Department of Nuclear Medicine, Peking University First Hospital, Beijing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, China.
Clin Cancer Res. 2023 Sep 1;29(17):3395-3407. doi: 10.1158/1078-0432.CCR-23-0609.
Nectin-4 is an emerging biomarker for cancer diagnosis and therapy. Recently, enfortumab vedotin (EV) was approved by the FDA as the first nectin-4 targeting antibody-drug conjugate for treating advanced urothelial carcinoma (UC). A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help to select patients most likely to respond to EV and predict the response.
In this study, we designed a bicyclic peptide-based nectin-4 targeting radiotracer 68Ga-N188. Initially, we performed preclinical evaluations of 68Ga-N188 in UC cell lines and xenograft mouse models. Next, we performed the translational study in healthy volunteers and a pilot cohort of patients with advanced UC on uEXPLORER total-body PET/CT.
In the preclinical study, 68Ga-N188 showed high affinity to nectin-4, specific uptake in a nectin-4(+) xenograft mouse model, and suitable pharmacokinetic and safety profiles. In the translational study, 2 healthy volunteers and 14 patients with advanced UC were enrolled. The pharmacokinetic profile was determined for 68Ga-N188, and the nectin-4 relative expression level in different organs was quantitatively imaged.
A clear correlation between PET SUV value and nectin-4 expression was observed, supporting the application of 68Ga-N188 PET as a companion diagnostic tool for optimizing treatments that target nectin-4. See related commentary by Jiang et al., p. 3259.
Nectin-4 是一种新兴的癌症诊断和治疗生物标志物。最近，FDA 批准 enfortumab vedotin（EV）作为首个用于治疗晚期尿路上皮癌（UC）的靶向 nectin-4 的抗体药物偶联物。一种非侵入性定量 nectin-4 表达水平的 PET 成像方法，可能有助于选择最有可能对 EV 产生反应的患者，并预测反应。
在这项研究中，我们设计了一种基于双环肽的 nectin-4 靶向放射性示踪剂 68Ga-N188。最初，我们在 UC 细胞系和异种移植小鼠模型中对 68Ga-N188 进行了临床前评估。接下来，我们在健康志愿者和一组晚期 UC 患者中进行了 uEXPLORER 全身 PET/CT 的转化研究。
在临床前研究中，68Ga-N188 对 nectin-4 具有高亲和力，在 nectin-4（+）异种移植小鼠模型中具有特异性摄取，并具有合适的药代动力学和安全性特征。在转化研究中，招募了 2 名健康志愿者和 14 名晚期 UC 患者。确定了 68Ga-N188 的药代动力学特征，并对不同器官的 nectin-4 相对表达水平进行了定量成像。
观察到 PET SUV 值与 nectin-4 表达之间存在明显的相关性，支持将 68Ga-N188 PET 用作靶向 nectin-4 的优化治疗的伴随诊断工具。请参阅 Jiang 等人的相关评论，第 3259 页。
