Development of novel human Fab probes for PET imaging of macrophages

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。

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.