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The latent TGF-\u03b2\u2013binding proteins (LTBPs) present TGF-\u03b21 in the extracellular matrix, and TGF-\u03b21 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-\u03b21 presented by LTBPs but did not bind to TGF-\u03b21 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-\u03b21 that is not accessible on GARP- or LRRC33-presented TGF-\u03b21, explaining the antibody\u2019s selectivity for LTBP-complexed TGF-\u03b21. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-\u03b21 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-\u03b2 inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-\u03b21 as an approach for treating fibrosis.<\/jats:p>","DOI":"10.1126\/scisignal.adn6052","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T14:05:45Z","timestamp":1720533945000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":30,"title":["An antibody that inhibits TGF-\u03b21 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5221-4778","authenticated-orcid":true,"given":"Justin W.","family":"Jackson","sequence":"first","affiliation":[{"name":"Scholar Rock Inc., 301 Binney Street, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7549-424X","authenticated-orcid":true,"family":"Frederick C. 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