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A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion
Melanie Ziegler1, Jan David Hohmann1, Amy Kate Searle1,2
1Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC 3004, Australia.
Insights
A novel fusion protein, Targ-CD39, targets activated platelets to protect heart tissue after myocardial infarction. This approach offers therapeutic benefits for heart attack treatment while minimizing bleeding risks.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Science
Background:
- CD39 is a cell membrane enzyme with anti-inflammatory and anti-platelet properties.
- Clinical application of CD39 is hindered by bleeding side effects.
- A fusion protein, Targ-CD39, was engineered to target activated platelets, aiming to mitigate hemostatic issues.
Purpose of the Study:
- To evaluate the therapeutic potential of Targ-CD39 in a myocardial infarction model.
- To assess if Targ-CD39 can protect cardiac tissue and improve function post-ischemia.
- To determine if Targ-CD39 can reduce infarct size and associated inflammation.
Main Methods:
- A mouse model of myocardial ischemia/reperfusion was utilized.
- Targ-CD39 was administered and compared to a non-binding control and PBS.
- Cardiac function was assessed using echocardiography, and infarct size/neovascularization via histology. Cytokine profiling analyzed inflammation.
Main Results:
- Targ-CD39 significantly protected reperfused cardiac tissue compared to controls.
- It restored cardiac function (ejection fraction, fractional shortening) to pre-injury levels.
- Histology showed reduced infarct size and increased neovascularization, with attenuated post-ischemic inflammation.
Conclusions:
- Targ-CD39 demonstrates significant promise for the treatment of myocardial infarction.
- Targeted delivery to activated platelets allows therapeutic enzyme activity while avoiding systemic bleeding.
- This strategy offers a potential new therapeutic avenue for heart attack patients.
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.
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