Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 19, Issue 11, Pages 2448-2455Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1ob00007a
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Funding
- National Cancer Institute, National Institutes of Health [R01 CA225105]
- Michigan Economic Development Corporation
- Michigan State University Foundation
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A synthetic MUC1-beta-Tf with enhanced stability was developed by altering the stereochemistry of the glycan/peptide linkage, leading to high levels of IgG antibodies in clinically relevant human MUC1 transgenic mice and recognizing MUC1 expressing tumor cells. This suggests a potential strategy for anti-cancer vaccine epitope design for glycopeptides.
MUC1 glycopeptides are attractive antigens for anti-cancer vaccine development. One potential drawback in using the native MUC1 glycopeptide for vaccine design is the instability of the O-glycosyl linkage between the glycan and the peptide backbone to glycosidase. To overcome this challenge, a MUC1 glycopeptide mimic has been synthesized with the galactose-galactosamine disaccharide linked with threonine (Thomsen-Friedenreich or Tf antigen) through an unnatural beta-glycosyl bond. The resulting MUC1-beta-Tf had a much-enhanced stability toward a glycosidase capable of cleaving the glycan from the corresponding MUC1 glycopeptide with the natural alpha-Tf linkage. The MUC1-beta-Tf was subsequently conjugated with a powerful carrier bacteriophage Q beta. The conjugate induced high levels of IgG antibodies in clinically relevant human MUC1 transgenic mice, which cross-recognized not only the natural MUC1-alpha-Tf glycopeptide but also MUC1 expressing tumor cells, supporting the notion that a simple switch of the stereochemistry of the glycan/peptide linkage can be a strategy for anti-cancer vaccine epitope design for glycopeptides.
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