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

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.

SUBMITTER: Shi X

PROVIDER: S-EPMC8100106 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Shi Xiaojie X Wan Yue Y Wang Nan N Xiang Jiangchao J Wang Tao T Yang Xiaofeng X Wang Ju J Dong Xuxue X Dong Liang L Yan Lei L Li Yu Y Liu Lili L Hou Shinchen S Zhong Zhenwei Z Wilson Ian A IA Yang Bei B Yang Guang G Lerner Richard A RA

Nature communications 20210505 1

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 10<sup>11</sup>-member antibody library using combinato ...[more]

PMID: 33953162

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Project description:ObjectivesThere is already substantial evidence indicating that neutrophil extracellular trap (NET) formation contributes to the inflammatory cascade in ulcerative colitis (UC). However, the precise regulatory mechanisms governing this process remain elusive. This study aimed to determine the role of NET-related genes in UC and reveal possible mechanisms.MethodsEmploying a two-sample MR methodology, we investigated the correlations between NET-associated genes (NRGs) and UC with summary data derived from a genome-wide association study (12,366 cases vs. 33,609 controls) and FinnGen (8,279 cases vs. 261,098 controls). The main analysis employed the inverse variance weighted method, supplemented by the MR-Egger method and weighted median method. Sensitivity analysis was conducted to rule out the interference of heterogeneity and pleiotropy among utilized instrument variables. The colocalization analysis was used to determine whether the identified NRGs and UC shared casual variants. Cross-tissue expression analysis was performed to characterize the expression patterns of target NRGs, while multi-gene correlation analysis and GSEA analysis were conducted to explore the mechanisms by which target NRGs promote UC and NET formation. Immunohistochemistry was used to validate the protein expression of target NRGs in the colon tissue of UC patients.ResultsAfter the validation of two datasets, seven NRGs were associated with the risk of UC. The higher expression of ITGB2 was associated with increased UC risk, while the expression of CXCR1, CXCR2, IRAK4, MAPK3, SIGLEC14, and SLC22A4 were inversely associated with UC risk. Colocalization analysis supported the correlation between CXCR1/2 and UC risk. Expression analysis indicated that CXCR1/2 were down-regulated in peripheral blood, but up-regulated in colon tissue. GSEA analysis and correlation analysis indicated that CXCR1/2 promoted UC and NET formation through neutrophil chemotaxis and PAD4-mediated pathways, separately. Immunohistochemical results confirmed the high expression of CXCR1/2 in colon tissues of UC patients.ConclusionsOur study identified CXCR1/2 as candidate targets in UC among all NRGs through multi-method argumentation, providing new insights of the regulation mechanisms of NET formation in the pathogenesis of UC.

Dataset Information

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

Publications

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

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