Abstract 11581: Longer Receptor Residence Times Improve the Effectiveness of CCR2 Antagonists in the Prevention of Atherosclerosis

The chemokine receptor CCR2 is known to be critically involved in atherosclerosis development, rendering blockade of the CCL2-CCR2 axis of therapeutic interest. CCR2 antagonists have, however, limited clinical success. Interestingly, it was shown for other drug targets that a measure for the dissociation of the drug-receptor complex, the so-called residence time (RT), can have a crucial impact on a drug’s efficacy. In this study, we thus aimed to determine whether an increased RT improves the therapeutic effectiveness of CCR2 antagonists. Carotid artery atherosclerosis was induced by collar placement in apoE -/- mice, followed by treatment with the short RT CCR2 antagonist 15b (RT=15 min, 150 μg/day), the long RT CCR2 antagonist 15a (RT=714 min, 150 μg/day) or vehicle control. After four weeks, atherosclerotic plaques were analyzed. Treatment with the CCR2 antagonists did not affect body weight or plasma cholesterol levels. At sacrifice, circulating CCR2 + monocyte numbers were only significantly reduced in the long RT 15a-treated mice (controls: 14.9±3.2*10 3 , 15b: 9.1±3.1*10 3 and 15a: 4.5±1.0*10 3 cells/mL, *P<0.05). Atherosclerotic plaque size was reduced from 64.4±11.8*10 3 μm 2 in control mice to 33.2±6.8*10 3 μm 2 in 15b-treated mice (-49%, *P<0.05), and even up to 17.6±4.1*10 3 μm 2 in 15a-treated mice (-73%, **P<0.01). Interestingly, relative plaque macrophage content was only decreased in 15a-treated mice compared to both control and 15b-treated mice (controls: 46±4%, 15b: 45±6%, 15a: 25±8%, *P<0.05), while neutrophil and mast cell numbers were not affected. In the aortic root, 15b did not significantly affect plaque size (controls: 252±25*10 3 μm 2 vs 15b: 196±17*10 3 μm 2 ), while the long RT CCR2 antagonist 15a inhibited plaque development to 157±15*10 3 μm 2 (-38%, **P<0.01). Also at that site of lesion development, macrophage area was only significantly reduced in the 15a-treated mice (controls: 35±4%, 15b: 32±3%, 15a: 23±4%, *P<0.05 compared to controls). In conclusion, our data demonstrate that the CCR2 antagonist with a long residence time was more effective in inhibiting atherosclerotic plaque development compared to the short RT antagonist, which implies that receptor residence time is an important parameter in drug development.