Targeted Delivery of Interferon-α to Hepatitis B Virus-Infected Cells Using T-Cell Receptor-Like Antibodies

During antiviral therapy, specific delivery of interferon-alpha (IFN alpha) to infected cells may increase its antiviral efficacy, trigger a localized immune reaction, and reduce the side effects caused by systemic administration. Two T-cell receptor-like antibodies (TCR-L) able to selectively bind hepatitis B virus (HBV)-infected hepatocytes of chronic hepatitis B patients and recognize core (HBc18-27) and surface (HBs183-91) HBV epitopes associated with different human leukocyte antigen (HLA)-A*02 alleles (A*02:01, A*02:02, A*02:07, A*02:11) were generated. Each antibody was genetically linked to two IFN alpha molecules to produce TCR-L/IFN alpha fusion proteins. We demonstrate that the fusion proteins triggered an IFN alpha response preferentially on the hepatocytes presenting the correct HBV-peptide HLA-complex and that the mechanism of the targeted IFN alpha response was dependent on the specific binding of the fusion proteins to the HLA/HBV peptide complexes through the TCR-like variable regions of the antibodies. Conclusion: TCR-L antibodies can be used to target cytokines to HBV-infected hepatocytes in vitro. Fusion of IFN alpha to TCR-L decreased the intrinsic biological activity of IFN alpha but preserved the overall specificity of the protein for the cognate HBV peptide/HLA complexes. This induction of an effective IFN alpha response selectively in HBV-infected cells might have a therapeutic advantage in comparison to the currently used native or pegylated IFN alpha (HEPATOLOGY 2012;56:2027-2038)