Comparative study of idursulfase beta and idursulfase in vitro and in vivo

Abstract

Hunter syndrome is an X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS), leading to the accumulation of glycosaminoglycans (GAGs). Two recombinant enzymes, idursulfase and idursulfase beta are currently available for enzyme replacement therapy for Hunter syndrome. These two enzymes exhibited some differences in various clinical parameters in a recent clinical trial. Regarding the similarities and differences of these enzymes, previous research has characterized their biochemical and physicochemical properties. We compared the in vitro and in vivo efficacy of the two enzymes on patient fibroblasts and mouse model. Two enzymes were taken up into the cell and degraded GAGs accumulated in fibroblasts. In vivo studies of two enzymes revealed similar organ distribution and decreased urinary GAGs excretion. Especially, idursulfase beta exhibited enhanced in vitro efficacy for the lower concentration of treatment, in vivo efficacy in the degradation of tissue GAGs and improvement of bones, and revealed lower anti-drug antibody formation. A biochemical analysis showed that both enzymes show largely a similar glycosylation pattern, but the several peaks were different and quantity of aggregates of idursulfase beta was lower.

Production and characterization of a human lysosomal recombinant iduronate‐2‐sulfatase produced in Pichia pastoris

“…Noteworthy, the addition of 0.3 μg mL −1 (∼ 3,750 pM) of this engineered IDS to MPS II patient fibroblasts allowed an 84% reduction of GAGs accumulation. Similarly, in vitro evaluation of idursulfase and idursulfase‐beta in MPS II patient fibroblasts led to a reduction of up to 40–60% of GAGs accumulations after addition of 5,000 pM IDS . Taken together, these reports suggest that significant GAGs reduction can be observed with enzymes showing enzyme activities lower than those reported for idursulfase or idursulfase‐beta.…”

“…Conventional ERT for lysosomal storage diseases is based on the capacity of the therapeutic enzymes to be taken up and delivery to the lysosome, where they catalyze the hydrolysis of the stored substrates . Recombinant IDS produced in mammalian cells (idursulfase and idursulfase‐beta) have highly sialylated and M6P‐containing N ‐glycans, which allow their cell uptake in normal and MPS II patient fibroblasts . In addition, the cell uptake and lysosomal delivery of both idursulfase and idursulfase‐beta is mediated by M6P receptors .…”

Pharmacoeconomic evaluation of drugs used in enzyme replacement therapy mucopolysaccharidosis type II

“…Единственным общепринятым подходом к лечению МПС II типа на сегодняшний день является пожизненная ферментная заместительная терапия (ФЗТ) для пациентов с врожденным дефектом метаболизма гликозаминогликанов (ГАГ) [3,4,5,6]. На российском рынке ФЗТ пред-…”

“…Наиболее частыми клиническими проявлениями МПС II типа являются грубые черты лица, папулезные высыпания, потеря слуха, обструктивные заболевания дыхательный путей, пневмонии, гепатоспленомегалия, сердечные заболевания, поражение ЦНС, тугоподвижность суставов. Ожидаемая продолжительность жизни пациентов, без терапии патогенетическими препаратами, не превышает двадцати лет; смерть возникает в результате обструкции дыхательных путей или сердечной недостаточности на фоне прогрессирующих неврологических симптомов [1,2].Единственным общепринятым подходом к лечению МПС II типа на сегодняшний день является пожизненная ферментная заместительная терапия (ФЗТ) для пациентов с врожденным дефектом метаболизма гликозаминогликанов (ГАГ) [3,4,5,6]. На российском рынке ФЗТ пред-…”

Case report of treatment experience with idursulfase beta (Hunterase) in an adolescent patient with MPS II

“…In addition, idursulfase beta exhibited significantly higher specific enzyme activity than idursulfase as a result of its higher formylglycine (FGly) content [7]. In a comparative study on patient fibroblasts and a murine model, idursulfase beta exhibited enhanced in vitro efficacy at a lower drug concentration and enhanced in vivo efficacy with regards to the degradation of tissue GAGs and improvement of bone, with reduced anti-drug antibody formation [6]. Clinical trial data in patients aged < 6 years [8] and those aged 6–35 years [9], confirm the efficacy of idursulfase beta in significantly reduced urinary GAGs in patients treated for up to 53 weeks and improved the 6-minute walk test, without serious treatment-related safety signals.…”