Abstact

BACKGROUND: Fibrosis is a hallmark of organ failure observed after chronic epithelial injury and inflammation. The transforming growth factor beta (TGF-beta) is the master regulator of fibrogenesis, so blockade of the TGF-beta pathway is a potential treatment strategy for fibrosis; however, the therapeutic potential of pan-TGF-beta blockade is limited by side effects. METHODS: We generated SOF10, a humanized antibody that targets latent TGF-beta1 and selectively blocks protease- and integrin alphavbeta8-mediated latent TGF-beta1 activation. We conducted gene expression and histological analyses in nonalcoholic steatohepatitis (NASH)/liver fibrosis and renal interstitial fibrosis models. We also evaluated the combination effect of SOF10 with an immune checkpoint inhibitor in a syngeneic mouse model and performed safety studies in mice and monkeys. RESULTS: Here we show that SOF10 reduces fibrosis in NASH/liver fibrosis and renal interstitial fibrosis models and improves renal function in a chronic kidney disease model. Furthermore, the combination of SOF10 with an anti-PD-L1 antibody decreases tumor growth in a syngeneic mouse model. SOF10 demonstrates safety in both mice and monkeys. CONCLUSIONS: Selective blockade of latent TGF-beta1 activation represents a promising approach for treating a broad range of fibrotic diseases and cancers. By specifically targeting TGF-beta1, SOF10 may offer a safer and more effective therapeutic option compared to non-selective TGF-beta inhibitors. This strategy has the potential to transform the treatment paradigm for fibrosis-related conditions.