Chief Scientific Officer Sulis Therapeutics Copenhagen N, Hovedstaden, Denmark
Disclosure(s):
Richard Bethell, DPhil: No relevant disclosure to display
Introduction/Rationale: 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.
