Trop-2.2–Directed Radioimmunotherapy with¹⁷⁷Lu,²²⁵Ac, and²¹²Pb in a Pancreatic Cancer Model

Purpose: Trophoblast cell surface antigen-2 (Trop-2) is a membrane-bound antigen associated with cancer invasiveness and poorer patient outcomes. Delivery of therapeutics via Trop-2 targeting antibody–drug conjugates (ADC) has proven to be a viable and FDAapproved model. However, in the clinic, ADC dosing is not based on Trop-2 positivity or expression, leading to potential adverse effects if the antigen membrane level on cancer cells is insufficient for targeting. The challenge of adequate patient and therapy selection can be overcome by leveraging the theranostic approach. We previously established a Trop-2.2 antibody for immunoPET imaging, allowing us to theoretically select patients with positive Trop-2 lesions. Experimental Design: In this work, the antibody Trop-2.2 was repurposed for lutetium-177, actinium-225, and lead-212 radiotherapies. We explored the benefits of direct, tandem, pretargeted, and fractionated approaches to radiopharmaceutical dosing. Results: Therapy with the α emitter²²⁵Ac regressed tumors, with eight out of 10 mice alive after 150 days. Alternatively,²¹²Pb, a shorter-lived in vivo α generator therapeutic, was found to be more effective when harnessing the pretargeting (PreT) strategy compared with a directly labeled approach. Our in-house²¹²Pb production allowed us to investigate fractionated dosing on a weekly basis. Fractionation resulted in tumor reductions through 12 weeks of therapy with minimal and reversible blood toxicity for the lowest dose. With repeat administrations, we found pathologically significant renal and ovarian toxicity attributable to²¹²Pb administration but an otherwise effective PreT method. Conclusions: In this study, we provide several direct and pretargeted radiopharmaceutical variants yielding therapeutic benefit for a Trop-2.2–expressing pancreatic cancer model.