[PDF][PDF] Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity

JD Graves, JJ Kordich, TH Huang, J Piasecki, TL Bush… - Cancer cell, 2014 - cell.com
JD Graves, JJ Kordich, TH Huang, J Piasecki, TL Bush, T Sullivan, IN Foltz, W Chang…
Cancer cell, 2014cell.com
Death receptor agonist therapies have exhibited limited clinical benefit to date.
Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of
clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to
increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG
655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure
determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher …
Summary
Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy.
cell.com