Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-05-10
2004-06-08
Moran, Marjorie (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S351000
Reexamination Certificate
active
06747002
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to systems and methods for obtaining optimized EPO dosage regimens for a desired pharmacodynamic/pharmacokinetic response.
BACKGROUND OF THE INVENTION
Erythropoietin (EPO) is the principal factor responsible for the regulation of red blood cell production during steady-state conditions and for accelerating recovery of red blood cell mass following hemorrhage. EPO is a glycoprotein hormone with a molecular mass of 30 KDa and is heavily glycosylated, which serves to protect the EPO molecule from rapid degradation in vivo. Serum EPO concentrations in humans normally range from 6 to 32 U/l (l), and the half-life (t
1/2
) of EPO is reported to range from 2 to 13 hours with a volume of distribution close to plasma volume. As expected for a large sialoglycoprotein, less than 10% of EPO is excreted in the urine (see, e.g., Lappin et al., 1996.
Clin. Lab Haem.
18:137-145.)
The primary site for EPO synthesis in adult organisms is the kidney; although the liver and bone marrow have also been implicated, the data remains inconclusive. The primary stimulus for increased EPO synthesis is tissue hypoxia, which results from decreased oxygen availability in the tissues. Hypoxia can result from the loss of large amounts of blood, destruction of red blood cells by radiation, or exposure to high altitudes. In addition, various forms of anemia cause hypoxia since red blood cells are responsible for oxygen transport in the body. In the normal state, an increased level of EPO stimulates the production of new red blood cells thereby raising the level of oxygen and reducing or eliminating the hypoxic condition.
The principal function of EPO is to act synergistically with other growth factors to stimulate the proliferation and differentiation of erythrocytic progenitor cells in the bone marrow leading to reticulocytosis and increased RBC numbers in the blood, a process also known as erythropoiesis (FIG.
1
). During erythropoiesis, cell differentiation along the erythroid lineage occurs over a two week span in humans. The earliest progenitor is the BFU-E (Burst-Forming Unit-Erythroid), which is small and without distinguishing histologic characteristics. The stage after the BFU-E is the CFU-E (Colony Forming Unit-Erythroid), which is larger than the BFU-E and immediately precedes the stage where hemoglobin production begins. The cells that begin producing hemoglobin are the immature erythrocytes, which not only begin producing hemoglobin, but also start condensing their nuclei to eventually become mature erythroblasts. The mature erythroblasts are smaller than the immature erythrocytes and have a tightly compacted nucleus, which is expelled as the cells become reticulocytes. Reticulocytes are so named because these cells contain reticular networks of polyribosomes and as the reticulocytes lose their polyribosomes, they become mature red blood cells (RBCs).
Until recently, the availability of EPO has been very limited. Although the protein is present in human urine, excreted levels are too low to make this a practical source of EPO for therapeutic uses. The identification, cloning, expression of genes encoding EPO and EPO purification techniques, e.g., as described in U.S. Pat. Nos. 4,703,008, 5,389,541, 5,441,868, 5,614,184, 5,688,679, 5,888,774, 5,888,772, and 5,856,298, has made EPO readily available for therapeutic applications. A description of the purification of recombinant EPO (rHuEPO) from cell medium that supported the growth of mammalian cells containing recombinant EPO plasmids for example, is included in U.S. Pat. No. 4,667,016. This recombinant EPO has an amino acid sequence identical to that of human urinary erythropoietin, and the two are indistinguishable in chemical, physical and immunological tests. The expression and recovery of biologically active recombinant EPO from mammalian cell hosts containing the EPO gene on recombinant plasmids has made available quantities of EPO suitable for therapeutic applications. In addition, knowledge of the gene sequence and the availability of larger quantities of purified protein has led to a better understanding of the mode of action of this protein.
The biological activity of a protein is dependent upon its structure. In particular, the primary structure of a protein, i.e., its amino acid sequence, provides information that allows the formation of secondary (e.g., &agr;-helix or &bgr;-pleated sheet) and tertiary (overall 3-dimensional folding) structures by a polypeptide during and after synthesis. Furthermore, not only is the biological activity of a protein governed by its structure, but also by modifications generated after the protein has been translated. Indeed, many cell surface proteins and secretory proteins are modified by one or more oligosacchride groups. This modification known as glycosylation, can dramatically affect the physical properties of proteins and can be important in protein stability, secretion, and subcellular localization. Proper glycosylation can be essential for biological activity.
Both human urinary derived and recombinant EPO (expressed in mammalian cells) having the amino acid sequence 1-165 of human EPO contain three N-linked and one O-linked oligosacchride chains which together comprise about 40% of the total molecular weight of the glycoprotein. The oligosacchride chains have been shown to be modified with terminal sialic acid residues. Enzymatic treatment of glycosylated EPO to remove all sialic acid residues results in a loss of in vivo activity, but does not affect its in vitro activity (Lowy et al., 1960,
Nature
185:102; Goldwasser et al., 1974,
J. Biol. Chem.
249:4202). This behavior has been explained by rapid clearance of asialoerythropoeitin from the circulation upon interaction with the hepatic asialoglycoprotein binding protein (Morrell et al., 1968,
J. Biol. Chem.
243:155; Briggs et al., 1974,
Am. J. Physiol.
227:1385; and Ashwell et al., 1978
Methods of Enzymol.
50:287). Thus, EPO possesses in vivo biological activity only when it is sialylated to avoid binding by the hepatic binding protein.
Deficient (or inefficient) EPO production relative to hemoglobin level is associated with certain forms of anemia. These include anemia of renal failure and end-stage renal disease, anemia of chronic disorders (chronic infections and rheumatoid arthritis), autoimmune disease, acquired immune deficiency disease (AIDS), and malignancy. Many of these conditions are associated with the generation of a factor that has been shown to be an inhibitor of EPO activity. Other anemias are clearly EPO-independent, and include aplastic anemia, iron deficiency anemia, the thalassemias, megaloblastic anemia, pure red cell aplasia, and myelodysplastic syndromes.
The measurement of EPO levels in human serum has clinical importance. Determination of EPO levels in patient serum can be useful in distinguishing those anemias and polycythemias that are associated with decreased or increased EPO levels from those that are not. Additionally, the demonstration of an inappropriately low level of serum EPO is a prerequisite for concluding that an anemic patient may benefit from treatment with exogenous EPO.
In clinical trials, Epoetin alfa has been evaluated in normal patients as well as in patients with various anemic conditions. Epoetin alfa induces a brisk haematological response in normal human volunteers, provided that adequate supplies of iron are available to support increased hemoglobin synthesis. A majority of trials have investigated the safety and effectiveness in the treatment of anemia associated with renal failure. In addition, Epoetin alfa may be used to correct anemia in other patient groups including anemia associated with platinum-based cancer chemotherapy, anemia associated with zidovudine therapy in patients with AIDS, and anemia associated with other drugs such as cisplatin. Also, the administration of Epoetin alfa has many other potential therapeutic applications: Epoetin alfa administration increases the capacity for autologous blood donation in patien
Cheung Wing
Cote Christine
Gibson David
Vercammen Els
Moran Marjorie
Ortho-McNeil Pharmaceutical , Inc.
Preston Gates Ellis & Rouvelas Meeds LLP
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