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

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 TanakaYutaka Sasaki, Hiroshi Watanabe, Masaki Otagiri, Toru Maruyama

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1067-1077
Number of pages11
JournalDrug Delivery
Volume25
Issue number1
DOIs
Publication statusPublished - 2018 Nov 1
Externally publishedYes

Fingerprint

Interferon Type I
Kupffer Cells
Hepatitis
Anti-Inflammatory Agents
Concanavalin A
Oligosaccharides
Albumins
Interferon Receptors
Interleukin 1 Receptor Antagonist Protein
Site-Directed Mutagenesis
Interleukin-10
Proteins
mannose-bovine serum albumin conjugate
Technology
Messenger RNA
Liver
Wounds and Injuries
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

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

In: Drug Delivery, Vol. 25, No. 1, 01.11.2018, p. 1067-1077.

Research output: Contribution to journalArticle

Minayoshi, Y, Maeda, H, Yanagisawa, H, Hamasaki, K, Mizuta, Y, Nishida, K, Kinoshita, R, Enoki, Y, Imafuku, T, Chuang, VTG, Koga, T, Fujiwara, Y, Takeya, M, Sonoda, K, Wakayama, T, Taguchi, K, Ishima, Y, Ishida, T, Iwakiri, Y, Tanaka, M, Sasaki, Y, Watanabe, H, Otagiri, M & Maruyama, T 2018, 'Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions', Drug Delivery, vol. 25, no. 1, pp. 1067-1077. https://doi.org/10.1080/10717544.2018.1464083
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. / Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions. In: Drug Delivery. 2018 ; Vol. 25, No. 1. pp. 1067-1077.
@article{998b1de2ebb544e3ba8dd6028a3445d0,
title = "Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions",
abstract = "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.",
keywords = "albumin fusion technology, anti-inflammation, immunomodulation, Kupffer cell, mannose, Type-I interferon",
author = "Yuki Minayoshi and Hitoshi Maeda and Hiroki Yanagisawa and Keisuke Hamasaki and Yuki Mizuta and Kento Nishida and Ryo Kinoshita and Yuki Enoki and Tadasi Imafuku and Chuang, {Victor Tuan Giam} and Tomoaki Koga and Yukio Fujiwara and Motohiro Takeya and Kayoko Sonoda and Tomohiko Wakayama and Kazuaki Taguchi and Yu Ishima and Tatsuhiro Ishida and Yasuko Iwakiri and Motohiko Tanaka and Yutaka Sasaki and Hiroshi Watanabe and Masaki Otagiri and Toru Maruyama",
year = "2018",
month = "11",
day = "1",
doi = "10.1080/10717544.2018.1464083",
language = "English",
volume = "25",
pages = "1067--1077",
journal = "Drug Delivery",
issn = "1071-7544",
publisher = "Informa Healthcare",
number = "1",

}

TY - JOUR

T1 - Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions

AU - Minayoshi, Yuki

AU - Maeda, Hitoshi

AU - Yanagisawa, Hiroki

AU - Hamasaki, Keisuke

AU - Mizuta, Yuki

AU - Nishida, Kento

AU - Kinoshita, Ryo

AU - Enoki, Yuki

AU - Imafuku, Tadasi

AU - Chuang, Victor Tuan Giam

AU - Koga, Tomoaki

AU - Fujiwara, Yukio

AU - Takeya, Motohiro

AU - Sonoda, Kayoko

AU - Wakayama, Tomohiko

AU - Taguchi, Kazuaki

AU - Ishima, Yu

AU - Ishida, Tatsuhiro

AU - Iwakiri, Yasuko

AU - Tanaka, Motohiko

AU - Sasaki, Yutaka

AU - Watanabe, Hiroshi

AU - Otagiri, Masaki

AU - Maruyama, Toru

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - albumin fusion technology

KW - anti-inflammation

KW - immunomodulation

KW - Kupffer cell

KW - mannose

KW - Type-I interferon

UR - http://www.scopus.com/inward/record.url?scp=85053734891&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053734891&partnerID=8YFLogxK

U2 - 10.1080/10717544.2018.1464083

DO - 10.1080/10717544.2018.1464083

M3 - Article

C2 - 29688069

AN - SCOPUS:85053734891

VL - 25

SP - 1067

EP - 1077

JO - Drug Delivery

JF - Drug Delivery

SN - 1071-7544

IS - 1

ER -