Please use this identifier to cite or link to this item: https://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.
Austin 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: 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.
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
Issue Date: 17-Sep-2013
Publication information: Clinical 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/11879
DOI: 10.1158/1078-0432.CCR-12-3104
Journal: Clinical Cancer Research
URL: https://pubmed.ncbi.nlm.nih.gov/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

Show full item record

Page view(s)

30
checked on Nov 1, 2024

Google ScholarTM

Check


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.