Selective blockade of latent TGF-β1 activation suppresses tissue fibrosis with good safety

Fibrosis is a hallmark of organ failure observed after chronic epithelial injury and inflammation. The transforming growth factor beta (TGF-β) is the master regulator of fibrogenesis, so blockade of the TGF-β pathway is a potential treatment strategy for fibrosis; however, the therapeutic potential of pan-TGF-β blockade is limited by side effects. We generated SOF10, a humanized antibody that targets latent TGF-β1 and selectively blocks protease- and integrin αvβ8-mediated latent TGF-β1 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. 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. Selective blockade of latent TGF-β1 activation represents a promising approach for treating a broad range of fibrotic diseases and cancers. By specifically targeting TGF-β1, SOF10 may offer a safer and more effective therapeutic option compared to non-selective TGF-β inhibitors. This strategy has the potential to transform the treatment paradigm for fibrosis-related conditions. Fibrosis, the excessive scarring of tissues, contributes to organ failure in many diseases. While increased amounts of a protein called TGF-β can encourage development of fibrosis, complete removal of its activity causes harmful side effects. We developed a protein called SOF10 that selectively blocks only some of the activities of TGF-β1. In our studies, SOF10 reduced scarring in models of liver and kidney disease, improved kidney function, and enhanced cancer treatment when combined with immunotherapy treatments. Importantly, SOF10 proved safe in both mice and monkeys. This selective approach to blocking TGF-β1 activity could be a promising strategy for treating various fibrotic diseases and cancers with fewer side effects than complete TGF-β blockade. Our findings could lead to new treatment options for patients suffering from chronic organ damage and certain cancers. Kanamori, Sato et al. develop SOF10, a humanized antibody that selectively blocks protease- and integrin αvβ8-mediated latent TGF-β1 activation. This selective blockade reduces fibrosis in multiple disease models, improves renal function, enhances anti-tumor immunity, and demonstrates safety in preclinical studies.