Development of novel human Fab probes for PET imaging of macrophages

项目总结 巨噬细胞是一类在多种疾病的预后和治疗中起重要作用的免疫细胞， 包括癌症。CD68是公认的泛巨噬细胞的临床生物标志物。目前，没有非 针对人或小鼠CD68的侵入性探针。我们计划为人类和人类开发新的探测器 小鼠CD68用于巨噬细胞的PET成像。该项目涉及噬菌体展示筛选人的Fab 文库(Aim 1a)；在CD68阳性的巨噬细胞中验证产生的“HITS”与CD68蛋白的结合(Aim 1b) 选择铅HuFabs(目标1c)；并评估所产生的铅放射性标记HuFabs的功能 适当的小鼠模型(目标2)。通过这项工作，我们将生产一个用于对人体进行成像的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合于 同一天成像。我们的长期目标是将我们的新型PET探针应用于体内巨噬细胞密度的量化 在人类和小鼠的不同疾病中。具体地说，我们设想联合临床试验将使用这些 用于对人类受试者和相应的小鼠疾病模型进行成像以监测其反应的探针 调节巨噬细胞活动的治疗。

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.