In Vitro and In Vivo Evaluation of 89Zr-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 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.

• Authors: 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
• Journal: Theranostics (Theranostics) Vol. 6 Issue 12 Pg. 2225-2234 ( 2016) ISSN: 1838-7640 [Electronic] Australia
• PMID: 27924159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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