Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Post-transcriptional control of cytokine and chemokine gene expression is an important checkpoint during inflammation. The MAPKAPK2 (MK2) pathway in particular is critical in regulating the expression of TNF-α and other inflammatory factors by promoting the stability and translation of their transcripts (Kotlyarov 1999 Nat Cell Biol; Neininger 2002 J Biol Chem). Illustrating the centrality of this pathway, MK2 knockout mice are protected from inflammation in various inflammatory models (Kotlyarov 1999 Nat Cell Biol; Hegen 2006 J Immunol). We hypothesized that inhibition of MK2 would regulate the production of TNF-α and other inflammatory mediators and would therefore ameliorate diseases in which these cytokines and chemokines play a role, including ankylosing spondylitis (AS).
Methods: A novel inhibitor of MK2 was evaluated in vitro for inhibition of lipopolysaccharide (LPS)-induced inflammatory cytokines from peripheral blood mononuclear cells (PBMCs), and for inhibition of IL-17 production from Th17 polarized cells. In addition, the impact of MK2 inhibition on osteoclast function was assessed using a bone resorption assay. The in vivo effect of the MK2 inhibitor was evaluated in an animal model of joint inflammation. The safety, tolerability, and pharmacokinetics (PK) of single ascending doses of the MK2 inhibitor were evaluated in an ongoing first-in-human (FIH) study. Ex vivo stimulation of PBMCs from participants in the FIH study was conducted to assess the pharmacodynamic properties.
Results: The MK2 inhibitor reduced production of TNF-α and chemokines such as monocyte chemoattractant protein-1 (MCP-1) following in vitro LPS stimulation of PBMCs from healthy donors and patients with AS in a concentration-dependent manner. In addition, decreased IL-17 production was observed in polarized Th17 cells from healthy volunteers. The MK2 inhibitor modulated osteoclastogenesis and reduced osteoclast activity in vitro. In an animal model of spondyloarthropathy, dose-dependent reduction in peripheral joint disease severity was observed. In the FIH study, the MK2 inhibitor was safe and well tolerated when administered orally as single ascending doses to healthy participants. A favorable PK profile was observed across the single dose range tested. In an ex vivo LPS-stimulation assay, PBMCs from study participants secreted reduced levels of TNF-α following administration of the MK2 inhibitor.
Conclusion: We describe an inhibitor of MK2 that reduces expression of inflammatory mediators in vitro and inhibits joint inflammation in an animal model of spondyloarthropathy. Inhibition of TNF-α production was demonstrated in PBMCs from healthy volunteers. Further investigation of this MK2 inhibitor in diseases mediated by MK2-modulated inflammatory factors, such as TNF-α and IL-17, is warranted.
To cite this abstract in AMA style:Ramírez-Valle F, Adams M, Beebe L, Chen J, Chuaqui C, Connarn J, Corin A, Dingley K, Ellis J, Gaur R, Hamann L, Malona J, Mensah K, Palmisano M. A Novel MK2 Inhibitor for the Treatment of Ankylosing Spondylitis and Other Inflammatory Diseases [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-novel-mk2-inhibitor-for-the-treatment-of-ankylosing-spondylitis-and-other-inflammatory-diseases/. Accessed May 30, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-mk2-inhibitor-for-the-treatment-of-ankylosing-spondylitis-and-other-inflammatory-diseases/