TIP Immunology, EMD Serono Billerica, MA, United States
Julia Bruttger1, Andrew Bender2, Sonja Reissig1, Amy Kao3 and Philipp Haselmayer1, 1the healthcare business of Merck KGaA, Darmstadt, Germany, 2TIP Immunology, EMD Serono, Billerica, MA, 3EMD Serono, Billerica, MA
Background/Purpose: Activation of toll-like receptor 7 and 8 (TLR7/8) signaling by single-stranded RNA results in immune cell stimulation and inflammatory cytokine production, a normal circumstance in a protective antiviral host response. In autoimmune conditions such as lupus, aberrant activation of TLR7/8 can be pathogenic and contribute to disease progression. The primary cell types stimulated by TLR7/8 activation are plasmacytoid dendritic cells, B cells, neutrophils and monocytes. In this study, we aimed to determine if a highly selective TLR7/8 inhibitor (TLR7/8i) can reverse established nephritis in a mouse model of lupus.
Methods: NZB/W mice were injected intravenously on two consecutive days with an adenovirus encoding for mouse interferon-alpha (IFN-α) to accelerate and synchronize disease progression. Approximately 4 weeks after IFN-α injection, mice developed proteinuria which was measured and reported as the urine protein:creatinine ratio (UPCR). Treatment with 10 mg/kg of an enpatoran-like TLR7/8i orally once daily was started after animals showed signs of proteinuria (UPCR >3 g/g).
Results: In independent experiments, we found that therapeutic TLR7/8 inhibition lowered proteinuria values as early as 2 weeks after the initiation of treatment. Over a total treatment period of 6 weeks, the majority of mice in the TLR7/8i-treated group were rescued from proteinuria and survival was increased from 0% in the vehicle group to 90% in TLR7/8i-treated group. Conversely, daily administration of 300 mg/kg mycophenolate mofetil did not reverse proteinuria and only rescued survival in 50% of the animals. The glomerulonephritis histology score was significantly reduced after TLR7/8i treatment compared to the vehicle group. Total splenocyte numbers, plasma cells and activated T cells were all reduced, providing insight into the mechanism of action of the TLR7/8i.
Conclusion: In the IFN-α-accelerated NZB/W mouse model, TLR7/8 inhibition effectively reduced established kidney disease, suggesting that this therapeutic strategy may be useful for the treatment of patients with lupus.
Disclosures: J. Bruttger, the healthcare business of Merck KGaA, Darmstadt, Germany; A. Bender, EMD Serono, Billerica, MA, USA, the healthcare business of Merck KGaA, Darmstadt, Germany; S. Reissig, the healthcare business of Merck KGaA, Darmstadt, Germany; A. Kao, EMD Serono, Billerica, MA, USA; P. Haselmayer, the healthcare business of Merck KGaA, Darmstadt, Germany.
