Preclinical Development of 3BP-3940, a Fibroblast Activation Protein-Targeted Cyclic Peptide-Based Radiotheranostic for Imaging and Therapy.

Abstract

Fibroblast activation protein (FAP) is highly expressed in the tumor microenvironment of many cancer types. Since the discovery of the FAP inhibitor series, which provided high-contrast images in patients, many radiolabeled FAP-targeting agents have been developed, with the cyclic peptide FAP-2286 currently being the most advanced theranostic compound in clinical development. Here, we introduce a novel peptide, 3BP-3940, which has been used to treat patients with cancer on a named-patient basis. <b>Methods:</b> The potency and selectivity of 3BP-3940 were evaluated in biochemical assays. Its biodistribution was assessed in mice and minipigs, and therapeutic efficacy was demonstrated in the HEK-FAP mouse model. <b>Results:</b> 3BP-3940 exhibited high affinity and specificity for FAP, with persistent uptake in HEK-FAP xenograft tumors, leading to strong tumor growth inhibition when radiolabeled with ¹⁷⁷Lu. 3BP-3940 showed minimal uptake in normal tissues of mice and minipigs. <b>Conclusion:</b> These findings support the clinical use of 3BP-3940 as a promising FAP-targeting agent for both imaging and radiopharmaceutical therapy in patients with cancer.