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

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

JOURNAL=Frontiers in Chemistry

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1322773

DOI=10.3389/fchem.2023.1322773

ISSN=2296-2646

ABSTRACT=<p><bold>Introduction:</bold> 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<sub>1/2</sub> = 26.8 min) in equilibrium with its daughter Bismuth-214 (Bi-214, t<sub>1/2</sub> = 19.7 min); referred to as Pb-214/Bi-214. In this study, Pb-214/Bi-214-TCMC-Trastuzumab was tested.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results and discussion:</bold> SKOV3 cells had 590,000 ± 5,500 HER2 receptors/cell compared with OVCAR3 cells at 7,900 ± 770. <italic>In vitro</italic> 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.</p>