Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans.
Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans.
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DOI：
10.1111/j.1365-2443.2011.01552.x
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Kato K
中科院分区：
文献类型：
--
作者：
Mizushima T;Yagi H;Takemoto E;Shibata-Koyama M;Isoda Y;Iida S;Masuda K;Satoh M;Kato K
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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