Volume 20, No 12, Dec 2010

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 20 Issue 12, December 2010: 1361-1371

ORIGINAL ARTICLES

Structural basis of immunosuppression by the therapeutic antibody daclizumab

Hui Yang^1,2,*, Jianchuan Wang^1,2,*, Jiamu Du^1,4, Chen Zhong¹, Dapeng Zhang³, Huaizu Guo³, Yajun Guo³ and Jianping Ding¹

¹State 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

²Graduate School of Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China

³International Joint Cancer Institute, Second Military Medical University, 800 Xiang-Yin Road, Shanghai 200433, China

⁴Current address: Memorial Sloan-Kettering Cancer Center, RRL 269, 430 E 67th Street, New York, NY 10021, USA. Correspondence: Jianping Ding,(jpding@sibs.ac.cn)

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 Å 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-2Rαβγ_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-2Rα.

Cell Research (2010) 20:1361-1371. doi:10.1038/cr.2010.130; published online 7 September 2010

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