%0 Journal Article
%T An antibody that inhibits TGF-β1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.
%A Jackson JW
%A Frederick C Streich 
%A Pal A
%A Coricor G
%A Boston C
%A Brueckner CT
%A Canonico K
%A Chapron C
%A Cote S
%A Dagbay KB
%A Danehy FT
%A Kavosi M
%A Kumar S
%A Lin S
%A Littlefield C
%A Looby K
%A Manohar R
%A Martin CJ
%A Wood M
%A Zawadzka A
%A Wawersik S
%A Nicholls SB
%A Datta A
%A Buckler A
%A Schürpf T
%A Carven GJ
%A Qatanani M
%A Fogel AI
%J Sci Signal
%V 17
%N 844
%D 2024 Jul 9
%M 38980922
%F 9.517
%R 10.1126/scisignal.adn6052
%X Inhibitors of the transforming growth factor-β (TGF-β) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-β homologs has safety liabilities. TGF-β1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-β-binding proteins (LTBPs) present TGF-β1 in the extracellular matrix, and TGF-β1 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-β1 presented by LTBPs but did not bind to TGF-β1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-β1 that is not accessible on GARP- or LRRC33-presented TGF-β1, explaining the antibody's selectivity for LTBP-complexed TGF-β1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-β1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-β inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-β1 as an approach for treating fibrosis.