A member of the JAK family, Tyrosine Kinase 2 (TYK2) is a key regulator of both innate and adaptive immunity by regulating type 1 interferon, IL-12 and IL-23 signaling. In multiple autoimmune diseases, these cytokine pathways are overactive and drive the disease pathology. Inhibition of the TYK2 pathway can disrupt the proinflammatory feedback loop and promote disease resolution.
TYK2 Immune Signaling
TYK2 signaling is initiated by the binding of type 1 interferon, IL-12 or IL-23 to their cognate transmembrane receptors. This results in the phosphorylation and subsequent activation of a family of transcription factors called signal transducer and activator of transcription (STAT). Activated STAT subsequently translocates to the cell nucleus where it induces the expression of genes that drive the immune response to cytokine signaling.
TYK2 Role in Disease
In autoimmune diseases such as psoriasis, lupus, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis and ankylosing spondylitis, overactive cytokine pathways drive the disease pathology. The essential role of TYK2 signaling in these diseases has been shown by studies of human naturally occurring genetic mutations and in genetic deletion/knockout animal disease models.
Human genetic association studies have demonstrated that TYK2 gene variants leading to loss of function provide a highly protective effect against multiple autoimmune diseases. In addition, a genotype was defined in which the protective effect of TYK2 loss of function was achieved without leading to immunodeficiency, supporting the potential to safely achieve the therapeutic benefits of TYK2 inhibition through pharmacological intervention1 .
Therapeutic Potential of TYK2 Inhibition
A selective inhibitor of TYK2 has the potential to promote resolution of multiple autoimmune diseases associated with overactivity of type 1 interferon, IL-12 or IL-23 signaling. Emerging data suggest that a selective, oral, small molecule inhibitor of TYK2 has the potential to achieve efficacy comparable to biologic therapies targeting the IL-12/IL-23 axis.
1 Dendrou et al., Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci Transl Med. (2016);8:363-149