Targeting the hepatitis B virus precore antigen with a novel IgNAR single variable domain intrabody
2011
Walsh, Renae | Nuttall, Stewart | Revill, Peter | Colledge, Danni | Cabuang, Liza | Soppe, Sally | Dolezal, Olan | Griffiths, Kate | Bartholomeusz, Angeline | Locarnini, Stephen
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-α) have significantly lower serum HBeAg levels. Here, we describe a novel reagent, a single variable domain (VNAR) of the shark immunoglobulin new antigen receptor (IgNAR) antibodies. VNARs possess advantages in stability, size (~14kDa) and cryptic epitope recognition compared to conventional antibodies. The VNAR 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 VNAR 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.
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