Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia
| Autor: | Midori Shima |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Emicizumab
emicizumab biology business.industry lcsh:RC633-647.5 Antithrombin Hematology lcsh:Diseases of the blood and blood-forming organs Pharmacology factor VIII prophylaxis Immune tolerance Tissue factor Tissue factor pathway inhibitor Coagulation Isth Congress State of the Art State of the Art Isth 2019 biology.protein hemophilia A therapy Medicine Antibody bispecific antibodies business Protein C medicine.drug |
| Zdroj: | Research and Practice in Thrombosis and Haemostasis Research and Practice in Thrombosis and Haemostasis, Vol 4, Iss 4, Pp 446-454 (2020) |
| ISSN: | 2475-0379 |
| Popis: | Regular prophylaxis has markedly improved the treatment for patients with hemophilia A, especially after the introduction of highly purified factor VIII (FVIII) concentrates. However, frequent intravenous infusions and the development of FVIII inhibitors remain as unsolved difficulties. To overcome these unmet needs, a bispecific antibody mimicking activated FVIII has been developed in Japan. This bispecific antibody, emicizumab, recognizes activated factor IX (FIXa) and activated factor X (FXa), and promotes FIXa‐catalyzed activation of FX in the absence of FVIII. Emicizumab initially reacts with FIXa generated by the action of factor VIIa/tissue factor complexes. Subsequently, thrombin generation is enhanced in the presence of higher amounts of FIXa derived from FXIa‐dependent mechanisms. Hence, emicizumab‐driven FXa and thrombin generation is maintained by a FXI activation loop in the intrinsic coagulation pathway. Reactions downstream of emicizumab are regulated by natural anticoagulants including activated protein C, antithrombin, and tissue factor pathway inhibitor. Phase 3 studies (HAVEN 1‐4 and HOHOEMI studies) demonstrated a remarkable reduction in bleeding rates together with a high percentage of patients with zero treated bleeds irrespective of the presence of inhibitors. In general, emicizumab proved to be well tolerated, although isolated thromboembolic and thrombotic microangiopathic complications were observed in the HAVEN 1 studies, and 3 out of a total of 400 patients developed neutralizing antidrug antibodies. In addition, several questions remain to be discussed with respect to open‐use clinical practice, including when to start treatment, how to monitor therapy, and optimum dosage for surgical procedures and immune tolerance induction. |
| Databáze: | OpenAIRE |
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