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Development of a targeted delivery platform for checkpoint inhibitors

检查点抑制剂靶向递送平台的开发

基本信息

批准号：
10468185
负责人：
Kun Cheng
金额：
$ 34.75万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468185
关键词：
Adopted Affinity Antibodies Bacteriophages Binding Biodistribution Blood Blood Circulation CD34 gene CT26 Cancer Patient Cells Clinical Trials Colon Carcinoma DU145 Development Distal Effectiveness Enzymes FDA approved FOLH1 gene Future Goals Growth Human Immune checkpoint inhibitor Immunotherapy Implant In Vitro Inbred BALB C Mice LNCaP Ligands Link Lymphoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mediating Modeling Molecular Weight Mus Neoplasm Metastasis Normal Cell Normal tissue morphology Nude Mice PC3 cell line PD-1/PD-L1 PD-L1 blockade PDL1 inhibitors Penetration Peptides Pharmaceutical Preparations Prostatic Neoplasms Reporting Research Serum Solid Neoplasm Specificity Stimulus Therapeutic Effect Tissues Toxicology Treatment Efficacy advanced prostate cancer anti-PD-L1 anti-cancer antibody inhibitor antitumor effect base cancer cell cancer immunotherapy cancer therapy castration resistant prostate cancer humanized mouse immune checkpoint immunogenicity improved in vivo interest interstitial melanoma mouse model neoplastic cell novel programmed cell death ligand 1 prostate cancer cell prostate cancer model protein aminoacid sequence receptor side effect small molecule synthetic peptide targeted delivery tumor tumor microenvironment

项目摘要

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.

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。