FRI0216B SELECTIVE IRAK4 INHIBITOR DAMPENS MYD88 SIGNALING AND AMELIORATES INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF LUPUS NEPHRITIS
Authors: Dania Rabah, Ramon Bonegio, Agnes Gardet, Holly Legault, Ian Rifkin, Ti Wang, Chris Roberts, Jeffery Vessels, Norm Alliare, Andrea Bertolotti-Ciarlet, Kevin Guckian
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> IRAK4 is an important signaling mediator of the innate immune system. IRAK4 initiates MyD88-dependent signaling from most TLRs and from IL-1Rs, resulting in downstream production of pro-inflammatory cytokines<sup>1</sup>. <h3>Objectives</h3> Inhibition of IRAK4 kinase activity is a promising therapeutic approach for the treatment of autoimmune diseases, such as lupus. To this end, we identified a potent and highly selective inhibitor of IRAK4 kinase activity, BIIB-IRAK4i. <h3>Methods</h3> Recombinant kinase assays and DiscoveRx kinomescan were used to measure BIIB-IRAK4i kinase inhibition and selectivity, respectively. BIIB-IRAK4i -mediated proximal and distal pharmacodynamics effects (PD) were measured in both cell lines and whole blood assays. The ability of BIIB-IRAK4i to inhibit cytokine production induced by TLR ligands was measured <i>in vitro</i> and <i>in vivo</i>. Acute antibody-mediated lupus nephritis mouse model, which is a TLR-7 dependent and characterized by severe glomerular proliferative lesions with crescent formation, was used to determine the efficacy of BIIB-IRAK4i. <h3>Results</h3> BIIB-IRAK4i displayed equipotent proximal inhibition of MYD88 signaling and distal inhibition of cytokine production <i>in vitro</i>. BIIB-IRAK4i led to potent inhibition of cytokine production in whole blood assays stimulated with various synthetic TLR ligands as well as more physiological stimuli such as immune complexes, a hallmark of lupus pathogenesis. BIIB-IRAK4i inhibited TLR9-mediated cytokine production with same potency in vitro and in vivo. In addition, BIIB-IRAK4i decreased both inflammation and fibrosis in an acute antibody-mediated lupus nephritis mouse model. BIIB-IRAK4i inhibited crescent formation as well as markers of tubulointerstitial fibrosis., which are both associated with decreased survival and adverse outcomes in human lupus nephritis. <h3>Conclusion</h3> Our study highlights that pharmacological inhibition of IRAK4 can reverse two key components of lupus nerhrtis; the inflammatory and the fibrotic response. <h3>References</h3> [1] O'Neill LA and Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signaling. Nat Rev Immunol. 200 7 May;7(5):353-64. <h3>Disclosure of Interests</h3> Dania Rabah Shareholder of: Employee and shareholder of Biogen, Employee of: Biogen, Ramon Bonegio Grant/research support from: Merck, Chugai Pharmaceuticals, Astra Zeneca, Aurinia Pharmacueticals, Consultant for: Merck, Chugai Pharmaceuticals, Agnes Gardet Shareholder of: Biogen, Employee of: Biogen, Holly Legault Shareholder of: Biogen, Employee of: Biogen, Ian Rifkin Grant/research support from: Chugai, Merck, Biogen, Kyowa Kirin, Consultant for: Eisai, Ti Wang Shareholder of: Biogen, Employee of: Biogen, Chris Roberts Shareholder of: Biogen, Employee of: Biogen, Jeffery Vessels Shareholder of: Biogen, Employee of: Biogen, Norm Alliare Shareholder of: Biogen, Employee of: Biogen, Andrea Bertolotti-Ciarlet Shareholder of: Biogen, Takeda, Employee of: Biogen, takeda, Kevin Guckian Shareholder of: Biogen, Employee of: Biogen