Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans.
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.
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
Tsunehiro
T
Mizushima
Hirokazu
H
Yagi
Emi
E
Takemoto
Mami
M
Shibata-Koyama
Yuya
Y
Isoda
Shigeru
S
Iida
Kazuhiro
K
Masuda
Mitsuo
M
Satoh
Koichi
K
Kato
D000906:Antibodies / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology*; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology; D011487:Protein Conformation; D017452:Receptors, IgG / Q000737:chemistry* / Q000276:immunology*
D000906:Antibodies; C496124:FCGR3A protein, human; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011134:Polysaccharides; D017452:Receptors, IgG