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

Shunsuke Minagawa; Jianlong Lou; Robert I Seed; 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

doi:10.1126/scitranslmed.3008074

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

Shunsuke Minagawa, Jianlong Lou, Robert I Seed, 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 McKnellyWeihua 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

Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	241ra79
Journal	Science Translational Medicine
Volume	6
Issue number	241
DOIs	https://doi.org/10.1126/scitranslmed.3008074
Publication status	Published - 18 Jun 2014

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10.1126/scitranslmed.3008074

Cite this

Minagawa, S., Lou, J., Seed, R. I., Cormier, A., Wu, S., Cheng, Y., Murray, L., Tsui, P., Connor, J., Herbst, R., Govaerts, C., Barker, T., Cambier, S., Yanagisawa, H., Goodsell, A., Hashimoto, M., Brand, O. J., Cheng, R., Ma, R., ... Nishimura, S. L. (2014). Selective targeting of TGF-β activation to treat fibroinflammatory airway disease. Science Translational Medicine, 6(241), Article 241ra79. https://doi.org/10.1126/scitranslmed.3008074

@article{725f88f787cd4f1e8f1177c2176f2c91,

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.",

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

note = "Copyright {\textcopyright} 2014, American Association for the Advancement of Science.",

year = "2014",

month = jun,

day = "18",

doi = "10.1126/scitranslmed.3008074",

language = "English",

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Minagawa, S, Lou, J, Seed, RI, Cormier, A, Wu, S, Cheng, Y, Murray, L, Tsui, P, Connor, J, Herbst, R, Govaerts, C, Barker, T, Cambier, S, Yanagisawa, H, Goodsell, A, Hashimoto, M, Brand, OJ, Cheng, R, Ma, R, McKnelly, KJ, Wen, W, Hill, A, Jablons, D, Wolters, P, Kitamura, H, Araya, J, Barczak, AJ, Erle, DJ, Reichardt, LF, Marks, JD, Baron, JL & Nishimura, SL 2014, 'Selective targeting of TGF-β activation to treat fibroinflammatory airway disease', Science Translational Medicine, vol. 6, no. 241, 241ra79. https://doi.org/10.1126/scitranslmed.3008074

TY - JOUR

T1 - Selective targeting of TGF-β activation to treat fibroinflammatory airway disease

AU - Minagawa, Shunsuke

AU - Lou, Jianlong

AU - Seed, Robert I

AU - Cormier, Anthony

AU - Wu, Shenping

AU - Cheng, Yifan

AU - Murray, Lynne

AU - Tsui, Ping

AU - Connor, Jane

AU - Herbst, Ronald

AU - Govaerts, Cedric

AU - Barker, Tyren

AU - Cambier, Stephanie

AU - Yanagisawa, Haruhiko

AU - Goodsell, Amanda

AU - Hashimoto, Mitsuo

AU - Brand, Oliver J

AU - Cheng, Ran

AU - Ma, Royce

AU - McKnelly, Kate J

AU - Wen, Weihua

AU - Hill, Arthur

AU - Jablons, David

AU - Wolters, Paul

AU - Kitamura, Hideya

AU - Araya, Jun

AU - Barczak, Andrea J

AU - Erle, David J

AU - Reichardt, Louis F

AU - Marks, James D

AU - Baron, Jody L

AU - Nishimura, Stephen L

PY - 2014/6/18

Y1 - 2014/6/18

N2 - 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.

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.

U2 - 10.1126/scitranslmed.3008074

DO - 10.1126/scitranslmed.3008074

M3 - Article

C2 - 24944194

SN - 1946-6234

VL - 6

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 241

M1 - 241ra79

ER -