Abstract
Cadherin 17 (CDH17) is highly expressed in digestive system cancers, and the potential of nanobodies targeting CDH17 as imaging probes and delivery vehicles for radioactive β-particles warrants exploration for their theranostic potential in CDH17-overexpressing gastric cancer (GC). In this study, we screened an anti-CDH17 nanobody library and constructed two antibodies: anti-CDH17 VHH (recombinant nanobody fused with a polyhistidine tag) and anti-CDH17 VHH-ABD (recombinant nanobody fused with an albumin-binding domain). VHH targeting CDH17 and its derivative VHH-ABD were conjugated with DOTA and labeled with radionuclide (177)Lu. The pharmacokinetics and theranostic efficacy of these agents were evaluated in the GC xenograft models. [(177)Lu]Lu-VHH and [(177)Lu]Lu-VHH-ABD exhibited high radiochemical purity (>99%, n = 3) and successfully delineated CDH17-positive gastric cancer tissues on SPECT/CT imaging. Compared with the rapid renal clearance of [(177)Lu]Lu-VHH, [(177)Lu]Lu-VHH-ABD demonstrated prolonged circulation times with increased and sustained tumor accumulation. Survival experiments in the MKN-45 tumor model revealed that two doses of [(177)Lu]Lu-VHH-ABD effectively suppressed tumor growth, with limited systemic biotoxicity. Histological analysis using hematoxylin and eosin (H&E) staining and Ki67 immunohistochemistry confirmed structural disruption and low tumor cell proliferative activity in the tumor tissue. In preclinical studies, [(177)Lu]Lu-anti-CDH17 VHH-ABD demonstrated substantial antitumor efficacy with manageable toxicity, offering promising clinical potential as a viable therapeutic option for CDH17-overexpressing GC.