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

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.

Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta‐cell protection in type 1 diabetes

“…Importantly, during the 12 weeks of the study there were no important side effects on blood counts, immunoglobulins, liver enzymes, electrocardiograms and vital signs, as is the case for JAK inhibitors 11 . The same compound also showed positive effects in preclinical models of lupus nephritis and inflammatory bowel disease 12 . In addition, preclinical evaluation of the TYK2 inhibitor NDI‐031301 showed significant activity against T‐cell acute lymphoblastic leukaemia both in vitro and in an in vivo mouse model, reducing tumour burden and improving survival 33 .…”

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis

“…While there are multiple inhibitors under development for JAK1-3 in autoimmune diseases, there are few TYK2-selective inhibitors, with only one other agent claiming to be TYK2-specific, BMS-986165 (53). BMS-986165 was recently reported as an effective therapeutic for psoriasis in phase II trials (54), and has been shown to inhibit the pseudokinase domain of TYK2 to provide a therapeutic effect against type I IFN-and IL-12-dependent autoimmune disease models in vivo (55). It has further been reported that nonspecific TYK2 inhibitors are effective at blocking IL-23-mediated inflammatory skin disease (56), in line with in vivo reports in TYK2-deficient mice (20).…”

TYK2 in Tumor Immunosurveillance

“…Comprehensive reviews list the cytokines and growth factors able to activate TYK2 by phosphorylation of the critical tyrosine residues in the activation loop [35,[104][105][106]. Here we focus on the cytokine-TYK2 signaling that transduces TYK2 phosphorylation into physiological changes validated by TYK2 deficiency in patients or mouse models (see Table 2) and/or by pharmacological inhibition of TYK2 [107][108][109][110]. Signaling molecules include the interleukin (IL)-12 family (IL-12, IL-23), the type I IFN subfamily (including IFNα subtypes, IFNβ), and the IL-10 family (IL-10, IL-22, IL-26, type III IFNs) [37,111,112].…”

“…Experiments in LOF mice have shown that TYK2 is required for IL-22 responses during skin and intestinal inflammation [95,96]. The only evidence for the role of the IL-22-TYK2 axis in men comes from the pharmacological inhibition of TYK2, which blocks IL-22 responses in various human cells [108,109].…”

“…Unperturbed or suboptimal IFNλ signal transduction is found in TYK2-deficient patient cells [42,43], and pharmacological inhibition of TYK2 reduces the IFNλ responses [107,108].…”