Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions

Drug Delivery

Hiroshi Watanabe¹  Tadasi Imafuku¹  Yuki Enoki¹  Kento Nishida¹  Keisuke Hamasaki¹  Hiroki Yanagisawa¹  Hitoshi Maeda¹  Toru Maruyama¹  Ryo Kinoshita¹  Yuki Minayoshi¹  Yuki Mizuta¹  Yukio Fujiwara²  Motohiro Takeya²  Yutaka Sasaki³  Motohiko Tanaka³  Kayoko Sonoda⁴  Tomohiko Wakayama⁴  Yasuko Iwakiri⁵  Tomoaki Koga⁶  Tatsuhiro Ishida⁷  Yu Ishima⁷  Kazuaki Taguchi⁸  Masaki Otagiri⁸  Victor Tuan Giam Chuang⁹ 

[1] Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japa;Department of Histology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;Department of Internal Medicine, Sections of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA;Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan;Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, Kumamoto, Japan;School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia;

关键词: Type-I interferon;    Kupffer cell;    albumin fusion technology;    mannose;    anti-inflammation;    immunomodulation;   

DOI  :  10.1080/10717544.2018.1464083

来源: publisher

【 摘 要 】

Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.

【 授权许可】

CC BY