LARIX BIOSCIENCE LLC — Department of Health and Human Services SBIR Phase I: NHLBI

Description

Novel anti-fibrotic therapy for IPF AbstractIdiopathic pulmonary fibrosis (IPF) is characterized by myofibroblast accumulation, deposition of extracellular matrix (ECM) (including collagen and fibronectin), and progressive diffuse fibrosis in the lung interstitium. Inappropriate proliferation of fibroblasts and transformation to myofibroblasts from mesenchymal progenitor cells (MPC) play key roles in disease pathology. Although the molecular mechanisms that underlie this idiopathic disease have been obscure, recent studies implicate S100A4 as a critical autocrine-paracrine mediator of MPC self-renewal. S100A4 is both necessary and sufficient for MPCs to worsen fibrosis, making this member of the small EF-hand motif Ca2+-binding proteins a promising disease-modifying target (Xia, 2017). Recent work confirms this contention (Li, 2018). Based on these studies, during this Phase 1 project, we will generate a panel of high-affinity human monoclonal antibodies (humAbs) that block S100A4 signaling. The panel will be rank- ordered using novel in vitro assays followed by evaluation of the top candidate humAb using a novel human MPC-augmented bleomycin murine model of IPF. We are optimistic that this approach will yield a best-in-class therapy for this devastating disease.NarrativeIdiopathic pulmonary fibrosis (IPF) is a devastating progressive and ultimately fatal lung disease. We have identified an antibody to a critical mediator of fibrosis as a potential therapeutic for IPF.