Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16526
Title: In vitro and in vivo evaluation of 89Zr-DS-8273a as a theranostic for anti-death receptor 5 therapy
Austin Authors: Burvenich, Ingrid JG;Lee, Fook-Thean;Guo, Nancy;Gan, Hui K ;Rigopoulos, Angela;Parslow, Adam C;O'Keefe, Graeme J;Gong, Sylvia J;Tochon-Danguy, Henri J ;Rudd, Stacey E;Donnelly, Paul S;Kotsuma, Masakatsu;Ohtsuka, Toshiaki;Senaldi, Giorgio;Scott, Andrew M 
Affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia
Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia
School of Engineering and Mathematical Sciences, La Trobe University, Melbourne, Victoria, Australia
School of Chemistry and Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co Ltd, Tokyo, Japan
Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co Ltd, Tokyo, Japan
Department of Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA
Issue Date: Sep-2016
metadata.dc.date: 2016-09-25
Publication information: Theranostics 2016; 6(12): 2225-2234
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 expression in vivo in 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 assessed in vitro. In vivo biodistribution 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 and 89Zr-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 × 1010 M-1). The number of antibodies bound per cell was 32,000. In vivo biodistribution studies showed high and specific uptake of 111In-CHX-A″-DTPA-DS-8273a and 89Zr-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 observed in vivo by 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16526
DOI: 10.7150/thno.16260
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/27924159
Type: Journal Article
Subjects: DS-8273a
Death receptor 5
Apoptosis
Zirconium-89
Colorectal cancer
PET/MRI
Appears in Collections:Journal articles

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