Development of new cancer vaccines derived fromsTn

sTn is a tumor-associated carbohydrate antigen (TACA) expressed in many types of human carcinoma. It is thus an important target for the development of new cancer therapies. Some sTn-based vaccines have been clinically examined for treating cancer, but the problem of immune tolerance of patients to sTn has severely hindered the clinical efficacy. To overcome this problem and develop useful cancer immunotherapy based on sTn, a new strategy has been designed. The basic concept is to inoculate the immune system of cancer patients with a synthetic vaccine consisting of a chemically modified sTn antigen, and after an immune response specific to the artificial sTn is established, tumors are glycoengineered to express the modified sTn. The activated immune system will thereby eliminate the marked tumors.; The main aim of this research is to investigate the influence of chemical modification of sTn on its immunogenicity and to identify a derivative that may be used as an effective vaccine. As described in Chapter 2, several N-modified sTn antigens and their protein conjugates were synthesized and their immunological properties were studied in mice. Furthermore, the glycoengineered expression of artificial sTn antigens on tumor cells was investigated in vitro. Chapter 3 describes the synthesis and immunological studies of glycoconjugates containing clustered sTn antigens as vaccines.; The studies have identified the KLH conjugate of sTnNPhAc as a promising candidate vaccine and ManNPhAc as an effective glycoengineering precursor for sTn on breast cancer cells. It was also demonstrated that the neoantigen sTnNPhAc expressed on tumor cells, e.g., MCF-7, could be targeted by anti-sTnNPhAc antibodies. It is concluded that the new strategy holds great promise as a cancer immunotherapy with sTn as the primary target.; Chapter 4 describes the development of a new solid-phase strategy for the chemical synthesis of complex oligosaccharides. This new approach combines polymer-supported synthesis with the cap and capture-release techniques to simplify the final product purification. The fundamental idea is to use p-(5-(ethoxycarbonyl)pentyloxy)benzyl group (CPB) as a tag of the terminal sugar unit. After all products formed on the polymer support are detached, the desired oligosaccharide containing a free carboxyl group derived from CPB is allowed to react with and attach to an amino resin. The resin is then readily isolated by filtration, leaving the by-products in the liquid phase. Treatment of the resin with acid releases the purified synthetic target. The strategy has been demonstrated in the synthesis of a trimannoside.