Figure 4. MIS416 induces pDC IFN-α production. Human pDCs were purified from PBMCs using magnetic bead selection of BDCA-2+
cells to high purity and viability. Sorted pDC were cultured at 2.6 x 105 cells/mL in the presence of assay positive control (TLR9 ligand (CpG A ODN 2216; 1 µm) or a dose-response of MIS416 for 24
hours. Supernatants were assayed for IFN-α content using flow cytometry cytokine bead array methodology.
Several innate immune responses are considered to be able to contribute to the control of viral infections. These effector
mechanisms are multifaceted and include direct antiviral activities and immunomodulatory effects on infected host immune cells
that contribute to the elimination of these cells. Direct antiviral activity may comprise soluble factors, such as CD8 antiviral
factor (CAF) and IFN-α, which have the capacity to directly affect viral transcription. Although a wide range of other innate
cytokines can mediate biologic functions regulating aspects of antiviral immunity, high levels of IFN-α/β appear to be dominant
in the context of viral infections and act to regulate other innate responses. The clinical use of IFN-α in treating a variety
of viral disorders such as chronic hepatitis B and C, and a broad range of human cancers, lies in its ability to induce a
dominant array of antiviral genes that drive pleiotropic host defense pathways that prevent viral replication. Virionyx's
MIS416 has been designed to induce both high levels of IFN-α and other key pro-inflammatory cytokines that are clinically
relevant to the induction of broad-spectrum innate antiviral immunity. Plasamocytoid dendritic cells demonstrate potent induction
of IFN-α following MIS416 uptake (Figure 4). Preclinical studies demonstrate MIS416 is able to inhibit mortality and ameliorate
morbidity in a mouse influenza A model when administered following viral exposure (Figure 5).