Prostate cancer is the most common cancer of men in the United States with an expected 234,460 new cases and 27,350 deaths in 2006. Recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas become hormone refractory and then rapidly progress. Hormone- refractory prostate cancer (HRPC) is notably chemoresistant. The only approved chemotherapy (docetaxel in combination with prednisone) provides a modest survival benefit; therefore, novel, targeted therapeutic strategies are urgently needed. Antibody-drug conjugates (ADCs) combine the molecular targeting of a monoclonal antibody (mAb) with the chemotherapeutic properties of a potent cytotoxic drug and hold great promise as targeted cancer therapies. Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer. PSMA is an integral, non-shed membrane protein that is expressed abundantly in nearly all prostatic carcinomas. PSMA expression increases with disease progression and is highest in HRPC. In addition, PSMA internalizes rapidly upon mAb binding, thus facilitating the introduction of chemotherapeutic drugs into the cytosol. Given its limited expression in normal tissues, PSMA represents a compelling target for ADC therapy of prostate cancer. In the Phase I project, we demonstrated compelling preclinical proof-of-concept for a novel ADC comprising a high-affinity, fully human PSMA mAb linked to a potent auristatin drug via a conditionally labile dipeptide linker, an emerging technology being developed in collaboration with Seattle Genetics, Inc. PSMA ADC eliminated PSMA-expressing prostate cancer cells with picomolar potency and nearly 1000-fold selectivity in vitro via antimitotic mechanisms. In a stringent xenograft model of HRPC, well-tolerated doses of PSMA ADC controlled established human tumors resulting in a 9-fold improvement in median survival and complete remission in some animals. The potent and selective antitumor activity of PSMA ADC in vitro and in vivo provides strong rationale for accelerated development of this promising approach in the Phase II project. In the Phase II project, we seek to complete definitive preclinical safety and pharmacology studies to support human testing of this new agent. We first will develop and scale-up procedures for manufacturing and testing a toxicology lot of PSMA ADC. In a second aim, we will perform IND-enabling toxicology studies in a relevant non-human primate species. In parallel, we will perform confirmatory xenograft efficacy studies of the product manufactured using the scaled-up process. Success in the Phase II project is defined as demonstrating favorable preclinical safety and activity profiles to support human testing of a promising molecularly targeted therapy for HRPC. Prostate cancer is the most common cancer of men in the United States and represents the second leading cause of cancer death. Localized prostate cancer typically is treated with surgery and/or radiation, and recurrent disease can be controlled temporarily with androgen ablation. However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress. Hormone-refractory prostate cancer (HRPC) has proven to be largely resistant to conventional chemotherapy. With the exception of palliative care, the only approved chemotherapy for HRPC is docetaxel in combination with prednisone, and this treatment provides a modest (2.4 month) increase in survival. Therefore, there is an urgent need for new, molecularly-targeted therapies for all stages of disease, but most critically for hormone-refractory and metastatic tumors. ? ? ?
