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The impact of sialylation linkage‐type on the pharmacokinetics of recombinant butyrylcholinesterases
Author(s) -
Chung ChengYu,
Wang Qiong,
Yang Shuang,
Chough Sandra,
Seo Younji,
Cipollo John F.,
Balthasar Joseph P.,
Betenbaugh Michael J.
Publication year - 2020
Publication title -
biotechnology and bioengineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.136
H-Index - 189
eISSN - 1097-0290
pISSN - 0006-3592
DOI - 10.1002/bit.27174
Subject(s) - chinese hamster ovary cell , sialic acid , glycoprotein , sialyltransferase , glycan , pharmacokinetics , chemistry , recombinant dna , biochemistry , glycosylation , in vivo , microbiology and biotechnology , pharmacology , biology , gene , genetics , receptor
Chinese hamster ovary (CHO) cells typically produce glycoproteins with N‐glycans terminating in α‐2,3 sialylation. Human cells produce glycoproteins that include α‐2,3 and α‐2,6 sialic acids. To examine the impact of altering protein sialylation on pharmacokinetic properties, recombinant human butyrylcholinesterase (BChE) was produced in CHO cells by knocking out the α‐2,3 sialyltransferase genes followed by overexpression of the α‐2,6 sialyltransferase (26BChE) enzyme. The N‐glycan composition of 26BChE was compared to BChE with α‐2,3 sialylation (23BChE) derived from wild‐type CHO cells. Both 23BChE and 26BChE exhibited comparable antennarity distributions with bi‐antennary di‐sialylated glycans representing the most abundant glycoform. CD‐1 mice were intravenously injected with the 23BChE or 26BChE, and residual BChE activities from blood collected at various time points for pharmacokinetic analyses. Although 23BChE contained a slightly lower initial sialylation level compared to 26BChE, the molecule exhibited higher residual activity between 5 and 24 hr postinjection. Pharmacokinetic analyses indicated that 23BChE exhibited an increase in area under the curve and a lower volume of distribution at steady state than that of 26BChE. These findings suggest that the type of sialylation linkage may play a significant role in the pharmacokinetic behavior of a biotherapeutic when tested in in vivo animal models.