Pretargeted Trop-2 immunoPET for rapid, selective detection of pancreatic tumors.

Purpose: Recent clinical advances with the approval of antibody-drug conjugates targeting Trop-2 such as sacituzumab-govitecan and datopotomab-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 ADC 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 pretargeting with [64Cu]Cu-Sar-Tz to yield the best images identifying Trop-2 positive tumors with optimal tumor-to-background ratios. Intriguingly we found the full-length antibody when directly conjugated, yielded rapid accumulation starting at 3 hours post injection and leading to over 50% injected activity per gram in the tumor before 24 hours.

Conclusions: [89Zr]Zr-DFO-Trop-2 as well as pretargeting with [64Cu]Cu-Sar-Tz are viable imaging strategies to quickly identify Trop-2 positive tumors for subsequent Trop-2 therapies.