Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn's Disease.
Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn's Disease.
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DOI：
10.1093/ecco-jcc/jjx121
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发表时间：
2018-01-05
期刊：
影响因子：
--
通讯作者：
Hung K
中科院分区：
文献类型：
--
作者：
Hassan-Zahraee M;Banerjee A;Cheng JB;Zhang W;Ahmad A;Page K;von Schack D;Zhang B;Martin SW;Nayak S;Reddy P;Xi L;Neubert H;Fernandez Ocana M;Gorelick K;Clare R;Vincent M;Cataldi F;Hung K
旨在确定克罗恩病 [CD] 患者使用 PF-00547659（一种抗人粘膜地址素细胞粘附分子 1 [MAdCAM-1] 单克隆抗体）治疗后外周血中的药效生物标志物。在这项 2 期、随机、双盲、对照研究 [OPERA] 中，分析了中度至重度活动性 CD 患者的血液样本，这些患者在基线和第 4 周和第 8 周皮下接受安慰剂或 22.5 mg、75 mg 或 225 mg PF-00547659，并在第 12 周进行随访。可溶性 MAdCAM [sMAdCAM] 通过质谱法测量，通过流式细胞术分析表达 β7 的 T 细胞，通过 RNA 测序分析基因转录组。从基线到第 12 周，安慰剂组的 sMAdCAM 略有增加 [6%]，而所有 PF-00547659 组的 sMAdCAM 均显着下降 [–87% 至 –98%]。从基线到第 12 周，安慰剂组中观察到 β7+ 中央记忆 T 细胞的等效可溶性荧光染料的频率和分子略有增加 [4%]，而活性治疗组中则有统计学上显着的增加 [48% 至 81%]。 β7+ 效应记忆 T 细胞也出现了类似的趋势 [安慰剂，8%；安慰剂，8%； PF-00547659, 84–138%] 和 β7+ 初始 T 细胞 [8%； 13–50%]。 CCR9 基因表达具有统计学上显着的上调 [p = 1.09e-06； PF-00547659 治疗的错误发现率 < 0.1]，并且与 β7+ T 细胞的增加相关。 OPERA 研究的结果证明了血液中药效生物标志物测量的积极药理学和剂量依赖性变化，包括淋巴细胞细胞组成的变化和相应的 CCR9 基因表达变化。
To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn’s disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, β7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [–87% to –98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for β7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for β7+ effector memory T cells [placebo, 8%; PF-00547659, 84–138%] and β7+ naïve T cells [8%; 13–50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in β7+ T cells. Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes.
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