Targeting the TRA-1-60 Glycoepitope Enables Selective ImmunoPET Imaging of Ovarian Cancer

<jats:p>Targeted radiopharmaceutical development for ovarian cancer (OC) has been limited by the lack of molecular targets that combine broad tumor expression with minimal normal-tissue distribution. TRA-1-60 (TRA) is a cancer-associated glycoepitope carried by podocalyxin. Here, we evaluated TRA as a target for OC and developed a TRA-directed immunoPET imaging platform. Immunohistochemical analysis demonstrated significantly higher TRA expression in ovarian tumors than in normal adjacent ovarian tissue, with expression maintained across epithelial OC histotypes and disease stages. An engineered anti-TRA single-chain variable fragment-Fc (scFv- Fc) demonstrated robust penetration of three-dimensional tumor spheroids and selective accumulation in intraperitoneal tumors in an immunocompetent syngeneic OC model. Radiolabeling with zirconium-89 generated [89Zr]Zr-DFO-anti-TRA scFv-Fc with &gt;98% radiochemical yield. Serial PET/CT imaging demonstrated progressive and sustained radiotracer accumulation at tumor sites through 96 hours, accompanied by declining liver-associated activity and low uptake in most normal tissues. Together, these findings identify TRA as a broadly expressed and accessible tumor-associated glycoepitope and establish TRA-targeted immunoPET as a promising strategy for noninvasive detection of OC. The selective and sustained tumor localization of this platform further provides a foundation for development of TRA-directed radiopharmaceutical therapy, supporting a potential theranostic approach for OC.</jats:p>