The School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fuzhou 350122, Fujian, China.
The School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China; Putian Lanhai Nuclear Medicine Research Center, Putian 351100, Fujian,China.
Int Immunopharmacol. 2024 Jan 5;126:111240. doi: 10.1016/j.intimp.2023.111240. Epub 2023 Nov 22.
Anti-TNF-α therapy fails in 30% of patients, where TNF-α may not be the key causative factor in these patients. We developed a bispecific single-domain antibody block TNF-α and VEGF (V5-3).The experiments showed that V5-3 effectively activated proliferation and migration of RA-FLS and HUVEC, tube-forming role of HUVEC, and expression of inflammatory factors in vitro. Besides, the experiments indicated that the anti-RA activity of V5-3 was superior to Anbainuo in vivo. Application of V5-3 reduced the expression of inflammatory factors, extent of synovial inflammation and angiogenesis and attenuated the severity of autoimmune arthritis in collagen-induced arthritis (CIA) mice. Mechanistically, V5-3 suppressed p65, AKT and VEGFR2 phosphorylation, as well as production of TNF-α and VEGF in joint tissues. These results demonstrated that V5-3 displayed a superior effect of anti-RA, may be a new therapy to overcome the limitations of anti-TNF-α monoclonal antibody.
抗 TNF-α 治疗在 30%的患者中失败，而 TNF-α 可能不是这些患者的关键致病因素。我们开发了一种双特异性单域抗体来阻断 TNF-α 和 VEGF（V5-3）。实验表明，V5-3 能有效激活 RA-FLS 和 HUVEC 的增殖和迁移，发挥 HUVEC 的管状形成作用，并在体外表达炎症因子。此外，实验表明 V5-3 在体内的抗 RA 活性优于安百诺。V5-3 的应用降低了炎症因子的表达、滑膜炎症和血管生成的程度，并减轻了胶原诱导性关节炎（CIA）小鼠自身免疫性关节炎的严重程度。在机制上，V5-3 抑制了关节组织中 p65、AKT 和 VEGFR2 的磷酸化以及 TNF-α 和 VEGF 的产生。这些结果表明，V5-3 表现出优越的抗 RA 作用，可能是克服抗 TNF-α 单克隆抗体局限性的一种新疗法。
