Selective Targeting of TGF-β Activation to Treat Fibroinflammatory Airway Disease

Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor-beta (TGF-beta) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-beta is expressed in a latent form that requires activation. The integrin avb8 (encoded by the itgb8 gene) is a receptor for latent TGF-beta and is essential for its activation. Expression of integrin avb8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human avb8 (B5) inhibited TGF-beta activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-beta activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that avb8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity avb8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-beta pathway to treat fibroinflammatory airway diseases.