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

Journal Article · Mon May 15 00:00:00 EDT 2023 · Clinical Cancer Research

DOI:https://doi.org/10.1158/1078-0432.ccr-22-3291· OSTI ID:2424949

Bidkar, Anil P. ^[1]; Wang, Sinan ^[1]; Bobba, Kondapa Naidu ^[1]; Chan, Emily ^[1]; Bidlingmaier, Scott ^[1]; Egusa, Emily A. ^[1]; Peter, Robin ^[2]; Ali, Umama ^[1]; Meher, Niranjan ^[1]; Wadhwa, Anju ^[1]; Dhrona, Suchi ^[1]; Dasari, Chandrashekhar ^[1]; Beckford-Vera, Denis ^[1]; Su, Yang ^[1]; Tang, Ryan ^[1]; Zhang, Li ^[3]; He, Jiang ^[4]; Wilson, David M. ^[1]; Aggarwal, Rahul ^[1]; VanBrocklin, Henry F. ^[1] ; Seo, Youngho ^[1]; Chou, Jonathan ^[1]; Liu, Bin ^[1]; Flavell, Robert R. ^[1]

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1. University of California, San Francisco, CA (United States)
2. University of California, San Francisco, CA (United States); University of California, Berkeley, CA (United States)
3. University of California, Berkeley, CA (United States)
4. University of Virginia, Charlottesville, VA (Untied States)

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.

• Research Organization: USDOE Office of Science (SC), Office of Isotope R&D and Production (IRP)
• Sponsoring Organization: USDOD; USDOE
• OSTI ID: 2424949
• Journal Information: Clinical Cancer Research, Journal Name: Clinical Cancer Research Journal Issue: 10 Vol. 29; ISSN 1078-0432
• Publisher: American Association for Cancer Research
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
Oncology