An integrated polymeric carrier for subunit cancer vaccines

项目摘要 癌症疫苗是一种很有前途的免疫肿瘤学方法，可以引起高度肿瘤特异性的免疫反应。 免疫系统的反应，从而延长抗癌保护。基于肽 疫苗特别有吸引力，因为它们具有低毒性风险并且易于生产。 具有良好的储存稳定性。然而，肽抗原固有地差 免疫原性和给药后易于快速降解和排泄。因此 基于肽的癌症疫苗的成功与其有效的制剂密切相关， 交付.理想的肽疫苗制剂将复制这些关键方面中的每一个： 树突状细胞的识别和内化，这些树突状细胞的活化，以及抗原 在一些实施方案中，该蛋白质可同时递送至MHC I（称为交叉呈递）和MHC II分子。在本申请中，我们 我建议开发一种基于聚合物的肽抗原载体， 在一个良好控制的、可扩展的系统中，通过集成 靶向配体、控释佐剂和胞质和溶酶体抗原递送 机制等我们的主要目标是：1）优化聚合物结构和合成， 材料工程，2）评估肽和佐剂递送并在体外和体内表征 运输和递送，3）在鼠黑素瘤模型中优化疫苗功效的制剂 和4）评价在鼠乳腺癌模型中预防癌症的功效和安全性， 疗法这些目标的成功完成将导致一个制剂准备GMP 生产和IND途径走向临床试验。

PROJECT SUMMARY Cancer vaccines are a promising immuno-oncology approach that can elicit highly tumor-specific responses from the immune system, resulting in prolonged anti-cancer protection. Peptide-based vaccines are especially attractive because they have low toxicity risk and can be produced easily at large scale with good storage stability. However, peptide antigens are inherently poorly immunogenic and susceptible to rapid degradation and excretion after administration. Thus, the success of peptide-based cancer vaccines are critically tied to their effective formulation and delivery. The ideal peptide vaccine formulation would replicate each of these critical aspects: recognition and internalization by dendritic cells, activation of these dendritic cells, and antigen delivery to both MHC I (called cross-presentation) and MHC II molecules. In this application, we propose to develop a polymer-based peptide antigen carrier that uniquely addresses all of the aforementioned delivery needs in a well-controlled, scalable system through the integration of targeting ligands, controlled release adjuvants, and cytosolic and lysosomal antigen delivery mechanisms. Our main objectives are to 1) optimize polymer structure and synthesis through material engineering, 2) assess peptide and adjuvant delivery and characterize in vitro and in vivo trafficking and delivery, 3) optimize formulations for vaccine efficacy in a murine melanoma model and 4) evaluate efficacy and safety in a murine breast cancer model for cancer prevention and therapy. Successful completion of these aims will lead to a formulation poised for GMP manufacturing and the IND pathway toward clinical testing.