A Synthetic Human Antibody Antagonizes IL-18Rβ Signaling Through an Allosteric Mechanism

被引：7

作者：

Liu, Shusu ^{[1
]}

Miersch, Shane ^{[2
]}

Li, Ping ^{[1
,3
]}

Bai, Bingxin ^{[1
]}

Liu, Chunchun ^{[1
]}

Qin, Wenming ^{[4
]}

Su, Jie ^{[1
]}

Huang, Haiming ^{[2
,5
]}

Pan, James ^{[2
]}

Sidhu, Sachdev S. ^{[1
,2
]}

Wu, Donghui ^{[1
]}

机构：

[1] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Lab Antibody Engn, Shanghai, Peoples R China

[2] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Banting & Best Dept Med Res, Toronto, ON, Canada

[3] Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Beijing, Peoples R China

[4] Chinese Acad Sci, Zhangjiang Lab, Shanghai Adv Res Inst, Natl Facil Prot Sci Shanghai, Shanghai, Peoples R China

[5] Shanghai Asian United Antibody Med Co, Shanghai, Peoples R China

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2020年 / 432卷 / 04期

基金：

中国国家自然科学基金;

关键词：

interleukin-1; family; interleukin-18; subfamily; IFN-gamma; antibody phage display; crystal structure; IL-18 RECEPTOR EXPRESSION; NF-KAPPA-B; STRUCTURAL INSIGHTS; T-CELLS; INTERLEUKIN-18; PROTEIN; TH1; CYTOKINE; MODEL; IL-18R-ALPHA;

D O I：

10.1016/j.jmb.2020.01.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The interleukin-18 subfamily belongs to the interleukin-1 family and plays an important role in modulating innate and adaptive immune responses. Dysregulation of IL-18 has been implicated in or correlated with numerous diseases, including inflammatory diseases, autoimmune disorders, and cancer. Thus, blockade of IL-18 signaling may offer therapeutic benefits in many pathological settings. Here, we report the development of synthetic human antibodies that target human IL-18R beta and block IL-18-mediated IFN-gamma secretion by inhibiting NE-kappa B and MAPK dependent pathways. The crystal structure of a potent antagonist antibody in complex with IL-18R beta revealed inhibition through an unexpected allosteric mechanism. Our findings offer a novel means for therapeutic intervention in the IL-18 pathway and may provide a new strategy for targeting cytokine receptors. (C) 2020 Elsevier Ltd. All rights reserved.

引用

页码：1169 / 1182

页数：14

共 56 条

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