Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency.
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.
Tillmann
H C
HC
Medical Research Center, University of Heidelberg, Klinikum, Mannheim, Germany.
Kuhn
B
B
Kränzlin
B
B
Sadick
M
M
Gross
J
J
Gretz
N
N
Pill
J
J
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
D006454:Hemoglobins; D011994:Recombinant Proteins; C508174:pegylated erythropoietin; D004921:Erythropoietin; D011092:Polyethylene Glycols