A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

Abstract

CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE−/− mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2+ monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.

Salt increases monocyte CCR2 expression and inflammatory responses in humans

“…Furthermore, proinflammatory activation and CCR2 have been implicated in acute and chronic kidney disease (9,40,41) and cardiovascular disease (6,42,43), underlining the relevance of our findings for kidney and cardiovascular patients. Patients with chronic kidney disease show increased arterial inflammation and increased proinflammatory phenotype of monocytes, as displayed by increased CCR7 and CCR2 expression (9).…”

“…6). Among others, anti-CCR2 and the absence of CCR2 reduce atherosclerosis in mice prone for atherosclerosis development (42,43). Taken together, our data may provide a link between salt and its deleterious outcomes, which is relevant for the healthy population, as well as for patients with cardiovascular and kidney disease.…”

Cilia‐localized LKB 1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney

“…Both diabetes and vascular disease are metabolic disorders. Of note, LKB1 is a metabolic sensor and CCL2 signaling has been implicated in diabetic kidneys and vascular disease (Sayyed et al , ; Bot et al , ). This raises the possibility that in metabolic disease, the ciliary LKB1 module could confer an inflammatory phenotype on renal epithelial cells to mediate chronic inflammation in the kidney.…”

Macrophage Plasticity and Function in the Eye and Heart

“…This trial, although also presenting negative interactions involving infection as a result of immunosuppression, highlights the potential of macrophage and inflammatory targeted treatments in the resolution of cardiovascular disease. Additional studies have demonstrated that, similarly to their role in MI, CCR2 + macrophages might also be detrimental in the case of atherosclerosis, further accentuating the potential of targeting CCR2 in predicting outcomes and developing treatments [125,126], although this warrants further investigation.…”