Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial.
OBJECTIVE
CCR2 is a chemokine receptor expressed by monocytes, macrophages, and a subset of T cells. Its ligand, CCL2 (monocyte chemotactic protein 1), is abundantly present in the synovium of patients with rheumatoid arthritis (RA). Blocking CCR2 prevents CCL2-mediated chemotaxis in vitro and modulates arthritis in animal models of RA. In this study we examined the effects of CCR2 blockade on synovial inflammation in RA.


METHODS
The study was designed as a phase IIa clinical trial with a human CCR2 blocking antibody (MLN1202) in patients with active RA. Thirty-two patients received 3 infusions, over a period of 6 weeks, with either placebo (n = 9) or anti-CCR2 monoclonal antibody at 0.5 mg/kg (n = 7), 1.5 mg/kg (n = 7), or 4.0 mg/kg (n = 9). Safety was monitored with laboratory tests, immunotoxicity assessments, and documenting of adverse events, and European League Against Rheumatism and American College of Rheumatology response criteria were used to assess clinical improvement. Synovial tissue was obtained at baseline and after 43 days of treatment, for pharmacodynamic analysis using immunohistochemistry and digital image analysis. The Kruskal-Wallis test was used to compare groups, and the Wilcoxon signed rank test was used to assess changes within the groups.


RESULTS
All patients completed the study. Treatment with CCR2 blocking antibody reduced the levels of free CCR2 on CD14+ monocytes by at least 57% and up to 94% (P < 0.001), demonstrating the biologic activity of the compound. However, there was no reduction in the levels or expression of any of the synovial biomarkers. Accordingly, no clinical improvement was observed.


CONCLUSIONS
Treatment with anti-CCR2 blocking antibody did not result in amelioration of synovial inflammation in active RA. The results do not support the notion that blockade of CCR2 may be sufficient to induce clinical improvement in RA.
Vergunst
Clarissa E
CE
Academic Medical Center, and University of Amsterdam, Amsterdam, The Netherlands.
Gerlag
Daniëlle M
DM
Lopatinskaya
Luba
L
Klareskog
L
L
Smith
M D
MD
van den Bosch
F
F
Dinant
Huib J
HJ
Lee
Yih
Y
Wyant
Timothy
T
Jacobson
Eric W
EW
Baeten
Dominique
D
Tak
Paul P
PP
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D018932:Chemokine CCL2 / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D054390:Receptors, CCR2 / Q000378:metabolism*; D013583:Synovial Membrane / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015415:Biomarkers; C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2