A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury

Melanie Ziegler, Jan David Hohmann, Amy Kate Searle, Meike-Kristin Abraham, Harshal H. Nandurkar, Xiaowei Wang

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis.

Methods and results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling.

Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction.
LanguageEnglish
Pages111-116
Number of pages6
JournalEuropean Heart Journal
Volume39
Issue number2
DOIs
StatePublished - 7 Jan 2018

Cite this

Ziegler, Melanie ; Hohmann, Jan David ; Searle, Amy Kate ; Abraham, Meike-Kristin ; Nandurkar, Harshal H. ; Wang, Xiaowei. / A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury. In: European Heart Journal. 2018 ; Vol. 39, No. 2. pp. 111-116
@article{fc0b9cbbc0d94b90875926b0c086b6b1,
title = "A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury",
abstract = "Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis.Methods and results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling.Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction.",
author = "Melanie Ziegler and Hohmann, {Jan David} and Searle, {Amy Kate} and Meike-Kristin Abraham and Nandurkar, {Harshal H.} and Xiaowei Wang",
year = "2018",
month = "1",
day = "7",
doi = "10.1093/eurheartj/ehx218",
language = "English",
volume = "39",
pages = "111--116",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "2",

}

A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury. / Ziegler, Melanie; Hohmann, Jan David; Searle, Amy Kate; Abraham, Meike-Kristin ; Nandurkar, Harshal H.; Wang, Xiaowei.

In: European Heart Journal, Vol. 39, No. 2, 07.01.2018, p. 111-116.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury

AU - Ziegler,Melanie

AU - Hohmann,Jan David

AU - Searle,Amy Kate

AU - Abraham,Meike-Kristin

AU - Nandurkar,Harshal H.

AU - Wang,Xiaowei

PY - 2018/1/7

Y1 - 2018/1/7

N2 - Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis.Methods and results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling.Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction.

AB - Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis.Methods and results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling.Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction.

U2 - 10.1093/eurheartj/ehx218

DO - 10.1093/eurheartj/ehx218

M3 - Article

VL - 39

SP - 111

EP - 116

JO - European Heart Journal

T2 - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 2

ER -