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Theranostics 2016; 6(12):2225-2234. doi:10.7150/thno.16260 This issue Cite

Research Paper

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

Ingrid J.G. Burvenich1,2#, Fook-Thean Lee1,2#, Nancy Guo1, Hui K. Gan1,2,4, Angela Rigopoulos1,2, Adam C. Parslow1,2, Graeme J. O'Keefe4,5, Sylvia J. Gong5,6, Henri Tochon-Danguy5, Stacey E. Rudd7, Paul S. Donnelly7, Masakatsu Kotsuma8, Toshiaki Ohtsuka9, Giorgio Senaldi10, Andrew M. Scott1,2,3,4,5✉

1. Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia;
2. School of Cancer Medicine, La Trobe University, Melbourne, Australia;
3. Department of Medicine, University of Melbourne, Melbourne, Australia;
4. Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia;
5. Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia;
6. School of Engineering and Mathematical Sciences, La Trobe University, 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.
#Authors contributed equally to this work.

✉ Corresponding author: Professor Andrew M. Scott, Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145-163 Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-39496-5876; Fax: 61-39496-5334; E-mail: andrew.scottorg.au. More

Citation:
Burvenich IJG, Lee FT, Guo N, Gan HK, Rigopoulos A, Parslow AC, O'Keefe GJ, Gong SJ, Tochon-Danguy H, Rudd SE, Donnelly PS, Kotsuma M, Ohtsuka T, Senaldi G, Scott AM. In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy. Theranostics 2016; 6(12):2225-2234. doi:10.7150/thno.16260. https://www.thno.org/v06p2225.htm
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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.

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

Citation styles

APA
Burvenich, I.J.G., Lee, F.T., Guo, N., Gan, H.K., Rigopoulos, A., Parslow, A.C., O'Keefe, G.J., Gong, S.J., Tochon-Danguy, H., Rudd, S.E., Donnelly, P.S., Kotsuma, M., Ohtsuka, T., Senaldi, G., Scott, A.M. (2016). In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy. Theranostics, 6(12), 2225-2234. https://doi.org/10.7150/thno.16260.

ACS
Burvenich, I.J.G.; Lee, F.T.; Guo, N.; Gan, H.K.; Rigopoulos, A.; Parslow, A.C.; O'Keefe, G.J.; Gong, S.J.; Tochon-Danguy, H.; Rudd, S.E.; Donnelly, P.S.; Kotsuma, M.; Ohtsuka, T.; Senaldi, G.; Scott, A.M. In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy. Theranostics 2016, 6 (12), 2225-2234. DOI: 10.7150/thno.16260.

NLM
Burvenich IJG, Lee FT, Guo N, Gan HK, Rigopoulos A, Parslow AC, O'Keefe GJ, Gong SJ, Tochon-Danguy H, Rudd SE, Donnelly PS, Kotsuma M, Ohtsuka T, Senaldi G, Scott AM. In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy. Theranostics 2016; 6(12):2225-2234. doi:10.7150/thno.16260. https://www.thno.org/v06p2225.htm

CSE
Burvenich IJG, Lee FT, Guo N, Gan HK, Rigopoulos A, Parslow AC, O'Keefe GJ, Gong SJ, Tochon-Danguy H, Rudd SE, Donnelly PS, Kotsuma M, Ohtsuka T, Senaldi G, Scott AM. 2016. In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy. Theranostics. 6(12):2225-2234.

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