Dual CCR2/CCR5 antagonism by Cenicriviroc efficiently inhibits both MCP-1 and RANTES induced chemokine receptor internalization in murine pro-inflammatory monocytes (CCR6P.221)

Abstract Persistent immune activation, driven in part by monocytes and macrophages (MO), has been implicated in HIV-associated comorbidities and progressive liver disease. Binding of chemokines MCP-1 and RANTES to their respective chemokine receptors (CKR), CCR2 and CCR5, selectively regulates the migration of MO. Cenicriviroc (CVC), an oral, dual CCR2 and CCR5 antagonist, has completed Phase 2b development in HIV and is undergoing Phase 2b evaluation in subjects with non-alcoholic steatohepatitis (NASH) and liver fibrosis. We assessed CVC receptor occupancy, measured by inhibition of MCP-1 and RANTES induced CKR internalization, compared to single antagonists BMS-22 (CCR2) and Maraviroc (MVC; CCR5) in pro-inflammatory (CD11c+F4/80+Ly6c+) MO in male BALB/c mice (n=6) by flow cytometry and quantified using Molecules of Equivalent Soluble Fluorochrome microspheres. CVC significantly reduced both MCP-1 induced internalization of CCR2 (p<0.01) and RANTES induced internalization of CCR5 (p<0.01). Doses of 0.25-1μM achieved >90% CCR2 and CCR5 occupancy by CVC compared to 49% CCR2 occupancy by BMS-22 and 69% CCR5 occupancy by MVC in blood pro-inflammatory MO. Doses of 0.02-1μM achieved >85% CCR2 and CCR5 occupancy by CVC compared to 72% CCR2 occupancy by BMS-22 and 73% CCR5 occupancy by MVC in spleen pro-inflammatory MO. These data suggest that CVC leads to efficient CCR2 and CCR5 target coverage in blood and tissues with effective doses lower than that of respective single CKR antagonists.