| BackgroundHepatitis B virus (HBV) is one the major causes of chronic liver diseases and hepatocellular carcinoma. Two agents are currently approved for the treatment of chronic hepatitis B: interferon alfa and lamivudine. Each agent has inherent limitations for use in the treatment of chronic hepatitis B. Interferon alfa is effective in a small number of patients and has serious side effects that limit its tolerability. The efficacy of lamivudine is limited by the emergence of drug-resistant hepatitis B virus mutants, restricting its utility as a long-term therapy for chronic hepatitis B. Intracellular antibodies (intrabodies) with specific and high-affinity binding properties have potential in therapy of human diseases, a new therapeutic strategy against HBV infection.Natural antibodies, which are secreted by plasma cells, have evolved to function in an extracellular environment. In contrast, intrabodies can in principle be expressed also in the cytoplasm of eukaryotic cells and directed to any compartment to target intracellular proteins and thus evoke specific biological effects. In the long run, intrabodies might even be used in therapeutic applications, possibly in gene therapy settings.Intrabodies are normally single chain Fv fragments comprising variable domains of the immunoglobulin heavy (VH) and light chains (VL). There are, however, rather few scFv which work efficiently as intrabodies because antibodies are usually made in the endoplasmic reticulum and in the reducing environment of the cell, e.g. in the cytoplasm, scFv cannot form disulphide bonds, which are critical in folding of almost all antibodies, and thus often exhibit insolubility, instability and/or incorrect protein folding. VH (immunoglobulin heavy chain variable domain) can function without the intradomain disulphide bond. Furthermore, current screening protocols require scFv antibody libraries of greater than 109 diversity to facilitate the isolation of a small number of intracellular... |
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