Abstract

<div>AbstractPurpose:<p>Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.</p>Experimental Design:<p>PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity <i>in vitro</i>. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated <i>in vivo</i> using cell line and patient-derived xenograft (PDX) models of prostate cancer.</p>Results:<p>PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis <i>in vitro</i>. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. <i>In vivo,</i> PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both <i>in vitro</i> and <i>in vivo</i>.</p>Conclusions:<p>The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).</p></div>

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