氟代肿瘤相关糖抗原的化学酶法合成及其在肿瘤糖疫苗中的应用

Tumor-associated carbohydrate antigens (TACAs) are important moleculor markers on the cancer cell surface and play pivital roles during the cancer metastasis and signal transduction.Its also has been considered as important target for the development of therapeutic cancer vaccine or cancer imunotherapies. However, most TACA-based vaccines failed in the clinical trials due to the poor immunogenicity and/or immunotolerance of naturally occurring TACAs. The development of TACA-based cancer vaccine also harmpered by the challenges posed to the large scale production and the stability issues of TACAs. To tackle these problems, the fluorinated TACA-based vaccines will be developed in this research project and the large scale synthesis of fluorinated TACAs will be carried out using our recent developed multi-enzyme chemoenzymatic synthesis system. Three specific aims for this project are (1) Chemoenzymatic large scale synthesis of seven types of fluorinated TACAs. (2) Stability studies of fluorinated TACAs upon various glycosidases and transglycosidases. (3) Synthesis and structure-activity relationship (SAR) studies of fluorinated TACA-based cancer vaccines. The research results obtained will help to provide more information related to the structure-activity relationships of fluorinated TACA-based vaccines and may provide a novel approach for the development of more efficient cancer immunotherapies.

肿瘤相关糖抗原在肿瘤的转移及信号传导中起着至关重要的作用，以肿瘤相关糖抗原为基础的肿瘤糖疫苗成为近年来肿瘤免疫疗法的热点和前沿领域。目前肿瘤糖疫苗研究面临着糖抗原的大量获得和天然肿瘤相关糖抗原免疫原性低、容易产生免疫耐受以及天然糖抗原稳定性差等难题和挑战，这些挑战也成为发展肿瘤糖疫苗的制约瓶颈。最近研究表明氟代糖抗原为基础的肿瘤疫苗可以激起机体产生强烈的免疫应答，且产生的抗体可以与相应的天然糖抗原产生交叉免疫反应。本项目中，我们将运用化学酶法合成实现目前七种常用肿瘤相关糖抗原的系统性氟代改造，和氟代肿瘤相关糖抗原的大量合成，系统地研究氟代肿瘤糖抗原的稳定性和基于交叉反应性氟代糖抗原疫苗的构效关系。项目研究成果将有望产生可以大量制备且能产生强烈特异性免疫反应的新型肿瘤氟代糖疫苗，为肿瘤糖疫苗研究提供新的途径。

肿瘤相关糖抗原在肿瘤的转移及信号传导中起着至关重要的作用，以肿瘤相关糖抗原为基础的肿瘤糖疫苗成为近年来肿瘤免疫疗法的热点和前沿领域。目前肿瘤糖疫苗研.究面临着糖抗原的大量获得和天然肿瘤相关糖抗原免疫原性低、容易产生免疫耐受以及天然糖抗原稳定性差等难题和挑战，这些挑战也成为发展肿瘤糖疫苗的制约瓶颈。在本项目中，我们构建了多个酶法组装模块，进一步丰富了本课题组发展的复杂糖链酶法模块化组装策略，实现了系列复杂肿瘤相关糖抗原，人血型抗原等的系统性合成，初步探究了相关糖链的生物学功能与应用。