This project is a strategic component of our long-term research goal to develop immuno-therapy for cancer based on Lewis oligosaccharide-based cancer vaccines and synthetic glucans that can activate natural killer cells. The project has three objectives designed to test our central hypothesis that multi-antigen glycopeptides (MAG's) and liposomes which contain synthetic carbohydrate B-epitopes and synthetic peptide T-epitopes will activate more efficiently helper T-cells than traditional protein-saccharide conjugates. Therefore, it is the expectation that these novel synthetic constructs will be superior for cancer vaccine development. A large number of immunological studies with similar multi-antigen peptides (MAP's) and liposomes that contain peptide B- and T-epitopes support this expectation. In addition, the safe use of Lewis oligosaccharides as cancer vaccines requires a detailed knowledge of the cross reactivity of antibodies raised against one Lewis antigen with respect to other Lewis antigens. To test these hypotheses, a series of monomeric and dimeric Lewis antigens, that are equipped with an artificial aminopropyl spacer, will be synthesized. A new synthetic methodology, which uses only three monosaccharide building blocks and a limited number of chemical steps, will be employed to prepare all Lewis oligosaccharides. Key features include a set of orthogonal protecting groups for amino sugars and a novel linker for liquid polymer supported synthesis. The oligosaccharides will be used for the preparation of multi-antigen glycopeptides, liposomes and traditional saccharide-protein conjugates. Mice will be immunized with these antigens and an ELISA assay will be used to determine IgM and IgG antibody titers. These studies will show whether the novel MAG's and liposomes are more efficient helper T-cell activators. The ELISA assay, which is based on the use of synthetic oligosaccharides, will also be employed to study possible cross reactivities of the antibodies with respect to all other Lewis antigens.
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