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Abstract Number: 0038

STING Antagonist (IFM4490) Inhibits STING Activation and STING Dependent Signal Transduction in Patients with STING-associated Vasculopathy with Onset in Infancy (SAVI)

Sachin Gaurav1, Bin Lin2, Sophia Park3, Shankar Venkatraman4, David Winkler4 and Raphaela Goldbach-Mansky5, 1Translational Autoinflammatory Diseases Section, LCIM, NIAID,, Bethesda, MD, 2NIH, Bethesda, MD, 3NIAID, Bethesda, MD, 4IFM Therapeutics, Boston, MA, 5NIH/NIAID, Potomac, MD

Meeting: ACR Convergence 2022

Keywords: Autoinflammatory diseases, immunology, Therapy, complementary, Vasculitis

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Session Information

Date: Saturday, November 12, 2022

Title: Pediatric Rheumatology – Basic Science Poster

Session Type: Poster Session A

Session Time: 1:00PM-3:00PM

Background/Purpose: SAVI is a rare, autoinflammatory type I interferonopathy caused by gain-of-function mutations that cause STING activation and excessive production of type I interferons and proinflammatory cytokines. SAVI is difficult-to-treat and is associated with increased morbidity and mortality. Although Janus Kinase (JAK) inhibitors are used to treat SAVI patients, their clinical benefit is limited, and side effects including infection and BK reactivation and cytopenias need to be monitored. Direct STING inhibition may present a strategy to more comprehensively suppress clinically relevant signaling pathways.

Methods: Various disease-causing STING1 mutants: class 1 variants: p.N154S, p.V155M, and p.V147L; Class 3 variants: p.R281Q, p.R284G, p.R284S and p.R281W, and class 4 varients:F153V, G158A, H72N were co-transfected with either IFNB1 firefly luciferase or an NF-kB-SEAP reporter to assess IFNB1 or NF-kB activation respectively. NF-kB activation was also examined in response to IFNAR inhibitor with anifrolumab (100ug/ml). When patients’ fibroblasts were used, cells were stimulated with 2’3’-cGAMP(20ug/ml); 5uM STING antagonist, IFM4490, was used to block STING activation. STING, TBK1, IRF3 phosphorylation and NFkB translocation were assessed. IFNscore were calculated by nanostring analysis. Student T-tests group comparisons were made.

Results: HEK293T cells transfected with mutant STING constructs showed spontaneous and cGAMP-stimulated IFNB1 and NF-kB activation. STING antagonist normalized the IFNB1 and NF-kB activation to levels of non-treated WT cells with most constructs, indicating significantly IFNB1 as well as NF-kB gene inhibition by the STING antagonist. In contrast, cGAMP-stimulated NF-kB-SEAP expression was not inhibited by the anti-interferon alpha receptor (IFNAR) antibody, anifrolumab. In SAVI patients’ and control fibroblasts the STING antagonist significantly blocked cGAMP-induced STING phosphorylation at pS366 residue as well as TBK1 and IRF3 phosphorylation. Fibroblasts do not spontaneously produce IFNb, but cGAMP stimulation resulted in prolonged ISG elevation in patient fibroblasts compared to WT fibroblasts with rising levels at 24 hours post stimulation. The STING inhibitor inhibited cGAMP stimulated IFNscore induction in WT and mutant fibroblasts with IFNscores almost normalized at 24 hours. The STING antagonist also suppressed 2′3′-cGAMP- induced nuclear translocation of p65 in SAVI patients’ fibroblast.

Conclusion: We show that the STING antagonist, IFM4490 blocks STING phosphorylation and phosphorylation of downstream targets, TBK1 and IRF3, as well as IFNB1 reporter activity. Inhibition of NFKB reporter activity with the STING antagonist but not interferon alpha receptor inhibition confirms the requirement of direct STING inhibition in blocking both IRF3 and NFKB activation and introduces STING inhibition as an attractive treatment strategy for SAVI patients and other STING-mediated diseases.

This study was funded in part by the IRP of NIAID, NIH.


Disclosures: S. Gaurav, None; B. Lin, None; S. Park, None; S. Venkatraman, None; D. Winkler, None; R. Goldbach-Mansky, None.

To cite this abstract in AMA style:

Gaurav S, Lin B, Park S, Venkatraman S, Winkler D, Goldbach-Mansky R. STING Antagonist (IFM4490) Inhibits STING Activation and STING Dependent Signal Transduction in Patients with STING-associated Vasculopathy with Onset in Infancy (SAVI) [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/sting-antagonist-ifm4490-inhibits-sting-activation-and-sting-dependent-signal-transduction-in-patients-with-sting-associated-vasculopathy-with-onset-in-infancy-savi/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sting-antagonist-ifm4490-inhibits-sting-activation-and-sting-dependent-signal-transduction-in-patients-with-sting-associated-vasculopathy-with-onset-in-infancy-savi/

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