Abstract LB522: Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors

Abstract

Small Molecule-Drug Conjugates (SMDCs) are modular anti-cancer pro-drugs that include a tumor-targeting small ligand, a cleavable linker and a potent cytotoxic agent. SMDC products that have been developed for clinical applications are targeting internalizing tumor-associated antigens expressed on the surface of tumor cells. We have recently developed a novel non-internalizing small organic ligand (named OncoFAP) of Fibroblast Activation Protein (FAP), a tumor-associated antigen highly expressed in the stroma of most of solid human malignancies. The tumor targeting performance of OncoFAP has been validated by nuclear medicine studies in patients with various solid tumors. In a previous study, we showed that OncoFAP can be used to produce non-internalizing SMDCs that are effective and well tolerated. Here, we describe a new series of OncoFAP-Drug derivatives based on the MMAE tubulin poison and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. We benchmarked the new SMDCs against OncoFAP-MMAE conjugates displaying linker modules which are widely used in approved and clinical stage Antibody-Drug Conjugates, including structures cleaved by Cathepsin B and by reducing agents. We selected OncoFAP-GlyPro-MMAE as the most efficacious and safe SMDC for further clinical development after quantitatively analyzing the biodistribution of MMAE released by OncoFAP-MMAE conjugates. OncoFAP-GlyPro-MMAE selectively delivers high amounts of MMAE at the site of disease, with a tumor-to-kidney ratio of 7-to-1 and of 16-to-1 at 6- and 24-hours post-injection, respectively. Our molecules based on the OncoFAP tumor-targeting ligand and FAP-cleavable linkers promise to be safe and effective against most of human malignancies. Citation Format: Aureliano Zana, Andrea Galbiati, Ettore Gilardoni, Jacopo Millul, Theo Sturm, Riccardo Stucchi, Matilde Bocci, Abdullah Elsayed, Lisa Nadal, Martina Cirillo, Dario Neri, Samuele Cazzamalli. Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB522.

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