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

Abstract

Imaging procedures based on small molecule-radio conjugates (SMRCs) targeting fibroblast activation protein (FAP) have recently emerged as a powerful tool for the diagnosis of a wide variety of tumours. 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 extended tumour residence time and favorable tumour-to-organ ratio. <b>Methods:</b> The binding properties of BiOncoFAP and its monovalent OncoFAP analogue were assayed against recombinant hFAP. Preclinical experiments with [¹⁷⁷Lu]Lu-OncoFAP-DOTAGA (¹⁷⁷Lu-OncoFAP) and [¹⁷⁷Lu]Lu-BiOncoFAP-DOTAGA (¹⁷⁷Lu-BiOncoFAP) were performed in mice bearing FAP-positive HT-1080 tumours. <b>Results:</b> OncoFAP and BiOncoFAP displayed comparable sub-nanomolar dissociation constants towards hFAP in solution, but the bivalent BiOncoFAP bound more avidly to the target immobilized on solid supports. In a comparative biodistribution study, ¹⁷⁷Lu-BiOncoFAP exhibited a more stable and prolonged tumour uptake than ¹⁷⁷Lu-OncoFAP (~20% ID/g vs ~4% ID/g, at 24h p.i., respectively). Notably, ¹⁷⁷Lu-BiOncoFAP showed favorable tumour-to-organ ratios with low kidney uptake. Both ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-BiOncoFAP displayed potent anti-tumour efficacy when administered at therapeutic doses in tumour bearing mice. <b>Conclusion:</b>¹⁷⁷Lu-BiOncoFAP is a promising candidate for radioligand therapy of cancer, with favorable in vivo tumour-to-organ ratio, long tumour residence time and potent anti-cancer efficacy.