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A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes

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Title: A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes
Authors: Wakui, Hajime Browse this author
Tanaka, Yoshikazu Browse this author
Ose, Toyoyuki Browse this author
Matsumoto, Isamu Browse this author
Kato, Koji Browse this author
Min, Yao Browse this author
Tachibana, Taro Browse this author
Sato, Masaharu Browse this author
Naruchi, Kentaro Browse this author
Martin, Fayna Garcia Browse this author
Hinou, Hiroshi Browse this author
Nishimura, Shin-Ichiro Browse this author →KAKEN DB
Issue Date: 21-May-2020
Publisher: Royal Society of Chemistry
Journal Title: Chemical science
Volume: 11
Issue: 19
Start Page: 4999
End Page: 5006
Publisher DOI: 10.1039/d0sc00317d
Abstract: Aberrantly truncated immature O-glycosylation in proteins occurs in essentially all types of epithelial cancer cells, which was demonstrated to be a common feature of most adenocarcinomas and strongly associated with cancer proliferation and metastasis. Although extensive efforts have been made toward the development of anticancer antibodies targeting MUC1, one of the most studied mucins having cancer-relevant immature O-glycans, no anti-MUC1 antibody recognises carbohydrates and the proximal MUC1 peptide region, concurrently. Here we present a general strategy that allows for the creation of antibodies interacting specifically with glycopeptidic neoepitopes by using homogeneous synthetic MUC1 glycopeptides designed for the streamlined process of immunization, antibody screening, three-dimensional structure analysis, epitope mapping and biochemical analysis. The X-ray crystal structure of the anti-MUC1 monoclonal antibody SN-101 complexed with the antigenic glycopeptide provides for the first time evidence that SN-101 recognises specifically the essential epitope by forming multiple hydrogen bonds both with the proximal peptide and GalNAc linked to the threonine residue, concurrently. Remarkably, the structure of the MUC1 glycopeptide in complex with SN-101 is identical to its solution NMR structure, an extended conformation induced by site-specific glycosylation. We demonstrate that this method accelerates dramatically the development of a new class of designated antibodies targeting a variety of "dynamic neoepitopes" elaborated by disease-specific O-glycosylation in the immunodominant mucin domains and mucin-like sequences found in intrinsically disordered regions of many proteins.
Type: article
Appears in Collections:生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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