Detailed analysis of anti-emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A
| Autor: | Yasushi Yoshimura, Makoto Kaneda, Mariko Sasaki-Noguchi, Toshiaki Oka, Yoshihito Tashiro, Hideyuki Yasuno, Hiroto Abe, Yuta Inokuchi, Ryohei Kawasaki, Tetsuhiro Soeda, Naoki Matsumoto |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
congenital hereditary and neonatal diseases and abnormalities Pharmacology Antibodies Monoclonal Humanized Hemophilia A chemistry.chemical_compound Antibodies Bispecific medicine Humans Emicizumab Factor VIII biology medicine.diagnostic_test Bispecific monoclonal antibody business.industry Factor X Hematology Discontinuation Antibodies Anti-Idiotypic Titer chemistry Hemostasis biology.protein Antibody business Partial thromboplastin time |
| Zdroj: | Journal of thrombosis and haemostasis : JTH. 19(12) |
| ISSN: | 1538-7836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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