Laura Lucaroni; Sebastian Oehler; Tony Georgiev; Marco Müller; Matilde Bocci; Roberto De Luca; Nicholas Favalli; Dario Neri; Samuele Cazzamalli; Luca Prati
Chem. Sci., 2024
https://doi.org/10.1039/D3SC06668A

Abstract

Prostate-Specific Membrane Antigen (PSMA) is a tumor-associated protein which has been successfully targeted with small organic ligands and with monoclonal antibodies. PluvictoTM is a PSMA-targeted Radio Ligand Therapeutic (RLT) recently approved by FDA for the treatment of metastatic castration-resistant prostate cancer (2022 FDA marketing authorization). Although a large Phase III clinical trial (VISION trial) demonstrated a clinical benefit in patients treated with PluvictoTM, the therapeutic window of the drug is narrowed by its undesired accumulation in healthy organs. Glutamate Carboxy Peptidase III (GCPIII), an enzyme sharing 70% identity with PSMA, may be responsible for the off-target accumulation of PSMA-RLTs in salivary glands and kidney. In this work, we designed and synthesized Affinity and Selectivity Maturation DNA-Encoded chemical Libraries (ASM-DELs) comprising 18’284’658 compounds, that were screened in parallel against PSMA and GCPIII with the aim to identify potent and selective PSMA ligands for tumor-targeting applications. Compound A70-B104 was isolated as the most potent and selective ligand (KD of 900 pM for PSMA, KD of 40 nM for GCPIII). 177Lu-A70-B104-DOTA, a radiolabeled derivative of compound A70-B104, presented a selective accumulation in PSMA-positive cancer lesions (i.e., 7.4% ID/g, 2 hours time point) after systemic administration in tumor-bearing mice. Results of autoradiography experiments showed that 177Lu-A70-B104-DOTA selectively binds to PSMA-positive cancer tissues, while negligible binding on human salivary glands was observed.