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.

项目摘要巨噬细胞是一类在预后和治疗多种疾病的免疫力中，包括癌症。 CD68是已建立的用于泛巨噬细胞的临床生物标志物。目前，没有针对人或小鼠CD68的侵入性问题。我们建议为人类和小鼠CD68用于巨噬细胞的宠物成像。该项目涉及人类工厂的噬菌体展示筛选图书馆（AIM 1A）;在CD68阳性巨噬细胞中验证的CD68蛋白（AIM 1B）的结合与CD68蛋白的结合选择铅HUFAB（AIM 1C）；并评估所得的铅辐射标记的HUFAB的功能适当的小鼠模型（AIM 2）。从这项工作中，我们将生产一个宠物成像工具包用于成像人类和具有高结合亲和力，特异性和药代动力学特性的小鼠巨噬细胞适合当日成像。我们的长期目标是应用我们的新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。具体而言，我们设想共同临床试验将采用这些试验成像人类受试者和相应疾病模型的问题，以监测对调节巨噬细胞活性的治疗。