Vollebregt Audrey A M, Hoogeveen-Westerveld Marianne, Ruijter George J, van den Hout Hannerieke, Oussoren Esmee, van der Ploeg Ans T, Pijnappel W W M Pim
Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Division of Metabolic Diseases and Genetics, Department of Pediatrics, Erasmus MC University Medical Center-Sophia, Rotterdam, The Netherlands.
Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
J Pediatr. 2022 Sep;248:100-107.e3. doi: 10.1016/j.jpeds.2022.05.008. Epub 2022 May 11.
To assess the relationship between anti-Iduronate 2-sulfatase (IDS) antibodies, IDS genotypes, phenotypes and their impact in patients with enzyme replacement therapy (ERT)-treated Mucopolysaccharidosis type II.
Dutch patients treated with ERT were analyzed in this observational cohort study. Antibody titers were determined by enzyme-linked immunosorbent assay. Neutralizing effects were measured in fibroblasts. Pharmacokinetic analysis of ERT was combined with immunoprecipitation. Urinary glycosaminoglycans were measured using mass spectrometry and dimethylmethylene blue.
Eight of 17 patients (47%) developed anti-IDS antibodies. Three patients with the severe, neuronopathic phenotype, two of whom did not express IDS protein, showed sustained antibodies for up to 10 years of ERT. Titers of 1:5120 or greater inhibited cellular IDS uptake and/or intracellular activity in vitro. In 1 patient who was neuronopathic with a titer of 1:20 480, pharmacokinetic analysis showed that all plasma recombinant IDS was antibody bound. This finding was not the case in 2 patients who were not neuronopathic with a titer of 1:1280 or less. Patients with sustained antibody titers showed increased urinary glycosaminoglycan levels compared with patients with nonsustained or no-low titers.
Patients with the neuronopathic form and lack of IDS protein expression were most at risk to develop sustained anti-IDS antibody titers, which inhibited IDS uptake and/or activity in vitro, and the efficacy of ERT in patients by lowering urinary glycosaminoglycan levels.
评估抗艾杜糖醛酸2-硫酸酯酶（IDS）抗体、IDS基因型、表型之间的关系及其对接受酶替代疗法（ERT）治疗的II型黏多糖贮积症患者的影响。
在这项观察性队列研究中分析接受ERT治疗的荷兰患者。通过酶联免疫吸附测定法测定抗体滴度。在成纤维细胞中测量中和作用。ERT的药代动力学分析与免疫沉淀相结合。使用质谱法和二甲基亚甲基蓝测量尿糖胺聚糖。
17例患者中有8例（47%）产生了抗IDS抗体。3例具有严重神经病变表型的患者，其中2例不表达IDS蛋白，在长达10年的ERT治疗期间抗体持续存在。滴度为1:5120或更高可在体外抑制细胞对IDS的摄取和/或细胞内活性。在1例神经病变且滴度为1:20480的患者中，药代动力学分析表明所有血浆重组IDS均与抗体结合。在2例非神经病变且滴度为1:1280或更低的患者中情况并非如此。与抗体滴度未持续或无低滴度的患者相比，抗体滴度持续的患者尿糖胺聚糖水平升高。
具有神经病变形式且缺乏IDS蛋白表达的患者最有可能产生持续的抗IDS抗体滴度，这在体外抑制了IDS的摄取和/或活性，并通过降低尿糖胺聚糖水平影响患者ERT的疗效。
