RT Journal Article
SR Electronic
T1 Selective Targeting of TGF-β Activation to Treat Fibroinflammatory Airway Disease
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 241ra79
OP 241ra79
DO 10.1126/scitranslmed.3008074
VO 6
IS 241
A1 Minagawa, Shunsuke
A1 Lou, Jianlong
A1 Seed, Robert I.
A1 Cormier, Anthony
A1 Wu, Shenping
A1 Cheng, Yifan
A1 Murray, Lynne
A1 Tsui, Ping
A1 Connor, Jane
A1 Herbst, Ronald
A1 Govaerts, Cedric
A1 Barker, Tyren
A1 Cambier, Stephanie
A1 Yanagisawa, Haruhiko
A1 Goodsell, Amanda
A1 Hashimoto, Mitsuo
A1 Brand, Oliver J.
A1 Cheng, Ran
A1 Ma, Royce
A1 McKnelly, Kate J.
A1 Wen, Weihua
A1 Hill, Arthur
A1 Jablons, David
A1 Wolters, Paul
A1 Kitamura, Hideya
A1 Araya, Jun
A1 Barczak, Andrea J.
A1 Erle, David J.
A1 Reichardt, Louis F.
A1 Marks, James D.
A1 Baron, Jody L.
A1 Nishimura, Stephen L.
YR 2014
UL http://stm.sciencemag.org/content/6/241/241ra79.abstract
AB 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–β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 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 αvβ8 (B5) inhibited TGF-β 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-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 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 αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases.