Post-ischaemic administration of the murine Canakinumab-surrogate antibody improves outcome in experimental stroke.

Authors:
Alexander Akhmedov
Alexander Akhmedov
University of Zurich
Switzerland
Fabrizio Montecucco
Fabrizio Montecucco
First Clinic of Internal Medicine
Washington | United States
Thomas F Luscher
Thomas F Luscher
University Heart Center
Switzerland

Eur Heart J 2018 Oct;39(38):3511-3517

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren, Switzerland.

Aims: The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1β inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1β in stroke, we tested the efficacy of the murine Canakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1β inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy.

Methods And Results: Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1β antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome.

Conclusion: Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1β blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.

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http://dx.doi.org/10.1093/eurheartj/ehy286DOI Listing
October 2018
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References

(Supplied by CrossRef)
Inflammation in atherosclerosis
Libby et al.
Nature 2002
Antiinflammatory therapy with Canakinumab for atherosclerotic disease
Ridker et al.
N Engl J Med 2017
Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond
Libby et al.
J Am Coll Cardiol 2017
Update on inflammatory biomarkers and treatments in ischemic stroke
Bonaventura et al.
Int J Mol Sci 2016
Aging: the next cardiovascular disease?
Camici et al.
Eur Heart J 2017
Interleukin-1 in stroke: from bench to bedside
Sobowale et al.
Stroke 2016
Deletion of the ageing gene p66(Shc) reduces early stroke size following ischaemia/reperfusion brain injury
Spescha et al.
Eur Heart J 2013

EMEA et al.
Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity
Osborn et al.
Cytokine 2008
Reducing vascular calcification by anti-IL-1beta monoclonal antibody in a mouse model of familial hypercholesterolemia
Awan et al.
Angiology 2016
Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1beta monoclonal antibody
Chakraborty et al.
Clin Pharmacokinet 2012

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