《免疫學(xué)雜志》（The Journal of Immunology）近日在線報(bào)道了中科院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所丁建平組的研究成果，揭示了單克隆抗體藥物Basiliximab（商品名Simulect,，Novartis）抑制人白細(xì)胞介素2（IL-2）信號(hào)通路的分子基礎(chǔ),。這是近年來(lái)丁建平組發(fā)表的又一項(xiàng)關(guān)于重要治療性抗體和抗原復(fù)合物結(jié)構(gòu)和功能研究的論文。
IL-2為免疫應(yīng)答中重要的細(xì)胞因子,，其受體由a,、b和g三個(gè)亞基組成。IL-2受體的a亞基（IL-2Ra）為IL-2特異性受體,。IL-2Ra在參與器官移植移植排斥反應(yīng),、某些自身免疫性疾病及T細(xì)胞白血病等病理過(guò)程的T細(xì)胞表面高表達(dá)，因此是很好的藥物靶標(biāo),。已有研究表明,，抗IL-2Ra抗體可以抑制其與IL-2的結(jié)合，從而抑制T細(xì)胞的活化和增殖,，減少器官移植后的免疫排斥反應(yīng),。
Basiliximab是抗IL-2Ra的人-鼠嵌合單克隆抗體藥物，主要應(yīng)用于器官移植,，尤其是腎臟移植的免疫抑制,。丁建平組的杜嘉木博士等運(yùn)用結(jié)構(gòu)生物學(xué)和生物化學(xué)的方法解析了Basiliximab的Fab片段與IL-2Ra的復(fù)合物的晶體結(jié)構(gòu)、分析了抗原-抗體相互作用的性質(zhì),；通過(guò)對(duì)復(fù)合物的結(jié)構(gòu)分析和與已報(bào)道的生化數(shù)據(jù)的比較,，鑒定了Basiliximab的抗原決定表位。結(jié)構(gòu)分析表明,，F(xiàn)ab片段的CDR環(huán)區(qū)與IL-2Ra兩個(gè)“shushi-like”結(jié)構(gòu)域D1和D2都有較強(qiáng)的親疏水相互作用,，奠定了它與CD25具有高親和力和高特異性的分子基礎(chǔ)。進(jìn)一步通過(guò)與已報(bào)道的IL-2/IL-2Ra及IL-2/IL-2Rabgc復(fù)合物的結(jié)構(gòu)比較,，發(fā)現(xiàn)Basiliximab的抗原表位與IL-2識(shí)別IL-2Ra的區(qū)域有很大程度上的重疊,，而且和IL-2相比Basiliximab與IL-2Ra具有更強(qiáng)的相互作用，因此可以競(jìng)爭(zhēng)性地結(jié)合IL-2Ra,，從而阻礙IL-2與IL-2Ra的結(jié)合,，進(jìn)一步抑制IL-2信號(hào)通路的激活,。這些研究結(jié)果在分子水平上揭示了Basiliximab抑制IL-2信號(hào)通路的分子機(jī)制，并合理地解釋了已有的生物化學(xué)和免疫學(xué)數(shù)據(jù),?；谘芯拷Y(jié)果，研究者們提出了通過(guò)對(duì)Basiliximab進(jìn)行定點(diǎn)突變以研發(fā)具有更高特異性和更強(qiáng)親和力的抗體藥物的策略,。這項(xiàng)研究成果對(duì)于抗IL-2Ra的抗體藥物的改造和新藥物的研發(fā)具有重要的指導(dǎo)意義,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
