Lanzarotto Francesco, Carpani Marta, Chaudhary Rakesh, Ghosh Subrata
Imperial College London, Hammersmith Hospital, London, UK.
Drugs. 2006;66(9):1179-89. doi: 10.2165/00003495-200666090-00002.
The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.
炎症性肠病（IBD）的病因复杂，许多方面仍不清楚。然而，在理解肠道慢性炎症的发病机制方面已取得显著进展，最近也有了新的见解。对IBD免疫病理学的更好理解促使开发出新型生物制剂，以靶向炎症级联反应中的关键分子和过程。IBD治疗中新型疗法的发展已从经验性转变为从实验室到临床的科学合理转化。克罗恩病（CD）中淋巴细胞浸润肠道是由淋巴细胞上表达的α4整合素与其特异性配体黏膜血管地址素细胞黏附分子-1（在炎症肠道微脉管系统的内皮细胞上表达）之间的相互作用介导的。针对α4整合素的单克隆抗体的开发使得将淋巴细胞进入肠道的迁移作为一种新型治疗干预成为可能。那他珠单抗是一种针对α4整合素的重组人源化单克隆抗体，在一项II期随机对照试验中对CD有效。在相隔4周给予两次3mg那他珠单抗输注后6周时，最高缓解率和应答率分别为71%和44%。那他珠单抗在该试验中耐受性良好。尽管未达到第10周应答这一主要疗效终点，但III期试验结果令人鼓舞。维持应答和缓解试验ENACT（那他珠单抗作为持续治疗的评估）-2报告称，在初始诱导缓解（ENACT-1）试验中有应答的患者中，那他珠单抗在维持应答和缓解方面疗效显著。这与生活质量参数的改善相关。第二种针对α4β7开发的人源化单克隆抗体MLN-02（LDP-02）在溃疡性结肠炎和CD中也显示出疗效证据。尽管临床试验表明抑制α4整合素耐受性良好，但那他珠单抗在多发性硬化症和CD中的使用引发了对少数患者中与进行性多灶性白质脑病（PML）关联的严重担忧，该药物已在等待进一步安全性评估期间退出市场。PML由多瘤JC病毒感染引起，具有进行性且通常致命，已知发生于严重免疫抑制患者中。初步安全性评估表明，尽管在一名接受开放标签那他珠单抗治疗的CD患者中出现了PML，但PML非常罕见。
