An anti-factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A.
autoantibodies
bispecific antibodies
blood coagulation
hemophilia A
pharmacokinetics
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
04
11
2019
revised:
31
12
2019
accepted:
17
01
2020
pubmed:
28
1
2020
medline:
15
5
2021
entrez:
28
1
2020
Statut:
ppublish
Résumé
Acquired hemophilia A (AHA) is caused by autoantibodies against factor (F)VIII, and is characterized by severe, spontaneous bleeding, which can be life-threatening. Emicizumab, an anti-FIXa/FX bispecific antibody, significantly reduces bleeding events in congenital hemophilia A (HA) with and without inhibitors. The known pathophysiological mechanisms and current preclinical data in HA suggest that emicizumab could provide effective treatment for AHA, but the coagulation activities of emicizumab in these patients remain unknown. To evaluate the coagulant effects of emicizumab in plasma from AHA patients. Tissue factor-triggered thrombin generation assays using normal plasma preincubated with anti-FVIII monoclonal antibodies recognizing different epitopes demonstrated that 20 µg/mL emicizumab recovered the depressed peak levels of thrombin generation to 46% to 72%. Further studies were devised, therefore, to simulate the clinical course in AHA patients, including during the acute phase for severe bleeding requiring FVIII-bypassing therapy, and during the subacute/chronic phase with less bleeding. Various concentrations of emicizumab were used to represent the potential changes in plasma levels based on the half-life of the antibody (~30 days). The ex vivo addition of emicizumab to plasma samples from AHA patients (n = 16) increased peak thrombin in all cases, irrespective of the inhibitor epitope specificity. Thrombin generation at 20 and 100 µg/mL emicizumab was restored to (median) 43.9% and 92.2%, respectively. Differences were evident in some cases, however, and recovery rates appeared likely to be greater in patients with type 2 inhibitor than those with type 1. Emicizumab improved ex vivo coagulation potential in plasma from AHA patients.
Identifiants
pubmed: 31984625
doi: 10.1111/jth.14746
pii: S1538-7836(22)00291-4
doi:
Substances chimiques
Antibodies, Bispecific
0
Antibodies, Monoclonal, Humanized
0
emicizumab
7NL2E3F6K3
Factor VIII
9001-27-8
Factor X
9001-29-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
825-833Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
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