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Recombinant human erythropoietin

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Gabrielle Clark

Recombinant human erythropoietin was developed to treat anemia. It was first isolated from urine in 1977 and its gene was cloned in 1985, allowing industrial production. This paved the way for FDA approval in 1989 for use in chronic renal patients on dialysis to increase red blood cell production. It is now used to treat anemia associated with renal failure, cancer, prematurity, and HIV. It can also support erythropoiesis after chemotherapy or transplants and increase hemoglobin levels before surgery or for athletes. Current research continues to explore new applications of recombinant human erythropoietin.

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Development and Clinical use of Recombinant Human Erythropoietin Foundations of Pharmacology November 16, 2017 Gabrielle Clark
Outline Introduction History in Development Clinical Use Current work
EPO What is Erythropoietin (EPO)?
EPO What is Erythropoietin (EPO)?
EPO What is Erythropoietin (EPO)?
EPO To increase erythropoiesis in an attempt to maintain oxygen delivery to vital organs. What is Erythropoietin (EPO)?
Mechanism of Action Binds to the erythropoietin receptor: a 72 78 kDa glycosylated and phosphorylated transmembrane polypeptide. Member of the superfamily of cytokine receptors. Binding results in homodimerisation of the receptor, followed by activation of several signal transduction pathways.
Recombinant Human Erythropoietin Structural and Biological Characteristics Chromosome7q11-22
Recombinant Human Erythropoietin Structural and Biological Characteristics Chromosome7q11-22
History of Development 1906 - Carnot and Deflandre Suggested a humoral factor haemopoietine to control RBC production Carnot and Deflandre . Comptes Rendu Acad辿mie Science Paris. 1906;143:384386. Donor Blood Anemic 20%-40%
History of Development 1950 Erslev- Provided definite evidence for the existence of EPO and predicted the therapeutic potential of EPO if purified. 1954 Hodgson and Toha- First to demonstrate EPO activity in urine. 1957 Jacobson et al- First to support EPO production of renal origin. 1961 Kuratowsha et al- Confirmed kidney as a source of EPO production. 1968 Katz et al -Confirmed liver as another source of EPO production.
History of Development 1977- Miyake et al were the first to isolate and purify EPO from urine in patients with aplastic anaemia. Miyake T, Kung CK, Goldwasser EJ. Biol Chem. 1977, 252(15):5558-64. Fig.1. SDS polyacrylamide electrophoretic analysis of the most active fraction from each step in the purification of human erythropoitien. Ion exchange chromatography Ethanol precipitation Gel filtration Adsorption chromatography
History of Development 1985-Jacob et al and Lin et al cloned the human erythropoietin gene and express this gene in mammalian cell. IMPORTANT: Paved the way for industrial manufacturing of recombinant EPO allowing sufficient quantity of EPO for clinical use Jacob et al. Nature.1985 Feb 28-Mar 6;313(6005):806-10. Lin et al. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7580-4. Fig.2. Restriction map of the humanEpo gene. ExonsI-V are indicated by boxes. The solid boxes denote the regions of the exons that are translated.
History of Development 1989- FDA approves recombinant EPO for use in chronic renal patients on dialysis
Clinical Applications Replacement therapy (low endogenous erythropoietin level) in anemia associated with: Chronic renal failure Malignancy Prematurity HIV infection
Clinical Applications Supportive therapy to maintain/accelerate erythropoiesis in: Post-chemotherapy/post-radiotherapy Post-bone marrow/stem cell transplantation
Clinical Applications Augmentative therapy to increase haemoglobin above physiological level in: Surgery Sports
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Recombinant human erythropoietin

  • 1. Development and Clinical use of Recombinant Human Erythropoietin Foundations of Pharmacology November 16, 2017 Gabrielle Clark
  • 2. Outline Introduction History in Development Clinical Use Current work
  • 6. EPO To increase erythropoiesis in an attempt to maintain oxygen delivery to vital organs. What is Erythropoietin (EPO)?
  • 7. Mechanism of Action Binds to the erythropoietin receptor: a 72 78 kDa glycosylated and phosphorylated transmembrane polypeptide. Member of the superfamily of cytokine receptors. Binding results in homodimerisation of the receptor, followed by activation of several signal transduction pathways.
  • 8. Recombinant Human Erythropoietin Structural and Biological Characteristics Chromosome7q11-22
  • 9. Recombinant Human Erythropoietin Structural and Biological Characteristics Chromosome7q11-22
  • 10. History of Development 1906 - Carnot and Deflandre Suggested a humoral factor haemopoietine to control RBC production Carnot and Deflandre . Comptes Rendu Acad辿mie Science Paris. 1906;143:384386. Donor Blood Anemic 20%-40%
  • 11. History of Development 1950 Erslev- Provided definite evidence for the existence of EPO and predicted the therapeutic potential of EPO if purified. 1954 Hodgson and Toha- First to demonstrate EPO activity in urine. 1957 Jacobson et al- First to support EPO production of renal origin. 1961 Kuratowsha et al- Confirmed kidney as a source of EPO production. 1968 Katz et al -Confirmed liver as another source of EPO production.
  • 12. History of Development 1977- Miyake et al were the first to isolate and purify EPO from urine in patients with aplastic anaemia. Miyake T, Kung CK, Goldwasser EJ. Biol Chem. 1977, 252(15):5558-64. Fig.1. SDS polyacrylamide electrophoretic analysis of the most active fraction from each step in the purification of human erythropoitien. Ion exchange chromatography Ethanol precipitation Gel filtration Adsorption chromatography
  • 13. History of Development 1985-Jacob et al and Lin et al cloned the human erythropoietin gene and express this gene in mammalian cell. IMPORTANT: Paved the way for industrial manufacturing of recombinant EPO allowing sufficient quantity of EPO for clinical use Jacob et al. Nature.1985 Feb 28-Mar 6;313(6005):806-10. Lin et al. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7580-4. Fig.2. Restriction map of the humanEpo gene. ExonsI-V are indicated by boxes. The solid boxes denote the regions of the exons that are translated.
  • 14. History of Development 1989- FDA approves recombinant EPO for use in chronic renal patients on dialysis
  • 15. Clinical Applications Replacement therapy (low endogenous erythropoietin level) in anemia associated with: Chronic renal failure Malignancy Prematurity HIV infection
  • 16. Clinical Applications Supportive therapy to maintain/accelerate erythropoiesis in: Post-chemotherapy/post-radiotherapy Post-bone marrow/stem cell transplantation
  • 17. Clinical Applications Augmentative therapy to increase haemoglobin above physiological level in: Surgery Sports

Editor's Notes

  • #4: The human body generates 2.5 million new red blood cells (RBCs) per second from the bone marrow to replenish the continuous removal of effete RBCs. The production of RBCs (erythropoiesis) is controlled by an intricate interaction between various humoral factors and cytokines.A specific cytokine, a sialoglycoprotein known as erythropoietin,which acts directly on certain RBC progenitors and precursors in the bone marrow, controls the proliferation, differentiation, and maturation of RBCs. The
  • #5: he human body generates 2.5 million new red blood cells (RBCs) per second from the bone marrow to replenish the continuous removal of effete RBCs. The production of RBCs (erythropoiesis) is controlled by an intricate interaction between various humoral factors and cytokines.A specific cytokine, a sialoglycoprotein known as erythropoietin,which acts directly on certain RBC progenitors and precursors in the bone marrow, controls the proliferation, differentiation, and maturation of RBCs. The
  • #6: he human body generates 2.5 million new red blood cells (RBCs) per second from the bone marrow to replenish the continuous removal of effete RBCs. The production of RBCs (erythropoiesis) is controlled by an intricate interaction between various humoral factors and cytokines.A specific cytokine, a sialoglycoprotein known as erythropoietin,which acts directly on certain RBC progenitors and precursors in the bone marrow, controls the proliferation, differentiation, and maturation of RBCs. The
  • #7: \
  • #11: Experiment on injected blood from anaemic rabbits to donor rabbits causing a 20%40% increased RBC in blood
  • #12: http://physrev.physiology.org.libproxy.tulane.edu:2048/content/physrev/72/2/449.full.pdf
  • #13: Purification of human erythropoietin.Miyake T, Kung CK, Goldwasser E J Biol Chem. 1977 Aug 10; 252(15):5558-64.