title: Epoetin beta pegol, but not recombinant erythropoietin, retains its hematopoietic effect in vivo in the presence of the sialic acid-metabolizing enzyme sialidase.
abstract: Erythropoiesis-stimulating agents (ESAs) are widely used for treating chronic kidney disease (CKD)-associated anemia. The biological activity of ESAs is mainly regulated by the number of sialic acid-containing carbohydrates on the erythropoietin (EPO) peptide. Sialidase, a sialic acid-metabolizing enzyme that accumulates in CKD patients, is suspected of contributing to shortening the circulation half-life of ESAs. Epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), is an EPO integrated with methoxypolyethylene glycol (PEG). It has been suggested that C.E.R.A. may exert a favorable therapeutic effect, even under conditions of elevated sialidase; however, no detailed investigation of the pharmacological profile of C.E.R.A. in the presence of sialidase has been reported. In the present study, we injected C.E.R.A. or EPO pre-incubated with sialidase into rats, and assessed the hematopoietic effect by reticulocyte count. The hematopoietic effect of C.E.R.A., but not EPO, was preserved after sialidase treatment, despite the removal of sialic acid. Proliferation of EPO-dependent leukemia cells (AS-E2) was significantly increased by desialylated C.E.R.A. and EPO compared to non-treated C.E.R.A. or EPO. In conclusion, we show that C.E.R.A. exerts a favorable hematopoietic effect even under conditions of elevated sialidase. Our findings may contribute to a better understanding of CKD and more effective therapeutic approaches based on a patient's profile of anemia.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, 247-8530, Japan. aizawa.ken85@chugai-pharm.co.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Aizawa
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, 247-8530, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kawasaki
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, 247-8530, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, 247-8530, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, 247-8530, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Endo
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, 247-8530, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
mesh_terms: D000818:Animals; D004921:Erythropoietin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D009439:Neuraminidase / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy; D017701:Reticulocyte Count; D012794:Sialic Acids / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D012794:Sialic Acids; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols; D009439:Neuraminidase
keywords: Epoetin beta pegol (C.E.R.A.); Hematopoiesis; Sialidase (neuraminidase)