177Lu-Labeled Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 Monoclonal Antibody-Targeted Therapy for Clear Cell Renal Cell Carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) remains a therapeutic challenge. Ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) is highly expressed in ccRCC tissues and cell lines, representing a promising target. This study aimed to conjugate lutetium-177 (177Lu) to an anti-human ENPP3 monoclonal antibody using tetra-azacyclododecanetetra-acetic acid (DOTA), creating the radioimmunoconjugate [177Lu]Lu-DOTA-ENPP3, and to evaluate its therapeutic effect in ccRCC. The characteristics and effects of [177Lu]Lu-DOTA-ENPP3 were evaluated using in vitro and vivo experiments. [177Lu]Lu-DOTA-ENPP3 exhibited high radiolabeling efficiency and affinity and good stability, specificity, binding, and internalization efficiency. It specifically accumulated at tumor sites. A 12 MBq dose significantly inhibited tumor growth and cell proliferation, without causing significant weight loss or damage to major organs. Therefore, [177Lu]Lu-DOTA-ENPP3 demonstrated good tumor specificity, significant antitumor activity, and favorable safety in treating ccRCC. Dosimetric analyses further quantified radiation exposure to tumors and major normal tissues and provided preliminary human dosimetry estimates. The study’s findings could help treat ccRCC.