An in vitro pharmacodynamic spiking study of befovacimab, a tissue factor pathway inhibitor monoclonal antibody, in blood samples from patients with severe FVIII deficiency
| Autor: | Janice Kuhn, Donald F. Brophy, Nils Pfaff, Erika J. Martin, Nicole Schmidt, Melinda E Nolte |
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| Rok vydání: | 2021 |
| Předmět: |
Lipoproteins
030204 cardiovascular system & hematology Pharmacology Hemophilia A 03 medical and health sciences Tissue factor 0302 clinical medicine Thrombin Tissue factor pathway inhibitor medicine Humans Genetics (clinical) Whole blood Prothrombin time Factor VIII medicine.diagnostic_test business.industry Antibodies Monoclonal Hematology General Medicine Thromboelastometry Coagulation Clotting time business 030215 immunology medicine.drug |
| Zdroj: | Haemophilia : the official journal of the World Federation of HemophiliaREFERENCES. 27(4) |
| ISSN: | 1365-2516 |
| Popis: | Introduction Tissue factor pathway inhibitor (TFPI) is an endogenous protein that inhibits the extrinsic (tissue factor) pathway and negatively regulates thrombin production during coagulation. Inhibiting TFPI may become a useful target for haemophilia drug development to allow greater thrombin generation without use of the intrinsic (contact) pathway. Aims The in vitro effects of befovacimab, a humanized TFPI neutralizing antibody, were studied in whole blood and plasma samples from patients with severe FVIII deficiency. Methods Blood and plasma obtained from participants was supplemented in vitro with befovacimab (0.5, 1, 5, 10 and 100 nM) or recombinant factor VIII (rFVIII) 5-, 10- and 40% and analysed using rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay. The in vitro coagulation effects of befovacimab were compared to samples supplemented with rFVIII. Results Befovacimab induced consistent pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in α-angle; induced reductions in dPT clotting time; and improvements in TGA parameters (reduced lag time and increased thrombin generation parameters). There was a modest concentration-dependent response generally from 0.5- to 10 nM, after which, the pharmacodynamic effect plateaued through the 100 nM concentration. Befovacimab concentrations of 5 to 10 nM showed pro-coagulant activity comparable to blood samples supplemented with rFVIII 10-40%. Conclusions Befovacimab has modest dose-response effects from 0.5 to 10 nM with minimal improvement with higher concentrations. In vitro befovacimab blood concentrations of 5 to 10 nM had pro-coagulant effects similar to blood supplemented with rFVIII 10- to 40%. |
| Databáze: | OpenAIRE |
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