Despite promising pre-clinical results, antibodies that antagonize the CCR2 chemokine receptor do not appear to improve the symptoms of rheumatoid arthritis (RA), results from a randomized double-blind study in humans suggest.
The abundant number of cells expressing CCR2 in synovial tissue from RA patients suggests a role for the receptor in promoting disease. Levels of the CCR2 ligand, CCL2, are also elevated in the synovial compartments of RA patients, highlighting the importance of this receptor in RA pathophysiology.
Some recent research has confirmed the importance of CCR2 and CCL2 as key mediators of inflammation in animal models of RA, but findings have been variable. If CCR2 does promote RA then blocking this receptor should ameliorate symptoms of the disease.
To test this idea, Paul Tak (University of Amsterdam, The Netherlands) and associates assigned 32 patients with RA to double-blind infusions of various doses of an anti-CCR2 monoclonal antibody or placebo once every 2 weeks for a total of 6 weeks.
Initial findings supported the efficacy of the anti-CCR2 antibody, showing that it reduced the expression of CCR2 receptors on monocytes isolated from synovial tissues by at least 57% and in some cases by 94%.
This significant biological activity did not appear to translate into improved clinical outcomes, however. Anti-CCR2 antibody treatment did not lead to significant reductions in levels of disease biomarkers such as lymphocytes or macrophages, or inflammatory factors such as tumor necrosis-factor alpha, or interleukin-6, and it was not associated with significant disease improvement in any patient.
Discussing their findings, Tak and team suggest that the lack of effect seen in their study may be because the doses of anti-CCR2 antibody used were too low, exposure to the drug was too short, or the relatively small number of patients tested produced a false-negative effect.
The authors also speculate that the inhibitory effect of CCR2 blockade on chemotaxis might be bypassed by activation of chemokine receptors other than CCR2.
"Alternatively, it is possible that CCR2 is not a good therapeutic target in RA," concede the investigators.