Relevance of Neutralizing Antibodies for the Pharmacokinetics of Pegunigalsidase Alfa in Patients with Fabry Disease.

IF 5.4 2区医学 Q1 IMMUNOLOGY BioDrugs Pub Date : 2025-01-01 Epub Date: 2024-11-30 DOI:10.1007/s40259-024-00690-1

Malte Lenders, Elise Raphaela Menke, Michael Rudnicki, Markus Cybulla, Eva Brand

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Abstract

Background: Pegunigalsidase alfa is a newly approved drug for the treatment of Fabry disease, designed to increase the plasma half-life and reduce immunogenicity of infused α-galactosidase A (AGAL). We provide the first comprehensive pharmacokinetic and immunogenic data apart from industry-initiated studies.

Methods: Pharmacokinetics of pegunigalsidase alfa, amino acid, and polyethylene glycol (PEG)-specific antibodies and immune complexes were measured in treated patients (11 switched, two naïve). Measurements were performed in serum samples drawn directly before and after infusions over three to ten consecutive infusions. Only three patients started directly with 1.0 mg/kg body weight.

Results: No infusion-associated reactions were reported under pegunigalsidase alfa during the observation. Patients without pre-existing neutralizing anti-AGAL antibodies showed high enzymatic AGAL peak activities and sustained AGAL serum concentrations until the next infusion, which was not observed in those with neutralizing anti-AGAL antibodies. Nine (69.2%) patients presented with pre-existing anti-PEG antibodies (IgG or IgM), which seemed to have no impact on pharmacokinetics during the observation. No new anti-PEG or anti-AGAL antibody formation was observed after treatment initiation. Three (75.0%) patients with pre-existing neutralizing anti-AGAL antibodies showed a titer increase and one (25.0%) patient a decrease. In patients with anti-AGAL antibodies (n = 4) immune-complex formation was detected.

Conclusion: The pharmacokinetics of pegunigalsidase alfa show different profiles depending on the presence of pre-existing neutralizing antibodies, with reduced plasma half-life and peak enzyme activity after infusion in patients with antibodies. The clinical significance of a reduced pegunigalsidase alfa half-life and the formation of immune complexes in antibody-positive patients needs to be analyzed in future studies.

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中和抗体与法布里病患者Pegunigalsidase Alfa药代动力学的相关性

背景：Pegunigalsidase alfa是一种新批准的治疗Fabry病的药物，旨在增加输注α-半乳糖苷酶a （AGAL）的血浆半衰期，降低免疫原性。我们提供第一个全面的药代动力学和免疫原性数据，除了行业发起的研究。方法：在治疗的患者中测定PEG特异性抗体和免疫复合物的药代动力学（11例切换，2例naïve）。在连续三到十次输注前后直接抽取血清样本进行测量。只有3例患者直接以1.0 mg/kg体重开始治疗。结果：观察过程中，未见pegunigalsidase - α输注相关反应。没有预先存在中和性抗AGAL抗体的患者表现出较高的酶促AGAL峰活性和持续的AGAL血清浓度，直到下一次输注，这在中和性抗AGAL抗体的患者中没有观察到。9例（69.2%）患者存在预先存在的抗peg抗体（IgG或IgM），在观察期间似乎对药代动力学没有影响。治疗开始后未观察到新的抗peg或抗agal抗体的形成。已有中和抗agal抗体的3例（75.0%）患者滴度升高，1例（25.0%）患者滴度降低。抗agal抗体患者（n = 4）检测到免疫复合物形成。结论：pegunigalsidase alfa的药代动力学表现出不同的特征，取决于预先存在的中和抗体的存在，抗体患者输注后血浆半衰期缩短，酶活性达到峰值。pegunigalsidase α半衰期缩短和抗体阳性患者免疫复合物形成的临床意义需要在未来的研究中分析。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

BioDrugs 医学-免疫学

CiteScore

12.60

自引率

2.90%

发文量

审稿时长

>12 weeks

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