| First Author | Zhang J | Year | 2021 |
| Journal | Sci Rep | Volume | 11 |
| Issue | 1 | Pages | 2118 |
| PubMed ID | 33483531 | Mgi Jnum | J:300452 |
| Mgi Id | MGI:6502177 | Doi | 10.1038/s41598-021-81253-0 |
| Citation | Zhang J, et al. (2021) Discovery of a new class of integrin antibodies for fibrosis. Sci Rep 11(1):2118 |
| abstractText | Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of alphav integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab's yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple alphav integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFbeta activation. In IPF patient lung fibroblasts, TGFbeta treatment induced profound alphaSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting alphaSMA expression, suggesting that the integrin antibody is able to modulate TGFbeta action though mechanisms beyond the inhibition of latent TGFbeta activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases. |
