Synthesis of Glycopeptide-Based Cancer Antigen Vaccines

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 DESCRIPTION (provided by applicant): Tumor-associated carbohydrate antigens (TACAs) are saccharides and oligosaccharides which show highly restricted expression on cancer cells. Since TACAs are unique to cancer cells, there is a great interest in generating an active immune response against TACAs as a means of reducing cancer metastasis or recurrence. Two major challenges to using TACAs in active immunotherapy are their poor antigenicity and the inherent difficulty of synthesizing oligosaccharides and related glycoconjugates by chemical means. Past work demonstrated that liposomal vaccines with a TACA- bearing peptide can generate immune responses to TACAs. If the liposome contains a xenobiotic carbohydrate such as rhamnose, natural antibodies against the carbohydrate will greatly enhance the generation of an immune response, presumably through Fc mediated antigen uptake. The first specific aim of this proposal seeks to determine in more detail the mechanism of enhancement by studying purified human anti-rhamnose antibodies and their role in antigen uptake in wild type and Fc humanized mice. The second specific aim will determine if a specific Fc region can serve as a more generally effective targeting ligand than rhamnose for this vaccine. The most effective vaccine formulation will be tested in humanized mice to better predict its efficacy in humans. Stimulation of invariant natural killer T cells by certain ceramides can serve as a vaccine adjuvant. The third specific aim involves synthesis of rhamnose-modified ceramides and determining if they can serve as improved vaccine adjuvants through binding to CD1d in addition to providing a recognition site for natural antibodies. This proposal takes advantage of a collaborative interaction between researchers trained in organic chemistry and immunology so that the structure and antigenicity of all vaccines will be well characterized in wild type mice an in mice bearing humanized immune cells.