Comparison of the Inhibition Mechanisms of Adalimumab and Infliximab in Treating Tumor Necrosis Factor α-Associated Diseases from a Molecular View
Comparison of the Inhibition Mechanisms of Adalimumab and Infliximab in Treating Tumor Necrosis Factor α-Associated Diseases from a Molecular View
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DOI：
10.1074/jbc.m113.491530
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发表时间：
2013-09-20
影响因子：
4.8
通讯作者：
Lou, Zhiyong
中科院分区：
文献类型：
--
作者：
Hu, Shi;Liang, Shuaiyi;Lou, Zhiyong
肿瘤坏死因子α靶向治疗结合药物依那西普、英夫利昔单抗和阿达利单抗用于各种炎症和免疫性疾病的临床治疗。尽管所有这些试剂都能破坏肿瘤坏死因子α与其受体之间的相互作用，但临床研究表明，与依那西普和英夫利昔单抗相比，阿达利玛单抗治疗具有优势。然而，Adalimumab的潜在分子作用机制仍不清楚。在我们之前的工作中，我们提供了关于Infliximab如何与肿瘤坏死因子α的E-F环结合并作为肿瘤坏死因子α受体结合阻滞剂发挥作用的结构数据。为了进一步阐明肿瘤坏死因子α抑制剂之间的差异，我们解决了肿瘤坏死因子α与Adalimumab Fab形成的络合物的晶体结构。结构观察和诱变分析为鉴定肿瘤坏死因子α上的Adalimumab表位提供了直接证据，并揭示了Adalimumab通过占据肿瘤坏死因子α受体结合部位而抑制肿瘤坏死因子α的机制。肿瘤坏死因子αAdalimumab中较大的抗原-抗体界面也在分子水平上为进一步了解Adalimumab与Infliximab相比的临床优势提供了信息。
TNF alpha-targeting therapy with the use of the drugs Etanercept, Infliximab, and Adalimumab is used in the clinical treatment of various inflammatory and immune diseases. Although all of these reagents function to disrupt the interaction between TNF alpha and its receptors, clinical investigations showed the advantages of Adalimumab treatment compared with Etanercept and Infliximab. However, the underlying molecular mechanism of action of Adalimumab remains unclear. In our previous work, we presented structural data on how Infliximab binds with the E-F loop of TNF alpha and functions as a TNF alpha receptor-binding blocker. To further elucidate the variations between TNF alpha inhibitors, we solved the crystal structure of TNF alpha in complex with Adalimumab Fab. The structural observation and the mutagenesis analysis provided direct evidence for identifying the Adalimumab epitope on TNF alpha and revealed the mechanism of Adalimumab inhibition of TNF alpha by occupying the TNF alpha receptor-binding site. The larger antigen-antibody interface in TNF alpha Adalimumab also provided information at a molecular level for further understanding the clinical advantages of Adalimumab therapy compared with Infliximab.