Anti‐tumor effects of toxins targeted to the prostate specific membrane antigen

Abstract

BACKGROUND There is presently no effective therapy for relapsing, metastatic, androgen‐independent prostate cancer. Immunotherapy with monoclonal antibody–vehicled toxins (Immunotoxins, ITs) may be a promising novel treatment option for the management of prostate cancer in these cases. METHODS Three anti–prostate specific membrane antigen (anti‐PSMA) monoclonals (J591, PEQ226.5, and PM2P079.1) were cross‐linked to ricin A‐chain (RTA; native or recombinant), and their cytotoxic effects were investigated in monolayer and three‐dimensional (3‐D) cell cultures of prostate carcinoma cells (LNCaP). RESULTS The various Immunotoxins showed effects in the nanomolar range (IC_50s of 1.6–99 ng/ml) against PSMA+ cells (IC₅₀ being the concentration inhibiting 50% cell proliferation or protein synthesis). PSMA⁻ cell lines were 62‐ to 277‐fold less sensitive to anti‐PSMA ITs, evidencing an appreciable therapeutic window. Treatment with J591‐smpt‐nRTA (0.35–31.7ng/ml) resulted in complete eradication of 3‐D tumor micromasses or in 1.46‐ to 0.35‐log reduction of target cells number, depending on the dose. CONCLUSION Anti‐PSMA ITs appear to be promising for use in the eradication of small prostate tumor cell aggregates present in tissues and in the bone marrow. Prostate 53: 9–23, 2002.