Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.

针对生物制药的抗药物抗体（anti-drug antibodies, ADA）在多个欧洲国家已成为多发性硬化（multiple sclerosis, MS）临床诊疗中的常规组成部分。欧洲多家合作机构整合了十余年来针对接受干扰素β（interferon beta, IFNβ）和那他珠单抗（natalizumab）治疗的MS患者开展ADA监测所产生的数据集，并完成了特征表征分析。本研究旨在报告欧洲ADA检测的临床实践现状，涵盖已实施的ADA检测总量、所用ADA检测试剂盒类型，并明确不同国家针对不同药物制剂开展ADA检测的频率。研究搭建了通用数据库平台（tranSMART），用于查询、分析及存储MS队列的回顾性数据，以实现数据标准化并开展多国ADA检测结果的对比分析。来自瑞典、奥地利、西班牙、瑞士、德国及丹麦六个国家的回顾性数据已导入tranSMART，涉及20695名患者及42555份样本，涵盖年龄、性别、治疗方案、样本信息及ADA检测结果等数据维度。本大型数据集证实了此前观察到的四种IFNβ制剂间的免疫原性差异。相较于免疫原性最低的IFNβ-1a肌内（intramuscular, i.m.）制剂，免疫原性较强的IFNβ-1a皮下（subcutaneous, s.c.）及IFNβ-1b s.c.制剂的临床使用比例有所下降。从治疗起始至首次ADA检测的中位时间与首次检测呈阳性的中位时间呈显著相关性。其中，IFNβ-1b-Extavia s.c.（中位时间分别为0.99年和0.94年）及那他珠单抗（0.25年和0.23年）的这两个时间更短——这两款药物在ADA检测已常规开展的时期才上市；而IFNβ-1a i.m.（1.41年和2.27年）、IFNβ-1b-Betaferon s.c.（2.51年和1.96年）及IFNβ-1a s.c.（2.11年和2.09年）则在常规检测开展前数年就已获批上市。在老年患者的检测样本中，抗IFNβ ADA的检出率更高。欧洲各国的ADA检测实践存在显著差异，且高度依赖各国自身的医疗政策。对于尚未推行ADA常规监测的药物，部分ADA检测呈阳性的患者仍可能持续接受治疗长达数年之久。而对于随药物上市同步推行ADA检测策略的药物，ADA阳性患者的比例更低，因此治疗无效的风险也随之降低。这表明通过开展ADA常规分析，有望实现医疗成本的潜在节约。