Glycobiology Advance Access originally published online on October 5, 2005
Glycobiology 2006 16(2):96-107; doi:10.1093/glycob/cwj044
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Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance
2 Department of Medical Biochemistry and Genetics, University of Copenhagen, Blegdamsvej 3, DK2200 Copenhagen, Denmark; 3 Institute of Molecular Pathology and Immunology, University of Porto, IPATIMUP, Rua Dr. Roberto Frias s/n, 4200 Porto, Portugal; 4 Cancer Research UK, Breast Cancer Biology Group, Thomas Guy House, Guy’s Hospital, London SE1 9RT, UK; 5 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198–6805; and 6 School of Dentistry, University of Copenhagen, Blegdamsvej 3, DK2200 Copenhagen, Denmark
1 To whom correspondence should be addressed; e-mail: hc{at}imbg.ku.dk
Received on June 22, 2005; revised on August 19, 2005; accepted on September 19, 2005
The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures.
Key words: cancer vaccine / glycopeptides / MUC1 / O-glycosylation / STn
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