Background/Purpose: Rheumatoid arthritis (RA) is a chronic disease leading to joint destruction. In the previous Phase 1/2 clinical study, E6011, a novel humanized anti-fractalkine (FKN) monoclonal antibody (mAb) demonstrated a promising efficacy in active RA patients who were inadequately controlled by MTX and/or TNF-a inhibitors. However, the effect of anti-FKN mAb on joint destruction remains to be elucidated. In RA, synovium-infiltrated monocytes/macrophages cause synovitis and cartilage damage by the induction of matrix metalloproteases and inflammatory cytokines. Osteoclasts are generated from osteoclast precursor cells (OCPs) and cause bone erosion. FKN is expressed on endothelial cells and fibroblast-like synoviocytes in synovium in both experimental arthritis model and RA patient. Moreover, it is reported that FKN expressed by osteoblasts in neonatal mouse calvariae. CX3CR1, the receptor for FKN, is expressed on monocytes/macrophages and OCPs. Therefore, the interaction of FKN and CX3CR1 might play important roles in migration, differentiation and activation of these cells, leading to cartilage damage and bone erosion. In this study, we examine the efficacy of anti-FKN mAb on collagen-induced arthritis (CIA) in mice, especially on joint destruction.

Methods:  For the induction of CIA, DBA/1J mice were immunized with intradermal injections of bovine type II collagen on days 0 and 21. Four hundred micrograms of anti-FKN mAb or control IgG intraperitoneally injected twice a week from the day of the 1^stimmunization (for the prophylactic treatment) or after the onset of CIA (for the therapeutic treatment). The clinical arthritis score was defined as the sum of the scores of four paws. Plasma concentration of Tartrate-Resistant Acid Phosphatase type 5b (TRAP-5b), Cartilage Oligomeric Matrix Protein (COMP), Matrix Metalloproteinase 3 (MMP-3) were measured using ELISA. Radiological score was measured by the soft x-ray for limb bones. For histopathological analysis, Alcian blue/Alizarin red and Tartrate-Resistant Acid Phosphatase (TRAP) staining were performed using frozen sections of ankle joints.

Results:  The prophylactic treatment of anti-FKN mAb significantly reduced the clinical arthritis score, soft x-ray score and plasma levels of TRAP-5b, COMP and MMP-3, compared with the treatment of control IgG. Histopathological analysis demonstrated almost complete suppression of synovitis, pannus formation, cartilage degradation and bone erosion by the treatment of anti-FKN mAb. The number of TRAP-positive cells was also dramatically decreased in anti-FKN mAb–treated mice. Importantly, therapeutic treatment of anti-FKN mAb significantly ameliorated clinical arthritis score and soft x-ray score compared with the treatment of control IgG.

Conclusion: Anti-FKN mAb demonstrated a remarkable efficacy in established mouse CIA and completely inhibited the cartilage damage and bone erosion with the reduction of osteoclasts. These results indicate that inhibition of FKN/CX3CR1 axis by a humanized anti-FKN mAb, E6011, is an attractive therapeutic strategy for the treatment of both inflammatory synovitis and joint destruction of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-fractalkine-monoclonal-antibody-inhibits-cartilage-destruction-and-bone-erosion-in-collagen-induced-arthritis-model/