Preclinical evaluation of the antibody fragment targeting fibronectin EDB in the theranostics of radioactive iodine-resistant thyroid cancer.

OBJECTIVE

Radioactive iodine-resistant thyroid cancer (RAIR-TC) poses diagnostic and therapeutic challenges due to the absence of sodium/iodide symporter (NIS) expression. This study aims to evaluate the preclinical value of 89Zr-DFO-EDB and 177Lu-DTPA-EDB, an antibody fragment targeting fibronectin EDB (FN-EDB), in the theranostics of RAIR-TC.

METHODS

A CAL-62 human iodine-resistant thyroid cancer xenograft mouse model was established. The EDB antibody fragment (approximately 100 kD), selected through phage display technology, was labeled with 89Zr and 177Lu, respectively. The targeting characteristics of 89Zr-DFO-EDB and 177Lu-DTPA-EDB in the CAL-62 and NIS-silenced models were analyzed using dynamic micro-PET/CT imaging and ex vivo biodistribution. The anti-tumor efficacy and safety were assessed by a single treatment with 100 μCi of 177Lu-DTPA-EDB.

RESULTS

The labeling efficiency of 89Zr-DFO-EDB was 90.9%, with a radiochemical purity (RCP) of >99% and stability >98% at 180 min. Imaging showed that tumor uptake peaked at 72 h (13.8 ± 3.32%ID/g) and the liver was the main metabolic organ. High tumor uptake (16.1 ± 1.85%ID/g) was observed in the NIS-silenced model, confirming that EDB antibody targeting is independent of NIS status. The labeling efficiency of 177Lu-DTPA-EDB was 87.7%, with an RCP of >98.6% and stability >95% at 48 h. In the treatment group, tumor volume decreased by 78.5%, with a relative proliferation rate T/C of 25.05% (<40%). Pathological examination revealed necrosis areas >65%, with only transient weight loss (5.2%) and mild hepatocyte degeneration observed.

CONCLUSION

89Zr-DFO-EDB and 177Lu-DTPA-EDB achieved precise theranostics of RAIR-TC by targeting EDB-FN, with excellent imaging contrast and significant therapeutic effects, providing an innovative strategy for clinical translation in NIS-negative thyroid cancer.