A Prostate-Specific Membrane Antigen-Targeted Monoclonal Antibody–Chemotherapeutic Conjugate Designed for the Treatment of Prostate Cancer

Abstract

MLN2704 is an antibody-chemotherapeutic conjugate designed to tar- get prostate-specific membrane antigen (PSMA). PSMA is a transmem- brane receptor whose expression is largely restricted to prostatic epithe- lium and prostate cancer cells with its expression level increasing during the progression of malignancy. MLN2704 consists of a de-immunized, monoclonal antibody that is specific for PSMA conjugated to drug may- tansinoid 1 (DM1), a microtubule-depolymerizing compound. After anti- body binding to PSMA and the subsequent cellular internalization of this complex, DM1 is released leading to cell death. MLN2704 has an approx- imate half-life of 39 hours in scid mice bearing CWR22 tumor tissue, and the antibody effectively penetrates xenograft tumor tissue. Optimization of dosage and schedule of MLN2704 administration defined interdepen- dency between these conditions that maximized efficacy with no apparent toxicity. Tumor growth delays of 100 days could be achieved on the optimized schedule of one dose of 60 mg/kg MLN2704 every 14 days for five doses (q14d5). The unconjugated antibody (MLN591) demonstrated essentially no antitumor activity and DM1 alone or a non-PSMA targeted antibody-DM1 conjugate was only weakly active. Furthermore, we show that MLN2704 is active in a novel model of osteoblastic prostate cancer metastasis.