Targeted delivery of interferon-α to hepatitis B virus-infected cells using T-cell receptor-like antibodies

Changhua Ji, Konduru S.R. Sastry, Georg Tiefenthaler, Jennifer Cano, Tenny Tang, Zi Zong Ho, Denise Teoh, Sandhya Bohini, Antony Chen, Surya Sankuratri, Paul A. Macary, Patrick Kennedy, Han Ma, Stefan Ries, Klaus Klumpp, Erhard Kopetzki, Antonio Bertoletti

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33 Citations (Scopus)

Abstract

During antiviral therapy, specific delivery of interferon-α (IFNα) 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 IFNα molecules to produce TCR-L/IFNα fusion proteins. We demonstrate that the fusion proteins triggered an IFNα response preferentially on the hepatocytes presenting the correct HBV-peptide HLA-complex and that the mechanism of the targeted IFNα 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 IFNα to TCR-L decreased the intrinsic biological activity of IFNα but preserved the overall specificity of the protein for the cognate HBV peptide/HLA complexes. This induction of an effective IFNα response selectively in HBV-infected cells might have a therapeutic advantage in comparison to the currently used native or pegylated IFNα.

Original languageEnglish
Pages (from-to)2027-2038
Number of pages12
JournalHepatology
Volume56
Issue number6
DOIs
Publication statusPublished - 1 Dec 2012

ASJC Scopus subject areas

  • Hepatology

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    Ji, C., Sastry, K. S. R., Tiefenthaler, G., Cano, J., Tang, T., Ho, Z. Z., Teoh, D., Bohini, S., Chen, A., Sankuratri, S., Macary, P. A., Kennedy, P., Ma, H., Ries, S., Klumpp, K., Kopetzki, E., & Bertoletti, A. (2012). Targeted delivery of interferon-α to hepatitis B virus-infected cells using T-cell receptor-like antibodies. Hepatology, 56(6), 2027-2038. https://doi.org/10.1002/hep.25875