《免疫学杂志》（The Journal of Immunology）近日在线报道了中科院上海生命科学研究院生物化学与细胞生物学研究所丁建平组的研究成果，揭示了单克隆抗体药物Basiliximab（商品名Simulect，Novartis）抑制人白细胞介素2（IL-2）信号通路的分子基础。这是近年来丁建平组发表的又一项关于重要治疗性抗体和抗原复合物结构和功能研究的论文。
IL-2为免疫应答中重要的细胞因子，其受体由a、b和g三个亚基组成。IL-2受体的a亚基（IL-2Ra）为IL-2特异性受体。IL-2Ra在参与器官移植移植排斥反应、某些自身免疫性疾病及T细胞白血病等病理过程的T细胞表面高表达，因此是很好的药物靶标。已有研究表明，抗IL-2Ra抗体可以抑制其与IL-2的结合，从而抑制T细胞的活化和增殖，减少器官移植后的免疫排斥反应。
Basiliximab是抗IL-2Ra的人-鼠嵌合单克隆抗体药物，主要应用于器官移植，尤其是肾脏移植的免疫抑制。丁建平组的杜嘉木博士等运用结构生物学和生物化学的方法解析了Basiliximab的Fab片段与IL-2Ra的复合物的晶体结构、分析了抗原-抗体相互作用的性质；通过对复合物的结构分析和与已报道的生化数据的比较，鉴定了Basiliximab的抗原决定表位。结构分析表明，Fab片段的CDR环区与IL-2Ra两个“shushi-like”结构域D1和D2都有较强的亲疏水相互作用，奠定了它与CD25具有高亲和力和高特异性的分子基础。进一步通过与已报道的IL-2/IL-2Ra及IL-2/IL-2Rabgc复合物的结构比较，发现Basiliximab的抗原表位与IL-2识别IL-2Ra的区域有很大程度上的重叠，而且和IL-2相比Basiliximab与IL-2Ra具有更强的相互作用，因此可以竞争性地结合IL-2Ra，从而阻碍IL-2与IL-2Ra的结合，进一步抑制IL-2信号通路的激活。这些研究结果在分子水平上揭示了Basiliximab抑制IL-2信号通路的分子机制，并合理地解释了已有的生物化学和免疫学数据。基于研究结果，研究者们提出了通过对Basiliximab进行定点突变以研发具有更高特异性和更强亲和力的抗体药物的策略。这项研究成果对于抗IL-2Ra的抗体药物的改造和新药物的研发具有重要的指导意义。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Immunology, 2010, 184, 1361 -1368 doi:10.4049/jimmunol.0903178
Structural Basis for the Blockage of IL-2 Signaling by Therapeutic Antibody Basiliximab
Jiamu Du,* Hui Yang,*, Dapeng Zhang, Jianchuan Wang,*, Huaizu Guo, Baozhen Peng,* Yajun Guo, and Jianping Ding*
*State Key Laboratory of Molecular Biology, Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Graduate School of Chinese Academy of Sciences; and International Joint Cancer Institute, Second Military Medical University, Shanghai, China
IL-2 signaling plays a central role in the initiation and activation of immune responses. Correspondingly, blockage of this pathway leads to inhibition of the immune system and would provide some therapeutic benefits. Basiliximab (Simulect), a therapeutic mAb drug with specificity against IL-2R of T cells, was approved by U.S. Food and Drug Administration in 1998. It has been proven to be effective in the suppression of the IL-2 pathway and hence has been widely used to prevent allograft rejection in organ transplantation, especially in kidney transplants. In this study, we report the crystal structure of the basiliximab Fab in complex with the ectodomain of IL-2R at 2.9 ? resolution. In the complex structure, the Fab interacts with IL-2R with extensive hydrophobic and hydrophilic interactions, accounting for a high binding affinity of 0.14 nM. The Ag binding site of basiliximab consists of all six CDR loops that form a large binding interface with a central shallow hydrophobic groove surrounded by four hydrophilic patches. The discontinuous epitope is composed of several segments from the D1 domain and a minor segment from the D2 domain that overlap with most of the regions responsible for the interactions with IL-2. Thus, basiliximab binding can completely block the interactions of IL-2 with IL-2R and hence inhibit the activation of the IL-2 signal pathway. The structural results also provide important implications for the development of improved and new IL-2R–targeted mAb drugs.
