Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients.
Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients.
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DOI：
10.1212/wnl.0000000000004485
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发表时间：
2017-10-10
期刊：
影响因子：
9.9
通讯作者：
Cree BAC
中科院分区：
文献类型：
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作者：
Plavina T;Muralidharan KK;Kuesters G;Mikol D;Evans K;Subramanyam M;Nestorov I;Chen Y;Dong Q;Ho PR;Amarante D;Adams A;De Sèze J;Fox R;Gold R;Jeffery D;Kappos L;Montalban X;Weinstock-Guttman B;Hartung HP;Cree BAC
目的：研究多发性硬化症(MS)患者治疗中断后，他他珠单抗介导的药代动力学/药效学变化的可逆性。药代动力学/药效学数据收集在纳他珠单抗治疗多发性硬化的安全性和有效性(确认)(每12周，共116周)和随机化治疗中断那他珠单抗(恢复)(每4周，共28周)研究中。采用免疫分析法检测血清纳他珠单抗和可溶性血管细胞黏附分子-1(sVCAM-1)水平。用流式细胞仪检测淋巴细胞亚群、α-4-整合素表达/饱和度和血管细胞黏附分子-1的结合。那他珠单抗治疗组外周血淋巴细胞计数(细胞/L)由治疗前的2.1×10 9增至3.5×10 9。从末次服用那他珠单抗8周后开始，中断治疗的患者的淋巴细胞计数显著低于继续治疗的患者(3.1x109vs3.5x109；p=0.031)，从第16周开始稳定在胎盘前的水平。所有测量的细胞亚群、α4-整合素表达/饱和度和血管内皮细胞黏附分子的变化都显示出相似的可逆性。淋巴细胞计数保持在正常范围内。体外VCAM-1与淋巴细胞的结合增加，直到最后一次服用那他珠单抗16周后的≈，然后趋于平稳，这表明免疫细胞功能是可逆的。Gd增强损伤的时间表现与药效学标志物逆转一致。那他珠单抗对外周免疫细胞和药效学标志物的影响是可逆的，从最后一次给药后8周开始变化；在最后一次给药16周后，未治疗的患者≈水平恢复到观察/预期的水平。这种可逆性将那他珠单抗与MS治疗区分开来，后者需要更长的恢复时间。表征那他珠单抗生物学效应的时间进程可能有助于临床医生做出治疗顺序的决定。这项研究提供了III类证据，证明他他珠单抗的药效学标志物在停药16周后被逆转≈。
To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule–1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule–1 (VCAM-1) binding were assessed using flow cytometry. Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 109 to 3.5 × 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 109 vs 3.5 × 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions. This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.