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

Abstract

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 (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.

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 (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.

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 21 Pg. 5984-93 (Nov 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24045184 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Indium Radioisotopes
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• tigatuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (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