OP0080 STAT3 DEGRADERS INHIBIT Th17 DEVELOPMENT AND CYTOKINE PRODUCTION RESULTING IN PROFOUND INHIBITION OF COLLAGEN-INDUCED AUTOIMMUNE MURINE ARTHRITIS

Background Signal transducer and activator of transcription 3 (STAT3) is a factor that belongs to class targets devoid catalytic function, thus deemed “undruggable” by standard modalities such as small molecule inhibitors or biologics. STAT3 can be activated various receptor- non-receptor tyrosine kinases, playing critical role in activation pathways triggered cytokines, hormones, growth factors, making it an attractive target for the treatment inflammatory diseases. Objectives Kymera has developed heterobifunctional molecules selectively degradation elimination ubiquitin-proteasome pathway. We sought evaluate pharmacologic potential these degraders through vitro vivo studies relevant human autoimmune disease, including murine collagen-induced arthritis. Methods evaluated impact on monocytes, dermal fibroblasts, CD4+ T cells, PBMC LPS, IL-6/IL-6R, IL-21, IL-23, well anti-CD3/CD28 plus cocktail cytokines antibodies. pSTAT3 inhibition were determined comparison JAK1/2 inhibitor. Inhibition chemokines, collagen release, Th17 (CD4+CD25-RORγt+CXCR6+) Treg (CD4+CD25+CD127lowFOXP3+) expansion used efficacy assays. Finally, tested vivo, mechanistic (IL-6 challenge) disease model (murine CIA) rheumatology indications. Results showed broad potent activity in-vitro against TLR receptor cytokine-induced immune stromal soluble mediator release MCP-1/CCL2 Collagen1a1. cells robustly inhibited development abrogating IL-17, IL-22, IL-8/CXCL8, TNFα production, increased numbers manner superior inhibition. In mice injected with IL-6, plasma levels serum amyloid A dose-dependently suppressed degradation. arthritis model, resulted robust, dose-dependent delay onset decreased incidence, clinical scores, local cytokine expression (paws) histopathological complete alleviation periosteal bone growth. Conclusion These data demonstrate alleviating inflammation models disease. Targeted protein represents novel therapeutic approach treating autoimmune/autoinflammatory diseases rheumatoid Disclosure Interests Cedric Hubeau Shareholder of: Therapeutics, Employee Jeffrey Sullivan Crystal Brown Michele Mayo Vaishali Dixit Bradley Enerson Haojing Rong Bin Yang Chris De Savi Jared Gollob Nello Mainolfi Anthony Slavin Therapeutics.