Systemic sclerosis (SSc) is induced by variety of factors and eventually causes multiple organ damage. In recent years, biological agents targeting cytokines and cell surface molecules have gradually come to market. Here, the anti-inflammatory and antifibrotic effects of a novel bispecific antibody (FL-BsAb1/17) targeting interleukin-17A (IL-17A) and interleukin-1β (IL-1β) were detected. Bleomycin (BLM) was subcutaneously injected for 21 consecutive days to establish the SSc mouse model, and mice were subsequently treated with etanercept or different doses (1, 5, 10 mg/kg) of FL-BsAb1/17. The results showed that FL-BsAb1/17 treatment (10 mg/kg, 5 mg/kg) significantly attenuated BLM-induced SSc-like inflammation by inhibiting the expression of inflammatory factors (IL-17A, IL-1β, IL-8, IL-22, IL-23, IL-6) and fibrosis, with specific outcomes of dermis thickening and lung fibrosis, by inhibiting the expression of fibrotic factors (TGF-β, α-sma, Col-1, Col-3) in the serum, skin and lungs. In addition, FL-BsAb1/17 (10 mg/kg, 5 mg/kg) downregulated protein levels of TGF-β and phosphorylated Smad2/3 in the skin and lungs and reduced collagen 1 protein levels. This indicated that FL-BsAb1/17 can inhibit the development of fibrosis by inhibiting the TGF-β/Smad2/3 signaling pathway. FL-BsAb1/17 (10 mg/kg, 5 mg/kg) could also effectively reduce the content of MDA, increase the activity of SOD and CAT, and improve the total antioxidant capacity (T-AOC). In conclusion, FL-BsAb1/17 alleviated BLM-induced SSc by downregulating inflammatory cascades, relieving oxidative stress and inhibiting TGF-β/Smad2/3 signaling. These data suggest that FL-BsAb1/17 has potential as a novel therapeutic candidate for SSc.

全身性硬化症（SSc）由多种因素引起，最终导致多器官损伤。近年来，靶向细胞因子和细胞表面分子的生物制剂已逐渐进入市场。在此，检测了针对白介素-17A（IL-17A）和白介素-1β（IL-1β）的新型双特异性抗体（FL-BsAb1 / 17）的抗炎和抗纤维化作用。连续21天皮下注射博来霉素（BLM）以建立SSc小鼠模型，随后用依那西普或不同剂量（1、5、10 mg / kg）FL-BsAb1 / 17治疗小鼠。结果表明，FL-BsAb1 / 17处理（10 mg / kg，5 mg / kg）通过抑制炎症因子（IL-17A，IL-1β，IL-8， IL-22，IL-23，IL-6）和纤维化，通过抑制血清，皮肤和肺中纤维化因子（TGF-β，α-sma，Col-1，Col-3）的表达而具有真皮增厚和肺纤维化的特定结果。此外，FL-BsAb1 / 17（10 mg / kg，5 mg / kg）下调了皮肤和肺中TGF-β和磷酸化Smad2 / 3的蛋白水平，并降低了胶原蛋白1的蛋白水平。这表明FL-BsAb1 / 17可通过抑制TGF-β/ Smad2 / 3信号通路来抑制纤维化的发展。FL-BsAb1 / 17（10 mg / kg，5 mg / kg）还可以有效降低MDA含量，增加SOD和CAT的活性，并提高总抗氧化能力（T-AOC）。总之，FL-BsAb1 / 17通过下调炎症级联反应，减轻氧化应激和抑制TGF-β/ Smad2 / 3信号传导来减轻BLM诱导的SSc。