LAUSR

ABSTRACT Interferon &agr; (IFN&agr;) so far is the only therapeutic option for chronic hepatitis B virus (HBV) infection that can lead to virus clearance. Unfortunately, its application is limited by side effects and response rates are low. The aim of this study was to generate a novel long‐acting IFN&agr; with the help of PASylation technology that adds a polypeptide comprising Proline, Alanine and Serine (PAS) to increase plasma half‐life. Following evaluation of four selected recombinant murine IFN&agr; (mIFN&agr;) subtypes in cell culture, the most active subtype, mIFN&agr;11, was fused with a 600 amino acid PAS chain. The activity of PAS‐mIFN&agr; was assessed by interferon bioassay and further evaluated for induction of interferon‐stimulated genes (ISG) and antiviral efficacy in cell culture as well as in HBV‐transgenic mice. PAS‐mIFN&agr; induced expression of ISG comparable to unmodified mIFN&agr; and, likewise, evoked dose‐dependent reduction of HBV replication in vitro. In vivo, PAS‐mIFN&agr; led to pronounced suppression of HBV replication without detectable liver damage whereas conventional mIFN&agr; treatment only had a modest antiviral effect. Importantly, all PAS‐mIFN&agr; treated mice showed an anti‐HBs antibody response, lost HBsAg and achieved seroconversion after three weeks. PASylated IFN&agr; showed a profoundly increased antiviral effect in vivo compared to the non‐modified version without toxicity, providing proof‐of‐concept that an improved IFN&agr; can achieve higher rates of HBV antiviral and immune control. HIGHLIGHTSA novel, long‐acting interferon taking advantage of the PASylation technology was generated.PASylated IFN&agr; induced interferon‐stimulated genes and controlled HBV as efficiently as unmodified mIFN&agr; in vitro.PASylated IFN&agr; was well tolerated and more efficiently suppressed HBV replication in vivo.PASylated but not the unmodified IFN&agr; induced loss of HBsAg as well as anti‐HBs seroconversion in HBV transgenic mice.