Emicizumab, the factor VIII mimetic bi-specific monoclonal antibody and its measurement in plasma
-
Armando Tripodi
,
Veena Chantarangkul
Abstract
Objectives
Emicizumab, a monoclonal antibody mimicking the function of factor (F) VIII in the activation of FX by FIXa, is widely used for prophylaxis in hemophilia patients with or without inhibitors to FVIII. Although it is administered at fixed dose, its measurement could be occasionally required. In principle, the emicizumab procoagulant effect could be assessed by the one-stage assay (OSA) currently used to measure FVIII. However, the OSA for FVIII presents with limitations. Furthermore, owing to its potent FVIII-like activity, emicizumab interferes with the measurement of the inhibitor to FVIII, which is often needed in patients on emicizumab.
Methods
We prepared test samples by spiking a FVIII-deficient plasma with graded amounts of emicizumab. We modified the OSA for FVIII and tested plasma samples for emicizumab concentrations. Furthermore the chromogenic assay (CA) for FVIII with bovine reagents was used to assess for the FVIII inhibitor in patients on emicizumab.
Results
Slight modification of the OSA for FVIII (i.e., higher test plasma dilution and longer coagulometer acquisition time) made the regular OSA as a reliable laboratory tool to measure emicizumab concentration as shown by the identity of the regression (observed vs. expected) lines. Furthermore, the inhibitors to FVIII in patients on emicizumab, which were negative when measured by the regular Bethesda assay, were reliably measured by the CA assay employing bovine reagents.
Conclusions
The methods currently used to measure FVIII can be easily modified to make the general clinical laboratory able to assist clinicians when dealing with patients on emicizumab.
Research funding: None declared.
Author contributions: AT conceived the work and wrote the manuscript. VC supervised the preparation of test plasmas, collected data and made statistical analysis. ES, MC, prepared test plasmas. CN, MBA and FR made laboratory testing. FP, revised the manuscript. All authors reviewed the data, revised the manuscript, accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: AT reports speaker’s fees from Werfen and Stago. CN personal fees from werfen, Roche, Bayer, Novonordisk, Sobi, outside the submitted work. FP personal fees from Bioverativ, Grifols, Roche, Sanofi, Sobi, Spark, and Takeda, outside the submitted work. The other authors none to declare.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The local Institutional Review Board deemed the study exempt from review as it was considered as an in vitro study.
References
1. Peyvandi, F, Garagiola, I, Young, G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016;388:187–97. https://doi.org/10.1016/s0140-6736(15)01123-x.Suche in Google Scholar
2. Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, Key, NS, Kitchen, S, Llinas, A, et al. Guidelines for the management of hemophilia. Haemophilia 2013;19:e1–47. https://doi.org/10.1111/j.1365-2516.2012.02909.x.Suche in Google Scholar PubMed
3. Petrini, P, Valentino, LA, Gringeri, A, Re, WM, Ewenstein, B. Individualizing prophylaxis in hemophilia: a review. Expet Rev Hematol 2015;8:237–46. https://doi.org/10.1586/17474086.2015.1002465.Suche in Google Scholar PubMed
4. Key, NS, Aledort, LM, Beardsley, D, Cooper, HA, Davignon, G, Ewenstein, BM, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998;80:912–18.10.1055/s-0037-1615388Suche in Google Scholar
5. Sjamsoedin, LJ, Heijnen, L, Mauser-Bunschoten, EP, van Geijlswijk, JL, van Houwelingen, H, van Asten, P, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII: a double-blind clinical trial. N Engl J Med 1981;205:717–21. https://doi.org/10.1056/nejm198109243051301.Suche in Google Scholar PubMed
6. Arruda, VR, Doshi, BS, Samelson-Jones, BJ. Novel approaches to hemophilia therapy: successes and challenges. Blood 2017;130:2251–6. https://doi.org/10.1182/blood-2017-08-742312.Suche in Google Scholar PubMed PubMed Central
7. Pasi, KJ, Rangarajan, S, Georgiev, P, Mant, T, Creagh, MD, Lissitchkov, T, et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med 2017;377:819–28. https://doi.org/10.1056/nejmoa1616569.Suche in Google Scholar PubMed
8. Waters, EK, Sigh, J, Friedrich, U, Hilden, I, Sørensen, BB. Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay. Haemophilia 2017;23:769–76. https://doi.org/10.1111/hae.13260.Suche in Google Scholar PubMed
9. Uchida, N, Sambe, T, Yoneyama, K, Fukazawa, N, Kawanishi, T, Kobayashi, S, et al. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016;127:1633–41. https://doi.org/10.1182/blood-2015-06-650226.Suche in Google Scholar PubMed PubMed Central
10. Shima, M, Hanabusa, H, Taki, M, Matsushita, T, Sato, T, Fukutake, K, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med 2016;374:2044–53. https://doi.org/10.1056/nejmoa1511769.Suche in Google Scholar
11. Oldenburg, J, Mahlangu, JN, Kim, B, Schmitt, C, Callaghan, MU, Young, G, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017;377:809–18. https://doi.org/10.1056/nejmoa1703068.Suche in Google Scholar PubMed
12. Mahlangu, J, Oldenburg, J, Paz-Priel, I, Negrier, C, Niggli, M, Mancuso, ME, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med 2018;379:811–22. https://doi.org/10.1056/nejmoa1803550.Suche in Google Scholar
13. Lenting, PJ, Denis, CV, Christophe, OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017;130:2463–8. https://doi.org/10.1182/blood-2017-08-801662.Suche in Google Scholar PubMed
14. Verbruggen, B, Novakova, I, Wessels, H, Boezeman, J, van den Berg, M, Mauser-Bunschoten, E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995;73:247–51. https://doi.org/10.1055/s-0038-1653759.Suche in Google Scholar
15. Adamkewicz, JI, Chen, DC, Paz-Priel, I. Effects and interferences of emicizumab, a humanised bispecific antibody mimicking activated factor VIII cofactor function, on coagulation assays. Thromb Haemost 2019;119:1084–93. https://doi.org/10.1055/s-0039-1688687.Suche in Google Scholar PubMed
© 2020 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Editorial
- Assuring the quality of examinations using faecal immunochemical tests for haemoglobin (FIT)
- Review
- Capillary electrophoresis based on nucleic acid analysis for diagnosing inherited diseases
- Mini Reviews
- Negative hair test result after long-term drug use. About a case involving morphine and literature review
- Prorenin and active renin levels in paediatrics: a bioanalytical review
- Opinion Paper
- From therapeutic drug monitoring to total drug monitoring and drug-omics
- Perspectives
- The internal quality control in the traceability era
- Genetics and Molecular Diagnostics
- External quality assessment (EQA) and alternative assessment procedures (AAPs) in molecular diagnostics: findings of an international survey
- General Clinical Chemistry and Laboratory Medicine
- An evaluation of ten external quality assurance scheme (EQAS) materials for the faecal immunochemical test (FIT) for haemoglobin
- Optimizing hepcidin measurement with a proficiency test framework and standardization improvement
- Development of a certified reference material for anti-β2-glycoprotein I IgG – commutability studies
- Influence of patients’ clinical features at intensive care unit admission on performance of cell cycle arrest biomarkers in predicting acute kidney injury
- Efficacy of weekly administration of cholecalciferol on parathyroid hormone in stable kidney-transplanted patients with CKD stage 1–3
- Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma
- Emicizumab, the factor VIII mimetic bi-specific monoclonal antibody and its measurement in plasma
- Reference Values and Biological Variations
- Age appropriate reference intervals for eight kidney function and injury markers in infants, children and adolescents
- Cardiovascular Diseases
- Comparison of acetylsalicylic acid and clopidogrel non-responsiveness assessed by light transmittance aggregometry and PFA-100® in patients undergoing neuroendovascular procedures
- Trimethylamine-N-oxide (TMAO) predicts short- and long-term mortality and poor neurological outcome in out-of-hospital cardiac arrest patients
- Non-lactate strong ion difference and cardiovascular, cancer and all-cause mortality
- Infectious Diseases
- Performance of three automated SARS-CoV-2 antibody assays and relevance of orthogonal testing algorithms
- Development, evaluation, and validation of machine learning models for COVID-19 detection based on routine blood tests
- Searching for a role of procalcitonin determination in COVID-19: a study on a selected cohort of hospitalized patients
- Association of kidney function with effectiveness of procalcitonin-guided antibiotic treatment: a patient-level meta-analysis from randomized controlled trials
- Erratum
- Corrigendum to: The role of hyperhomocysteinemia as well as folate, vitamin B6 and B12 deficiencies in osteoporosis – a systematic review
- Letter to the Editors
- Harmonization of antineutrophil cytoplasmic antibodies (ANCA) testing by reporting test result-specific likelihood ratios: position paper
- Independent internal quality control (IQC) for faecal immunochemical tests (FIT) for haemoglobin: use of FIT manufacturers’ IQC for other FIT systems
- Parallel testing of 241 clinical nasopharyngeal swabs for the detection of SARS-CoV-2 virus on the Cepheid Xpert Xpress SARS-CoV-2 and the Roche cobas SARS-CoV-2 assays
- Sustained SARS-CoV-2 nucleocapsid antibody levels in nonsevere COVID-19: a population-based study
- Evidence for increased circulating procoagulant phospholipids in patients with COVID-19 pneumonia and their prognostic role
- Complete blood counts and cell population data from Sysmex XN analyser in the detection of SARS-CoV-2 infection
- Macro creatine kinase in an asymptomatic patient: a case report
- Implementation of pre-labelled barcode tubes and the GeT-System in a general hospital for the exact documentation of the time of venous blood sample and improvement of sample quality
- Determination of free light chains: assay-dependent differences in interpretation
- Association between SOX17, Wif-1 and RASSF1A promoter methylation status and response to chemotherapy in patients with metastatic gastric cancer
- Effect of two organizational interventions on the frequency of haemoglobin A1c and erythrocyte sedimentation rate testing
- Haemoglobin A1c determination from dried blood spots prepared with HemaSpot™ blood collection devices: comparison with fresh capillary blood
- Stability of catecholamines in whole blood: influence of time between collection and centrifugation
Artikel in diesem Heft
- Frontmatter
- Editorial
- Assuring the quality of examinations using faecal immunochemical tests for haemoglobin (FIT)
- Review
- Capillary electrophoresis based on nucleic acid analysis for diagnosing inherited diseases
- Mini Reviews
- Negative hair test result after long-term drug use. About a case involving morphine and literature review
- Prorenin and active renin levels in paediatrics: a bioanalytical review
- Opinion Paper
- From therapeutic drug monitoring to total drug monitoring and drug-omics
- Perspectives
- The internal quality control in the traceability era
- Genetics and Molecular Diagnostics
- External quality assessment (EQA) and alternative assessment procedures (AAPs) in molecular diagnostics: findings of an international survey
- General Clinical Chemistry and Laboratory Medicine
- An evaluation of ten external quality assurance scheme (EQAS) materials for the faecal immunochemical test (FIT) for haemoglobin
- Optimizing hepcidin measurement with a proficiency test framework and standardization improvement
- Development of a certified reference material for anti-β2-glycoprotein I IgG – commutability studies
- Influence of patients’ clinical features at intensive care unit admission on performance of cell cycle arrest biomarkers in predicting acute kidney injury
- Efficacy of weekly administration of cholecalciferol on parathyroid hormone in stable kidney-transplanted patients with CKD stage 1–3
- Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma
- Emicizumab, the factor VIII mimetic bi-specific monoclonal antibody and its measurement in plasma
- Reference Values and Biological Variations
- Age appropriate reference intervals for eight kidney function and injury markers in infants, children and adolescents
- Cardiovascular Diseases
- Comparison of acetylsalicylic acid and clopidogrel non-responsiveness assessed by light transmittance aggregometry and PFA-100® in patients undergoing neuroendovascular procedures
- Trimethylamine-N-oxide (TMAO) predicts short- and long-term mortality and poor neurological outcome in out-of-hospital cardiac arrest patients
- Non-lactate strong ion difference and cardiovascular, cancer and all-cause mortality
- Infectious Diseases
- Performance of three automated SARS-CoV-2 antibody assays and relevance of orthogonal testing algorithms
- Development, evaluation, and validation of machine learning models for COVID-19 detection based on routine blood tests
- Searching for a role of procalcitonin determination in COVID-19: a study on a selected cohort of hospitalized patients
- Association of kidney function with effectiveness of procalcitonin-guided antibiotic treatment: a patient-level meta-analysis from randomized controlled trials
- Erratum
- Corrigendum to: The role of hyperhomocysteinemia as well as folate, vitamin B6 and B12 deficiencies in osteoporosis – a systematic review
- Letter to the Editors
- Harmonization of antineutrophil cytoplasmic antibodies (ANCA) testing by reporting test result-specific likelihood ratios: position paper
- Independent internal quality control (IQC) for faecal immunochemical tests (FIT) for haemoglobin: use of FIT manufacturers’ IQC for other FIT systems
- Parallel testing of 241 clinical nasopharyngeal swabs for the detection of SARS-CoV-2 virus on the Cepheid Xpert Xpress SARS-CoV-2 and the Roche cobas SARS-CoV-2 assays
- Sustained SARS-CoV-2 nucleocapsid antibody levels in nonsevere COVID-19: a population-based study
- Evidence for increased circulating procoagulant phospholipids in patients with COVID-19 pneumonia and their prognostic role
- Complete blood counts and cell population data from Sysmex XN analyser in the detection of SARS-CoV-2 infection
- Macro creatine kinase in an asymptomatic patient: a case report
- Implementation of pre-labelled barcode tubes and the GeT-System in a general hospital for the exact documentation of the time of venous blood sample and improvement of sample quality
- Determination of free light chains: assay-dependent differences in interpretation
- Association between SOX17, Wif-1 and RASSF1A promoter methylation status and response to chemotherapy in patients with metastatic gastric cancer
- Effect of two organizational interventions on the frequency of haemoglobin A1c and erythrocyte sedimentation rate testing
- Haemoglobin A1c determination from dried blood spots prepared with HemaSpot™ blood collection devices: comparison with fresh capillary blood
- Stability of catecholamines in whole blood: influence of time between collection and centrifugation
