Pretargeted Trop-2 ImmunoPET for Rapid, Selective Detection of Pancreatic Tumors

Purpose: Recent clinical advances with the approval of antibody–drug conjugates targeting trophoblast cell-surface antigen 2 (Trop-2), such as sacituzumab govitecan and datopotamab deruxtecan, have garnered tremendous interest for their therapeutic efficacy in numerous tumor types, including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for antibody–drug conjugate therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide. Experimental Design: Here, we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2–positive cancers and leverage different site-selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for fluorine-18, copper-64, and zirconium-89 were explored in addition to site-specific bioconjugation. Results: We found that pretargeting with [⁶⁴Cu]Cusarcophagine-tetrazine yielded the best images, identifying Trop-2–positive tumors with optimal tumor-to-background ratios. Intriguingly, we found that the full-length antibody, when directly conjugated, yielded rapid accumulation, starting at 3 hours after injection, and led to more than 50% injected activity per gram in the tumor before 24 hours. Conclusions: [⁸⁹Zr]Zr-deferoxamine-Trop-2 and pretargeting with [⁶⁴Cu]Cu-sarcophagine-tetrazine are viable imaging strategies to quickly identify Trop-2–positive tumors for subsequent Trop-2 therapies.