R&D Department, Philochem AG, Otelfingen, Switzerland;
R&D Department, Philochem AG, Otelfingen, Switzerland.
J Nucl Med. 2024 Oct 1;65(10):1604-1610. doi: 10.2967/jnumed.124.268200.
Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. OncoFAP-23 was radiolabeled with the theranostic radionuclide Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. Lu-OncoFAP and Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ∼16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and Lu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.
成纤维细胞激活蛋白 (FAP) 在大多数人类实体瘤的基质中大量表达。临床阶段放射性标记的 FAP 配体越来越多地被用作检测各种癌症病变的工具。为了释放 FAP 靶向剂的全部治疗潜力，配体需要在给药后几天内留在肿瘤部位。我们最近描述了 OncoFAP 的发现，这是一种 FAP 的高亲和力小分子有机配体，在癌症患者中具有快速在肿瘤中积累和在健康组织中摄取低的特点。OncoFAP 的三聚化提供了一种衍生物（命名为 TriOncoFAP，或 OncoFAP-23），其 FAP 亲和力得到了改善。在这项工作中，我们评估了 OncoFAP-23 在荷瘤小鼠中的组织分布特征和治疗性能。OncoFAP-23 用治疗放射性核素 Lu 进行放射性标记。在携带 SK-RC-52.hFAP（BALB/c 裸鼠）或 CT-26.hFAP（BALB/c 小鼠）肿瘤的小鼠中进行了临床前实验。Lu-OncoFAP 和 Lu-FAP-2286 作为对照包含在生物分布研究中。通过分别给 Wistar 大鼠和 CD1 小鼠注射高剂量的 OncoFAP-23 或其冷标记物，对其进行了毒理学评价。Lu-OncoFAP-23 因其最佳的生物分布特征、高且持续的肿瘤摄取（即，96 小时时约为 16% 注入剂量/克）和在健康器官中的低积累而脱颖而出，这与其在低放射性给药水平下的有效单药抗癌活性很好地相关。与肿瘤靶向白细胞介素 2（L19-IL2，一种临床阶段的免疫细胞因子）联合治疗进一步通过增强其体内抗肿瘤活性来扩大 Lu-OncoFAP-23 的治疗窗口。蛋白质组学研究表明，联合治疗会引发强烈的肿瘤导向免疫反应。OncoFAP-23 和 Lu-OncoFAP-23 表现出良好的毒理学特征，没有显示出任何副作用或毒性迹象。OncoFAP-23 表现出增强的肿瘤摄取和肿瘤保留以及在健康器官中的低积累，这些发现与体内抗肿瘤疗效的显著改善相对应。本工作中提供的数据支持 Lu-OncoFAP-23 用于治疗 FAP 阳性实体瘤的临床开发。
