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


CONCLUSIONS
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.
Virology Discovery, Roche Pharma Research and Early Development, Nutley, NJ, USA. changhua.ji@roche.com
Changhua
C
Ji
Konduru S R
KS
Sastry
Georg
G
Tiefenthaler
Jennifer
J
Cano
Tenny
T
Tang
Zi Zong
ZZ
Ho
Denise
D
Teoh
Sandhya
S
Bohini
Antony
A
Chen
Surya
S
Sankuratri
Paul A
PA
Macary
Patrick
P
Kennedy
Han
H
Ma
Stefan
S
Ries
Klaus
K
Klumpp
Erhard
E
Kopetzki
Antonio
A
Bertoletti
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D019677:Artificial Gene Fusion; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D004337:Drug Carriers / Q000494:pharmacology; D015234:HLA-A Antigens / Q000276:immunology*; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D000914:Antibodies, Viral; D000998:Antiviral Agents; D018925:Chemokines; D004337:Drug Carriers; D015234:HLA-A Antigens; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins