1. Characterization of the neutralizing anti-emicizumab antibody in a patient with hemophilia A and inhibitor.
- Author
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Valsecchi C, Gobbi M, Beeg M, Adams T, Castaman G, Schiavone L, Huntington JA, and Peyvandi F
- Subjects
- Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Child, Factor VIII, Humans, Antibodies, Bispecific, Hemophilia A diagnosis, Hemophilia A drug therapy
- Abstract
Background: The genetically engineered, humanized, bispecific monoclonal antibody emicizumab (Hemlibra) that mimics the cofactor activity of activated factor VIII (FVIII) has been approved for treatment of hemophilia A patients with and without inhibitor. In the pivotal premarketing clinical trials, emicizumab prophylaxis significantly reduced bleeding rates compared with previous treatments and was well tolerated. However, a consequence of this novel therapy may be the host immune response to a foreign protein., Objective: Characterization of the neutralizing anti-emicizumab antibody associated with the loss of treatment efficacy., Patient: A pediatric hemophilia A patient with inhibitor enrolled in the HAVEN2 (Study of Emicizumab Administered Subcutaneously (SC) in Pediatric Participants With Hemophilia A and Factor VIII (FVIII) Inhibitors) clinical trial., Methods: The anti-emicizumab antibody has been characterized with Western blot and enzyme-linked immunosorbent assay (ELISA). The antibody was affinity purified and sequenced. Binding affinity to full-length and papain-digested emicizumab was analyzed using surface plasmon resonance and byo-layer interferometry., Results: The neutralizing anti-emicizumab antibody was highly polyclonal with high-affinity binding mainly to the Fab portion of emicizumab with a small amount of binding to the Fc portion. Molecular interaction experiments between emicizumab and the purified antibody indicated the presence of at least two components with similar affinities., Conclusions: Although the incidence of neutralizing anti-emicizumab antibody is rare, this study highlights the importance of a close monitoring and the need of a simple laboratory assay to promptly detect these antibodies in patients with a history of poor drug efficacy., (© 2021 International Society on Thrombosis and Haemostasis.)
- Published
- 2021
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