Abstract
Abstract
Arginine auxotrophy is a metabolic defect that renders tumor cells vulnerable towards arginine-depleting substances, such as arginine deiminase (ADI) from Streptococcus pyogenes (SpyADI). Previously, we confirmed SpyADI susceptibility on patient-derived glioblastoma multiforme (GBM) models in vitro and in vivo. For application in patients, serum half-life of the enzyme has to be increased and immunogenicity needs to be reduced. For this purpose, we conjugated the S. pyogenes-derived SpyADI with 20 kDa polyethylene glycol (PEG20) moieties, achieving a PEGylation of seven to eight of the 26 accessible primary amines of the SpyADI. The PEGylation reduced the overall activity of the enzyme by about 50% without affecting the Michaelis constant for arginine. PEGylation did not increase serum stability of SpyADI in vitro, but led to a longer-lasting reduction of plasma arginine levels in mice. Furthermore, SpyADI-PEG20 showed a higher antitumoral capacity towards GBM cells in vitro than the native enzyme.
Key points
• PEGylation has no effect on the affinity of SpyADI for arginine
• PEGylation increases the antitumoral effects of SpyADI on GBM in vitro
• PEGylation prolongs plasma arginine depletion by SpyADI in mice
Funder
Universitätsmedizin Rostock
Publisher
Springer Science and Business Media LLC
Subject
Applied Microbiology and Biotechnology,General Medicine,Biotechnology
Cited by
5 articles.
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