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

Jonathan D Graves; Jennifer J Kordich; Tzu-Hsuan Huang; Julia Piasecki; Tammy L Bush; Timothy Sullivan; Ian N Foltz; Wesley Chang; Heather Douangpanya; Thu Dang; Jason W O'Neill; Rommel Mallari; Xiaoning Zhao; Daniel G Branstetter; John M Rossi; Alexander M Long; Xin Huang; Pamela M Holland

doi:10.1016/j.ccr.2014.04.028

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.

Authors

Jonathan D Graves¹, Jennifer J Kordich¹, Tzu-Hsuan Huang², Julia Piasecki³, Tammy L Bush², Timothy Sullivan², Ian N Foltz⁴, Wesley Chang⁵, Heather Douangpanya¹, Thu Dang², Jason W O'Neill⁶, Rommel Mallari⁷, Xiaoning Zhao⁷, Daniel G Branstetter⁸, John M Rossi⁹, Alexander M Long¹⁰, Xin Huang¹⁰, Pamela M Holland¹¹

Affiliations

¹ Department of Oncology Research, Amgen Inc., Seattle, WA 98119, USA.
² Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA.
³ Therapeutic Innovation Unit, Amgen Inc., Seattle, WA 98119, USA.
⁴ Department of Biologic Discovery, Amgen British Columbia, Burnaby, BC V5A 1V7, Canada.
⁵ Department of Clinical Immunology, Amgen Inc., South San Francisco, CA 94080, USA.
⁶ Department of Biologic Optimization, Amgen Inc., Seattle, WA 98119, USA.
⁷ Department of Molecular Structure and Characterization, Amgen, South San Francisco, CA, 94080, USA.
⁸ Department of Pathology, Amgen Inc., Seattle, WA 98119, USA.
⁹ Department of Molecular Sciences and Computational Biology, Amgen Inc., Thousand Oaks, CA 91320, USA.
¹⁰ Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, MA 02142, USA.
¹¹ Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA. Electronic address: [email protected].

PMID: 25043603
DOI: 10.1016/j.ccr.2014.04.028

Abstract

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

Substances

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

Associated data

PDB/4N90