Please use this identifier to cite or link to this item: http://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
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
Issue Date: Sep-2016
EDate: 2016-09-25
Citation: 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://www.ncbi.nlm.nih.gov/pubmed/27924159
Type: Journal Article
Subjects: DS-8273a
Death receptor 5
Apoptosis
Zirconium-89
Colorectal cancer
PET/MRI
Appears in Collections:Journal articles

Files in This Item:
There are no files associated with this item.


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.