CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

Chemokine (C-C motif) receptor 2 ( CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2knockin mice were generated and rendered diabetic with either a high-fat diet ( diet-induced obesity) or by deletion of the leptin receptorgene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocytedensity. Moreover, treatment of diet-induced obesemice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessmentof insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2antagonists, CCX140-B had no effect on plasma levels of the CCR2ligand CCL2or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.