Universität Stuttgart, Institut für Zellbiologie und Immunologie, Allmandring 31, 70569 Stuttgart, Germany +49 711 68566989 ; +49 711 68567484 ;
Expert Opin Drug Discov. 2009 Mar;4(3):279-92. doi: 10.1517/17460440902785167.
TNF is a central mediator of inflammation and key target for intervention in inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. The four at present approved protein therapeutics directly target TNF and inhibit binding to its two TNF receptors. Treatment with TNF antagonists results in significant clinical responses and is generally well tolerated.
Ten years of clinical experience with 1 million patients treated also revealed the limits of the available antagonists and potential therapy-associated risks, foremost being tuberculosis reactivation, but also neurologic and hematologic events, and even malignancies. These findings ask for improvement of established therapies.
We here review published literature on strategies interfering with TNF action and provide an overview of the now approved antagonists of TNF action as well as new reagents under development.
Clinical experience with approved TNF antagonists shows that there is a demand for minimizing risks associated with persistent blocking of TNF action. With new TNF pathway-targeting reagents and new concepts based on receptor-selective intervention under development, it is foreseeable that efficacy and safety will be further improved and that TNF-targeting strategies will be exploited in further inflammatory and other diseases, including metabolic diseases and cancer.
TNF 是炎症的主要介质，也是类风湿关节炎、银屑病和克罗恩病等炎症性疾病干预的关键靶点。目前批准的四种蛋白质治疗药物直接针对 TNF，并抑制其与两种 TNF 受体的结合。使用 TNF 拮抗剂治疗可显著改善临床症状，且通常具有良好的耐受性。
100 万接受治疗的患者的临床经验也揭示了现有拮抗剂的局限性和潜在的治疗相关风险，首要的是结核分枝杆菌再激活，但也包括神经系统和血液系统事件，甚至恶性肿瘤。这些发现要求改进现有的治疗方法。
我们在此回顾了已发表的关于干扰 TNF 作用的策略的文献，并概述了目前已批准的 TNF 作用拮抗剂以及正在开发的新试剂。
TNF 拮抗剂的临床经验表明，需要最小化与持续阻断 TNF 作用相关的风险。随着新的 TNF 通路靶向试剂和基于受体选择性干预的新概念的开发，预计疗效和安全性将进一步提高，TNF 靶向策略将在进一步的炎症和其他疾病中得到应用，包括代谢疾病和癌症。
