B77-17 S100A4 Inhibition as a Novel Approach to Modulate STAT3-driven Pathways in Idiopathic Pulmonary Fibrosis

Abstract Rationale Current antifibrotic agents slow IPF progression but leave key inflammatory and fibrotic pathways unaddressed. Recent large-scale single-cell and regulatory network analyses of IPF lung tissue (McKenna et al., ATS 2025 abstract) identified STAT3 as a dominant transcriptional driver in both untreated disease and the unresponsive to current antifibrotics. The analysis also revealed strong correlations between the STAT3 footprint and several profibrotic receptor pathways, with EGFR showing the highest association as an established upstream regulator of STAT3 activity. However, complete STAT3 inhibition may be detrimental in IPF. S100A4, a profibrotic DAMP molecule elevated systemically and locally in IPF, interacts extracellularly with several receptors including TLR4, RAGE and EGFR. CAL101, a S100A4 neutralizing antibody, recently completed a Phase 1 study (ClinicalTrials.gov ID NCT05965089) and showed downregulation of pSTAT3 in fibroblasts within psoriatic skin, in agreement with earlier in vivo and ex vivo data. These investigations aimed to further strengthen the rationale for targeting S100A4 in IPF, including its mechanistic linkage to the EGFR-STAT3 signaling axis. Methods 1 - Generation of gene expression profiles in (A) normal fibroblasts treated with recombinant S100A4 versus untreated controls, and (B) systemic sclerosis dermal fibroblasts treated with CAL101. 2 - Identify the overlapping genes between Conditions A and B. 3 - Compare the overlapping gene signature with publicly available IPF single-cell RNA-seq datasets and examine the relationship between S100A4, EGFR, and STAT3 expression patterns. Results S100A4-stimulated fibroblasts exhibited gene expression changes overlapping with those seen in CAL101-treated systemic sclerosis fibroblasts and IPF fibroblasts. Several of the most regulated genes were also strongly linked to the STAT3 pathway (IL11, HBEGF etc). Single-cell analysis revealed high S100A4 expression in macrophage and fibroblast subsets in IPF patient lung biopsies. EGFR expression correlated strongly with STAT3 across a specific number of cell types, including fibroblasts, AT1 and AT2 cells. Conclusions Targeting S100A4 may allow for a controlled attenuation, rather than a complete blockade, of STAT3-associated inflammatory and fibrotic pathways in IPF, potentially improving outcomes within the current therapeutic gap. CAL101 is currently being investigated in a Ph2 IPF trial with completion expected Sept 2027. This abstract is funded by: None