JP6663428B2 - Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 - Google Patents
Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 Download PDFInfo
- Publication number
- JP6663428B2 JP6663428B2 JP2017522852A JP2017522852A JP6663428B2 JP 6663428 B2 JP6663428 B2 JP 6663428B2 JP 2017522852 A JP2017522852 A JP 2017522852A JP 2017522852 A JP2017522852 A JP 2017522852A JP 6663428 B2 JP6663428 B2 JP 6663428B2
- Authority
- JP
- Japan
- Prior art keywords
- polypeptide
- amino acid
- acid sequence
- gdf15
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 101000893549 Homo sapiens Growth/differentiation factor 15 Proteins 0.000 title claims description 344
- 239000000203 mixture Substances 0.000 title claims description 27
- 210000003743 erythrocyte Anatomy 0.000 title description 102
- 238000000034 method Methods 0.000 title description 91
- 230000001965 increasing effect Effects 0.000 title description 57
- 150000001413 amino acids Chemical class 0.000 claims description 155
- 208000007502 anemia Diseases 0.000 claims description 108
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 91
- 102100040896 Growth/differentiation factor 15 Human genes 0.000 claims description 88
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 83
- 229920001184 polypeptide Polymers 0.000 claims description 80
- 239000008280 blood Substances 0.000 claims description 77
- 210000004369 blood Anatomy 0.000 claims description 76
- 230000010437 erythropoiesis Effects 0.000 claims description 66
- 238000011282 treatment Methods 0.000 claims description 49
- 150000007523 nucleic acids Chemical class 0.000 claims description 39
- 102000039446 nucleic acids Human genes 0.000 claims description 33
- 108020004707 nucleic acids Proteins 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 23
- 239000002773 nucleotide Substances 0.000 claims description 22
- 125000003729 nucleotide group Chemical group 0.000 claims description 22
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 19
- 239000012190 activator Substances 0.000 claims description 16
- 108010075944 Erythropoietin Receptors Proteins 0.000 claims description 14
- 102100036509 Erythropoietin receptor Human genes 0.000 claims description 14
- 230000001154 acute effect Effects 0.000 claims description 14
- 230000000295 complement effect Effects 0.000 claims description 10
- 208000032843 Hemorrhage Diseases 0.000 claims description 9
- 238000009396 hybridization Methods 0.000 claims description 9
- 230000000740 bleeding effect Effects 0.000 claims description 7
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 5
- 108010019673 Darbepoetin alfa Proteins 0.000 claims description 4
- 108010002601 epoetin beta Proteins 0.000 claims description 4
- 108010074604 Epoetin Alfa Proteins 0.000 claims description 3
- 108010084052 continuous erythropoietin receptor activator Proteins 0.000 claims description 3
- 229960005029 darbepoetin alfa Drugs 0.000 claims description 3
- 229960003388 epoetin alfa Drugs 0.000 claims description 3
- 229960004579 epoetin beta Drugs 0.000 claims description 3
- 108010067416 epoetin delta Proteins 0.000 claims description 3
- 229950002109 epoetin delta Drugs 0.000 claims description 3
- 108010090921 epoetin omega Proteins 0.000 claims description 3
- 229950008767 epoetin omega Drugs 0.000 claims description 3
- 229960001046 methoxy polyethylene glycol-epoetin beta Drugs 0.000 claims description 3
- 208000018525 Postpartum Hemorrhage Diseases 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- 230000008733 trauma Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 28
- 102000003951 Erythropoietin Human genes 0.000 description 140
- 108090000394 Erythropoietin Proteins 0.000 description 140
- 229940105423 erythropoietin Drugs 0.000 description 138
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 123
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 100
- 108090000623 proteins and genes Proteins 0.000 description 73
- 210000004027 cell Anatomy 0.000 description 65
- 108010054147 Hemoglobins Proteins 0.000 description 55
- 102000001554 Hemoglobins Human genes 0.000 description 55
- 102000004169 proteins and genes Human genes 0.000 description 54
- 235000018102 proteins Nutrition 0.000 description 52
- 229910052742 iron Inorganic materials 0.000 description 50
- 230000014509 gene expression Effects 0.000 description 43
- 102000005962 receptors Human genes 0.000 description 43
- 108020003175 receptors Proteins 0.000 description 43
- 108091006084 receptor activators Proteins 0.000 description 39
- 235000001014 amino acid Nutrition 0.000 description 36
- 230000000694 effects Effects 0.000 description 35
- 229940024606 amino acid Drugs 0.000 description 33
- 208000007056 sickle cell anemia Diseases 0.000 description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- 230000000925 erythroid effect Effects 0.000 description 25
- 238000005534 hematocrit Methods 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 23
- 239000013598 vector Substances 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 21
- 239000002243 precursor Substances 0.000 description 21
- 102000046181 human GDF15 Human genes 0.000 description 20
- 101100392289 Mus musculus Gdf15 gene Proteins 0.000 description 19
- 206010028980 Neoplasm Diseases 0.000 description 17
- 230000004927 fusion Effects 0.000 description 17
- 208000035475 disorder Diseases 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 15
- 201000011510 cancer Diseases 0.000 description 15
- 208000020832 chronic kidney disease Diseases 0.000 description 15
- 230000035772 mutation Effects 0.000 description 15
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 14
- 210000001185 bone marrow Anatomy 0.000 description 14
- 229960001330 hydroxycarbamide Drugs 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 210000000952 spleen Anatomy 0.000 description 14
- 230000004044 response Effects 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- 108060003951 Immunoglobulin Proteins 0.000 description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 208000005980 beta thalassemia Diseases 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 102000018358 immunoglobulin Human genes 0.000 description 12
- 210000001995 reticulocyte Anatomy 0.000 description 12
- 238000004820 blood count Methods 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 239000013612 plasmid Substances 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- 208000011580 syndromic disease Diseases 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- 208000002903 Thalassemia Diseases 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000036772 blood pressure Effects 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 230000004069 differentiation Effects 0.000 description 10
- 210000003013 erythroid precursor cell Anatomy 0.000 description 10
- 102000037865 fusion proteins Human genes 0.000 description 10
- 108020001507 fusion proteins Proteins 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 206010065973 Iron Overload Diseases 0.000 description 9
- 230000002411 adverse Effects 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000000913 erythropoietic effect Effects 0.000 description 9
- 239000013604 expression vector Substances 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 208000031162 sideroblastic anemia Diseases 0.000 description 9
- 206010020772 Hypertension Diseases 0.000 description 8
- 206010021143 Hypoxia Diseases 0.000 description 8
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 8
- 108091028043 Nucleic acid sequence Proteins 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 239000004202 carbamide Substances 0.000 description 8
- 210000003527 eukaryotic cell Anatomy 0.000 description 8
- 230000013595 glycosylation Effects 0.000 description 8
- 238000006206 glycosylation reaction Methods 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 239000011159 matrix material Substances 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 230000035882 stress Effects 0.000 description 8
- 239000013589 supplement Substances 0.000 description 8
- XJOTXKZIRSHZQV-RXHOOSIZSA-N (3S)-3-amino-4-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S,3S)-1-[[(1R,6R,12R,17R,20S,23S,26R,31R,34R,39R,42S,45S,48S,51S,59S)-51-(4-aminobutyl)-31-[[(2S)-6-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]-20-benzyl-23-[(2S)-butan-2-yl]-45-(3-carbamimidamidopropyl)-48-(hydroxymethyl)-42-(1H-imidazol-4-ylmethyl)-59-(2-methylsulfanylethyl)-7,10,19,22,25,33,40,43,46,49,52,54,57,60,63,64-hexadecaoxo-3,4,14,15,28,29,36,37-octathia-8,11,18,21,24,32,41,44,47,50,53,55,58,61,62,65-hexadecazatetracyclo[32.19.8.26,17.212,39]pentahexacontan-26-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)[C@@H](C)O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H]4CSSC[C@H](NC(=O)[C@H](Cc5ccccc5)NC(=O)[C@@H](NC1=O)[C@@H](C)CC)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1cnc[nH]1)NC3=O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N2)C(=O)NCC(=O)N4)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJOTXKZIRSHZQV-RXHOOSIZSA-N 0.000 description 7
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 7
- 241000282412 Homo Species 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 108010076504 Protein Sorting Signals Proteins 0.000 description 7
- 230000009286 beneficial effect Effects 0.000 description 7
- 208000034158 bleeding Diseases 0.000 description 7
- 210000000988 bone and bone Anatomy 0.000 description 7
- 239000002738 chelating agent Substances 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 102000018511 hepcidin Human genes 0.000 description 7
- 108060003558 hepcidin Proteins 0.000 description 7
- 229940066919 hepcidin Drugs 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 230000004936 stimulating effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 206010072684 Refractory cytopenia with unilineage dysplasia Diseases 0.000 description 6
- 206010041660 Splenomegaly Diseases 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- -1 fusion Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 210000003924 normoblast Anatomy 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 210000001236 prokaryotic cell Anatomy 0.000 description 6
- 230000001177 retroviral effect Effects 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 239000003656 tris buffered saline Substances 0.000 description 6
- 206010010356 Congenital anomaly Diseases 0.000 description 5
- 101000707567 Homo sapiens Splicing factor 3B subunit 1 Proteins 0.000 description 5
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 5
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 208000007536 Thrombosis Diseases 0.000 description 5
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 201000006288 alpha thalassemia Diseases 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 238000011284 combination treatment Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 230000007812 deficiency Effects 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 230000011132 hemopoiesis Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 241000701447 unidentified baculovirus Species 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 101150002621 EPO gene Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010022971 Iron Deficiencies Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 208000008601 Polycythemia Diseases 0.000 description 4
- 208000009527 Refractory anemia Diseases 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 102100031711 Splicing factor 3B subunit 1 Human genes 0.000 description 4
- 229940123237 Taxane Drugs 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 4
- 229940030600 antihypertensive agent Drugs 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 230000009920 chelation Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 229960000958 deferoxamine Drugs 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 208000028208 end stage renal disease Diseases 0.000 description 4
- 201000000523 end stage renal failure Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000012953 feeding on blood of other organism Effects 0.000 description 4
- 238000001415 gene therapy Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 230000035800 maturation Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 230000003319 supportive effect Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 206010069754 Acquired gene mutation Diseases 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 208000017667 Chronic Disease Diseases 0.000 description 3
- 241000699802 Cricetulus griseus Species 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-N 0.000 description 3
- 102100035233 Furin Human genes 0.000 description 3
- 108090001126 Furin Proteins 0.000 description 3
- 102000005720 Glutathione transferase Human genes 0.000 description 3
- 108010070675 Glutathione transferase Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 3
- 108091005902 Hemoglobin subunit alpha Proteins 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 3
- 206010027540 Microcytosis Diseases 0.000 description 3
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 3
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 3
- 101100238610 Mus musculus Msh3 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000714474 Rous sarcoma virus Species 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 208000006756 X-linked sideroblastic anemia Diseases 0.000 description 3
- 208000022440 X-linked sideroblastic anemia 1 Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 238000001042 affinity chromatography Methods 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 150000001720 carbohydrates Chemical group 0.000 description 3
- 230000000973 chemotherapeutic effect Effects 0.000 description 3
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 208000034737 hemoglobinopathy Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000013632 homeostatic process Effects 0.000 description 3
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 231100001016 megaloblastic anemia Toxicity 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 3
- 239000000816 peptidomimetic Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 201000007245 sideroblastic anemia 1 Diseases 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 238000010572 single replacement reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000037439 somatic mutation Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011285 therapeutic regimen Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- 208000030090 Acute Disease Diseases 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- 206010002965 Aplasia pure red cell Diseases 0.000 description 2
- 241000701822 Bovine papillomavirus Species 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 206010058314 Dysplasia Diseases 0.000 description 2
- 108010013369 Enteropeptidase Proteins 0.000 description 2
- 102100029727 Enteropeptidase Human genes 0.000 description 2
- 229940087983 Erythropoietin receptor agonist Drugs 0.000 description 2
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 2
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 2
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 101710154606 Hemagglutinin Proteins 0.000 description 2
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 2
- 101000886562 Homo sapiens Growth/differentiation factor 8 Proteins 0.000 description 2
- 101100095662 Homo sapiens SF3B1 gene Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 201000002980 Hyperparathyroidism Diseases 0.000 description 2
- 206010021137 Hypovolaemia Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 2
- 208000029725 Metabolic bone disease Diseases 0.000 description 2
- 241000713869 Moloney murine leukemia virus Species 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 101000987583 Mus musculus Eosinophil peroxidase Proteins 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 230000004988 N-glycosylation Effects 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 2
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 206010033661 Pancytopenia Diseases 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 101710176177 Protein A56 Proteins 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 201000004224 Schnyder corneal dystrophy Diseases 0.000 description 2
- 206010040642 Sickle cell anaemia with crisis Diseases 0.000 description 2
- 208000005485 Thrombocytosis Diseases 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 238000005349 anion exchange Methods 0.000 description 2
- 238000005571 anion exchange chromatography Methods 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 238000010322 bone marrow transplantation Methods 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000005341 cation exchange Methods 0.000 description 2
- 238000005277 cation exchange chromatography Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000003636 conditioned culture medium Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 208000024389 cytopenia Diseases 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- BOFQWVMAQOTZIW-UHFFFAOYSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N1C(C=2C(=CC=CC=2)O)=NC(C=2C(=CC=CC=2)O)=N1 BOFQWVMAQOTZIW-UHFFFAOYSA-N 0.000 description 2
- 229960001489 deferasirox Drugs 0.000 description 2
- FMSOAWSKCWYLBB-VBGLAJCLSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N(N\C(N\1)=C\2C(C=CC=C/2)=O)C/1=C\1C(=O)C=CC=C/1 FMSOAWSKCWYLBB-VBGLAJCLSA-N 0.000 description 2
- 229960003266 deferiprone Drugs 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000022811 deglycosylation Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000003028 elevating effect Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 210000003372 endocrine gland Anatomy 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000002449 erythroblastic effect Effects 0.000 description 2
- 230000005713 exacerbation Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 239000000185 hemagglutinin Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 2
- 208000003532 hypothyroidism Diseases 0.000 description 2
- 230000002989 hypothyroidism Effects 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 229940082629 iron antianemic preparations Drugs 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 108020001756 ligand binding domains Proteins 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- VDXZNPDIRNWWCW-JFTDCZMZSA-N melittin Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(N)=O)CC1=CNC2=CC=CC=C12 VDXZNPDIRNWWCW-JFTDCZMZSA-N 0.000 description 2
- 208000010555 moderate anemia Diseases 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 208000004235 neutropenia Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 230000001323 posttranslational effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000008844 regulatory mechanism Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000010979 ruby Substances 0.000 description 2
- 229910001750 ruby Inorganic materials 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 108700022380 synthetic erythropoiesis Proteins 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 108091005703 transmembrane proteins Proteins 0.000 description 2
- 102000035160 transmembrane proteins Human genes 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 229940078499 tricalcium phosphate Drugs 0.000 description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 210000005253 yeast cell Anatomy 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- SBKVPJHMSUXZTA-MEJXFZFPSA-N (2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CNC=N1 SBKVPJHMSUXZTA-MEJXFZFPSA-N 0.000 description 1
- YYMCVDNIIFNDJK-XFQWXJFMSA-N (z)-1-(3-fluorophenyl)-n-[(z)-(3-fluorophenyl)methylideneamino]methanimine Chemical compound FC1=CC=CC(\C=N/N=C\C=2C=C(F)C=CC=2)=C1 YYMCVDNIIFNDJK-XFQWXJFMSA-N 0.000 description 1
- CDKIEBFIMCSCBB-UHFFFAOYSA-N 1-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one;hydrochloride Chemical compound Cl.C1C=2C=C(OC)C(OC)=CC=2CCN1C(=O)C=CC(C1=CC=CN=C1N1C)=C1C1=CC=CC=C1 CDKIEBFIMCSCBB-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 1
- HRBYEPVOFCWVAZ-UHFFFAOYSA-N 3-(2H-triazol-4-yl)benzene-1,2-diol Chemical compound Oc1cccc(-c2c[nH]nn2)c1O HRBYEPVOFCWVAZ-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- OSJPPGNTCRNQQC-UWTATZPHSA-N 3-phospho-D-glyceric acid Chemical compound OC(=O)[C@H](O)COP(O)(O)=O OSJPPGNTCRNQQC-UWTATZPHSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 108010044267 Abnormal Hemoglobins Proteins 0.000 description 1
- 102000013563 Acid Phosphatase Human genes 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000714235 Avian retrovirus Species 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010010957 Copper deficiency Diseases 0.000 description 1
- 201000006306 Cor pulmonale Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 102100024812 DNA (cytosine-5)-methyltransferase 3A Human genes 0.000 description 1
- 108010024491 DNA Methyltransferase 3A Proteins 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 206010012559 Developmental delay Diseases 0.000 description 1
- 108010010256 Dietary Proteins Proteins 0.000 description 1
- 102000015781 Dietary Proteins Human genes 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 101150050927 Fcgrt gene Proteins 0.000 description 1
- 108010044495 Fetal Hemoglobin Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- 102000011852 GATA2 Transcription Factor Human genes 0.000 description 1
- 108010075641 GATA2 Transcription Factor Proteins 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- KOSRFJWDECSPRO-WDSKDSINSA-N Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(O)=O KOSRFJWDECSPRO-WDSKDSINSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000017278 Glutaredoxin Human genes 0.000 description 1
- 108050005205 Glutaredoxin Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 206010059484 Haemodilution Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 108010068323 Hemoglobin E Proteins 0.000 description 1
- 108091005880 Hemoglobin F Proteins 0.000 description 1
- 208000012925 Hemoglobin H disease Diseases 0.000 description 1
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010066244 Hepatic sequestration Diseases 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000653374 Homo sapiens Methylcytosine dioxygenase TET2 Proteins 0.000 description 1
- 101000609255 Homo sapiens Plasminogen activator inhibitor 1 Proteins 0.000 description 1
- 101000728236 Homo sapiens Polycomb group protein ASXL1 Proteins 0.000 description 1
- 101000587430 Homo sapiens Serine/arginine-rich splicing factor 2 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000658084 Homo sapiens U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 208000006031 Hydrops Fetalis Diseases 0.000 description 1
- 206010020529 Hydrops foetalis Diseases 0.000 description 1
- 229940122439 Hydroxylase inhibitor Drugs 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000018434 Iron-Regulatory Proteins Human genes 0.000 description 1
- 108010066420 Iron-Regulatory Proteins Proteins 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 206010026865 Mass Diseases 0.000 description 1
- 108010038049 Mating Factor Proteins 0.000 description 1
- 206010027439 Metal poisoning Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100030803 Methylcytosine dioxygenase TET2 Human genes 0.000 description 1
- 208000037547 Mitochondrial myopathy and sideroblastic anemia Diseases 0.000 description 1
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 1
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 1
- 101001065556 Mus musculus Lymphocyte antigen 6G Proteins 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 108010056852 Myostatin Proteins 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 102000002001 Non-Receptor Type 6 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 108010015793 Non-Receptor Type 6 Protein Tyrosine Phosphatase Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- 230000004989 O-glycosylation Effects 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 101150012394 PHO5 gene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000035467 Pancreatic insufficiency Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 102100029799 Polycomb group protein ASXL1 Human genes 0.000 description 1
- 241000097929 Porphyria Species 0.000 description 1
- 208000010642 Porphyrias Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 1
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 1
- 229940078467 Prolyl hydroxylase inhibitor Drugs 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108700014121 Pyruvate Kinase Deficiency of Red Cells Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 108060004934 SLC25A38 Proteins 0.000 description 1
- 102000016696 SLC25A38 Human genes 0.000 description 1
- 108091006976 SLC40A1 Proteins 0.000 description 1
- 102100029666 Serine/arginine-rich splicing factor 2 Human genes 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 102000007374 Smad Proteins Human genes 0.000 description 1
- 108010007945 Smad Proteins Proteins 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 102000043168 TGF-beta family Human genes 0.000 description 1
- 108091085018 TGF-beta family Proteins 0.000 description 1
- 206010043390 Thalassaemia alpha Diseases 0.000 description 1
- 206010043391 Thalassaemia beta Diseases 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 102100036407 Thioredoxin Human genes 0.000 description 1
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 description 1
- 101710128901 Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 1
- 102100035036 U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 206010053648 Vascular occlusion Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 208000034698 Vitreous haemorrhage Diseases 0.000 description 1
- 208000037054 X-linked sideroblastic anemia and spinocerebellar ataxia Diseases 0.000 description 1
- 201000006821 X-linked sideroblastic anemia with ataxia Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 206010051895 acute chest syndrome Diseases 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940115115 aranesp Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 208000022806 beta-thalassemia major Diseases 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 239000003462 bioceramic Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000005312 bioglass Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000746 body region Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 231100001018 bone marrow damage Toxicity 0.000 description 1
- 208000015322 bone marrow disease Diseases 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 230000022159 cartilage development Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000002655 chelation therapy Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012539 chromatography resin Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 208000024858 congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940099217 desferal Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 235000021245 dietary protein Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940075117 droxia Drugs 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000009786 epithelial differentiation Effects 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- 210000000267 erythroid cell Anatomy 0.000 description 1
- 201000008220 erythropoietic protoporphyria Diseases 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229940024583 exjade Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229940025452 ferriprox Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000009067 heart development Effects 0.000 description 1
- 108010013846 hematide Proteins 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 108010076770 hemoglobin polymer Proteins 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 208000009601 hereditary spherocytosis Diseases 0.000 description 1
- 108010045676 holotransferrin Proteins 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 201000004108 hypersplenism Diseases 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229960003284 iron Drugs 0.000 description 1
- 230000010438 iron metabolism Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000010983 kinetics study Methods 0.000 description 1
- 208000008127 lead poisoning Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000003039 myelosuppressive effect Effects 0.000 description 1
- 201000010256 myopathy, lactic acidosis, and sideroblastic anemia Diseases 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229940124583 pain medication Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 230000006343 physiological stress response Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 201000011264 priapism Diseases 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000007261 regionalization Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 201000005956 sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay Diseases 0.000 description 1
- 230000022379 skeletal muscle tissue development Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 201000009225 splenic sequestration Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 208000035203 thalassemia minor Diseases 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 108060008226 thioredoxin Proteins 0.000 description 1
- 229940094937 thioredoxin Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1841—Transforming growth factor [TGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/495—Transforming growth factor [TGF]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
EPOを用いた処置は、典型的には、健康なヒトにおいて、数週間にわたるヘモグロビンの約1〜3g/dLの上昇を引き起こす。この処置レジメンを貧血の個体に施すと、多くの場合、ヘモグロビンおよび赤血球レベルの相当な上昇が生じ、生活の質の改善および生存の延長がもたらされる。EPOは一様に有効ではなく、多くの個体が高用量でさえも不応性である(Horlら(2000年)Nephrol Dial Transplant、15巻、43〜50頁)。がんの患者の50%超がEPOに対する不十分な応答を有し、末期腎疾患の患者のおよそ10%が低応答性であり(Glaspyら(1997年)J Clin Oncol、15巻、1218〜1234頁;Demetriら(1998年)J Clin Oncol、16巻、3412〜3425頁)、骨髄異形成症候群の患者で好都合に応答するのは10%未満である(Estey(2003年)Curr Opin Hematol、10巻、60〜67頁)。炎症、鉄およびビタミン欠乏、不十分な透析、アルミニウム毒性、および副甲状腺機能亢進症を含めたいくつかの因子により、不十分な治療応答が予測され得る。EPOに対して抵抗性の分子機構は未だ不明である。最近の証拠により、高用量のEPOは、一部の患者集団において心血管罹患率、腫瘍の成長、および死亡率に関する危険性の上昇に関連し得ることが示唆される(Krapfら、2009年、Clin J Am Soc Nephrol、4巻:470〜480頁;Glaspy、2009年、Annu Rev Med、60巻:181〜192頁)。したがって、EPOベースの治療用化合物(エリスロポエチン刺激剤、ESA)は、赤血球輸血の必要性を回避するのに十分な最低用量で投与することが推奨されている(Jelkmannら、2008年、Crit Rev Oncol. Hematol、67巻:39〜61頁)。
本発明は、例えば、以下の項目を提供する。
(項目1)
患者において、赤血球レベルを高めるため、ヘモグロビンレベルを高めるため、および/または網状赤血球レベルを高めるための方法であって、それを必要とする患者に、有効量のGDF15ポリペプチドを投与することを含む方法。
(項目2)
患者において貧血を処置または予防する方法であって、それを必要とする患者に、有効量のGDF15ポリペプチドを投与することを含む方法。
(項目3)
患者において無効赤血球生成を処置または予防する方法であって、それを必要とする患者に、有効量のGDF15ポリペプチドを投与することを含む方法。
(項目4)
前記患者が、異常ヘモグロビン症を有する、項目3に記載の方法。
(項目5)
前記患者が、鎌状赤血球症を有する、項目4に記載の方法。
(項目6)
前記患者が、サラセミア症候群を有する、項目4に記載の方法。
(項目7)
前記患者が、βサラセミアを有する、項目6に記載の方法。
(項目8)
患者において骨髄異形成症候群を処置する方法であって、それを必要とする患者に、有効量のGDF15ポリペプチドを投与することを含む方法。
(項目9)
前記GDF15ポリペプチドが、
a)配列番号1のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
b)配列番号2のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
c)配列番号3のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
d)配列番号4のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
e)配列番号5のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
f)配列番号6のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
g)配列番号7のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
h)配列番号8のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
i)配列番号9のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
j)配列番号10のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
k)配列番号11のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
l)配列番号12のアミノ酸配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、および
m)配列番号1のアミノ酸30〜196の配列と、少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド
からなる群から選択されるアミノ酸配列を含む、項目1から8のいずれか一項に記載の方法。
(項目10)
前記GDF15ポリペプチドが、配列番号13のヌクレオチド589〜924の配列と相補的な核酸とストリンジェントなハイブリダイゼーション条件下でハイブリダイズする核酸によりコードされるアミノ酸配列を含む、項目1から8のいずれか一項に記載の方法。
(項目11)
前記GDF15ポリペプチドが、医薬調製物で投与される、項目1から10のいずれか一項に記載の方法。
(項目12)
前記医薬調製物が、GDF15プロドメインポリペプチドを含む、項目11に記載の方法。
(項目13)
前記GDF15プロドメインポリペプチドが、配列番号1のアミノ酸30〜196の配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、項目12に記載の方法。
(項目14)
前記医薬調製物が、前記GDF15プロドメインポリペプチドと非共有結合により会合したGDF15ポリペプチドを含む、項目12または13に記載の方法。
(項目15)
前記患者が、慢性腎疾患と関連する貧血を有する、項目1、2、および8から14のいずれか一項に記載の方法。
(項目16)
前記患者が、化学療法処置と関連する貧血を有する、項目1、2、および8から14のいずれか一項に記載の方法。
(項目17)
前記化学療法処置が、タキサンである、項目16に記載の方法。
(項目18)
前記患者が、がんと関連する貧血を有する、項目1、2、および8から14のいずれか一項に記載の方法。
(項目19)
前記患者が、失血の結果として貧血を有する、項目1、2、および8から14のいずれか一項に記載の方法。
(項目20)
前記患者が、炎症による貧血を有する、項目1、2、および8から14のいずれか一項に記載の方法。
(項目21)
配列番号4、5、6、7、8、または9のいずれか1つの配列を含む、またはそれからなる、アミノ酸配列を含むポリペプチド。
(項目22)
項目21に記載のポリペプチドを含む医薬調製物。
(項目23)
患者において、赤血球レベルを高めるため、ヘマトクリットレベルを高めるため、および/もしくは網状赤血球レベルを高めるため、ならびに/または、貧血、無効赤血球生成、もしくは骨髄異形成症候群を処置するための方法であって、それを必要とする患者に、
(i)エリスロポエチン受容体活性化因子、および
(ii)GDF15ポリペプチド
を投与することを含む方法。
(項目24)
前記GDF15ポリペプチドが、
a)配列番号1のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
b)配列番号2のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
c)配列番号3のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
d)配列番号4のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
e)配列番号5のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
f)配列番号6のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
g)配列番号7のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
h)配列番号8のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
i)配列番号9のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
j)配列番号10のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
l)配列番号11のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
k)配列番号12のアミノ酸配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、
l)配列番号1のアミノ酸30〜196の配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、それから本質的になる、またはそれからなるポリペプチド、および
m)配列番号13のヌクレオチド589〜924の配列と相補的な核酸とストリンジェントなハイブリダイゼーション条件下でハイブリダイズする核酸によりコードされるアミノ酸配列を含むポリペプチド
からなる群から選択され、
前記エリスロポエチン受容体活性化因子および該ポリペプチドが、有効量で投与される、
項目23に記載の方法。
(項目25)
エリスロポエチン受容体活性化因子の投与される量が、それだけでは赤血球レベルを高めるのに有効でない、項目23または24に記載の方法。
(項目26)
ポリペプチドの投与される量が、それだけでは前記患者において赤血球レベルを高めるのに有効ではないが、併用処置では有効である、項目23または24に記載の方法。
(項目27)
前記エリスロポエチン受容体活性化因子が、赤血球生成刺激因子である、項目23から26に記載の方法。
(項目28)
前記赤血球生成刺激因子が、
a.エポエチンアルファ
b.エポエチンベータ(NeoRecormon(商標))
c.エポエチンデルタ(Dynepo(商標))
d.エポエチンオメガ
e.ダルベポエチンアルファ(Aranesp(商標))
f.メトキシポリエチレングリコールエポエチンベータ(Micera(商標))
g.合成赤血球生成タンパク質(SEP)
からなる群から選択されるEPOベースの誘導体である、項目27に記載の方法。
(項目29)
前記エリスロポエチン受容体活性化因子が、エリスロポエチン受容体のアゴニストである、項目23から26のいずれか一項に記載の方法。
(項目30)
前記エリスロポエチン受容体のアゴニストが、
a.エリスロポエチン模倣ペプチド
b.持続時間延長型エリスロポエチン受容体制限アゴニスト
c.エリスロポエチン模倣ドメインとFcドメインとを含む融合タンパク質
d.エリスロポエチン受容体を標的とするアゴニスト抗体
e.多量体エリスロポエチン模倣ペプチド
からなる群から選択される化合物である、項目29に記載の方法。
(項目31)
前記エリスロポエチン受容体活性化因子が、赤血球生成に対するその効果が、内因性エリスロポエチンのレベルの上昇によって媒介される間接因子である、項目23から26のいずれか一項に記載の方法。
(項目32)
前記間接因子が、低酸素症誘導性転写因子アルファを安定化することによって内因性エリスロポエチン遺伝子発現を増大させる、項目31に記載の方法。
(項目33)
前記間接因子が、プロリルヒドロキシラーゼ阻害剤である、項目31に記載の方法。
(項目34)
前記患者が、腎臓障害と関連する貧血を有する、項目23から33のいずれか一項に記載の方法。
(項目35)
前記患者が、慢性腎疾患と関連する貧血を有する、項目34に記載の方法。
(項目36)
前記患者が、化学療法処置と関連する貧血を有する、項目23から33のいずれか一項に記載の方法。
(項目37)
前記化学療法処置が、タキサンである、項目36に記載の方法。
(項目38)
前記患者が、がんと関連する貧血を有する、項目23から33のいずれか一項に記載の方法。
(項目39)
前記患者が、失血の結果として貧血を有する、項目23から33のいずれか一項に記載の方法。
(項目40)
前記GDF15ポリペプチドが、医薬調製物で投与される、項目23から39のいずれか一項に記載の方法。
(項目41)
前記医薬調製物が、GDF15プロドメインポリペプチドを含む、項目40に記載の方法。
(項目42)
前記GDF15プロドメインポリペプチドが、配列番号1のアミノ酸30〜196の配列と少なくとも68%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、項目41に記載の方法。
(項目43)
前記医薬調製物が、前記GDF15プロドメインポリペプチドと非共有結合により会合したGDF15ポリペプチドを含む、項目41または42のいずれか一項に記載の方法。
(項目44)
赤血球レベルを高めること、ヘマトクリットレベルを高めること、および/もしくは網状赤血球レベルを高めること、ならびに/または貧血、無効赤血球生成、もしくは骨髄異形成症候群を処置することを必要とする患者において、赤血球レベルを高めること、ヘマトクリットレベルを高めること、および/もしくは網状赤血球レベルを高めること、ならびに/または貧血、無効赤血球生成、もしくは骨髄異形成症候群を処置することにおける使用のためのエリスロポエチン受容体活性化因子およびGDF15ポリペプチドを有効量で投与することを含む、
エリスロポエチン受容体活性化因子、および
GDF15ポリペプチド。
(項目45)
赤血球レベルを高めること、ヘマトクリットレベルを高めること、および/もしくは網状赤血球レベルを高めること、ならびに/または貧血、無効赤血球生成、もしくは骨髄異形成症候群を処置することを必要とする患者において、赤血球レベルを高めること、ヘマトクリットレベルを高めること、および/もしくは網状赤血球レベルを高めること、ならびに/または貧血、無効赤血球生成、もしくは骨髄異形成症候群を処置することにおける使用のためのエリスロポエチン受容体活性化因子およびGDF15ポリペプチドを有効量で投与することを含む、
GDF15ポリペプチド、および
エリスロポエチン受容体活性化因子。
EPOとは、赤血球系前駆細胞のエリスロサイトへの増殖および成熟に関与する糖タンパク質ホルモンである。EPOは、胎児期には肝臓により生成され、成人期には腎臓により生成される。成人期において、腎不全の帰結として一般的に生じるEPOの生成の減少は、貧血をもたらす。EPOは、遺伝子操作法により、EPO遺伝子をトランスフェクトされた宿主細胞からの、タンパク質の発現および分泌に基づき生成されている。このような組換えEPOの投与は、貧血の処置において有効となっている。例えば、Eschbachら(1987年、N Engl J Med、316巻:73頁)は、慢性腎不全により引き起こされる貧血を是正するためのEPOの使用について記載している。
2.GDF15ポリペプチドおよび核酸
GDF15ポリペプチドの例としては、以下が挙げられる:
3.例示的な治療的使用
4.医薬調製物
(実施例1)
生物活性のあるGDF15ポリペプチドの生成
CHO細胞におけるGDF15の安定発現
ヒトGDF15の精製
マウスGDF15の精製
配列確認および生物活性
(実施例2)
野生型マウスにおける組換えGDF15投与の赤血球指標に対する効果
(実施例3)
GDF15による処置は、エクスビボにおける赤血球系前駆体からの赤血球の形成を急速に促進する
(実施例4)
ストレスによる赤血球生成のマウスモデルにおけるGDF15とEPOの相乗効果
(実施例5)
内在性GDF15は、マウスにおける失血による貧血からの回復に関与した
参照による組み込み
主題の特定の実施形態が考察されているが、上記の明細書は例示的なものであり、限定的なものではない。本明細書および以下の特許請求の範囲を精査すれば、多くの変形が当業者には明らかになると予想される。本発明の全範囲は、特許請求の範囲を均等物の全範囲と共に、明細書をそのような変形と共に参照することによって決定されるものとする。
Claims (12)
- 患者におけるストレスによる赤血球生成に関連した貧血の処置における使用のための組成物であって、有効量のGDF15ポリペプチドを含む組成物。
- 前記GDF15ポリペプチドが、
a)配列番号1のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
b)配列番号2のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
c)配列番号3のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
d)配列番号4のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
e)配列番号5のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
f)配列番号6のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
g)配列番号7のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
h)配列番号8のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
i)配列番号9のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
j)配列番号10のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
k)配列番号11のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、
l)配列番号12のアミノ酸配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド、および
m)配列番号1のアミノ酸30〜196の配列と、少なくとも85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含むポリペプチド
からなる群から選択されるアミノ酸配列を含む、請求項1に記載の使用のための組成物。 - 前記GDF15ポリペプチドが、配列番号13のヌクレオチド589〜924の配列と相補的な核酸とストリンジェントなハイブリダイゼーション条件下でハイブリダイズする核酸によりコードされるアミノ酸配列を含む、請求項1または2に記載の使用のための組成物。
- 前記GDF15ポリペプチドが、医薬調製物で投与される、請求項1から3のいずれか一項に記載の使用のための組成物。
- 前記医薬調製物が、GDF15プロドメインポリペプチドを含む、請求項4に記載の使用のための組成物。
- 前記GDF15プロドメインポリペプチドが、配列番号1のアミノ酸30〜196の配列と少なくとも80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む、請求項5に記載の使用のための組成物。
- 前記医薬調製物が、前記GDF15プロドメインポリペプチドと非共有結合により会合したGDF15ポリペプチドを含む、請求項5または6に記載の使用のための組成物。
- 前記GDF15ポリペプチドが、エリスロポエチン受容体活性化因子と組み合わせて投与され、前記エリスロポエチン受容体活性化因子が、エポエチンアルファ、エポエチンベータ、エポエチンデルタ、エポエチンオメガ、ダルベポエチンアルファおよびメトキシポリエチレングリコールエポエチンベータからなる群より選択される、請求項1から7のいずれか一項に記載の使用のための組成物。
- 前記ストレスによる赤血球生成が急性失血によって引き起こされる、請求項1から8のいずれか一項に記載の使用のための組成物。
- 前記ストレスによる赤血球生成が出血によって引き起こされる、請求項1から8のいずれか一項に記載の使用のための組成物。
- 前記ストレスによる赤血球生成が分娩後の出血によって引き起こされる、請求項1から8のいずれか一項に記載の使用のための組成物。
- 前記ストレスによる赤血球生成が外傷によって引き起こされる、請求項1から8のいずれか一項に記載の使用のための組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462072889P | 2014-10-30 | 2014-10-30 | |
US62/072,889 | 2014-10-30 | ||
PCT/US2015/058116 WO2016069925A1 (en) | 2014-10-30 | 2015-10-29 | Methods and compositions using gdf15 polypeptides for increasing red blood cells |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020023090A Division JP7154241B2 (ja) | 2014-10-30 | 2020-02-14 | Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017533910A JP2017533910A (ja) | 2017-11-16 |
JP2017533910A5 JP2017533910A5 (ja) | 2018-12-06 |
JP6663428B2 true JP6663428B2 (ja) | 2020-03-11 |
Family
ID=55858354
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017522852A Active JP6663428B2 (ja) | 2014-10-30 | 2015-10-29 | Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 |
JP2020023090A Active JP7154241B2 (ja) | 2014-10-30 | 2020-02-14 | Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020023090A Active JP7154241B2 (ja) | 2014-10-30 | 2020-02-14 | Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 |
Country Status (6)
Country | Link |
---|---|
US (2) | US10603359B2 (ja) |
EP (2) | EP3922259A1 (ja) |
JP (2) | JP6663428B2 (ja) |
AU (2) | AU2015339134B2 (ja) |
CA (1) | CA2964808C (ja) |
WO (1) | WO2016069925A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10588980B2 (en) | 2014-06-23 | 2020-03-17 | Novartis Ag | Fatty acids and their use in conjugation to biomolecules |
WO2016069925A1 (en) * | 2014-10-30 | 2016-05-06 | Acceleron Pharma Inc. | Methods and compositions using gdf15 polypeptides for increasing red blood cells |
WO2017079591A2 (en) | 2015-11-04 | 2017-05-11 | Acceleron Pharma Inc. | Methods for increasing red blood cell levels and treating ineffective erythropoiesis |
US10336812B2 (en) * | 2016-05-10 | 2019-07-02 | Janssen Biotech, Inc. | GDF15 fusion proteins and uses thereof |
TW201741333A (zh) | 2016-05-24 | 2017-12-01 | 諾佛 儂迪克股份有限公司 | Mic-1化合物及其用途 |
TWI724392B (zh) | 2018-04-06 | 2021-04-11 | 美商美國禮來大藥廠 | 生長分化因子15促效劑化合物及其使用方法 |
US20230002460A1 (en) * | 2019-11-26 | 2023-01-05 | Yuhan Corporation | Long-acting gdf15 fusion protein and pharmaceutical composition comprising same |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987005330A1 (en) | 1986-03-07 | 1987-09-11 | Michel Louis Eugene Bergh | Method for enhancing glycoprotein stability |
US4965251A (en) | 1987-04-03 | 1990-10-23 | The Board Of Regents Of The University Of Washington | Pulse treatment of hemoglobinopathies with erythropoietin |
WO1990008822A1 (en) | 1989-02-03 | 1990-08-09 | Genetics Institute, Inc. | Erythropoietin receptor |
US5885574A (en) | 1994-07-26 | 1999-03-23 | Amgen Inc. | Antibodies which activate an erythropoietin receptor |
US5541087A (en) | 1994-09-14 | 1996-07-30 | Fuji Immunopharmaceuticals Corporation | Expression and export technology of proteins as immunofusins |
CA2340465A1 (en) * | 1998-08-21 | 2000-03-02 | Princeton University | Genes that regulate hematopoietic blood forming stem cells and uses thereof |
EP2124999B1 (en) | 2006-12-18 | 2012-10-03 | Acceleron Pharma, Inc. | Activin-actrii antagonists and uses for treating anemia |
SI3494986T1 (sl) | 2008-08-14 | 2020-10-30 | Acceleron Pharma Inc. | GDF pasti |
US8216997B2 (en) * | 2008-08-14 | 2012-07-10 | Acceleron Pharma, Inc. | Methods for increasing red blood cell levels and treating anemia using a combination of GDF traps and erythropoietin receptor activators |
ES2434996T3 (es) * | 2008-10-31 | 2013-12-18 | St Vincent's Hospital Sydney Limited | Métodos de pronóstico en enfermedad renal crónica |
KR20180085825A (ko) * | 2009-08-13 | 2018-07-27 | 악셀레론 파마 인코포레이티드 | 적혈구 수준을 증가시키기 위한 gdf 트랩과 에리트로포이에틴 수용체 활성인자의 병용 |
CA2831284C (en) * | 2011-03-29 | 2023-12-12 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of tmprss6 gene |
US20140315752A1 (en) * | 2011-11-22 | 2014-10-23 | Astute Medical, Inc. | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
MX357708B (es) * | 2011-12-14 | 2018-07-20 | Abbvie Deutschland | Composicion y metodo para el diagnostico y tratamiento de trastornos relacionados con hierro. |
EA201491413A1 (ru) | 2012-01-26 | 2015-03-31 | Эмджен Инк. | Полипептиды фактора роста и дифференцировки 15 (gdf-15) |
EP2644278B1 (en) | 2012-03-27 | 2014-12-10 | Alfa Laval Corporate AB | Centrifugal separator and method of controlling intermittent discharge |
JP6758832B2 (ja) | 2012-12-21 | 2020-09-30 | アベオ ファーマシューティカルズ, インコーポレイテッド | 抗gdf15抗体 |
BR112015018104A2 (pt) * | 2013-01-30 | 2017-11-21 | Ngm Biopharmaceuticals Inc | polipeptídeos de gdf15 modificados, seu uso, composições compreendendo os mesmos e recipiente estéril compreendendo as referidas composições |
US9161966B2 (en) * | 2013-01-30 | 2015-10-20 | Ngm Biopharmaceuticals, Inc. | GDF15 mutein polypeptides |
WO2014182676A2 (en) * | 2013-05-06 | 2014-11-13 | Scholar Rock, Inc. | Compositions and methods for growth factor modulation |
EP3036262A4 (en) | 2013-08-22 | 2017-03-01 | Acceleron Pharma Inc. | Tgf-beta receptor type ii variants and uses thereof |
KR20160127148A (ko) * | 2014-03-21 | 2016-11-02 | 악셀레론 파마 인코포레이티드 | 액티빈 b 및/또는 gdf11을 억제함으로써 적혈 혈액 세포 수준을 증가시키고 비효율적인 적혈구 생성을 치료하는 방법 |
JP6768527B2 (ja) * | 2014-06-20 | 2020-10-14 | アベオ ファーマシューティカルズ, インコーポレイテッド | Gdf15調節剤を用いた慢性腎臓病及びその他の腎機能不全の治療 |
WO2016069925A1 (en) * | 2014-10-30 | 2016-05-06 | Acceleron Pharma Inc. | Methods and compositions using gdf15 polypeptides for increasing red blood cells |
TWI621976B (zh) | 2015-07-24 | 2018-04-21 | 瑞鼎科技股份有限公司 | 內嵌式觸控面板驅動方法 |
US20170299608A1 (en) * | 2016-03-04 | 2017-10-19 | Ngm Biopharmaceuticals, Inc. | Compositions and methods for modulating body weight |
-
2015
- 2015-10-29 WO PCT/US2015/058116 patent/WO2016069925A1/en active Application Filing
- 2015-10-29 US US15/523,025 patent/US10603359B2/en active Active
- 2015-10-29 EP EP21170026.5A patent/EP3922259A1/en active Pending
- 2015-10-29 CA CA2964808A patent/CA2964808C/en active Active
- 2015-10-29 EP EP15854065.8A patent/EP3212213B1/en active Active
- 2015-10-29 AU AU2015339134A patent/AU2015339134B2/en not_active Ceased
- 2015-10-29 JP JP2017522852A patent/JP6663428B2/ja active Active
-
2020
- 2020-02-14 JP JP2020023090A patent/JP7154241B2/ja active Active
- 2020-02-28 US US16/804,459 patent/US11642394B2/en active Active
-
2021
- 2021-09-14 AU AU2021232680A patent/AU2021232680A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
JP7154241B2 (ja) | 2022-10-17 |
US20180207236A1 (en) | 2018-07-26 |
EP3212213A1 (en) | 2017-09-06 |
JP2020073603A (ja) | 2020-05-14 |
CA2964808A1 (en) | 2016-05-06 |
EP3922259A1 (en) | 2021-12-15 |
EP3212213A4 (en) | 2018-05-30 |
US11642394B2 (en) | 2023-05-09 |
AU2015339134A1 (en) | 2017-04-27 |
US10603359B2 (en) | 2020-03-31 |
AU2021232680A1 (en) | 2021-10-07 |
JP2017533910A (ja) | 2017-11-16 |
EP3212213B1 (en) | 2021-04-28 |
AU2015339134B2 (en) | 2021-06-17 |
WO2016069925A1 (en) | 2016-05-06 |
CA2964808C (en) | 2023-06-27 |
US20200397863A1 (en) | 2020-12-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6796626B2 (ja) | 無効赤血球生成を処置するための方法および組成物 | |
JP7154241B2 (ja) | Gdf15ポリペプチドを使用する、赤血球を増加させるための方法および組成物 | |
JP6968917B2 (ja) | 赤血球レベルを高めるためのgdfトラップの使用 | |
JP6860533B2 (ja) | 赤血球レベルを増大させるための、gdfトラップとエリスロポエチン受容体活性化因子とを組み合わせた使用 | |
JP6643432B2 (ja) | アクチビン−ActRIIaのアンタゴニストおよび赤血球レベルを高めるためのその使用 | |
US11807673B2 (en) | Methods and compositions for increasing red blood cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181026 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20181026 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190731 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191031 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20191224 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200123 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200214 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6663428 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: R3D02 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: R3D04 |