Pharmacokinetics and Pharmacodynamics of Recombinant Human EPO-Fc Fusion Protein In Vivo

Xunlong Shi,Guizhen Han,Dianwen Ju,Yuanyuan Liu,Minghui Yao,Li Ye,Haiyan Zhu,Pei Zhou,Hai Huang,Cecily R Y Sun,Bill N C Sun,Qun Tao,Meiqing Feng,Jianjun Yang,Dan Ye,Lee-Hwei K Sun,Jiyang Li,David L Mccormick

doi:10.1371/journal.pone.0072673

Xunlong Shi, Guizhen Han + Show 16 more

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https://doi.org/10.1371/journal.pone.0072673

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Abstract

In this study, the in vivo pharmacokinetics and pharmacodynamics of a novel recombinant human erythropoietin (rhEPO) Fc fusion protein, rhEPO-Fc, were studied in both rodents and rhesus monkeys. Animal models of anemia induced by irradiation, cyclophosphamide and partial renal ablation were used to evaluate therapeutic effects of rhEPO-Fc. We have demonstrated that serum half-life of rhEPO-Fc was 29.5 to 38.9 h at doses of 8, 25, 80 µg/kg in rhesus monkeys and 35.5 to 43.5 h at doses of 16, 50, 160 µg/kg in rats. In anemia animal models, rhEPO-Fc dose-dependently (7.5–30.0 µg/kg in mice, 5.4–21.4 µg/kg in rats and 5.0–10.0 µg/kg in rhesus monkeys) increased reticulocyte level, followed by an increase of RBC count, hemoglobin and hematocrit levels. At reduced intervention frequency of weekly treatments, rhEPO-Fc showed similar hematopoietic effects as compared with rhEPO given three times a week. These results indicated that rhEPO-Fc could potentially be used in treatment of anemia and warrants future clinical trials.

Highlights

Erythropoietin (EPO) is a glycoprotein that stimulates the production of erythrocytes [1,2]
Pharmacokinetics To evaluate pharmacokinetic behavior of the recombinant human EPO (rhEPO)-Fc fusion protein in vivo, both single and repeated rhEPO-Fc injections were conducted in both rats and rhesus monkeys
To maintain its erythropoietic property and to avoid unpredicted risk of immunogenicity in clinical application, no mutation was introduced into EPO in our rhEPO-Fc fusion protein

Summary

Introduction

Erythropoietin (EPO) is a glycoprotein that stimulates the production of erythrocytes [1,2]. It promotes proliferation, differentiation and maturation of erythroid progenitor cells, and inhibits their apoptosis [3]. Since initial clinical usage of rhEPO-a in the 1980s, clinicians quickly recognized the need of frequent administration as one of major drawbacks of the drug. This imposes a burden on both patients and health care providers, as in vivo half-lives of rhEPO-a and rhEPO-b administered intravenously or subcutaneously in humans are only about 8.5 and 17 hours respectively [9,10]. There has been a longstanding need to develop recombinant EPO analogs with longer in vivo half-lives

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