Characterization of the neutralizing anti‐emicizumab antibody in a patient with hemophilia A and inhibitor

Abstract

BackgroundThe 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. ObjectiveCharacterization of the neutralizing anti‐emicizumab antibody associated with the loss of treatment efficacy. PatientA 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. MethodsThe 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. ResultsThe 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. ConclusionsAlthough 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.