Selective tumor targeting enabled by picomolar fibroblast activation protein inhibitors isolated from a DNA-encoded affinity maturation library

The availability of ultra-high-affinity small organic ligands, which are specific to accessible cancer antigens, is crucially important to enable efficient and selective tumor targeting applications. In this article, we describe the isolation of highly potent inhibitors of fibroblast activation protein (FAP), an enzyme that is abundantly and selectively expressed in the stroma of most of aggressive human solid malignancies. Affinity-maturation DNA-encoded chemical libraries, based on three series of 50,730 propargylglycine derivatives, enabled the identification of picomolar FAP inhibitors. A 177Lu-DOTAGA conjugate of the most potent novel ligand (named “OncoFAP-11”) localized to tumors implanted in mice, with tumor-to-blood ratios of ∼220:1 17 h after intravenous administration. A dimeric derivative (named “BiOncoFAP-11”) further enhanced tumor residence time with a low uptake in healthy organs.