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Erythropoiesis Stimulating Agents: Approaches to Modulate Activity

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Erythropoiesis Stimulating Agents: Approaches to Modulate Activity Biologics: Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Erythropoiesis stimulating agents: approaches to modulate activity Angus M Sinclair Abstract: Recombinant human erythropoietin (rHuEPO), such as the approved agents Amgen Inc, Thousand Oaks, epoetin alfa and epoetin beta, has been used successfully for over 20 years to treat anemia in CA, USA millions of patients. However, due to the relatively short half-life of the molecule (approximately 8 hours), frequent dosing may be required to achieve required hemoglobin levels. Therefore, a need was identified in some anemic patient populations for erythropoiesis stimulating agents with longer half-lives that required less frequent dosing. This need led to the development of second generation molecules which are modified versions of rHuEPO with improved pharma- cokinetic and pharmacodynamic properties such as darbepoetin alfa, a hyperglycosylated analog of rHuEPO, and pegzyrepoetin, a pegylated rHuEPO. Third generation molecules, such as peginesatide, which are peptide mimetics that have no sequence homology to rHuEPO have also recently been developed. The various molecular, pharmacokinetic, and pharmacodynamic prop- erties of these and other erythropoiesis stimulating agents will be discussed in this review. Keywords: darbepoetin alfa, erythropoiesis, erythropoietin, glycosylation, pharmacokinetics, pharmacology, polyethylene glycols Introduction Anemia is a condition whereby the number of red blood cells, the amount of hemo- globin in blood, and/or the volume of packed red blood cells is lower than normal. Anemia frequently occurs in patients with renal failure, cancer, and other conditions, such as HIV infection. The treatments for anemia include transfusion, iron supple- mentation, and dosing with erythropoiesis stimulating agents (ESAs). Along with the benefits of each of these treatment options, there are potential safety risks that are reviewed elsewhere.1,2 Red blood cell production, the process of erythropoiesis, occurs in the bone marrow and is controlled by the natural hormone erythropoietin (EPO), a 165 amino acid glycoprotein primarily produced by interstitial fibroblasts in the kidney.3 The EPO molecule has a compact globular structure that contains one O-linked and three N-linked carbohydrate side chains that constitute approximately 40% of its mass.3 EPO production is regulated at the transcriptional level by hypoxia inducible transcription factor (HIF) subunits HIF-1α and HIF-2α, part of the cellular oxygen sensory machinery.4 Under normal conditions, the HIF-α transcription factor proteins are produced but are rapidly hydroxylated by HIF prolylhydroxylases and Correspondence: Angus M Sinclair targeted for degradation by the Von Hippel Lindau complex before having the ability Amgen Inc, 1 Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA to activate transcription of the EPO gene. However, under low oxygen conditions, the Tel +1 805 447 7138 HIF- proteins are not hydroxylated and are therefore stabilized, and able to bind to Fax +1 805 499 0953 α Email [email protected] the DNA regulatory elements (hypoxia regulatory elements) of the EPO gene and submit your manuscript | www.dovepress.com Biologics: Targets and Therapy 2013:7 161–174 161 Dovepress © 2013 Sinclair, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/BTT.S45971 which permits unrestricted noncommercial use, provided the original work is properly cited. Sinclair Dovepress activate EPO gene transcription and consequently protein EPOR is a type-1, single transmembrane receptor that production. Pharmacologic modulation of the HIF-α proteins exists in preformed homodimers on the cell surface.5 Two has recently been investigated as an approach to treat anemia4 regions of the EPO molecule have been shown to bind but will not be discussed in this review. EPOR, one with a high affinity (∼Km 1 nM) and the other EPO acts on early erythroid progenitors resident in the bone a low affinity site (∼Km 1 µM).6 A single EPO molecule is marrow, along with other cytokines, to promote erythroid pro- proposed to bind to the high affinity EPOR site first and then genitor survival, proliferation, and differentiation into mature bind to the other EPOR molecule through the second lower erythrocytes (Figure 1).3 Hematopoietic stem cells resident affinity site. The generation of EPOR protein and subse- in the bone marrow differentiate into multiple myeloid and quent trafficking to the cell surface is an inefficient process lymphoid lineages, including the erythroid lineage. The earliest with only 1%–10% of total cellular EPOR molecules being committed erythroid progenitors are classified as burst forming trafficked to the membrane.7–11 A key accessory protein is units-erythroid. It is these erythroid progenitors that upregu- Janus kinase-2 (JAK2) which binds EPOR in the endoplasmic late the expression of the erythropoietin receptor (EPOR) reticulum, induces correct protein folding, promotes surface and become responsive to EPO. The EPO:EPOR interaction expression, and is essential for EPOR signaling.12 Binding induces signaling cascades that induce the differentiation of of EPO to EPOR induces a receptor conformational change, these progenitors to form colony forming units-erythroid, which brings two receptor-associated JAK2 molecules into which themselves are highly responsive to EPO. EPO induces close proximity.13 Transphosphorylation of JAK2 results the expansion and further differentiation of colony forming in phosphorylation of tyrosine residues located within the units-erythroid cells into proerythroblasts and erythroblasts. cytoplasmic tail of EPOR, which serve as docking sites for Erythroblasts extrude their nuclei and form reticulocytes that signaling adaptor proteins.14,15 EPOR stimulation induces the are released from the bone marrow into the circulation and activation of signal transducer and activator of transcription-5 subsequently terminally differentiate into hemoglobin con- (STAT5), phosphoinositol 3′-kinase (PI3K), the MAP kinase taining erythrocytes. In healthy humans, erythrocytes have a (MAPK), and protein kinase C (PKC) pathways.14,15 These lifespan of approximately 100 to 120 days. signaling pathways promote the survival, differentiation CFU-GEMM IL-3 GM-CSF Bone marrow G-CSF BFU-E – early IL-3 GM-CSF IL-9 IGF-1 BFU-E – late IL-3 GM-CSF IL-9 EPO CFU-E Pro- erythroblast Basophilic erythroblast EPO Polychromatic erythroblast Orthochromatic erythroblast Reticulocyte Erythrocyte Reticulocyte Blood vessel Figure 1 Schematic diagram of the process of erythropoiesis. The various stages of erythroid differentiation are shown including the key cytokines that are involved in the proliferation, survival and differentiation of the erythroid progenitors. Abbreviations: BFU-E, burst forming unit-erythroid; CFU-E, colony forming unit-erythroid; CFU-GEMM, colony forming unit-granulocyte, erythroid, macrophage, megakaryocyte; EPO, erythropoietin; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte monocyte colony stimulating factor; IL-3, interleukin 3; IL-9, interleukin 9, IGF-1, insulin-like growth factor 1. 162 submit your manuscript | www.dovepress.com Biologics: Targets and Therapy 2013:7 Dovepress Dovepress Modulation of ESA activity and proliferation of the erythroid progenitors. A number of in vitro and in vivo biological activity. These properties are molecules have been implicated in the negative regulation of described below. EPOR signaling including, Src homology region 2 domain- containing phosphatase 1 (SHP-1), and suppressor of cytokine Molecular stability signaling proteins SOCS-1 and SOCS-3.16,17 Absence of nega- A protein therapeutic needs to be stable in order to main- tive regulation of EPOR signaling is associated with familial tain activity and reduce the potential for immunogenicity. polycythemia due to cytoplasmic truncations of EPOR that Glycosylation can play an important role in maintain- remove SHP-1 and other suppressor binding sites.18,19 Though ing molecular integrity and can reduce the potential for other receptor complexes have been suggested for EPO, these proteolysis. For example, the carbohydrate on rHuEPO helps data are controversial and are reviewed elsewhere.2 maintain molecular integrity and activity. The in vitro bio- logical activities of asialo-rHuEPO and fully deglycosylated Glycosylation of recombinant rHuEPO were reduced to 35% and 11% of initial activity human EPO (rHuEPO) respectively upon heat treatment, whereas glycosylated In 1985, two independent groups reported the cloning of rHuEPO lost no activity.29 Under denaturing conditions, the human erythropoietin gene.20,21 The use of rHuEPO such as guanidine-HCl, heat, and acidic pH, unglycosylated was approved in 1988 and 1989 in Europe and the USA, rHuEPO was more readily aggregated and precipitated, respectively for the treatment of anemia associated with renal whereas glycosylated rHuEPO was able to refold and insufficiency, and subsequently approved for anemia associ- remain soluble.30,31 Furthermore, the peptide component of ated with myelosuppressive chemotherapy associated with rHuEPO was protected from oxygen free radical damage if cancer treatment. rHuEPO protein is produced in genetically glycosylated.32 engineered Chinese Hamster Ovary cells and has a molecular weight of 30.4 kDa and is composed of ∼60% amino acids Solubility and ∼40% carbohydrates.22 Like naturally occurring
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