Efficacy of novel bispecific antibody targeting TNF-α/CXCL10 in the treatment of experimental arthritis
Efficacy of novel bispecific antibody targeting TNF-α/CXCL10 in the treatment of experimental arthritis
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DOI：
10.1016/j.trsl.2021.01.004
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发表时间：
2021-05-04
影响因子：
7.8
通讯作者：
Song，Yeong Wook
中科院分区：
文献类型：
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作者：
Kang，Shin Eui;Park，Jin Kyun;Song，Yeong Wook
本研究旨在制备一种新型单克隆双特异性抗体（BsAb），并研究其联合抑制肿瘤坏死因子-α（TNF-α）和CXCL 10作为类风湿关节炎（RA）治疗选择的疗效。将抗CXCL 10单克隆抗体的单链可变区（scFv）与阿达木单抗（ADA）的Fc区偶联，制备了一种新型的抗肿瘤坏死因子-α（TNF-α）和CXCL 10的双抗。在人TNF转基因（hTNF-Tg）小鼠和K/BxN血清转移关节炎模型中评价BsAb对关节炎和关节破坏的体外和体内发展中的炎症反应的影响。BsAb抑制CXCL 10介导的CD 8 +T细胞迁移。BsAb与TNF-α的结合亲和力与ADA相当，并抑制TNF-α诱导的RA成纤维样滑膜细胞（FLS）的细胞死亡和抑制TNF-α诱导的ICAM-1和VCAM-1。BsAb可抑制TNF-α和CXCL 10刺激的RA-FLS细胞中TNF-α 11的表达和IL-6的产生。用BsAb治疗减轻了hTNF-Tg小鼠中关节炎的发展，并抑制了LPS诱导的骨侵蚀。在K/BxN血清转移模型中，BsAb有效地减轻踝关节肿胀、滑膜炎症、软骨损伤和骨破坏，减少破骨细胞的活化。在RA的体外和体内模型中，用新型BsAb治疗的TNF-α和CXCL 10的额外中和比单独的TNF-α抑制更有效。因此，同时靶向TNF-α和CXCL 10的BsAb可能为对单一细胞因子阻断无效的RA患者提供新的治疗机会。
This study was aimed at generating and investigating the efficacy of a novel monoclonal bispecific antibody (BsAb) for the combined inhibition of tumor necrosis factor-α (TNF-α) and CXCL10 as a treatment option for rheumatoid arthritis (RA). A novel BsAb targeting TNF-α and CXCL10 was generated by conjugating a single-chain variable fragment (scFv) of the anti-CXCL10 monoclonal antibody to the Fc region of adalimumab (ADA). The effects of the BsAb on the inflammatory response in the in vitro and in vivo development of arthritis and joint destruction were evaluated in human TNF transgenic (hTNF-Tg) mice, and K/BxN serum transfer arthritis models. The BsAb inhibited CXCL10-mediated CD8+T cell migration. The binding affinity of the BsAb to TNF-α was comparable to that of ADA and suppressed TNF-α induced cell death and inhibited TNF-α induced ICAM-1 and VCAM-1 in RA fibroblast-like synoviocytes (FLSs). The BsAb decreased the expression ofTNFSF11and the production of IL-6 in RA-FLS cells stimulated with TNF-α and CXCL10. Treatment with the BsAb attenuated the development of arthritis in hTNF-Tg mice and suppressed LPS-induced bone erosion. In the K/BxN serum transfer model, BsAb effectively attenuated ankle swelling, synovial inflammation, cartilage damage, and bone destruction, reducing the activation of osteoclasts. The additional neutralization of TNF-α and CXCL10 from treatment with the novel BsAb was more effective than TNF-α inhibition alone in the in vitro and in vivo models of RA. Thus, the BsAb, targeting both TNF-α and CXCL10, may provide a new therapeutic opportunity for RA patients who fail to respond to the blockade of a single cytokine.