Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists
Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists
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DOI：
10.1016/j.cyto.2016.08.014
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发表时间：
2018-01-01
期刊：
影响因子：
3.8
通讯作者：
Ueda, Naoyasu
中科院分区：
文献类型：
--
作者：
Mitoma, Hiroki;Horiuchi, Takahiko;Ueda, Naoyasu
肿瘤坏死因子（TNF）-α是炎性疾病如类风湿性关节炎和炎性肠病中的强效促炎和病理性细胞因子。抗TNF-α治疗已被确立为这些疾病的有效治疗策略。在临床环境中，三种单克隆抗TNF-α，全IgG 1抗体英夫利西单抗、阿达木单抗和戈利木单抗，抗TNF-α抗体赛妥珠单抗的聚乙二醇化Fab'片段，TNF受体2/IgG 1-Fc融合蛋白依那西普的细胞外结构域，对类风湿性关节炎几乎同样有效。尽管单克隆完整IgG 1抗体能够诱导炎症性肠病的临床和内镜缓解，但与完整IgG 1抗体相比，无Fc部分的赛妥珠单抗对炎症性肠病的有效性较差。此外，没有证据表明依那西普导致炎症性肠病的临床缓解。除了抗TNF-α药物对中和可溶性TNF-α的共同作用外，每种抗TNF-α药物都具有其独特的药理学特性，这导致临床疗效的差异。在此，我们重点关注抗TNF-α药物作用的区别，特别是以下几点：（1）对配体、跨膜TNF-α和光敏素的阻断能力，（2）对跨膜TNF-α表达细胞的作用，（3）对Fc γ受体表达细胞的作用，（4）在炎症组织中的降解和分布。不断积累的证据将为我们提供如何修饰抗TNF-α药物以提高炎症性疾病的临床疗效的想法。(C)2016爱思唯尔有限公司版权所有。
Tumor necrosis factor (TNF)-alpha is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-alpha therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-alpha, full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-alpha antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-alpha agents on neutralization of soluble TNF-alpha, each anti-TNF-alpha agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-alpha agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-alpha, and lymphotoxin, (2) effects toward transmembrane TNF-alpha-expressing cells, (3) effects toward Fc gamma receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-alpha agents to enhance the clinical efficacy in inflammatory diseases. (C) 2016 Elsevier Ltd. All rights reserved.