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铅-214/铋-214-三甲基壳聚糖-曲妥珠单抗在临床前小鼠模型中抑制卵巢癌生长。

Pb-214/Bi-214-TCMC-Trastuzumab inhibited growth of ovarian cancer in preclinical mouse models.

作者信息

Metebi Abdullah, Kauffman Nathan, Xu Lu, Singh Satyendra Kumar, Nayback Chelsea, Fan Jinda, Johnson Nathan, Diemer John, Grimm Terry, Zamiara Mike, Zinn Kurt R

机构信息

Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States.

Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, MI, United States.

出版信息

Front Chem. 2024 Jan 25;11:1322773. doi: 10.3389/fchem.2023.1322773. eCollection 2023.

DOI:10.3389/fchem.2023.1322773
PMID:38333550
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10850308/
Abstract

Better treatments for ovarian cancer are needed to eliminate residual peritoneal disease after initial debulking surgery. The present study evaluated Trastuzumab to deliver Pb-214/Bi-214 for targeted alpha therapy (TAT) for HER2-positive ovarian cancer in mouse models of residual disease. This study is the first report of TAT using a novel Radon-222 generator to produce short-lived Lead-214 (Pb-214, t = 26.8 min) in equilibrium with its daughter Bismuth-214 (Bi-214, t = 19.7 min); referred to as Pb-214/Bi-214. In this study, Pb-214/Bi-214-TCMC-Trastuzumab was tested. Trastuzumab and control IgG antibody were conjugated with TCMC chelator and radiolabeled with Pb-214/Bi-214 to yield Pb-214/Bi-214-TCMC-Trastuzumab and Pb-214/Bi-214-TCMC-IgG1. The decay of Pb-214/Bi-214 yielded α-particles for TAT. SKOV3 and OVAR3 human ovarian cancer cell lines were tested for HER2 levels. The effects of Pb-214/Bi-214-TCMC-Trastuzumab and appropriate controls were compared using clonogenic assays and in mice bearing peritoneal SKOV3 or OVCAR3 tumors. Mice control groups included untreated, Pb-214/Bi-214-TCMC-IgG1, and Trastuzumab only. SKOV3 cells had 590,000 ± 5,500 HER2 receptors/cell compared with OVCAR3 cells at 7,900 ± 770. clonogenic assays with SKOV3 cells showed significantly reduced colony formation after Pb-214/Bi-214-TCMC-Trastuzumab treatment compared with controls. Nude mice bearing luciferase-positive SKOV3 or OVCAR3 tumors were treated with Pb-214/Bi-214-TCMC-Trastuzumab or appropriate controls. Two 0.74 MBq doses of Pb-214/Bi-214-TCMC-Trastuzumab significantly suppressed the growth of SKOV3 tumors for 60 days, without toxicity, compared with three control groups (untreated, Pb-214/Bi-214-TCMC-IgG1, or Trastuzumab only). Mice-bearing OVCAR3 tumors had effective therapy without toxicity with two 0.74 MBq doses of Pb-214/Bi-214-TCMC-trastuzumab or Pb-214/Bi-214-TCMC-IgG1. Together, these data indicated that Pb-214/Bi-214 from a Rn-222 generator system was successfully applied for TAT. Pb-214/Bi-214-TCMC-Trastuzumab was effective to treat mouse xenograft models. Advantages of Pb-214/Bi-214 from the novel generator systems include high purity, short half-life for fractioned therapy, and hourly availability from the Rn-222 generator system. This platform technology can be applied for a variety of cancer treatment strategies.

摘要

需要更好的卵巢癌治疗方法来消除初次肿瘤细胞减灭术后残留的腹膜疾病。本研究评估了曲妥珠单抗携带Pb-214/Bi-214用于对残留疾病小鼠模型中的HER2阳性卵巢癌进行靶向α治疗（TAT）。本研究是关于使用新型氡-222发生器产生与其子体铋-214（Bi-214，半衰期t = 19.7分钟）处于平衡状态的短寿命铅-214（Pb-214，半衰期t = 26.8分钟）进行TAT的首次报告；称为Pb-214/Bi-214。在本研究中，对Pb-214/Bi-214-TCMC-曲妥珠单抗进行了测试。曲妥珠单抗和对照IgG抗体与TCMC螯合剂偶联，并用Pb-214/Bi-214进行放射性标记，得到Pb-214/Bi-214-TCMC-曲妥珠单抗和Pb-214/Bi-214-TCMC-IgG1。Pb-214/Bi-214的衰变产生用于TAT的α粒子。对SKOV3和OVAR3人卵巢癌细胞系进行了HER2水平检测。使用克隆形成试验并在携带腹膜SKOV3或OVCAR3肿瘤的小鼠中比较了Pb-214/Bi-214-TCMC-曲妥珠单抗和适当对照的效果。小鼠对照组包括未治疗组、Pb-214/Bi-214-TCMC-IgG1组和仅曲妥珠单抗组。与OVCAR3细胞（7900±770个HER2受体/细胞）相比，SKOV3细胞有590000±5500个HER2受体/细胞。对SKOV3细胞进行的克隆形成试验显示，与对照组相比，Pb-214/Bi-214-TCMC-曲妥珠单抗治疗后集落形成显著减少。对携带荧光素酶阳性SKOV3或OVCAR3肿瘤的裸鼠用Pb-214/Bi-214-TCMC-曲妥珠单抗或适当对照进行治疗。与三个对照组（未治疗组、Pb-214/Bi-214-TCMC-IgG1组或仅曲妥珠单抗组）相比，两次0.74 MBq剂量的Pb-214/Bi-214-TCMC-曲妥珠单抗在60天内显著抑制了SKOV3肿瘤的生长，且无毒性。携带OVCAR3肿瘤的小鼠接受两次0.74 MBq剂量的Pb-214/Bi-214-TCMC-曲妥珠单抗或Pb-214/Bi-214-TCMC-IgG1治疗后有效且无毒性。总之，这些数据表明来自氡-222发生器系统的Pb-214/Bi-214成功应用于TAT。Pb-214/Bi-214-TCMC-曲妥珠单抗对治疗小鼠异种移植模型有效。新型发生器系统产生的Pb-214/Bi-214的优点包括高纯度、用于分次治疗的短半衰期以及氡-222发生器系统每小时的供应量。这种平台技术可应用于多种癌症治疗策略。

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