Tags

Type your tag names separated by a space and hit enter

A hemophilia A mouse model for the in vivo assessment of emicizumab function.
Blood. 2020 08 06; 136(6):740-748.Blood

Abstract

The bispecific antibody emicizumab is increasingly used for hemophilia A treatment. However, its specificity for human factors IX and X (FIX and FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here, we describe a novel mouse model that allows emicizumab function to be examined. Briefly, FVIII-deficient mice received IV emicizumab 24 hours before tail-clip bleeding was performed. A second infusion with human FIX and FX, administered 5 minutes before bleeding, generated consistent levels of emicizumab (0.7-19 mg/dL for 0.5-10 mg/kg doses) and of both FIX and FX (85 and 101 U/dL, respectively, after dosing at 100 U/kg). Plasma from these mice display FVIII-like activity in assays (diluted activated partial thromboplastin time and thrombin generation), similar to human samples containing emicizumab. Emicizumab doses of 1.5 mg/kg and higher significantly reduced blood loss in a tail-clip-bleeding model using FVIII-deficient mice. However, reduction was incomplete compared with mice treated with human FVIII concentrate, and no difference in efficacy between doses was observed. From this model, we deducted FVIII-like activity from emicizumab that corresponded to a dose of 4.5 U of FVIII per kilogram (ie, 9.0 U/dL). Interestingly, combined with a low FVIII dose (5 U/kg), emicizumab provided enough additive activity to allow complete bleeding arrest. This model could be useful for further in vivo analysis of emicizumab.

Authors+Show Affiliations

Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Research Department of Haematology, University College London (UCL) Cancer Institute, London, United Kingdom; and. Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom.Research Department of Haematology, University College London (UCL) Cancer Institute, London, United Kingdom; and. Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.Unité Mixte de Recherche Scientifique (UMR_S) 1176, INSERM/Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32369559

Citation

Ferrière, Stephen, et al. "A Hemophilia a Mouse Model for the in Vivo Assessment of Emicizumab Function." Blood, vol. 136, no. 6, 2020, pp. 740-748.
Ferrière S, Peyron I, Christophe OD, et al. A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood. 2020;136(6):740-748.
Ferrière, S., Peyron, I., Christophe, O. D., Kawecki, C., Casari, C., Muczynski, V., Nathwani, A., Kauskot, A., Lenting, P. J., & Denis, C. V. (2020). A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood, 136(6), 740-748. https://doi.org/10.1182/blood.2019004334
Ferrière S, et al. A Hemophilia a Mouse Model for the in Vivo Assessment of Emicizumab Function. Blood. 2020 08 6;136(6):740-748. PubMed PMID: 32369559.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A hemophilia A mouse model for the in vivo assessment of emicizumab function. AU - Ferrière,Stephen, AU - Peyron,Ivan, AU - Christophe,Olivier D, AU - Kawecki,Charlotte, AU - Casari,Caterina, AU - Muczynski,Vincent, AU - Nathwani,Amit, AU - Kauskot,Alexandre, AU - Lenting,Peter J, AU - Denis,Cécile V, PY - 2019/11/27/received PY - 2020/04/12/accepted PY - 2020/5/6/pubmed PY - 2021/3/10/medline PY - 2020/5/6/entrez SP - 740 EP - 748 JF - Blood JO - Blood VL - 136 IS - 6 N2 - The bispecific antibody emicizumab is increasingly used for hemophilia A treatment. However, its specificity for human factors IX and X (FIX and FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here, we describe a novel mouse model that allows emicizumab function to be examined. Briefly, FVIII-deficient mice received IV emicizumab 24 hours before tail-clip bleeding was performed. A second infusion with human FIX and FX, administered 5 minutes before bleeding, generated consistent levels of emicizumab (0.7-19 mg/dL for 0.5-10 mg/kg doses) and of both FIX and FX (85 and 101 U/dL, respectively, after dosing at 100 U/kg). Plasma from these mice display FVIII-like activity in assays (diluted activated partial thromboplastin time and thrombin generation), similar to human samples containing emicizumab. Emicizumab doses of 1.5 mg/kg and higher significantly reduced blood loss in a tail-clip-bleeding model using FVIII-deficient mice. However, reduction was incomplete compared with mice treated with human FVIII concentrate, and no difference in efficacy between doses was observed. From this model, we deducted FVIII-like activity from emicizumab that corresponded to a dose of 4.5 U of FVIII per kilogram (ie, 9.0 U/dL). Interestingly, combined with a low FVIII dose (5 U/kg), emicizumab provided enough additive activity to allow complete bleeding arrest. This model could be useful for further in vivo analysis of emicizumab. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/32369559/A_hemophilia_A_mouse_model_for_the_in_vivo_assessment_of_emicizumab_function_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)61823-7 DB - PRIME DP - Unbound Medicine ER -