Cancer is one of the leading causes of death in the United States. Because of its overexpression and aberrant glycosylation on multiple types of cancer, Mucin-1 (MUC1) has emerged an attractive antigen for vaccine development. Vaccination studies have found that the peptide sequence SAPDTRPAP, from the tandem repeat region, is an important epitope, which includes an O-glycosylation site. The stability of vaccines containing O-glycosylated peptide antigens has long been a concern. Premature cleavage of the carbohydrate moiety could prejudice the immune response towards the peptide only, instead of the whole glycopeptide. In an attempt to increase the stability of the glycopeptide we synthesized a MUC1 glycopeptide containing the Thomsen-Friedenreich (Tf) antigen linked to the peptide backbone through the unnatural β-linkage. Compared to the natural α-linkage, the MUC1-βTf antigen was more stable to enzymatic degradation. Upon conjugation to the carrier bacteriophage Qβ and vaccination in clinically relevant MUC1 transgenic mice, high titers of IgG antibodies capable of recognizing the natural MUC1-αTf antigen were elicited. Additionally, these cross-reactive antibodies were able to kill MUC1 expressing tumor cells. Taken together, the evidence points to a simple switch of stereochemistry at the glycosylation site can improve design of vaccines targeting MUC1 glycopeptides.

Synthesis and Immunological evaluation of βTf-MUC1 conjugate vaccines

ACS Spring 2022

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