Journal
VIROLOGY
Volume 411, Issue 1, Pages 132-141Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2010.12.034
Keywords
Hepatitis B e antigen; Precore; Chronic hepatitis B; New antigen receptor; Intrabody; Endoplasmic reticulum; BIAcore kinetics; Bacteriophage display
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Funding
- Co-operative Research Centre for Diagnostics
- Bristol-Myers Squibb
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The Hepatitis B virus precore protein is processed in the endoplasmic reticulum (ER) into secreted hepatitis B e antigen (HBeAg), which acts as an immune tolerogen to establish chronic infection. Downregulation of secreted HBeAg should improve clinical outcome, as patients who effectively respond to current treatments (IFN-alpha) have significantly lower serum HBeAg levels. Here, we describe a novel reagent, a single variable domain (V(NAR)) of the shark immunoglobulin new antigen receptor (IgNAR) antibodies. V(NARS) possess advantages in stability, size (similar to 14 kDa) and cryptic epitope recognition compared to conventional antibodies. The V(NAR) domain displayed biologically useful affinity for recombinant and native HBeAg, and recognised a unique conformational epitope. To assess therapeutic potential in targeting intracellular precore protein to reduce secreted HBeAg, the V(NAR) was engineered for ER-targeted in vitro delivery to function as an intracellular antibody (intrabody). In vitro data from HBV/precore hepatocyte cell lines demonstrated effective intrabody regulation of precore/HBeAg. (C) 2010 Elsevier Inc. All rights reserved.
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