Amsterdam UMC location University of Amsterdam, Laboratory Genetic Metabolic Diseases F0-220, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Drugs R D. 2023 Jun;23(2):141-153. doi: 10.1007/s40268-023-00421-x. Epub 2023 Apr 21.
Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta.
Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice.
AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO.
These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development.
法布里病(FD)是一种罕见的溶酶体贮积病,由α-半乳糖苷酶 A(aGal A)缺乏引起。自 2001 年以来,已有两种不同的酶替代疗法获得批准,β-半乳糖苷酶在西方世界的大部分地区得到应用。目前,正在开发几种昂贵的酶疗法的生物类似物,以提高患者的可及性。我们介绍了开发β-半乳糖苷酶生物类似物的临床前结果。
生物类似物 aGal A Biosidus(AGABIO)在中国仓鼠卵巢(CHO)细胞系统中产生,与β-半乳糖苷酶相比,在氨基酸序列、糖基化、特定的α-半乳糖苷酶活性、在血浆中的稳定性以及对培养的人法布里成纤维细胞和法布里小鼠的影响方面进行了比较。
AGABIO 的氨基酸组成、糖基化、酶活性和稳定性与β-半乳糖苷酶相似。在成纤维细胞中摄取后,α-半乳糖苷酶 A 活性呈剂量依赖性增加,24 小时后达到最大摄取量,至少 48 小时内保持稳定。两种酶均定位于溶酶体。AGABIO 和β-半乳糖苷酶均可使培养的法布里成纤维细胞中累积的神经酰胺三己糖苷(Gb3)和溶酶体Gb3减少,其剂量反应曲线相似。在法布里敲除小鼠中,单次注射后,两种酶均迅速从血浆中清除,组织和血浆神经鞘脂的减少程度相同。在大鼠中的重复剂量研究未引起任何安全性问题。用β-半乳糖苷酶治疗的 FD 患者的抗药物抗体对 AGABIO 表现出相同的中和活性。
这些发现支持 AGABIO 与β-半乳糖苷酶的生物相似性。目前正在开发临床研究阶段。