Erythropoietins, Erythropoietic Factors, and Erythropoiesis (eBook)

Contents 6
List of contributors 8
Preface to the first edition 10
Preface to the second edition 13
Abbreviations 14
Background 18
Erythropoiesis: an overview 19
Normal erythropoiesis 19
Erythropoietin 23
Abnormal erythropoiesis 27
A bright horizon or dark clouds? 28
References 30
Regulation of endogenous erythropoietin production 35
Hypoxic regulation of erythropoietin 35
Renal oxygenation and erythropoietin 36
cis-acting regulatory elements of the erythropoietin gene 37
EPO – a paradigm for widespread hypoxic gene regulation 40
Hypoxia inducible-factor (HIF) 42
Differential functions of the HIF isoforms 43
Regulation of HIF by oxygen 45
Von Hippel-Lindau disease 48
Integration of hypoxic, metabolic, and redox signals 49
Renal anaemia and erythropoietin regulation 50
Pharmacologic manipulation of the HIF response 51
Summary 52
References 52
Biology of erythropoietin 57
Introduction 57
Control of EPO production 58
Erythropoiesis 59
Assays 64
Interaction with iron 68
Rationale for rHuEPO treatment in disease 69
References 72
Erythropoiesis – genetic abnormalities 77
Introduction 77
Erythropoiesis 77
Polycythemias 78
Anemias 85
Conclusion 87
References 87
Erythropoiesis-stimulating agents 91
Studies of erythropoiesis and the discovery and cloning of recombinant human erythropoietin 92
Introduction 92
Early studies in erythropoiesis 93
The role of kidney and bone marrow in erythropoiesis 94
Isolation of EPO from urine 95
Cloning of the EPO gene 95
Expression of the EPO gene 97
Discussion 97
References 98
Commercial production of recombinant erythropoietins 101
Introduction 101
Cell line development 101
Cell bank 103
Cell culture process 105
Recovery and purification of erythropoietin 112
Dosage form (drug product) manufacturing 115
References 118
Biosimilar epoetins 119
Introduction 119
Immunogenicity of proteins 120
Consequences of antibodies 121
The biosimilars assessed by the EMEA 122
Conclusions 125
References 126
New molecules and formulations 129
Introduction 129
Considerations of new formulations and drug entities 131
Erythropoiesis-stimulating agents 132
Conclusions 148
References 149
Erythropoietin receptor 155
Structural basis for the signal transduction of erythropoietin 156
Introduction 156
Conclusion 165
References 165
Intracellular signaling by the erythropoietin receptor 167
Introduction 167
EPOR-activated STAT5 signaling 168
The role of STAT5 in the erythropoietic stress response 173
EPOR-stimulated PI3-kinase/AKT signaling 173
Signaling by activated AKT (PKB) protein kinase 174
EPOR-stimulation of RAS/MAPK pathways 177
Negative regulators of EPO signaling 179
Unresolved issues 181
References 182
Mechanism of erythropoietin receptor activation 187
Introduction 187
Functional challenges to EPOR from the unique features of the red blood cell compartment 187
EPOR is activated as a dimer 196
Dimer reorientation in EPO-induced EPOR activation 198
Preformed EPOR dimers are required for oncogenic signaling by the JAK2 V617F in polycythemia vera 203
Conclusion 204
References 205
Clinical utility 209
Pharmacokinetics of erythropoiesis-stimulating agents 210
Introduction 210
Mechanism of action 211
Regulation of erythropoietin 212
Pharmacokinetics 213
Summary 227
References 227
Use of erythropoietic stimulating agents in the setting of renal disease 235
Introduction 235
Benefits of ESA treatment of anemia in patients with CKD 236
Adverse effects of ESA therapy in CKD 242
Target hemoglobin/hematocrit 244
ESA prescription 248
Hyporesponse to ESA therapy 251
Novel ESA therapy: what’s next? 252
References 253
Abuse of recombinant erythropoietins and blood products by athletes 259
History 259
Doping by expanding the red cell mass 262
Detecting erythropoietic proteins in body fluids 268
Detecting homologous blood transfusion 282
Summary 283
References 284
Role and regulation of iron metabolism in erythropoiesis and disease 289
Introduction 289
Molecular coordination of iron metabolism 289
Disorders of iron metabolism 296
References 304
Nonhematopoietic effects of erythropoiesisstimulating agents 309
Introduction 309
Effects of ESA in the central nervous system 311
Effects of ESA in the cardiovascular system 314
Effects of ESA on renal cells 316
Effects of ESA on tumor growth 318
Conclusions 322
References 323
Index 328
The MDT-Series Milestones in Drug Therapy 336
Index 328