新型TLR4激动剂用于肿瘤相关糖抗原疫苗的构建与优化及其抗肿瘤免疫活性研究

Tumor associated carbohydrate antigens (TACAs) are abundantly and uniquely expressed on the surface of cancer cells, and the development of TACAs-based vaccines becomes a hot topic of cancer immunotherapy. However, the weak immunogenicity of TACAs is one of the major impediments to successful vaccines. Conjugating the saccharide to the carried protein was the traditionally strategy to improve immunogenicity of carbohydrate antigens. In addition, it is difficult to control the loading levels of carbohydrates in protein conjugates and the conjugating sites between the carrier protein and saccharides, which causes problems in their quality control. To overcome these problems, Toll-like receptor 4 (TLR4) agonist MPLA has been employed as vaccine carrier instead of the protein, and it was demonstrated that the MPLA vaccines provoked stronger immune response than protein conjugates in our previous studies. This research project aims at the design and synthesis of a series of structurally novel and complex TLR4 agonists derivatives with higher biological activity compared with MPLA, containing the core of αGlcNαMan, which conjugate with STn to give two-component vaccines for optimization of their structure-immunogenicity relationships. Five series of three-component vaccines are further constructed by intervening helper T-cell peptides between these new carriers and potential TACAs, such as STn、GM2、GD2、GD3 and Globo H. The current studies will explore a comprehensive understanding of structure-immunological activity relationships of the three components, TLR4 agonists, T helper peptides and carbohydrate antigens, and also provide new growth points in the development of the fully synthetic TACAs cancer vaccine in future.

肿瘤相关糖抗原（TACAs）具有高度保守性和特异性，是最具潜力的癌症疫苗靶点之一，但有免疫性差的弱点。传统策略是将糖抗原与载体蛋白偶联来增强其免疫原性，但糖蛋白疫苗有偶联位点不确定、偶联率不稳定、组成成分复杂等缺点。而我们前期全合成的TLR4激动剂MPLA与TACAs两组分疫苗，能产生较强的免疫应答。在此基础上，本研究拟构建合成一系列结构新型、活性比MPLA更强的TLR4激动剂αGlcNαMan衍生物与STn两组分疫苗，探究此类疫苗载体与TACAs之间的构效关系及其代替载体蛋白的可能性；同时引入T细胞表位肽来增强TACAs的免疫反应；再选取具有临床开发价值的STn、GM2、GD2、GD3及Globo H等糖抗原，全合成具有化学结构明确的TACAs三组分肿瘤疫苗，以期克服TACAs自身的弱点和糖蛋白类缀合疫苗的缺点，且能产生更强的免疫反应和有效地杀死肿瘤细胞，为下一代抗肿瘤疫苗研发奠定基础。

肿瘤相关糖抗原（TACAs）具有高度保守性和特异性，是最具潜力的癌症疫苗靶点之一，但有免疫性差的弱点。传统策略是将糖抗原与载体蛋白偶联来增强其免疫原性，但糖蛋白疫苗有偶联位点不确定、偶联率不稳定、组成成分复杂等缺点。而我们前期全合成的TLR4激动剂MPLA与TACAs两组分疫苗，能产生较强的免疫应答。在此基础上，本研究构建合成了一系列结构新型、活性比MPLA更强的TLR4激动剂αGlcNαMan衍生物、新型MPLA衍生物、RC529等新型疫苗载体，再选取具有临床开发价值的Tn、TF、STn等TACAs糖抗原与以上疫苗载体偶联，全合成了一系列化学结构明确的TACAs两组分抗肿瘤糖疫苗，并且进行了抗肿瘤免疫活性评价，探究了此类全合成糖疫苗载体与TACAs之间的构效关系及其代替载体蛋白的可能性，结果显示具有克服TACAs自身的弱点和糖蛋白类缀合疫苗缺点的潜力，能产生更强的免疫反应和有效地杀死肿瘤细胞，为下一代抗肿瘤疫苗研发奠定基础。

内容获取失败，请点击重试