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AbstractPurpose: 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 225AcDOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. Experimental Design: 225AcDOTA-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 225AcDOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Results: Biodistribution study shows that 225AcDOTA-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. 225AcDOTA-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. Conclusions: 225AcDOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including PSMA-positive and deficient models. Overall, this preclinical study confirms that 225AcDOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46 targeted radioligand therapy in PCa.
Bidkar et al. (Mon,) studied this question.