title: The impact of sialic acids on the pharmacokinetics of a PEGylated erythropoietin.
abstract: Erythropoietin (EPO) is an important molecule in the erythropoiesis and various forms of EPO have been marketed in managing anemia in humans. Long acting EPOs for less frequent dosing have been generated either by increasing the number of glycosylation sites of the EPO molecule or by linking it to a polyethylene glycol (PEG). We have generated recombinant human EPO (rhEPO) using glycoengineered Pichia pastoris strains and evaluated the pharmacokinetics (PK) in rats of this molecule linked to a 40 kDa PEG (PEGylated rhEPO), in relation to its glycosylation patterns. As expected, the PEGylated rhEPO exhibited a significant improvement in half-life of serum when compared with the non-PEGylated version. Interestingly, the PK properties of the PEGylated rhEPO molecule were also significantly influenced by the glycosylation profile. Specifically, PEGylated rhEPO with a significantly higher sialic acid content in the biantennary structure (high A2) exhibited lower systemic clearance and higher systemic exposure than those with a lower sialic acid content (low A2) following either intravenous or subcutaneous administrations. These results suggest that A2 content may be one of the important criteria for release in manufacturing PEGylated rhEPO to ensure consistent PK.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. liming_liu2@merck.com
authors.forename: Liming
authors.initials: L
authors.lastname: Liu
authors.forename: Huijuan
authors.initials: H
authors.lastname: Li
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Sujatha
authors.initials: S
authors.lastname: Gomathinayagam
authors.forename: William J
authors.initials: WJ
authors.lastname: Rayfield
authors.forename: Marc
authors.initials: M
authors.lastname: van Maanen
authors.forename: Kuo-Chang
authors.initials: KC
authors.lastname: Yin
authors.forename: Laura
authors.initials: L
authors.lastname: Hong
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
mesh_terms: D000818:Animals; D002240:Carbohydrate Sequence; D004921:Erythropoietin / Q000097:blood* / Q000737:chemistry* / Q000235:genetics; D006031:Glycosylation; D006207:Half-Life; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010843:Pichia / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics; D012794:Sialic Acids / Q000737:chemistry*
chemical_list: D011994:Recombinant Proteins; D012794:Sialic Acids; C508174:pegylated erythropoietin; D004921:Erythropoietin; D011092:Polyethylene Glycols