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Targeted delivery of interferon‐α to hepatitis B virus‐infected cells using T‐cell receptor‐like antibodies
Author(s) -
Ji Changhua,
Sastry Konduru S.R.,
Tiefenthaler Georg,
Cano Jennifer,
Tang Tenny,
Ho Zi Zong,
Teoh Denise,
Bohini Sandhya,
Chen Antony,
Sankuratri Surya,
Macary Paul A.,
Kennedy Patrick,
Ma Han,
Ries Stefan,
Klumpp Klaus,
Kopetzki Erhard,
Bertoletti Antonio
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25875
Subject(s) - t cell receptor , epitope , hepatitis b virus , virology , antibody , biology , interferon , antigen , human leukocyte antigen , t cell , immune system , immunology , virus
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. (H EPATOLOGY 2012;56:2027–2038)