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

51 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)111-116
Number of pages6
JournalEuropean Heart Journal
Volume39
Issue number2
DOIs
Publication statusPublished - 7 Jan 2018

Keywords

  • Activated platelets
  • Ischaemia/reperfusion injury
  • Myocardial infarction
  • Targeted-CD39

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