Abstract
Background
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.
Methods
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.
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-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.
Plain language summary
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.
Data availability
All data associated with this study are presented in the paper or the Supplementary Materials. The sequences of SOF10 have been published in the patent application (WO 2021/039945)74. The structures of SOF10 Fab and latent-TGF-β have been deposited in the RCSB Protein Data Bank under the PDB code 9VJJ. Cif and Pdb file of the structure are provided as Supplementary Data 1 and 2. Source data for Figs. 1, 3, 4, and 5 and Figure S3, S5, S6, and S7 is in Supplementary Data 3.
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Acknowledgements
We thank A. Sakamoto and T. Tsushima for protein preparation, and Y. Ruike, S. Ishi, and Y. Teranishi for antibody generation or optimization. We also thank D. Kashiwagi, T. Mizuno, S. Yamamoto, K. Ohtake, Y. Tsuboi, S. Usami, S. Matsuo for conducting experiments. We are grateful to T. Kuramochi, Y. Tomii, M. Endo, T. Torizawa, N. Horiba, A. Kato, M. Azuma for advice on the research. We thank all the research assistants at Chugai Pharmaceutical Co. Ltd. and Chugai Pharmabody Research Pte. Ltd. for their excellent experimental assistance.
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M.K., I.S., H.K., K.A., K.O., and H.S. wrote the original draft of the manuscript. M.K., I.S., and H.S. conceptualized and formulated the project. M.K., I.S., H.K., K.N., A.M., Y.K., and N.H. performed experiments. M.K., I.S., C.X.K., Y.S1., H.K., K.N., K.A., S.W.G., C.L.P., Y.S2., M.S.-K., C.K, K.O., coordinated the experiment. T.K., J.N., T.I., and H.S. supervised the work. M.K., I.S., Y.S1., H.K., K.N., A.M., K.A., S.W.G., N.H., K.O., T.K., T.I., and H.S. reviewed and edited the manuscript.
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M.K., I.S., H.K., K.N, A.M, K.A., Y.S2., M.S.-K., C.K., Y.K., N.H., K.O., T.K., T.I., and H.S. are employees of Chugai Pharmaceutical Co. Ltd. (Chugai). Y.S1., and S.W.G. are employees of Chugai’s subsidiary, Chugai Pharmabody Research Pte. Ltd.(Chugai Pharmabody Research). J.N was employees of Chugai, and C.X.K and C.L.P. were employees of Chugai Pharmabody Research at the time of the study. H.S. was a Chief Executive Officer of Chugai Pharmabody Research Pte. Ltd. M.K., I.S., H.K., K.N., A.M., K.A., Y.S2., M.S.-K., C.K., Y.K., N.H., K.O., J.N., T.K., T.I., and H.S. have stock in Chugai. Chugai has filed patent applications related to the anti-latent TGF-β1 antibodies. M.K. is the inventor of the following patent: CROSS-SPECIES ANTI-LATENT TGF-BETA 1 ANTIBODIES AND METHODS OF USE (WO2019/163927). M.K., H.S., and C.X.K. are the inventors of the following patent: CROSS-SPECIES ANTI-LATENT TGF-BETA 1 ANTIBODIES AND METHODS OF USE (WO2021/039945) and USES OF CROSS-SPECIES ANTI-LATENT TGF-BETA 1 ANTIBODIES (WO2022/180764).
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Communications Medicine thanks Christian Klein, Ruchi Bansal and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Kanamori, M., Sato, I., Koo, C.X. et al. Selective blockade of latent TGF-β1 activation suppresses tissue fibrosis with good safety. Commun Med (2026). https://doi.org/10.1038/s43856-026-01408-w
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DOI: https://doi.org/10.1038/s43856-026-01408-w
