Carbohydrate-based anti cancer vaccines

我们研究的主要目标是通过化学合成开发安全的抗癌疫苗。在肿瘤细胞表面发现了异常的糖聚合物(称为寡糖)。它们被称为肿瘤相关碳水化合物抗原(TACA)，因为它们可以参与免疫反应，在免疫反应中它们被免疫系统识别为抗原(异物结构)。这种免疫反应会产生抗体，这些抗体专门与抗原显示的三维结构结合，被称为表位。反过来，抗体与肿瘤细胞上显示的表位结合是导致免疫系统破坏细胞的第一步。以碳水化合物为基础的抗肿瘤疫苗包括训练免疫系统识别显示在肿瘤细胞表面的异常糖类，以触发细胞破坏。然而，一些TACA，如二聚体Lewis X和Lewis A-Lewis X是大的寡糖，也分别包含在正常细胞上表达的小结构Lewis X和Lewis A。因此，如果用作抗癌疫苗，这些TACA很可能会引发免疫反应，可能会导致正常细胞的破坏。我们提出了两种基于二聚体Lewis X和Lewis A-Lewis X的抗癌疫苗的设计方法：1.合成和研究定义Lex或Lea三糖的三种糖中的任何一种被另一糖残基(即GlcNAc替换为Glu，Gal替换为Glu，Fuc替换为Rha)的dimLeX和lealex类似物。这些类似物可以保留同样存在于dimLex和lealex中的内部表位，但它们的非还原端将不再携带lex或lea抗原。2.制备和研究DimLeX和Lealex的截短结构，以发现和定位肿瘤相关碳水化合物内部表位(TACEs)，该表位可以靶向癌细胞表面展示的全部六糖，而不会触发对天然抗原Lex和Lea的免疫反应。

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.