基于一类非天然神经节苷脂糖抗原的新型癌症疫苗的研制

GD2和GD3神经节苷脂是开发癌症疫苗的理想抗原之一，但尚无临床上成功的神经节苷脂癌症疫苗。目前该领域存在的技术瓶颈是现有疫苗的功效不足且副作用大。申请者先前证明GD2糖抗原的9-N-乙酰化修饰可以显著增强体液免疫。我们推测该结论也适用于GD3糖抗原。在本项目中，我们拟合成9-N-乙酰基GD2和9-N-乙酰基GD3糖抗原，并将它们分别与临床成功载体白喉毒素突变体（CRM197）结合，构建CRM197结合疫苗。为了降低因候选疫苗不足的风险，我们还将9-N-乙酰基GD2与聚酰胺-胺（PAMAM）结合形成寡聚体，将寡聚体与CRM197偶联以获得寡聚体-CRM197结合疫苗；接下来，将结合疫苗和佐剂共同封装在缩醛化葡聚糖（Ac-Dex）颗粒中，以获得新型纳米糖疫苗。最后，评估这些疫苗的体液免疫性能和细胞免疫性能。本项目通过新疫苗合成、免疫学评估和新机理解析，为癌症疫苗的开发提供技术和理论储备。

GD2 and GD3 gangliosides are part of the ideal antigens for the development of cancer vaccines, but there are no clinically successful ganglioside-based cancer vaccines. Currently, ganglioside-based cancer vaccines have key technical bottlenecks, such as insufficient efficacy and considerable side effects. The applicant has previously demonstrated that 9-N-acetylation modification of the GD2 carbohydrate antigen can significantly enhance humoral immunity. We speculate that this conclusion is also applicable to the GD3 carbohydrate antigen. In this project, we plan to synthesize 9-N-acetyl GD2 and 9-N-acetyl GD3 carbohydrate antigens and combine them with the clinically successful carrier diphtheria toxin mutant (CRM197) to construct CRM197 conjugate vaccines. To reduce the risk of insufficient vaccine candidates, 9-N-acetyl GD2 is also combined with polyamideamine (PAMAM) to form an oligomer, which is then coupled with CRM197 to obtain the oligomer-CRM197 conjugate vaccine. Next, the conjugate vaccine and adjuvant are co-encapsulated in acetalated dextran (Ac-Dex) particles to obtain a new nano-glyco-vaccine. Finally, the humoral and cellular immune properties of these vaccines will be evaluated. This project provides technical and theoretical reserves for the development of cancer vaccines by synthesizing new vaccines, conducting immunological assessments and analyzing new mechanisms.