title: Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity.
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.
authors.affiliation: Department of Oncology Research, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Graves
authors.affiliation: Department of Oncology Research, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kordich
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA.
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Piasecki
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Bush
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.affiliation: Department of Biologic Discovery, Amgen British Columbia, Burnaby, BC V5A 1V7, Canada.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Foltz
authors.affiliation: Department of Clinical Immunology, Amgen Inc., South San Francisco, CA 94080, USA.
authors.forename: Wesley
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Oncology Research, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Douangpanya
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA.
authors.forename: Thu
authors.initials: T
authors.lastname: Dang
authors.affiliation: Department of Biologic Optimization, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: O'Neill
authors.affiliation: Department of Molecular Structure and Characterization, Amgen, South San Francisco, CA, 94080, USA.
authors.forename: Rommel
authors.initials: R
authors.lastname: Mallari
authors.affiliation: Department of Molecular Structure and Characterization, Amgen, South San Francisco, CA, 94080, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Amgen Inc., Seattle, WA 98119, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Branstetter
authors.affiliation: Department of Molecular Sciences and Computational Biology, Amgen Inc., Thousand Oaks, CA 91320, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Rossi
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, MA 02142, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, MA 02142, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Therapeutic Innovation Unit, Amgen Inc., Cambridge, MA 02142, USA. Electronic address: hollandp@amgen.com.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Holland
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C554537:conatumumab