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Hinge-Deficient IgG1 Fc Fusion: Application to Human Lactoferrin
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00221 Yuki Shiga 1 , Daisuke Murata 1 , Akinori Sugimoto 1 , Yuta Oshima 1 , Minoru Tada 2 , Akiko Ishii-Watabe 2 , Kenichiro Imai 3, 4 , Kentaro Tomii 3, 4 , Takashi Takeuchi 5 , Shinji Kagaya 6 , Atsushi Sato 1
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00221 Yuki Shiga 1 , Daisuke Murata 1 , Akinori Sugimoto 1 , Yuta Oshima 1 , Minoru Tada 2 , Akiko Ishii-Watabe 2 , Kenichiro Imai 3, 4 , Kentaro Tomii 3, 4 , Takashi Takeuchi 5 , Shinji Kagaya 6 , Atsushi Sato 1
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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.
更新日期：2017-08-19
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