Abstract
Epithelial cell adhesion molecule (EpCAM) is overexpressed in 55%–75% of ovarian carcinomas (OC). EpCAM might be used as a target for a treatment of disseminated OC. Designed ankyrin repeats protein (DARPin) Ec1 is a small (18 kDa) protein, which binds to EpCAM with subnanomolar affinity. We tested a hypothesis that Ec1 labeled with a non-residualizing label might serve as a companion imaging diagnostic for stratification of patients for EpCAM-targeting therapy. Ec1 was labeled with 125I using N-succinimidyl-para-iodobenzoate. Binding affinity, specificity, and cellular processing of [125I]I-PIB-Ec1 were evaluated using SKOV-3 and OVCAR-3 ovarian carcinoma cell lines. Biodistribution and tumor-targeting properties of [125I]I-PIB-Ec1 were studied in Balb/c nu/nu mice bearing SKOV-3 and OVCAR-3 xenografts. EpCAM-negative Ramos lymphoma xenografts served as specificity control. Binding of [125I]I-PIB-Ec1 to ovarian carcinoma cell lines was highly specific and had affinity in picomolar range. Slow internalization of [125I]I-PIB-Ec1 by OC cells confirmed utility of non-residualizing label for in vivo imaging. [125I]I-PIB-Ec1 provided 6 h after injection tumor-to-blood ratios of 30 ± 11 and 48 ± 12 for OVCAR-3 and SKOV-3 xenografts, respectively, and high contrast to other organs. Tumor targeting was highly specific. Saturation of tumor uptake at a high dose of Ec1 in SKOV-3 model provided a rationale for dose selection in further studies using therapeutic conjugates of Ec1 for targeted therapy. In conclusion, [125I]I-PIB-Ec1 is a promising agent for visualizing EpCAM expression in OC.
Highlights
Efficient diagnosis and treatment of disseminated ovarian cancer (OC) remains an unmet clinical need
Up to 85% of OC patients are diagnosed at advanced stages, when cancer has spread to the abdomen or outside the abdomen and to liver [1]
It was found that the epithelial cell adhesion molecule (EpCAM) overexpression level is higher in metastatic and recurrent ovarian tumors compared to primary lesions [5]
Summary
Efficient diagnosis and treatment of disseminated ovarian cancer (OC) remains an unmet clinical need. A potential molecular target for OC is epithelial cell adhesion molecule (EpCAM). It is considered a pancarcinoma antigen due to its overexpression in many carcinomas [2,3]. It was found that the EpCAM overexpression level is higher in metastatic and recurrent ovarian tumors compared to primary lesions [5]. These studies suggest that EpCAM might be a potential biomarker for evaluating the progression of OC and represent a promising molecular therapeutic target
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