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PDBsum entry 4n90
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Apoptosis/immune system
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PDB id
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4n90
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Contents |
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108 a.a.
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155 a.a.
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214 a.a.
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218 a.a.
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References listed in PDB file
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Key reference
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Title
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Apo2l/trail and the death receptor 5 agonist antibody amg 655 cooperate to promote receptor clustering and antitumor activity.
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Authors
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J.D.Graves,
J.J.Kordich,
T.H.Huang,
J.Piasecki,
T.L.Bush,
T.Sullivan,
I.N.Foltz,
W.Chang,
H.Douangpanya,
T.Dang,
J.W.O'Neill,
R.Mallari,
X.Zhao,
D.G.Branstetter,
J.M.Rossi,
A.M.Long,
X.Huang,
P.M.Holland.
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Ref.
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Cancer Cell, 2014,
26,
177-189.
[DOI no: ]
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PubMed id
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Abstract
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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.
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