Slevin Stephanie M, Egan Laurence J
*Immunology Research Group, REMEDI, National University of Ireland, Galway, Ireland; and †Department of Pharmacology and Therapeutics, Clinical Science Institute, National University of Ireland, Galway, Ireland.
Inflamm Bowel Dis. 2015 Dec;21(12):2909-20. doi: 10.1097/MIB.0000000000000533.
Tumor necrosis factor alpha (TNF-α) has been widely accepted as a therapeutic target for inflammatory disorders including inflammatory bowel disease. Anti-TNF-α monoclonal antibodies (mAbs) including infliximab, adalimumab, golimumab, and certolizumab pegol have revolutionized therapy for these chronic inflammatory disorders. These agents are potent inhibitors of TNF-α, but significant evidence points to the fact that their actions extend beyond simple neutralization of the cytokine. Recent advances in understanding the mechanism of action of anti-TNF-α mAbs has discovered a number of previously unrecognized actions that are likely to be relevant in mediating their anti-inflammatory effects. Many of those actions are mediated by the binding of the antibodies to transmembrane TNF-α (tmTNF-α) and involve complex interactions with other molecular factors and cells. In this review, we have highlighted new information on the mechanism of actions of anti-TNF-α mAbs, from in vitro and in vivo studies. Despite obvious benefits in many patients, the clinical use of these antibodies are hampered by the fact that some patients do not respond to them, and among patients who do respond, many will develop recurrent disease despite continued dosing. Although pharmacokinetic factors explain some of the observed cases of partial or complete resistance to the effects of anti-TNF-α mAbs, other nonresponder patients may be resistant to those agents mechanism of action. A more thorough understanding of the mechanism of action of anti-TNF-α mAbs may allow the development of strategies to individualize therapy and to overcome resistance.
肿瘤坏死因子α（TNF-α）已被广泛公认为包括炎症性肠病在内的炎症性疾病的治疗靶点。抗TNF-α单克隆抗体（mAb），如英夫利昔单抗、阿达木单抗、戈利木单抗和赛妥珠单抗聚乙二醇化制剂，彻底改变了这些慢性炎症性疾病的治疗方法。这些药物是TNF-α的强效抑制剂，但大量证据表明它们的作用不仅仅局限于简单地中和细胞因子。最近在理解抗TNF-α mAb作用机制方面的进展发现了许多以前未被认识的作用，这些作用可能与介导它们的抗炎效应相关。其中许多作用是由抗体与跨膜TNF-α（tmTNF-α）的结合介导的，并且涉及与其他分子因子和细胞的复杂相互作用。在这篇综述中，我们重点介绍了来自体外和体内研究的关于抗TNF-α mAb作用机制的新信息。尽管这些抗体对许多患者有明显益处，但它们在临床应用中受到一些患者对其无反应这一事实的阻碍，而且在有反应的患者中，许多人尽管持续给药仍会复发疾病。虽然药代动力学因素解释了一些观察到的对抗TNF-α mAb部分或完全耐药的病例，但其他无反应患者可能对这些药物的作用机制具有抗性。更深入地了解抗TNF-α mAb的作用机制可能有助于制定个体化治疗策略并克服耐药性。
