Article
Author: Wawersik, Stefan ; Boston, Chris ; Jackson, Justin W. ; Dagbay, Kevin B. ; Littlefield, Christopher ; Canonico, Kaleigh ; Pal, Ajai ; Chapron, Christopher ; Lin, Susan ; Looby, Kailyn ; Nicholls, Samantha B. ; Fogel, Adam I. ; Danehy, Francis T. ; Datta, Abhishek ; Coricor, George ; Manohar, Rohan ; Buckler, Alan ; Schürpf, Thomas ; Frederick C. Streich Jr. ; Martin, Constance J. ; Zawadzka, Agatha ; Carven, Gregory J. ; Kumar, Sandeep ; Wood, Marcie ; Cote, Shaun ; Brueckner, Christopher T. ; Qatanani, Mohammed ; Kavosi, Mania
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.