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

• 批准号: 10884038
• 负责人: Bernadette Marquez-Nostra
• 金额: $ 52.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10884038
• 关键词: Address; Affinity; Aftercare; Binding; Biological; Biological Assay; Body part; CSF1R gene; Cancer Model; Cardiovascular Diseases; Cd68; Cell Separation; Cells; Clinical Research; Companions; Cytoplasm; Data; Development; Disease; Disease model; Drug Kinetics; Goals; Half-Life; Human; Image; Immune; Immune checkpoint inhibitor; Immune system; In Vitro; Infiltration; Label; Lead; Libraries; Macrophage; Malignant Neoplasms; Modeling; Monitor; Mus; Neurodegenerative Disorders; Orthologous Gene; Peripheral Blood Mononuclear Cell; Phage Display; Play; Positron-Emission Tomography; Prognosis; Property; Protein Glycosylation; Proteins; Radiolabeled; Role; Sampling; Specificity; Stains; Structure; Surface; Techniques; Testing; Tissues; Translating; Tumor-associated macrophages; Work; clinical application; clinical biomarkers; clinical translation; co-clinical trial; cross reactivity; cytotoxic; density; fighting; human imaging; human subject; imaging probe; immunogenicity; in vivo; 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

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 巨噬细胞是一类在几种疾病的预后和治疗中很重要的免疫细胞， 包括癌症CD 68是泛巨噬细胞的既定临床生物标志物。目前，没有非- 特异于人或小鼠CD 68的侵入性探针。我们建议开发新的探针， 小鼠CD 68用于巨噬细胞的PET成像。该项目涉及噬菌体展示筛选人Fab抗体， 文库（Aim 1a）;在CD 68阳性巨噬细胞中验证所得“命中”与CD 68蛋白的结合（Aim 1b） 以选择铅huFab（Aim 1c）;并评价所得的铅放射性标记的huFab在 合适的小鼠模型（目的2）。从这项工作中，我们将产生一个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性质， 当天成像。我们的长期目标是应用我们的新型PET探针定量体内巨噬细胞密度 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 用于成像人类受试者和相应的疾病小鼠模型以监测对 调节巨噬细胞活性的治疗。