Development and Clinical use of 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

3. EPO
What is Erythropoietin (EPO)?

4. EPO
What is Erythropoietin (EPO)?

5. EPO
What is Erythropoietin (EPO)?

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 Académie Science Paris. 1906;143:384–386.
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

18. Current work

19. Thank You