Affiliations 

  • 1 a Department of Biopharmaceutics , Graduate School of Pharmaceutical Sciences, Kumamoto University , Kumamoto , Japan
  • 2 b School of Pharmacy , Monash University Malaysia , Bandar Sunway , Malaysia
  • 3 c Department of Molecular Medicine , Graduate School of Pharmaceutical Sciences, Kumamoto University , Kumamoto , Japan
  • 4 d Department of Cell Pathology , Graduate School of Medical Sciences, Kumamoto University , Kumamoto , Japan
  • 5 e Department of Histology , Graduate School of Medical Sciences, Kumamoto University , Kumamoto , Japan
  • 6 f Faculty of Pharmaceutical Sciences and DDS Research Institute , Sojo University , Kumamoto , Japan
  • 7 g Department of Pharmacokinetics and Biopharmaceutics , Institute of Biomedical Sciences, Tokushima University , Tokushima , Japan
  • 8 h Department of Internal Medicine , Sections of Digestive Diseases, Yale University School of Medicine , New Haven , CT , USA
  • 9 i Department of Gastroenterology and Hepatology , Graduate School of Medical Sciences, Kumamoto University , Kumamoto , Japan
Drug Deliv, 2018 Nov;25(1):1067-1077.
PMID: 29688069 DOI: 10.1080/10717544.2018.1464083

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.