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.
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