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

Shusu Liu; Shane Miersch; Ping Li; Bingxin Bai; Chunchun Liu; Wenming Qin; Jie Su; Haiming Huang; James Pan; Sachdev S Sidhu; Donghui Wu

doi:10.1016/j.jmb.2020.01.012

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

J Mol Biol. 2020 Feb 14;432(4):1169-1182. doi: 10.1016/j.jmb.2020.01.012. Epub 2020 Jan 15.

Authors

Shusu Liu¹, Shane Miersch², Ping Li³, Bingxin Bai¹, Chunchun Liu¹, Wenming Qin⁴, Jie Su¹, Haiming Huang⁵, James Pan², Sachdev S Sidhu⁶, Donghui Wu⁷

Affiliations

¹ Laboratory of Antibody Engineering, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
² Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
³ Laboratory of Antibody Engineering, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, China.
⁴ National Facility for Protein Science (Shanghai), Shanghai Advanced Research Institute (Zhangjiang Lab), Chinese Academy of Sciences, Shanghai, China.
⁵ Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Shanghai Asian United Antibody Medical Co., Shanghai, China.
⁶ Laboratory of Antibody Engineering, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China; Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada. Electronic address: sachdev.sidhu@utoronto.ca.
⁷ Laboratory of Antibody Engineering, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. Electronic address: wudh@shanghaitech.edu.cn.

PMID: 31954129
DOI: 10.1016/j.jmb.2020.01.012

Abstract

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-18Rβ and block IL-18-mediated IFN-γ secretion by inhibiting NF-κB and MAPK dependent pathways. The crystal structure of a potent antagonist antibody in complex with IL-18Rβ 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.

Keywords: IFN-γ; antibody phage display; crystal structure; interleukin-1 family; interleukin-18 subfamily.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme-Linked Immunosorbent Assay
HEK293 Cells
Humans
Interferon-gamma / metabolism
Interleukin-18 / chemistry*
Interleukin-18 / immunology
Interleukin-18 / metabolism*
NF-kappa B / metabolism
Protein Structure, Secondary
Signal Transduction

Substances

IL18 protein, human
Interleukin-18
NF-kappa B
Interferon-gamma