The pharmacokinetic and pharmacodynamic properties of site-specific pegylated genetically modified recombinant human interleukin-11 in normal and thrombocytopenic monkeys

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 119; pp. 185 - 191
• Main Authors: Ma, Shan-shan, Ho, Seong-Hyun, Ma, Su-yong, Li, Yue-juan, Li, Kai-tong, Tang, Xiao-chuang, Zhao, Guang-Rong, Xu, Song-shan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2017
• Subjects: Animals; Cell Proliferation - drug effects; Cell Proliferation - physiology; Dose-Response Relationship, Drug; Haplorhini; Humans; Interleukin-11 - genetics; Interleukin-11 - pharmacokinetics; Interleukin-11 - therapeutic use; Macaca fascicularis; Male; PEGylation; Pharmacodynamics; Pharmacokinetics; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - therapeutic use; Recombinant human interleukin-11 mutein (mIL-11); Recombinant Proteins - genetics; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Thrombocytopenia; Thrombocytopenia - drug therapy; Thrombocytopenia - genetics; Thrombocytopenia - metabolism; mPEG-SC; Thrombocytopenia; PEG-mIL-11; Cmax; Pharmacodynamics; EPO; G-CSF; IL-11; AUC; PEGylation; mIL-11; Recombinant human interleukin-11 mutein (mIL-11); Pharmacokinetics
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2017.05.013

[Display omitted] In order to improve the pharmacokinetic and pharmacodynamic properties of recombinant human interleukin-11 mutein (mIL-11) and to reduce the frequency of administration, we examined the feasibility of chemical modification of mIL-11 by methoxy polyethylene glycol succinimidyl carbonate (mPEG-SC). PEG-mIL-11 was prepared by a pH controlled amine specific method. Bioactivity of the protein was determined in a IL-11-dependent in vitro bioassay, its pharmacodynamic and pharmacokinetic properties were investigated by using normal and thrombocytopenic monkey models. N-terminus sequencing and peptide mapping analysis revealed that Lys33 is the PEGylated position for PEG-mIL-11. Bioactivity of PEG-mIL-11 assessed by B9-11 cell proliferation assay was comparable to that of mIL-11. More than 79-fold increase in area-under-the curve (AUC) and 26-fold increase in maximum plasma concentration (Cmax) was observed in pharmacokinetic analysis. Single dose administration of the PEG-mIL-11 induced blood platelets number increase and the effect duration were comparable to that of 7 to 10 consecutive daily administration of mIL-11 to the normal and thrombocytopenic monkey models. PEG-mIL-11 is a promising therapeutic for thrombocytopenia.