title: Pre-clinical toxicokinetics and safety study of M2ES, a PEGylated recombinant human endostatin, in rhesus monkeys.
abstract: PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30mg/kg body weight per day) for 3months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study.
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou 730000, China; National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Guo
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
authors.forename: Xingchao
authors.initials: X
authors.lastname: Geng
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Qi
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
authors.forename: Yufa
authors.initials: Y
authors.lastname: Miao
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Lin
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
authors.forename: Zuogang
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China. Electronic address: libo@nifdc.org.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China; Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: yluo@mail.tsinghua.edu.cn.
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D019540:Area Under Curve; D043169:Endostatins / Q000493:pharmacokinetics*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D011994:Recombinant Proteins / Q000493:pharmacokinetics*; D012449:Safety; D066007:Toxicokinetics
chemical_list: D043169:Endostatins; D011994:Recombinant Proteins
keywords: M(2)ES; Pre-clinical; Rhesus monkeys; Safety; Toxicokinetics