DK2414380T3 - Fremgangsmåde til oprensning af rekombinant fsh - Google Patents
Fremgangsmåde til oprensning af rekombinant fsh Download PDFInfo
- Publication number
- DK2414380T3 DK2414380T3 DK10713424.9T DK10713424T DK2414380T3 DK 2414380 T3 DK2414380 T3 DK 2414380T3 DK 10713424 T DK10713424 T DK 10713424T DK 2414380 T3 DK2414380 T3 DK 2414380T3
- Authority
- DK
- Denmark
- Prior art keywords
- chromatography
- fsh
- anion exchange
- exchange chromatography
- recombinant
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 91
- 230000008569 process Effects 0.000 title claims description 11
- 238000000746 purification Methods 0.000 title description 13
- 238000005571 anion exchange chromatography Methods 0.000 claims description 56
- 108010082302 Human Follicle Stimulating Hormone Proteins 0.000 claims description 51
- 102000003864 Human Follicle Stimulating Hormone Human genes 0.000 claims description 51
- 238000004191 hydrophobic interaction chromatography Methods 0.000 claims description 49
- 239000012528 membrane Substances 0.000 claims description 44
- 239000011347 resin Substances 0.000 claims description 42
- 229920005989 resin Polymers 0.000 claims description 42
- 238000001042 affinity chromatography Methods 0.000 claims description 36
- 150000007523 nucleic acids Chemical class 0.000 claims description 29
- 238000005277 cation exchange chromatography Methods 0.000 claims description 23
- 238000001542 size-exclusion chromatography Methods 0.000 claims description 21
- 238000000108 ultra-filtration Methods 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 11
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 11
- 229920000936 Agarose Polymers 0.000 claims description 10
- 125000000524 functional group Chemical group 0.000 claims description 10
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 238000004271 weak anion exchange chromatography Methods 0.000 claims description 9
- 238000005341 cation exchange Methods 0.000 claims description 8
- 238000001728 nano-filtration Methods 0.000 claims description 8
- 238000004113 cell culture Methods 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 239000012609 strong anion exchange resin Substances 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
- 108020004707 nucleic acids Proteins 0.000 claims description 6
- 102000039446 nucleic acids Human genes 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000011324 bead Substances 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- 239000012475 sodium chloride buffer Substances 0.000 claims description 3
- JQYMGXZJTCOARG-UHFFFAOYSA-N Reactive blue 2 Chemical compound C1=2C(=O)C3=CC=CC=C3C(=O)C=2C(N)=C(S(O)(=O)=O)C=C1NC(C=C1S(O)(=O)=O)=CC=C1NC(N=1)=NC(Cl)=NC=1NC1=CC=CC(S(O)(=O)=O)=C1 JQYMGXZJTCOARG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims 2
- 238000012258 culturing Methods 0.000 claims 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 132
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 132
- 229940028334 follicle stimulating hormone Drugs 0.000 description 131
- 108090000623 proteins and genes Proteins 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 23
- 102000004169 proteins and genes Human genes 0.000 description 23
- 239000000872 buffer Substances 0.000 description 20
- 108091028043 Nucleic acid sequence Proteins 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 13
- 241000282414 Homo sapiens Species 0.000 description 12
- 229920002684 Sepharose Polymers 0.000 description 12
- 150000001768 cations Chemical class 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 125000003275 alpha amino acid group Chemical group 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 8
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 8
- 239000003957 anion exchange resin Substances 0.000 description 7
- 230000013595 glycosylation Effects 0.000 description 7
- 238000006206 glycosylation reaction Methods 0.000 description 7
- 125000001453 quaternary ammonium group Chemical group 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 238000011210 chromatographic step Methods 0.000 description 6
- 238000011026 diafiltration Methods 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 239000013017 sartobind Substances 0.000 description 6
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 239000003729 cation exchange resin Substances 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 229920006393 polyether sulfone Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000004627 regenerated cellulose Substances 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- 108091026890 Coding region Proteins 0.000 description 4
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 229940023913 cation exchange resins Drugs 0.000 description 4
- 239000012504 chromatography matrix Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000011067 equilibration Methods 0.000 description 4
- 238000003306 harvesting Methods 0.000 description 4
- 208000021267 infertility disease Diseases 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 210000001672 ovary Anatomy 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 238000013060 ultrafiltration and diafiltration Methods 0.000 description 4
- 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 3
- 108700010070 Codon Usage Proteins 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- YKCWQPZFAFZLBI-UHFFFAOYSA-N cibacron blue Chemical compound C1=2C(=O)C3=CC=CC=C3C(=O)C=2C(N)=C(S(O)(=O)=O)C=C1NC(C=C1S(O)(=O)=O)=CC=C1NC(N=1)=NC(Cl)=NC=1NC1=CC=CC=C1S(O)(=O)=O YKCWQPZFAFZLBI-UHFFFAOYSA-N 0.000 description 3
- -1 dimethylaminoethyl Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 230000005661 hydrophobic surface Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000021595 spermatogenesis Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000002305 strong-anion-exchange chromatography Methods 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- XELISBQUZZAPQK-CIUDSAMLSA-N Cys-His-Cys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N XELISBQUZZAPQK-CIUDSAMLSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 2
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- SOACHCFYJMCMHC-BWBBJGPYSA-N Ser-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N)O SOACHCFYJMCMHC-BWBBJGPYSA-N 0.000 description 2
- 239000012505 Superdex™ Substances 0.000 description 2
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 2
- 239000007994 TES buffer Substances 0.000 description 2
- 239000007997 Tricine buffer Substances 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 208000034953 Twin anemia-polycythemia sequence Diseases 0.000 description 2
- 108010087924 alanylproline Proteins 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000007998 bicine buffer Substances 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 239000012930 cell culture fluid Substances 0.000 description 2
- 229960004407 chorionic gonadotrophin Drugs 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 108010004073 cysteinylcysteine Proteins 0.000 description 2
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000012149 elution buffer Substances 0.000 description 2
- 239000006167 equilibration buffer Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000003325 follicular Effects 0.000 description 2
- 108010081934 follitropin beta Proteins 0.000 description 2
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001155 isoelectric focusing Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000012465 retentate Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000012610 weak anion exchange resin Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- GUPXYSSGJWIURR-UHFFFAOYSA-N 3-octoxypropane-1,2-diol Chemical compound CCCCCCCCOCC(O)CO GUPXYSSGJWIURR-UHFFFAOYSA-N 0.000 description 1
- 108010076441 Ala-His-His Proteins 0.000 description 1
- BUQICHWNXBIBOG-LMVFSUKVSA-N Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)N BUQICHWNXBIBOG-LMVFSUKVSA-N 0.000 description 1
- BSGSDLYGGHGMND-IHRRRGAJSA-N Arg-Phe-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N BSGSDLYGGHGMND-IHRRRGAJSA-N 0.000 description 1
- FVBZXNSRIDVYJS-AVGNSLFASA-N Arg-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N FVBZXNSRIDVYJS-AVGNSLFASA-N 0.000 description 1
- JEPNYDRDYNSFIU-QXEWZRGKSA-N Asn-Arg-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(N)=O)C(O)=O JEPNYDRDYNSFIU-QXEWZRGKSA-N 0.000 description 1
- UXHYOWXTJLBEPG-GSSVUCPTSA-N Asn-Thr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UXHYOWXTJLBEPG-GSSVUCPTSA-N 0.000 description 1
- KVPHTGVUMJGMCX-BIIVOSGPSA-N Asp-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N)C(=O)O KVPHTGVUMJGMCX-BIIVOSGPSA-N 0.000 description 1
- KPSHWSWFPUDEGF-FXQIFTODSA-N Asp-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(O)=O KPSHWSWFPUDEGF-FXQIFTODSA-N 0.000 description 1
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 101800005309 Carboxy-terminal peptide Proteins 0.000 description 1
- XEEIQMGZRFFSRD-XVYDVKMFSA-N Cys-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CS)N XEEIQMGZRFFSRD-XVYDVKMFSA-N 0.000 description 1
- DVKQPQKQDHHFTE-ZLUOBGJFSA-N Cys-Cys-Asn Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)N)C(=O)N DVKQPQKQDHHFTE-ZLUOBGJFSA-N 0.000 description 1
- QJUDRFBUWAGUSG-SRVKXCTJSA-N Cys-Cys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)N QJUDRFBUWAGUSG-SRVKXCTJSA-N 0.000 description 1
- KVGPYKUIHZJWGA-BQBZGAKWSA-N Cys-Met-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)NCC(O)=O KVGPYKUIHZJWGA-BQBZGAKWSA-N 0.000 description 1
- HJXSYJVCMUOUNY-SRVKXCTJSA-N Cys-Ser-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N HJXSYJVCMUOUNY-SRVKXCTJSA-N 0.000 description 1
- PXEGEYISOXISDV-XIRDDKMYSA-N Cys-Trp-Lys Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@@H](N)CS)=CNC2=C1 PXEGEYISOXISDV-XIRDDKMYSA-N 0.000 description 1
- FCXJJTRGVAZDER-FXQIFTODSA-N Cys-Val-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O FCXJJTRGVAZDER-FXQIFTODSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LXAUHIRMWXQRKI-XHNCKOQMSA-N Glu-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O LXAUHIRMWXQRKI-XHNCKOQMSA-N 0.000 description 1
- UENPHLAAKDPZQY-XKBZYTNZSA-N Glu-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)O)N)O UENPHLAAKDPZQY-XKBZYTNZSA-N 0.000 description 1
- NUSWUSKZRCGFEX-FXQIFTODSA-N Glu-Glu-Cys Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O NUSWUSKZRCGFEX-FXQIFTODSA-N 0.000 description 1
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 1
- BBBXWRGITSUJPB-YUMQZZPRSA-N Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(O)=O BBBXWRGITSUJPB-YUMQZZPRSA-N 0.000 description 1
- NTOWAXLMQFKJPT-YUMQZZPRSA-N Gly-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)CN NTOWAXLMQFKJPT-YUMQZZPRSA-N 0.000 description 1
- CCBIBMKQNXHNIN-ZETCQYMHSA-N Gly-Leu-Gly Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CCBIBMKQNXHNIN-ZETCQYMHSA-N 0.000 description 1
- VLIJYPMATZSOLL-YUMQZZPRSA-N Gly-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN VLIJYPMATZSOLL-YUMQZZPRSA-N 0.000 description 1
- YLEIWGJJBFBFHC-KBPBESRZSA-N Gly-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 YLEIWGJJBFBFHC-KBPBESRZSA-N 0.000 description 1
- KZTLOHBDLMIFSH-XVYDVKMFSA-N His-Ala-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O KZTLOHBDLMIFSH-XVYDVKMFSA-N 0.000 description 1
- KAXZXLSXFWSNNZ-XVYDVKMFSA-N His-Ser-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KAXZXLSXFWSNNZ-XVYDVKMFSA-N 0.000 description 1
- BRQKGRLDDDQWQJ-MBLNEYKQSA-N His-Thr-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O BRQKGRLDDDQWQJ-MBLNEYKQSA-N 0.000 description 1
- FFYYUUWROYYKFY-IHRRRGAJSA-N His-Val-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O FFYYUUWROYYKFY-IHRRRGAJSA-N 0.000 description 1
- 206010058359 Hypogonadism Diseases 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 1
- YESNGRDJQWDYLH-KKUMJFAQSA-N Leu-Phe-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)O)N YESNGRDJQWDYLH-KKUMJFAQSA-N 0.000 description 1
- AEDWWMMHUGYIFD-HJGDQZAQSA-N Leu-Thr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O AEDWWMMHUGYIFD-HJGDQZAQSA-N 0.000 description 1
- LZWNAOIMTLNMDW-NHCYSSNCSA-N Lys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N LZWNAOIMTLNMDW-NHCYSSNCSA-N 0.000 description 1
- PLDJDCJLRCYPJB-VOAKCMCISA-N Lys-Lys-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PLDJDCJLRCYPJB-VOAKCMCISA-N 0.000 description 1
- YRNRVKTYDSLKMD-KKUMJFAQSA-N Lys-Ser-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YRNRVKTYDSLKMD-KKUMJFAQSA-N 0.000 description 1
- TVOOGUNBIWAURO-KATARQTJSA-N Lys-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N)O TVOOGUNBIWAURO-KATARQTJSA-N 0.000 description 1
- PNDCUTDWYVKBHX-IHRRRGAJSA-N Met-Asp-Tyr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PNDCUTDWYVKBHX-IHRRRGAJSA-N 0.000 description 1
- USBFEVBHEQBWDD-AVGNSLFASA-N Met-Leu-Val Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O USBFEVBHEQBWDD-AVGNSLFASA-N 0.000 description 1
- LCPUWQLULVXROY-RHYQMDGZSA-N Met-Lys-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LCPUWQLULVXROY-RHYQMDGZSA-N 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 description 1
- INHMISZWLJZQGH-ULQDDVLXSA-N Phe-Leu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 INHMISZWLJZQGH-ULQDDVLXSA-N 0.000 description 1
- CBENHWCORLVGEQ-HJOGWXRNSA-N Phe-Phe-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CBENHWCORLVGEQ-HJOGWXRNSA-N 0.000 description 1
- GPLWGAYGROGDEN-BZSNNMDCSA-N Phe-Phe-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O GPLWGAYGROGDEN-BZSNNMDCSA-N 0.000 description 1
- XUSDDSLCRPUKLP-QXEWZRGKSA-N Pro-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 XUSDDSLCRPUKLP-QXEWZRGKSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- UGDMQJSXSSZUKL-IHRRRGAJSA-N Pro-Ser-Tyr Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O UGDMQJSXSSZUKL-IHRRRGAJSA-N 0.000 description 1
- 239000012564 Q sepharose fast flow resin Substances 0.000 description 1
- GXXTUIUYTWGPMV-FXQIFTODSA-N Ser-Arg-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O GXXTUIUYTWGPMV-FXQIFTODSA-N 0.000 description 1
- WTPKKLMBNBCCNL-ACZMJKKPSA-N Ser-Cys-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N WTPKKLMBNBCCNL-ACZMJKKPSA-N 0.000 description 1
- JWOBLHJRDADHLN-KKUMJFAQSA-N Ser-Leu-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JWOBLHJRDADHLN-KKUMJFAQSA-N 0.000 description 1
- WUXCHQZLUHBSDJ-LKXGYXEUSA-N Ser-Thr-Asp Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC(O)=O)C(O)=O WUXCHQZLUHBSDJ-LKXGYXEUSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010042573 Superovulation Diseases 0.000 description 1
- GLQFKOVWXPPFTP-VEVYYDQMSA-N Thr-Arg-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GLQFKOVWXPPFTP-VEVYYDQMSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- VGYVVSQFSSKZRJ-OEAJRASXSA-N Thr-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CC=CC=C1 VGYVVSQFSSKZRJ-OEAJRASXSA-N 0.000 description 1
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 1
- DIHPMRTXPYMDJZ-KAOXEZKKSA-N Thr-Tyr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N)O DIHPMRTXPYMDJZ-KAOXEZKKSA-N 0.000 description 1
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-N 0.000 description 1
- SBYQHZCMVSPQCS-RCWTZXSCSA-N Thr-Val-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O SBYQHZCMVSPQCS-RCWTZXSCSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- JISIQDCOHJOOPU-WFBYXXMGSA-N Trp-Cys-Ala Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O JISIQDCOHJOOPU-WFBYXXMGSA-N 0.000 description 1
- VCXWRWYFJLXITF-AUTRQRHGSA-N Tyr-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VCXWRWYFJLXITF-AUTRQRHGSA-N 0.000 description 1
- GFZQWWDXJVGEMW-ULQDDVLXSA-N Tyr-Arg-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O GFZQWWDXJVGEMW-ULQDDVLXSA-N 0.000 description 1
- BODHJXJNRVRKFA-BZSNNMDCSA-N Tyr-Cys-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BODHJXJNRVRKFA-BZSNNMDCSA-N 0.000 description 1
- KOVXHANYYYMBRF-IRIUXVKKSA-N Tyr-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O KOVXHANYYYMBRF-IRIUXVKKSA-N 0.000 description 1
- WVGKPKDWYQXWLU-BZSNNMDCSA-N Tyr-His-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CCCCN)C(=O)O)N)O WVGKPKDWYQXWLU-BZSNNMDCSA-N 0.000 description 1
- XGZBEGGGAUQBMB-KJEVXHAQSA-N Tyr-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC2=CC=C(C=C2)O)N)O XGZBEGGGAUQBMB-KJEVXHAQSA-N 0.000 description 1
- COYSIHFOCOMGCF-UHFFFAOYSA-N Val-Arg-Gly Natural products CC(C)C(N)C(=O)NC(C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-UHFFFAOYSA-N 0.000 description 1
- CVIXTAITYJQMPE-LAEOZQHASA-N Val-Glu-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CVIXTAITYJQMPE-LAEOZQHASA-N 0.000 description 1
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 1
- SJRUJQFQVLMZFW-WPRPVWTQSA-N Val-Pro-Gly Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SJRUJQFQVLMZFW-WPRPVWTQSA-N 0.000 description 1
- RLVTVHSDKHBFQP-ULQDDVLXSA-N Val-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=C(O)C=C1 RLVTVHSDKHBFQP-ULQDDVLXSA-N 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003011 anion exchange membrane Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 206010003883 azoospermia Diseases 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 108010069495 cysteinyltyrosine Proteins 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 108010077515 glycylproline Proteins 0.000 description 1
- 230000001456 gonadotroph Effects 0.000 description 1
- 229940057854 gonal f Drugs 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 230000002706 hydrostatic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 201000003368 hypogonadotropic hypogonadism Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000001592 luteinising effect Effects 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000008634 oligospermia Diseases 0.000 description 1
- 230000036616 oligospermia Effects 0.000 description 1
- 231100000528 oligospermia Toxicity 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 1
- 108010065135 phenylalanyl-phenylalanyl-phenylalanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000003751 purification from natural source Methods 0.000 description 1
- 238000003571 reporter gene assay Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000009450 sialylation Effects 0.000 description 1
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000012799 strong cation exchange Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 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
- C07K14/575—Hormones
- C07K14/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- 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
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/18—Ion-exchange chromatography
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- 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
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
-
- 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
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/20—Partition-, reverse-phase or hydrophobic interaction chromatography
-
- 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
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
-
- 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
- C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
-
- 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
- C12P21/005—Glycopeptides, glycoproteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Reproductive Health (AREA)
- Zoology (AREA)
- Analytical Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Claims (22)
1. Fremgangsmåde til oprensning af rekombinant FSH eller rekombinant FSH-variant, omfattende trinnene at underkaste en væske indeholdende FSH eller FSH-varianten for: - anionbytterkromatografi, - hydrofob interaktionskromatografi, og - farveaffinitetskromatografi, der udføres i en hvilken som helst rækkefølge, hvor fremgangsmåden enten omfatter svag anionbytterkromatografi eller revers fasekromatografi.
2. Fremgangsmåden ifølge krav 1, hvor trinnene udføres i følgende rækkefølge: a) anionbytterkromatografi b) hydrofob interaktionskromatografi, og c) farveaffinitetskromatografi.
3. Fremgangsmåden ifølge krav 1 eller 2, hvor anionbytterkromatografi udføres under anvendelse af en stærk anionbytterresin med -N+(CH3)3 funktionelle grupper, eller en resin med lignende karakteristika.
4. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor den hydrofobe interaktionskromatografi udføres under anvendelse af en resin bestående af tværbundne agaroseperler derivatiseret med phenyl- eller butylgrupper, eller en resin med lignende karakteristika.
5. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor farveaffinitetskromatografi udføres med Cibacron Blue 3G som liganden, kovalent bundet til en hvilken som helst matriks.
6. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor kromatografien udføres under anvendelse af en Tris-HCI/natriumchloridbuffer som elueringsmiddel ved et pH i området mellem 7,0 og 9,0.
7. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, fremgangsmåden endvidere omfattende kationbytterkromatografi.
8. Fremgangsmåden ifølge krav 7, hvor kationbytterkromatografien udføres med en stærk sur kationbyttersulfonsyre fastgjort på en membran, eller en bytter med lignende karakteristika.
9. Fremgangsmåden ifølge krav 7 eller 8, hvor trinnene udføres i følgende rækkefølge: a) anionbytterkromatografi, b) hydrofob interaktionskromatografi, c) farveaffinitetskromatografi, og d) kationbytterkromatografi.
10. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 6, endvidere omfattende yderligere anionbytterkromatografi.
11. Fremgangsmåden ifølge krav 10, hvor anionbytterkromatografi udføres under anvendelse af en stærk anionbytterresin med -N+(CH3)3 funktionelle grupper, eller en resin med lignende karakteristika.
12. Fremgangsmåden ifølge krav 10 or 11, hvor anionbytterkromatografi udføres under anvendelse af en Tris-HCI /natriumchloridbuffer som elueringsmiddel ved en pH i området mellem 7,0 og 9,0.
13. Fremgangsmåden ifølge et hvilket som helst af kravene 10 til 12, hvor trinnene udføres i følgende rækkefølge: a) en første anionbytterkromatografi, b) hydrofob interaktionskromatografi, c) farveaffinitetskromatografi, d) eventuel kationbytterkromatografi, og e) en anden anionbytterkromatografi.
14. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 6, fremgangsmåden endvidere omfattende størrelseseksklusionskromatografi.
15. Fremgangsmåden ifølge krav 14, hvor størrelseseksklusionskromatografien udføres under anvendelse af en matriks af sfærisk komposit af tværbunden agarose og dextran.
16. Fremgangsmåden ifølge krav 14 eller 15, hvor trinnene udføres i følgende rækkefølge: a) en første anionbytterkromatografi, b) hydrofob interaktionskromatografi, c) farveaffinitetskromatografi, d) eventuel kationbytterkromatografi, e) en eventuel anden anionbytterkromatografi, og f) størrelseseksklusionskromatografi.
17. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, omfattende følgende trin i følgende rækkefølge: a) en første anionbytterkromatografi, b) hydrofob interaktionskromatografi, c) farveaffinitetskromatografi, d) membrankationbytning, e) en anden anionbytterkromatografi, og f) størrelseseksklusionskromatografi.
18. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, yderligere omfattende ét eller flere ultrafiltrerings- og/eller nanofiltreringstrin.
19. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor ingen metalion-affinitetskromatografi udføres.
20. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor ingen immuno-affinitetskromatografi udføres.
21. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor FSH har en α-underenhed ifølge SEQ ID No. 1 og en β-underenhed ifølge SEQ ID No. 2.
22. Fremgangsmåde til fremstilling af rekombinant humant FSH omfattende trinnene at a) generere en CHO-celleklon der producerer rekombinant humant FSH fra én eller flere rekombinante nukleinsyremolekyler der koder for α-kæden og β-kæden af humant FSH, b) dyrkning af CHO-værtscellerne under egnede betingelser, og c) oprense rekombinant humant FSH fra cellekulturen ifølge fremgangsmåden ifølge et hvilket som helst af kravene 1 til 21.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09157133 | 2009-04-01 | ||
| PCT/EP2010/002111 WO2010115586A2 (en) | 2009-04-01 | 2010-04-01 | Method for purifying recombinant fsh |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2414380T3 true DK2414380T3 (da) | 2015-10-19 |
Family
ID=42153744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK10713424.9T DK2414380T3 (da) | 2009-04-01 | 2010-04-01 | Fremgangsmåde til oprensning af rekombinant fsh |
Country Status (26)
| Country | Link |
|---|---|
| US (3) | US9096683B2 (da) |
| EP (1) | EP2414380B1 (da) |
| JP (2) | JP5845170B2 (da) |
| KR (1) | KR101761168B1 (da) |
| CN (1) | CN102448979B (da) |
| AU (1) | AU2010234028B2 (da) |
| BR (1) | BRPI1012647B1 (da) |
| CA (1) | CA2755927A1 (da) |
| CY (1) | CY1116963T1 (da) |
| DK (1) | DK2414380T3 (da) |
| EA (1) | EA028065B1 (da) |
| ES (1) | ES2552055T3 (da) |
| HR (1) | HRP20151086T1 (da) |
| HU (1) | HUE025959T2 (da) |
| IL (1) | IL215234A (da) |
| ME (1) | ME02277B (da) |
| MX (1) | MX2011010480A (da) |
| NZ (1) | NZ595661A (da) |
| PL (1) | PL2414380T3 (da) |
| PT (1) | PT2414380E (da) |
| RS (1) | RS54318B1 (da) |
| SI (1) | SI2414380T1 (da) |
| SM (1) | SMT201500276B (da) |
| UA (1) | UA106369C2 (da) |
| WO (1) | WO2010115586A2 (da) |
| ZA (1) | ZA201106800B (da) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5845170B2 (ja) * | 2009-04-01 | 2016-01-20 | ラティオファーム ゲーエムベーハー | 組換えｆｓｈを精製する方法 |
| CN103570820B (zh) * | 2012-08-06 | 2015-11-18 | 齐鲁制药有限公司 | 一种重组人促卵泡激素的纯化方法 |
| KR101516054B1 (ko) * | 2012-11-21 | 2015-05-06 | 씨제이헬스케어 주식회사 | 신규한 지속형 인간 성장호르몬 단량체를 제조하는 방법 |
| CN103059125B (zh) * | 2012-12-27 | 2015-08-12 | 浙江海正药业股份有限公司 | 重组人促卵泡激素的纯化方法 |
| US20160024181A1 (en) | 2013-03-13 | 2016-01-28 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
| CN103539860B (zh) * | 2013-11-01 | 2014-12-03 | 广州优联康医药科技有限公司 | 一种长效重组人促卵泡激素融合蛋白 |
| CN103539861B (zh) * | 2013-11-01 | 2015-02-18 | 广州联康生物科技有限公司 | 长效重组人促卵泡激素融合蛋白 |
| CA2945591A1 (en) * | 2014-04-18 | 2015-10-22 | Cadila Healthcare Limited | Novel purification process of gonadotropin |
| CN104479005B (zh) * | 2014-09-05 | 2017-10-31 | 上海丽珠制药有限公司 | 一种促性腺激素纯化的方法 |
| CN105461799A (zh) * | 2015-12-31 | 2016-04-06 | 哈药集团技术中心 | 一种重组人促卵泡生成素的纯化方法 |
| CN106117342B (zh) * | 2016-07-07 | 2020-01-03 | 江西浩然生物医药有限公司 | 一种高纯度尿促卵泡素的制备方法 |
| RU2694598C1 (ru) * | 2018-08-07 | 2019-07-16 | Федеральное государственное бюджетное учреждение науки институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наук (ИБХ РАН) | Клеточная линия huFSHKKc6 - продуцент рекомбинантного человеческого фолликулостимулирующего гормона (ФСГ) и способ получения ФСГ с использованием данной линии |
| KR102752765B1 (ko) * | 2019-12-26 | 2025-01-14 | 주식회사 엘지화학 | 여포 자극 호르몬의 정제 방법 |
| KR102283871B1 (ko) * | 2021-03-02 | 2021-08-02 | 한국원자력연구원 | 크로마토그래피를 이용한 무담체 홀뮴-166의 분리 방법, 분리 장치 및 이에 의하여 분리된 무담체 홀뮴-166 |
| CN113372433B (zh) * | 2021-03-12 | 2022-10-11 | 上海景泽生物技术有限公司 | 纯化fsh方法 |
| CN114591414A (zh) * | 2022-03-24 | 2022-06-07 | 江西浩然生物制药有限公司 | 一种人绒毛膜促性腺激素的制备方法 |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4923805A (en) | 1983-11-02 | 1990-05-08 | Integrated Genetics, Inc. | Fsh |
| US6455282B1 (en) * | 1983-11-02 | 2002-09-24 | Genzyme Corporation | Cells, vectors and methods for producing biologically active TSH |
| US4840896A (en) | 1983-11-02 | 1989-06-20 | Integrated Genetics, Inc. | Heteropolymeric protein |
| IT1206302B (it) | 1987-06-26 | 1989-04-14 | Serono Cesare Ist Ricerca | Ormone follicolo-stimolante urinario |
| CA2018676C (en) | 1989-06-20 | 2003-05-06 | Christie A. Kelton | Novel heteropolymeric protein production methods |
| US5021160A (en) * | 1990-01-09 | 1991-06-04 | Gelman Sciences, Inc. | Strongly acidic microporous membranes for cation exchange |
| DE4440587A1 (de) | 1994-11-14 | 1996-05-15 | Fliether Karl Gmbh & Co | Basquill-Schloß |
| US6261823B1 (en) * | 1996-12-13 | 2001-07-17 | Schering Corporation | Methods for purifying viruses |
| AU747179B2 (en) | 1997-06-25 | 2002-05-09 | Merck Serono Sa | Disulfide cross-linked glycoprotein hormone analogs, their preparation and use |
| US6414123B1 (en) * | 1997-10-21 | 2002-07-02 | Vitro Diagnostics, Inc. | Method for purifying FSH |
| US5990288A (en) * | 1997-10-21 | 1999-11-23 | Vitro Diagnostics, Inc. | Method for purifying FSH |
| ATE358139T1 (de) | 1999-04-16 | 2007-04-15 | Inst Massone S A | Verfahren zur herstelllung von gonadotropin- zusammensetzungen |
| WO2001058493A1 (en) | 2000-02-11 | 2001-08-16 | Maxygen Aps | Conjugates of follicle stimulating hormones |
| US7157277B2 (en) * | 2001-11-28 | 2007-01-02 | Neose Technologies, Inc. | Factor VIII remodeling and glycoconjugation of Factor VIII |
| AU2003240832A1 (en) | 2002-05-31 | 2003-12-19 | E.I. Du Pont De Nemours And Company | Copolymers having tunable energy levels and color of emission |
| WO2004087213A1 (en) | 2003-04-02 | 2004-10-14 | Ares Trading S.A. | Liquid pharmaceutical formulations of fsh and lh together with a non-ionic surfactant |
| ATE446314T1 (de) * | 2003-12-22 | 2009-11-15 | Ares Trading Sa | Methode zur reinigung von fsh |
| EP1809663B1 (en) | 2004-11-09 | 2008-09-17 | Ares Trading S.A. | Method for purifying fsh |
| TW200728316A (en) * | 2005-12-09 | 2007-08-01 | Ares Trading Sa | Method for purifying FSH or a FSH mutant |
| JP5199112B2 (ja) * | 2005-12-09 | 2013-05-15 | アレス トレーディング ソシエテ アノニム | Ｆｓｈ又はｆｓｈ変異体を精製するための方法 |
| CN101720332B (zh) | 2007-06-28 | 2014-08-13 | 拉蒂奥法姆有限责任公司 | 生产促卵泡激素的细胞克隆 |
| CL2008002054A1 (es) * | 2007-07-17 | 2009-05-29 | Hoffmann La Roche | Metodo para la regeneracion de una columna de cromatografia de intercambio cationico despues de la elusion de eritropoyetina monopeguilada y metodo para obtener una eritropoyetina monopeguilada, incorporando el metodo de regeneracion de la columna de intercambio cationico. |
| JP5845170B2 (ja) * | 2009-04-01 | 2016-01-20 | ラティオファーム ゲーエムベーハー | 組換えｆｓｈを精製する方法 |
-
2010
- 2010-04-01 JP JP2012502514A patent/JP5845170B2/ja not_active Expired - Fee Related
- 2010-04-01 BR BRPI1012647-3A patent/BRPI1012647B1/pt not_active IP Right Cessation
- 2010-04-01 EP EP10713424.9A patent/EP2414380B1/en active Active
- 2010-04-01 PT PT107134249T patent/PT2414380E/pt unknown
- 2010-04-01 MX MX2011010480A patent/MX2011010480A/es unknown
- 2010-04-01 RS RS20150682A patent/RS54318B1/sr unknown
- 2010-04-01 KR KR1020117025974A patent/KR101761168B1/ko not_active Expired - Fee Related
- 2010-04-01 US US13/262,622 patent/US9096683B2/en not_active Expired - Fee Related
- 2010-04-01 NZ NZ595661A patent/NZ595661A/xx not_active IP Right Cessation
- 2010-04-01 PL PL10713424T patent/PL2414380T3/pl unknown
- 2010-04-01 WO PCT/EP2010/002111 patent/WO2010115586A2/en not_active Ceased
- 2010-04-01 HU HUE10713424A patent/HUE025959T2/en unknown
- 2010-04-01 UA UAA201112796A patent/UA106369C2/ru unknown
- 2010-04-01 ES ES10713424.9T patent/ES2552055T3/es active Active
- 2010-04-01 AU AU2010234028A patent/AU2010234028B2/en not_active Ceased
- 2010-04-01 DK DK10713424.9T patent/DK2414380T3/da active
- 2010-04-01 CA CA2755927A patent/CA2755927A1/en not_active Abandoned
- 2010-04-01 ME MEP-2015-172A patent/ME02277B/me unknown
- 2010-04-01 CN CN201080022681.1A patent/CN102448979B/zh active Active
- 2010-04-01 HR HRP20151086TT patent/HRP20151086T1/hr unknown
- 2010-04-01 SI SI201031050T patent/SI2414380T1/sl unknown
- 2010-04-01 EA EA201171199A patent/EA028065B1/ru not_active IP Right Cessation
-
2011
- 2011-09-15 ZA ZA2011/06800A patent/ZA201106800B/en unknown
- 2011-09-19 IL IL215234A patent/IL215234A/en active IP Right Grant
-
2015
- 2015-06-15 US US14/739,935 patent/US20150353599A1/en not_active Abandoned
- 2015-09-09 JP JP2015177674A patent/JP6231056B2/ja not_active Expired - Fee Related
- 2015-10-30 CY CY20151100971T patent/CY1116963T1/el unknown
- 2015-11-04 SM SM201500276T patent/SMT201500276B/it unknown
-
2016
- 2016-07-01 US US15/200,714 patent/US20160304575A1/en not_active Abandoned
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2010234028B2 (en) | Method for purifying recombinant FSH | |
| KR101173717B1 (ko) | Ｆｓｈ를 정제하는 방법 | |
| KR101160985B1 (ko) | Ｆｓｈ를 정제하는 방법 | |
| EP2325194A1 (en) | Process for the purification of glycoproteins | |
| EP1960419A2 (en) | Method for purifying fsh or a fsh mutant | |
| JP4933439B2 (ja) | Ｆｓｈの精製方法 | |
| WO2024233992A2 (en) | Methods of manufacturing highly glycosylated glycoprotein hormones and their analogs | |
| HK1108704B (en) | Method for purifying fsh | |
| HK1099031B (en) | Method for purifying fsh |