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Figure S8 from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy

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journal contribution
posted on 2023-05-15, 08:20 authored by Anil P. Bidkar, Sinan Wang, Kondapa Naidu Bobba, Emily Chan, Scott Bidlingmaier, Emily A. Egusa, Robin Peter, Umama Ali, Niranjan Meher, Anju Wadhwa, Suchi Dhrona, Chandrashekhar Dasari, Denis Beckford-Vera, Yang Su, Ryan Tang, Li Zhang, Jiang He, David M. Wilson, Rahul Aggarwal, Henry F. VanBrocklin, Youngho Seo, Jonathan Chou, Bin Liu, Robert R. Flavell

Figure S8: Acute toxicity study of the [225Ac]DOTA-YS5 in nude mice (n=5). A The body weights of mice injected with [225Ac]DOTA-YS5 showed no significant change in treatment groups over the 15 days study period. B&C: Liver and kidney function tests (B) and blood parameters (C) show no significant changes for saline vs. treated groups indicating the short-term safety of [225Ac]DOTA-YS5.

Funding

DOD Prostate Cancer Research Program (PCRP)

University of California, San Francisco (UCSF)

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ARTICLE ABSTRACT

Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody–drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. [225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line–derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi. [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen–positive and prostate-specific membrane antigen–deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.

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