Structural Basis for Improved Efficacy of Therapeutic Antibodies on Defucosylation of Their Fc Glycans

Overview

Journal Genes Cells

Specialties Cell Biology
Molecular Biology

Date 2011 Oct 26

PMID 22023369

Citations 122

Authors

Tsunehiro Mizushima

Hirokazu Yagi

Emi Takemoto

Mami Shibata-Koyama

Yuya Isoda

Shigeru Iida

Kazuhiro Masuda

Mitsuo Satoh

Koichi Kato

Affiliations

Soon will be listed here.

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 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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