JP2007535306A - 線維芽細胞成長因子21の突然変異タンパク質 - Google Patents
線維芽細胞成長因子21の突然変異タンパク質 Download PDFInfo
- Publication number
- JP2007535306A JP2007535306A JP2006543822A JP2006543822A JP2007535306A JP 2007535306 A JP2007535306 A JP 2007535306A JP 2006543822 A JP2006543822 A JP 2006543822A JP 2006543822 A JP2006543822 A JP 2006543822A JP 2007535306 A JP2007535306 A JP 2007535306A
- Authority
- JP
- Japan
- Prior art keywords
- mutein
- leucine
- fgf
- glycine
- alanine
- 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.)
- Granted
Links
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 title claims description 95
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 title claims description 95
- 210000004027 cell Anatomy 0.000 claims abstract description 45
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 30
- 208000008589 Obesity Diseases 0.000 claims abstract description 20
- 235000020824 obesity Nutrition 0.000 claims abstract description 20
- 101000846529 Homo sapiens Fibroblast growth factor 21 Proteins 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 17
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 102000056713 human FGF21 Human genes 0.000 claims abstract description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 74
- 235000001014 amino acid Nutrition 0.000 claims description 54
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 53
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 52
- 229940024606 amino acid Drugs 0.000 claims description 48
- 150000001413 amino acids Chemical class 0.000 claims description 48
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 38
- 239000004471 Glycine Substances 0.000 claims description 37
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 36
- 235000004279 alanine Nutrition 0.000 claims description 36
- 239000004475 Arginine Substances 0.000 claims description 33
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 29
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 29
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 28
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 27
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 27
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 26
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 26
- 108091033319 polynucleotide Proteins 0.000 claims description 24
- 102000040430 polynucleotide Human genes 0.000 claims description 24
- 239000002157 polynucleotide Substances 0.000 claims description 24
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 22
- 235000003704 aspartic acid Nutrition 0.000 claims description 22
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 22
- 229920001184 polypeptide Polymers 0.000 claims description 21
- 238000006467 substitution reaction Methods 0.000 claims description 18
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 16
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 16
- 239000013604 expression vector Substances 0.000 claims description 14
- 201000001421 hyperglycemia Diseases 0.000 claims description 14
- 208000024891 symptom Diseases 0.000 claims description 14
- 102000004877 Insulin Human genes 0.000 claims description 13
- 108090001061 Insulin Proteins 0.000 claims description 13
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 13
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 13
- 239000004472 Lysine Substances 0.000 claims description 13
- 235000018417 cysteine Nutrition 0.000 claims description 13
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 13
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 13
- 229940125396 insulin Drugs 0.000 claims description 13
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 13
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 11
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 11
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 11
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 11
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 11
- 201000008980 hyperinsulinism Diseases 0.000 claims description 11
- 206010022489 Insulin Resistance Diseases 0.000 claims description 10
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 10
- 235000013922 glutamic acid Nutrition 0.000 claims description 9
- 239000004220 glutamic acid Substances 0.000 claims description 9
- 229960000310 isoleucine Drugs 0.000 claims description 9
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 9
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 8
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 8
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000004474 valine Substances 0.000 claims description 8
- 102000008300 Mutant Proteins Human genes 0.000 claims description 7
- 108010021466 Mutant Proteins Proteins 0.000 claims description 7
- 102220470039 Sodium channel and clathrin linker 1_S163E_mutation Human genes 0.000 claims description 7
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 6
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 6
- 239000004473 Threonine Substances 0.000 claims description 6
- 235000009582 asparagine Nutrition 0.000 claims description 6
- 229960001230 asparagine Drugs 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 102220546571 Coiled-coil domain-containing protein 27_Q54E_mutation Human genes 0.000 claims description 3
- 102220543785 Leucine-rich repeat-containing protein 2_A145E_mutation Human genes 0.000 claims description 3
- 102220584872 Protein PEAK3_L146E_mutation Human genes 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 102220275855 rs764016359 Human genes 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- 230000004060 metabolic process Effects 0.000 claims description 2
- 210000005253 yeast cell Anatomy 0.000 claims 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 35
- 102000004169 proteins and genes Human genes 0.000 abstract description 32
- 239000013598 vector Substances 0.000 abstract description 11
- 150000007523 nucleic acids Chemical class 0.000 abstract description 6
- 102000039446 nucleic acids Human genes 0.000 abstract description 3
- 108020004707 nucleic acids Proteins 0.000 abstract description 3
- 241000894007 species Species 0.000 abstract description 2
- 235000018102 proteins Nutrition 0.000 description 28
- 238000009472 formulation Methods 0.000 description 18
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 13
- 239000008103 glucose Substances 0.000 description 13
- 239000003755 preservative agent Substances 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 10
- 241000588724 Escherichia coli Species 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 9
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 9
- 206010040047 Sepsis Diseases 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 8
- 230000002335 preservative effect Effects 0.000 description 8
- 108091026890 Coding region Proteins 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 238000004220 aggregation Methods 0.000 description 7
- 125000003275 alpha amino acid group Chemical group 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 206010013975 Dyspnoeas Diseases 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 210000001789 adipocyte Anatomy 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 230000004190 glucose uptake Effects 0.000 description 6
- 230000002685 pulmonary effect Effects 0.000 description 6
- 208000000059 Dyspnea Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 108020004705 Codon Proteins 0.000 description 4
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 4
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 4
- 241000235058 Komagataella pastoris Species 0.000 description 4
- 208000004852 Lung Injury Diseases 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 206010069363 Traumatic lung injury Diseases 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 208000018875 hypoxemia Diseases 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 229930027917 kanamycin Natural products 0.000 description 4
- 229960000318 kanamycin Drugs 0.000 description 4
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 4
- 229930182823 kanamycin A Natural products 0.000 description 4
- 231100000515 lung injury Toxicity 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 208000013016 Hypoglycemia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 3
- 230000008383 multiple organ dysfunction Effects 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000012460 protein solution Substances 0.000 description 3
- 208000002815 pulmonary hypertension Diseases 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 108091008146 restriction endonucleases Proteins 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- MYGCFWRBKKQKCG-GBWOLBBFSA-N (z,2r,3s,4r)-hex-5-ene-1,2,3,4,6-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)\C=C/O MYGCFWRBKKQKCG-GBWOLBBFSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 101150094690 GAL1 gene Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 208000019693 Lung disease Diseases 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- 239000012614 Q-Sepharose Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008020 pharmaceutical preservative Substances 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 239000013615 primer Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 201000004193 respiratory failure Diseases 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000000153 supplemental effect Effects 0.000 description 2
- 238000004114 suspension culture Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- MSBLMBWXUVQCDY-UHFFFAOYSA-N 1-(4,4-dimethyl-1-piperazin-4-iumyl)ethanone Chemical compound CC(=O)N1CC[N+](C)(C)CC1 MSBLMBWXUVQCDY-UHFFFAOYSA-N 0.000 description 1
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 108010025188 Alcohol oxidase Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 102100036826 Aldehyde oxidase Human genes 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 206010003598 Atelectasis Diseases 0.000 description 1
- 108010016529 Bacillus amyloliquefaciens ribonuclease Proteins 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000003870 Drug Overdose Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 101000925646 Enterobacteria phage T4 Endolysin Proteins 0.000 description 1
- 241000701867 Enterobacteria phage T7 Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 208000003241 Fat Embolism Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 1
- 108090000569 Fibroblast Growth Factor-23 Proteins 0.000 description 1
- 102100024802 Fibroblast growth factor 23 Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100028501 Galanin peptides Human genes 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000928314 Homo sapiens Aldehyde oxidase Proteins 0.000 description 1
- 101100121078 Homo sapiens GAL gene Proteins 0.000 description 1
- 101000988793 Homo sapiens Host cell factor C1 regulator 1 Proteins 0.000 description 1
- 101000613207 Homo sapiens Pre-B-cell leukemia transcription factor-interacting protein 1 Proteins 0.000 description 1
- 102100029105 Host cell factor C1 regulator 1 Human genes 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-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
- 108010054278 Lac Repressors Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 208000004221 Multiple Trauma Diseases 0.000 description 1
- 101001051974 Mus musculus Fibroblast growth factor 21 Proteins 0.000 description 1
- 241001460678 Napo <wasp> Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 241001452677 Ogataea methanolica Species 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033296 Overdoses Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 208000007123 Pulmonary Atelectasis Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 108020005067 RNA Splice Sites Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010039163 Right ventricular failure Diseases 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000222481 Schizophyllum commune Species 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 241000499912 Trichoderma reesei Species 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
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 206010001053 acute respiratory failure Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 238000003236 bicinchoninic acid assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000013378 biophysical characterization Methods 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000004665 defense response Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 231100000725 drug overdose Toxicity 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000013156 embolectomy Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 101150073818 gap gene Proteins 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000009215 host defense mechanism Effects 0.000 description 1
- 230000002157 hypercatabolic effect Effects 0.000 description 1
- 208000000122 hyperventilation Diseases 0.000 description 1
- 230000000870 hyperventilation Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 101150109249 lacI gene Proteins 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000005980 lung dysfunction Effects 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000000059 patterning Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000013492 plasmid preparation Methods 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 208000008203 tachypnea Diseases 0.000 description 1
- 206010043089 tachypnoea Diseases 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 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 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 1
Classifications
-
- 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
- C07K14/50—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Obesity (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Child & Adolescent Psychology (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Physics & Mathematics (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
Abstract
Description
大腸菌におけるFGF−21突然変異タンパク質の発現および精製
本実施例における細菌発現のためには、細菌発現ベクターpET30aが使用される(Novagen,Inc.,Madison、Wisconsin)。pET30aは、カナマイシン抗生物質耐性遺伝子をコードし、多くの独特の制限エンドヌクレアーゼ切断部位と共に、細菌複製開始点(「ori」)、強力なT7ファージ−IPTG誘導性プロモーター、リボソーム結合部位(「RBS」)、および適切なMCSを含む。精製目的のために都合よくは、ベクターは、N末端のペプチド融合のためのHisおよびSタグ、並びにC末端のHisタグ融合をコードすることができる。しかし、本発明の目的を達成するためには、FGF−21変異体をコードするcDNAが、それぞれ制限部位NdeIとBamHIとの間に挿入されており、生じる構築物は、記載したタグのいずれも利用しない。
HEK293EBNA細胞におけるFGF−21突然変異タンパク質の発現および精製
あるいは、FGF−21突然変異タンパク質は、HEK293EBNA細胞(EdgeBiosystems,Gaiethersburg,MD)などの、哺乳類細胞発現系において産生することができる。FGF−21突然変異タンパク質は、市販のpEAK10の制限部位の修飾を示す専売の発現ベクターに、MCS内のNheIとXbaIとの間にサブクローニングする。組織培地における所望の産物の分泌を増強するために、成熟FGF−21をコードするcDNA配列をIgκリーダー配列とフレームに融合させる。発現は、強力なウイルスCMVプロモーターによって駆動される。HEK293EBNA細胞には、Fugene(Roche Diagnostics,Indianapolis,IN)などの標準的なトランスフェクション試薬および組換えプラスミドの適切な量を使用して、単層または懸濁培養としてのいずれかとして、十分な細胞密度にて一過性にトランスフェクトする。細胞を無血清培地において、37℃および5%のCO2にてインキュベートし、5日間毎日、収集を行う。典型的には、HEK239EBNA懸濁培養中の発現レベルは、〜30mg/Lである。哺乳動物細胞におけるヒトFGF−21の発現により、HPIPの天然のN末端配列、すなわちN末端のメチオニン残基なしを得る。DPP−IV(ブタの腎臓、SIGMA St Louis)での、HEK239EBNA細胞からのFGF−21の酵素処置により、4アミノ酸までのN末端の切断を生じることが発見された。マウス3T3−L1脂肪細胞アッセイ法(実施例4を参照されたい)においてアッセイしたときに、この切断されたFGF−21の変異体は、野生型FGF−21のものに相当するレベルでグルコース摂取を刺激する(表1)。
酵母におけるFGF−21突然変異タンパク質の発現および精製
FGF−21突然変異タンパク質の産生のためのさらにもう一つの発現系は、ピチア・パストリス、ピチア・メタノリカ(Pichia methanolica)、またはサッカロマイセス・セレビジエなどの酵母である。ピチア・パストリスにおける産生のためには、市販の系(Invitrogen,Carlsbad,CA)により、組換えタンパク質の高レベル発現を駆動するための強力なAOX1(アルコールオキシダーゼ)プロモーターをもつベクターを使用する。あるいは、GAP遺伝子(グリセルアルデヒド−3−リン酸デヒドロゲナーゼ)由来プロモーターを使用するベクターも、高レベルの構成的発現のために利用できる。多コピーのピチア発現ベクターにより、ゲノムに組み込まれた関心対象の遺伝子の複数のコピーをもつ株を得ることができる。組換えピチア株における関心対象の遺伝子のコピーの数を増大することにより、タンパク質発現レベルを増大することができる。さらにもう一つの酵母発現系は、サッカロマイセス・セレビジエ(Saccharomyces cerevisiae)である。発現ベクターは、GAL1遺伝子由来のプロモーターおよびエンハンサー配列を含む。GAL1プロモーターは、ガラクトースで誘導する際のその強力な転写活性のため、最も広く使用されている酵母プロモーターのうちの1つである。
マウス3T3−L1脂肪細胞におけるグルコース摂取
3T3−L1細胞は、アメリカンタイプカルチャーコレクション(ATCC、Rockville、MD)から入手される。細胞をダルベッコ修飾イーグル培地中に10%の鉄を補充したウシ胎児血清を含む増殖培地(GM)中で培養する。標準的な脂肪細胞分化については、細胞が周密状態に達した2日後に(0日という)、細胞を10%のウシ胎児血清、10μg/mlインスリン、1μMデキサメサゾン、および0.5μMイソブチルメチルキサンチンを含む分化培地(DM)に48時間曝露する。次いで、細胞を10%のウシ胎児血清、および10μg/mlインスリンを含む分化後培地中で維持する。
Ob/obマウスモデル
媒体およびインスリン対照群と比較して、FGF−21で処置後の血漿グルコースレベルおよびトリグリセリドレベルを監視するために、雄ob/obマウスを使用する肥満症モデルにおける研究を行った。雄ob/obマウス(7週間目)の試験群には、媒体(0.9%のNaCl)単独、またはFGF−21突然変異タンパク質(0.125mg/kg)(0.1mL、毎日一回)を皮下に7日間注射した。7日目の最後の化合物注射の1時間後に、血液を尾部クリップ出血によって収集し、標準的プロトコルを使用して血漿グルコースレベルを測定した。媒体対照と比較して、FGF−21突然変異タンパク質が、より血漿グルコースレベルを低下する能力を表2に示してある。表2のデータは、本発明の突然変異タンパク質が、媒体対照と比較して血漿グルコースレベルを低下させたことを示す。媒体対照と比較して、FGF−21突然変異タンパク質が、トリグリセリドレベルを低下にする能力は、表3に示してある。
FGF−21突然変異タンパク質の薬剤的安定性
本発明のFGF−21突然変異タンパク質の安定性を、シミュレートされた生理学的および製剤条件下で解析した。生理学的条件をシミュレートするために、突然変異タンパク質を、10mg/ml(pH7.4)の標的タンパク質濃度における室温(RT)でのPBS中の安定性について解析した。PBS中での突然変異タンパク質の溶解度/物理安定度は、サイズ排除および/または逆相クロマトグラフィーによって測定される調製後のタンパク質の回収により、RTにおいて>90%の回収を生じる場合に満足なものであるとみなす。表4および5に示した本発明の突然変異タンパク質は、この基準を満たす。
Claims (41)
- ヒト線維芽細胞成長因子21(FGF−21)の突然変異タンパク質またはこれらの生物活性ペプチドであって、以下の1つまたは複数のアミノ酸:グリシン42、グルタミン54、アルギニン77、アラニン81、ロイシン86、フェニルアラニン88、リジン122、ヒスチジン125、アルギニン126、プロリン130、アルギニン131、ロイシン139、アラニン145、ロイシン146、イソロイシン152、アラニン154、グルタミン156、グリシン161、セリン163、グリシン170、またはセリン172(式中、アミノ酸の番号付けは、配列番号:1に基づく)の、荷電した、および/または極性であるが、無電荷のアミノ酸での置換を含む、突然変異タンパク質。
- 負に荷電したアミノ酸が、アスパラギン酸、グルタミン酸、およびこれらの天然には存在しない類似体からなる群より選択される、請求項1記載の突然変異タンパク質。
- 極性であるが、無電荷のアミノ酸が、セリン、スレオニン、アスパラギン、グルタミン、およびこれらの天然には存在しない類似体からなる群より選択される、請求項1記載の突然変異タンパク質。
- 前記突然変異タンパク質が、Leu139Glu、Ala145Glu、Leu146Glu、Ile152Glu、Gln156Glu、Ser163Glu、Ile152Glu、Ser163Glu、およびGln54Gluからなる群より選択される、請求項1記載の突然変異タンパク質。
- 前記突然変異タンパク質が、N末端で最大4アミノ酸が切断されている、請求項4記載の突然変異タンパク質。
- 請求項1記載の突然変異タンパク質をコードするポリヌクレオチド。
- 前記ポリヌクレオチドがDNAである、請求項6記載のポリヌクレオチド。
- 請求項7記載のDNAを含む発現ベクター。
- 請求項8記載の発現ベクターを含む宿主細胞。
- 前記宿主細胞が酵母細胞である、請求項9記載の宿主細胞。
- 以下の工程を含むポリペプチドを産生するための方法:
(a)請求項10記載の宿主細胞から前記ポリペプチドを発現する工程、および、
(b)前記ポリペプチドを単離する工程。 - 請求項1記載のFGF−21突然変異タンパク質の治療上有効な量と、薬剤的に許容される担体とを含む薬剤的組成物であって、前記組成物は、肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数を示す患者を治療するために有用である薬剤的組成物。
- 肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数を示す患者を治療するための、患者に請求項1記載のFGF−21突然変異タンパク質の治療上有効な量を投与することを含む方法。
- 前記患者が2型糖尿病を示す、請求項13記載の方法。
- アルギニン19、チロシン20、ロイシン21、チロシン22、スレオニン23、アスパラギン酸24、アスパラギン酸25、アラニン26、グルタミン27、グルタミン28、アラニン31、ロイシン33、イソロイシン35、ロイシン37、バリン41、グリシン42、グリシン43、グルタミン酸50、グルタミン54、ロイシン58、バリン62、ロイシン66、グリシン67、リジン69、アルギニン72、フェニルアラニン73、グルタミン76、アルギニン77、アスパラギン酸79、グリシン80、アラニン81、ロイシン82、グリシン84、セリン85、プロリン90、アラニン92、セリン94、フェニルアラニン95、ロイシン100、アスパラギン酸102、チロシン104、チロシン107、セリン109、グルタミン酸110、プロリン115、ヒスチジン117、ロイシン118、プロリン119、アスパラギン121、リジン122、セリン123、プロリン124、ヒスチジン125、アルギニン126、アスパラギン酸127、アラニン129、プロリン130、グリシン132、アラニン134、アルギニン135、ロイシン137、プロリン138、またはロイシン139(アミノ酸の番号付けは、配列番号:1に基づく)の2つ以上のアミノ酸のシステインでの置換を含む、ヒトFGF−21の突然変異タンパク質またはこれらの生物活性ペプチド。
- 前記突然変異タンパク質が、Leu21Cys−Leu33Cys/Leu118Cys−Ala134Cys、Leu21Cys/Leu33Cys、Leu118Cys/Ala134Cys、またはAla26Cys/Lys122Cysからなる群より選択される、請求項15記載の突然変異タンパク質。
- 前記突然変異タンパク質が、N末端で最大4アミノ酸が切断されている、請求項16記載の突然変異タンパク質。
- 前記突然変異タンパク質が、des−HPIP−Leu118Cys/Ala134Cysである、請求項17記載の突然変異タンパク質。
- 請求項15記載の突然変異タンパク質をコードするポリヌクレオチド。
- 前記ポリヌクレオチドがDNAである、請求項19記載のポリヌクレオチド。
- 請求項20記載のDNAを含む発現ベクター。
- 請求項21記載の発現ベクターを含む宿主細胞。
- 前記宿主細胞が酵母細胞である、請求項22記載の宿主細胞。
- 以下の工程を含むポリペプチドを産生するための方法:
(a)請求項23の宿主細胞から前記ポリペプチドを発現する工程、および、
(b)前記ポリペプチドを単離する工程。 - 請求項15記載のFGF−21突然変異タンパク質の治療上有効な量と、薬剤的に許容される担体とを含む薬剤的組成物であって、前記組成物は、肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数を示す患者を治療するために有用である薬剤的組成物。
- 肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数を示す患者を治療するための、患者に請求項15記載のFGF−21突然変異タンパク質の治療上有効な量を投与する工程を含む方法。
- 前記患者が2型糖尿病を示す、請求項26記載の方法。
- グリシン42、グルタミン54、アルギニン77、アラニン81、ロイシン86、フェニルアラニン88、リジン122、ヒスチジン125、アルギニン126、プロリン130、アルギニン131、ロイシン139、アラニン145、ロイシン146、イソロイシン152、アラニン154、グルタミン156、グリシン161、セリン163、グリシン170、またはセリン172(アミノ酸の番号付けは、配列番号:1に基づく)のうちのアミノ酸1以上の、荷電および/または極性であるが無荷電のアミノ酸での置換を、
アルギニン19、チロシン20、ロイシン21、チロシン22、スレオニン23、アスパラギン酸24、アスパラギン酸25、アラニン26、グルタミン27、グルタミン28、アラニン31、ロイシン33、イソロイシン35、ロイシン37、バリン41、グリシン42、グリシン43、グルタミン酸50、グルタミン54、ロイシン58、バリン62、ロイシン66、グリシン67、リジン69、アルギニン72、フェニルアラニン73、グルタミン76、アルギニン77、アスパラギン酸79、グリシン80、アラニン81、ロイシン82、グリシン84、セリン85、プロリン90、アラニン92、セリン94、フェニルアラニン95、ロイシン100、アスパラギン酸102、チロシン104、チロシン107、セリン109、グルタミン酸110、プロリン115、ヒスチジン117、ロイシン118、プロリン119、アスパラギン121、リジン122、セリン123、プロリン124、ヒスチジン125、アルギニン126、アスパラギン酸127、アラニン129、プロリン130、グリシン132、アラニン134、アルギニン135、ロイシン137、プロリン138、またはロイシン139におけるアミノ酸2以上の、システインでの置換と組み合わせて含む(アミノ酸の番号付けは、配列番号:1に基づく)、
ヒトFGF−21の突然変異タンパク質またはこれらの生物活性ペプチド。 - 請求項28記載の突然変異タンパク質をコードするポリヌクレオチド。
- 前記ポリヌクレオチドがDNAである、請求項29記載のポリヌクレオチド。
- 請求項30記載のDNAを含む発現ベクター。
- 請求項31記載の発現ベクターを含む宿主細胞。
- 前記宿主細胞が酵母細胞である、請求項32記載の宿主細胞。
- 以下の工程を含むポリペプチドを産生するための方法:
(a)請求項33の宿主細胞から前記ポリペプチドを発現する工程、および、
(b)前記ポリペプチドを単離する工程。 - 請求項28記載のFGF−21突然変異タンパク質の治療上有効な量と、薬剤的に許容される担体とを含む薬剤的組成物であって、前記組成物は、肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数を示す患者を治療するために有用である組成物。
- 患者に請求項28記載のFGF−21突然変異タンパク質の治療上有効な量を投与することを含む、肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数を示す患者を治療するための方法。
- 前記患者が2型糖尿病を示す、請求項36記載の方法。
- 前記突然変異タンパク質が、N末端で最大4アミノ酸が切断されている、請求項28記載の突然変異タンパク質。
- 肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数の治療のための医薬の製造のための、請求項1記載のFGF−21突然変異タンパク質の使用。
- 肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数の治療のための医薬の製造のための、請求項15記載のFGF−21突然変異タンパク質の使用。
- 肥満症、2型糖尿病、インスリン耐性、高インスリン血症、グルコース不耐性、高血糖、または代謝症候群からなる群からの徴候の1つまたは複数の治療のための医薬の製造のための、請求項28記載のFGF−21突然変異タンパク質の使用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52858203P | 2003-12-10 | 2003-12-10 | |
PCT/US2004/037200 WO2005061712A1 (en) | 2003-12-10 | 2004-12-01 | Muteins of fibroblast growth factor 21 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2007535306A true JP2007535306A (ja) | 2007-12-06 |
JP4477013B2 JP4477013B2 (ja) | 2010-06-09 |
Family
ID=34710086
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006543822A Expired - Fee Related JP4477013B2 (ja) | 2003-12-10 | 2004-12-01 | 線維芽細胞成長因子21の突然変異タンパク質 |
Country Status (14)
Country | Link |
---|---|
US (2) | US7491697B2 (ja) |
EP (2) | EP1702067A1 (ja) |
JP (1) | JP4477013B2 (ja) |
KR (1) | KR20060135648A (ja) |
CN (1) | CN1890371A (ja) |
AR (1) | AR046877A1 (ja) |
AU (1) | AU2004303783A1 (ja) |
BR (1) | BRPI0416683A (ja) |
CA (1) | CA2549249A1 (ja) |
EA (1) | EA200601121A1 (ja) |
IL (1) | IL175736A0 (ja) |
NO (1) | NO20062662L (ja) |
TW (1) | TW200520772A (ja) |
WO (1) | WO2005061712A1 (ja) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011523561A (ja) * | 2008-06-04 | 2011-08-18 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2012504965A (ja) * | 2008-10-10 | 2012-03-01 | アムジエン・インコーポレーテツド | Fgf21変異体およびその使用 |
JP2012515747A (ja) * | 2009-01-23 | 2012-07-12 | ノヴォ・ノルディスク・アー/エス | アルブミンバインダーa−b−c−d−e−を有するfgf21誘導体及びそれらの使用 |
JP2013532644A (ja) * | 2010-07-20 | 2013-08-19 | ノヴォ ノルディスク アー/エス | N末端が修飾されたfgf21化合物 |
JP2014500880A (ja) * | 2010-11-19 | 2014-01-16 | ノバルティス アーゲー | Fgf21関連障害を処置する方法 |
JP2014530220A (ja) * | 2011-10-04 | 2014-11-17 | イーライ リリー アンド カンパニー | 線維芽細胞増殖因子21変異体 |
KR20170095256A (ko) * | 2014-12-23 | 2017-08-22 | 노보 노르디스크 에이/에스 | Fgf21 유도체 및 그것의 용도 |
JP2020518287A (ja) * | 2017-05-05 | 2020-06-25 | トレフォイル セラピューティクス,インク. | 組み換え修飾された繊維芽細胞成長因子及びその治療用途 |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7459540B1 (en) | 1999-09-07 | 2008-12-02 | Amgen Inc. | Fibroblast growth factor-like polypeptides |
US9453251B2 (en) | 2002-10-08 | 2016-09-27 | Pfenex Inc. | Expression of mammalian proteins in Pseudomonas fluorescens |
CN101031655A (zh) | 2004-07-26 | 2007-09-05 | 陶氏环球技术公司 | 通过株工程改进蛋白表达的方法 |
EP2161281A1 (en) * | 2004-09-02 | 2010-03-10 | Eli Lilly & Company | Muteins of fibroblast growth factor 21 |
US7622445B2 (en) * | 2004-09-02 | 2009-11-24 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
US7655627B2 (en) * | 2004-12-14 | 2010-02-02 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
MY143274A (en) | 2005-12-22 | 2011-04-15 | Genentech Inc | Recombinant production of heparin binding proteins |
US20080125580A1 (en) | 2006-07-14 | 2008-05-29 | Genentech, Inc. | Refolding of Recombinant Proteins |
BRPI0809583B1 (pt) * | 2007-03-30 | 2022-02-22 | Ambrx, Inc | Polipeptídeo fgf-21 modificado, composição compreendendo o mesmo, método para produzir o referido polipetídeo fgf-21 e célula compreendendo um polinucleotídeo |
WO2008134461A2 (en) | 2007-04-27 | 2008-11-06 | Dow Global Technologies, Inc. | Method for rapidly screening microbial hosts to identify certain strains with improved yield and/or quality in the expression of heterologous proteins |
US9580719B2 (en) | 2007-04-27 | 2017-02-28 | Pfenex, Inc. | Method for rapidly screening microbial hosts to identify certain strains with improved yield and/or quality in the expression of heterologous proteins |
ES2646614T3 (es) * | 2007-08-03 | 2017-12-14 | Eli Lilly And Company | Uso de un compuesto de FGF 21 y un compuesto de GLP 1 para el tratamiento de la obesidad |
WO2009117622A2 (en) * | 2008-03-19 | 2009-09-24 | Ambrx, Inc. | Modified fgf-23 polypeptides and their uses |
AU2016203765B2 (en) * | 2008-10-10 | 2017-04-13 | Amgen Inc. | FGF21 mutants and uses thereof |
WO2010065439A1 (en) * | 2008-12-05 | 2010-06-10 | Eli Lilly And Company | Variants of fibroblast growth factor 21 |
SG10201402038WA (en) | 2009-05-05 | 2014-07-30 | Amgen Inc | FGF21 Mutants And Uses Thereof |
US20120052069A1 (en) | 2009-05-05 | 2012-03-01 | Amgen Inc | Fgf21 mutants and uses thereof |
EP2440235A1 (en) * | 2009-06-11 | 2012-04-18 | Novo Nordisk A/S | Glp-1 and fgf21 combinations for treatment of diabetes type 2 |
EP2443145A1 (en) * | 2009-06-17 | 2012-04-25 | Amgen, Inc | Chimeric fgf19 polypeptides and uses thereof |
WO2011068893A1 (en) * | 2009-12-02 | 2011-06-09 | Amgen Inc. | BINDING PROTEINS THAT BIND TO HUMAN FGFR1C, HUMAN β-KLOTHO AND BOTH HUMAN FGFR1C AND HUMANβ-KLOTHO |
UA109888C2 (uk) | 2009-12-07 | 2015-10-26 | ІЗОЛЬОВАНЕ АНТИТІЛО АБО ЙОГО ФРАГМЕНТ, ЩО ЗВ'ЯЗУЄТЬСЯ З β-КЛОТО, РЕЦЕПТОРАМИ FGF І ЇХНІМИ КОМПЛЕКСАМИ | |
EP2460527A1 (en) | 2010-01-21 | 2012-06-06 | Sanofi | Pharmaceutical composition for treating a metabolic syndrome |
MX2012011986A (es) | 2010-04-15 | 2013-03-05 | Amgen Inc | RECEPTOR FGF HUMANO Y PROTEINAS ENLAZADAS A ß-KLOTHO. |
EP2558115B1 (en) | 2010-04-16 | 2019-07-31 | The Salk Institute for Biological Studies | Methods for treating metabolic disorders using fgf |
CA2815967A1 (en) * | 2010-11-05 | 2012-05-10 | Covx Technologies Ireland Limited | Anti-diabetic compounds |
WO2012121428A1 (ko) * | 2011-03-07 | 2012-09-13 | 주식회사 웰스킨 | 다이펩타이드를 유효성분으로 포함하는 섬유모세포 증식 조성물 및 상기 조성물을 포함하는 제품 |
AU2012279237B2 (en) | 2011-07-01 | 2016-09-29 | Ngm Biopharmaceuticals, Inc. | Compositions, uses and methods for treatment of metabolic disorders and diseases |
EP2548570A1 (en) | 2011-07-19 | 2013-01-23 | Sanofi | Pharmaceutical composition for treating a metabolic syndrome |
TWI593708B (zh) * | 2011-09-26 | 2017-08-01 | 諾華公司 | 治療代謝病症之融合蛋白質 |
TW201315742A (zh) | 2011-09-26 | 2013-04-16 | Novartis Ag | 治療代謝病症之雙功能蛋白質 |
TWI560202B (en) | 2011-12-22 | 2016-12-01 | Pfizer | Anti-diabetic compounds |
WO2013131091A1 (en) | 2012-03-02 | 2013-09-06 | New York University | Chimeric fgf21 proteins with enhanced binding affinity for beta-klotho for the treatment of type ii diabetes, obesity and related metabolic disorders |
US9464126B2 (en) | 2012-06-07 | 2016-10-11 | New York University | Chimeric fibroblast growth factor 21 proteins and methods of use |
US9474785B2 (en) | 2012-06-07 | 2016-10-25 | New York University | Chimeric fibroblast growth factor 19 proteins and methods of use |
US9657075B2 (en) | 2012-06-07 | 2017-05-23 | New York University | Chimeric fibroblast growth factor 23 proteins and methods of use |
KR20150006059A (ko) | 2012-06-11 | 2015-01-15 | 일라이 릴리 앤드 캄파니 | 섬유모세포 성장 인자 21 변이체 |
TWI513705B (zh) | 2012-06-11 | 2015-12-21 | Lilly Co Eli | 纖維母細胞生長因子21蛋白質 |
US9290557B2 (en) | 2012-11-28 | 2016-03-22 | Ngm Biopharmaceuticals, Inc. | Compositions comprising variants and fusions of FGF19 polypeptides |
WO2014085365A2 (en) | 2012-11-28 | 2014-06-05 | Ngm Biopharmaceuticals, Inc. | Compositions and methods for treatment of metabolic disorders and diseases |
US9273107B2 (en) | 2012-12-27 | 2016-03-01 | Ngm Biopharmaceuticals, Inc. | Uses and methods for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
JP6403685B2 (ja) | 2012-12-27 | 2018-10-17 | エヌジーエム バイオファーマシューティカルス,インコーポレーテッド | 胆汁酸ホメオスタシス調整並びに胆汁酸障害及び疾患の治療の方法 |
US9550820B2 (en) | 2013-02-22 | 2017-01-24 | New York University | Chimeric fibroblast growth factor 23/fibroblast growth factor 19 proteins and methods of use |
EP3057605A1 (en) | 2013-10-18 | 2016-08-24 | Novartis AG | Methods of treating diabetes and related disorders |
WO2015061331A1 (en) | 2013-10-21 | 2015-04-30 | Salk Institute For Biological Studies | Chimeric fibroblast growth factor (fgf) 2/fgf1 peptides and methods of use |
EP3060238A4 (en) | 2013-10-21 | 2017-06-07 | Salk Institute for Biological Studies | Mutated fibroblast growth factor (fgf) 1 and methods of use |
NZ718962A (en) | 2013-10-28 | 2019-12-20 | Ngm Biopharmaceuticals Inc | Cancer models and associated methods |
WO2015103782A1 (en) * | 2014-01-13 | 2015-07-16 | Wenzhou Medical College Biological Pharmaceuticals And Nature Products Ltd., Co | Fgf21 mutant and conjugate thereof |
US9738716B2 (en) | 2014-01-24 | 2017-08-22 | Ngm Biopharmaceuticals, Inc. | Beta klotho binding proteins and methods of use thereof |
EP3125921B1 (en) | 2014-03-11 | 2020-07-08 | Novartis AG | Fgf21 variants for use in treating hiv-haart induced partial lipodystrophy |
US10398758B2 (en) | 2014-05-28 | 2019-09-03 | Ngm Biopharmaceuticals, Inc. | Compositions comprising variants of FGF19 polypeptides and uses thereof for the treatment of hyperglycemic conditions |
AU2015277438B2 (en) | 2014-06-16 | 2020-02-27 | Ngm Biopharmaceuticals, Inc. | Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases |
CN104311656B (zh) * | 2014-10-14 | 2017-04-05 | 哈尔滨博翱生物医药技术开发有限公司 | cFGF‑21蛋白及其在治疗类风湿关节炎中的应用 |
RU2729161C2 (ru) | 2014-10-23 | 2020-08-04 | ЭнДжиЭм БАЙОФАРМАСЬЮТИКАЛЗ, ИНК. | Фармацевтические композиции, содержащие варианты пептидов, и способы их применения |
UY36370A (es) | 2014-10-24 | 2016-04-29 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Polipéptidos fgf-21 modificados y sus usos |
US10434144B2 (en) | 2014-11-07 | 2019-10-08 | Ngm Biopharmaceuticals, Inc. | Methods for treatment of bile acid-related disorders and prediction of clinical sensitivity to treatment of bile acid-related disorders |
US10800843B2 (en) | 2015-07-29 | 2020-10-13 | Ngm Biopharmaceuticals, Inc. | Beta klotho-binding proteins |
JP2018535964A (ja) | 2015-10-30 | 2018-12-06 | ソーク インスティテュート フォー バイオロジカル スタディーズ | 線維芽細胞増殖因子(fgf)1アナログによるステロイド誘導性高血糖の処置 |
US10744185B2 (en) | 2015-11-09 | 2020-08-18 | Ngm Biopharmaceuticals, Inc. | Methods of using variants of FGF19 polypeptides for the treatment of pruritus |
TW201731867A (zh) | 2015-12-02 | 2017-09-16 | 賽諾菲公司 | Fgf21變異體 |
WO2017220706A1 (en) * | 2016-06-22 | 2017-12-28 | Novo Nordisk A/S | Pharmaceutical compositions of fgf21 derivatives and uses thereof |
US11370841B2 (en) | 2016-08-26 | 2022-06-28 | Ngm Biopharmaceuticals, Inc. | Methods of treating fibroblast growth factor 19-mediated cancers and tumors |
US20220127322A1 (en) | 2017-03-14 | 2022-04-28 | Sunshine Lake Pharma Co., Ltd. | Dual-target fusion proteins comprising the fc portion of an immunoglobulin |
AU2018329850A1 (en) | 2017-09-08 | 2020-04-23 | Bristol-Myers Squibb Company | Modified fibroblast growth factor 21 (FGF-21) for use in methods for treating nonalcoholic steatohepatitis (NASH) |
WO2019119673A1 (zh) | 2017-12-19 | 2019-06-27 | 北京吉源生物科技有限公司 | 一种双基因修饰的干细胞及其用途 |
EP3749683A4 (en) | 2018-02-08 | 2022-03-16 | Sunshine Lake Pharma Co., Ltd. | FGF21 VARIANT, FUSION PROTEIN AND USE THEREOF |
WO2020010117A2 (en) | 2018-07-03 | 2020-01-09 | Bristol-Myers Squibb Company | Fgf21 formulations |
CN110791517A (zh) * | 2018-08-01 | 2020-02-14 | 中国农业大学 | 成纤维细胞生长因子21的制备、纯化及其结晶 |
CN109836486B (zh) * | 2019-01-30 | 2020-09-08 | 北京双因生物科技有限公司 | 成纤维生长因子21变体、其融合蛋白及其用途 |
CN114853908B (zh) | 2019-05-16 | 2024-06-07 | 浙江道尔生物科技有限公司 | 一种治疗代谢疾病的融合蛋白 |
US11542309B2 (en) | 2019-07-31 | 2023-01-03 | Salk Institute For Biological Studies | Fibroblast growth factor 1 (FGF1) mutant proteins that selectively activate FGFR1B to reduce blood glucose |
AR122359A1 (es) | 2020-01-08 | 2022-09-07 | Bristol Myers Squibb Co | Formulaciones de fgf-21 conjugado |
CN113728013B (zh) | 2020-01-11 | 2022-06-14 | 北京质肽生物医药科技有限公司 | Glp-1和fgf21的融合蛋白的缀合物 |
EP4144375A1 (en) * | 2020-04-29 | 2023-03-08 | Onegene Biotechnology Inc. | Novel protein conjugate, and use thereof for preventing or treating nonalcoholic steatohepatitis, obesity and diabetes |
EP4192495A1 (en) | 2020-08-07 | 2023-06-14 | Bristol-Myers Squibb Company | Fgf21 combined with ccr2/5 antagonists for the treatment of fibrosis |
US20240123031A1 (en) | 2020-11-25 | 2024-04-18 | Bristol-Myers Squibb Company | Methods of treating liver diseases |
CN113633756A (zh) * | 2021-06-17 | 2021-11-12 | 温州医科大学 | Fgf21温敏缓释载体和基因修饰方法以及其制备方法 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7459540B1 (en) | 1999-09-07 | 2008-12-02 | Amgen Inc. | Fibroblast growth factor-like polypeptides |
US7408047B1 (en) * | 1999-09-07 | 2008-08-05 | Amgen Inc. | Fibroblast growth factor-like polypeptides |
AU7368100A (en) | 1999-09-10 | 2001-04-10 | Curagen Corporation | Fibroblast growth factor polypeptide and nucleic acids encoding same |
WO2001032678A1 (en) | 1999-11-05 | 2001-05-10 | Smithkline Beecham Corporation | sbgFGF-19a |
US6716626B1 (en) | 1999-11-18 | 2004-04-06 | Chiron Corporation | Human FGF-21 nucleic acids |
EP2163626A1 (en) * | 1999-11-18 | 2010-03-17 | Novartis Vaccines and Diagnostics, Inc. | Human FGF-21 gene and gene expression products |
AU2631001A (en) | 2000-01-05 | 2001-07-16 | Zymogenetics Inc. | Novel fgf homolog zfgf11 |
US20020001825A1 (en) | 2000-03-31 | 2002-01-03 | Nobuyuki Itoh | Fibroblast growth factor-like molecules and uses thereof |
CA2409342A1 (en) | 2000-06-06 | 2001-12-13 | Incyte Genomics, Inc. | Extracellular messengers |
US20050048507A1 (en) | 2001-01-11 | 2005-03-03 | Mei Zhong | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
WO2003011213A2 (en) | 2001-07-30 | 2003-02-13 | Eli Lilly And Company | Method for treating diabetes and obesity |
WO2003059270A2 (en) | 2002-01-15 | 2003-07-24 | Eli Lilly And Company | Method for reducing morbidity and mortality in critically ill patients |
BRPI0515252B1 (pt) * | 2004-09-13 | 2018-02-06 | Cooper Technologies Company | Módulo e dispositivos de desconexão por comutação com fusível |
-
2004
- 2004-12-01 EA EA200601121A patent/EA200601121A1/ru unknown
- 2004-12-01 CN CNA200480035794XA patent/CN1890371A/zh active Pending
- 2004-12-01 EP EP04810531A patent/EP1702067A1/en not_active Withdrawn
- 2004-12-01 WO PCT/US2004/037200 patent/WO2005061712A1/en active Application Filing
- 2004-12-01 BR BRPI0416683-3A patent/BRPI0416683A/pt not_active Application Discontinuation
- 2004-12-01 KR KR1020067011358A patent/KR20060135648A/ko not_active Application Discontinuation
- 2004-12-01 EP EP10184261A patent/EP2270163A1/en not_active Withdrawn
- 2004-12-01 CA CA002549249A patent/CA2549249A1/en not_active Abandoned
- 2004-12-01 JP JP2006543822A patent/JP4477013B2/ja not_active Expired - Fee Related
- 2004-12-01 AU AU2004303783A patent/AU2004303783A1/en not_active Abandoned
- 2004-12-01 US US10/579,510 patent/US7491697B2/en not_active Expired - Fee Related
- 2004-12-09 AR ARP040104584A patent/AR046877A1/es unknown
- 2004-12-10 TW TW093138483A patent/TW200520772A/zh unknown
-
2006
- 2006-05-18 IL IL175736A patent/IL175736A0/en unknown
- 2006-06-09 NO NO20062662A patent/NO20062662L/no not_active Application Discontinuation
-
2009
- 2009-01-06 US US12/349,119 patent/US20090118190A1/en not_active Abandoned
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7191076B2 (ja) | 2008-06-04 | 2022-12-16 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2016128449A (ja) * | 2008-06-04 | 2016-07-14 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2019187417A (ja) * | 2008-06-04 | 2019-10-31 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2011523561A (ja) * | 2008-06-04 | 2011-08-18 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2021052780A (ja) * | 2008-06-04 | 2021-04-08 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2018082699A (ja) * | 2008-06-04 | 2018-05-31 | アムジエン・インコーポレーテツド | Fgf21突然変異体及びその使用 |
JP2012504965A (ja) * | 2008-10-10 | 2012-03-01 | アムジエン・インコーポレーテツド | Fgf21変異体およびその使用 |
JP2012515747A (ja) * | 2009-01-23 | 2012-07-12 | ノヴォ・ノルディスク・アー/エス | アルブミンバインダーa−b−c−d−e−を有するfgf21誘導体及びそれらの使用 |
JP2013532644A (ja) * | 2010-07-20 | 2013-08-19 | ノヴォ ノルディスク アー/エス | N末端が修飾されたfgf21化合物 |
US9655974B2 (en) | 2010-07-20 | 2017-05-23 | Novo Nordisk A/S | N-terminal modified FGF21 compounds |
JP2014500880A (ja) * | 2010-11-19 | 2014-01-16 | ノバルティス アーゲー | Fgf21関連障害を処置する方法 |
JP2017110010A (ja) * | 2010-11-19 | 2017-06-22 | ノバルティス アーゲー | Fgf21関連障害を処置する方法 |
JP2014530220A (ja) * | 2011-10-04 | 2014-11-17 | イーライ リリー アンド カンパニー | 線維芽細胞増殖因子21変異体 |
US9744213B2 (en) | 2014-12-23 | 2017-08-29 | Novo Nordisk A/S | FGF21 derivatives and uses thereof |
US10124039B2 (en) | 2014-12-23 | 2018-11-13 | Novo Nordisk A/S | FGF21 derivatives and uses thereof |
US9895417B2 (en) | 2014-12-23 | 2018-02-20 | Novo Nordisk A/S | FGF21 derivatives and uses thereof |
KR102427527B1 (ko) | 2014-12-23 | 2022-08-01 | 노보 노르디스크 에이/에스 | Fgf21 유도체 및 그것의 용도 |
KR20170095256A (ko) * | 2014-12-23 | 2017-08-22 | 노보 노르디스크 에이/에스 | Fgf21 유도체 및 그것의 용도 |
JP2020518287A (ja) * | 2017-05-05 | 2020-06-25 | トレフォイル セラピューティクス,インク. | 組み換え修飾された繊維芽細胞成長因子及びその治療用途 |
US11479591B2 (en) | 2017-05-05 | 2022-10-25 | Trefoil Therapeutics, Inc. | Recombinant modified fibroblast growth factors and therapeutic uses thereof |
Also Published As
Publication number | Publication date |
---|---|
TW200520772A (en) | 2005-07-01 |
US7491697B2 (en) | 2009-02-17 |
WO2005061712A1 (en) | 2005-07-07 |
NO20062662L (no) | 2006-08-07 |
CA2549249A1 (en) | 2005-07-07 |
IL175736A0 (en) | 2008-02-09 |
JP4477013B2 (ja) | 2010-06-09 |
CN1890371A (zh) | 2007-01-03 |
EP1702067A1 (en) | 2006-09-20 |
US20070142278A1 (en) | 2007-06-21 |
EP2270163A1 (en) | 2011-01-05 |
KR20060135648A (ko) | 2006-12-29 |
BRPI0416683A (pt) | 2007-01-30 |
AU2004303783A1 (en) | 2005-07-07 |
US20090118190A1 (en) | 2009-05-07 |
AR046877A1 (es) | 2005-12-28 |
EA200601121A1 (ru) | 2006-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4477013B2 (ja) | 線維芽細胞成長因子21の突然変異タンパク質 | |
JP4809352B2 (ja) | 線維芽細胞成長因子21の突然変異タンパク質 | |
US7622445B2 (en) | Muteins of fibroblast growth factor 21 | |
US7655627B2 (en) | Muteins of fibroblast growth factor 21 | |
US7576190B2 (en) | FGF-21 fusion proteins | |
US20090111742A1 (en) | Use of fgf-21 and thiazolidinedione for treating type 2 diabetes | |
US8809499B2 (en) | Fusion protein of human fibroblast growth factor-21 and exendin-4 | |
US20070265200A1 (en) | Glycol Linked Fgf-21 Compounds | |
EP2468858B1 (en) | Fusion protein regulating plasma glucose and lipid, its preparation method and use | |
MXPA06006616A (en) | Muteins of fibroblast growth factor 21 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090407 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090707 |
|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20090707 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20090908 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100108 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20100120 |
|
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: 20100209 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100310 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130319 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140319 Year of fee payment: 4 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |