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，其中它们被免疫系统识别为抗原（外来结构）。这样的免疫反应导致抗体的产生，所述抗体特异性地结合由抗原展示的三维结构并且被称为表位。反过来，抗体与肿瘤细胞上展示的表位的结合是导致免疫系统破坏细胞的第一步。基于碳水化合物的抗肿瘤疫苗接种包括训练免疫系统识别显示在肿瘤细胞表面的不寻常的糖，以触发细胞破坏。然而，一些TACA如二聚体刘易斯X和刘易斯A-刘易斯X是大寡糖，其还分别含有在正常细胞上表达的较小结构刘易斯X和刘易斯A。因此，如果用作抗癌疫苗，这些TACA可能会引发免疫反应，从而可能导致正常细胞的破坏。我们提出了两种基于二聚体刘易斯X和刘易斯A-刘易斯X：1设计抗癌疫苗的原创方法。合成和研究dimLeX和LeALEX的类似物，其中定义LeX或莱亚三糖中的任何一种被另一种糖残基取代（即GlcNAc被Glu取代，Gal被Glu取代，Fuc被Rha取代）。这些类似物可以保留也存在于dimLeX和LeALEX中的内部表位，但它们将不再在其非还原末端携带LeX或莱亚抗原。2.制备和研究dimLeX和LeALEX的截短结构，以发现和定位内部肿瘤相关碳水化合物表位（TACE），其可用于靶向癌细胞表面展示的完整六糖，而不会引发针对天然抗原LeX和莱亚的免疫应答。

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.