新型共享新生抗原肽-STING激动剂偶联物的构建、免疫抗肿瘤活性及作用机制研究

新生抗原介导的免疫抗肿瘤新疗法特异性强、安全性好，研发前景广阔。但单一新生抗原疗法存在免疫应答效率低和普适性差等局限性。前期研究发现，新生抗原肽佐以STING激动剂治疗能在一定程度上增强抗原肽的免疫应答强度，但无法改善抗原肽的代谢稳定性，且药物靶向共递送效率低，难以获得最佳疗效。本项目拟构建在肿瘤患者间高频出现且共同存在的新生抗原衍生多肽库，提高普适性；再将优选抗原肽与STING激动剂通过酶敏感连接键共价缀合，获得响应型“广谱”新生抗原肽-STING激动剂偶联物，期望增强目标分子的免疫应答强度和代谢稳定性，拓宽抗肿瘤范围，达到稳定、持续、高效的免疫抑瘤效果。对优选偶联物进行系统的活性评估，结合作用机制探索和构效关系分析，全面揭示该偶联体系启动抗原特异性免疫反应的具体机制，为新型新生抗原介导的免疫治疗药物研发和肿瘤的免疫治疗奠定坚实的理论基础。

The novel antitumor immunotherapy mediated by neoantigen with strong specificity and good safety has broad prospects for development. However, single neoantigen therapy still has some limitations, such as low clinical response rate and poor universality. Our previous studies have found that combination therapy of neoantigen peptide and STING agonist can enhance immune response rate to a certain extent. Unfortunately, the simple co-administration of the two leads to several issues, including poor metabolic stability of the antigenic peptide, inefficient delivery of the antigenic peptide as well as STING agonist, and unsatisfactory response. This project is aimed to build a library of highly mutated neoantigen-derived peptides shared among multiple tumors for improving universality, and then covalently conjugate different selected neoantigen peptides to the optimized STING agonist by incorporating enzyme-sensitive linkage to generate response-type “broad-spectrum” neoantigen-STING agonist conjugates, in the hopes of improving the metabolic stability and immune response rate of the target molecules, broadening the antitumor activities of neoantigens, and achieving stable, continuous and highly potent antitumor effects. The activity and pharmacodynamics of these selected conjugates will be systematically assessed, and the specific mechanism of the conjugate system in initiating neoantigen-specific immune responses will be fully elucidated through exploration of the structure-activity relationship and the mechanism of action. We hope that our project will provide a solid theoretical support for the development of novel neoantigen-mediated immunotherapy drugs and strategies in tumor immunotherapy.