Dual aV beta 6/aV beta 1 inhibitor PLN-74809 blocks multiple TGF-beta activation pathways associated with IPF

Integrin αVβ6 (epithelial cell) and αVβ1 (fibroblast)-mediated activation of TGF-β have been shown to promote fibrosis in the bleomycin lung injury model, and elevated levels of αVβ6 have been found in human IPF lung tissue. Through the development of novel immuno- and cell adhesion assays, we confirmed significantly elevated levels of αVβ1 in IPF lung tissue and demonstrated αVβ1-specific binding of human lung fibroblasts to latent TGF-β. We then compared a dual-specific small molecule inhibitor of αVβ6/αVβ1 (PLN-74809) to a pan-αV inhibitor and specific inhibitors of αVβ6 and αVβ1 in the bleomycin mouse model or precision cut lung slices (PCLS; bleomycin-injured mouse/human IPF tissue) to assess which integrin inhibition strategy was most effective at blocking fibrogenesis. Characterization of inhibitor potency, selectivity, and functional activity was performed by ligand-binding and TGF-β reporter cell-based assays. Prophylactic dosing of PLN-74809 and a pan-αV inhibitor via minipump had similar plateau effects in the bleomycin model, reducing total lung hydroxyproline (OHP) and collagen gene expression by 40%. Oral therapeutic dosing of PLN-74809 also resulted in dose-dependent inhibition of OHP levels. Comparison of single and dual inhibitors in murine PCLS showed an additive effect of dual αVβ6/αVβ1 inhibition vs αVβ6 or αVβ1 inhibition alone, and PLN-74809 potency was higher than that of nintedanib or pirfenidone. PLN-74809 was also confirmed to inhibit collagen gene expression in PCLS from IPF patient tissue (p