱导了CD19+B细胞的过度聚集，这可能是与Alemtuzumab相关的B细胞自身免疫的底物。根据先前的CD4+T细胞耗竭研究，克拉曲滨仅导致T细胞适度耗尽，这可能与对MS的显著影响不一致。Cladriine的治疗药物反应关系与持续的B细胞耗竭更一致，再加上单抗CD20+耗尽的成功，表明B细胞抑制可能是主要的直接作用机制。
To understand the efficacy of cladribine (CLAD) treatment in MS through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction therapies. The regulatory submissions of the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed. Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized relapse rate to 0.16–0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T-cell depletion was rather modest. Cladribine 3.5 mg/kg depleted CD4+ cells by 40%–45% and CD8+ cells by 15%–30%, whereas alemtuzumab suppressed CD4+ cells by 70%–95% and CD8+ cells by 47%–55%. However, either dose of cladribine induced 70%–90% CD19+ B-cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15%–25% of baseline before cladribine redosing. However, alemtuzumab induced hyperrepopulation of CD19+ B cells 6–12 months after infusion, which probably forms the substrate for B-cell autoimmunities associated with alemtuzumab. Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T-cell depletion studies. The therapeutic drug-response relationship with cladribine is more consistent with lasting B-cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests that B-cell suppression could be the major direct mechanism of action.