Anti‐S100A4 monoclonal antibody treatment ameliorates experimental skin fibrosis and SSc‐specific transcriptional signatures in human skin

Abstract

ObjectivesS100A4 is a Damage Associated Molecular Pattern (DAMP) protein. S100A4 is overexpressed in systemic sclerosis (SSc) patients and levels correlate with organ involvement and disease activity. S100A4‐/‐ mice are protected from fibrosis. The aims of this study were to assess the antifibrotic effects of anti‐S100A4 monoclonal antibody (mAb) in murine models of SSc and in precision cut skin slices of SSc patients.MethodsThe effects of anti‐S100A4 mAbs were evaluated in a bleomycin‐induced skin fibrosis model and in tight‐skin 1 mice with therapeutic dosing regimen. In addition, the effects of anti‐S100A4 mAb on precision cut SSc skin slices were analyzed by RNASeq.ResultsInhibition of S100A4 was effective in the treatment of pre‐established bleomycin‐induced skin fibrosis and in regression of pre‐established fibrosis with reduced dermal thickening, myofibroblast counts, and collagen accumulation. Transcriptional profiling demonstrated targeting of multiple profibrotic and proinflammatory processes relevant to the pathogenesis of SSc upon targeted S100A4 inhibition in bleomycin‐induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation‐ and fibrosis‐relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4 such as AMPK, CASQ1, and pSTAT3 were validated on protein level and STAT3 inhibition was shown to prevent the profibrotic effects of S100A4 on fibroblasts in human skin.ConclusionsInhibition of S100A4 confers dual targeting of inflammatory and fibrotic pathways in complementary mouse models of fibrosis and in SSc skin. These effects support the further development of anti‐S100A4 mAbs as disease‐modifying targeted therapies for SSc.