近期,，Cell Research在線報道了上海生科院生化與細胞所丁建平組關于單克隆抗體藥物daclizumab抑制人白細胞介素2(IL-2)信號通路的研究成果,。近年來丁建平組對一些重要治療性抗體和抗原復合物結構和功能展開了系統(tǒng)性的研究，已發(fā)表一系列文章,，特別是于今年初已揭示了治療性抗體basiliximab抑制IL-2信號通路的分子機制,。該項工作是這些研究工作的延續(xù)。
IL-2是免疫應答過程中發(fā)揮重要作用的細胞因子,，其受體由α、β和γ三個亞基組成,，其中α亞基(IL-2Rα)是IL-2的特異性受體,。研究表明,，IL-2Rα在參與器官移植排斥反應、某些自身免疫性疾病,、以及T細胞白血病等病理過程的T細胞表面上高表達,，因此是很好的藥物靶標?？笽L-2Rα抗體可以抑制其與IL-2的結合,，阻斷IL-2信號通路，從而抑制T細胞的活化和增殖,，減少器官移植后的免疫排斥反應,。單克隆抗體藥物daclizumab是第一株通過美國FDA認證的治療性抗體，主要應用于器官移植,，尤其是腎臟移植的免疫抑制,。丁建平組的博士生楊薈和王建船等人解析了daclizumab的Fab片段與IL-2Rα胞外區(qū)的復合物的晶體結構，分析了抗原-抗體之間的相互作用,。進一步通過對復合物的結構分析和與已報道的生化數(shù)據(jù)的比較,，鑒定了daclizumab的抗原決定表位。結構分析表明,，F(xiàn)ab片段的CDR環(huán)區(qū)主要通過一個帶正電的表面及其兩側兩個相對疏水的區(qū)域與IL-2Rα兩個“shushi-like”結構域D1和D2發(fā)生較強的親水和疏水相互作用,，因此daclizumab對IL-2Rα的識別具有高親和力和高特異性。進一步與已報道的IL-2/IL-2Rα及IL-2/IL-2Rαβγc復合物的結構比較,，發(fā)現(xiàn)daclizumab的抗原表位與IL-2識別IL-2Raα區(qū)域有很大程度上的重疊,，而且和IL-2相比daclizumab與IL-2Rα具有更強的相互作用，因此可以競爭性地結合IL-2Rα,，從而阻斷IL-2與IL-2Rα的結合而抑制IL-2信號通路的激活,。這些研究結果在分子水平上揭示了daclizumab抑制IL-2信號通路的分子機制，并合理地解釋了已有的生物化學和免疫學數(shù)據(jù),?；谘芯拷Y果，研究者們提出了通過對daclizumab進行定點突變以研發(fā)具有更高特異性和更強親和力的抗體藥物的策略,。這項研究成果對于抗IL-2Rα的抗體藥物的改造和新藥物的研發(fā)具有重要的指導意義,。
該項工作得到國家科技部、國家自然科學基金委,、中科院和上海市科委的經費支持,。（生物谷Bioon.com）
生物谷推薦英文摘要：
Cell Research , (7 September 2010) | doi:10.1038/cr.2010.130
Structural basis of immunosuppression by the therapeutic antibody daclizumab
Hui Yang, Jianchuan Wang, Jiamu Du, Chen Zhong, Dapeng Zhang, Huaizu Guo, Yajun Guo and Jianping Ding
Interleukin-2 (IL)-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody (mAb) daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Rα. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by daclizumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Rα ectodomain at 2.6 and 2.8 ? resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL-2Rα ectodomain. The antigen-binding site of daclizumab is mainly composed of five complementarity determining regions (CDRs) that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Rα ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Rα would prevent the IL-2 binding to IL-2Rα and the subsequent formation of the IL-2/IL-2Rαβγc complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Rα.
