OP0275 THE PI3KΔ INHIBITOR INCB050465 AMELIORATES SALIVARY GLAND PATHOLOGY AND REDUCES AUTOANTIBODY FORMATION IN A MURINE MODEL OF SJÖGREN’S SYNDROME

Abstract

Background Sjogren’s syndrome (SS) is a chronic autoimmune exocrinopathy affecting the glands that produce tears, saliva and vaginal and bronchial secretions. SS represents a complex interaction between the adaptive immune system and specific tissue regions of exocrine glands. Germinal ectopic lymphoid structures that are rich in autoimmune B-cells are thought to play an important role in local chronic B-cell activation and clonal expansion, autoantibody production, and Ig class switching in SS1. Genetic deletion or pharmacological inhibition of PI3Kδ leads to defective B-cell activation, reduced proliferation and functional suppression. INCB050465, an oral small molecule selective PI3Kδ inhibitor, is currently being evaluated in clinical trials for the treatment of B-cell driven autoimmune diseases: SS and autoimmune hemolytic anemia (NCT03627065 & NCT03538041). Objectives To evaluate INCB050465 efficacy as a monotherapy in a spontaneous murine model of Sjogren’s syndrome. Methods The NOD.ShiLtJ mice develop progressive autoimmunity primarily targeting salivary glands that share many disease characteristics with SS. Histological assessment of salivary glands constituted a primary efficacy endpoint. Additional readouts included autoantibody and cytokine quantification in serum and saliva. INCB050465 efficacy was also assessed in a mechanistic dinitrophenol-keyhole limpet hemocyanin (DNP-KLH) mouse model of B-cell activation and de novo anti-specific immunoglobulin production. Serum was collected to quantify DNP-specific immunoglobulin levels. Spleen tissue was investigated for B-cell subsets using flow cytometry. Results INCB050465 treatment (0.1-1 mg/kg, b.i.d.) dose-dependently ameliorated the severity of salivary gland inflammation (p Conclusion INCB050465 administration ameliorated germinal center formation, inhibited salivary gland inflammation and reduced autoantibody titers as a single agent in a dose-dependent manner. Together, the data suggest that INCB050465, a selective PI3Kδ inhibitor, may have potential as a therapeutic agent for the treatment of Sjogren’s syndrome. Reference [1] Salomonsson, et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren’s syndrome. Arthritis Rheum. 2003; 48(11): 3187-3201. Disclosure of Interests Brittany Fay Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Monika Scuron Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Niu Shin Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Yan-ou Yang Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Eddy Yue Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Andrew Combs Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Julian Oliver Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Felicia Thomas Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Roni Page Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Eduardo Huarte Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation., Paul Smith Shareholder of: The author is an employee and/or shareholder of Incyte Corporation., Employee of: The author is an employee and/or shareholder of Incyte Corporation.