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

• Main Authors: Yuki Minayoshi, Hitoshi Maeda, Hiroki Yanagisawa, Keisuke Hamasaki, Yuki Mizuta, Kento Nishida, Ryo Kinoshita, Yuki Enoki, Tadasi Imafuku, Victor Tuan Giam Chuang, Tomoaki Koga, Yukio Fujiwara, Motohiro Takeya, Kayoko Sonoda, Tomohiko Wakayama, Kazuaki Taguchi, Yu Ishima, Tatsuhiro Ishida, Yasuko Iwakiri, Motohiko Tanaka, Yutaka Sasaki, Hiroshi Watanabe, Masaki Otagiri, Toru Maruyama
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2018-01-01
• Series: Drug Delivery
• Subjects: type-i interferon; kupffer cell; albumin fusion technology; mannose; anti-inflammation; immunomodulation
• Online Access: http://dx.doi.org/10.1080/10717544.2018.1464083

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.