A hemophilia A mouse model for the in vivo assessment of emicizumab function - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Blood Year : 2020

A hemophilia A mouse model for the in vivo assessment of emicizumab function

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.

Domains

Hematology
Fichier principal
Vignette du fichier
Ferrière et al 2020.pdf (12.87 Mo) Télécharger le fichier
Origin Files produced by the author(s)
Loading...

Dates and versions

inserm-02916896 , version 1 (10-09-2020)

Identifiers

Cite

Stephen Ferrière, Ivan Peyron, Olivier D. Christophe, Charlotte Kawecki, Caterina Casari, et al.. A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood, 2020, 136 (6), pp.740-748. ⟨10.1182/blood.2019004334⟩. ⟨inserm-02916896⟩
229 View
225 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More