Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


The Human C5a Receptor (hC5aR) Antagonist CCX168 Effectively Ameliorates a Model of ANCA Glomerulonephritis (GN) in hC5aR Knock-in Mice.

Xiao2,  Hong, Jennette3,  J. C., Dairaghi1,  D. J., Ertl1,  L., Baumgart1,  T., Miao1,  S., Powers1,  J. P.

ChemoCentryx
University of North Carolina, Chapel Hill, NC
University of North Carolina

Purpose:

Intravenous injection of mouse anti-myeloperoxidase (anti-MPO) IgG causes GN and vasculitis in mice that mimics antineutrophil cytoplasmic autoantibody (ANCA) disease in patients. We have shown that alternative pathway complement activation and resultant C5a are involved in pathogenesis. Here we study the effects on this model of CCX168, an orally active antagonist of human C5a receptor (hC5aR) that has completed Phase 1 trials. We also evaluated CCX168 pharmacokinetic, pharmacodynamic and therapeutic endpoints in mice using the same assays of hC5aR blockade used in the human Phase 1 trial.

Methods:

Humanized mice with knock-in of human C5aR and knock-out of mouse C5aR (hC5aR KI mice) were injected with anti-MPO IgG; and received CCX168 doses ranging from 0.1–30 mg/kg qd, or vehicle alone. The potency of CCX168 for C5aR in hC5aR KI mice was assessed by 125I-C5a binding and chemotaxis assays. C5a-induced neutrophil CD11b expression was used to assess CCX168 C5aR blockade in mice and compared to results using the same assay in humans.

Results:

CCX168 had similar C5aR antagonist potency on human and hC5aR KI mouse neutrophils (inhibition of C5a-mediated chemotaxis in blood, IC50 2 nM; inhibition of C5a-induced CD11b upregulation in blood, IC50 4 nM). 30 mg/kg CCX168 markedly reduced the severity of anti-MPO induced GN. Glomerular crescent formation was reduced from 29.3% with vehicle alone to 3.3% with CCX168 (p<0.0001) and glomerular necrosis from 8.2% to 1.1% (p<0.0001). Urine protein, leukocytes and RBCs, and serum BUN and creatinine also were reduced in mice receiving CCX168. 0.1 mg/kg/d CCX168 caused 30% reduction in crescents. The lowest dose that produced a near-maximal therapeutic benefit was 4 mg/kg CCX168 bid (with plasma levels from 35 to 200 ng/mL throughout the day, and C5aR blockade ranging from 95 to 99%). As reported in a separate meting abstract, plasma CCX168 levels of 197 ng/mL (~400 nM) were reached with a 100-mg dose in a human Phase 1 trial.

Conclusions:

Orally active human C5aR antagonist CCX168 markedly suppresses the induction of GN by anti-MPO IgG in mice with knocked-in human C5aR. CCX168 doses that induce a near-maximal therapeutic benefit in mice produce CCX168 plasma levels and C5aR blockade that were attainable and well tolerated in Phase I human trials. These results support an important role for C5aR engagement by C5a in the pathogenesis of anti-MPO induced GN, which is a model for human ANCA GN, and thus support the possible therapeutic benefit of C5aR blockade in human ANCA disease.

To cite this abstract, please use the following information:
Xiao, Hong, Jennette, J. C., Dairaghi, D. J., Ertl, L., Baumgart, T., Miao, S., et al; The Human C5a Receptor (hC5aR) Antagonist CCX168 Effectively Ameliorates a Model of ANCA Glomerulonephritis (GN) in hC5aR Knock-in Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2048
DOI: 10.1002/art.29813

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