Modulation of CCR2 in rheumatoid arthritis: A double‐blind, randomized, placebo‐controlled clinical trial

Abstract

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.Conclusion. 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.Chemokines control the directed movement of cells expressing matching receptors (1,2). Chemokine receptor CCR2 is mainly expressed on monocytes and a subset of T cells, implying that ligands of CCR2 may attract these cell types (3). CCR2 has 5 known ligands, This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.

An Engineered GM-CSF-CCL2 Fusokine Is a Potent Inhibitor of CCR2-Driven Inflammation As Demonstrated in a Murine Model of Inflammatory Arthritis

“…Surprisingly, previous clinical studies using inhibitors or neutralizing Abs for CCR2 in RA showed limited amelioration for various reasons. For example, the administration of the therapeutic Ab MLN102 failed due to its inefficiency in fully covering the entire CCR2 repertoire (32). Another small molecule inhibitor of CCR2, MK0812, failed due to poorly tolerated off-target effects (33).…”

A Novel C–C Chemokine Receptor 2 Antagonist Prevents Progression of Albuminuria and Atherosclerosis in Mouse Models

“…16) Currently, several antagonists of CCL2 receptor CCR2 are under development for treatment of liver fibrosis, DN and MS. 14) However, despite extensive animal studies and clinical trials, the therapeutic potential of CCR2 antagonists remains inconclusive. For example, human monoclonal antibodies for CCL2 (ABN912) 17) and CCR2 (MLN-1202) 18) failed to show improvement in patients with RA, and rather increased C-reactive protein (CRP) levels at the highest dose of ABN912, while MLN-1202 successfully completed a phase II trial in patients with MS 19) and reduced CRP levels in patients at risk for atherosclerosis. 20) Furthermore, studies in nephrotoxic serum-induced glomerulonephritis models have indicated that special attention should be paid to CCL2 expression patterns in organs and time point for evaluation of therapeutic potential of test compounds.…”

Recommendations for the development and validation of flow cytometry‐based receptor occupancy assays

“…This rule is not as easily applied to RO assays given that large phycobiliproteins like APC and PE may interfere with each other due to steric hindrance or even lead to altered or aberrant fluorescence due to resonance energy transfer (22), often called F€ orster or fluorescent resonance energy transfer (FRET). Thus use of smaller organic dyes such as the Fluorescein isothiocyanate (FITC) and the Alex Fluor series, may be required for certain RO assay configurations provided that an adequate fluorescent signal can be obtained (8,23). The emerging class of small, polymer-based dyes (e.g.…”