A straightforward approach to antibodies recognising cancer specific glycopeptidic neoepitopes.

Chemical Science
Hajime WakuiShin-Ichiro Nishimura

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 glyco...Continue Reading

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Citations

Oct 7, 2020·Immunotherapy·Mona PourjafarMassoud Saidijam
Nov 20, 2020·Chemical Communications : Chem Comm·Javier Macías-LeónFrancisco Corzana
Mar 7, 2021·International Journal of Molecular Sciences·Maria Rita GulottaLaura De Luca
Mar 12, 2021·The Journal of Organic Chemistry·Martin KurfiřtJindřich Karban

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Methods Mentioned

BETA
X-ray
Enzyme-Linked Immunosorbent Assay
chip
ELISA
NMR
the
glycosylation
surface plasmon resonance
size exclusion chromatography
Assay

Software Mentioned

Array Vison
GraphPad
BIA evaluation
COOT
PyMOL Molecular Graphics System
Phenix
PHASER
MolProbity

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