《antibody-chemoCR》.pdf

[CANCER RESEARCH 64, 7995–8001, November 1, 2004] A Prostate-Specific Membrane Antigen-Targeted Monoclonal Antibody–Chemotherapeutic Conjugate Designed for the Treatment of Prostate Cancer Michael D. Henry,1 Shenghua Wen,1 Matthew D. Silva,2 Sudeep Chandra,2 Mark Milton,3 and Peter J. Worland1 Departments of 1Cancer Pharmacology, 2Imaging Sciences and 3Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts ABSTRACT Our approach to targeting PSMA uses the deimmunized anti- PSMA, monoclonal antibody MLN591. MLN591 is derived from the MLN2704 is an antibody-chemotherapeutic conjugate designed to tar- murine anti-human PSMA monoclonal antibody J591, specific for the get prostate-specific membrane antigen (PSMA). PSMA is a transmem- extracellular domain of PSMA (6). The antibody variable domains of brane receptor whose expression is largely restricted to prostatic epithe- J591 were first deimmunized by site-directed mutagenesis of putative lium and prostate cancer cells with its expression level increasing during the progression of malignancy. MLN2704 consists of a de-immunized, T-cell reactive epitopes and were then fused to a human IgG1 back- monoclonal antibody that is specific for PSMA conjugated to drug may- bone to further reduce the immunogenic potential of this antibody in tansinoid 1 (DM1), a microtubule-depolymerizing compound. After anti- humans (9). MLN2704 (Fig. 1) was constructed by the conjugation of body binding to PSMA and the subsequent cellular inter