Emfret presents novel anticoagulant

Together with an academic research group led by Emfret founder Bernhard Nieswandt from the University Hospital of Würzburg, Emfret Analytics presented its glycoprotein VI (GPVI) inhibitor EMA601 as a novel anticoagulant in the renowned European Heart Journal. CPVI is a platelet collagen/fibrin(ogen) receptor whose targeted inhibition by the humanised antibody glenzocimab (ACT017) has already yielded promising clinical data from Phase II trials in the indications of stroke and heart attack treatment and prevention that have now been completed by the French INSERM spin-off Acticor Biotech SA , whose heart attack candidate is already being tested in a pivotal phase II/III trial. However, the humanised Fab fragment EMA601 developed by Emfret and now functionally analysed by Nieswandt’s group showed a 50-fold potency compared to Glenzocimab in preclinical in vivo and in vitro blood coagulation assays.

Using complementary-determining region grafting, a humanised version of Emf6.1^Fab (EMA601) was generated. Emf6.1^Fab/EMA601 interaction with human (h)GPVI was mapped in array format and kinetics and quantified by bio-layer interferometry. Emf6.1^Fab (K_D: 0.427 nM) blocked GPVI function in human and hGP6^tg/tg mouse platelets in multiple assays in vitro at concentrations ≥5 µg/mL. Emf6.1^Fab (4 mg/kg)-treated hGP6^tg/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. Emf6.1^Fab binds to a so far undescribed membrane proximal epitope in GPVI. The humanised variant EMA601 displayed further increased affinity for hGPVI (K_D: 0.195 nM) and fully inhibited the receptor at 0.5 µg/mL.

Nieswandt sees this as an indication that EMA601 could therefore be used for the efficient prevention and treatment of arterial thrombosis and thrombosis-induced inflammatory reactions without an increased risk of bleeding – a dangerous side effect of previously marketed anticoagulants. The normal coagulation reaction does not appear to be affected by EMA601. According to the discoverer of GPVI, this appears to be related to the fact that the surface receptor is found exclusively in platelets and their precursor cells in the bone marrow, but unlike coagulation factors is not involved in the blood coagulation cascade. GPVI is primarily responsible for the binding of collagen to the injured vessel wall, which triggers the activation and aggregation, i.e. clumping of the platelets.

Excessive activation of GPVI leads to the formation of thrombi and heart attacks or strokes caused by vascular occlusion. Platelets are also significantly involved in inflammatory reactions in vascular diseases such as atherosclerosis.