Remission induction of established nephritis by therapeutic administration of a novel BTK inhibitor in an inducible model of lupus nephritis

• Published in: The Journal of immunology (1950) Vol. 198; no. 1_Supplement; pp. 224 - 224.16
• Main Authors: Chalmers, Samantha A., Doerner, Jessica L, Bosanac, Todd, Khalil, Sara, Smith, Dustin, Harcken, Christian, Dimock, Janice, Herlitz, Leal, Webb, Deborah, Seccareccia, Elise, Feng, Di, Fine, Jay S, Ramanujam, Meera, Klein, Elliott, Putterman, Chaim
• Format: Journal Article
• Language: English
• Published: 01.05.2017
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.224.16

Abstract Lupus nephritis (LN) patients currently lack highly effective and safe treatment options. Bruton’s tyrosine kinase (BTK) is a tyrosine kinase which is important for B cell and macrophage function. Based on preliminary studies in an inducible model of nephritis that highlighted the importance of BTK dependent macrophage effector function in the pathogenesis of disease, we extended our studies to explore the effect of BTK inhibition on remission induction of established, proliferative nephritis. Nephritis was induced in female 129 sv/J mice (10 weeks of age) via the passive transfer of nephrotoxic serum (NTS). Once a mouse developed severe nephritis (>300 mg/dl proteinuria for two consecutive days, or a single measurement of >2000 mg/dl), treatment begun via daily oral gavage with 3 mg/kg of BI-BTK-1, a novel, highly selective and potent BTK inhibitor. Each treated mouse was matched to a control mouse that received daily gavage of the vehicle alone. Within two days of beginning treatment, mice treated with BI-BTK-1 had a significant reversal of the proteinuria compared to vehicle control treated mice (p<0.05). Terminal urine revealed a significantly reduced A:C ratios (p <0.001). Additionally, terminal serum revealed normalized BUN levels. Histological assessment revealed significant structural protection in the treated compared to control treated mice, including both glomerular (p<0.001) and tubular compartments (p < 0.001). Kidney RT-PCR and RNA-seq analysis are currently in progress. Therapeutic treatment with BI-BTK-1 reversed severe, established nephritis induced by pathogenic antibodies. These exciting results indicate the novel therapeutic potential of BTK inhibition for treating LN patients with established disease.