In vitro and in vivo evaluation of 89Zr-DS-8273a as a theranostic for anti-death receptor 5 therapy
journal contributionposted on 13.08.2021, 01:56 by IJG Burvenich, Fook-Thean LeeFook-Thean Lee, N Guo, Hui GanHui Gan, Angela RigopoulosAngela Rigopoulos, Adam ParslowAdam Parslow, GJ O'Keefe, Sylvia GongSylvia Gong, H Tochon-Danguy, SE Rudd, PS Dormelly, M Kotsuma, T Ohtsuka, G Senaldi, Andrew ScottAndrew Scott
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.
The authors acknowledge the Australian Cancer Research Foundation for providing funds to purchase the PET/MRI and nanoSPECT/CT imaging equipment and the Operational Infrastructure Support program of the Victorian State Government. This research was also undertaken using the Solid Target Laboratory, an ANSTO-Austin-LICR Partnership.
Pagination10p. (p. 2225-2234)
PublisherIvyspring International Publisher
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Science & TechnologyLife Sciences & BiomedicineMedicine, Research & ExperimentalResearch & Experimental MedicineDS-8273adeath receptor 5apoptosiszirconium-89colorectal cancerPET/MRIMETASTATIC COLORECTAL-CANCERMONOCLONAL-ANTIBODYTRAILTRIALAPOPTOSISCS-1008ZR-89-TRASTUZUMABBIODISTRIBUTIONHEPATOCYTESEXPRESSIONCell Line, TumorAnimalsMice, Inbred BALB CHumansAdenocarcinomaDisease Models, AnimalIndiumZirconiumRadioisotopesAntibodiesPositron-Emission TomographyTomography, Emission-Computed, Single-PhotonMagnetic Resonance ImagingTreatment OutcomeRadiotherapyReceptors, TNF-Related Apoptosis-Inducing LigandHeterograftsTheranostic NanomedicinePET/MRI.