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

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

doi:10.3389/fchem.2023.1322773

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

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

Authors

Abdullah Metebi^{1

2

3}, Nathan Kauffman^{1

2}, Lu Xu^{1

4}, Satyendra Kumar Singh¹, Chelsea Nayback^{1

2}, Jinda Fan^{1

5

6}, Nathan Johnson⁷, John Diemer⁷, Terry Grimm⁷, Mike Zamiara⁷, Kurt R Zinn^{1

2

4

6

8}

Affiliations

¹ Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States.
² Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, MI, United States.
³ Radiological Sciences Department, Taif University, Taif, Saudi Arabia.
⁴ Biomedical Engineering, Michigan State University, East Lansing, MI, United States.
⁵ Department of Chemistry, Michigan State University, East Lansing, MI, United States.
⁶ Radiology, Michigan State University, East Lansing, MI, United States.
⁷ Niowave Inc., Lansing, MI, United States.
⁸ Small Animal Clinical Sciences, Michigan State University, East Lansing, MI, United States.

Abstract

Introduction: 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_1/2 = 26.8 min) in equilibrium with its daughter Bismuth-214 (Bi-214, t_1/2 = 19.7 min); referred to as Pb-214/Bi-214. In this study, Pb-214/Bi-214-TCMC-Trastuzumab was tested. Methods: 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. Results and discussion: SKOV3 cells had 590,000 ± 5,500 HER2 receptors/cell compared with OVCAR3 cells at 7,900 ± 770. In vitro 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.

Keywords: Lead-214/Bismuth-214 (Pb-214/Bi-214); Trastuzumab; ovarian cancer; preclinical mouse model; targeted alpha-particle therapy.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Niowave, Inc., KZ’s start-up funds (MSU), NIH 5PO1CA221775-05, and funding available to KZ, recipient of the Hickman Family Endowed Chair in Oncology at Michigan State University.