OP0164 Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase

Background Lupus nephritis (LN) causes significant morbidity and mortality in SLE patients. Autoantibody-containing immune complexes (ICs) can activate complement cascades and Fc receptors on resident and infiltrating cells within the kidney, thus promoting inflammation. Bruton9s tyrosine kinase (BTK) is a tyrosine kinase important for B cell development, Fc receptor signaling, and macrophage polarization. Objectives To assess the role of BTK in the pathogenesis of nephritis in an inducible model of LN, and to evaluate the therapeutic potential of BTK inhibition. Methods A novel, highly selective, and potent (mouse whole blood CD69 IC 50 =13±2 nM) BTK inhibitor, BI-BTK-1 (Boehringer Ingelheim), was tested in female 129 sv/J mice (10 weeks of age) injected with nephrotoxic serum (NTS), an experimental model which closely mimics LN. Mice pre-immunized with rabbit IgG (Day 0) were administered NTS containing rabbit anti-mouse glomerular antibodies (Day 5), inducing a severe IC-mediated crescentic glomerulonephritis. Mice that did not receive the NTS transfer were used as healthy controls. Mice were treated once daily with vehicle alone or BI-BTK-1 (0.3–10 mg/kg, n=16/group), before the transfer of NTS as a prophylactic assessment, or after the transfer of NTS as a therapeutic assessment. Results NTS-challenged mice treated with BI-BTK-1 exhibited a statistically significant, dose responsive protection from kidney disease. Compared to vehicle treated mice, NTS-challenged mice treated with 10 mg/kg BI-BTK-1 had significantly less proteinuria (1220 mg/dl vs 10 mg/dl, respectively, p Conclusions Our results further confirm the important role for BTK activation in the pathogenesis of immune complex-mediated nephritis, and highlight BTK as a valuable therapeutic target. Taken together with previously published studies and our preliminary results in spontaneous lupus models, these findings further strengthen the rationale for selective BTK inhibition as a promising approach to the treatment of LN. Disclosure of Interest S. Chalmers: None declared, J. Doerner: None declared, T. Bosanac Employee of: Boehringer Ingelheim, S. Khalil Employee of: Boehringer Ingelheim, D. Smith Employee of: Boehringer Ingelheim, C. Harcken Employee of: Boehringer Ingelheim, J. Dimock Employee of: Boehringer Ingelheim, E. Der: None declared, L. Herlitz: None declared, D. Webb Employee of: Boehringer Ingelheim, E. Seccareccia Employee of: Boehringer Ingelheim, D. Feng Employee of: Boehringer Ingelheim, J. Fine Employee of: Boehringer Ingelheim, M. Ramanujam Employee of: Boehringer Ingelheim, E. Klein Employee of: Boehringer Ingelheim, C. Putterman Grant/research support from: Boehringer Ingelheim