Syntheses and immunological studies of tumor associated carbohydrate antigens.

摘要

Cancer is one of the most harmful diseases that exist nowadays. According to a report published by the World Health Organization, cancer is the disease responsible for 13% of all deaths worldwide in 2005. In spite of years of effort, it is the disease that remains extremely difficult to cure and prevent. Recently, unique oligosaccharides have been found to be expressed at abnormal levels on cancer cell surfaces, connecting them to the differentiation between a cancer cell and a normal cell. The characterization of these saccharides has led to the identification of several tumor associated carbohydrate antigens (TACAs), which are characteristic of cancer cells.;Due to the low immunogenicity of TACAs, their conjugation to an immunogenic protein carrier is an attractive approach for anti-cancer vaccine development. The Tn antigen has been identified on numerous cancer cell surface and thus it became an excellent target for immunotherapy. Despite several designs using different protein carriers, to date it has been difficult to induce a high T-cell dependent immune response. Recently, viral capsids have shown very promising properties and such carriers would actually allow a highly organized and consistent display of antigens. The effect of patterned display of carbohydrates on their immunogenicity was examined, using the Cow Pea Mosaic Virus (CPMV) and the Tobacco Mosaic Virus capsids as protein carriers. Several Tn antigen analogs were synthesized and then conjugated to these protein carriers. The immunological properties of such conjugates were evaluated in vivo by inoculation of mice. High antibody titers and more importantly high IgG titers were induced when mice were inoculated with such conjugates. It was also shown that the antibodies produced by the mice can recognize the Tn antigen in its native environment, i.e., on breast cancer cell surface.;The LewisX pentasaccharide and the LewisY tetrasaccharide have also been identified as TACAs and therefore are possible targets for immunotherapy. However they both present a high degree of structural complexity, both being branched oligosaccharides. Recently, a preactivation based chemoselective one-pot glycosylation method has been developed, where a thioglycosyl donor is activated in the absence of an acceptor. Multiple glycosylations can be performed in a single reaction flask without intermediate oligosaccharide purifications, thus significantly expediting the glycoassembly process. The LewisX pentasaccharide was assembled in one-pot using this methodology with a very good 40-60% yield. The LewisY tetrasaccharide was also synthesized with an overall yield of about 50% yield.