Targeting CD133 In Androgen Receptor Indifferent, Neuroendocrine Differentiated Aggressive Variant Prostate Cancer

Abstract

An increasing number of men are developing a lethal, non-androgen receptor (AR) driven form of prostate cancer (PCa) known as aggressive variant prostate cancer (AVPC). Therapeutic options for AVPC are limited, and the development of novel therapeutics is significantly hindered by the inability to accurately monitor the disease through imaging. This underscores the critical need to develop improved imaging agents for AVPC. Targeted imaging agents, such as those developed for prostate-specific membrane antigen (PSMA) have made significant progress in imaging metastatic prostate adenocarcinoma; however, numerous studies have shown that non-AR driven prostate cancer does not express PSMA. Thus, there is an urgent unmet need to identify novel antigens and targeted imaging agents for the detection and monitoring of this lethal form of PCa. In these studies, we have identified the pentaspan transmembrane glycoprotein, CD133, as a targetable antigen that is overexpressed on the surface of non-AR driven, neuroendocrine-differentiated prostate cancer. Additionally, we have developed a novel antibody, termed HA10 IgG, which was found to bind to a glycosylation-independent epitope on CD133. HA10 IgG was validated in numerous cell lines and demonstrated similar or more accurate binding to CD133 when compared to a frequently used commercial antibody in vitro. To assess the imaging potential of HA10 IgG, the antibody was labeled for near-infrared and positron emission tomography imaging. Our CD133 probe was validated in imaging studies and shown to be highly selective for CD133-expressing PCa cells, suggesting its potential as a non-invasive imaging agent for lethal, non-AR-driven AVPC.