title: The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti-inflammatory activities.
abstract: The plasma protein factor XII (FXII) is the initiating protease of the procoagulant and proinflammatory contact system. FXII activates both the bradykinin (BK) producing kallikrein-kinin system and the intrinsic pathway of coagulation. Contact with negatively charged surfaces induces auto-activation of zymogen FXII that results in activated FXII (FXIIa). Various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, nucleic acids and polyphosphate. Murine models have established a central role of FXII in arterial and venous thromboembolic diseases. Despite the central function of FXII in pathologic thrombosis, its deficiency does not impair hemostasis in animals or humans. The selective role of FXIIa in thrombosis, but not hemostasis, offers an exciting novel strategy for safe anticoagulation based on interference with FXIIa. We have generated the recombinant fully human FXIIa-blocking antibody 3F7, which abolished FXIIa enzymatic activity and prevented thrombosis in a cardiopulmonary bypass system in large animals, in the absence of increased therapy-associated bleeding. Furthermore, 3F7 also interfered with BK-driven edema in the severe swelling disorder hereditary angioedema (HAE) type III. Taken together, targeting FXIIa with 3F7 appears to be a promising approach to treat edema disorders and thrombosis.
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Worm
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Elodie C
authors.initials: EC
authors.lastname: Köhler
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Rachita
authors.initials: R
authors.lastname: Panda
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Long
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Butler
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Evi X
authors.initials: EX
authors.lastname: Stavrou
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Nickel
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.affiliation: 1 Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany ; 2 Division of Clinical Chemistry, Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden ; 3 Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA ; 4 Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, Ohio, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
keywords: Cardiovascular; angioedema; anticoagulation; coagulation; factor XII (FXII); hereditary angioedema (HAE) type III; thrombosis