Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy

Audrey A. M. Vollebregt; Marianne Hoogeveen-Westerveld; George J. Ruijter; Hannerieke van den Hout; Esmee Oussoren; Ans T. van der Ploeg; W. W. M. Pim Pijnappel

doi:10.1016/j.jpeds.2022.05.008

Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy

Audrey A. M. Vollebregt, Marianne Hoogeveen-Westerveld, George J. Ruijter, Hannerieke van den Hout, Esmee Oussoren, Ans T. van der Ploeg, W. W. M. Pim Pijnappel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Objective 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.

Study design 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.

Results 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.

Conclusions 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. (J Pediatr 2022;248:100-7).

Original language	English
Pages (from-to)	100-+
Number of pages	11
Journal	Journal of Pediatrics
Volume	248
DOIs	https://doi.org/10.1016/j.jpeds.2022.05.008
Publication status	Published - 1 Sep 2022

Bibliographical note

Funding Information:
A.v.d.P. had no conflict of interests concerning any aspect of the current study. However, she gives advice to several pharmaceutical companies about the implementation and development of innovative therapies, mainly for Pompe disease, but also for other LSDs and neuromuscular disorders. Furthermore, she received funds for research via agreements between Erasmus MC and pharmaceutical companies. She also advices public or private charities, who aim to improve the care for patients with metabolic diseases. The other authors declare no conflicts of interest.

Publisher Copyright:
© 2022 The Author(s)

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PIIS0022347622004140Final published version, 1.64 MBLicence: CC BY

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@article{3838166f8a4542e2b3df0dd529927a8b,

title = "Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy",

abstract = "Objective 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.Study design 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.Results 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.Conclusions 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. (J Pediatr 2022;248:100-7).",

author = "Vollebregt, {Audrey A. M.} and Marianne Hoogeveen-Westerveld and Ruijter, {George J.} and {van den Hout}, Hannerieke and Esmee Oussoren and {van der Ploeg}, {Ans T.} and Pijnappel, {W. W. M. Pim}",

note = "Funding Information: A.v.d.P. had no conflict of interests concerning any aspect of the current study. However, she gives advice to several pharmaceutical companies about the implementation and development of innovative therapies, mainly for Pompe disease, but also for other LSDs and neuromuscular disorders. Furthermore, she received funds for research via agreements between Erasmus MC and pharmaceutical companies. She also advices public or private charities, who aim to improve the care for patients with metabolic diseases. The other authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = sep,

day = "1",

doi = "10.1016/j.jpeds.2022.05.008",

language = "English",

volume = "248",

pages = "100--+",

journal = "Journal of Pediatrics",

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TY - JOUR

T1 - Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy

AU - Vollebregt, Audrey A. M.

AU - Hoogeveen-Westerveld, Marianne

AU - Ruijter, George J.

AU - van den Hout, Hannerieke

AU - Oussoren, Esmee

AU - van der Ploeg, Ans T.

AU - Pijnappel, W. W. M. Pim

N1 - Funding Information: A.v.d.P. had no conflict of interests concerning any aspect of the current study. However, she gives advice to several pharmaceutical companies about the implementation and development of innovative therapies, mainly for Pompe disease, but also for other LSDs and neuromuscular disorders. Furthermore, she received funds for research via agreements between Erasmus MC and pharmaceutical companies. She also advices public or private charities, who aim to improve the care for patients with metabolic diseases. The other authors declare no conflicts of interest. Publisher Copyright: © 2022 The Author(s)

PY - 2022/9/1

Y1 - 2022/9/1

N2 - Objective 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.Study design 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.Results 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.Conclusions 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. (J Pediatr 2022;248:100-7).

AB - Objective 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.Study design 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.Results 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.Conclusions 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. (J Pediatr 2022;248:100-7).

U2 - 10.1016/j.jpeds.2022.05.008

DO - 10.1016/j.jpeds.2022.05.008

M3 - Article

VL - 248

SP - 100-+

JO - Journal of Pediatrics

JF - Journal of Pediatrics

SN - 0022-3476

ER -

Effect of Anti-Iduronate 2-Sulfatase Antibodies in Patients with Mucopolysaccharidosis Type II Treated with Enzyme Replacement Therapy

Abstract

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