A PEGylated Fab' fragment against tumor necrosis factor for the treatment of Crohn disease - Exploring a new mechanism of action
A PEGylated Fab' fragment against tumor necrosis factor for the treatment of Crohn disease - Exploring a new mechanism of action
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DOI：
10.2165/00063030-200822050-00005
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发表时间：
2008-01-01
期刊：
影响因子：
6.8
通讯作者：
Nesbitt, Andrew
中科院分区：
文献类型：
--
作者：
Bourne, Tim;Fossati, Gianluca;Nesbitt, Andrew
抗体对其特定靶点具有高特异性，越来越多地被用作具有激动剂、拮抗剂和靶向药物递送等功能的治疗剂。包括抗体片段在内的许多生物疗法的使用通常因其从血浆中迅速清除而受到限制。一种常用的延长暴露于生物疗法的方法是聚乙二醇的附着。肿瘤坏死因子(TNF)- α是一种参与免疫反应调节的多功能细胞因子。TNF α水平升高可在多种疾病中发现，包括慢性炎症性疾病类风湿性关节炎、牛皮癣和克罗恩病（CD）。抗tnf α抗体已被证明在治疗这些疾病方面非常有效。此外，它们在研究TNF α在疾病病因学中的作用方面被证明是无价的。基于TNF α中和抗体在CD动物模型中有效的证据，在临床试验中对抗TNF α抗体治疗进行了评估。有趣的是，尽管抗TNF α抗体依那西普能有效中和可溶性TNF α，但对活动性CD的缓解无效。这表明抗tnf α药物阿达木单抗、certolizumab pegol和英夫利昔单抗在CD中的疗效也涉及另一种作用模式；一种说法是细胞凋亡。然而，依那西普与阿达木单抗和英夫利昔单抗一样，可诱导细胞凋亡。此外，certolizumab pegol（已证明对CD有效）不会引起补体依赖性细胞毒性、抗体依赖性细胞介导的细胞毒性、细胞凋亡或中性粒细胞坏死，这些都是在体外测量的。用certolizumab pegol观察到的这些功能差异源于其独特的结构，不包括其他抗TNF α药物中存在的可结晶片段（Fc）部分，以及它通过TNF膜发出信号的方式。已经确定细菌是CD炎症过程的主要部分。已经确定的反映抗tnf α药物依那西普、阿达木单抗、certolizumab pegol和英夫利昔单抗在CD中的有效性的特性是能够抑制由细菌脂多糖诱导的单核细胞产生细胞因子。因此，这种作用方式可能对乳糜泻的疗效很重要。
Antibodies, having a high specificity for their particular target, are increasingly being used as therapeutic agents with functions including agonist, antagonist, and targeted drug delivery. The use of many biologic therapies, including antibody fragments, is generally limited by their rapid clearance from plasma. A commonly used approach to extend exposure to biologic therapies is the attachment of polyethylene glycol.Tumor necrosis factor (TNF)-alpha is a multifunctional cytokine involved in the regulation of immune responses. Elevated levels of TNF alpha are found in a wide range of diseases, including the chronic inflammatory conditions rheumatoid arthritis, psoriasis, and Crohn disease (CD). Anti-TNF alpha antibodies have proved highly efficacious in the treatment of these conditions. In addition, they have proved invaluable for investigating the role of TNF alpha in disease etiology.Based on evidence showing that neutralizing antibodies to TNF alpha were effective in animal models of CD, anti-TNF alpha antibody treatments were assessed in clinical trials. Interestingly, the anti-TNF alpha antibody etanercept proved ineffective at achieving remission in active CD despite potently neutralizing soluble TNF alpha. This indicated that an additional mode of action is also involved in the efficacy of the anti-TNF alpha agents adalimumab, certolizumab pegol, and infliximab in CD; one suggestion was apoptosis. However, etanercept, like adalimumab and infliximab, can induce apoptosis. Furthermore, certolizumab pegol (which has demonstrated efficacy in CD) does not cause complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, apoptosis, or necrosis of neutrophils, all measured in vitro. These functional differences observed with certolizumab pegol stem from its unique structure that does not include the crystallizable fragment (Fc) portion present in the other anti-TNF alpha agents, and the way in which it signals through membrane TNF.It is well established that bacteria are a major part of the inflammatory process in CD. The property identified that reflected the efficacies of the anti-TNF alpha agents etanercept, adalimumab, certolizumab pegol, and infliximab in CD was the ability to inhibit the cytokine production by monocytes that is induced by bacterial lipopolysaccharide. It may therefore be the case that this mode of action is important for efficacy in CD.