Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
Hospital San Borja Arriarán, Santiago, Chile.
Inflamm Bowel Dis. 2019 Jan 10;25(2):270-282. doi: 10.1093/ibd/izy269.
After 20 years of successful targeting of pro-inflammatory cytokines for the treatment of IBD, an alternative therapeutic strategy has emerged, based on several decades of advances in understanding the pathogenesis of IBD. The targeting of molecules involved in leukocyte traffic has recently become a safe and effective alternative. With 2 currently approved drugs (ie, natalizumab, vedolizumab) and several others in phase 3 trials (eg, etrolizumab, ozanimod, anti-MAdCAM-1), the blockade of trafficking molecules has firmly emerged as a new therapeutic era for IBD. We discuss the targets that have been explored in clinical trials: chemokines and its receptors (eg, IP10, CCR9), integrins (eg, natalizumab, AJM300, vedolizumab, and etrolizumab), and its endothelial ligands (MAdCAM-1, ICAM-1). We also discuss a distinct strategy that interferes with lymphocyte recirculation by blocking lymphocyte egress from lymph nodes (small molecule sphingosine-phosphate receptor [S1PR] agonists: fingolimod, ozanimod, etrasimod, amiselimod). Strategies on the horizon include additional small molecules, allosteric inhibitors that specifically bind to the active integrin form and nanovectors that allow for the use of RNA interference in the quest to modulate pro-inflammatory leukocyte trafficking in IBD.
经过 20 年成功针对促炎细胞因子治疗 IBD 的研究，一种新的治疗策略出现了，这是基于几十年来对 IBD 发病机制的深入理解。靶向参与白细胞迁移的分子已成为一种安全有效的替代方法。目前已有 2 种获批药物（即那他珠单抗、维得利珠单抗）和其他几种处于 3 期临床试验阶段（如依特利珠单抗、奥扎那利单抗、抗 MAdCAM-1），阻断迁移分子已成为 IBD 的一个新的治疗时代。我们讨论了在临床试验中探索的靶点：趋化因子及其受体（如 IP10、CCR9）、整合素（如那他珠单抗、AJM300、维得利珠单抗和依特利珠单抗）及其内皮配体（MAdCAM-1、ICAM-1）。我们还讨论了一种通过阻断淋巴细胞从淋巴结中流出而干扰淋巴细胞再循环的独特策略（小分子鞘氨醇-1-磷酸受体[S1PR]激动剂：芬戈莫德、奥扎那利单抗、埃特拉莫德、阿塞那平）。即将出现的策略包括其他小分子、特异性结合整合素活性形式的变构抑制剂和纳米载体，以寻求利用 RNA 干扰来调节 IBD 中的促炎白细胞迁移。
