Association of Vedolizumab Level, Anti-Drug Antibodies, and α4β7 Occupancy With Response in Patients With Inflammatory Bowel Diseases
Association of Vedolizumab Level, Anti-Drug Antibodies, and α4β7 Occupancy With Response in Patients With Inflammatory Bowel Diseases
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DOI：
10.1016/j.cgh.2017.11.050
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发表时间：
2018-05-01
影响因子：
12.6
通讯作者：
Ben-Horin, Shomron
中科院分区：
文献类型：
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作者：
Ungar, Bella;Kopylov, Uri;Ben-Horin, Shomron
背景和目的：关于维多珠单抗（一种针对整合素 α 4 β 7 的单克隆抗体）的真实药代动力学和药效学特征的数据很少。我们对接受维多珠单抗治疗的炎症性肠病（IBD）患者进行了一项前瞻性研究，以确定血清药物浓度、抗多珠单抗抗体（AVA）的形成和整合素 α 4 β 7 饱和度。方法：我们对 106 例患者进行了前瞻性研究。 2014 年 9 月至 2017 年 3 月期间，以色列 2 个三级医疗中心接受维多珠单抗治疗的 IBD 患者（67 名克罗恩病患者和 39 名溃疡性结肠炎患者）。在诱导和维持治疗之前和期间收集临床数据和血清样本。临床缓解定义为 Harvey-Bradshaw 指数评分低于 5 或简单临床结肠炎活动指数评分为 3 或更低。我们测量了维多珠单抗、AVAs 和炎症标志物的血清水平。在指定的谷时间点从一些患者中获取外周血单核细胞，并从 36 个样本中分离出 CD3+ CD45RO+ T 细胞。将细胞与荧光缀合的维多珠单抗一起孵育，并使用流式细胞术来量化α4β7整合素饱和度。我们还对从无 IBD 患者（非 IBD 对照，n = 6）、未接受维多珠单抗治疗的 IBD 患者（未经治疗的 IBD 对照，n = 8）和接受维多珠单抗治疗的 IBD 患者（n = 15）的肠粘膜中分离出的 CD3D CD45ROD 固有层 T 细胞进行了流式细胞术分析。结果：106 名患者中的 48 名患者（45%）在一周内实现了临床缓解治疗第 14 周时，106 名患者中的 6 名和 50 名患者 (48%) 出现了这种情况。第 6 周时，临床缓解患者的维多珠单抗中位水平 (40.2 μg/mL) 高于活动性疾病患者 (29.7 μg/mL；P = 05)。维持治疗期间，C 反应蛋白水平正常的患者 (21.8 μg/mL 维多珠单抗) 维多珠单抗的中位血清水平显着高于 C 反应蛋白水平高的患者 (11.9 μg/mL 维多珠单抗) (P = .0006)。测量的其他临床结果与任何检查时间点的维多珠单抗中位血清水平无关。诱导治疗期间 17% 的患者和维持治疗期间 3% 的患者检测到 AVA，但与临床结果无关。外周血记忆 T 细胞 (n = 36) 的流式细胞术分析显示，无论反应状态或药物水平如何，在第 2 周和第 14 周以及维持阶段，α 4 β 7 整合素几乎完全占据。健康和IBD对照的大多数肠道CD3+CD45RO+记忆T细胞表达α4β7（72%；四分位数范围，56%-81%）。相比之下，无论反应如何，在接受维多珠单抗治疗的患者中，只有 5.6% 的肠道记忆细胞（四分位数范围，4.4%-11.2%）（P < .0001）可检测到游离 α 4 β 7，无论反应如何。 结论：在一项针对真实 IBD 患者的前瞻性研究中，我们将维多珠单抗药物水平与缓解和炎症标志物水平相关联。无论药物的血清水平或对治疗的反应如何，接受维多珠单抗治疗的患者的几乎所有 T 细胞中的整合素 α 4 β 7 均被阻断。这些发现表明需要探索阻止对维多珠单抗产生反应的替代机制。
BACKGROUND & AIMS: There are few data available on the real-life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin alpha 4 beta 7. We performed a prospective study of patients with inflammatory bowel diseases (IBDs) treated with vedolizumab to determine serum drug concentrations, formation of antivedolizumab antibodies (AVAs), and integrin alpha 4 beta 7 saturation.METHODS: We performed a prospective study of 106 patients with IBD (67 with Crohn's disease and 39 with ulcerative colitis) treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel. Clinical data and serum samples were collected before and during induction and maintenance therapy. Clinical remission was defined as Harvey-Bradshaw index scores below 5 or as Simple Clinical Colitis Activity Index scores of 3 or less. We measured serum levels of vedolizumab, AVAs, and markers of inflammation. Peripheral blood mononuclear cells were obtained from some patients at designated trough time points and CD3+ CD45RO+ T cells were isolated from 36 samples. Cells were incubated with fluorescent-conjugated vedolizumab and flow cytometry was used to quantify alpha 4 beta 7 integrin saturation. We also performed flow cytometry analyses of CD3D CD45ROD lamina propria T cells isolated from intestinal mucosa of patients without IBD (non-IBD controls, n = 6), patients with IBD not treated with vedolizumab (untreated IBD controls, n = 8), and patients with IBD treated with vedolizumab (n = 15).RESULTS: Clinical remission was achieved by 48 of 106 patients (45%) by week 6 and 50 of 106 patients (48%) by week 14 of treatment. The median level of vedolizumab at week 6 was higher in patients in clinical remission (40.2 mu g/mL) than in patients with active disease (29.7 mu g/mL; P = 05). The median serum level of vedolizumab was significantly higher in patients with a normal level of C-reactive protein (21.8 mu g/mL vedolizumab) vs the level in those with a high level of C-reactive protein (11.9 mu g/mL vedolizumab) during maintenance treatment (P = .0006). The other clinical outcomes measured were not associated with median serum level of vedolizumab at any time point examined. AVAs were detected in 17% of patients during induction therapy and 3% of patients during maintenance therapy, but did not correlate with clinical outcomes. Flow-cytometry analysis of peripheral blood memory T cells (n = 36) showed near-complete occupancy of alpha 4 beta 7 integrin at weeks 2 and 14 and during the maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+memory T cells of healthy and IBD controls expressed alpha 4 beta 7 (72%; interquartile range, 56%-81%). In contrast, free alpha 4 beta 7 was detectable on only 5.6% of intestinal memory cells (interquartile range, 4.4%-11.2%) (P < .0001) from vedolizumab-treated patients, regardless of response.CONCLUSIONS: In a prospective study of real-life patients with IBD, we associated vedolizumab drug levels with remission and inflammatory marker level. Integrin alpha 4 beta 7 was blocked in almost all T cells from patients treated with vedolizumab, regardless of serum level of the drug or response to treatment. These findings indicate a need to explore alternative mechanisms that prevent response to vedolizumab.