IRAK4 degradation abrogates cytokine release and improves disease endpoints in murine models of IL-33/36- as well as Th17-driven inflammation

• Published in: The Journal of immunology (1950) Vol. 206; no. 1_Supplement; pp. 66 - 66.16
• Main Authors: Hubeau, Cedric J, Campbell, Veronica, Lee, Albert, Lurier, Emily, Skouras, Stephanie, Mayo, Michele, Fitzgerald, Michael, Wang, Amy, Chen, Dapeng, Rong, Haojing, Zheng, Xiaozhang, Chesworth, Richard, Gollob, Jared, Mainolfi, Nello, Slavin, Anthony
• Format: Journal Article
• Language: English
• Published: 01.05.2021
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.66.16

Abstract Interleukin-1 receptor associated kinase 4 (IRAK4) plays a critical role in TLR and IL-1R mediated inflammation through its catalytic and scaffolding functions, making it an attractive target for the treatment of immune-inflammatory diseases. Kymera has developed oral heterobifunctional molecules that selectively target IRAK4 for degradation by the ubiquitin-proteasome pathway. These degraders have broad and potent activity in-vitro against LPS + IL-1β-induced proinflammatory cytokine and chemokine production that is superior to IRAK4 kinase inhibitors. We evaluated their efficacy in comparison to kinase inhibition in-vivo in both mechanistic, and disease models of skin and CNS inflammation. IRAK4 degraders were administered to mice in models of skin inflammation induced by either IL-33 or IL-36, as well as in an EAE model of Th17-mediated CNS inflammation. In IL-33- and IL-36-induced skin inflammation, IRAK4 degradation resulted in dose-dependent decreases in ear thickness as well as local and systemic cytokines/chemokines that was superior to kinase inhibition. In MOG-induced EAE, IRAK4 degradation was superior to kinase inhibition and significantly reduced disease scores to levels comparable to a S1P receptor agonist. These data demonstrate the broad activity of IRAK4 degradation and its superiority over kinase inhibition in alleviating inflammation induced by IL-1 family cytokines as well as antigen-dependent Th17-mediated inflammation in models relevant to human disease.