A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

Nadine D. Arnold, Josephine A. Pickworth, Laura E. West, Sarah Dawson, Joana A. Carvalho, Helen Casbolt, Adam T. Braithwaite, James Iremonger, Lewis Renshall, Volker Germaschewski, Matthew McCourt, Philip Bland-Ward, Hager Kowash, Abdul G. Hameed, Alexander M. K. Rothman, Maria G. Frid, A. A. Roger Thompson, Holly R. Evans, Mark Southwood, Nicholas W. Morrell, David C. Crossman, Moira K. B. Whyte, Kurt R. Stenmark, Christopher M. Newman, David G. Kiely, Sheila E. Francis and Allan Lawrie ()
Additional contact information
Nadine D. Arnold: University of Sheffield
Josephine A. Pickworth: University of Sheffield
Laura E. West: University of Sheffield
Sarah Dawson: University of Sheffield
Joana A. Carvalho: Kymab Ltd, Babraham Research Campus
Helen Casbolt: University of Sheffield
Adam T. Braithwaite: University of Sheffield
James Iremonger: University of Sheffield
Lewis Renshall: University of Sheffield
Volker Germaschewski: Kymab Ltd, Babraham Research Campus
Matthew McCourt: Kymab Ltd, Babraham Research Campus
Philip Bland-Ward: Kymab Ltd, Babraham Research Campus
Hager Kowash: University of Sheffield
Abdul G. Hameed: University of Sheffield
Alexander M. K. Rothman: University of Sheffield
Maria G. Frid: University of Colorado Anschutz Medical Campus
A. A. Roger Thompson: University of Sheffield
Holly R. Evans: University of Sheffield
Mark Southwood: University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospital
Nicholas W. Morrell: University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospital
David C. Crossman: University of St. Andrews, St
Moira K. B. Whyte: University of Edinburgh, The Queens Medical Research Institute
Kurt R. Stenmark: University of Colorado Anschutz Medical Campus
Christopher M. Newman: University of Sheffield
David G. Kiely: University of Sheffield
Sheila E. Francis: University of Sheffield
Allan Lawrie: University of Sheffield

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.

Date: 2019
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DOI: 10.1038/s41467-019-13139-9

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