Detailed analysis of anti-emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A.
emicizumab
factor VIII
hemophilia A
hemostasis
neutralizing antibodies
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:
12 2021
12 2021
Historique:
received:
30
06
2021
accepted:
19
08
2021
pubmed:
22
8
2021
medline:
15
12
2021
entrez:
21
8
2021
Statut:
ppublish
Résumé
Emicizumab is a humanized bispecific monoclonal antibody that bridges activated factor IX (FIXa) and factor X (FX) to mimic the function of factor VIII (FVIII). It suppresses the bleeding tendency in hemophilia A patients with or without FVIII inhibitors. A case of an adult FVIII inhibitor-positive hemophilia A patient in whom treatment with emicizumab was discontinued owing to the repeated bleeding events and prolonged activated partial thromboplastin time. To analyze the mechanisms of decreased efficacy of emicizumab. Residual plasma samples were used to measure the following: emicizumab concentration in plasma, measured by enzyme-linked immunosorbent assay; titer of anti-drug antibody (ADA) against emicizumab, measured by electrochemiluminescence; and neutralizing activity against emicizumab, measured by Bethesda method modified by using emicizumab-spiked FVIII-deficient plasma. At week 31, emicizumab concentration was 15.0 μg/ml, and ADAs were measured as positive. Emicizumab concentration continued to decrease until emicizumab discontinuation point at week 49, and after week 50, emicizumab concentrations were below the limitation of quantification. The ADA titer increased transiently from week 31, even past the emicizumab discontinuation point at week 49. The ADA titer then gradually decreased until the last sampling point at week 93. Neutralizing activity against emicizumab was detected after emicizumab discontinuation. Epitope analysis showed that the ADAs recognize the anti-FIXa and anti-FX Fab arms of emicizumab, but not the Fc region. The appearance of ADAs with emicizumab-neutralizing activity and potential to accelerate emicizumab clearance decreased the efficacy of emicizumab.
Sections du résumé
BACKGROUND
Emicizumab is a humanized bispecific monoclonal antibody that bridges activated factor IX (FIXa) and factor X (FX) to mimic the function of factor VIII (FVIII). It suppresses the bleeding tendency in hemophilia A patients with or without FVIII inhibitors. A case of an adult FVIII inhibitor-positive hemophilia A patient in whom treatment with emicizumab was discontinued owing to the repeated bleeding events and prolonged activated partial thromboplastin time.
OBJECTIVE
To analyze the mechanisms of decreased efficacy of emicizumab.
METHODS
Residual plasma samples were used to measure the following: emicizumab concentration in plasma, measured by enzyme-linked immunosorbent assay; titer of anti-drug antibody (ADA) against emicizumab, measured by electrochemiluminescence; and neutralizing activity against emicizumab, measured by Bethesda method modified by using emicizumab-spiked FVIII-deficient plasma.
RESULTS
At week 31, emicizumab concentration was 15.0 μg/ml, and ADAs were measured as positive. Emicizumab concentration continued to decrease until emicizumab discontinuation point at week 49, and after week 50, emicizumab concentrations were below the limitation of quantification. The ADA titer increased transiently from week 31, even past the emicizumab discontinuation point at week 49. The ADA titer then gradually decreased until the last sampling point at week 93. Neutralizing activity against emicizumab was detected after emicizumab discontinuation. Epitope analysis showed that the ADAs recognize the anti-FIXa and anti-FX Fab arms of emicizumab, but not the Fc region.
CONCLUSION
The appearance of ADAs with emicizumab-neutralizing activity and potential to accelerate emicizumab clearance decreased the efficacy of emicizumab.
Identifiants
pubmed: 34418287
doi: 10.1111/jth.15506
pmc: PMC9292660
pii: S1538-7836(22)00541-4
doi:
Substances chimiques
Antibodies, Anti-Idiotypic
0
Antibodies, Bispecific
0
Antibodies, Monoclonal, Humanized
0
emicizumab
7NL2E3F6K3
Factor VIII
9001-27-8
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2938-2946Subventions
Organisme : Chugai Pharmaceutical
Informations de copyright
© 2021 Chugai Pharmaceutical Co., Ltd. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.
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