Internalization of secreted antigen–targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis
Menée sur des lignées cellulaires de cancer de la prostate et à l'aide de tissus humains ou de xénogreffes sur des modèles murins, cette étude analyse l'accumulation intracellulaire, via un mécanisme impliquant le récepteur FcRn, d'anticorps fluorescents ou radiomarqués ciblant une enzyme (hK2) produite dans les cellules cancéreuses de la prostate ainsi que dans les tumeurs mammaires sensibles aux androgènes, et permettant de suivre l'activité de la voie de signalisation des récepteurs androgéniques
Prostate cancer is typically treated by targeting the androgen receptor, at least initially, but there is no convenient way to monitor the receptor’s activity or to determine when a tumor is becoming resistant to treatment. Although the androgen receptor cannot be imaged directly at this time, Thorek et al. identified an enzyme called human kallikrein-related peptidase 2 (hK2), whose activation requires signaling through the androgen receptor pathway. The authors used a radiolabeled antibody against hK2 in mouse models and human tissues to accurately detect prostate cancer lesions, including bone metastases, and to monitor their status during the course of treatment.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 , résumé, 2015