Abstract
<div>Abstract<p>Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for therapy. PSMA ADC is an antibody-drug conjugate (ADC) that consists of a fully human anti-PSMA monoclonal antibody conjugated to monomethylauristatin E through a valine-citrulline linker. In this study, the antitumor activity of PSMA ADC was evaluated against a panel of prostate cancer cell lines <i>in vitro</i> and in a novel <i>in vivo</i> model of taxane-refractory human prostate cancer. <i>In vitro</i> cell killing was efficient for cells with abundant PSMA expression (>10<sup>5</sup> molecules/cell; IC<sub>50</sub> ≤ 0.022 nmol/L) and 1,000-fold less efficient for cells with undetectable PSMA (IC<sub>50</sub> > 30 nmol/L). Intermediate potency (IC<sub>50</sub> = 0.80 nmol/L) was observed for cells with approximately 10<sup>4</sup> molecules of PSMA per cell, indicating a threshold PSMA level for selective cell killing. Similar <i>in vitro</i> activity was observed against androgen-dependent and -independent cells that had abundant PSMA expression. <i>In vitro</i> activity of PSMA ADC was also dependent on internalization and proper <i>N</i>-glycosylation/folding of PSMA. In contrast, less potent and nonselective cytotoxic activity was observed for a control ADC, free monomethylauristatin E, and other microtubule inhibitors. PSMA ADC showed high <i>in vivo</i> activity in treating xenograft tumors that had progressed following an initial course of docetaxel therapy, including tumors that were large (>700 mm<sup>3</sup>) before treatment with PSMA ADC. This study defines determinants of antitumor activity of a novel ADC. The findings here support the clinical evaluation of this agent in advanced prostate cancer. <i>Mol Cancer Ther; 10(9); 1728–39. ©2011 AACR</i>.</p></div>
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