Why CCR2 and CCR5 Blockade Failed and Why CCR1 Blockade Might Still Be Effective in the Treatment of Rheumatoid Arthritis

Abstract

BackgroundThe aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model.Methodology/Principal FindingsMonocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis.Conclusions/SignificanceThe RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo.

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

“…The use of antibodies against CCR2 and CCR5 was recently reported to have failed in inhibiting synovial fluidinduced monocyte chemotaxis. Interestingly the use of either an anti-CCR1 Ab or a CCR1 antagonist (BX471) inhibited synovial fluid-induced monocyte chemotaxis, highlighting this receptor as a potential target in reducing monocyte recruitment to RA synovium (Lebre et al, 2011). In terms of animal models, conflicting evidence surrounding CC chemokine receptors has been reported.…”

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

“…A range of therapeutic agents that target CCR2 or CCL2 are being developed (6)(7)(8), although initial trial results for CCR2 blockade in RA patients have been disappointing (9). Nevertheless, CCR2/CCL2 inhibition may ultimately find utility in the treatment of a range of conditions (6)(7)(8).…”

The Chemokine Receptor CCR1 Is Constitutively Active, Which Leads to G Protein-independent, β-Arrestin-mediated Internalization

“…CCR1 has been demonstrated to play a key role in diseases associated with inappropriate leukocyte infiltration and activation, such as multiple sclerosis (23,24), rheumatoid arthritis (25,26), progressive kidney disease (27)(28)(29), and transplant rejection (20,30,31). Many attempts have been made to develop small molecule drugs that effectively inhibit receptor signaling, but thus far all have failed during clinical trials primarily due to lack of efficacy (32)(33)(34). Despite its biomedical relevance, relatively little has been reported on the molecular pharmacology of the receptor in its apo (i.e.…”