Interferons (IFNs) were first described for their ability to protect cells from viral infections 1. Since these initial reports, three major types of IFNs have been described. Type I IFNs, including IFNβ and multiple IFNα subtypes, induce antiviral gene programs through the IFNα/β receptor, IFNAR; many of these genes are directly or indirectly involved in curbing viral replication and spread 2. Type I IFNs have been used to treat both chronic viral infections, such as hepatitis B and C, and a variety of neoplastic conditions, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma 3, 4, 5, 6, 7. Recently, PEGylated IFNs, which show decreased clearance as compared to recombinant IFNs, have emerged as the standard of care. Although PEGylation has increased the therapeutic efficacy of IFN therapy, a wide variety of unpleasant and serious side-effects exist. In this study, we set out to determine whether antibody-IFN fusions could be used as an alternative and allow for specific targeting of IFNs, which we believe would be beneficial in reducing undesired side-effects.

In addition to increasing the potency, a potential advantageous feature of antibody-conjugated type I IFN is the possibility of using the antibody specificity to target type I IFN to specific cells. Therefore, we used anti-HER2-IgG3-IFNα, in which IFNα is fused to a HER2/neu-specific antibody, and 38C13 cells stably expressing the HER2/neu receptor (38C13-HER2). 38C13-HER2 cells infected with MHV-68-Luc were treated with IgG3-IFNα or anti-HER2-IgG3-IFNα. Luciferase activity was reduced more effectively after treatment with anti-HER2-IgG3-IFNα across a broad range of therapeutic doses (Figure 1B, right panel). Importantly, the difference between anti-HER2-IgG3-IFNα and IgG3-IFNα was more prominent at low concentrations, suggesting that anti-HER2-IgG3-IFNα increases the effectiveness of IFNα by targeting IFNα to HER2/neu-expressing cells. When parental 38C13 cells that did not express HER2/neu were used, both fusion proteins similarly inhibited viral replication (data not shown).

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