Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Germany.
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Germany.
J Thromb Haemost. 2023 Jun;21(6):1503-1514. doi: 10.1016/j.jtha.2023.03.011. Epub 2023 Mar 18.
The standard therapy for patients with hemophilia A (HA) is the replacement with factor VIII (FVIII) therapeutics. To overcome the limitation of short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics.
We aimed to characterize antibodies developed against a FVIII therapeutic PEGylated with a 40-kDa PEG (40PEG-BDD) in 2 patients with mild HA.
An inhouse bead-based immunoassay was developed to characterize and confirm the specificity of the detected antibodies. The neutralizing nature of the antibodies toward PEGylated therapeutics was determined by a modified Nijmegen-Bethesda assay.
Two out of 46 patients treated with 40PEG-BDD developed inhibitory antibodies toward the drug. Switching to a non-PEGylated FVIII successfully increased the FVIII activity in both patients. In patient 1, antibodies were raised against FVIII and PEG. Anti-FVIII antibodies were of the immunoglobulin (Ig)G isotype, whereas anti-PEG antibodies were of IgG, IgM, and IgA isotypes. In patient 2, antibodies of IgG and IgA isotypes were directed only against the PEG moiety. Competitive assays confirmed the specificity of the antibodies against PEG. The applied Nijmegen-Bethesda assay revealed that patients' anti-PEG antibodies and AGP3, an antibody against the backbone of PEG, can inhibit all currently available PEGylated therapeutics but to different degrees. No inhibitory FVIII antibodies were detected.
Antibodies against the PEG moiety of 40PEG-BDD abolished the efficacy of the drug. This is the first report on real-world experiences with the development of neutralizing anti-PEG antibodies after treatment with PEGylated FVIII therapeutics in mild HA.
对于甲型血友病（HA）患者，标准治疗方法是使用凝血因子 VIII（FVIII）治疗药物进行替代治疗。为了克服野生型 FVIII 蛋白半衰期短的限制，可以将聚乙二醇（PEG）与治疗性 FVIII 偶联以改善药代动力学。
我们旨在研究 2 例轻度 HA 患者对 FVIII 治疗药物进行聚乙二醇化（PEG 化）的 40kDa PEG（40PEG-BDD）产生的抗体。
开发了一种基于珠子的内部免疫测定法来鉴定和确认检测到的抗体的特异性。通过改良的 Nijmegen-Bethesda 测定法确定了抗体对 PEG 化治疗药物的中和性质。
在接受 40PEG-BDD 治疗的 46 例患者中，有 2 例出现针对该药物的抑制性抗体。转换为非 PEG 化的 FVIII 成功地增加了这 2 例患者的 FVIII 活性。在患者 1 中，抗体针对 FVIII 和 PEG 产生。抗 FVIII 抗体为 IgG 同种型，而抗 PEG 抗体为 IgG、IgM 和 IgA 同种型。在患者 2 中，仅 IgG 和 IgA 同种型的抗体针对 PEG 部分。竞争性测定法证实了抗体对 PEG 的特异性。应用的 Nijmegen-Bethesda 测定法表明，患者的抗 PEG 抗体和 AGP3（一种针对 PEG 骨架的抗体）可以抑制目前所有可用的 PEG 化治疗药物，但抑制程度不同。未检测到抑制性 FVIII 抗体。
针对 40PEG-BDD 的 PEG 部分的抗体使药物的疗效丧失。这是首例关于在轻度 HA 患者中使用 PEG 化 FVIII 治疗药物后产生中和性抗 PEG 抗体的真实世界经验的报告。
