Cancer Biology, Cleveland Clinic, Cleveland, OH.
Prostate-specific membrane antigen (PSMA) is a membrane protein that is over-expressed 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 in vitro and in a novel in vivo model of taxane-refractory human prostate cancer. In vitro cell killing was efficient for cells with abundant PSMA expression (>10(5) molecules/cell; IC(50)≤ 0.022 nM) and 1,000-fold less efficient for cells with undetectable PSMA (IC(50)>30 nM). Intermediate potency (IC(50)=0.80 nM) was observed for cells with ~10(4) molecules of PSMA per cell, indicating a threshold PSMA level for selective cell killing. Similar in vitro activity was observed against androgen-dependent and independent cells that had abundant PSMA expression. In vitro activity of PSMA ADC was also dependent on internalization and proper N-glycosylation/folding of PSMA. In contrast, less potent and non-selective cytotoxic activity was observed for a control ADC, free monomethylauristatin E and other microtubule inhibitors. PSMA ADC demonstrated high in vivo activity in treating xenograft tumors that had progressed following an initial course of docetaxel therapy, including tumors that were large (>700 mm(3)) prior to treatment with PSMA ADC. This study defines determinants of antitumor activity of a novel antibody-drug conjugate. The findings here support the clinical evaluation of this agent in advanced prostate cancer.
Wang X, Ma D, Olson WC, Heston WD. Are you the author?
Reference: Mol Cancer Ther. 2011 Jul 12. Epub ahead of print.