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Selective targeting of TGF-β activation to treat fibroinflammatory airway disease

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Published copy (DOI)

Author(s)

  • Shunsuke Minagawa
  • Jianlong Lou
  • Anthony Cormier
  • Shenping Wu
  • Yifan Cheng
  • Lynne Murray
  • Ping Tsui
  • Jane Connor
  • Ronald Herbst
  • Cedric Govaerts
  • Tyren Barker
  • Stephanie Cambier
  • Haruhiko Yanagisawa
  • Amanda Goodsell
  • Mitsuo Hashimoto
  • Oliver J Brand
  • Ran Cheng
  • Royce Ma
  • Kate J McKnelly
  • Weihua Wen
  • Arthur Hill
  • David Jablons
  • Paul Wolters
  • Hideya Kitamura
  • Jun Araya
  • Andrea J Barczak
  • David J Erle
  • Louis F Reichardt
  • James D Marks
  • Jody L Baron
  • Stephen L Nishimura

Department/unit(s)

Publication details

JournalScience Translational Medicine
DatePublished - 18 Jun 2014
Issue number241
Volume6
Original languageEnglish

Abstract

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.

Bibliographical note

Copyright © 2014, American Association for the Advancement of Science.

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