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In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy.
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; Donnelly, Paul S; Kotsuma, Masakatsu; Ohtsuka, Toshiaki; Senaldi, Giorgio; Scott, Andrew M.
Afiliação
  • Burvenich IJ; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
  • Lee FT; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
  • Guo N; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
  • Gan HK; 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.
  • Rigopoulos A; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
  • Parslow AC; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
  • O'Keefe GJ; Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia;; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
  • Gong SJ; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia;; School of Engineering and Mathematical Sciences, La Trobe University, Melbourne, Australia.
  • Tochon-Danguy H; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
  • Rudd SE; School of Chemistry and Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
  • Donnelly PS; School of Chemistry and Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
  • Kotsuma M; Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co Ltd, Tokyo, Japan.
  • Ohtsuka T; Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co Ltd, Tokyo, Japan.
  • Senaldi G; Department of Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
  • Scott AM; 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,
Theranostics ; 6(12): 2225-2234, 2016.
Article em En | MEDLINE | ID: mdl-27924159
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Radioisótopos / Zircônio / Adenocarcinoma / Receptores do Ligante Indutor de Apoptose Relacionado a TNF / Nanomedicina Teranóstica / Anticorpos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Radioisótopos / Zircônio / Adenocarcinoma / Receptores do Ligante Indutor de Apoptose Relacionado a TNF / Nanomedicina Teranóstica / Anticorpos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article