Molecular imaging of death receptor 5 occupancy and saturation kinetics in vivo by humanized monoclonal antibody CS-1008

Ingrid J.G. Burvenich, Fook T. Lee, Glenn A. Cartwright, Graeme J. O'Keefe, Dahna Makris, Diana Cao, Sylvia Gong, Anderly C. Chueh, John M. Mariadason, Martin W. Brechbiel, Robert A. Beckman, Kosaku Fujiwara, Reinhard Von Roemeling, Andrew M. Scott

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15 Citations (Scopus)


Purpose: 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 111In-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. Experimental Design: 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. Results: Scatchard analysis showed high and specific binding affinity (Kd, 1.05 ± 0.12 nmol/L) of 111Inlabeled CS-1008. 111In-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 111In-labeled CS-1008. Saturation of DR5 corresponded to maximal in vivo antitumor efficacy. Conclusions: 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.

Original languageEnglish
Pages (from-to)5984-5993
Number of pages10
JournalClinical Cancer Research
Issue number21
Publication statusPublished - 1 Nov 2013
Externally publishedYes

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