Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: 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. FKN is expressed on endothelial cells and fibroblast-like synoviocytes in synovium and also expressed on osteoblasts. CX3CR1, the receptor for FKN, is expressed on monocytes/macrophages and osteoclast precursors (OCPs). Therefore, the FKN-CX3CR1 interaction might play pivotal roles in these cells function. To elucidate the precise roles of the FKN-CX3CR1 pathway in joint destruction, we examined the effect of treatment with anti-mouse FKN (mFKN) mAb, using the CIA model mice.
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 CIA synovium, 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 were also decreased, while those of serum amyloid A, TNF-α and IL-6 were unaffected after the anti-mFKN mAb treatment. 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 CIA synovium, whereas etanercept or tofacitinib had no effect. Importantly, synovial cell death was abundantly found in CIA synovium after the anti-mFKN mAb treatment.
Conclusion: In CIA model mice, anti-mFKN mAb suppressed local inflammatory cytokine expression in the inflamed joints, without affecting systemic inflammatory parameters. Anti-mFKN mAb remarkably ameliorated the joint destruction with the reduction of osteoclasts by the inhibition of both OCP migration and osteoclast formation in inflamed joint. In addition, anti-mFKN mAb immediately induced synovial cell death in the synovium, suggesting the direct inhibitory effect in the synovitis. These results indicate that inhibition of FKN-CX3CR1 axis by a humanized anti-FKN mAb, E6011, could be an attractive and affected joints-selective therapeutic option for the treatment of both inflammatory synovitis and joint destruction in RA patients.
To cite this abstract in AMA style:Hoshino-Negishi K, Ohkuro M, Nakatani T, Ikeda W, Kuboi Y, Ishii N, Yasuda N, Imai T. Anti-Fractalkine Monoclonal Antibody Inhibits Joint Destruction through Suppression of Osteoclast Precursor Migration and Induces Synovial Cell Death in Collagen-Induced Arthritis Model Mice [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/anti-fractalkine-monoclonal-antibody-inhibits-joint-destruction-through-suppression-of-osteoclast-precursor-migration-and-induces-synovial-cell-death-in-collagen-induced-arthritis-model-mice/. Accessed April 8, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-fractalkine-monoclonal-antibody-inhibits-joint-destruction-through-suppression-of-osteoclast-precursor-migration-and-induces-synovial-cell-death-in-collagen-induced-arthritis-model-mice/