Non-competing Trop2 nanobody-based radiotheranostics for precision imaging and therapy of pancreatic cancer

Pancreatic cancer remains one of the most lethal malignancies, marked by late-stage detection, resistance to conventional therapies, and dismal overall survival. The transmembrane glycoprotein trophoblast cell-surface antigen 2 (Trop2) is frequently upregulated in pancreatic tumors and drives aggressive phenotypes, positioning it as a compelling target for precision oncology interventions. Here, we reported the development of a novel Trop2-specific nanobody-based theranostic pair, [⁶⁸Ga]Ga-T142 and [¹⁷⁷Lu]Lu-T142, capable of both non-invasive molecular imaging and targeted radionuclide therapy. The nanobody T142 was conjugated site-specifically with NODAGA or DOTA chelators, preserving its high Trop2-binding affinity alongside exceptional radiochemical purity and stability. In Trop2-positive pancreatic cancer xenograft models, [⁶⁸Ga]Ga-T142 demonstrated rapid and high-contrast tumor accumulation, minimal off-target uptake, and pharmacokinetic profiles characteristic of nanobody tracers. Epitope mapping revealed that T142 recognized a region distinct from that targeted by the clinically approved ADC Trodelvy, allowing accurate, interference-free quantification of Trop2 expression during ADC therapy. Longitudinal PET imaging detected early Trop2 downregulation post-ADC treatment, preceding observable tumor shrinkage, and showed superior performance to [¹⁸F]FDG in monitoring therapeutic response. On the therapeutic front, [¹⁷⁷Lu]Lu-T142 elicited marked tumor regression in Trop2-positive models, while its combination with Trodelvy produced synergistic antitumor effects without significant systemic toxicity. Collectively, these results highlighted [⁶⁸Ga]Ga-T142 and [¹⁷⁷Lu]Lu-T142 as a highly promising Trop2-targeted theranostic platform, with strong potential for precise diagnosis, therapy monitoring, and personalized treatment of Trop2-expressing pancreatic cancer.