Trop-2.2 directed radioimmunotherapy with 177Lu, 225Ac, and 212Pb in a pancreatic cancer model

Abstract 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 has proven to be a viable and FDA-approved model. However, in the clinic, antibody-drug-conjugate 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 alpha emitter Actinium-225 regressed tumors, with 8/10 mice alive after 150 days. Alternatively, Lead-212, a shorter-lived in vivo alpha generator therapeutic, was found to be more effective when harnessing the pretargeting strategy compared to a directly labeled approach. Our in-house Lead-212 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 to Lead-212 administration, but an otherwise effective pretargeting method. Conclusions: Here, we provide several direct and pretargeted radiopharmaceutical variants yielding therapeutic benefit for a Trop-2.2 expressing pancreatic cancer model.