Targeted antiplatelet therapy: novel treatment options for ischaemic heart disease

This editorial refers to ‘A single-chain antibody-CD39 fusion protein targeting activated platelets protects from cardiac ischaemia/reperfusion injury’†, by M. Ziegler et al., on page 111. Platelets play a major role in the development of ischaemic heart disease.1 At sites of vascular lesions, platelets adhere to plaque erosions and trigger thrombus formation leading to acute myocardial infarction. Sustained platelet activation induces significant impairment of microcirculation within the infarcted myocardium during reperfusion and contributes substantially to reperfusion injury.2 Inhibition of platelet aggregation by blocking the fibrinogen receptor glycoprotein (GP) IIb-IIIa (GPIIb-IIIa) via abciximab improves the recovery of microvascular perfusion and augments contractile function in the area of risk of the infarcted myocardium.3 An intensified antiplatelet therapy [dual antiplatelet therapy with aspirin and adenosine diphosphate (ADP) receptor blockers] is the current antithrombotic standard therapy in myocardial infarction.4 To date, several antiplatelet inhibitors, including acetyl salicylic acid, P2Y12 inhibitors, and GPIIb-IIIa (integrin αIIbβ3) receptor blockers, have become available to prevent or treat arterial thrombosis in affected patients.5 However, all current antiplatelet drugs inhibit both resting and activated platelets resulting in the inhibition of haemostasis. Thus, current antiplatelet therapy is associated with enhanced risk of bleeding. Novel antiplatelet strategies are warranted to control undesired platelet activation without disrupting haemostasis and risking life-threatening bleeding complications. A promising concept to control thrombosis at sites of vascular (plaque rupture) or acute ischaemic myocardium (microcirculation) without a systemic effect on haemostasis, and with an improved safety profile, is the targeted antiplatelet therapy. The concept of targeted antiplatelet therapy is to guide antiplatelet drugs primarily towards activated platelets at the site of thrombus formation. Previously, Peter’s group have generated and validated a conformation-specific single-chain antibody directed against the activated fibrinogen receptor GPIIb-IIIa. Upon activation, the integrin GPIIb-IIIa changes its conformation, which provides a unique opportunity to design agents that specifically block only activated platelets.6 Activation-specific anti-GPIIb-IIIa single-chain antibodies inhibit platelet-dependent thrombosis without affecting bleeding time in mice. Further, the same group has shown that a bifunctional molecule consisting of an activation-specific GPIIb-IIIa antibody and a fibrinolytic domain limits thrombus formation and facilitates resolution in vivo. 7 In the current issue of the European Heart Journal, Ziegler et al. extent their research on targeted antiplatelet therapy and describe an innovative and promising approach to target thrombus development using a novel bifunctional recombinant molecule.8 The authors have combined two antiplatelet strategies in terms of blocking GPIIb-IIIa and degrading the potent platelet agonist ADP in the environment of a growing arterial thrombus. The authors have linked the ectonucleoside triphosphate diphosphohydrolase-1 CD39 to an activation-specific GPIIb-IIIa antibody. The ectonucleotidase CD39 degrades ADP to adenosine monophosphate and Pi (phosphate group) and thus inactivates ADP, which results in the attenuation of ADP-induced platelet activation. The authors elegantly show in a mouse model of ischaemia/reperfusion that their bifunctional molecule (Targ-CD39) significantly reduces platelet accumulation in the infarcted area and preserves myocardial function without enhancing bleeding (Take home figure). The results of their study show that modulation of ADP in the setting of myocardial infarction is a critical mechanism and that a targeted degradation of ADP through enhancing CD39 activity attenuates platelet accumulation within the infarcted myocardium. Further, the data of the manuscript emphasizes the pathophysiological importance of ADP for myocardial regeneration. Ziegler et al. provide strong evidence that modulation of ADP via Targ-CD39 reduces infarct size, increases neovascularization, and attenuates post-ischaemic inflammation. This concept may not only be a novel treatment option for patients with myocardial infarction, but may also be promising for other diseases, such as acute ischaemic stroke or reperfusion injury following organ transplantation; basically, in all diseases where thromboinflammation is a prominent pathophysiological feature. Bifunctional molecule (Targ-CD39) significantly reduces platelet accumulation in the infarcted area and preserves myocardial function without enhancing bleeding in a mouse model of ischaemia/reperfusion. Biotechnology enables the design and tailoring of novel drugs to improve medical treatment in cardiovascular diseases. The concept of recombinant biologicals and antibodies is increasingly recognized as a valuable pharmacological therapy in cardiovascular diseases and beyond. Previously, bifunctional biologicals consisting of the CXCL12 chemokine9 or a single-chain antibody directed to circulating progenitor cells (anti-CD133)10 and a soluble form of the platelet collagen receptor glycoprotein protein VI (GPVI)11 have been shown to favour myocardial regeneration following acute ischaemia in vivo. Only recently, the combination of GPVI with CD39 (GPVI-CD39) has been shown to effectively control thrombus formation in vivo without compromising haemostasis.12 To date, two biologicals have become established treatment options in clinical cardiology. The GPIIb-IIIa inhibitor abciximab has been described to limit thrombus formation in acute myocardial infarction13 and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to control hypercholesterolaemia in patients with coronary artery disease.14 Thus, it is likely that in the near future novel biologicals will enrich the pharmacological arsenal for a more individualized therapy of various cardiovascular diseases, including the regeneration of myocardium following acute or chronic ischaemia. Only recently, a human monoclonal antibody, canakinumab, which inhibits interleukin-1b, has been shown to significantly attenuate vascular inflammation15 and reduce cardiovascular risk in patients who survive a heart attack [Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS trial)]. In summary, the manuscript from Ziegler et al. 8 places a spotlight on the great potential of biotechnology in the treatment of acute ischaemic heart disease and beyond. The authors show that the desire of cardiologists to control thrombosis without risk of bleeding can be met in the future. Although targeted antiplatelet therapy6 , 11 is still in the preclinical phase, platelet-related recombinant biologicals may provide new treatment options in the foreseeable future. In the field of antiplatelet therapy, biotechnology opens up a new age of research, and novel platelet inhibitors are currently developed preclinically that have greater individual efficacy and favourable safety profiles. Targeting platelet adhesion receptors with activation-specific inhibitors (e.g. directed against GPIIb-IIIa) or soluble receptors (e.g. collagen receptor GPVI), which allow lesion-specific platelet inhibition at the site of vulnerable plaques without enhancing the risk of bleeding, has the potential to change antiplatelet therapy in the near future. Conflict of interest: none declared.