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

Cancer Cell. 2014 Aug 11;26(2):177-89. doi: 10.1016/j.ccr.2014.04.028. Epub 2014 Jul 17.


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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival
  • Crystallography, X-Ray
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Humans
  • Mice
  • Models, Molecular
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / chemistry
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / chemistry
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • conatumumab

Associated data

  • PDB/4N90