Radiopharmaceutical therapy is changing the standard of care in prostate cancer (PCa) and other malignancies. We previously reported high CD46 expression in PCa 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) PCa 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 h, 96 h, 168 h, and 408 h, respectively), compared to the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line 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 PSMA-positive and 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 PCa.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Mar 14 [Epub ahead of print]
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
University of California, San Francisco, San Francisco, CA, United States., University of California, San Francisco, San Francisco, California, China., University of California, San Francisco, San Franciso, United States., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States., University of California, Berkeley, CA, USA, United States., University of South Florida, Tampa, FL, United States., University of Virginia, Charlottesville, VA, United States.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/36917693