Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Transl Res. 2021 Jun;232:75-87. doi: 10.1016/j.trsl.2021.01.004. Epub 2021 Jan 13.
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 of TNFSF11 and 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.
本研究旨在生成并研究一种新型单克隆双特异性抗体（BsAb），用于联合抑制肿瘤坏死因子-α（TNF-α）和 CXCL10，作为类风湿关节炎（RA）的治疗选择。通过将抗 CXCL10 单克隆抗体的单链可变片段（scFv）与阿达木单抗（ADA）的 Fc 区域缀合，生成了一种新型靶向 TNF-α和 CXCL10 的 BsAb。在人 TNF 转基因（hTNF-Tg）小鼠和 K/BxN 血清转移关节炎模型中，评估了 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 抑制了 CXCL10 介导的 CD8 T 细胞迁移。BsAb 与 TNF-α 的结合亲和力与 ADA 相当，抑制了 TNF-α 诱导的细胞死亡，并抑制了 RA 成纤维样滑膜细胞（FLSs）中 TNF-α 诱导的 ICAM-1 和 VCAM-1。BsAb 降低了 TNF-α 和 CXCL10 刺激的 RA-FLS 细胞中 TNFSF11 的表达和 IL-6 的产生。BsAb 治疗减轻了 hTNF-Tg 小鼠关节炎的发展，并抑制了 LPS 诱导的骨质侵蚀。在 K/BxN 血清转移模型中，BsAb 有效减轻了踝关节肿胀、滑膜炎症、软骨损伤和骨破坏，减少了破骨细胞的激活。与单独抑制 TNF-α 相比，新型 BsAb 对 TNF-α 和 CXCL10 的双重中和作用在 RA 的体外和体内模型中更有效。因此，靶向 TNF-α 和 CXCL10 的 BsAb 可能为那些对单一细胞因子阻断反应不佳的 RA 患者提供新的治疗机会。
