Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with significant clinical burden characterized by aberrant epithelial remodeling and excessive extracellular matrix deposition. Connective tissue growth factor (CTGF/CCN2), a key mediator of fibrogenesis, is consistently upregulated in IPF and is linked to disease onset and progression. However, the recent failure of pamrevlumab, an anti-CTGF therapy, highlights the need for deeper mechanistic insights and improved treatment strategies. Using single-cell and spatial transcriptomics, we identified a fibrotic airway niche in IPF lungs enriched in aberrant basaloid epithelial cells, activated myofibroblasts, and dysfunctional macrophages. Within this niche, CTGF and matrix metalloproteinase 7 (MMP7) were co-expressed, suggesting a proteolytic axis that activates CTGF. Plasma profiling confirmed elevated levels of MMP7, full-length CTGF (FL), and its N-terminal fragment (NTF), with MMP7 correlating with lung function decline. Functional assays revealed that MMP7 cleaves CTGF into a bioactive NTF, which promotes mesenchymal migration and impairs macrophage efferocytosis, contributing to fibrosis. A novel high-affinity anti-CTGF antibody (BI3810477), targeting a previously uncharacterized conformational epitope, effectively blocked CTGF cleavage and downstream signaling. BI3810477 showed superior binding affinity, a different mode of action and superior efficacy compared to pamrevlumab in patient-derived models, reducing myofibroblast activation and restoring alveolar cell fate under fibrotic conditions. These findings establish the CTGF-MMP7 axis as a critical driver of fibrotic remodeling with direct implications for lung function and IPF patient outcomes and introduce a next-generation therapeutic approach aiming at targeting CTGF cleavage and fragments. By integrating spatial biology, proteomics, and functional validation, this study provides a mechanistic rationale for advancing BI3810477 as a promising next-generation anti-CTGF candidate for IPF treatment. This abstract is funded by: Boehringer Ingelheim
Lizé et al. (Fri,) studied this question.