SP2H selectively depletes Stimulator of Interferon Genes (STING), reducing inflammation and improving survival in Trex1-/- mice 2255319

Abstract

Abstract Introduction STING contributes to the pathogenesis of autoimmune diseases, e.g. systemic sclerosis (SSc) and lupus (SLE). SP2H is a targeted STING degrader that depletes STING in cell lines and human fibroblasts (HFs), potently inhibiting interferon (IFN)-beta and chemokine expression induced by STING agonists, e.g. diABZI. Methods Proteomic analyses were performed in primary HFs after 26h exposure to 1 micromolar SP2H with and without exposure to 0.3 micromolar diABZI for the final 6h of incubation. C57Bl/6 and Trex1-/- mice were treated with SP2H subcutaneously (sc), either with single doses or once-daily in repeat dose studies. Trex1-/- mice were randomized by sex, body weight, serum anti-double stranded DNA antibody titre and serum lactate dehydrogenase level before the initiation of treatment at age 6 weeks. Chemokines and cytokines in mouse serum samples were quantified by ELISA. Results HFs incubated with SP2H showed selective STING depletion (>95%) and potent inhibition of diABZI-induced inflammatory protein expression, e.g. ISG15 and COX-2. When given to mice 16h before an iv dose of diABZI, a single sc dose of 3mg/kg SP2H resulted in 1.6-, 2.3-, 2.7- and >1.2log10 reductions in serum CXCL10, CCL2, IL-6, and IFN-beta (all p < 0.01). Immunohistochemistry with AI-assisted quantification showed large and significant reductions in STING levels in lung, kidney and other tissues from mice treated for 14d with SP2H compared to controls. Treatment of Trex1-/- mice with 0.3 or 3mg/kg SP2H sc qd for 8 weeks was well tolerated and improved overall survival compared to control (Kaplan-Meier, p = 0.0494), with 100% survival at the 3mg/kg dose. This dose lowered serum CXCL10 and TNF-alpha by > 4.5-fold compared to the control arm and significantly reduced inflammatory gene expression (Cxcl10, Tnfa, Ifnb, Isg15, Ifi44) in the heart at the end of treatment. Conclusion Given its excellent biological and safety profile, SP2H is being developed for diseases involving pathological STING activation including SSc and SLE. Funding Source Sulis Therapeutics Topic Categories Therapeutic Approaches to Autoimmunity (THER)