title: 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.
authors.affiliation: 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.|Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daniel L J
authors.initials: DL
authors.lastname: Thorek
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Watson
authors.affiliation: Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sang-Gyu
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anson T
authors.initials: AT
authors.lastname: Ku
authors.affiliation: Leonard Wagner Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Bournazos
authors.affiliation: Department of Urology, University Hospital of the Ruhr-University of Bochum, Marien Hospital Herne, Herne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Braun
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Kim
authors.affiliation: Innovagen AB, Lund, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Sjöström
authors.affiliation: Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Doran
authors.affiliation: Department of Biochemistry, University of Turku, Turku, Finland.
authors.forename: Urpo
authors.initials: U
authors.lastname: Lamminmäki
authors.affiliation: Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Elmer
authors.initials: E
authors.lastname: Santos
authors.affiliation: Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Veach
authors.affiliation: Molecular Cytology Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mesruh
authors.initials: M
authors.lastname: Turkekul
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Casey
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: 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.
authors.forename: Diane S
authors.initials: DS
authors.lastname: Abou
authors.affiliation: 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.|Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Marise R H
authors.initials: MR
authors.lastname: van Voss
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Urology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Scardino
authors.affiliation: Department of Medical Radiation Physics, Lund University, Lund, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Strand
authors.affiliation: Departments of Biology and Biomedical and Translational Sciences, Rowan University, Glassboro, NJ 08028, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Alpaugh
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ulmerth@mskcc.org liljah@mskcc.org larsons@mskcc.org.|Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Nuffield Department of Surgical Sciences, University of Oxford, Oxford, U.K.|Department of Laboratory Medicine, Lund University, Malmö, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.affiliation: Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ulmerth@mskcc.org liljah@mskcc.org larsons@mskcc.org.|Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ulmerth@mskcc.org liljah@mskcc.org larsons@mskcc.org.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Division of Urological Research, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Ulmert
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D001859:Bone Neoplasms / Q000000981:diagnostic imaging* / Q000556:secondary; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010641:Phenotype; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D011944:Receptors, Androgen / Q000737:chemistry*; D011961:Receptors, Fc / Q000737:chemistry*; D020840:Tissue Kallikreins / Q000737:chemistry*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D011944:Receptors, Androgen; D011961:Receptors, Fc; D020840:Tissue Kallikreins; C100688:Fc receptor, neonatal