Development of a targeted delivery platform for checkpoint inhibitors

摘要 本研究的目标是开发一个针对性的检查点交付平台 抑制剂的该平台将含有靶向配体、酶响应性接头和肽- 检查点抑制剂。我们最近发现了几种基于肽的PD-L1抑制剂， 可能用于癌症免疫治疗。在这项研究中，我们将评估该平台在一个先进的 前列腺癌模型。特别地，我们建议将PSMA特异性配体连接到抗PD-L1 通过PSA-可切割接头将肽与肽连接。 本项目的总体目标是：1）开发针对癌症的靶向抗PD-L1肽 免疫治疗; 2）使用植入人源化小鼠的人源化小鼠评估其治疗效果 去势抵抗性前列腺癌（CRPC）细胞。该项目的长期目标是开发一个 基于靶向肽的癌症免疫治疗平台。我们的核心假设是癌症 通过将抗PD-L1肽靶向递送至癌症可以有效地抑制生长和转移 细胞 在此项目完成后，我们期望为未来的发展铺平道路， PD-L1抑制剂用于癌症免疫治疗。成功完成拟议的研究也是 预期提供基于肽的平台（通过改变靶向配体和组织特异性配体）。 接头）用于其它基于肽的检查点抑制剂。

Abstract The goal of this proposed research is to develop a targeted delivery platform for checkpoint inhibitors. The platform will contain a targeting ligand, an enzyme-responsive linker, and a peptide- based checkpoint inhibitor. We recently discovered several peptide-based PD-L1 inhibitors that can be potentially used for cancer immunotherapy. In this study, we will evaluate the platform in an advanced prostate cancer model. Particularly, we propose to link a PSMA-specific ligand to the anti-PD-L1 peptides via a PSA-cleavable linker. The overall objectives of this project are: 1) to develop a targeted anti-PD-L1 peptide for cancer immunotherapy; 2) to evaluate its therapeutic effect using humanized mice implanted with human castration-resistant prostate cancer (CRPC) cells. The long-term goal of the project is to develop a targeted peptide-based platform for cancer immunotherapy. Our central hypothesis is that cancer growth and metastasis can be effectively inhibited by targeted delivery of anti-PD-L1 peptides to cancer cells. At the completion of this project, we expect to pave the way for the future development of a targeted PD-L1 inhibitor for cancer immunotherapy. Successful completion of the proposed studies is also expected to provide a peptide-based platform (by changing the targeting ligand and the tissue-specific linker) for other peptide-based checkpoint inhibitors.