National Institute for Biological Standards and Control, Hertfordshire, UK.
University of Pennsylvania, Philadelphia, PA, USA.
Br J Haematol. 2021 Jun;193(5):976-987. doi: 10.1111/bjh.17227. Epub 2021 May 10.
The development of anti-drug antibodies (ADAs) is a serious outcome of treatment strategies involving biological medicines. Coagulation factor VIII (FVIII) is used to treat haemophilia A patients, but its immunogenicity precludes a third of severe haemophiliac patients from receiving this treatment. The availability of patient-derived anti-drug antibodies can help us better understand drug immunogenicity and identify ways to overcome it. Thus, there were two aims to this work: (i) to develop and characterise a panel of recombinant, patient-derived, monoclonal antibodies covering a range of FVIII epitopes with varying potencies, kinetics and mechanism of action, and (ii) to demonstrate their applicability to assay development, evaluation of FVIII molecules and basic research. For the first objective we used recombinant antibodies to develop a rapid, sensitive, flexible and reproducible ex vivo assay that recapitulates inhibitor patient blood using blood from healthy volunteers. We also demonstrate how the panel can provide important information about the efficacy of FVIII products and reagents without the need for patient or animal material. These materials can be used as experimental exemplars or controls, as well as tools for rational, hypothesis-driven research and assay development in relation to FVIII immunogenicity and FVIII-related products.
抗药物抗体（ADA）的产生是涉及生物药物治疗策略的严重后果。凝血因子 VIII（FVIII）用于治疗甲型血友病患者，但它的免疫原性使三分之一的重症血友病患者无法接受这种治疗。患者来源的抗药物抗体的可用性可以帮助我们更好地了解药物的免疫原性，并确定克服它的方法。因此，这项工作有两个目的：（i）开发和表征一系列涵盖不同效力、动力学和作用机制的 FVIII 表位的重组、患者衍生的单克隆抗体，（ii）证明它们在检测开发、FVIII 分子评估和基础研究中的适用性。对于第一个目标，我们使用重组抗体开发了一种快速、灵敏、灵活和可重复的体外检测方法，使用健康志愿者的血液来模拟抑制剂患者的血液。我们还展示了该抗体组合如何在不需要患者或动物材料的情况下提供有关 FVIII 产品和试剂功效的重要信息。这些材料可以用作实验范例或对照，以及与 FVIII 免疫原性和 FVIII 相关产品相关的理性、假设驱动的研究和检测开发的工具。
