CCR1-specific non-peptide antagonist: efficacy in a rabbit allograft rejection model

The classic signs of acute cellular rejection during organ transplantation include the infiltration of mononuclear cells into the interstitium. This recruitment of leukocytes into the transplanted tissue is promoted by chemokines like RANTES. Since RANTES is a potent agonist for the CC chemokine receptor CCR1, we examined whether the CCR1 antagonist EX 471 was efficacious in a rabbit kidney transplant rejection model. EX 471 was able to compete with high affinity with the CCR1 ligands MIP-1 alpha and RANTES for binding to HEK 293 cells expressing rabbit CCR1. EX 471 was a competitive antagonist of rabbit CCR1 in Ca2+ flux studies. Two separate studies in which animals were subcutaneously implanted with slow release pellets of EX 471 demonstrated that animals implanted with EX 471 had increased survival compared with untreated controls or animals implanted with placebo. The mean survival time for the placebo group was 12.33 +/- 1.7 days. The animals in the EX 471 treated group had mean survival times of 16.9 +/- 2.1 and 16.0 +/- 1.7 days, respectively, for the two studies. Analysis of the combined data by Student I-test gave a P value of 0.03 that is significant at the 0.05 level. In addition, there was a marked reduction in the urea and creatinine levels in the EX 471 treated animals compared with the control and placebo groups in both studies. Finally, pathologic analysis of the kidneys in the rabbit renal transplantation model from animals in the different groups showed that EX 471 was similar to cyclosporin in its ability to prevent extensive infarction of transplanted kidneys. Based on the data from these studies, EX 471 shows clear efficacy at the single dose tested compared with animals treated with placebo. (C) 2001 Elsevier Science B.V. All rights reserved.