ArticleEuropean heart journal2024
The humanized platelet glycoprotein VI Fab inhibitor EMA601 protects from arterial thrombosis and ischaemic stroke in mice.
Article in European heart journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- 3-Hydroxydehydroleucodin ameliorates neuroinflammation and ischemic brain injury by blocking the TRIM21-PRDX1 interaction.Acta pharmacologica Sinica · 2026Article
- Partial downregulation of platelet glycoprotein VI by low affinity antibodies confers sustained and safe antithrombotic protection.Signal transduction and targeted therapy · 2026Article
- Platelet-Collagen Interactions in Hemostatic Mechanisms.Advanced healthcare materials · 2026Review
- Procoagulant platelets: linking coagulation and thromboinflammation in cardiovascular disease.Nature reviews. Cardiology · 2026Review
- The fibrinogen αC region promotes arterial thrombosis in the context of hypofibrinogenemia.Blood · 2026Article
- When GPVI Goes Rogue: Pathogenesis and Therapeutic Horizons in ITP.Expert reviews in molecular medicine · 2026Review
- Research advances on platelet glycoprotein VI in ischemic stroke.Thrombosis journal · 2026Review
- Hemostasis-Sparing Antiplatelet Therapy: Current Concepts and Emerging Targets in Arterial Thrombosis.Biomolecules & therapeutics · 2026Review
- Humanized murine models of platelet function.Current opinion in hematology · 2025Review
- Glycoprotein VI inhibitors: glenzocimab and EMA601 two inhibitory Fabs.European heart journal · 2025Article
- A New Perspective on Mechanisms of Neurodegeneration in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis: the Early and Critical Role of Platelets in Neuro/Axonal Loss.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Review
- Comparative Effects of Glenzocimab and Eptifibatide on Bleeding Severity in 2 Mouse Models of Intracranial Hemorrhage.Journal of the American Heart Association · 2025Article
- Specificities of Myocardial Infarction and Heart Failure in Women.Journal of clinical medicine · 2024Review
- Ischemia/reperfusion injury in acute human and experimental stroke: focus on thrombo-inflammatory mechanisms and treatments.Neurological research and practice · 2024Review
- Thromboinflammation is associated with clinical outcome after ST-elevation myocardial infarction.Blood advances · 2024Observational
- One immune cell to bind them all: platelet contribution to neurodegenerative disease.Molecular neurodegeneration · 2024Review
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10 authors.
Funding
Abstract
BACKGROUND AND
aimsGlycoprotein VI (GPVI) is a platelet collagen/fibrin(ogen) receptor and an emerging pharmacological target for the treatment of thrombotic and thrombo-inflammatory diseases, notably ischaemic stroke. A first anti-human GPVI (hGPVI) antibody Fab-fragment (ACT017/glenzocimab, KD: 4.1 nM) recently passed a clinical phase 1b/2a study in patients with acute ischaemic stroke and was found to be well tolerated, safe, and potentially beneficial. In this study, a novel humanized anti-GPVI antibody Fab-fragment (EMA601; KD: 0.195 nM) was developed that inhibits hGPVI function with very high potency in vitro and in vivo.
methodsFab-fragments of the mouse anti-hGPVI IgG Emf6.1 were tested for functional GPVI inhibition in human platelets and in hGPVI expressing (hGP6tg/tg) mouse platelets. The in vivo effect of Emf6.1Fab was assessed in a tail bleeding assay, an arterial thrombosis model and the transient middle cerebral artery occlusion (tMCAO) model of ischaemic stroke. Using complementary-determining region grafting, a humanized version of Emf6.1Fab (EMA601) was generated. Emf6.1Fab/EMA601 interaction with hGPVI was mapped in array format and kinetics and quantified by bio-layer interferometry.
resultsEmf6.1Fab (KD: 0.427 nM) blocked GPVI function in human and hGP6tg/tg mouse platelets in multiple assays in vitro at concentrations ≥5 µg/mL. Emf6.1Fab (4 mg/kg)-treated hGP6tg/tg mice showed potent hGPVI inhibition ex vivo and were profoundly protected from arterial thrombosis as well as from cerebral infarct growth after tMCAO, whereas tail-bleeding times remained unaffected. Emf6.1Fab binds to a so far undescribed membrane proximal epitope in GPVI. The humanized variant EMA601 displayed further increased affinity for hGPVI (KD: 0.195 nM) and fully inhibited the receptor at 0.5 µg/mL, corresponding to a >50-fold potency compared with ACT017.
conclusionsEMA601 is a conceptually novel and promising anti-platelet agent to efficiently prevent or treat arterial thrombosis and thrombo-inflammatory pathologies in humans at risk.
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