Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans.
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Mizushima T, Yagi H, Takemoto E, Shibata-Koyama M, Isoda Y, Iida S, Masuda K, Satoh M, Kato K
Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans.
Genes Cells. 2011 Nov;16(11):1071-80. doi: 10.1111/j.1365-2443.2011.01552.x.
- PubMed ID
- 22023369 [ View in PubMed]
- Abstract
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 Fcgamma receptor IIIa (FcgammaRIIIa). Here, we present the 2.2-A structure of the complex formed between nonfucosylated IgG1-Fc and a soluble form of FcgammaRIIIa (sFcgammaRIIIa) with two N-glycosylation sites. The crystal structure shows that one of the two N-glycans of sFcgammaRIIIa 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.