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; Allan Lawrie

doi:10.1038/s41467-019-13139-9

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 MorrellDavid C Crossman, Moira K B Whyte, Kurt R Stenmark, Christopher M Newman, David G Kiely, Sheila E Francis, Allan Lawrie

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

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.

Original language	English
Article number	5183
Number of pages	18
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-13139-9
Publication status	Published - 15 Nov 2019

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Final published version, 3.73 MBLicence: CC BY

David Christopher Crossman
- dcc7st-andrews.acuk
- School of Medicine - Professor, Dean of Medicine
- Sir James Mackenzie Institute for Early Diagnosis
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Arnold, N. D., Pickworth, J. A., West, L. E., Dawson, S., Carvalho, J. A., Casbolt, H., Braithwaite, A. T., Iremonger, J., Renshall, L., Germaschewski, V., McCourt, M., Bland-Ward, P., Kowash, H., Hameed, A. G., Rothman, A. M. K., Frid, M. G., Roger Thompson, A. A., Evans, H. R., Southwood, M., ... Lawrie, A. (2019). A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension. Nature Communications, 10, Article 5183. https://doi.org/10.1038/s41467-019-13139-9

@article{d14ab30acf93400b982f7e6bf3644790,

title = "A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension",

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.",

author = "Arnold, {Nadine D} and Pickworth, {Josephine A} and West, {Laura E} and Sarah Dawson and Carvalho, {Joana A} and Helen Casbolt and Braithwaite, {Adam T} and James Iremonger and Lewis Renshall and Volker Germaschewski and Matthew McCourt and Philip Bland-Ward and Hager Kowash and Hameed, {Abdul G} and Rothman, {Alexander M K} and Frid, {Maria G} and {Roger Thompson}, {A A} and Evans, {Holly R} and Mark Southwood and Morrell, {Nicholas W} and Crossman, {David C} and Whyte, {Moira K B} and Stenmark, {Kurt R} and Newman, {Christopher M} and Kiely, {David G} and Francis, {Sheila E} and Allan Lawrie",

note = "Funding for this study was provided by a British Heart Foundation Senior Basic Science Research Fellow (FS/13/48/30453 and FS/18/52/33808, AL), Medical Research Council Career Development Award (G0800318, AL); Medical Research Council Confidence In Concepts (MC/PC12022), Medical Research Council Developmental Pathway Funding Scheme (MR/L023040/1), British Heart Foundation Clinical Research Training Fellowship (FS/08/061/25740, AGH); Medical Research Council Clinical Research Training Fellowship (MR/K002406/1) and Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z), AMKR, British Heart Foundation Intermediate Clinical Fellowship (FS/18/13/33281, AART), National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit (NA/JP/DC); Cambridge National Institute of Health Research Biomedical Research Centre.",

year = "2019",

month = nov,

day = "15",

doi = "10.1038/s41467-019-13139-9",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature publishing group",

}

Arnold, ND, Pickworth, JA, West, LE, Dawson, S, Carvalho, JA, Casbolt, H, Braithwaite, AT, Iremonger, J, Renshall, L, Germaschewski, V, McCourt, M, Bland-Ward, P, Kowash, H, Hameed, AG, Rothman, AMK, Frid, MG, Roger Thompson, AA, Evans, HR, Southwood, M, Morrell, NW, Crossman, DC, Whyte, MKB, Stenmark, KR, Newman, CM, Kiely, DG, Francis, SE & Lawrie, A 2019, 'A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension', Nature Communications, vol. 10, 5183. https://doi.org/10.1038/s41467-019-13139-9

TY - JOUR

T1 - A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

AU - Arnold, Nadine D

AU - Pickworth, Josephine A

AU - West, Laura E

AU - Dawson, Sarah

AU - Carvalho, Joana A

AU - Casbolt, Helen

AU - Braithwaite, Adam T

AU - Iremonger, James

AU - Renshall, Lewis

AU - Germaschewski, Volker

AU - McCourt, Matthew

AU - Bland-Ward, Philip

AU - Kowash, Hager

AU - Hameed, Abdul G

AU - Rothman, Alexander M K

AU - Frid, Maria G

AU - Roger Thompson, A A

AU - Evans, Holly R

AU - Southwood, Mark

AU - Morrell, Nicholas W

AU - Crossman, David C

AU - Whyte, Moira K B

AU - Stenmark, Kurt R

AU - Newman, Christopher M

AU - Kiely, David G

AU - Francis, Sheila E

AU - Lawrie, Allan

N1 - Funding for this study was provided by a British Heart Foundation Senior Basic Science Research Fellow (FS/13/48/30453 and FS/18/52/33808, AL), Medical Research Council Career Development Award (G0800318, AL); Medical Research Council Confidence In Concepts (MC/PC12022), Medical Research Council Developmental Pathway Funding Scheme (MR/L023040/1), British Heart Foundation Clinical Research Training Fellowship (FS/08/061/25740, AGH); Medical Research Council Clinical Research Training Fellowship (MR/K002406/1) and Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z), AMKR, British Heart Foundation Intermediate Clinical Fellowship (FS/18/13/33281, AART), National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit (NA/JP/DC); Cambridge National Institute of Health Research Biomedical Research Centre.

PY - 2019/11/15

Y1 - 2019/11/15

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-13139-9

DO - 10.1038/s41467-019-13139-9

M3 - Article

C2 - 31729368

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 5183

ER -

A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

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