Imaging, Diagnosis, Prognosis Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

نویسندگان

  • 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
چکیده

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 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 (COLO205 andWiDr). Pharmacokinetic and biodistribution studies were conducted in BALB/c nu/nu mice bearing COLO 205, WiDr, or DR5negative 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 Inlabeled CS-1008. 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 1⁄4 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 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. Clin Cancer Res; 19(21);

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

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تاریخ انتشار 2013