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MUC1 is a transmembrane mucin family protein consisting of highly conserved 20 amino acid repeats (HGVTSAPDTRPAPGSTAPPA) decorated with a dense O-linked glycosylation pattern. MUC1 is highly expressed in an underglycosylated form in multiple tumour types of epithelial origin, including over 90% of breast cancers. The glycosylation changes expose new peptide epitopes and oligosaccharides, making MUC1 an attractive target for antibody and vaccine approaches that exploit the tumourspecific epitopes created.
Several antibodies were raised against MUC1 and are commercialised, to enable use of antibody technologies targeting cancer cells via MUC1 and drug development for cancer patients. We are seeking licensees for a package of patents, materials and know-how for development of our antibodies against the MUC1 tumour antigen.
Two MAbs (5E5 and 2D9) with specificity similar to the elicited immune response were generated. Characterisation of the antibodies led to the identification of a new cancer-specific combined glycopeptide epitope defined by Tn-/STn-glycosylation at the GSTA position of the MUC1 tandem repeat. Noteably, the vast majority of MUC1 antibodies reported to date are directed to the peptide backbone in the PDTR region of the repeat, considered to be immunodominant in wildtype mice, with a small number binding the peptide backbone at different epitopes. As such, 5E5 and 2D9 have unique specificity. They also seem to offer distinct advantages over existing anti-MUC1 antibodies since in immunohistology studies they demonstrate superior selectivity for tumour versus normal tissue (Figure 1). Similar results were observed in other subtypes of breast cancer, as well as tumour tissue from ovary, pancreas, small intestine, bladder and cervix. These data suggest both that the 5E5/2D9 antibodies, and the Tn/STn glycopeptides make prime candidates for new therapeutic approaches to MUC1-expressing tumours.
Other antibodies, like SM3, HMFG-1 and HMFG-2 were also raised against MUC1. SM3 is highly specific to tumour-associated MUC1, making this antibody a good diagnostic or targeting candidate. The antibodies HMFG-1 and HMFG-2 were purified from human milk, recognising human Mucin. In studies identifying staining patterns, both antibodies were found to also bind the highly-unglycosylated and non–Lectin binding Mucin.
Prof. Joyce Taylor-Papadimitriou; Dr Joy Burchell