Abstract：
Fibroblast activation protein (FAP) is a protein biomarker widely expressed in most solid human malignancies of epithelial origin. In recent years, a number of FAP-targeted small organic radioligands, including OncoFAP, have been utilized in the clinic for the detection and diagnosis of cancer. Despite their selective accumulation, conventional FAP ligands present a relatively short half-life in tumors, corresponding to a few hours after systemic administration. In order to maximize their efficacy, FAP-targeted radioligand therapeutics must possess prolonged tumor retention, thus irradiating tumor cells for days. In this work, we describe the development of compact OncoFAP multimers with improved FAP affinity (low picomolar IC50s), aimed at increasing tumor-residence time for therapeutic applications. An in silico analysis of the interaction of the multimers with FAP revealed a wide and deep pocket and six additional secondary binding sites. TriOncoFAP-DOTAGA emerged for its favorable in vitro profile and superior in vivo biodistribution performance in tumor-bearing mice.
摘要：
成纤维细胞活化蛋白(FAP)是在大多数上皮起源的实体人类恶性肿瘤中广泛表达的蛋白质生物标志物。近年来,一些FAP靶向的小型有机配体，包括OncoFAP,已在临床上用于癌症的检测和诊断。尽管它们有选择性地积累，传统的FAP配体在肿瘤中的半衰期相对较短，对应于系统给药后几小时。为了最大限度地发挥它们的功效，FAP靶向的放射性配体疗法必须具有延长的肿瘤滞留，从而照射肿瘤细胞数天。在这项工作中,我们描述了具有改善的FAP亲和力（低皮摩尔IC50）的紧凑型OncoFAP多聚体的发展，旨在增加治疗应用的肿瘤停留时间。多聚体与FAP相互作用的计算机模拟分析显示了一个宽且深的口袋和六个额外的二级结合位点。TriOncoFAP-DOTAGA因其在荷瘤小鼠中的良好体外分布和优异的体内生物分布性能而出现。
