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PDBsum entry 4kjy
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Immune system
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PDB id
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4kjy
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References listed in PDB file
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Key reference
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Title
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Engineered sirpα variants as immunotherapeutic adjuvants to anticancer antibodies.
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Authors
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K.Weiskopf,
A.M.Ring,
C.C.Ho,
J.P.Volkmer,
A.M.Levin,
A.K.Volkmer,
E.Ozkan,
N.B.Fernhoff,
M.Van de rijn,
I.L.Weissman,
K.C.Garcia.
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Ref.
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Science, 2013,
341,
88-91.
[DOI no: ]
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PubMed id
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Abstract
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CD47 is an antiphagocytic signal that cancer cells employ to inhibit
macrophage-mediated destruction. Here, we modified the binding domain of human
SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered
high-affinity SIRPα variants with about a 50,000-fold increased affinity for
human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they
potently antagonized CD47 on cancer cells but did not induce macrophage
phagocytosis on their own. Instead, they exhibited remarkable synergy with all
tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro
and enhancing antitumor responses in vivo. This "one-two punch"
directs immune responses against tumor cells while lowering the threshold for
macrophage activation, thereby providing a universal method for augmenting the
efficacy of therapeutic anticancer antibodies.
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