Tanaka Yoshiya, Hoshino-Negishi Kana, Kuboi Yoshikazu, Tago Fumitoshi, Yasuda Nobuyuki, Imai Toshio
First Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
KAN Research Institute Inc, Hyogo, Japan.
Immunotargets Ther. 2020 Nov 4;9:241-253. doi: 10.2147/ITT.S277991. eCollection 2020.
Rheumatoid arthritis (RA) is an autoimmune disorder that affects joints and is characterized by synovial hyperplasia and bone erosion associated with neovascularization and infiltration of proinflammatory cells. The introduction of biological disease-modifying anti-rheumatic drugs has dramatically changed the treatment of RA over the last 20 years. However, fewer than 50% of RA patients enter remission, and 10-15% are treatment refractory. There is currently no cure for RA. Fractalkine (FKN, also known as CX3CL1) is a cell membrane-bound chemokine that can be induced on activated vascular endothelial cells. FKN has dual functions as a cell adhesion molecule and a chemoattractant. FKN binds specifically to the chemokine receptor CX3CR1, which is selectively expressed on subsets of immune cells such as patrolling monocytes and killer lymphocytes. The FKN-CX3CR1 axis is thought to play important roles in the initiation of the inflammatory cascade and can contribute to exacerbation of tissue injury in inflammatory diseases. Accordingly, studies in animal models have shown that inhibition of the FKN-CX3CR1 axis not only improves rheumatic diseases but also reduces associated complications, such as pulmonary fibrosis and cardiovascular disease. Recently, a humanized anti-FKN monoclonal antibody, E6011, showed promising efficacy with a dose-dependent clinical response and favorable safety profile in a Phase 2 clinical trial in patients with RA (NCT02960438). Taken together, the preclinical and clinical results suggest that E6011 may represent a new therapeutic approach for rheumatic diseases by suppressing a major contributor to inflammation and mitigating concomitant cardiovascular and fibrotic diseases. In this review, we describe the role of the FKN-CX3CR1 axis in rheumatic diseases and the therapeutic potential of anti-FKN monoclonal antibodies to fulfill unmet clinical needs.
类风湿性关节炎（RA）是一种自身免疫性疾病，会影响关节，其特征是滑膜增生以及与新血管形成和促炎细胞浸润相关的骨侵蚀。在过去20年中，生物性改善病情抗风湿药物的引入极大地改变了RA的治疗方式。然而，不到50%的RA患者实现缓解，10 - 15%的患者对治疗无效。目前RA无法治愈。趋化因子（FKN，也称为CX3CL1）是一种可在活化的血管内皮细胞上诱导产生的细胞膜结合趋化因子。FKN具有细胞黏附分子和趋化因子的双重功能。FKN特异性结合趋化因子受体CX3CR1，CX3CR1在诸如巡逻单核细胞和杀伤淋巴细胞等免疫细胞亚群上选择性表达。FKN - CX3CR1轴被认为在炎症级联反应的启动中起重要作用，并且可能导致炎症性疾病中组织损伤的加剧。因此，动物模型研究表明，抑制FKN - CX3CR1轴不仅能改善风湿性疾病，还能减少相关并发症，如肺纤维化和心血管疾病。最近，一种人源化抗FKN单克隆抗体E6011在RA患者的2期临床试验（NCT02960438）中显示出有前景的疗效，具有剂量依赖性临床反应和良好的安全性。综上所述，临床前和临床结果表明，E6011可能通过抑制炎症的主要促成因素并减轻伴随的心血管和纤维化疾病，代表一种针对风湿性疾病的新治疗方法。在本综述中，我们描述了FKN - CX3CR1轴在风湿性疾病中的作用以及抗FKN单克隆抗体满足未满足临床需求的治疗潜力。
