Lee Jee Un, Shin Woori, Son Ji Young, Yoo Ki-Young, Heo Yong-Seok
Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
Int J Mol Sci. 2017 Jan 23;18(1):228. doi: 10.3390/ijms18010228.
Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.
抗TNFα的单克隆抗体，包括英夫利昔单抗、阿达木单抗、戈利木单抗和聚乙二醇化赛妥珠单抗，被广泛用于治疗类风湿性关节炎和炎症性肠病等炎症性疾病。最近，TNFα与英夫利昔单抗和阿达木单抗的Fab片段复合物的晶体结构揭示了这些抗体药物的分子机制。在此，我们报告TNFα与聚乙二醇化赛妥珠单抗的Fab片段复合物的晶体结构，以阐明精确的抗原-抗体相互作用以及这种治疗性抗体中和TNFα的结构基础。结构分析和诱变研究表明，表位仅限于TNFα三聚体的单个原体。此外，TNFα的DE环和GH环在与聚乙二醇化赛妥珠单抗的相互作用中起关键作用，表明该药物通过部分占据TNFα的受体结合位点发挥作用。此外，聚乙二醇化赛妥珠单抗的结合诱导了DE环的构象变化，从而中断了TNFα-受体相互作用。对TNFα阻滞剂与TNFα相互作用的全面比较揭示了TNFα表面的表位多样性，有助于更好地理解TNFα阻滞剂的分子机制。这些结构研究的积累可为改进抗TNFα治疗性抗体提供依据。
