SAT0048 ANTI-FRACTALKINE MONOCLONAL ANTIBODY AMELIORATE JOINT DESTRUCTION AND SYNOVIUM THROUGH SUPPRESSION OF OSTEOCLAST PRECURSOR MIGRATION AND INDUCTION OF SYNOVIAL CELL DEATH IN COLLAGEN-INDUCED ARTHRITIS MODEL
ANNALS OF THE RHEUMATIC DISEASES(2019)
Abstract
Background In the Phase 1/2 clinical study, E6011, a novel humanized anti-fractalkine (FKN) mAb demonstrated a promising efficacy in active RA patients who were inadequately controlled by MTX and/or TNF-α inhibitors (NCT 02196558)1.In RA joint tissue, increased expression of fractalkine (FKN) and abundant infiltration of CX3CR1-positive cells were observed2. FKN is expressed on endothelial cells and fibroblast-like synoviocytes in synovium and also expressed on osteoblasts. CX3CR1 is expressed on monocytes/macrophages and osteoclast precursors (OCPs). Therefore, FKN-CX3CR1 interaction could play pivotal roles in migration, differentiation and activation of those cells. However, the precise mechanism(s) of FKN-CX3CR1 axis in RA, especially on joint destruction remains to be elucidated. Objectives To elucidate the roles of FKN-CX3CR1 axis in cartilage destruction, bone damage and proliferated synovial cells by using anti-mouse FKN mAb (anti-mFKN mAb). Methods For the induction of CIA, mice were immunized with bovine type II collagen. Anti-mFKN mAb was injected twice a week. The clinical arthritis score was monitored, and joint destruction was evaluated by soft x-ray and histology. The mRNA expression levels were assessed by quantitative RT-PCR. Blood parameters were measured using ELISA. In in vitro, effect of immobilized FKN on RANK ligand (RANKL)-induced osteoclast differentiation was examined. In in vivo, bone marrow-derived OCPs were fluorescein-labeled and transferred to CIA mice to evaluate the migration of OCPs into synovium. Inhibitory effect of anti-mFKN mAb, etanercept or tofacitinib against OCP migration was assessed. To examine the effect of anti-mFKN mAb against proliferated synovial cells, propidium iodide (PI) was injected to anti-mFKN mAb-treated CIA mice to detect the synovial cell death. Results Anti-mFKN mAb significantly reduced the arthritis and soft x-ray scores in both prophylactic and therapeutic treatment. Anti-mFKN mAb histologically improved synovitis, cartilage destruction and bone damage, with marked reduction of osteoclast numbers. Plasma levels of COMP and MMP-3 were also decreased. Interestingly, anti-mFKN mAb significantly suppressed Tnf and Il6 mRNA expression in the affected joints. In in vitro, RANKL-induced osteoclast differentiation was enhanced by immobilized FKN, and anti-mFKN mAb suppressed FKN-dependent osteoclast formation. In in vivo, anti-mFKN mAb strongly inhibited the migration of OCPs into the proliferated synovial cells of mice with CIA, whereas etanercept or tofacitinib had no significantly effect. Importantly, synovial cell death was abundantly found in proliferated synovial cells of mice with CIA after the anti-mFKN mAb treatment3. Conclusion Anti-mFKN mAb remarkably ameliorated the joint destruction with the marked reduction of osteoclasts by the inhibition of both OCP survival and OCP migration in inflamed joint tissues. In addition, anti-mFKN mAb immediately induced synovial cell death in the proliferated synovial cells, suggesting the direct inhibitory effect in the synovitis. These results strongly indicate that inhibition of FKN-CX3CR1 axis by a humanized anti-FKN mAb, E6011, is an attractive and affected joints-selective therapeutic strategy for the treatment of both inflammatory synovitis, cartilage destruction and bone damage in RA patients. References [1] Tanaka Y, et al., Mod Rheumatol (2018) 28, 58-65 [2] Nanki T, et al., Arthritis Rheum (2002) 46, 2878-83 [3] Hoshino K, et al., Arthritis Rheumatol (2018) Aug 6 [Epub ahead of print] Disclosure of Interests NAOTO ISHII Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Kana Hoshino-Negishi Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Masayoshi Ohkuro Employee of: EA Pharma Co., Ltd., Tomoya Nakatani Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Wataru Ikeda Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Yoshikazu Kuboi Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Nobuyuki Yasuda Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Toshio Imai Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.)
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Key words
synovial cell death,monoclonal antibody,osteoclast precursor migration,anti-fractalkine,collagen-induced
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