Lenabasum inhibits inflammasome activation, may benefit systemic sclerosis
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Lenabasum, an experimental cannabinoid receptor type 2 agonist, was associated with inhibition of interleukin-1beta and interleukin-18 activation, according to data presented at the EULAR 2020 E-Congress.
“In pre-clinical and clinical studies, lenabasum [Corbus Pharmaceuticals] resolves inflammation and limited fibrosis,” Barbara White, MD, of Corbus Pharmaceuticals, told Healio Rheumatology.
Looking closer at the possible mechanism of action, White said that lenabasum may activate the resolution phase of certain immune responses triggered through Toll-like receptor activation. This process favors production of pro-resolving lipid mediators, reduces inflammatory infiltrates and increases bacterial clearance, according to the researchers.
“We therefore asked whether lenabasum may inhibit inflammasome activation,” White said.
The researchers derived primary human macrophages from monocytes. The macrophages were then stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) and cultured with lenabasum. The researchers then used enzyme-linked immunosorbent assay to measure interleukin (IL)-1beta and IL-18 in cell supernatants.
Additionally, peripheral blood mononuclear cells “were activated with 0.1 µg/mL LPS ± 10 µM lenabasum for 24 hours,” according to the findings.
Results showed that lenabasum was associated with significant inhibition of IL-1beta (IC50 = 66.73 ± 3.92nM) and IL-18 (IC50 = 349.23 ± 21.27nM) secretion by monocyte-derived macrophages.
The data set also included findings for MCC950, which was used as a control inflammasome activator. This yielded IL-1beta activation of IC50 = 18.33 ± 1.22nM and IL-18 activation of IC50 = 21.43 ± 0.81nM.
“Lenabasum inhibited activation of IL-1 beta and IL-18 in a dose-dependent fashion in this experimental system,” White said. “Based on these results, we think that potential beneficial effects of lenabasum in humans with inflammatory and fibrotic diseases may be mediated in part by inhibiting inflammasome activation.”
White added that the researchers believe there is a “synergistic mechanism by which lenabasum could reduce chronic inflammation.”
She said, however, that lenabasum remains in the experimental stage and does not currently have FDA approval for any indication in the U.S. or EU.
“These mechanistic data provide additional support for the potential of lenabasum to provide clinical benefit to patients with chronic autoimmune rheumatic diseases, such as systemic sclerosis,” she said. “Results of ongoing clinical studies, including phase 3 studies in systemic sclerosis and dermatomyositis and a phase 2 study in lupus, will directly address this potential benefit.”
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Chintalacharuvu S, et al. AB0152. Presented at: EULAR 2020 E-Congress; June 3-6, 2020 (virtual meeting).
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