title: Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency.
abstract: Recombinant human erythropoietin (rhEPO) is used to treat anemia in chronic renal insufficiency. Erythropoietin (EPO) immunogenicity can lead to EPO-resistant anemia. Conjugating proteins with polyethylene glycol (PEG) can prolong elimination half-life and diminish protein immunogenicity. We investigated the efficacy of new erythropoietic agents, synthesized by single (Ro 50-3821) and multiple (MIX) integrations of PEG and succinimidyl butanoic acid with rhEPO, in rats with chronic renal insufficiency. Sprague-Dawley rats with surgically induced renal insufficiency received Ro 50-3821 or MIX subcutaneously (s.c.) over 4-12 weeks compared to rhEPO and NaCl. Hemoglobin and antibody levels served as primary efficacy and safety variables. Dosing intervals and dose-response characteristics were investigated. Ro 50-3821 (2.5 microg/kg once weekly) increased hemoglobin levels by 7 g/dl after 4 weeks compared to 1 g/dl in NaCl controls (P<0.05). MIX (2.5 microg/kg once weekly) and rhEPO (0.25 microg/kg three times weekly) increased hemoglobin levels by 3 g/dl. Ro 50-3821 administered for 12 weeks (0.75 microg/kg once weekly) increased hemoglobin levels (from 13 to 19 g/dl) more effectively than rhEPO (0.75 microg/kg once weekly, decline from 13 to 11 g/dl, P<0.05). No antibodies against Ro 50-3821 were detected after 12 weeks of treatment. Antibodies against rhEPO were seen in 69% of animals (P<0.00001). Ro 50-3821 increased hemoglobin levels with once weekly s.c. dosing. Multiple pegylated EPO is less effective. In rats, rhEPO failed to increase hemoglobin levels with once weekly long-term dosing. Antibody formation following rhEPO may explain this finding. Therefore, Ro 50-3821 may provide important clinical advantages compared to unpegylated EPO. It can be administered in longer dosing intervals and has a lower risk of unfavorable immunological responses.
authors.affiliation: Medical Research Center, University of Heidelberg, Klinikum, Mannheim, Germany.
authors.forename: H C
authors.initials: HC
authors.lastname: Tillmann
authors.forename: B
authors.initials: B
authors.lastname: Kuhn
authors.forename: B
authors.initials: B
authors.lastname: Kränzlin
authors.forename: M
authors.initials: M
authors.lastname: Sadick
authors.forename: J
authors.initials: J
authors.lastname: Gross
authors.forename: N
authors.initials: N
authors.lastname: Gretz
authors.forename: J
authors.initials: J
authors.lastname: Pill
mesh_terms: D000818:Animals; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D006454:Hemoglobins / Q000032:analysis; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008297:Male; D011092:Polyethylene Glycols / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013599:Systole / Q000187:drug effects
chemical_list: D006454:Hemoglobins; D011994:Recombinant Proteins; C508174:pegylated erythropoietin; D004921:Erythropoietin; D011092:Polyethylene Glycols