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Development of novel human Fab probes for PET imaging of macrophages

开发用于巨噬细胞 PET 成像的新型人类 Fab 探针

基本信息

批准号：
10461963
负责人：
Bernadette Marquez-Nostra
金额：
$ 67.75万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-01-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461963
关键词：
Address Affinity Aftercare Binding Biological Biological Assay Body part CSF1R gene Cancer Model Cardiovascular Diseases Cells Clinical Clinical Research Companions Cytoplasm Data Development Disease Disease model Drug Kinetics Goals Gold Half-Life Human Image Immune Immune checkpoint inhibitor Immune system In Vitro Infiltration Label Lead Libraries Malignant Neoplasms Modeling Monitor Mus Neurodegenerative Disorders Orthologous Gene Peripheral Blood Mononuclear Cell Phage Display Play Positron-Emission Tomography Prognosis Property Proteins Radiolabeled Role Sampling Specificity Stains Structure Surface Techniques Testing Tissues Translating Work base clinical biomarkers clinical translation co-clinical trial cross reactivity cytotoxic density fighting human imaging human subject imaging probe immunogenicity in vivo macrophage matrigel mouse model novel novel therapeutics pathogen patient derived xenograft model pre-clinical preclinical study radioligand radiotracer screening trafficking treatment effect treatment response tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Macrophages are a class of immune cells important in the prognosis and treatment of several diseases, including cancer. CD68 is the established clinical biomarker for pan-macrophage. Currently, there are no non- invasive probes specific for human or mouse CD68. We propose to develop novel probes for human and mouse CD68 for PET imaging of macrophages. This project involves phage display screening of a human Fab library (Aim 1a); binding of resulting “hits” to CD68 proteins (Aim 1b) validating in CD68-positive macrophages to select lead huFabs (Aim 1c); and evaluating the function of the resulting lead radiolabeled huFabs in appropriate mice models (Aim 2). From this work, we will produce a PET imaging toolkit for imaging human and mouse macrophages with high binding affinity, specificity, and pharmacokinetic properties suitable for same-day imaging. Our long-term goal is to apply our novel PET probes to quantify macrophage density in vivo in different diseases in humans and mice. Specifically, we envision that co-clinical trials will employ these probes for imaging human subjects and corresponding mice models of disease to monitor response to treatments that modulate macrophage activity.

项目概要巨噬细胞是一类在多种疾病的预后和治疗中发挥重要作用的免疫细胞，包括癌症。 CD68 是已建立的泛巨噬细胞临床生物标志物。目前，没有非针对人类或小鼠 CD68 的侵入性探针。我们建议开发用于人类和小鼠 CD68 用于巨噬细胞 PET 成像。该项目涉及人类 Fab 的噬菌体展示筛选图书馆（目标 1a）；所得“命中”与 CD68 蛋白的结合（目标 1b）在 CD68 阳性巨噬细胞中得到验证选择领先的 huFab（目标 1c）；并评估所得铅放射性标记 huFab 的功能合适的小鼠模型（目标 2）。通过这项工作，我们将生产一个用于人体成像的 PET 成像工具包和小鼠巨噬细胞具有高结合亲和力、特异性和药代动力学特性，适用于当日成像。我们的长期目标是应用我们的新型 PET 探针来量化体内巨噬细胞密度在人类和小鼠的不同疾病中。具体来说，我们设想联合临床试验将采用这些用于对人类受试者和相应的疾病小鼠模型进行成像的探针，以监测对疾病的反应调节巨噬细胞活性的治疗。