Initiated by the intravenous injection of cells from IPF lung biopsy or explants into SCID mouse strains, IPF cells promote persistent, non-resolving, lung remodeling in SCID mice, unlike cells from normal lung samples. Potential advantages and pitfalls of human-specific targeting approaches in a humanized SCID model of pulmonary fibrosis will also be addressed. 

Galectin-3 is a ß-galactoside-binding lectin highly expressed in fibrotic tissue of diverse etiologies and has been shown to play a key role in organ fibrosis. Galecto, Inc. has developed a number of high-affinity and selective galectin-3 inhibitors currently undergoing clinical investigation in fibrotic diseases of the lung and liver. This talk will focus on the translational pharmacology of these galectin-3 inhibitors and their potential as anti-fibrotic therapies.

PLN-74809 is an avb6/avb1 dual integrin inhibitor which blocks the activation of latent TGF-b1 and 3 by epithelial cells and fibroblasts. TGF-b is a well-established pro-fibrotic cytokine, however previous attempts to broadly inhibit TGF-b with antibodies or kinase inhibitors have produced unacceptable side effects, preventing their use in the treatment of fibrosis. By targeting the activation of TGF-b with a selective inhibitor of avb6 and avb1 we are able to reduce the activity of TGF-b in the areas where there is upregulation of these integrin targets. We have shown by PET imaging, immunohistochemistry and protein quantification, that avb6 and avb1 are upregulated in the fibrotic regions of idiopathic pulmonary fibrosis (IPF) and primary sclerosing cholangitis (PSC). Furthermore, we have demonstrated in animal models and human precision cut tissue slices that treatment with PLN-74809 can significantly reduce fibrosis. In Phase 1 clinical trials we have demonstrated proof of mechanism in alveolar macrophages isolated from healthy volunteers dosed with PLN74809. PLN-74809 is currently being studied in two Phase 2 clinical trials, INTEGRIS-IPF and INTEGRIS-PSC.

Calpains are non-lysosomal, calcium-activated cysteine proteases that play multiple roles in a wide range of cell types. A subgroup of this calpain family, dimeric calpains (CAPN1, 2 and 9), have been shown to play a role in fibrotic disease models. Blade Therapeutics has developed selective calpain inhibitors that are active at inhibiting collagen production in in vitro systems and they reduce lung and liver fibrosis in vivo.

Caveolin-1 (Cav-1) regulates numerous cell signaling pathways related to fibrotic processes. As the loss of cell membrane Cav-1 protein is observed in many fibrotic diseases, it has remained elusive as a target for fibrosis. We have developed LTI-03, a peptide derived from the Cav-1 scaffolding domain, which has demonstrated efficacy in a variety of preclinical fibrosis models via multiple routes of administration. Our data indicates that LTI-03 attenuates profibrotic mechanisms and protects lung epithelial cells critical for surfactant production and lung homeostasis.

Integrin-alpha V serves as a master driver of fibroproliferative diseases in multiple organs. We investigated roles for integrin-alpha V interactions on fibroblasts and cholangiocytes, and defined novel roles for cell-specific expression of ITGAV in the regulation of inflammatory responses and in driving microenvironmental fibrogenesis.