糖肽疫苗的合成与免疫学评价

Vaccine is the most promising method for the prevention and cure of diseases,such as tumor therapeutic, cancer diagnose and relevant in immunological process. Because of their low immunogenicity to induce strong immune reaction, the complicated structure to synthesize, the precise immune mechanism of glycopeptide vaccines is still unclear, which limit further exploration in this field. Herein, our project is based on the understanding of the immune decision domain of tumor associate glycoprotein, we will design and synthesize (both chemical and enzymatic method), screen antigen structure of strong immunogenicity. With the utilization of the α-GalCer, we will synthesize a new dual efficiency vaccine with good hydrophilicity and lipophilicity. This vaccine will self-assemble from cylindrical micelles into nanofibers, to form a novel multivalent high effective vaccine system. This glycopeptide vaccine can also be used as molecular probe to explore the mechanism of tumor immune process. This novel vaccine can combine the anti-tumor activity of different components together in a co-stimulation way. Through this research, we can obtain glycopeptide vaccine with high activity. Furthermore, it can lay foundation of discovering the immune mechanism of glycopeptide vaccines.

糖肽肿瘤疫苗在肿瘤治疗、诊断以及相关免疫研究中的应用已愈来愈受到关注。目前糖肽类疫苗存在免疫原性低、疫苗结构复杂、免疫机制不清楚等瓶颈问题。.本项目拟从抗原相关蛋白的免疫决定域入手，设计、合成（化学和酶法）并筛选出具有良好免疫活性的抗原结构；以α-GalCer为载体，合成双功效新型肽-烃两亲性疫苗分子，以柱状胶束的形式自组装成纳米纤维，构筑新型、多价、高效的疫苗体系；并利用这些糖肽疫苗分子作为探针，探究免疫过程的机制。发挥免疫组分的协同抗肿瘤作用，研究新型疫苗组分和体系。该研究将为获得高免疫活性的糖肽疫苗，并探讨糖肽疫苗免疫机制作出探索。

治疗性肿瘤疫苗通过激发抗肿瘤特异性免疫应答，来抑制和杀伤肿瘤。黏蛋白1(MUC1) 在大多数腺体肿瘤细胞中表达异常，显著特征是MUC1的糖基侧链变短，暴露出许多新的多肽表位，同时Tn、TF、STn等糖抗原过量表达，这些特征使得MUC1成为肿瘤疫苗研究的新靶点。本项目以MUC1糖肽作为抗原表位，设计并合成了多种新的疫苗佐剂和载体系统，包括Toll样受体2/6的配体脂多肽FSL-1, NKT细胞激动剂α-GalCer,自组装多肽和金纳米课颗粒。通过使这些佐剂和载体与MUC1糖肽偶联，来提高MUC1糖肽抗原的免疫原性，进而发展MUC1糖肽抗肿瘤疫苗。研究结果表明：1）基于FSL-1的疫苗能刺激机体产生很高的抗体滴度，并对小鼠黑色素瘤的生长产生明显的抑制；2）以α-GalCer作为免疫佐剂，金纳米颗粒（AuNP）为多价载体，构建的AuNP 为多价载体的疫苗产生了较高的抗体滴度，并且抗原与佐剂的比例与免疫效果有正相关；3）自组装多肽与MUC1 糖肽的连接方式对其自组装形态及免疫效果有很大影响，与非共价键相比，抗原与佐剂通过共价键相连得到的疫苗表现出了更好的免疫效果。总之，本研究设计的新型抗肿瘤糖肽疫苗打破机体的免疫耐受，提高抗原的免疫原性，有望为疫苗的研发提供一种新的思路和研究策略。