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

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...

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Published inBioconjugate chemistry Vol. 29; no. 5; p. 1630
Main Authors Ruderfer, Ilya, Shulman, Avidor, Kizhner, Tali, Azulay, Yaniv, Nataf, Yakir, Tekoah, Yoram, Shaaltiel, Yoseph
Format Journal Article
LanguageEnglish
Published Washington American Chemical Society 16.05.2018
Subjects
a-Galactosidase
Analytical chemistry
Cell culture
Chemical bonds
Chemical modification
Clinical trials
Crosslinking
Enzymes
Epitopes
Fabry's disease
Galactosidase
Genetic disorders
Masking
Medical research
Medical treatment
Organic chemistry
Patients
Pharmacology
Polyethylene glycol
Protein structure
Proteins
Thermal stability
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Summary: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.
ISSN:1043-1802
1520-4812