Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab
Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab
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DOI：
10.1001/jamaneurol.2017.0676
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发表时间：
2017-08-01
期刊：
影响因子：
29
通讯作者：
Schmierer, Klaus
中科院分区：
文献类型：
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作者：
Baker, David;Herrod, Samuel S.;Schmierer, Klaus
重要性阿仑单抗是一种CD 52耗竭单克隆抗体，可有效抑制复发性多发性硬化症（MS），但与继发性B细胞自身免疫的高发生率相关，限制了使用。这些影响可以通过控制B细胞过度增殖来避免。目的研究在3期试验计划期间收集的描述Alemtuzumab对淋巴细胞亚群影响的数据是否揭示了解释MS治疗的疗效和继发性自身免疫风险的机制。和受试者来自Alemtuzumab和Rebif在多发性硬化I和多发性硬化II中的疗效关键比较的监管提交资料的淋巴细胞重建数据II（CARE-MS I和II）试验通过信息自由要求从欧洲药品管理局获得。结果阿仑单抗清除CD 4（+）T细胞95%以上，包括调节性T细胞（-80%）和CD 8（+）T细胞（-80%），并对CD 8（+）T细胞的杀伤作用进行了研究。（>80%消耗），其在整个试验中保持远低于参考水平。然而，尽管CD 19（+）B细胞最初也被耗尽（>85%），但随着时间的推移，未成熟B细胞的过度增殖随着向成熟B细胞的转化而发生显著（增加180%）。这些淋巴细胞动力学与Alemtuzumab结合和中和抗体的快速形成以及继发性B细胞自身免疫的发生相关。B细胞的过度增殖掩盖了CD 19+记忆B细胞的显著长期耗竭，这可能是MS疗效的基础。结论和相关性尽管记忆T和B细胞的阻断可能限制MS，但在缺乏有效T细胞调节的情况下，CD 19 + B细胞亚群的快速增殖对Alemtuzumab的安全性和疗效有影响。控制B细胞增殖直到T细胞调节恢复可能会限制继发性自身免疫，这不会发生与其他B细胞耗竭剂。
IMPORTANCE Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.OBJECTIVE To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.DESIGN, SETTING, AND PARTICIPANTS Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016.MAIN OUTCOMES AND MEASURES Tabulated data from T-and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.RESULTS Alemtuzumab depleted CD4(+) T cells by more than 95%, including regulatory cells (-80%) and CD8(+) T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19(+) B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.CONCLUSIONS AND RELEVANCE Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell-depleting agents.