Erythropoietin, recombinant

The availability of a cDNA for erythropoietin has made it possible to produce substantial amounts of this hormone for analysis and for therapeutic purposes previously the isolation of erythropoietin from human urine yielded very small amounts of the protein. The major use of recombinant erythropoietin has been in the treatment of a small number of anemic states, such as that due to renal failure. 

Watson, E. and Yao, F., Capillary electrophoretic separation of human recombinant erythropoietin (r-HuEPO) glycoforms, Anal. Biochem., 210, 389, 1993. 

Bottomley, A., Thomas, R., van Steen, K., Flechtner, H., Djulbegovic, B. 2002. Human recombinant erythropoietin and quality of life a wonder drug or something to wonder about Lancet Oncology 3(3), 145-153. 

Kharagjitsingh, A.V. et al., Incidence of recombinant erythropoietin (EPO) hyporesponse, EPO-associated antibodies, and pure red cell aplasia in dialysis patients, Kidney Int., 68, 1215, 2005. 

Toxicity studies traditionally are conducted using normal animals. However, studies in animal disease models may provide additional safety information regarding the possibility of disease exacerbation. For example, the administration of human recombinant erythropoietin was associated with hypertension in patients with chronic renal failure, and also in uraemic dogs, but not in normal dogs. 

Lopez-Soto-Yarritu, P., Diez-Masa, J. C., de Frutos, M., and Cifuentes, A. (2002). Comparison of different capillary electrophoresis methods for analysis of recombinant erythropoietin glycoforms. /. Sep. Sci. 25, 1112-1118. 

Johnson Johnson researchers say that they currently have no explanation for this unexpected response to Eprex . Interestingly enough, no similar immune response has been observed with either another of Johnson Johnson s recombinant erythropoietins, Procrit , or with a competitor s comparable product, Amgen s Epogen . 

Pure red cell aplasia (PRCA) PRCA has been reported in a limited number of patients exposed to epoetin alfa. This has been reported predominantly in patients with CRF. Evaluate any patient with loss of response to epoetin alfa for the etiology of loss of effect. Discontinue epoetin alfa in any patient with evidence of PRCA and evaluate the patient for the presence of binding and neutralizing antibodies to epoetin alfa, native erythropoietin, and any other recombinant erythropoietin administered to the patient. In patients with PRCA secondary to neutralizing antibodies to erythropoietin, do not administer epoetin alfa, and do not switch such patients to another product as anti-erythropoietin antibodies cross-react with other erythropoietins. 

In the absence of another etiology, evaluate the patient for evidence of PRCA and test sera for the presence of antibodies to recombinant erythropoietins. 

Recombinant erythropoietin, a hormone normally secreted by the kidney, which stimulates the production of red blood corpuscles, also shows interesting clearance mechanisms. Arguing from the G-CSF case you might guess that it will be taken up by the cells of the bone marrow which is its site of action. This is the case, and up to half of the clearance of erythropoietin is through the marrow itself. 

Androgens stimulate erythrocytosis and are effective in the treatment of certain anemias that are secondary to endocrine hypofunction or myeloid hypoplasia. In high dosages, these compounds in the past were used in the treatment of several forms of anemia. However recombinant erythropoietin has replaced the androgens as a more effective treatment of most forms of anemia. 

Anemia of chronic disease is the second most common form of anemia. Recombinant erythropoietin frequently corrects the anemia with few or no transfusions. Anemia may also develop during radiotherapy or chemotherapy. Recombinant erythropoietin has been shown to increase hematocrit and decrease transfusion requirements after the first month of therapy in anemic cancer patients undergoing chemotherapy. 

E. Therapeutic response Two studies have evaluated the efficacy of darbepoetin for the correction of anemia in adult patients with chronic renal failure. In one study, the hemoglobin target was reached by 72% of dialysis patients treated with darbepoetin and 84% treated with recombinant erythropoietin. In the other, the primary end point was achieved by 93% of predialysis patients treated with darbepoetin and 92% of patients treated with recombinant erythropoietin. 

Strategy was used to develop a long-acting human recombinant erythropoietin. 

In the past, large doses of androgens were employed in the treatment of refractory anemias such as aplastic anemia, Fanconi s anemia, sickle cell anemia, myelofibrosis, and hemolytic anemias. Recombinant erythropoietin has largely replaced androgens for this purpose. 

Epoetin alfa, recombinant erythropoietin, is a glycoprotein that simulates erythrocyte production. Epoetin alfa is administered three times weekly subcutaneously or intravenously. Epoetin is used to treat anemia in patients with chronic renal failure, HIV infection, and patients receiving chemotherapy [104]. Development of a safe, effective nasal formulation of epoetin alfa, containing an absorption enhancer could once again improve the efficacy of epoetin alfa therapy, and reduce the number of injections required in these sensitive patient populations. 

Anemia. Testosterone and similar compounds are potent stimulators of erythropoietin synthesis from the kidneys and other tissues.109 Erythropoietin, in turn, stimulates production of red blood cell synthesis in bone marrow. Human erythropoietin, however, can now be synthesized using recombinant DNA techniques. Hence, various types of anemia that occur secondary to renal disease, cancer chemotherapy, and so forth are usually treated directly with recombinant erythropoietin.109 Nonetheless, androgens may be used as an adjunct to erythropoietin and other drugs to stimulate red blood cell production in certain patients with severe or recalcitrant anemia.10... 

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Antibodies directed against recombinant erythropoietin have been obtained from rabbits immunized with the hormone and Freunds complete adjuvant [64], Two sets of antibodies are present in the serum of rabbits that have been immunized, Fig. (3C). The results of oxidation of the erythropoietin with periodate, Fig. (25A), reaction of the antibodies with lectins of known carbohydrate specificity, Fig. (25B) and inhibition of the antibodies with the structural monosaccharide residues of the hormone, Fig. (26), have established the types of antibodies to be anti-carbohydrate antibodies and the immunodeterminants for these antibodies are oligosaccharides with the following structure N-acetyl neuraminyl a(2->3)... 

EMEA/CHMP/94526/05 Annex guideline— preclinical and clinical issues on similar medicinal products containing recombinant erythropoietins [41] Testing guideline 2006... 

European Medicines Agency—Committee for Medicinal Products for Human Use. Annex Guideline Nonclinical and Clinical Issues on Similar Medicinal Products Containing Recombinant Erythropoietins. EMEA/CHMP/94526/05. 22 March... 

Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V,Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002 346 469-75. 

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