Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease

Ilya Ruderfer; Avidor Shulman; Tali Kizhner; Yaniv Azulay; Yakir Nataf; Yoram Tekoah; Yoseph Shaaltiel

doi:10.1021/acs.bioconjchem.8b00133

Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease

Ilya Ruderfer, Avidor Shulman, Tali Kizhner, Yaniv Azulay, Yakir Nataf, Yoram Tekoah, Yoseph Shaaltiel

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

16 Scopus citations

Abstract

The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.

Original language	English
Pages (from-to)	1630-1639
Number of pages	10
Journal	Bioconjugate Chemistry
Volume	29
Issue number	5
DOIs	https://doi.org/10.1021/acs.bioconjchem.8b00133
State	Published - 16 May 2018
Externally published	Yes

ASJC Scopus subject areas

Biotechnology
Bioengineering
Biomedical Engineering
Pharmacology
Pharmaceutical Science
Organic Chemistry

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title = "Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease",

abstract = "The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.",

author = "Ilya Ruderfer and Avidor Shulman and Tali Kizhner and Yaniv Azulay and Yakir Nataf and Yoram Tekoah and Yoseph Shaaltiel",

note = "Funding Information: This study has been partially funded by a grant from the Israeli Innovation Authority, The Israeli Ministry of Economy and Industry. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

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doi = "10.1021/acs.bioconjchem.8b00133",

language = "English",

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T1 - Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease

AU - Ruderfer, Ilya

AU - Shulman, Avidor

AU - Kizhner, Tali

AU - Azulay, Yaniv

AU - Nataf, Yakir

AU - Tekoah, Yoram

AU - Shaaltiel, Yoseph

N1 - Funding Information: This study has been partially funded by a grant from the Israeli Innovation Authority, The Israeli Ministry of Economy and Industry. Publisher Copyright: © 2018 American Chemical Society.

PY - 2018/5/16

Y1 - 2018/5/16

N2 - The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.

AB - The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.

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JO - Bioconjugate Chemistry

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ER -

Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease

Abstract

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UN SDGs

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