Purpose:

Metastatic castration-resistant prostate cancer has limited treatment options and a poor prognosis. Recently, prostate-specific membrane antigen (PSMA)-targeted alpha-particle therapy agents using actinium-225 (225Ac) have shown promising results in prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5, and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5, in disseminated prostate cancer tumors.

Experimental Design:

Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5.

Results:

Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared with surrounding liver tissues, although in larger lesions (>1 mm diameter), the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with a uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response.

Conclusions:

Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
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Supplementary data

Supplementary Table S1

Supplementary Table S1: The %IA/g values for biodistribution (4 days p.i.) of [89Zr]DFO-YS5 in 22Rv1-Luc disseminated tumor models performed at week 5 post inoculations.

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Supplementary Table S2

Supplementary Table S2: The %IA/g values for biodistribution study of [89Zr]DFO-YS5 in PC3-Luc disseminated tumors, conducted 4 days post-injection (p.i.), utilized mice with PC3-Luc tumors at 5 weeks post-cell inoculations. The large intestine tissue from Mouse 1 was not recorded due to a technical error in the instrument.

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Supplementary Table S3

Supplementary Table S3: The %IA/g values for biodistribution (4 days p.i.) of [89Zr]DFO-YS5 in 5-week-old DU145-Luc disseminated tumor models.

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Supplementary Table S4

Supplementary Table S4: The %IA/g values for biodistribution (4 days p.i.) of [89Zr]DFO-YS5 in C42B-Luc disseminated tumor models performed at 9 weeks post inoculations of cells.

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Supplementary Table S5

Supplementary Table S5: The %IA/g values for biodistribution of [89Zr]DFO-YS5 in 22Rv1-luc tumor models at week 1 post intracardiac injections.

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Supplementary Table S6

Supplementary Table S6: The %IA/g values for biodistribution of [89Zr]DFO-YS5 in 22Rv1-luc tumor models at week 3 post intracardiac injections.

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Supplementary Table S7

Supplementary Table S7: The %IA/g values for biodistribution of [225Ac]Macropa-PEG4-YS5 in 22Rv1-luc tumor models at week 3 post intracardiac injections.

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Supplementary Table S8

Supplementary Table S8: The %IA/g values for biodistribution of [89Zr]DFO-YS5 in the mice from early treatment (week 1 post inoculations) treated with 4.2 and 9.2 kBq of [225Ac]Macropa-PEG4-YS5.

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Supplementary Table S9

Supplementary Table S9: Biodistribution of [89Zr]DFO-YS5 in the mice from late treatment study (week 3 post inoculations) treated with 4.6 and 9.2 kBq of [225Ac]Macropa-PEG4-YS5.

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Supplementary Figure S1-S34

Supplementary Figure S1-S34

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