Glycobiology Advance Access originally published online on October 18, 2006
Glycobiology 2007 17(2):197-209; doi:10.1093/glycob/cwl061
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Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat
2 Department of Cellular and Molecular Medicine
3 Department of Oral Diagnostics, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
4 Department of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
5 Cancer Research UK, Breast Cancer Biology Group, King's College London, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK
1 To whom correspondence should be addressed; e-mail: hc{at}imbg.ku.dk
Received on June 22, 2006; revised on October 5, 2006; accepted on October 15, 2006
The cell membrane mucin MUC1 is over-expressed and aberrantly glycosylated in many cancers, and cancer-associated MUC1 glycoforms represent potential targets for immunodiagnostic and therapeutic measures. We have recently shown that MUC1 with GalNAc
1-O-Ser/Thr (Tn) and NeuAc2-6GalNAc1-O-Ser/Thr (STn) O-glycosylation is a cancer-specific glycoform, and that Tn/STn-MUC1 glycopeptide-based vaccines can override tolerance in human MUC1 transgenic mice and induce humoral immunity with high specificity for MUC1 cancer-specific glycoforms (Sorensen AL, Reis CA, Tarp MA, Mandel U, Ramachandran K, Sankaranarayanan V, Schwientek T, Graham R, Taylor-Papadimitriou J, Hollingsworth MA, et al. 2006. Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. Glycobiology. 16:96–107). In order to further characterize the immune response to Tn/STn-MUC1 glycoforms, we generated monoclonal antibodies with specificity similar to the polyclonal antibody response found in transgenic mice. In the present study, we define the immunodominant epitope on Tn/STn-MUC1 glycopeptides to the region including the amino acids GSTA of the MUC1 20-amino acid tandem repeat (HGVTSAPDTRPAPGSTAPPA). Most other MUC1 antibodies are directed to the PDTR region, although patients with antibodies to the GSTA region have been identified. A panel of other MUC1 glycoform-specific monoclonal antibodies was included for comparison. The study demonstrates that the GSTA region of the MUC1 tandem repeat contains a highly immunodominant epitope when presented with immature short O-glycans. The cancer-specific expression of this glycopeptide epitope makes it a prime candidate for immunodiagnostic and therapeutic measures.
Key words: MUC1 / monoclonal antibody / epitope mapping / O-glycosylation / cancer-specific
None declared.
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