Sara Puglioli; Eleonore Schmidt; Christian Pellegrino; Luca Prati; Sebastian Oehler; Roberto De Luca; Andrea Galbiati; Claudia Comacchio; Lisa Nadal; Jörg Scheuermann; Markus G. Manz; Dario Neri; Samuele Cazzamalli; Gabriele Bassi; Nicholas Favalli Chem, 2023, 9, 411-429 https://doi.org/10.1016/j.chempr.2022.10.006
Abstract
The Bigger Picture The discovery of tumor-targeting ligands with exquisite accumulation at the site of disease represents an innovative avenue for the delivery of bioactive payloads which include radionuclides, drugs, and immunomodulators. This approach promises to overcome limitations associated with cancer therapy based on the use of external beam radiation and untargeted cytotoxic drugs. Fibroblast activation protein (FAP) is an antigen that is abundantly expressed on the surface of activated fibroblasts in the stroma of most of solid malignancies. Through DNA-encoded chemical library technology, we have isolated OncoFAP-11, a novel and highly potent ligand which overcomes the limitations of previously described FAP binders. The ligand presented in this article shows high accumulation and prolonged residence time in tumors. A bivalent version of the molecule further improves tumor uptake and represents a promising clinical candidate for radioligand therapy and other targeted therapeutic modalities. Summary 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.