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Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans
Author(s) -
Mizushima Tsunehiro,
Yagi Hirokazu,
Takemoto Emi,
ShibataKoyama Mami,
Isoda Yuya,
Iida Shigeru,
Masuda Kazuhiro,
Satoh Mitsuo,
Kato Koichi
Publication year - 2011
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2011.01552.x
Subject(s) - fucosylation , antibody dependent cell mediated cytotoxicity , fragment crystallizable region , glycan , immunoglobulin fc fragments , antibody , fucose , glycosylation , fc receptor , immunoglobulin g , biology , receptor , steric effects , microbiology and biotechnology , biochemistry , immunology , chemistry , stereochemistry , glycoprotein , monoclonal antibody
Removal of the fucose residue from the N ‐glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody‐dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2‐Å structure of the complex formed between nonfucosylated IgG1‐Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N ‐glycosylation sites. The crystal structure shows that one of the two N ‐glycans of sFcγRIIIa mediates the interaction with nonfucosylated Fc, thereby stabilizing the complex. However, fucosylation of the Fc N ‐glycans inhibits this interaction, because of steric hindrance, and furthermore, negatively affects the dynamics of the receptor binding site. Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation.
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