Comprehensive Evaluation of Anti-Emicizumab Antibodies in Acquired Hemophilia A: A Detailed Case Study and Methodological Evaluation.

BACKGROUND: Acquired hemophilia A (AHA) is a rare and severe bleeding disorder characterized by autoantibodies inhibiting coagulation factor VIII (FVIII). Current treatment of AHA involves bypassing agents, or FVIII replacement therapy, yet their efficacy is limited in cases of high inhibitor titers. Emicizumab, a humanized bispecific monoclonal antibody, has shown promising hemostatic effectiveness in congenital hemophilia A (HA) patients and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.

MATERIALS AND METHODS: We present a comprehensive characterization of anti-emicizumab antibodies in a patient with AHA experiencing diminished emicizumab efficacy from week 10 of treatment. We developed a method for analysis of anti-emicizumab antibodies, distinguishing immunoglobulin subclasses and IgG subtype profiling. ADAs' neutralizing activity was evaluated using a modified clotting assay.

RESULTS: The Luminex-based assay demonstrated the presence of anti-emicizumab antibodies, confirmed through competitive analysis. We detected anti-emicizumab IgG antibodies in the patient's plasma between week 16 and 29. IgG and IgG subclasses were identified. Longitudinal analysis showed IgG isotype antibodies against both emicizumab and FVIII. Anti-emicizumab antibodies exhibited non-inhibitory activity, confirmed by a modified Bethesda assay. Moreover, no accelerated clearance of emicizumab was observed in plasma samples from the patient.

CONCLUSIONS: This study presents the first documented case of anti-emicizumab antibodies in AHA. Our study provides insights into ADA development against emicizumab, emphasizing the need for monitoring tools. The developed method enables comprehensive evaluation of ADAs, aiding in personalized treatment strategies. These findings contribute to understanding emicizumab's immunogenicity profile in AHA, facilitating its optimized clinical use.

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

PMID: 39401737