Preclinical Evaluation of 5T4-Targeted [⁸⁹Zr]Zr-DFO-HB5 Immuno-PET Imaging and Comparison of ¹⁶¹Tb vs ¹⁷⁷Lu Radionuclide Therapy for Colorectal Cancer

The oncofetal antigen 5T4 is highly expressed in colorectal cancer (CRC), making it a promising theranostic target. In this study, we developed the diagnostic tracer [89Zr]Zr-DFO-HB5 (5T4 monoclonal antibody) and therapeutic agents [177Lu]Lu/[161Tb]Tb-DOTA-HB5, establishing a novel theranostic strategy for CRC. We selected two 5T4-positive colorectal cancer cell lines and established subcutaneous xenograft models. Immuno-PET imaging revealed specific tumor targeting of [89Zr]Zr-DFO-HB5 in 5T4-positive CRC mouse models. Ex vivo biodistribution studies showed high and sustained tumor uptake of [177Lu]Lu/[161Tb]Tb-DOTA-HB5, with gradually decreasing radioactivity accumulation in normal organs over time. Targeted radionuclide therapy (TRT) further confirmed that [177Lu]Lu/[161 Tb]Tb-DOTA-HB5 significantly inhibited tumor growth in both models. Biosafety evaluation revealed only mild hematological toxicity, without obvious short-term organ damage. In conclusion, [89Zr]Zr-DFO-HB5 enables noninvasive detection of 5T4 expression, while [177Lu]Lu/[161Tb]Tb-DOTA-HB5 exhibits potent antitumor efficacy and favorable biosafety. The study provides a potential theranostic platform for 5T4-positive CRC and related malignancies.