Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans

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  • Tsunehiro Mizushima
    Graduate School of Pharmaceutical Sciences, Nagoya City University, 3‐1 Tanabe‐dori, Mizuho‐ku, Nagoya 467‐8603, Japan
  • Hirokazu Yagi
    Graduate School of Pharmaceutical Sciences, Nagoya City University, 3‐1 Tanabe‐dori, Mizuho‐ku, Nagoya 467‐8603, Japan
  • Emi Takemoto
    Graduate School of Pharmaceutical Sciences, Nagoya City University, 3‐1 Tanabe‐dori, Mizuho‐ku, Nagoya 467‐8603, Japan
  • Mami Shibata‐Koyama
    Antibody Research Laboratories, Kyowa Hakko Kirin Co., Ltd, 3‐6‐6 Asahi‐machi, Machida‐shi, Tokyo 194‐8533, Japan
  • Yuya Isoda
    Antibody Research Laboratories, Kyowa Hakko Kirin Co., Ltd, 3‐6‐6 Asahi‐machi, Machida‐shi, Tokyo 194‐8533, Japan
  • Shigeru Iida
    Antibody Research Laboratories, Kyowa Hakko Kirin Co., Ltd, 3‐6‐6 Asahi‐machi, Machida‐shi, Tokyo 194‐8533, Japan
  • Kazuhiro Masuda
    Antibody Research Laboratories, Kyowa Hakko Kirin Co., Ltd, 3‐6‐6 Asahi‐machi, Machida‐shi, Tokyo 194‐8533, Japan
  • Mitsuo Satoh
    Antibody Research Laboratories, Kyowa Hakko Kirin Co., Ltd, 3‐6‐6 Asahi‐machi, Machida‐shi, Tokyo 194‐8533, Japan
  • Koichi Kato
    Graduate School of Pharmaceutical Sciences, Nagoya City University, 3‐1 Tanabe‐dori, Mizuho‐ku, Nagoya 467‐8603, Japan

Description

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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