Cytokine Signalling Forum

Publications





June 19

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Haselmayer P, Camps M, Liu-Bujalski L, Nguyen N, Morandi F, Head J, O’Mahony A, Zimmerli SC, Bruns L, Bender AT, Schroeder P, Grenningloh.
J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583

BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evob...

Keywords: BTK, Preclinical, PK-PD

May 14

Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants

Hartkamp LM, Fine JS, van Es IE et al.
Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissu...

Keywords: BTK, Preclinical, MOA

January 14

PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models

Winkler DG, Faia KL, DiNitto JP et al.
Chemistry and Biology Nov 13 20, 1364-1374

Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in ...

Keywords: Cytokine Signalling, Preclinical, MOA

The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss

Shinohara M, Chang BY, Buggy JJ et al.
Bone 2014;60:8-15

Ibrutinib is a first-in-class, orally available Btk (Bruton’s tyrosine kinase) inhibitor which has been shown to be effective in the treatment against certain types of leukemia and autoimmune disorders. Btk regulates the expression of genes involved in the differentiation and function of osteoclasts, and therefore inhibiting Btk suppresses osteoclastic bone resorption. Results from in vitro testing showed the suppressive effects on osteoclasts and murine models of RA showed ibrutinib treat...

Keywords: BTK, Preclinical, MOA