サトウ　アツシ   佐藤　淳    所属   応用生物学部 応用生物学科    職種   教授
言語種別	英語
発行・発表の年月	2017/08
形態種別	学術論文
査読	査読あり
標題	Hinge-deficient IgG1 Fc fusion: Application to human lactoferrin
執筆形態	共著
掲載誌名	Molecular pharmaceutics
掲載区分	国外
出版社・発行元	American Chemical Society
著者・共著者	Yuki Shiga, Daisuke Murata, Akinori Sugimoto, Yuta Oshima, Minoru Tada, Akiko Ishii-Watabe, Kenichiro Imai, Kentaro Tomii, Takashi Takeuchi, Shinji Kagaya, Atsushi Sato
概要	Fusion of therapeutic proteins with the antibody Fc domain is a strategy widely applied to increase protein half-life in plasma. In our previous study, we generated a recombinant human lactoferrin (hLF)-immunoglobulin G1 Fc fusion protein (hLF-hinge-CH2-CH3) with improved stability, biological activity, and pharmacokinetics (Shiga, Y. et al., Eur J Pharm Sci., 2015, 67, 136-143). However, the Fc domain in fusion proteins can potentially induce antibody-dependent and complement-dependent cytotoxicity and serious side effects. To overcome these drawbacks, we engineered an hLF-Fc fusion protein (hLF-CH2-CH3) without the Fc hinge region which is essential for engaging Fc receptors on immune cells and inducing complement-mediated cell lysis. The hLF-CH2-CH3 protein was stably expressed in Chinese hamster ovary (CHO) DG44 cells and compared for in vitro activities, thermal stability, pharmacokinetics, and attenuation of Fc-mediated immune effector functions with the conventional hinge-containing Fc fusion protein. Both hLF-hinge-CH2-CH3 and hLF-CH2-CH3 exhibited iron-binding activity, superior uptake by Caco-2 cells, similar thermal stability, and longer plasma half-life compared to recombinant hLF. However, in contrast to conventional hLF-hinge-CH2-CH3, hinge-deficient hLF-CH2-CH3 did not elicit Fc-mediated effector response potentially damaging for the target cells. Our findings demonstrate that conjugation of hinge-deficient Fc to therapeutic proteins is a promising strategy for improving their pharmacokinetic properties without enhancing effector functions. Cell-expressed hinge-deficient hLF-CH2-CH3 is a potential drug candidate with improved plasma half-life for parenteral administration.
外部リンクURL	http://pubs.acs.org/doi/10.1021/acs.molpharmaceut.7b00221