Abstract
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 αv 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 αv 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 TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.
Highlights
Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need
A report by Henderson et al demonstrated that depletion of αv integrin in myofibroblasts lead to protection against hepatic fibrosis induced by carbon tetrachloride, renal fibrosis induced by unilateral ureter obstruction, and lung fibrosis induced by bleomycin[6]
We used MK-0429 as a tool molecule to further validate the role of αv integrins in preclinical lung fibrosis model
Summary
The scarring of the lung, is a devastating disease with huge unmet medical need. Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429 Both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. An αvβ[6] antibody (BG00011/Biogen) and a small molecule inhibitor GSK3008348 were used in clinical trials of IPF patients (clinicaltrials.gov identifier NCT03573505, NCT03069989). The role of a pan-αv inhibitor has not been extensively tested in the clinic for lung indications, evidence from multiple lines of work suggest that modulating αv integrin activity will lead to anti-fibrotic effects in various tissues. Ab-31 demonstrated potent in vitro activity at inhibiting TGFβ-induced αSMA expression in lung fibroblasts derived from IPF patients than did MK-0429 and another benchmarking molecule. Our work has provided further experimental validation of targeting αv integrin for the treatment of fibrotic lung diseases
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