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

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

  • Nat Commun. 2021 May 5;12(1):2547. doi: 10.1038/s41467-021-22810-z.
Xiaojie Shi  # 1,  Yue Wan  # 1 2 3 4,  Nan Wang  # 1 2 3 4,  Jiangchao Xiang  # 1 2 3 4,  Tao Wang 1 2 3,  Xiaofeng Yang 1,  Ju Wang 1,  Xuxue Dong 1 2 3,  Liang Dong 1 2,  Lei Yan 1,  Yu Li 1 2 3,  Lili Liu 1,  Shinchen Hou 1,  Zhenwei Zhong 1,  Ian A Wilson 5 6,  Bei Yang 1,  Guang Yang 7,  Richard A Lerner 8 9
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
  • 5 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, CA, USA.
  • 6 The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, La Jolla, CA, USA.
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. [email protected].
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. [email protected].
  • 9 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 33953162 DOI: 10.1038/s41467-021-22810-z
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.

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