Synthesis of oligosaccharides and glycoconjugates to develop anti-cancer vaccines

我们研究小组的基本专长是合成碳水化合物化学。本课题的主要目标是通过化学合成设计基于肿瘤相关碳水化合物抗原（TACAs）的安全抗癌疫苗。我们的研究计划针对抗原：二聚体lex， LeaLex, Ley， LebLea和LeyLex （KH-1）。我们的目标是发现能够分别触发针对结直肠癌细胞和鳞状肺癌细胞的安全免疫应答的dimericLex和LeaLex片段。我们还通过研究一类由Ley抗原与两性离子多糖（PS A1）连接而成的新分子，旨在提高TACAs触发有效（t细胞依赖性）免疫反应的能力。PS A1是从脆弱拟杆菌中提取的，并已被证明可以在不需要佐剂或载体蛋白的情况下引起所需的免疫反应。鉴于我们的专业知识，我们也在设计高效的合成策略来制备更具挑战性的七糖：LebLea和LeyLex (KH-1)，这两种糖都与腺癌有关。由于已经确定癌细胞在细胞发育过程中表达几种不同水平的TACAs，我们将使用这两种抗原通过酰胺键形成和无铜点击化学来研究二价破伤风类毒素缀合物的制备。

The basic expertise of our research group resides in synthetic carbohydrate chemistry. The main goal of research program is to design through chemical synthesis safe anti-cancer vaccines based on Tumor Associated Carbohydrates Antigens (TACAs). Our research program targets the antigens: dimericLex, LeaLex, Ley, LebLea and LeyLex (KH-1). We aim at discovering fragments of dimericLex and LeaLex that are able to trigger safe immune responses targeted against colorectal cancer cells and squamous lung carcinoma cells, respectively. We also aim at increasing the ability of the TACAs to trigger an efficient (T-cell dependent) immune response by investigating a new class of molecules made of the Ley antigen linked to a zwitterionic polysaccharide (PS A1). PS A1 is extracted from Bacteroides fragilis and has been shown to elicit the desired immune response without the need for an adjuvant or carrier protein. Given our expertise, we are also designing efficient synthetic strategies to prepare the more challenging heptasaccharides: LebLea and LeyLex (KH-1) which are both associated with adenocarcinomas. Because it has been well-established that cancer cells express several different TACAs at levels that vary over the course of cellular development, we will use these two antigens to investigate the preparation of divalent tetanus toxoid conjugates via amide bond formation and copper-free click chemistry.