title: In VitroandIn VivoEvaluation of89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy.
abstract: Background:DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expressionin vivoin mouse tumor models using SPECT/CT and PET/MRI, as a tool for drug development and trial design.Methods:DS-8273a was radiolabeled with indium-111 and zirconium-89. Radiochemical purity, immunoreactivity, antigen binding affinity and serum stability were assessedin vitro.In vivobiodistribution and pharmacokinetic studies were performed, including SPECT/CT and PET/MR imaging. A dose-escalation study using a PET/MR imaging quantitative analysis was also performed to determine DR5 receptor saturability in a mouse model.Results:111In-CHX-A″-DTPA-DS-8273a and89Zr-Df-Bz-NCS-DS-8273a showed high immunoreactivity (100%), high serum stability, and bound to DR5 expressing cells with high affinity (Ka, 1.02-1.22 × 1010M-1). The number of antibodies bound per cell was 32,000.In vivobiodistribution studies showed high and specific uptake of111In-CHX-A″-DTPA-DS-8273a and89Zr-Df-Bz-NCS-DS-8273a in DR5 expressing COLO205 xenografts, with no specific uptake in normal tissues or in DR5-negative CT26 xenografts. DR5 receptor saturation was observedin vivoby biodistribution studies and quantitative PET/MRI analysis.Conclusion:89Zr-Df-Bz-NCS-DS-8273a is a potential novel PET imaging reagent for human bioimaging trials, and can be used for effective dose assessment and patient response evaluation in clinical trials.
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Ingrid J G
authors.initials: IJ
authors.lastname: Burvenich
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
authors.forename: Nancy
authors.initials: N
authors.lastname: Guo
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia;; Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia.
authors.forename: Hui K
authors.initials: HK
authors.lastname: Gan
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Rigopoulos
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Parslow
authors.affiliation: Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia;; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: O'Keefe
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia;; School of Engineering and Mathematical Sciences, La Trobe University, Melbourne, Australia.
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Gong
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Henri
authors.initials: H
authors.lastname: Tochon-Danguy
authors.affiliation: School of Chemistry and Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Stacey E
authors.initials: SE
authors.lastname: Rudd
authors.affiliation: School of Chemistry and Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co Ltd, Tokyo, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Kotsuma
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co Ltd, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohtsuka
authors.affiliation: Department of Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Senaldi
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia;; Department of Medicine, University of Melbourne, Melbourne, Australia;; Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia;; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D007204:Indium / Q000008:administration & dosage / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography; D011868:Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011878:Radiotherapy / Q000379:methods; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors*; D000068936:Theranostic Nanomedicine / Q000379:methods*; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D015040:Zirconium / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000906:Antibodies; D011868:Radioisotopes; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505640:Tnfrsf10b protein, mouse; D007204:Indium; D015040:Zirconium
keywords: DS-8273a; PET/MRI.; apoptosis; colorectal cancer; death receptor 5; zirconium-89