title: Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk.
abstract: In patients with acute myocardial infarction undergoing reperfusion therapy to restore blood flow through blocked arteries, simultaneous inhibition of platelet P2Y12 receptors with the current standard of care neither completely prevents recurrent thrombosis nor provides satisfactory protection against reperfusion injury. Additionally, these antiplatelet drugs increase the risk of bleeding. To devise a different strategy, we engineered and optimized the apyrase activity of human nucleoside triphosphate diphosphohydrolase-3 (CD39L3) to enhance scavenging of extracellular adenosine diphosphate, a predominant ligand of P2Y12 receptors. The resulting recombinant protein, APT102, exhibited greater than four times higher adenosine diphosphatase activity and a 50 times longer plasma half-life than did native apyrase. Treatment with APT102 before coronary fibrinolysis with intravenous recombinant human tissue-type plasminogen activator in conscious dogs completely prevented thrombotic reocclusion and significantly decreased infarction size by 81% without increasing bleeding time. In contrast, clopidogrel did not prevent coronary reocclusion and increased bleeding time. In a murine model of myocardial reperfusion injury caused by transient coronary artery occlusion, APT102 also decreased infarct size by 51%, whereas clopidogrel was not effective. These preclinical data suggest that APT102 should be tested for its ability to safely and effectively maximize the benefits of myocardial reperfusion therapy in patients with arterial thrombosis.
authors.affiliation: Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Moeckel
authors.affiliation: APT Therapeutics Inc., 4041 Forest Park Avenue, St. Louis, MO 63108, USA.
authors.forename: Soon Soeg
authors.initials: SS
authors.lastname: Jeong
authors.affiliation: Division of Gastroenterology/Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Sun
authors.affiliation: Thrombosis Research Laboratory, Research Service, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: M Johan
authors.initials: MJ
authors.lastname: Broekman
authors.affiliation: Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Thrombosis Research Laboratory, Research Service, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Joan H F
authors.initials: JH
authors.lastname: Drosopoulos
authors.affiliation: Thrombosis Research Laboratory, Research Service, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Marcus
authors.affiliation: Division of Gastroenterology/Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: APT Therapeutics Inc., 4041 Forest Park Avenue, St. Louis, MO 63108, USA. rchen@apt-therapeutics.com dabendsc@DOM.wustl.edu.
authors.forename: Ridong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. rchen@apt-therapeutics.com dabendsc@DOM.wustl.edu.
authors.forename: Dana
authors.initials: D
authors.lastname: Abendschein
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001081:Apyrase / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077144:Clopidogrel; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005342:Fibrinolysis / Q000187:drug effects; D006470:Hemorrhage / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D000068799:Prasugrel Hydrochloride; D012307:Risk Factors; D013876:Thiophenes / Q000494:pharmacology; D013927:Thrombosis / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome; D014654:Vascular Patency / Q000187:drug effects
chemical_list: D010879:Piperazines; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D010959:Tissue Plasminogen Activator; D001081:Apyrase; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
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