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

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

来源：Theranostics, 2016, 6(12): 2225-2234.

• DS-8273a
• death receptor 5
• apoptosis
• zirconium-89
• colorectal cancer
• PET/MRI

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: In-111-CHX-A''-DTPA-DS-8273a and Zr-89-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 x 10(10) M-1). The number of antibodies bound per cell was 32,000. In vivo biodistribution studies showed high and specific uptake of In-111-CHX-A"-DTPA-DS-8273a and Zr-89-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: Zr-89-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.

• 出版日期2016