Microlyse
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Microlyse : a thrombolytic agent that targets VWF for clearance of microvascular thrombosis. / de Maat, Steven; Clark, Chantal C; Barendrecht, Arjan D; Smits, Simone; van Kleef, Nadine D; El Otmani, Hinde; Waning, Manon; van Moorsel, Marc; Szardenings, Michael; Delaroque, Nicolas; Vercruysse, Kristof; Urbanus, Rolf T; Sebastian, Silvie; Lenting, Peter J; Hagemeyer, Christoph; Renné, Thomas; Vanhoorelbeke, Karen; Tersteeg, Claudia; Maas, Coen.
in: BLOOD, Jahrgang 139, Nr. 4, 27.01.2022, S. 597-607.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Microlyse
T2 - a thrombolytic agent that targets VWF for clearance of microvascular thrombosis
AU - de Maat, Steven
AU - Clark, Chantal C
AU - Barendrecht, Arjan D
AU - Smits, Simone
AU - van Kleef, Nadine D
AU - El Otmani, Hinde
AU - Waning, Manon
AU - van Moorsel, Marc
AU - Szardenings, Michael
AU - Delaroque, Nicolas
AU - Vercruysse, Kristof
AU - Urbanus, Rolf T
AU - Sebastian, Silvie
AU - Lenting, Peter J
AU - Hagemeyer, Christoph
AU - Renné, Thomas
AU - Vanhoorelbeke, Karen
AU - Tersteeg, Claudia
AU - Maas, Coen
N1 - © 2022 by The American Society of Hematology.
PY - 2022/1/27
Y1 - 2022/1/27
N2 - Thrombotic microangiopathies are hallmarked by attacks of disseminated microvascular thrombosis. In thrombotic thrombocytopenic purpura (TTP), this is caused by a rise in thrombogenic ultra-large von Willebrand factor (VWF) multimers because of ADAMTS13 deficiency. We previously reported that systemic plasminogen activation is therapeutic in a TTP mouse model. In contrast to its natural activators (ie, tissue plasminogen activator and urokinase plasminogen activator [uPA]), plasminogen can directly bind to VWF. For optimal efficacy and safety, we aimed to focus and accelerate plasminogen activation at sites of microvascular occlusion. We here describe the development and characterization of Microlyse, a fusion protein consisting of a high-affinity VHH targeting the CT/CK domain of VWF and the protease domain of uPA, for localized plasminogen activation on microthrombi. Microlyse triggers targeted destruction of platelet-VWF complexes by plasmin on activated endothelial cells and in agglutination studies. At equal molar concentrations, Microlyse degrades microthrombi sevenfold more rapidly than blockade of platelet-VWF interactions with a bivalent humanized VHH (caplacizumab*). Finally, Microlyse attenuates thrombocytopenia and tissue damage (reflected by increased plasma lactate dehydrogenase activity, as well as PAI-1 and fibrinogen levels) more efficiently than caplacizumab* in an ADAMTS13-/- mouse model of TTP, without affecting hemostasis in a tail-clip bleeding model. These findings show that targeted thrombolysis of VWF by Microlyse is an effective strategy for the treatment of TTP and might hold value for other forms of VWF-driven thrombotic disease.
AB - Thrombotic microangiopathies are hallmarked by attacks of disseminated microvascular thrombosis. In thrombotic thrombocytopenic purpura (TTP), this is caused by a rise in thrombogenic ultra-large von Willebrand factor (VWF) multimers because of ADAMTS13 deficiency. We previously reported that systemic plasminogen activation is therapeutic in a TTP mouse model. In contrast to its natural activators (ie, tissue plasminogen activator and urokinase plasminogen activator [uPA]), plasminogen can directly bind to VWF. For optimal efficacy and safety, we aimed to focus and accelerate plasminogen activation at sites of microvascular occlusion. We here describe the development and characterization of Microlyse, a fusion protein consisting of a high-affinity VHH targeting the CT/CK domain of VWF and the protease domain of uPA, for localized plasminogen activation on microthrombi. Microlyse triggers targeted destruction of platelet-VWF complexes by plasmin on activated endothelial cells and in agglutination studies. At equal molar concentrations, Microlyse degrades microthrombi sevenfold more rapidly than blockade of platelet-VWF interactions with a bivalent humanized VHH (caplacizumab*). Finally, Microlyse attenuates thrombocytopenia and tissue damage (reflected by increased plasma lactate dehydrogenase activity, as well as PAI-1 and fibrinogen levels) more efficiently than caplacizumab* in an ADAMTS13-/- mouse model of TTP, without affecting hemostasis in a tail-clip bleeding model. These findings show that targeted thrombolysis of VWF by Microlyse is an effective strategy for the treatment of TTP and might hold value for other forms of VWF-driven thrombotic disease.
U2 - 10.1182/blood.2021011776
DO - 10.1182/blood.2021011776
M3 - SCORING: Journal article
C2 - 34752601
VL - 139
SP - 597
EP - 607
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 4
ER -
