Treatment of prostate cancer with CD46 targeted²²⁵Ac alpha particle radioimmunotherapy

Abstract

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. Our radiolabeled antibody retains binding efficacy and shows a high tumor to background ratio in PCa xenografts. Furthermore, we show that radiolabeled antibody was able to suppress the growth of cell-derived and patient-derived xenografts, including PSMA-positive and deficient models. Nephrotoxicity, not seen at low radioactive doses, is evident at higher radioactivity dose levels, likely due to redistribution of daughter isotope213Bi. 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.

Evaluation of134Ce/134La as a PET Imaging Theranostic Pair for225Ac α-Radiotherapeutics

“…An immuno-PET agent, 89 Zr-DFO-YS5, has successfully imaged both PSMA-positive and PSMA-negative tumor xenografts and patient-derived PDX models ( 19 ). Development of cognate 225 Ac-YS5 radiopharmaceuticals for therapy is currently under way ( 20 – 22 ). These therapeutic approaches would significantly benefit from a companion imaging agent.…”