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PDBsum entry 3wjj
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Immune system
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PDB id
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3wjj
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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 antibody fc variant with selectively enhanced fcγriib binding over both fcγriia(r131) and fcγriia(h131).
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Authors
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F.Mimoto,
H.Katada,
S.Kadono,
T.Igawa,
T.Kuramochi,
M.Muraoka,
Y.Wada,
K.Haraya,
T.Miyazaki,
K.Hattori.
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Ref.
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Protein Eng Des Sel, 2013,
26,
589-598.
[DOI no: ]
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PubMed id
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Abstract
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Engaging inhibitory FcγRIIb by Fc region has been recently reported to be an
attractive approach for improving the efficacy of antibody therapeutics.
However, the previously reported S267E/L328F variant with enhanced binding
affinity to FcγRIIb, also enhances binding affinity to FcγRIIa(R131) allotype
to a similar degree because FcγRIIb and FcγRIIa(R131) are structurally
similar. In this study, we applied comprehensive mutagenesis and
structure-guided design based on the crystal structure of the Fc/FcγRIIb
complex to identify a novel Fc variant with selectively enhanced FcγRIIb
binding over both FcγRIIa(R131) and FcγRIIa(H131). This novel variant has more
than 200-fold stronger binding affinity to FcγRIIb than wild-type IgG1, while
binding affinity to FcγRIIa(R131) and FcγRIIa(H131) is comparable with or
lower than wild-type IgG1. This selectivity was achieved by conformational
change of the C(H)2 domain by mutating Pro to Asp at position 238. Fc variant
with increased binding to both FcγRIIb and FcγRIIa induced platelet
aggregation and activation in an immune complex form in vitro while our novel
variant did not. When applied to agonistic anti-CD137 IgG1 antibody, our variant
greatly enhanced the agonistic activity. Thus, the selective enhancement of
FcγRIIb binding achieved by our Fc variant provides a novel tool for improving
the efficacy of antibody therapeutics.
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