Internalization of secreted antigen–targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis

Abstract

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.

Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

“…We have developed an antibodybased platform that targets hK2, an enzyme that is prostate tissue-specific and under direct regulation of AR, the central driver of prostate adenocarcinoma. Our lead antibody, hu11B6, has been thoroughly evaluated for tumor detection and monitoring of disease activity by positron emission tomography and single photon emission computed tomography 12,14 . We have reported that hu11B6 can be applied for RIT applications 3,11,13 .…”

“…Our group has previously reported on the targeting specificity, efficacy and biological response of radiolabeled hu11B6 as an immunotheranostic vehicle. Preclinical evaluations have been carried out in multiple immunodeficient and immunocompetent, rodent disease models as well as in non-human primates 3,[11][12][13][14] . In addition, studies of the uptake mechanism have revealed that hu11B6 is internalized by hK2 expressing cells via a mechanism driven by the neonatal Fc receptor (FcRn); while uncomplexed hu11B6 is released from the cell by recycling endosomes after binding to FcRn, the hu11B6-hK2 complex is routed to lysosomes for processing 12 .…”

“…Preclinical evaluations have been carried out in multiple immunodeficient and immunocompetent, rodent disease models as well as in non-human primates 3,[11][12][13][14] . In addition, studies of the uptake mechanism have revealed that hu11B6 is internalized by hK2 expressing cells via a mechanism driven by the neonatal Fc receptor (FcRn); while uncomplexed hu11B6 is released from the cell by recycling endosomes after binding to FcRn, the hu11B6-hK2 complex is routed to lysosomes for processing 12 . The proximity of the internalized radionuclide-labeled hu11B6 to the nucleus results in efficient cell kill, which is further accelerated by inherent AR and hK2 upregulation related to DNA-repair 3 .…”

PSMA Expression in the Hi-Myc Model; Extended Utility of a Representative Model of Prostate Adenocarcinoma for Biological Insight and as a Drug Discovery Tool

“…There are many agents under development for improved detection and targeted therapy of prostate adenocarcinoma [15][16][17][18][19] . The widespread use of high-sensitivity and robust methods to detect PSMA in particular in the locally advanced and metastatic settings by PET and SPECT are poised to revolutionize management for those afflicted with the disease.…”

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

“…Mice undergoing 18 F-DCFPyL PET imaging were administered radiotracer (7.4-9 MBq) either anesthetized (isoflurane) on camera with a tail vein catheter for kinetic studies, or via the retroorbital sinus for static images. A dedicated high resolution small animal PET scanner (R4, Concorde Microsystems; 7.8 cm axial by 10 cm transaxial field of view) was used to acquire whole body mouse scans (in the prone position) in list-mode configuration with a 350-700 keV energy range and a coincidence-timing window of 6 nsec for a minimum of 20x10 6 coincident events as previously described (28). PET image data were corrected for detector non-uniformity, dead time, random coincidences and physical decay and normalized to injected activity (determined by Capintec CR15 dose calibrator with setting #457).…”