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Sci Transl Med. 2014 Jun 18;6(241):241ra79. doi: 10.1126/scitranslmed.3008074.

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

Author information

1
Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA.
2
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
3
The Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94110, USA.
4
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878, USA. Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Cambridge CB21 6GH, UK.
5
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Gaithersburg, MD 20878, USA.
6
Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Cambridge CB21 6GH, UK.
7
Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
8
Department of Surgery, University of California, San Francisco, San Francisco, CA 94110, USA.
9
Department of Pulmonary Medicine, Jikei University, Tokyo 105 8461, Japan.
10
Genetics, Development, and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94110, USA.
11
Department of Pathology, University of California, San Francisco, San Francisco, CA 94110, USA. stephen.nishimura@ucsf.edu.

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.

PMID:
24944194
PMCID:
PMC4341974
DOI:
10.1126/scitranslmed.3008074
[Indexed for MEDLINE]
Free PMC Article

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