Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer

Area of Science:

• Oncology
• Radiochemistry
• Molecular Biology

Background:

• Prostate cancer (PCa) is driven by the androgen receptor (AR), which also regulates DNA repair.
• Human kallikrein peptidase 2 (hK2) is a prostate-specific enzyme regulated by AR.
• Targeted alpha particle irradiation offers a promising therapeutic approach for PCa.

Purpose of the Study:

• To develop a molecularly-specific alpha particle irradiation strategy for PCa.
• To exploit the interplay between AR, DNA repair, and hK2 expression for enhanced therapeutic targeting.
• To evaluate the efficacy and targeting specificity of a novel antibody-drug conjugate.

Main Methods:

• Development and characterization of a humanized monoclonal antibody (hu11B6) targeting hK2.
• Labeling of hu11B6 with the alpha-emitter actinium-225 (225Ac).
• In vivo evaluation of 225Ac-hu11B6 efficacy and targeting in preclinical PCa models and nonhuman primates.

Main Results:

• hu11B6 demonstrated exquisite targeting specificity for hK2.
• A single administration of 225Ac-hu11B6 eradicated PCa in animal models and significantly prolonged survival.
• Alpha particle irradiation induced AR and subsequently hK2 expression, creating a feed-forward loop that enhanced hu11B6 binding.

Conclusions:

• The hormone-DNA repair circuit can be exploited for targeted alpha particle therapy in PCa.
• 225Ac-hu11B6 represents a potent and specific therapeutic agent for PCa.
• Preclinical data support the potential clinical translation of hu11B6 for human PCa treatment.