Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cell-specific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.
Science translational medicine. 2016 Nov 30 [Epub]
Daniel L J Thorek, Philip A Watson, Sang-Gyu Lee, Anson T Ku, Stylianos Bournazos, Katharina Braun, Kwanghee Kim, Kjell Sjöström, Michael G Doran, Urpo Lamminmäki, Elmer Santos, Darren Veach, Mesruh Turkekul, Emily Casey, Jason S Lewis, Diane S Abou, Marise R H van Voss, Peter T Scardino, Sven-Erik Strand, Mary L Alpaugh, Howard I Scher, Hans Lilja, Steven M Larson, David Ulmert
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Leonard Wagner Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA., Department of Urology, University Hospital of the Ruhr-University of Bochum, Marien Hospital Herne, Herne, Germany., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Innovagen AB, Lund, Sweden., Department of Biochemistry, University of Turku, Turku, Finland., Molecular Cytology Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Medical Radiation Physics, Lund University, Lund, Sweden., Departments of Biology and Biomedical and Translational Sciences, Rowan University, Glassboro, NJ 08028, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ., Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. .