A short sequence, within the amino acid tandem repeat of a cancer‐associated mucin, contains immunodominant epitopes

Abstract

The polymorphic epithelial mucin (PEM) appears to be the target molecule for many monoclonal antibodies (MAbs) which react with tumour-associated and epithelium-specific antigens. PEM contains a large domain made up of 20 amino-acid tandem repeats which are highly immunodominant as many of the antibodies reactive with this molecule recognize epitopes within this area. Using overlapping peptide octamers, we have precisely mapped the epitopes of 4 MAbs reactive with the tandem repeats including one, SM-3, which shows enhanced tumour specificity. We report that the core of the SM-3 epitope corresponds to the continuous amino acid sequence Pro-Asp-Thr-Arg-Pro. We also show that the epitopes recognized by 3 other antibodies, which show reactivity with normal and malignant tissues, map to within this area of the tandem repeat. However, none of these epitopes contain the proline found at the amino end of the SM-3 determinant. These results are consistent with the idea that, in the cancer-associated mucin, premature termination of the carbohydrate side-chains results in the exposure of the SM-3 epitope.

Patterns of MUC1 Tissue Expression Defined by an Anti-MUC1 Cytoplasmic Tail Monoclonal Antibody in Breast Cancer

“…MAb SM3 binds the pentapeptide PDTRP and the glycopen- tapeptide PDT( O -alpha-d-GalNAc)RP; these epitopes are recognized when the mucin is under-glycosylated (Burchell et al 1989;Möller et al 2002).…”

The Relative Activities of the C2GnT1 and ST3Gal-I Glycosyltransferases Determine O-Glycan Structure and Expression of a Tumor-associated Epitope on MUC1

“…The loss of the SM3 binding to MUC1 is apparently due to the core 2 branch masking the polypeptide PDTRP motif recognized by SM3 (10). This steric hindrance by the core 2 branch of access to the VNTR region of the MUC1 polypeptide could also explain the approximate 2-fold reduction in actual number of O-glycans attached to MUC1 in normal cells compared with T47D cells (6).…”

“…Thus, the cancer-associated glycoprotein is antigenically distinct from the normally processed mucins (7). This difference in antigenic profile is detected by the antibody SM3 (8,9), which recognizes a core protein epitope selectively exposed in the tandem repeat of the cancer-associated MUC1 mucin (10).…”

MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form

“…26 Most react with a dominant epitope within the variable number of tandem repeats of the protein core; namely, the hydrophilic sequence of PDTRPAP. [26][27][28] The specificity of antibody binding to the protein core depends largely on the extent of MUC1 glycosylation; during the ISOBM TD-4 workshop, clusters of monoclonal antibodies were identified that distinguish between the various glycoforms of MUC1. 29 30 Although MUC1 is defined as an epithelial antigen, in 1984 Delsol et al reported that lymphoid cells and malignancies express EMA.…”