Dept. of Gastroenterology, Univ. Hospital of Heraklion, PO Box 1352, Voutes, Heraklion, GR-71100, Crete, Greece.
Am J Physiol Gastrointest Liver Physiol. 2013 Dec;305(11):G763-85. doi: 10.1152/ajpgi.00004.2013. Epub 2013 Aug 29.
During the last decade, biological therapies have an increasing share in the modern therapeutics of various diseases including inflammatory bowel diseases (IBD). Animal models of IBD have often been used to identify the targets of biological therapies, to test their relevance to disease pathogenesis, to assess their therapeutic efficacy in vivo, and to check for drug toxicity. In the field of inflammatory diseases the majority of biologics under development have failed to reach the clinic. This review examines the ability of preclinical data from animal models of IBD to predict success or failure of biologics in human IBD. Specifically, it describes the murine models of IBD, the mechanism of disease induction, the phenotype of the disease, its relevance to human IBD, and the specific immunological features of disease pathogenesis in each model and mainly compares the results of the phase II and III trials of biologics in IBD with preclinical data obtained from studies in animal models. Finally, it examines the possible reasons for low success in translation from bench to bedside and offers some suggestions to improve translation rates.
在过去十年中,生物疗法在包括炎症性肠病(IBD)在内的各种疾病的现代治疗中占有越来越大的份额。IBD 的动物模型常用于确定生物疗法的靶点,检验它们与疾病发病机制的相关性,评估其在体内的治疗效果,并检查药物毒性。在炎症性疾病领域,大多数正在开发的生物制剂都未能进入临床。本综述检查了 IBD 动物模型的临床前数据预测生物制剂在人类 IBD 中成功或失败的能力。具体来说,它描述了 IBD 的鼠类模型、疾病诱导机制、疾病表型、与人类 IBD 的相关性以及每种模型中疾病发病机制的特定免疫学特征,并主要比较了生物制剂在 IBD 中的 II 期和 III 期临床试验结果与从动物模型研究中获得的临床前数据。最后,它探讨了从实验室到临床转化成功率低的可能原因,并提出了一些提高转化率的建议。