Preclinical Development and Comparison of [ 99m Tc]Tc/[ 177 Lu]Lu-Labeled Anti-Trop2 Fc-Fused Nanobodies as Pancreatic Cancer Theranostics

作者：Feng Yuan, Wenzhu Hu, Xingyi Wang, Yan Wang, Zaijie Wu, Biao Yang, Yonglu Chen, Teng Li, Dawei Jiang, Yaxin Shi, Xiaoli Lan, Yongkang Gai · 发表于：Molecular Pharmaceutics · 年份：2025 · DOI：10.1021/acs.molpharmaceut.5c01039 · 被引用次数：1 · 研究领域：Radiopharmaceutical Chemistry and Applications、Monoclonal and Polyclonal Antibodies Research、Peptidase Inhibition and Analysis

Antibody-based radiotheranostics hold significant promise for tumor diagnosis and treatment; however, the clinical translation of radiotherapeutic agents is significantly hindered by suboptimal pharmacokinetics, particularly undesirable retention in healthy tissues. In this study, we developed novel high-affinity anti-Trop2 nanobodies using phage display technology and then generated two VHH-Fc constructs, B9 and C10, which are recombinant single-chain antibodies fused with IgG1-Fc. These were radiolabeled with [ 99m Tc]Tc and [ 177 Lu]Lu. A systematic comparison was then conducted against the clinically relevant monoclonal antibody hRS7 (sacituzumab). The [ 99m Tc]Tc-labeled-B9 exhibited high Trop2-binding affinity, rapid tumor accumulation, and substantially decreased hepatic and renal uptake in BxPC-3 xenograft models compared with [ 99m Tc]Tc-hRS7. Comprehensive SPECT/CT imaging and quantitative biodistribution studies further corroborated its prolonged intratumoral retention. When radiolabeled with [ 177 Lu]Lu, [ 177 Lu]Lu-B9 maintained robust tumor uptake while demonstrating faster clearance from nontarget tissues than the monoclonal antibody (hRS7). Quantitative analysis over 168 h postinjection revealed a 56.17% reduction in hepatic uptake and a 23.68% decrease in renal uptake compared to [ 177 Lu]Lu-hRS7. In a preclinical mouse model, two-cycle administration of [ 177 Lu]Lu-B9 induced significant tumor growth inhibition, prolonged survival, and minimal systemic toxic...