Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/11879
Title: Molecular imaging of death receptor 5 occupancy and saturation kinetics in vivo by humanized monoclonal antibody CS-1008.
Authors: Burvenich, Ingrid J G;Lee, Fook-Thean;Cartwright, Glenn A;O'Keefe, Graeme J;Makris, Dahna;Cao, Diana;Gong, Sylvia J;Chueh, Anderly C;Mariadason, John M;Brechbiel, Martin W;Beckman, Robert A;Fujiwara, Kosaku;von Roemeling, Reinhard;Scott, Andrew M
Affiliation: Authors' Affiliations: Tumour Targeting Laboratory and Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research; Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia; Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Cancer Research Centre, Bethesda, Maryland; Clinical Development-Oncology, Daiichi Sankyo Pharmaceutical Development, Edison, New Jersey; and Global Project Management Department, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
Issue Date: 17-Sep-2013
Citation: Clinical Cancer Research : An Official Journal of the American Association For Cancer Research 2013; 19(21): 5984-93
Abstract: CS-1008 (tigatuzumab; phase I/II), an antihuman death receptor 5 (DR5) agonist, induces apoptosis and has cytotoxic activity against human cancer cell lines. This study reports on the preclinical validation of (111)In-labeled anti-DR5 humanized antibody CS-1008 as a diagnostic tool to study the DR5 occupancy in patients with cancer and establish dose ranges for receptor saturation kinetics in vivo.CS-1008 was radiolabeled and characterized for DR5 binding and labeling efficiency on TRAIL-sensitive DR5-positive colorectal cancer cells (COLO 205 and WiDr). Pharmacokinetic and biodistribution studies were conducted in BALB/c nu/nu mice bearing COLO 205, WiDr, or DR5-negative CT26 colon tumors. Planar gamma camera imaging and computerized tomography (CT) images were obtained to study receptor occupancy in vivo.Scatchard analysis showed high and specific binding affinity (Kd, 1.05 ± 0.12 nmol/L) of (111)In-labeled CS-1008. (111)In-labeled CS-1008 was specifically taken up in mice bearing COLO 205 and WiDr tumors with prolonged tumor retention (26.25 ± 2.85%ID/g vs. 12.20 ± 2.24 at 168 hours post injection; n = 5, SD), and uptake correlated both with DR5 expression on tumor cells and antitumor activity. DR5 saturation was shown in vivo via both biodistribution studies and planar gamma camera imaging/CT imaging of (111)In-labeled CS-1008. Saturation of DR5 corresponded to maximal in vivo antitumor efficacy.Imaging of DR5 receptor occupancy in vivo correlates with tumor concentration and in vivo efficacy, and is a novel molecular imaging technique that can be used to determine receptor occupancy and effective dose levels of DR5 agonist antibodies in the clinic.
Internal ID Number: 24045184
URI: http://ahro.austin.org.au/austinjspui/handle/1/11879
DOI: 10.1158/1078-0432.CCR-12-3104
URL: http://www.ncbi.nlm.nih.gov/pubmed/24045184
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal, Humanized.diagnostic use.metabolism.pharmacokinetics
Cell Line, Tumor
Disease Models, Animal
Female
Humans
Indium Radioisotopes
Isotope Labeling
Kinetics
Mice
Molecular Imaging
Protein Binding
Radionuclide Imaging
Receptors, TNF-Related Apoptosis-Inducing Ligand.antagonists & inhibitors.metabolism
Tissue Distribution
Appears in Collections:Journal articles

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