Cancer Cell
Volume 26, Issue 2, 11 August 2014, Pages 177-189
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Article
Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity

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Highlights

  • Apo2L/TRAIL and AMG 655 show superior tumor cell killing over either agent alone

  • Cells resistant to soluble Apo2L/TRAIL are sensitized by the combination

  • The X-ray structure of the complex provides a model of higher order clustering

  • Apo2L/TRAIL and a DR5 antibody demonstrate a therapeutic window in syngeneic models

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.

Cited by (0)

11

Present address: Belmont, MA 02478, USA

12

Present address: Van Andel Institute, Grand Rapids, MI 49503, USA

13

Present address: Seattle Genetics, Bothell, WA 98021, USA

14

Present address: AbbVie, North Chicago, IL 60064, USA