Work carried out by JM was funded by the
National Institutes of Health (NIH). NIH contract
number is HHSN272201000039I/HHSN27200001/
A19

Adam Walker

AM Wu

Armin Sepp

CL Van Broekhoven

Daniel Rycroft

DJ Peng

E Buster

E Coulstock

E Dieperink

Edward Coulstock

ES Ward

F Pacifico

Fiona Kelly

G Dusheiko

Jane Sosabowski

JD Morrey

JH Park

John Morrey

KA Deal

Laura Goodall

LC Platanias

LJ Holt

M Spiess

Marie Davies

Milan Ovečka

R Duncan

R Iorio

Rafael Aldabe

Rob Prince

Robert Hamatake

Sarah Friel

T Eto

U Iyer

U Treichel

WGE Cooksley

WM Pardridge

XQ Zhang

Y Zhang

YI Jeong

YY Seow

PLoS ONE

Interferon alpha (IFNα) is used for the treatment of hepatitis B virus infection, and whilst efficacious, it is associated with multiple adverse events caused by systemic exposure to interferon. We therefore hypothesise that targeting IFN directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. Furthermore we investigated whether directing IFN to the reservoir of infection in the liver may improve antiviral efficacy by increasing local concentration in target organs and tissues. Our previous results show that the mIFNα2 fused to an ASGPR specific liver targeting antibody, DOM26h-196-61, results in a fusion protein which retains the activity of both fusion partners when measured in vitro. In vivo targeting of the liver by mIFNα2-DOM26h-196-61, hereafter referred to as targeted mIFNα2, was observed in microSPECT imaging studies in mice. In this study we show by pharmacokinetic analysis that antibody mediated liver-targeting results in increased uptake and exposure of targeted mIFNα2 in target tissues, and correspondingly reduced uptake and exposure in systemic circulation, clearance organs and non-target tissues. We also show that cytokine activity and antiviral activity of liver-targeted IFN is observed in vivo, but that, contrary to expectations, liver-targeting of mIFNα2 using ASGPR specific dAbs actually leads to a reduced pharmacodynamic effect in target organs and lower antiviral activity in vivo when compared to non-targeted mIFNα2-dAb fusions

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Pharmacokinetic characteristics, pharmacodynamic effect and in vivo antiviral efficacy of liver-targeted interferon alpha.

Crossref

Pharmacokinetic Characteristics, Pharmacodynamic Effect and In Vivo Antiviral Efficacy of Liver-Targeted Interferon Alpha

Rycroft, D

Sosabowski, J

Coulstock, E

Davies, M

Morrey, J

Friel, S

Kelly, F

Hamatake, R

Ovecka, M

Prince, R

Goodall, L

Sepp, A

Walker, A

Queen Mary Research Online

Rycroft Daniel

Sosabowski Jane

Coulstock Edward

Davies Marie

Morrey John

Friel Sarah

Kelly Fiona

Hamatake Robert

Ovečka Milan

Prince Rob

Goodall Laura

Sepp Armin

Walker Adam

Public Library of Science (PLOS)

 Antiviral Efficacy of Liver-Targeted Interferon Alpha

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/15123/Sosabowski%20Pharmacokinetic%20characteristics%202015%20Published.pdf?sequence=1

Pharmacokinetic Characteristics, Pharmacodynamic Effect and In Vivo Antiviral Efficacy of Liver-Targeted Interferon Alpha

Abstract

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Directory of Open Access Journals

Crossref

Queen Mary Research Online

Public Library of Science (PLOS)