Immunogenic Structural Features of a Breast Tumor Specific Epitope for Cancer Immunotherapy.
Abstract
The objectives of the research program are to study the structure-immunogenicity relationships of a hypoglycosylated human tumor-specific mucin common to breast and other adenocarcinomas. Hypo-glycosylation of breast mucin leads to exposure of a tumor-specific epitope (TSE). The structural and immunogenic properties of the TSE are being examined using synthetic mucin peptide and recombinant mucin proteins that contain the TSE and/or mutations in potential glycosylation sites surrounding the TSE. One TSE is the pentapeptide PDTRP of the 20 amino acid mucin tandem repeat sequence PDTRPAPGSTAPPAHGVTSA. Immunogenic cross-reactivity with tumor-specific monoclonal antibodies show that antigenicity is maximized with the 40 amino acid MUC1-mtr2. By contrast, the MUC1-mtr3 elicited a 9-fold better cellular response compared to either single or double tandem repeat peptide. The single, double and triple tandem repeat peptide show few elements of preferred conformation, based on 1H-NMR spectroscopy. A model of the distribution of the oligosaccharide side chains along the mucin core protein was developed showing that the carbohydrates may not surround the protein in a uniform 'coating'. Thus, regions of the core protein are exposed under normal circumstances, yet tumor-specific epitopes remain masked by the sugars in the non-malignant cells. Further understanding of the structure-immunogenicity relationships of tumor-specific immunogen is essential for maximizing the use of synthetic peptide immunogen and tumor-specific cells as a potential adoptive immunotherapy for patients with cancer, and the development of a potential vaccine.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1997
- Accession Number
- ADA337006
Entities
People
- Kenneth E. Dombrowski
- Stephen E. Wright