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

Abstract

UNLABELLED:

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.

• Authors: 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
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 56 Issue 6 Pg. 2027-38 (Dec 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22684948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Antibodies, Viral
• Antiviral Agents
• Chemokines
• Drug Carriers
• HLA-A Antigens
• Interferon-alpha
• Recombinant Fusion Proteins

Topics

• Animals
• Antibodies, Viral (immunology, pharmacology)
• Antiviral Agents (pharmacology)
• Artificial Gene Fusion
• CD8-Positive T-Lymphocytes (drug effects)
• Chemokines (metabolism)
• Drug Carriers (pharmacology)
• HLA-A Antigens (immunology)
• Hep G2 Cells
• Hepatitis B (drug therapy, immunology, virology)
• Hepatitis B virus (genetics, immunology)
• Humans
• Interferon-alpha (pharmacology)
• Lymphocyte Activation (drug effects)
• Mice
• Recombinant Fusion Proteins (pharmacology)