Structural basis of immunosuppression by the therapeutic antibody daclizumab  

作　　者：Hui Yang Jianchuan Wang Jiamu Du Chen Zhong Dapeng Zhang Huaizu Guo Yajun Guo Jianping Ding 

机构地区：[1]State Key Laboratory of Molecular Biology and Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2]Graduate School of Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China [3]International Joint Cancer Institute, Second Military Medical University, 800 Xiang-Yin Road, Shanghai 200433, China

出　　处：《Cell Research》2010年第12期1361-1371,共11页细胞研究（英文版）

基　　金：Acknowledgments We are grateful to the staff members at Shanghai Synchrotron Radiation Facility for support in diffraction data collection and other members of our group for helpful discussion. This work was supported by grants from the Ministry of Science and Technology of China （2010CB833601, 2006AA02A313, and 2009ZX09503- 009）, the National Natural Science Foundation of China （30730028 and 90713046）, and the Chinese Academy of Sciences （KSCX2-YW-R- 107 and SIBS2008002）.

摘　　要：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-2Ra. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by dacllzumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Ra ectodomain at 2.6 and 2.8 A resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL- 2Ra ectodomain. The antigen-binding site of daclizumab is mainly composed of live 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-2Ru ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ra would prevent the IL-2 binding to IL-2Ra and the subsequent formation of the IL-2fIL-2Ra[~/c 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-2Ra.

关 键 词：IL-2Ra IL-2 signaling DACLIZUMAB therapeutic antibody crystal structure 

分 类 号：Q257[生物学—细胞生物学] S858.31[农业科学—临床兽医学]