Bone‐ and Cartilage‐Protective Effects of a Monoclonal Antibody Against Colony‐Stimulating Factor 1 Receptor in Experimental Arthritis

Abstract

Objective. Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA.Methods. CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collageninduced arthritis (CIA) and serum-transfer arthritis.Results. CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R؉. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b؉Gr-1؊ monocytes.Conclusion. CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.Joint destruction in rheumatoid arthritis (RA) is mediated by inflammatory synovial tissue and subsequent osteoclastic bone resorption (1). This process is guided by inflammatory cytokines, which induce the expression of key factors involved in osteoclast differentiation. While numerous studies have shown the importance of RANKL in osteoclast-mediated bone resorption in both experimental inflammatory arthritis and human RA, data have been very limited to date concerning the role of the second essential factor for osteoclast differentiation, colony-stimulating factor 1 (CSF-1).The human CSF-1 receptor (CSF-1R; c-Fms) is a Drs. Toh, Bonnefoy, Haegel, Preville, Guillen, and Ancian and Ms Cochin, Mr. De Meyer, and Ms Thioudellet own stock or stock options in Transgene SA. Dr. Haegel and Ms Thioudellet are inventors of the anti-colony-stimulating factor 1 receptor monoclonal antibody CXIIG6 and its derivative, patents for which are assigned to Transgene SA.

Among human macrophages polarised to different phenotypes, the M-CSF-oriented cells present the highest pro-inflammatory response to the rheumatoid arthritis-specific immune complexes containing ACPA

“…Conversely, its neutralisation reduces the severity of established CIA 46. Finally, recent data support the evidence that blockade of the M-CSF receptor reduces inflammation in CIA and abrogates cartilage damage and bone erosion 47. Moreover, inhibitors of M-CSF and its receptor are in preclinical development for the treatment of RA and other autoimmune diseases 47 48…”

CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface

“…Macrophages are key contributors to highly prevalent immunological diseases [3–5] such as rheumatoid arthritis, inflammatory bowel disease, and demyelinating neurological diseases [6–8]. Macrophages also play key homeostatic roles in non-immune tissues and contribute to diseases such as atherosclerosis and cancer [9–11].…”

Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System

“…Thus, these models indicate that CSF-1 neutralization can result in fewer inflammatory macrophages in a lesion, with perhaps significance for clinical approaches (11), but is in disagreement with the findings of others (27,31). A number of studies have found that CSF-1R and CSF-1 neutralization/depletion can reduce inflammatory/autoimmune disease (2,10,29,(69)(70)(71)(72)(73)(74), suggesting that targeting of this system may provide therapeutic options. One possible mechanism for the reduction in inflammatory MPS populations found in the earlier models after CSF-1 neutralization is that the removal of a resident macrophage population by such an approach lessens the signal(s) governing overall cellular infiltration; in support of this concept, in the AIP model, fewer CD115 2 cells were also noted.…”