Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity

被引：135

作者：

Graves, Jonathan D. ^{[1
]}

Kordich, Jennifer J. ^{[1
]}

Huang, Tzu-Hsuan ^{[2
]}

Piasecki, Julia ^{[3
]}

Bush, Tammy L. ^{[2
]}

Sullivan, Timothy ^{[2
]}

Foltz, Ian N. ^{[4
]}

Chang, Wesley ^{[5
]}

Douangpanya, Heather ^{[1
]}

Thu Dang ^{[2
]}

O'Neil, Jason W. ^{[6
]}

Mallari, Rommel ^{[7
]}

Zhao, Xiaoning ^{[7
]}

Branstetter, Daniel G. ^{[8
]}

Rossi, John M. ^{[9
]}

Long, Alexander M. ^{[10
]}

Huang, Xin ^{[10
]}

Holland, Pamela M. ^{[2
]}

机构：

[1] Amgen Inc, Dept Oncol Res, Seattle, WA 98119 USA

[2] Amgen Inc, Therapeut Innovat Unit, Cambridge, MA 02142 USA

[3] Amgen Inc, Therapeut Innovat Unit, Seattle, WA 98119 USA

[4] Amgen British Columbia, Dept Biol Discovery, Burnaby, BC V5A 1V7, Canada

[5] Amgen Inc, Dept Clin Immunol, South San Francisco, CA 94080 USA

[6] Amgen Inc, Dept Biol Optimizat, Seattle, WA 98119 USA

[7] Amgen Inc, Dept Mol Struct & Characterizat, South San Francisco, CA 94080 USA

[8] Amgen Inc, Dept Pathol, Seattle, WA 98119 USA

[9] Amgen Inc, Dept Mol Sci & Computat Biol, Thousand Oaks, CA 91320 USA

[10] Amgen Inc, Dept Mol Struct & Characterizat, Cambridge, MA 02142 USA

来源：

CANCER CELL | 2014年 / 26卷 / 02期

关键词：

TRAIL-INDUCED APOPTOSIS; CELL LUNG-CANCER; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; TUMOR-GROWTH; TUMORICIDAL ACTIVITY; DECOY RECEPTORS; TARGETING DEATH; CROSS-LINKING; TNF FAMILY;

D O I：

10.1016/j.ccr.2014.04.028

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：177 / 189

页数：13

共 51 条

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