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Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

Reputable Mentor II
Reputable Mentor II
Steentoft C, Schjoldager KT, Cló E, Mandel U, Levery SB, Pedersen JW, Jensen K, Blixt O, Clausen H.
Glycoconj J. 2010 Aug;27(6):571-82.
Auto-antibodies induced by cancer represent promising sensitive biomarkers and probes to identify immunotherapeutic targets without immunological tolerance. Surprisingly few epitopes for such auto-antibodies have been identified to date. Recently, a cancer-specific syngeneic murine monoclonal antibody 237, developed to a spontaneous murine fibrosarcoma, was shown to be directed to murine podoplanin (OTS8) with truncated Tn O-glycans. Our understanding of such cancer-specific auto-antibodies to truncated glycoforms of glycoproteins is limited. Here we have investigated immunogenicity of a chemoenzymatically produced Tn-glycopeptide derived from the putative murine podoplanin O-glycopeptide epitope. We found that the Tn O-glycopeptide was highly immunogenic in mice and produced a Tn-glycoform specific response with no reactivity against unglycosylated peptides or the O-glycopeptide with extended O-glycan (STn and T glycoforms). The immunodominant epitope was strictly dependent on the peptide sequence, required Tn at a specific single Thr residue (Thr(77)), and antibodies to the epitope were not found in naive mice. We further tested a Tn O-glycopeptide library derived from human podoplanin by microarray analysis and demonstrated that the epitope was not conserved in man. We also tested human cancer sera for potential auto-antibodies to similar epitopes, but did not detect such antibodies to the Tn-library of podoplanin. The reagents and methods developed will be valuable for further studies of the nature and timing of induction of auto-antibodies to distinct O-glycopeptide epitopes induced by cancer. The results demonstrate that truncated O-glycopeptides constitute highly distinct antibody epitopes with great potential as targets for biomarkers and immunotherapeutics.
Department of Basic Sciences and Environment (IGM)-Bioorganic Chemistry, University of Copenhagen, Faculty of Life Sciences, Thorvaldsensvej 40, DK-1871, Frederiksberg C, Denmark.
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