Research ArticleAutoimmunity

Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain

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Science Translational Medicine  24 Jul 2019:
Vol. 11, Issue 502, eaaw1736
DOI: 10.1126/scitranslmed.aaw1736

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Taming cytokine signaling through TYK2 inhibition

Targeting Janus kinases can interrupt cytokine signaling in autoimmune disease, but the current inhibitors are not specific. Burke et al. investigated inhibiting a related kinase, TYK2. The inhibitor, BMS-986165, was selective and able to prevent human cells from responding to IL-12, IL-23, or type I IFN. BMS-986165 prevented disease in mouse models of colitis or systemic lupus erythematosus. BMS-986165 treatment of cells from patients with lupus resulted in diminished IFN signature. The drug was well tolerated by healthy volunteers during a phase 1 trial and dampened responses to an in vivo IFN challenge. The drug has already shown promise in a separate phase 2 study of patients with psoriasis and could be broadly applied to other autoimmune diseases.

Abstract

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

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