Development of a targeted delivery platform for checkpoint inhibitors

摘要 这项研究的目标是为检查点开发一个有针对性的交付平台 抑制剂。该平台将包含靶向配体、酶反应连接物和多肽- 基于检查点抑制器。我们最近发现了几种基于多肽的PD-L1抑制剂，可以 有可能用于癌症免疫治疗。在这项研究中，我们将对该平台进行高级评估 前列腺癌模型。特别是，我们建议将PSMA特异的配体连接到抗PD-L1 通过PSA可裂解接头的多肽。 该项目的总体目标是：1)开发一种针对癌症的抗PD-L1多肽 免疫治疗；2)用植入人的人源化小鼠评价其治疗效果 耐去势前列腺癌(CRPC)细胞。该项目的长期目标是开发一种 肿瘤免疫治疗靶向多肽平台。我们的中心假设是癌症 抗PD-L1多肽靶向肿瘤治疗可有效抑制肿瘤生长和转移 细胞。 在这个项目完成后，我们希望为未来的发展铺平道路，有针对性的 用于癌症免疫治疗的PD-L1抑制剂。成功完成拟议的研究也是 期望提供基于多肽的平台(通过改变靶向配体和组织特异性 连接物)用于其他基于多肽的检查点抑制物。

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.