Preclinical Evaluation of 5T4-Targeted [ 89 Zr]Zr-DFO-HB5 Immuno-PET Imaging and Comparison of 161 Tb vs 177 Lu 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.