A Dimeric FAP-Targeting Small-Molecule Radioconjugate with High and Prolonged Tumor Uptake.

Imaging procedures based on small-molecule radioconjugates targeting fibroblast activation protein (FAP) have recently emerged as a powerful tool for the diagnosis of a wide variety of tumors. However, the therapeutic potential of radiolabeled FAP-targeting agents is limited by their short residence time in neoplastic lesions. In this work, we present the development and in vivo characterization of BiOncoFAP, a new dimeric FAP-binding motif with an extended tumor residence time and favorable tumor-to-organ ratio. The binding properties of BiOncoFAP and its monovalent OncoFAP analog were assayed against recombinant human FAP. Preclinical experiments with Lu-OncoFAP-DOTAGA (Lu-OncoFAP) and Lu-BiOncoFAP-DOTAGA (Lu-BiOncoFAP) were performed on mice bearing FAP-positive HT-1080 tumors. OncoFAP and BiOncoFAP displayed comparable subnanomolar dissociation constants toward recombinant human FAP in solution, but the bivalent BiOncoFAP bound more avidly to the target immobilized on solid supports. In a comparative biodistribution study, Lu-BiOncoFAP exhibited a more stable and prolonged tumor uptake than Lu-OncoFAP (∼20 vs. ∼4 percentage injected dose/g, respectively, at 24 h after injection). Notably, Lu-BiOncoFAP showed favorable tumor-to-organ ratios with low kidney uptake. Both Lu-OncoFAP and Lu-BiOncoFAP displayed potent antitumor efficacy when administered at therapeutic doses to tumor-bearing mice. Lu-BiOncoFAP is a promising candidate for radioligand therapy of cancer, with favorable in vivo tumor-to-organ ratios, a long tumor residence time, and potent anticancer efficacy.