Carbohydrate-based anti cancer vaccines

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The main goal of our research is the development through chemical synthesis of safe vaccines against cancer. Abnormal sugar polymers (called oligosaccharides) are found at the surface of tumor cells. They are called Tumor Associated Carbohydrate Antigens (TACAs) because they can be involved in immune responses in which they are recognized as antigens (foreign structures) by the immune system. Such immune reactions result in the production of antibodies that bind specifically to three-dimensional structures displayed by the antigen and that are called epitopes. In turn, the binding of antibodies to the epitopes displayed on the tumor cell is the first step that leads to cell destruction by the immune system. Carbohydrate-based anti-tumor vaccination consists of training the immune system to recognize the unusual sugars that are displayed at the surface of tumor cells to trigger cell destruction. However, some TACAs such as dimeric Lewis X and Lewis A-Lewis X are large oligosaccharides that also contain the smaller structures Lewis X and Lewis A, respectively, that are expressed on normal cells. Therefore, if used as anti-cancer vaccines, these TACAs are likely to trigger immune reactions that can potentially lead to the destruction of normal cells. We propose two original approaches to design anti-cancer vaccines based on dimeric Lewis X and Lewis A-Lewis X: 1. To synthesize and study analogues of dimLeX and LeALeX in which any one of the three sugars defining the LeX or the LeA trisaccharides is replaced by another sugar residue (i.e. GlcNAc by Glu, Gal by Glu, Fuc by Rha). These analogues could retain internal epitopes also present in dimLeX and LeALeX but they will no longer carry the LeX or the LeA antigens at their non-reducing end. 2. To prepare and study truncated structures of dimLeX and LeALeX to discover and map internal Tumor Associated Carbohydrate Epitopes (TACEs) that can be used to target the full hexasaccharide displayed at the surface of cancer cells without trigerring an immune response against the natural antigens LeX and LeA.