In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy

Ingrid J G Burvenich; Fook-Thean Lee; Nancy Guo; Hui K Gan; Angela Rigopoulos; Adam C Parslow; Graeme J O'Keefe; Sylvia J Gong; Henri Tochon-Danguy; Stacey E Rudd; Paul S Donnelly; Masakatsu Kotsuma; Toshiaki Ohtsuka; Giorgio Senaldi; Andrew M Scott

doi:10.7150/thno.16260

In Vitro and In Vivo Evaluation of ⁸⁹Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy

Theranostics. 2016 Sep 25;6(12):2225-2234. doi: 10.7150/thno.16260. eCollection 2016.

Authors

Affiliations

¹ Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
² Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
³ 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.
⁴ Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia;; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
⁵ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia;; School of Engineering and Mathematical Sciences, La Trobe University, Melbourne, Australia.
⁶ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
⁷ School of Chemistry and Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
⁸ Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co Ltd, Tokyo, Japan.
⁹ Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co Ltd, Tokyo, Japan.
¹⁰ Department of Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
¹¹ 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.

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 (K_a, 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.

Keywords: DS-8273a; PET/MRI.; apoptosis; colorectal cancer; death receptor 5; zirconium-89.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / diagnostic imaging*
Adenocarcinoma / therapy*
Animals
Antibodies / administration & dosage*
Cell Line, Tumor
Disease Models, Animal
Heterografts
Humans
Indium / administration & dosage
Indium / pharmacokinetics
Magnetic Resonance Imaging
Mice, Inbred BALB C
Positron-Emission Tomography
Radioisotopes / administration & dosage*
Radioisotopes / pharmacokinetics
Radiotherapy / methods
Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors*
Theranostic Nanomedicine / methods*
Tomography, Emission-Computed, Single-Photon
Treatment Outcome
Zirconium / administration & dosage*
Zirconium / pharmacokinetics

Substances

Antibodies
Radioisotopes
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNFRSF10B protein, human
Tnfrsf10b protein, mouse
Indium
Zirconium