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CCR2/5 Antagonist Plus FGF21
Analog Quell Liver Fat, Fibrosis in Mice
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EASL 2020, Digital International Liver Congress, August 27-29, 2020
Mark Mascolini
A dual CCR2/CCR5 antagonist plus an FGF21 analog synergized to rein in progressive steatohepatitis and possibly fibrosis in a mouse model [1]. The two agents had additive impacts on other measures of metabolism and impaired liver function.
With novel targets emerging in the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), researchers from Aachen, Ghent, and Berlin collaborated to test the activity of two agents-alone or together-in mouse models of acute and chronic liver injury. The first agent, a dual chemokine receptor type 2 and 5 (CCR2/5), antagonist can improve fibrosis by quelling monocyte infiltration and altering macrophage subsets in the liver. The second agent, fibroblast growth factor 21 (FGF21), is a hormone that regulates lipid and glucose metabolism. A pegylated FGF21 analog can improve steatosis, liver injury, and fibrosis markers in people with NASH.
First the researchers measured CCL2 in 85 people with biopsy-proven NAFLD. Monocytes that migrate to adipose tissue release CCL2, a chemokine that can promote further inflammation [2]. In 85 people with biopsy-proven NAFLD, the Aachen-Ghent-Berlin team determined that CCL2 levels correlate with fibrosis severity (r = 0.2189, P = 0.0469) [1].
The investigators then tested a CCR2/5 antagonist (BMS-687681) with or without a pegylated FGF21 variant (PEG-FGF21v, BMS-986171) in male C57BL/6J mice that had (1) acute liver injury (via single carbon tetrachloride injection) or (2) chronic steatohepatitis and fibrosis (via a choline-deficient, L-amino acid-defined high-fat diet for up to 12 weeks). Previous work showed that CCR2/5 antagonists are safe and have antifibrotic activity in people with NASH [3].
In mice with acute liver injury, those treated with a CCR2/5 antagonist had significantly lower circulating and hepatic Ly6C+ inflammatory monocytes and monocyte-derived macrophages (MoMFs). Treatment with PEG-FGF21v did not affect hepatic MoMFs levels but did reduce alanine aminotransferase (ALT) and hepatocellular necrosis.
In mice with chronic steatohepatitis, the researchers started each therapy separately or together after 6 weeks of the high-fat diet and assessed effects after 2 weeks or 6 weeks. CCR2/5 antagonists reduced MoMFs, inflammatory markers, and hepatic fibrosis, while PEG-FGF21v lowered body weight, liver triglycerides, steatosis, and NASH activity.
Combining CCR2/5 antagonists and PEG-FGF21v yielded additive benefits in controlling weight gain, hepatic fat, ALT, and fibrosis. Combining the two therapies had synergistic effects on NAFLD activity score.
Further experiments showed that these combined agents have activity in early disease stages.
The researchers conclude CCR2/5 antagonism blocks chemokine-mediated monocyte infiltration and MoMF accumulation in experimental acute and chronic liver injury in mice. PEG-FGF21v lowers ALT and improves steatosis in diet-induced obesity. Combination therapy with CCR2/5 antagonists and PEG-FGF21v, the authors propose, "ameliorates experimental steatohepatitis and possibly fibrosis more effectively than either agent alone." They believe these findings support the therapeutic potential of combining these two classes in people with advanced NASH.
References
1. Puengel T, Lefere S, Hundertmark J, et al. Combination therapy with a dual CCR2/CCR5 antagonist and a FGF21 analogue synergizes in ameliorating steatohepatitis and fibrosis. EASL 2020, Digital International Liver Congress, August 27-29, 2020. Abstract AS016.
2. Guzman-Ornelas MO, Petri MH, Vazquez-Del Mercado M, et al. CCL2 serum levels and adiposity are associated with the polymorphic phenotypes -2518A on CCL2 and 64ILE on CCR2 in a Mexican population with insulin resistance. J Diabetes Res. 2016;2016:5675739. doi: 10.1155/2016/5675739.
3. Lefere S, Devisscher L, Tacke F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges. Expert Opin Investig Drugs. 2020;29:89-92. doi: 10.1080/13543784.2020.1718106.
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