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

作者：Minayoshi Yuki; Maeda Hitoshi; Yanagisawa Hiroki; Hamasaki Keisuke; Mizuta Yuki; Nishida Kento; Kinoshita Ryo; Enoki Yuki; Imafuku Tadasi; Chuang Victor Tuan Giam; Koga Tomoaki; Fujiwara Yukio; Takeya Motohiro; Sonoda Kayoko; Wakayama Tomohiko; Taguchi Kazuaki; Ishima Yu; Ishida Tatsuhiro; Iwakiri Yasuko; Tanaka Motohiko; Sasaki Yutaka; Watanabe Hiroshi; Otagiri Masaki; Maruyama Toru^*

来源：Drug Delivery, 2018, 25(1): 1067-1077.

DOI：10.1080/10717544.2018.1464083

• Type-I interferon
• Kupffer cell
• albumin fusion technology
• mannose
• anti-inflammation
• immunomodulation

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-IFN2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFN2b, 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 IFN2b, Man-HSA(D494N)-IFN2b 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)-IFN2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFN2b 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)-IFN2b at 2h 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.

• 出版日期2018-4-24