Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

Alison E. John, Rebecca H. Graves, K. Tao Pun, Giovanni Vitulli, Ellen J. Forty, Paul F. Mercer, Josie L. Morrell, John W. Barrett, Rebecca F. Rogers, Maryam Hafeji, Lloyd I. Bibby, Elaine Gower, Valerie S. Morrison, Yim Man, James A. Roper, Jeni C. Luckett, Lee A. Borthwick, Ben S. Barksby, Rachel A. Burgoyne, Rory Barnes, Joelle Le, David J. Flint, Susan Pyne, Anthony Habgood, Louise A. Organ, Chitra Joseph, Rochelle C. Edwards-Pritchard, Toby M. Maher, Andrew J. Fisher, Natasja Stæhr Gudmann, Diana J. Leeming, Rachel C. Chambers, Pauline T. Lukey, Richard P. Marshall, Simon J. F. Macdonald, R. Gisli Jenkins () and Robert J. Slack
Additional contact information
Alison E. John: University of Nottingham
Rebecca H. Graves: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
K. Tao Pun: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Giovanni Vitulli: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Ellen J. Forty: University College London
Paul F. Mercer: University College London
Josie L. Morrell: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
John W. Barrett: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Rebecca F. Rogers: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Maryam Hafeji: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Lloyd I. Bibby: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Elaine Gower: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Valerie S. Morrison: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Yim Man: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
James A. Roper: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Jeni C. Luckett: University of Nottingham
Lee A. Borthwick: Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute
Ben S. Barksby: Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute
Rachel A. Burgoyne: Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute
Rory Barnes: Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute
Joelle Le: Drug Design and Selection - Molecular Design, Respiratory TAU, GlaxoSmithKline
David J. Flint: University of Strathclyde
Susan Pyne: University of Strathclyde
Anthony Habgood: University of Nottingham
Louise A. Organ: University of Nottingham
Chitra Joseph: University of Nottingham
Rochelle C. Edwards-Pritchard: University of Nottingham
Toby M. Maher: NIHR Respiratory Clinical Research Facility, Royal Brompton Hospital
Andrew J. Fisher: Newcastle University Biosciences Institute and Newcastle University Translational and Clinical Research Institute
Natasja Stæhr Gudmann: Nordic Bioscience A/S, Biomarkers and Research
Diana J. Leeming: Nordic Bioscience A/S, Biomarkers and Research
Rachel C. Chambers: University College London
Pauline T. Lukey: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Richard P. Marshall: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
Simon J. F. Macdonald: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline
R. Gisli Jenkins: University of Nottingham
Robert J. Slack: Fibrosis DPU, Respiratory TAU, GlaxoSmithKline

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Date: 2020
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DOI: 10.1038/s41467-020-18397-6

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