JP6377527B2 - 高圧タンパク質リフォールディングのための方法およびシステム - Google Patents
高圧タンパク質リフォールディングのための方法およびシステム Download PDFInfo
- Publication number
- JP6377527B2 JP6377527B2 JP2014544977A JP2014544977A JP6377527B2 JP 6377527 B2 JP6377527 B2 JP 6377527B2 JP 2014544977 A JP2014544977 A JP 2014544977A JP 2014544977 A JP2014544977 A JP 2014544977A JP 6377527 B2 JP6377527 B2 JP 6377527B2
- Authority
- JP
- Japan
- Prior art keywords
- protein
- inclusion body
- high pressure
- refolding
- dispersion
- 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.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims description 83
- 230000030788 protein refolding Effects 0.000 title claims description 5
- 210000003000 inclusion body Anatomy 0.000 claims description 223
- 102000004169 proteins and genes Human genes 0.000 claims description 181
- 108090000623 proteins and genes Proteins 0.000 claims description 181
- 239000002245 particle Substances 0.000 claims description 112
- 239000006185 dispersion Substances 0.000 claims description 90
- 238000002360 preparation method Methods 0.000 claims description 76
- 239000004094 surface-active agent Substances 0.000 claims description 32
- 230000002776 aggregation Effects 0.000 claims description 25
- 239000000872 buffer Substances 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000004220 aggregation Methods 0.000 claims description 17
- 108091005804 Peptidases Proteins 0.000 claims description 15
- 239000004365 Protease Substances 0.000 claims description 15
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 15
- 230000007717 exclusion Effects 0.000 claims description 15
- 238000000265 homogenisation Methods 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 102000037865 fusion proteins Human genes 0.000 claims description 6
- 108020001507 fusion proteins Proteins 0.000 claims description 6
- 238000003776 cleavage reaction Methods 0.000 claims description 5
- 230000007017 scission Effects 0.000 claims description 5
- 241000710778 Pestivirus Species 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 108010011170 Ala-Trp-Arg-His-Pro-Gln-Phe-Gly-Gly Proteins 0.000 claims description 2
- 229920002101 Chitin Polymers 0.000 claims description 2
- 102000005720 Glutathione transferase Human genes 0.000 claims description 2
- 108010070675 Glutathione transferase Proteins 0.000 claims description 2
- HVLSXIKZNLPZJJ-TXZCQADKSA-N HA peptide Chemical compound C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HVLSXIKZNLPZJJ-TXZCQADKSA-N 0.000 claims description 2
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 claims description 2
- 101710135898 Myc proto-oncogene protein Proteins 0.000 claims description 2
- 102100038895 Myc proto-oncogene protein Human genes 0.000 claims description 2
- 241001195348 Nusa Species 0.000 claims description 2
- 102100036407 Thioredoxin Human genes 0.000 claims description 2
- 241000723792 Tobacco etch virus Species 0.000 claims description 2
- 101710150448 Transcriptional regulator Myc Proteins 0.000 claims description 2
- 102000044159 Ubiquitin Human genes 0.000 claims description 2
- 108090000848 Ubiquitin Proteins 0.000 claims description 2
- 239000000427 antigen Substances 0.000 claims description 2
- 102000036639 antigens Human genes 0.000 claims description 2
- 108091007433 antigens Proteins 0.000 claims description 2
- 102000028861 calmodulin binding Human genes 0.000 claims description 2
- 108091000084 calmodulin binding Proteins 0.000 claims description 2
- 238000010008 shearing Methods 0.000 claims description 2
- 238000010257 thawing Methods 0.000 claims description 2
- 108060008226 thioredoxin Proteins 0.000 claims description 2
- 229940094937 thioredoxin Drugs 0.000 claims description 2
- 101710121765 Endo-1,4-beta-xylanase Proteins 0.000 claims 1
- 230000004927 fusion Effects 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 description 170
- 239000000243 solution Substances 0.000 description 46
- 238000004062 sedimentation Methods 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 23
- 238000009826 distribution Methods 0.000 description 23
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 238000012545 processing Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000009931 pascalization Methods 0.000 description 15
- 239000000523 sample Substances 0.000 description 14
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 13
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 102000002265 Human Growth Hormone Human genes 0.000 description 10
- 108010000521 Human Growth Hormone Proteins 0.000 description 10
- 239000000854 Human Growth Hormone Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 238000005054 agglomeration Methods 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 9
- 238000001542 size-exclusion chromatography Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000000527 sonication Methods 0.000 description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 7
- 239000007983 Tris buffer Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- 230000005653 Brownian motion process Effects 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- 150000001413 amino acids Chemical group 0.000 description 6
- 238000005537 brownian motion Methods 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 6
- 238000005063 solubilization Methods 0.000 description 6
- 230000007928 solubilization Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000036425 denaturation Effects 0.000 description 5
- 238000004925 denaturation Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000011179 visual inspection Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 108010074604 Epoetin Alfa Proteins 0.000 description 4
- 238000010268 HPLC based assay Methods 0.000 description 4
- 102000003996 Interferon-beta Human genes 0.000 description 4
- 108090000467 Interferon-beta Proteins 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 239000000084 colloidal system Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 229960001388 interferon-beta Drugs 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229960004532 somatropin Drugs 0.000 description 4
- 239000004034 viscosity adjusting agent Substances 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 239000007987 MES buffer Substances 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000000149 argon plasma sintering Methods 0.000 description 3
- 238000000429 assembly Methods 0.000 description 3
- 230000000712 assembly Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005277 cation exchange chromatography Methods 0.000 description 3
- 230000003196 chaotropic effect Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000000326 densiometry Methods 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 238000002296 dynamic light scattering Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000005484 gravity Effects 0.000 description 3
- 238000012538 light obscuration Methods 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 238000009928 pasteurization Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 239000008000 CHES buffer Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 102100023804 Coagulation factor VII Human genes 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 108010023321 Factor VII Proteins 0.000 description 2
- 108010054218 Factor VIII Proteins 0.000 description 2
- 102000001690 Factor VIII Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- MKWKNSIESPFAQN-UHFFFAOYSA-N N-cyclohexyl-2-aminoethanesulfonic acid Chemical compound OS(=O)(=O)CCNC1CCCCC1 MKWKNSIESPFAQN-UHFFFAOYSA-N 0.000 description 2
- 208000025174 PANDAS Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000021155 Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Diseases 0.000 description 2
- 240000004718 Panda Species 0.000 description 2
- 235000016496 Panda oleosa Nutrition 0.000 description 2
- 108010039185 Tenecteplase Proteins 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis 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
- 239000003398 denaturant Substances 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940012413 factor vii Drugs 0.000 description 2
- 229960000301 factor viii Drugs 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 229940048921 humira Drugs 0.000 description 2
- 230000002706 hydrostatic effect Effects 0.000 description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000003262 industrial enzyme Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229940029359 procrit Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229960000216 tenecteplase Drugs 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108010081589 Becaplermin Proteins 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010049951 Bone Morphogenetic Protein 3 Proteins 0.000 description 1
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 description 1
- 102100024504 Bone morphogenetic protein 3 Human genes 0.000 description 1
- 102100022544 Bone morphogenetic protein 7 Human genes 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 108010019673 Darbepoetin alfa Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100034120 Golgin subfamily A member 6A Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 101000663639 Homo sapiens Kunitz-type protease inhibitor 2 Proteins 0.000 description 1
- 101001018026 Homo sapiens Lysosomal alpha-glucosidase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 108010005716 Interferon beta-1a Proteins 0.000 description 1
- 108010005714 Interferon beta-1b Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 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
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100033342 Lysosomal acid glucosylceramidase Human genes 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 108010069013 Phenylalanine Hydroxylase Proteins 0.000 description 1
- 108700023158 Phenylalanine ammonia-lyases Proteins 0.000 description 1
- 102100038223 Phenylalanine-4-hydroxylase Human genes 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 108010073771 Soybean Proteins Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010092464 Urate Oxidase Proteins 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000011162 ammonium carbonates Nutrition 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940115115 aranesp Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 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 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- 238000003508 chemical denaturation Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- ZZTURJAZCMUWEP-UHFFFAOYSA-N diaminomethylideneazanium;hydrogen sulfate Chemical compound NC(N)=N.OS(O)(=O)=O ZZTURJAZCMUWEP-UHFFFAOYSA-N 0.000 description 1
- FBELJLCOAHMRJK-UHFFFAOYSA-L disodium;2,2-bis(2-ethylhexyl)-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCC(CC)CC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CC(CC)CCCC FBELJLCOAHMRJK-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960003388 epoetin alfa Drugs 0.000 description 1
- 229940089118 epogen Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229940063135 genotropin Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-O guanidinium Chemical compound NC(N)=[NH2+] ZRALSGWEFCBTJO-UHFFFAOYSA-O 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 229940051250 hexylene glycol Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- 102000045921 human GAA Human genes 0.000 description 1
- 102000046824 human IL1RN Human genes 0.000 description 1
- 102000052154 human SPINT2 Human genes 0.000 description 1
- 229940065770 humatrope Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- DNZMDASEFMLYBU-RNBXVSKKSA-N hydroxyethyl starch Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O.OCCOC[C@H]1O[C@H](OCCO)[C@H](OCCO)[C@@H](OCCO)[C@@H]1OCCO DNZMDASEFMLYBU-RNBXVSKKSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960002127 imiglucerase Drugs 0.000 description 1
- 108010039650 imiglucerase Proteins 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 229940065638 intron a Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000001368 micro-extraction in a packed syringe Methods 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229940103023 myozyme Drugs 0.000 description 1
- CGVLVOOFCGWBCS-RGDJUOJXSA-N n-octyl β-d-thioglucopyranoside Chemical compound CCCCCCCCS[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O CGVLVOOFCGWBCS-RGDJUOJXSA-N 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 238000001426 native polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229940063137 norditropin Drugs 0.000 description 1
- 229960000470 omalizumab Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940002988 pegasys Drugs 0.000 description 1
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 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 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 230000006432 protein unfolding Effects 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 229960000160 recombinant therapeutic protein Drugs 0.000 description 1
- 238000002407 reforming Methods 0.000 description 1
- 229940116157 regranex Drugs 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 229940063153 saizen Drugs 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 108700004121 sarkosyl Proteins 0.000 description 1
- 229940016590 sarkosyl Drugs 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229940067741 sodium octyl sulfate Drugs 0.000 description 1
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 1
- WFRKJMRGXGWHBM-UHFFFAOYSA-M sodium;octyl sulfate Chemical compound [Na+].CCCCCCCCOS([O-])(=O)=O WFRKJMRGXGWHBM-UHFFFAOYSA-M 0.000 description 1
- UPUIQOIQVMNQAP-UHFFFAOYSA-M sodium;tetradecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCOS([O-])(=O)=O UPUIQOIQVMNQAP-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940001941 soy protein Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/145—Extraction; Separation; Purification by extraction or solubilisation
-
- 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
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
-
- 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
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/503—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses
- C12N9/506—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses derived from RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
- C07K1/1136—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure by reversible modification of the secondary, tertiary or quarternary structure, e.g. using denaturating or stabilising agents
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Virology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Analytical Chemistry (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
本出願は、2011年12月1日に出願された米国仮特許出願第61/565,768号の優先権および利益を主張するものであり、上記仮特許出願はその全体が参照により本明細書に組み込まれる。
式2 Ek=1.5*kb *T
式中、Ekは1分子あたりの運動エネルギー、kbはボルツマン定数、そして、Tは温度(K)である(LaidlerおよびMeiser、1995)。
究は、封入体1つの密度は1.26g/mlだと示した(Thomas, Middelbergら、1990)。水密度として1g/mlを用いて沈降時間を30分と踏まえ、粒径の関数として粒子が移動した距離を図3に示す。ストークス式は直径5μmの粒子は30分を通して0.6cm沈降することを示し、リフォールド反応中にタンパク質濃度勾配を生成するのに十分な距離である。本発明に従った追加処理のないFab 1664、rhG−CSF、封入体Aおよび封入体B試料タンパク質調製物に対する沈降距離は、それぞれ、429、4.5、307および734cmであると測定され、封入体が30分後に撹拌していない高圧リフォールド反応の底に境界層を形成するのに十分であり、さらにリフォールドしたタンパク質収率の低下につながるであろう。目視検査によって、試料はすべて急速に沈降したことが観察された。
リフォールド懸濁液を50mMのCHES(pH10.0)、1M尿素、0.01%トリトンX−100および4mMのシステインの最適化されていない高圧リフォールディング条件で0.45mg/mlの一定タンパク質濃度にした。本発明による、処理された(「均質化した」)rhG−CSF安定タンパク質調製物または分散液を試料の調製後懸濁したままで、一方で、未処理対照(非均質化した)調製物は容器の底に沈降した。試料は200μL、600μL、1000μLおよび10mlの体積で、16時間2500バールで加圧処理した。
参照
Arakawa,T.およびS.N.Timasheff(1982).“Stabilization Of Protein−Structure By Sugars.”Biochemistry 21(25):6536−6544.
Bowden,G.A.,A.M.Paredesら(1991).“Structure and morphology of protein inclusion−bodies in escherichia coli.”Biotechnology 9(8):725−730.
de Nevers,N.(1970).Fluid Mechanics for Chemical Engineers,McGraw Hill.
Duffy,D.およびA.Hill(2011).Suspension Stability:Why Particle Size,Zeta Potential and Rheology are Important,www.malvern.comf.
Laidler,K.およびJ.Meiser編(1995).Physical Chemistry 2nd Edition.マサチューセッツ州、ボストン、ホートン・ミフリン社.
Qoronfleh,W.,L.K.Hesterbergら(2007).“Confronting high−throughput protein refolding using high pressure and solution screens.”Protein Expression and Purification 55:209−224.
Seefeldt,M.B.,C.Crouchら(2007).“Specific volume and adiabatic compressibility measurements of native and aggregated recombinant human interleukin−1 receptor antagonist:Density differences enable pressure−modulated refolding.”Biotechnology And Bioengineering 98(2):476−485.
Seefeldt,M.B.,J.Ouyangら(2004).“High−pressure refolding of bikunin: Efficacy and thermodynamics.”Protein Science 13(10):2639−2650.
St.John,R.J.,J.F.Carpenterら(2001).“High pressure refolding of recombinant human growth hormone from insoluble aggregates − Structural transformations, kinetic barriers, and energetics.”Journal of Biological Chemistry 276(50):46856−46863.
St.John,R.J.,J.F.Carpenterら(1999).“High pressure fosters protein refolding from aggregates at high concentrations.”Proceedings of the National Academy of Sciences of the United States of America 96(23):13029−13033.
Thomas,J.C.,A.P.J.Middelbergら(1990).“Sizing Biological Samples by Photosedimentation Techniques.”Biotechnology Progress 6:255−261.
Timasheff,S.N.(1992).“Water as Ligand−Preferential Binding and Exclusion of Denaturants in Protein Unfolding.”Biochemistry 31(41):9857−9864.
Timasheff,S.N.(1993).“The Control of Protein Stability and Association by Weak−Interactions with Water−How Do Solvents Affect These Processes.”Annual Review of Biophysics and Biomolecular Structure 22:67−97.
Claims (27)
- 封入体からタンパク質を製造するための方法であり、
a)封入体粒子を含むタンパク質調製物を提供すること、
b)安定な封入体分散液を調製することであって、前記分散液中の封入体粒子の50%超が1時間あたり10cm以下の沈降速度を有すること、および
c)前記封入体分散液を、容積が5L以上の圧力容器内で高圧に曝露すること、
を含み、それによって、前記封入体タンパク質を脱凝集およびリフォールディングする、方法。 - 前記封入体分散液が、非変性である、請求項1に記載の方法。
- 前記封入体分散液が、高圧の不在下で封入体を可溶化するのに十分なカオトロープおよび/または界面活性剤を含まない、請求項1または2に記載の方法。
- 前記圧力容器の体積が、10L以上である、請求項1〜3のいずれかに記載の方法。
- 前記圧力容器の体積が、50L以上である、請求項4に記載の方法。
- 前記タンパク質が、抗原結合領域または抗体Fc領域を含む治療用タンパク質である、請求項1〜5のいずれかに記載の方法。
- 前記封入体粒子の50%超が、10μm以下のサイズを有する、請求項1〜6のいずれかに記載の方法。
- 前記封入体粒子の50%超が、5μm以下のサイズを有する、請求項7に記載の方法。
- 前記封入体粒子の50%超が、3μm以下のサイズを有する、請求項7に記載の方法。
- 前記封入体粒子の50%超が、2.2μm以下のサイズを有する、請求項7に記載の方法。
- 分散前の前記封入体の調整物が、相当な数の20μmより大きい封入体粒子を含む、請求項1〜10のいずれかに記載の方法。
- 分散前の前記封入体の調製物が、30μmより大きい封入体粒子を含む、請求項11に記載の方法。
- 分散前の前記封入体の調製物が、50μmより大きい封入体粒子を含む、請求項11に記載の方法。
- 前記封入体分散液が、機械的せん断によって、または高圧均質化によって調製された、請求項1〜13のいずれかに記載の方法。
- 前記分散液の化学的性質が非変性界面活性剤、緩衝剤、塩、リフォールディング併用剤、増粘剤、または選択的排除性化合物の1つ以上を加えることで調節される、請求項1〜14のいずれかに記載の方法。
- 前記粒子のゼータ電位が、±10の範囲外になるよう調節される、請求項1〜15のいずれかに記載の方法。
- 前記粒子のゼータ電位が、±20の範囲外になるよう調節される、請求項16に記載の方法。
- 前記粒子のゼータ電位が、±30の範囲外になるよう調節される、請求項16に記載の方法。
- 選択的排除性化合物が、凝集を阻止する濃度で加えられる、請求項15に記載の方法。
- 前記封入体分散液が、凍結/解凍に供され、凝集しない、請求項1〜19のいずれかに記載の方法。
- 封入体タンパク質が、プロテアーゼ切断部位を有する融合タンパク質であり、プロテアーゼ切断に十分なプロテアーゼと一緒に高圧に供せられる、請求項1〜20のいずれかに記載の方法。
- 前記プロテアーゼが、ペスチウィルスプロテアーゼである、請求項21に記載の方法。
- 前記圧力容器の1つの軸が、前記圧力容器の第2の軸の少なくとも2倍であり、長い方の軸が水平になるよう前記圧力容器が配置される、請求項1〜22のいずれかに記載の方法。
- 10Lを超える圧力容器内でのタンパク質リフォールディングのための方法であり、
(a)封入体調製物として、封入体を含むタンパク質調製物を提供すること;
(b)高圧処理中の沈降速度が1時間あたり5cm未満になるように機械的せん断によって封入体の直径を縮小すること;
(c)pH、イオン強度および誘電率の1つ以上に基づいてリフォールディング溶液の化学的性質を選択すること;
(d)前記封入体タンパク質調製物を圧力容器内で高圧に曝露すること、
を含む、方法。 - 前記機械的せん断が、高圧均質化、微細流動装置、または固定オリフィスもしくは定圧処理機によって生成される、請求項24に記載の方法。
- 前記封入体タンパク質が、HIS−タグ、マルトース結合タンパク質、チオレドキシン、グルタチオン−s−トランスフェラーゼ、DsbA、gphD、FLAG、カルモジュリン結合タンパク質、strepタグII、ペスチウィルスプロテアーゼ、HA−タグ、Sofタグ1、Sofタグ3、c−myc、T7−タグ、S−タグ、NusA、キチン結合領域、キシナラーゼ10A、タバコエッチ病ウィルスおよびユビキチンから選択される融合パートナーを1つ以上伴う融合タンパク質として発現される、請求項24または25に記載の方法。
- 前記融合タンパク質が、プロテアーゼを含む、請求項26に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161565768P | 2011-12-01 | 2011-12-01 | |
US61/565,768 | 2011-12-01 | ||
PCT/US2012/067608 WO2013082599A1 (en) | 2011-12-01 | 2012-12-03 | Methods and systems for protein refolding |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2015504848A JP2015504848A (ja) | 2015-02-16 |
JP2015504848A5 JP2015504848A5 (ja) | 2015-12-24 |
JP6377527B2 true JP6377527B2 (ja) | 2018-08-22 |
Family
ID=48536165
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014544977A Expired - Fee Related JP6377527B2 (ja) | 2011-12-01 | 2012-12-03 | 高圧タンパク質リフォールディングのための方法およびシステム |
Country Status (8)
Country | Link |
---|---|
US (3) | US20140302589A1 (ja) |
EP (1) | EP2785196B1 (ja) |
JP (1) | JP6377527B2 (ja) |
CN (1) | CN104080357A (ja) |
BR (1) | BR112014013369A2 (ja) |
CA (1) | CA2857307A1 (ja) |
ES (1) | ES2829560T3 (ja) |
WO (1) | WO2013082599A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020152644A (ja) * | 2019-03-18 | 2020-09-24 | 国立大学法人愛媛大学 | Vnarのリフォールディング方法およびvnarの製造方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1095056B1 (en) | 1998-07-09 | 2006-12-27 | BaroFold, Inc. | High pressure refolding of protein aggregates and inclusion bodies |
DE10022258A1 (de) * | 2000-05-08 | 2001-11-15 | Bayer Ag | Reinigung von Proteineinschlusskörpern durch Querstrom-Mikrofiltration |
WO2002062827A2 (en) | 2000-10-31 | 2002-08-15 | The Regents Of The University Of Colorado, A Body Corporate | Improved protein disaggregation and refolding using high pressure |
EP1971435A2 (en) | 2005-11-21 | 2008-09-24 | BaroFold, Inc. | Devices and methods for high-pressure refolding of proteins |
US7829681B2 (en) | 2007-04-05 | 2010-11-09 | Barofold Inc. | High-pressure inclusion body solubilization and protease clipping of recombinant fusion proteins |
EP2205622A1 (en) * | 2007-09-10 | 2010-07-14 | BaroFold, Inc. | High-pressure refolding of monoclonal antibody aggregates |
WO2009045553A1 (en) * | 2007-10-05 | 2009-04-09 | Barofold, Inc. | High pressure treatment of aggregated interferons |
ES2352489B1 (es) | 2008-12-30 | 2012-01-04 | CONSEJO SUPERIOR DE INVESTIGACIONES CIENTÍFICAS (Titular al 41%) | Cuerpos de inclusión, celulas bacterianas y composiciones que los contienen y sus usos. |
-
2012
- 2012-12-03 CA CA2857307A patent/CA2857307A1/en active Pending
- 2012-12-03 WO PCT/US2012/067608 patent/WO2013082599A1/en unknown
- 2012-12-03 CN CN201280068811.4A patent/CN104080357A/zh active Pending
- 2012-12-03 ES ES12854533T patent/ES2829560T3/es active Active
- 2012-12-03 BR BR112014013369A patent/BR112014013369A2/pt not_active Application Discontinuation
- 2012-12-03 EP EP12854533.2A patent/EP2785196B1/en active Active
- 2012-12-03 JP JP2014544977A patent/JP6377527B2/ja not_active Expired - Fee Related
-
2014
- 2014-05-30 US US14/291,612 patent/US20140302589A1/en not_active Abandoned
-
2018
- 2018-08-14 US US16/103,812 patent/US20190218247A1/en not_active Abandoned
-
2020
- 2020-04-24 US US16/857,633 patent/US20200354400A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP2785196B1 (en) | 2020-08-05 |
CN104080357A (zh) | 2014-10-01 |
CA2857307A1 (en) | 2013-06-06 |
US20140302589A1 (en) | 2014-10-09 |
EP2785196A1 (en) | 2014-10-08 |
US20200354400A1 (en) | 2020-11-12 |
US20190218247A1 (en) | 2019-07-18 |
ES2829560T3 (es) | 2021-06-01 |
WO2013082599A1 (en) | 2013-06-06 |
EP2785196A4 (en) | 2015-07-29 |
JP2015504848A (ja) | 2015-02-16 |
BR112014013369A2 (pt) | 2017-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Vázquez‐Rey et al. | Aggregates in monoclonal antibody manufacturing processes | |
KR102572453B1 (ko) | 단백질 가공 처리를 위한 부형제 화합물 | |
JP2013521323A (ja) | 免疫グロブリン溶液を精製するための方法 | |
EP2956467B1 (en) | High ph protein refolding methods | |
US20230065872A1 (en) | Excipient compounds for protein processing | |
JP2016538267A (ja) | 抗体精製 | |
JP2009533429A (ja) | 陽イオン界面活性剤によるタンパク質の精製 | |
WO2005068489A1 (ja) | 2価陽イオン存在下加熱処理によるヒト血清アルブミンの製造方法 | |
US20200354400A1 (en) | Methods and systems for protein refolding | |
AU2007294680A1 (en) | High pressure treatment of proteins for reduced immunogenicity | |
EP3119412A1 (en) | Terminal nanofiltration of solubilized protein compositions for removal of immunogenic aggregates | |
US20090054628A1 (en) | Method and system for in vitro protein folding | |
WO2017143286A1 (en) | Functionalized nanoparticles for enhanced affinity precipitation of proteins | |
JP7449243B2 (ja) | 安定な融合タンパク質製剤 | |
US20150183876A1 (en) | High pressure refolding of monoclonal antibody aggregates | |
AU2013202965B2 (en) | Improved method for producing factor h from a plasma precipitation fraction | |
TWI779002B (zh) | 用於在酵母菌中製造重組介白素-11之系統及方法 | |
Sánchez-Moguel et al. | On-column refolding and off-column assembly of parvovirus B19 virus-like particles from bacteria-expressed protein | |
CN103608463A (zh) | 由使具有免疫球蛋白折叠结构的蛋白和能够形成亚单元结构的蛋白融合而得到的单体蛋白组成的多聚体蛋白的制备方法 | |
JP2015504848A5 (ja) | ||
TW202400229A (zh) | 用於生產抗體之細胞培養方法(二) | |
JP2011172602A (ja) | 組換え体ヒトfshの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151105 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20151105 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20161104 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170203 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170712 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20171012 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20171204 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180111 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20180111 |
|
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: 20180702 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180725 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6377527 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
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 |