title: Selective targeting of TGF-β activation to treat fibroinflammatory airway disease.
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.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Seed
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cormier
authors.affiliation: The Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Shenping
authors.initials: S
authors.lastname: Wu
authors.affiliation: The Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878, USA. Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Cambridge CB21 6GH, UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: Murray
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Tsui
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Connor
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Cambridge CB21 6GH, UK.
authors.forename: Cedric
authors.initials: C
authors.lastname: Govaerts
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Tyren
authors.initials: T
authors.lastname: Barker
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cambier
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Goodsell
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Brand
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Royce
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Kate J
authors.initials: KJ
authors.lastname: McKnelly
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Hill
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jablons
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Wolters
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Department of Pulmonary Medicine, Jikei University, Tokyo 105 8461, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Araya
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Barczak
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
authors.affiliation: Genetics, Development, and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Marks
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Jody L
authors.initials: JL
authors.lastname: Baron
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA. stephen.nishimura@ucsf.edu.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014136:Tracheitis / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta