{"title":"全面评估获得性血友病 A 的抗伊米珠单抗抗体：详细病例研究与方法评估","authors":"Behnaz Pezeshkpoor, Nadja Sereda, Janine Becker-Gotot, Ann-Cristin Berkemeier, Isabell Matuschek, Jens Müller, Samhitha Urs Ramaraje Urs, Sneha Singh, Claudia Klein, Natascha Marquardt, Johannes Oldenburg","doi":"10.1016/j.jtha.2024.10.003","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Acquired hemophilia A (AHA) is a rare and severe bleeding disorder characterized by autoantibodies inhibiting coagulation factor (F)VIII. 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 persons with congenital hemophilia A (HA) and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.</p><p><strong>Objectives: </strong>This study aims to characterize the development and impact of anti-emicizumab antibodies in a patient with acquired hemophilia A (AHA) who experienced reduced efficacy of emicizumab treatment.</p><p><strong>Methods: </strong>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 (Ig) subclasses and IgG subtype profiling. ADAs' neutralizing activity was evaluated using a modified clotting assay.</p><p><strong>Results: </strong>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<sub>1</sub> and IgG<sub>2</sub> subclasses were identified. Longitudinal analysis showed IgG isotype antibodies against both emicizumab and FVIII. Anti-emicizumab antibodies exhibited noninhibitory activity, confirmed by a modified Bethesda assay. Moreover, no accelerated clearance of emicizumab was observed in plasma samples from the patient.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5000,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Comprehensive evaluation of anti-emicizumab antibodies in acquired hemophilia A: a detailed case study and methodological evaluation.\",\"authors\":\"Behnaz Pezeshkpoor, Nadja Sereda, Janine Becker-Gotot, Ann-Cristin Berkemeier, Isabell Matuschek, Jens Müller, Samhitha Urs Ramaraje Urs, Sneha Singh, Claudia Klein, Natascha Marquardt, Johannes Oldenburg\",\"doi\":\"10.1016/j.jtha.2024.10.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Acquired hemophilia A (AHA) is a rare and severe bleeding disorder characterized by autoantibodies inhibiting coagulation factor (F)VIII. 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 persons with congenital hemophilia A (HA) and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.</p><p><strong>Objectives: </strong>This study aims to characterize the development and impact of anti-emicizumab antibodies in a patient with acquired hemophilia A (AHA) who experienced reduced efficacy of emicizumab treatment.</p><p><strong>Methods: </strong>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 (Ig) subclasses and IgG subtype profiling. ADAs' neutralizing activity was evaluated using a modified clotting assay.</p><p><strong>Results: </strong>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<sub>1</sub> and IgG<sub>2</sub> subclasses were identified. Longitudinal analysis showed IgG isotype antibodies against both emicizumab and FVIII. Anti-emicizumab antibodies exhibited noninhibitory activity, confirmed by a modified Bethesda assay. Moreover, no accelerated clearance of emicizumab was observed in plasma samples from the patient.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":17326,\"journal\":{\"name\":\"Journal of Thrombosis and Haemostasis\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2024-10-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Thrombosis and Haemostasis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jtha.2024.10.003\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thrombosis and Haemostasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtha.2024.10.003","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：获得性血友病 A（AHA）是一种罕见的严重出血性疾病，其特点是自身抗体抑制凝血因子 VIII（FVIII）。目前治疗 AHA 的方法包括旁路药物或 FVIII 替代疗法，但在抑制剂滴度较高的情况下，其疗效有限。Emicizumab是一种人源化双特异性单克隆抗体，在先天性A型血友病（HA）患者和AHA患者中显示出良好的止血效果，但少数患者产生了抗药性抗体（ADA），影响了其疗效：我们对一名从治疗第 10 周起埃米珠单抗疗效下降的 AHA 患者体内的抗埃米珠单抗抗体进行了全面鉴定。我们开发了一种分析抗伊米珠单抗抗体的方法，可区分免疫球蛋白亚类和IgG亚型。我们使用改良的凝血试验评估了 ADAs 的中和活性：结果：基于 Luminex 的检测证明了抗emicizumab 抗体的存在，并通过竞争性分析得到了证实。我们在第 16 周至第 29 周期间在患者血浆中检测到了抗emicizumab IgG 抗体。确定了 IgG1 和 IgG2 亚类。纵向分析表明，埃米珠单抗和 FVIII 都有 IgG 同型抗体。经改良的贝塞斯达试验证实，抗埃米珠单抗抗体具有非抑制性活性。此外，在患者的血浆样本中没有观察到埃米珠单抗的加速清除：本研究首次记录了AHA中抗埃米珠单抗抗体的病例。我们的研究深入揭示了抗伊米珠单抗的 ADA 发展情况，强调了监测工具的必要性。所开发的方法可对ADA进行全面评估，有助于制定个性化治疗策略。这些发现有助于了解埃米珠单抗在 AHA 中的免疫原性概况，从而促进其临床应用的优化。
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 (F)VIII. 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 persons with congenital hemophilia A (HA) and AHA, but a minority of patients developed anti-drug antibodies (ADAs), compromising its efficacy.
Objectives: This study aims to characterize the development and impact of anti-emicizumab antibodies in a patient with acquired hemophilia A (AHA) who experienced reduced efficacy of emicizumab treatment.
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 (Ig) 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. IgG1 and IgG2 subclasses were identified. Longitudinal analysis showed IgG isotype antibodies against both emicizumab and FVIII. Anti-emicizumab antibodies exhibited noninhibitory activity, confirmed by a modified Bethesda assay. Moreover, no accelerated clearance of emicizumab was observed in plasma samples from the patient.
Conclusion: 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.
期刊介绍：
The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community.
Types of Publications:
The journal publishes a variety of content, including:
Original research reports
State-of-the-art reviews
Brief reports
Case reports
Invited commentaries on publications in the Journal
Forum articles
Correspondence
Announcements
Scope of Contributions:
Editors invite contributions from both fundamental and clinical domains. These include:
Basic manuscripts on blood coagulation and fibrinolysis
Studies on proteins and reactions related to thrombosis and haemostasis
Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms
Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases
Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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