An antibody that inhibits TGF-ß1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.

ABSTRACT

Inhibitors of the transforming growth factor-ß (TGF-ß) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-ß homologs has safety liabilities. TGF-ß1 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-ß-binding proteins (LTBPs) present TGF-ß1 in the extracellular matrix, and TGF-ß1 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-ß1 presented by LTBPs but did not bind to TGF-ß1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-ß1 that is not accessible on GARP- or LRRC33-presented TGF-ß1, explaining the antibody's selectivity for LTBP-complexed TGF-ß1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-ß1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-ß inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-ß1 as an approach for treating fibrosis.