Selection of a picomolar antibody that targets CXCR2-mediated neutrophil activation and alleviates EAE symptoms

Xiaojie Shi, Yue Wan, Nan Wang, Jiangchao Xiang, Tao Wang, Xiaofeng Yang, Ju Wang, Xuxue Dong, Liang Dong, Lei Yan, Yu Li, Lili Liu, Shinchen Hou, Zhenwei Zhong, Ian A. Wilson, Bei Yang, Guang Yang () and Richard A. Lerner ()
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Xiaojie Shi: ShanghaiTech University
Yue Wan: ShanghaiTech University
Nan Wang: ShanghaiTech University
Jiangchao Xiang: ShanghaiTech University
Tao Wang: ShanghaiTech University
Xiaofeng Yang: ShanghaiTech University
Ju Wang: ShanghaiTech University
Xuxue Dong: ShanghaiTech University
Liang Dong: ShanghaiTech University
Lei Yan: ShanghaiTech University
Yu Li: ShanghaiTech University
Lili Liu: ShanghaiTech University
Shinchen Hou: ShanghaiTech University
Zhenwei Zhong: ShanghaiTech University
Ian A. Wilson: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla
Bei Yang: ShanghaiTech University
Guang Yang: ShanghaiTech University
Richard A. Lerner: ShanghaiTech University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Receptors and their ligands are important therapeutic targets for about one third of marketed drugs. Here, we describe an epitope-guided approach for selection of antibodies that modulate cellular signaling of targeted receptors. We chose CXC chemokine receptor 2 (CXCR2) in the G-protein coupled receptor superfamily as receptor and a CXCR2 N-terminal peptide for antibody selection. We obtain a highly selective, tight-binding antibody from a 1011-member antibody library using combinatorial enrichment. Structural and Hydrogen-Deuterium-Exchange mass spectrometry analyses demonstrate antibody interaction with an N-terminal region of CXCR2 that is part of the IL-8 epitope. The antibody strongly inhibits IL-8-induced and CXCR2-mediated neutrophil chemotaxis in vitro and alleviates hCXCR2-dependent experimental autoimmune encephalomyelitis symptoms in mice. As inappropriate neutrophil migration accompanies many diseases including inflammatory bowel disease, glomerulonephritis, allergic asthma, chronic obstructive pulmonary disease, and cancer, this antibody has potential for development as a therapeutic agent, akin to anti-TNF antibodies. However, an important difference here is that the antibody targets the chemokine receptor and competes with natural ligand, rather than targeting the ligand itself.

Date: 2021
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DOI: 10.1038/s41467-021-22810-z

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