A novel bispecific antibody alleviates bleomycin-induced systemic sclerosis injury.

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.