Neutralizing Antibodies Against Emicizumab – Detailed Analysis Based on a Case Study
Japanese authors investigated the mechanism of reduced efficacy of emicizumab in an adult patient with hemophilia A and an inhibitor, whose treatment was discontinued due to repeated bleeding episodes with prolonged aPTT.
Emicizumab and Anti-Drug Antibodies
Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of FVIII, reduces bleeding tendencies in patients with hemophilia A with or without an FVIII inhibitor. Very rarely, cases of antibodies against emicizumab have been described.
The authors of the cited work examined residual plasma samples and measured the following parameters - plasma concentration of emicizumab, titer of anti-drug antibodies (ADA) against emicizumab, and neutralizing activity against emicizumab - using the Bethesda method with FVIII-deficient plasma supplemented with emicizumab.
Case Description
The patient was a 62-year-old man whose activated partial thromboplastin time (aPTT) was prolonged (> 240 s) just before starting emicizumab treatment. The patient was administered a standard loading dose of emicizumab and continued with a maintenance dose of 1.5 mg/kg given once weekly. Shortly after beginning treatment, there was a reduction in aPTT and no bleeding was observed. However, 41 weeks after starting emicizumab, the patient presented with a significant bleeding tendency, a subsequent prolonged aPTT was confirmed, and by the 49th week of treatment, emicizumab therapy was discontinued. Bleeding was further managed with bypassing agents.
For this patient, serial blood samples were available: At 31 weeks of treatment, the concentration of emicizumab was 15 μg/ml, and ADA were positive. The concentration of emicizumab continued to decrease until its discontinuation at 49 weeks, after which it was below the limit of quantification by 50 weeks. The ADA titer gradually increased from 31 weeks, even after stopping emicizumab application, and then gradually declined until the sample taken at 93 weeks. Neutralizing activity against emicizumab was observed even after its discontinuation. Epitope analysis indicated ADA targeting the anti-FIXa and anti-FX FAb arms of emicizumab, not the Fc region.
Conclusion
This case study demonstrated that the presence of ADA with neutralizing activity against emicizumab and the potential for accelerated clearance of emicizumab leads to reduced efficacy of the drug. Although the results were obtained from a single patient, they suggest that measuring aPTT and emicizumab plasma concentration may be effective for monitoring potential reductions in the efficacy of emicizumab.
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Source: Kaneda M., Kawasaki R., Matsumoto N. et al. Detailed analysis of anti-emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A. J Thromb Haemost 2021; 19 (12): 2938−2946, doi: 10.1111/jth.15506.
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