JP2008541748A - 組換えil−18結合タンパク質の生産 - Google Patents
組換えil−18結合タンパク質の生産 Download PDFInfo
- Publication number
- JP2008541748A JP2008541748A JP2008514112A JP2008514112A JP2008541748A JP 2008541748 A JP2008541748 A JP 2008541748A JP 2008514112 A JP2008514112 A JP 2008514112A JP 2008514112 A JP2008514112 A JP 2008514112A JP 2008541748 A JP2008541748 A JP 2008541748A
- Authority
- JP
- Japan
- Prior art keywords
- perfusion
- cell
- cells
- protein
- production
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010070145 interleukin-18 binding protein Proteins 0.000 title claims abstract description 161
- 102000044166 interleukin-18 binding protein Human genes 0.000 title claims abstract description 159
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 105
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 230000008569 process Effects 0.000 claims abstract description 15
- 230000010412 perfusion Effects 0.000 claims description 88
- 210000004027 cell Anatomy 0.000 claims description 66
- 108090000623 proteins and genes Proteins 0.000 claims description 46
- 102000004169 proteins and genes Human genes 0.000 claims description 46
- 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 claims description 35
- 239000008103 glucose Substances 0.000 claims description 31
- 230000002378 acidificating effect Effects 0.000 claims description 21
- 230000010261 cell growth Effects 0.000 claims description 19
- 238000004113 cell culture Methods 0.000 claims description 16
- 210000004962 mammalian cell Anatomy 0.000 claims description 13
- 230000009450 sialylation Effects 0.000 claims description 9
- 238000010790 dilution Methods 0.000 claims description 8
- 239000012895 dilution Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 241000699802 Cricetulus griseus Species 0.000 claims description 5
- 239000012228 culture supernatant Substances 0.000 claims description 5
- 210000001672 ovary Anatomy 0.000 claims description 4
- 230000035899 viability Effects 0.000 claims description 4
- 230000016507 interphase Effects 0.000 claims description 3
- 230000013595 glycosylation Effects 0.000 abstract description 10
- 238000006206 glycosylation reaction Methods 0.000 abstract description 10
- 235000018102 proteins Nutrition 0.000 description 45
- 102000001708 Protein Isoforms Human genes 0.000 description 32
- 108010029485 Protein Isoforms Proteins 0.000 description 32
- 239000000047 product Substances 0.000 description 32
- 102000003810 Interleukin-18 Human genes 0.000 description 28
- 108090000171 Interleukin-18 Proteins 0.000 description 28
- 239000002609 medium Substances 0.000 description 28
- 238000011282 treatment Methods 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 238000005515 capillary zone electrophoresis Methods 0.000 description 17
- 239000000523 sample Substances 0.000 description 15
- 230000003612 virological effect Effects 0.000 description 15
- 102000037865 fusion proteins Human genes 0.000 description 14
- 108020001507 fusion proteins Proteins 0.000 description 14
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 11
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 11
- 125000000539 amino acid group Chemical group 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 102000003886 Glycoproteins Human genes 0.000 description 7
- 108090000288 Glycoproteins Proteins 0.000 description 7
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 238000000746 purification Methods 0.000 description 6
- 230000007704 transition Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical group CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 5
- 108010076504 Protein Sorting Signals Proteins 0.000 description 5
- 125000003275 alpha amino acid group Chemical group 0.000 description 5
- 230000003698 anagen phase Effects 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001962 electrophoresis Methods 0.000 description 5
- 238000003306 harvesting Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000013507 mapping Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 238000011020 pilot scale process Methods 0.000 description 5
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000004448 titration Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001042 affinity chromatography Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- -1 polyethylene Polymers 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 239000012925 reference material Substances 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000002109 Argyria Diseases 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000012679 serum free medium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 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 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102100035017 Interleukin-18-binding protein Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 2
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 2
- 208000012868 Overgrowth Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 150000001720 carbohydrates Chemical group 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 230000019522 cellular metabolic process Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000011033 desalting Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 102000035122 glycosylated proteins Human genes 0.000 description 2
- 108091005608 glycosylated proteins Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000002751 oligonucleotide probe Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 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
- 230000002265 prevention Effects 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 239000012521 purified sample Substances 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000037351 starvation Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004114 suspension culture Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102100037080 C4b-binding protein beta chain Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010009208 Cirrhosis alcoholic Diseases 0.000 description 1
- 208000018652 Closed Head injury Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100029951 Estrogen receptor beta Human genes 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CHDWDBPJOZVZSE-KKUMJFAQSA-N Glu-Phe-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O CHDWDBPJOZVZSE-KKUMJFAQSA-N 0.000 description 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
- 108700023372 Glycosyltransferases Proteins 0.000 description 1
- 238000012855 HCP-ELISA Methods 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000740689 Homo sapiens C4b-binding protein beta chain Proteins 0.000 description 1
- 101000960954 Homo sapiens Interleukin-18 Proteins 0.000 description 1
- 101001019591 Homo sapiens Interleukin-18-binding protein Proteins 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
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 101710205006 Interleukin-18-binding protein Proteins 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
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- KFEUJDWYNGMDBV-LODBTCKLSA-N N-acetyllactosamine Chemical group O[C@@H]1[C@@H](NC(=O)C)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KFEUJDWYNGMDBV-LODBTCKLSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102000000447 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Human genes 0.000 description 1
- 108010055817 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 241000583281 Sugiura Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 208000010002 alcoholic liver cirrhosis Diseases 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- YETHWGOYCQLNKG-FHERGOJNSA-N alpha-D-Manp-(1->3)-[alpha-D-Manp-(1->6)]-alpha-D-Manp-(1->2)-alpha-D-Manp-(1->2)-D-Manp Chemical group O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@H]1O[C@@H]1[C@@H](O[C@@H]2[C@H]([C@@H](O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 YETHWGOYCQLNKG-FHERGOJNSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000000947 anti-immunosuppressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 238000002869 basic local alignment search tool Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000011072 cell harvest Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012526 feed medium Substances 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 1
- 102000045442 glycosyltransferase activity proteins Human genes 0.000 description 1
- 108700014210 glycosyltransferase activity proteins Proteins 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 102000043959 human IL18 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000003917 human chromosome Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 102000014909 interleukin-1 receptor activity proteins Human genes 0.000 description 1
- 108040006732 interleukin-1 receptor activity proteins Proteins 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 101150103303 mioC gene Proteins 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 235000006286 nutrient intake Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 238000012868 site-directed mutagenesis technique Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Communicable Diseases (AREA)
- Vascular Medicine (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
Abstract
Description
a) 生産処理の全体に渡り、不変値でかん流量を固定すること。
このアプローチは、堅実且つ継続的に操作するためにより簡便であるから、一般に工業生産工程において好適である。また処理間のかん流量にばらつきがないため、工程の中間コストを定めるのに利点を有する。
b) 細胞数及び/またはグルコース(Oh等. 1994) (Dowd等. 2001) (Gorenflo等. 2003)、グルタミン(Gorenflo等. 2002)、または酸素(Kyung等. 1994)等の栄養消費量に応じて、かん流量を調整すること。
このアプローチは、かん流量を調整するためのより科学的な論拠を提供するが、過剰発育培養及びかん流量の“制御不能”な増加をもたらし得る。細胞を懸濁様式で培養する場合は、"培養流出(culture bleed)"をして培養の過剰発育を回避するが、細胞を担体上に固定する場合はこれを回避できない。ゆえに一般にこのアプローチは、堅実且つ継続的な方法で操作することが困難であり、また毎日培地かん流量の再調整を行う必要があるような製造操作には向かない。
c) a)とb)の両戦略を初期細胞増殖期(または"成長期")と組み合せること。
ここでは細胞代謝を比較的低い不変レベルで安定化し保持するために、温度及び/またはpH等の培養条件を移行した後の成長期の間に、かん流量を細胞成長の要求に従って徐々に増加させる。この段階でのかん流量は生産期の間の細胞の減少した要求に合致する固定値まで減少させることができる。
本発明は、無血清の培養条件下にあるバイオリアクター中の哺乳動物細胞において組換えインターロイキン-18結合タンパク質(IL-18BP)を生産するための方法の開発に関し、約37℃での細胞増殖期、及び約29℃〜約34℃の範囲の温度での生産期を含んで成る。
a) 37℃で一定のかん流量(100%)での細胞増殖期;
b) 33.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期I;
c) 32.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期II、を含んで成る。
a. 37℃での細胞増殖期;
b. 任意に33℃での間期;
c. 29℃での生産期、を含んで成る。
本発明は、無血清の細胞培養条件下にあるバイオリアクター中で組換えIL-18BPを生産するための効率的な方法の開発に基づく。したがって本発明は、無血清の培養条件下にあるバイオリアクター中の哺乳動物細胞において組換えインターロイキン-18結合タンパク質(IL-18BP)を生産するための方法に関し、約37℃での細胞増殖期、及び約29℃〜約34℃の範囲の温度での生産期を含んで成る。
a) 37℃で一定のかん流量(100%)での細胞増殖期;
b) 33.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期I;
c) 32.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期II、を含んで成る。
a. 37℃での細胞増殖期;
b. 任意に33℃での間期;
c. 29℃での生産期、を含んで成る。
本実施例は、充填層バイオリアクター中での組換えCHO細胞の高細胞密度培養に基づく方法を発表する。ここでのかん流量は、成長期の間は細胞成長の要求に伴い調整し、その後の生産期の間は方法の生産性またはタンパク質の品質を落とさずに顕著に減少させた。
細胞培養−実験系
Fibra-Cel(商標)担体(Bibby Sterilin, 英国)を有する充填層バイオリアクター(Ducommun等. 2002a; Ducommun等. 2002b)を、CHO細胞(Laboratoires Serono S.A., Corsier-sur-Vevey, スイス)を培養するために使用し、無血清培地(Sigma C-9486)中でIL-18BPを発現及び分泌させた。かん流量の減少を調査するために用いた小規模系では、バイオリアクターと充填層は、15リットル及び5リットルの処理容量をそれぞれ有した。
培養中は、サンプルを毎日取り除いた。グルコースと乳酸塩の濃度はEML 105分析器(Radiometer Medical A/S, Bronshoj, デンマーク)で定量した。
かん流量の減少
最初の試みは、生産期の間のかん流量を2.6 vvdから2.0 vvd及び1.3 vvdに減少させること(図1)、及びその細胞代謝への影響、体積生産性、及び製品の品質を追跡することであった。
図5A、B及びCに示した結果は、参照処理-100と減少した培地かん流での処理において生産した組換えタンパク質の比較を示す(体積生産性、全生産量、および滴定濃度)。
2.6 vvdから2.0 vvd及び1.3 vvdまでのかん流量の減少について、処理-100、処理-75、及び処理-50に関して試験した。組換えタンパク質の滞留時間(t)は、それぞれ0.4日から0.5日及び0.8日に増加した(t=1/D)。
生産された組換えIL-18BPのサンプルは、注目のタンパク質の多様なシアル化形態の比率を定量するために、上記で示した方法に従いN-グリカンマッピングに供した。N-グリカンマッピングの結果は、比較可能なN-グリカンの比率が試験された全てのかん流量で得られたことを示す表2に要約した。これは図6に示した対応のHPLCプロファイルによっても説明されている。
本研究では、Fibra-Cel(商標)ディスク担体でできている充填層バイオリアクター中での組換えCHO細胞株の連続培養に使用される最適な培地かん流量を決定した。
小規模で得られた結果から、かん流量の−25%の減少は、生産性の最大化の利益と−25%の培地消費の節約の利益が組み合されたことが明白である。
懸濁培養における組換えヒトIL-18発現細胞による流加方法も同様に開発された。合計で3つの処理を5 L (n=2)または300 L (n=1)の標準容量のバイオリアクターを用いて実行した。
表3:流加製造方法スキーム
2) 5Lと300Lのバイオリアクターは、それぞれ小規模(5L)とパイロット規模(300L)のの操作用である。
3) 供給-1の最初の付加は、c(グルコース)<1.0 g/L (+80 g/kg)のときに起こる。
4) 供給-1のその後の付加は、c(グルコース)<5.5 g/L (+30 g/kg)のときに起こる。
* WD=処理日数
** VCs=生存細胞
IL-18BPを生産するための更なるかん流方法を設定した。かん流処理は、4.4 kgのFibracel(商標)-ディスクでパックした160 Lの総容量(40 Lの外部カラムを含む)を含むバイオリアクター中で、33.5または32.5℃の生産温度で、2.75 vvdのかん流量で実施した。
Z=A (中性)×0+A (モノ)×1+A (ジ)×2+A (トリ)×3+A (テトラ)×4+A (ペンタ)×5。
CZE溶液
- 5 mMのホスフェートCZE洗浄/処理緩衝液:
50 mMのホスフェート貯蔵溶液pH 7.0を1:10に希釈して調製する。0.22 μmのフィルターを通しろ過する。新たに調製する。
- 0.5 MのNaOH (CZE洗浄液):
26.2 μlの50%のNaOHを水に付加し、1 mLの総容量とする。新たに調製する。
- 1 MのNaOH (CZE再生液):
52.4μlの50%のNaOHを水に付加し、1 mLの総容量とする。新たに調製する。
- 中性マーカー(1:10000に希釈)
10 μlの中性マーカー貯蔵溶液を水に付加し、1 mLの総容量とする。10 μLのこの中性マーカー1:100希釈物を水に付加し、1 mlの総容量とする。3ヶ月間、4℃で貯蔵する。
≧20 μLのサンプル/参照を1/10の容積の中性マーカーを含むPCRバイアル中に移して、泡を立てずにリバースピペッティングで混合する。
極性 陽性対陰性(前進)
温度 キャピラリー=25±2℃
サンプル台 =10±2℃
検出 214 nm
キャピラリー調整の目的のために、少なくとも3つの標準参照物質を注入すべきである。
標準参照1(開始)
サンプル1の単回注入
サンプル2の単回注入
サンプル3の単回注入
サンプル4の単回注入
標準参照2(終了)
注:再生産能を増加させるために、参照1と参照2の間の1順で、同一のCZE処理緩衝剤を用いて最大で4つのサンプルを分析することができる。
標準参照(開始1)
サンプル1の単回注入
標準参照(終了1/開始2)
サンプル2の単回注入
標準参照反復(終了2/開始3)
サンプル3の単回注入
標準参照反復(終了3)
標準参照物質はサンプルデータの比較のために使用される。重層され、また積み重ねられたエレクトロフェログラムのサンプルと両括弧内の参照標準(開始/終了)はプリントアウトして保管される。
参照標準(開始)の−3と+3のピークの左と右の谷間で移行時間MT2及びMT3が決定される。0ピークは、参照の主要ピークである。
IL-18BP糖タンパク質の強い酸性プロファイルによって、MT2とMT3の間のアイソフォームは"酸性アイソフォーム"と名付けられた。MT3よりも長い移行時間を有するアイソフォームは"強酸性アイソフォーム"と名付けられた。MT2よりも短い移行時間を有するアイソフォームは"弱酸性アイソフォーム"と名付けられた。
参照とそれぞれのサンプルを、MT1-M2、MT2-MT3及びMT3-MT4の間のマニュアルピーク;5分と28分の間のマニュアルベースライン、並びに0とMT1の間、及びMT4と30分の間のインテグレーションオフの機能を用いて分析した。マニュアル的に幅(Width)と基準点(Threshold)の機能を改変して、上記の参照標準と類似するMT1-M2(より弱酸性のアイソフォーム)、MT2-MT3(酸性アイソフォーム)及びMT3-MT4(より強酸性のアイソフォーム)の間の3つのピークの群の統合を得る。
本CZE法は粗採取物サンプル、並びにかん流方法及び流加方法の両方の精製サンプルに適用された(図9)。前処理された採取物サンプルで多少の相違が観察されたが(例えばかん流方法による塩基性アイソフォームの高い比率)、これらの塩基性アイソフォームは精製工程の間のイオン交換クロマトグラフィーでうまく除去された(データは示されていない)。したがって精製生産物に関しては、比較可能なアイソフォームプロファイルが両方法で得られた(図10)。
Altschul S F等(1990) Basic local alignment search tool. J Mol Biol, 215, 403-410.
Altschul S F等(1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res., 25:389-3402
Andersen DC, Bridges T, Gawlitzek M,及びHoy C (2000) Multiple cell culture factors can affect the glycosylation of Asn-184 in CHO-produced tissue-type Plasminogen Activator. Biotechnol Bioeng 70 1 : 25-31.
Chuppa S., Tsai Y.-S., Yoon S., Shackleford S., Rozales C, Bhat R., Tsay G., Matanguihan C, Konstantinov K.,及びNaveh D. (1997) Fermentor temperature as a tool for control of high-density perfusion cultures of mammalian cells. Biotechnol Bioeng 55 2: 328-338.
Devereux J等(1984) A comprehensive set of sequence analysis programs for the VAX Nucleic Acids Res, 12, 387-395.
Dowd J. E., Kwok K. E.,及びPiret J. M. (2001) Glucose-based optimization of CHO-cell perfusion cultures. Biotechnology and Bioengineering 75 2: 252-256.
Ducommun P., Kadouri A., von Stockar U., 及びMarison I.W. (2002a) On-line determination of animal cell concentration in two industrial high-density culture processes by dielectric spectroscopy. Biotechnology and Bioengineering 77 3:316-323.
Ducommun P., Ruffieux P.-A., von Stockar U., 及びMarison I. W. (2002b) Monitoring of temperature effects on animal cell metabolism in a packed bed process. Biotechnol Bioeng 77 7: 838-842.
Gervais A, Hammel YA, Pelloux S, Lepage P, Baer G., Carte N, Sorokine O, Strub JM, Koerner R, Leize E, 及び Van Dorsselaer A (2003) Glycosylation of human recombinant gonadotrophins : characterization and batch-to-batch consistency.
Glycobiology 13 3: 179-189.
Goldman MH, James D.C, Rendall M., lson A.P., Hoare M., 及びBull A.T. (1998)
Monitoring recombinant human interferon-gamma N-glycosilation during perfused fluidized-bed and stirred-tank batch culture of CHO cells. Biotech. Bioeng. 60 5: 596-607.
Goochee C.F., Gramer M.J., Andersen D.C, Bahr J.B.,及びRasmussen J.R. (1991)
The oligosaccharides of glycoproteins: bioprocess factors affecting oligosaccharide structure and their effect on glycoprotein properties.Biotechnology (N.Y.) 9 12: 1347-1355.
Goochee C. F.及びMonica T. (1990) Environmental effects on protein glycosylation. Biotechnology (N.Y.) 8 5: 421-427.
Grantham等. (1974) Amino acid difference formula to help explain protein evolution. Science, Vol. 185, pp. 862-864
Harvey (2001) Identification of protein-bound carbohydrates by mass spectrometry. Proteomics 1 , 311-238
Hayter P.M., Curling E.M.A., Gould M.L., Baines A.J., Jenkins N., Salmon I., Strange P.G.,及びBull A.T. (1993) The effect of the dilution rate on CHO cell physiology and recombinant interferon-gamma production in glucose-limited chemostat culture. Biotechnology and Bioengineering 42 9: 1077-1085.
Hermentin P, Witzel R, Kanzy EJ, Diderrich G, Hoffmann D, Metzner H, Vorlop J, Haupt H. The hypothetical N-glycan charge: a number that characterizes protein glycosylation. Glycobiology. 1996 Mar;6(2):217-30.
Hooker AD, Goldman MH, Markham N., James D.C, lson A.P., Bull A.T., Strange P.G., Salmon I., Baines A.J., 及びJenkins N (1995) N-Glycans of recombinant human interferon-g change during batch culture of Chinese hamster ovary cells. Biotech. Bioeng. 48 : 639-648.
Hu W.-S.及びAunins J.G. (1997) Large-scale mammalian cell culture. Current Opinion in Biotechnology 8 : 148-153.
Jenkins N., Parekh R.B,及びJames D.C.(1996) Getting the glycosilation right: Implications for the biotechnology industry. Nature Biotechnology 14 : 975-981.
Kadouri A.及びSpier R.E.(1997) Some myths and messages concerning the batch and continuous culture of animal cells. Cytotechnology 24 : 89-98.
Kim SH, Eisenstein M, Reznikov L, Fantuzzi G, Novick D, Rubinstein M, Dinarello CA.
Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci U S A 2000;97:1190-1195.
Kyung Yun-Seung, Peshwa Madhusudan V., Gryte David M.,及びHu Wei-Shou (1994) High density culture of mammalian cells with dynamic perfusion based on online oxygen uptake rate measurements. Cytotechnology 14 : 183-190.
Novick, D, Kim, S-H, Fantuzzi, G, Reznikov, L, Dinarello, C, 及びRubinstein, M (1999)。Immunity 10, 127-136
Oh D.J., Choi S.K.,及びChang H.N.(1994) High-density continuous cultures of hybridoma cells in a depth filter perfusion system. Biotechnology and Bioengineering 44 : 895-901.
Pearson (1990) Rapid and sensitive sequence comparison with FASTP and FASTA Methods Enzymol. 1990; 183:63-98
Puren等. (1999) Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci U S A. 96(5):2256-61.
Racher A.J.及びGriffiths J.B.(1993) Investigation of parameters affecting a fixed bed bioreactor process for recombinant cell lines. Cytotechnology 13 : 125-131.
Racher A.J., Looby D.,及びGriffiths J. B. (1993) Influence of ammonium ion and glucose on mAb production in suspension and fixed bed hybridoma cultures. Journal of Biotechnology 29: 145-156.
Sugiura T.及びKakuzaki M. (1998) Dynamics of recombinant protein production by mammalian cells in immobilized perfusion culture. Enzyme and Microbial Technology 22 : 699-704.
Vigers等., Nature. 1997 Mar 13;386(6621):190-4.
Wang M-D., Yang M.,及びButler M.(2002) Erythropoietin production from CHO cells grown by continuous culture in a fluidized-bed bioreactor. Biotechnology and Bioengineering 77 2: 194-203.
Claims (18)
- 無血清の培養条件下にあるバイオリアクター中の哺乳動物細胞において組換えインターロイキン-18結合タンパク質(IL-18BP)を生産するための方法であって、約37℃の温度での細胞増殖期と約29℃〜約34℃の範囲の温度での生産期を含んで成る方法。
- 前記方法がかん流方法であって、以下のステップ:
a. 37℃で、一定のかん流量(100%)での細胞増殖期;
b. 33.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期I;
c. 32.5℃で、ステップ(a)のかん流量の約85〜約65%または約80〜約70%の範囲、或いは約75%のかん流量での生産期II、を含んで成る、請求項1に記載の方法。 - 前記ステップ(a)のかん流量が約2〜約3 vvdの範囲、好適には約2.5 vvdの希釈率を有する、請求項2に記載の方法。
- 前記細胞が担体に結合され、且つステップ(b)の生産期Iが担体のキログラムあたり、約250〜350 gのグルコース消費量で開始される、請求項2または3に記載の方法。
- 前記哺乳動物細胞がチャイニーズハムスター卵巣(CHO)細胞である、請求項1〜4のいずれか1項に記載の方法。
- 細胞培養の上澄みを収集するステップを更に含んで成る、請求項1〜5のいずれか1項に記載の方法。
- IL-18BPを精製するステップを更に含んで成る、請求項1〜6のいずれか1項に記載の方法。
- IL-18BPを医薬組成物に製剤化するステップを更に含んで成る、請求項1〜7のいずれか1項に記載の方法。
- 請求項1〜8のいずれか1項に記載の方法によって生産されたIL-18BP組成物であって、約15〜約25%のシアル化されていないN-グリカン、約15〜約30%のモノ-シアル化グリカン、約35〜約55%のジ-シアル化N-グリカン、約5〜約15%のトリ-シアル化N-グリカン、及び約1〜約5%のテトラ-シアル化N-グリカンを含むシアル化プロファイルによって特徴付けられるIL-18BP組成物。
- 前記方法が流加方法であって、以下のステップ:
a. 37℃での細胞増殖期;
b. 任意に33℃での間期;
c. 29℃での生産期、を含んで成る、請求項1に記載の方法。 - 前記生産期における総細胞密度が、好適には少なくとも10日間の細胞培養で、1日あたり、1mlあたり、4〜8×106個の細胞の範囲である、請求項10に記載の方法。
- 好適には少なくとも10日間の細胞培養で、生存能が100〜80%の範囲である、請求項10または11に記載の方法。
- タンパク質生産性が約150 mgまたは約250 mgより高い、或いはIあたり、1日あたり約350より高い請求項10〜12のいずれか1項に記載の方法。
- 前記哺乳動物細胞がチャイニーズハムスター卵巣(CHO)細胞である、請求項10〜13のいずれか1項に記載の方法。
- 細胞培養の上澄みを収集するステップを更に含んで成る、請求項10〜14のいずれか1項に記載の方法。
- IL-18BPを精製するステップを更に含んで成る、請求項10〜15のいずれか1項に記載の方法。
- IL-18BPを医薬組成物に製剤化するステップを更に含んで成る、請求項10〜16のいずれか1項に記載の方法。
- 請求項10〜17のいずれか1項に記載の方法によって生産されたIL-18BP組成物であって、約0〜約15%の塩基性の糖型、約15〜約30%の弱酸性の糖型、約45〜約65%の酸性の糖型、及び約10〜約25%の強酸性の糖型を含む糖型プロファイルを有するIL-18BP組成物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US68763105P | 2005-06-03 | 2005-06-03 | |
EP05104878 | 2005-06-03 | ||
US60/687,631 | 2005-06-03 | ||
EP05104878.3 | 2005-06-03 | ||
EP05106429.3 | 2005-07-13 | ||
EP05106429 | 2005-07-13 | ||
PCT/EP2006/062851 WO2006128908A1 (en) | 2005-06-03 | 2006-06-01 | Production of recombinant il-18 binding protein |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012247547A Division JP5837476B2 (ja) | 2005-06-03 | 2012-11-09 | 組換えil−18結合タンパク質の生産 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2008541748A true JP2008541748A (ja) | 2008-11-27 |
JP5199073B2 JP5199073B2 (ja) | 2013-05-15 |
Family
ID=44352415
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008514112A Active JP5199073B2 (ja) | 2005-06-03 | 2006-06-01 | 組換えil−18結合タンパク質の生産 |
JP2012247547A Active JP5837476B2 (ja) | 2005-06-03 | 2012-11-09 | 組換えil−18結合タンパク質の生産 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012247547A Active JP5837476B2 (ja) | 2005-06-03 | 2012-11-09 | 組換えil−18結合タンパク質の生産 |
Country Status (15)
Country | Link |
---|---|
US (2) | US7691611B2 (ja) |
EP (2) | EP1885753B1 (ja) |
JP (2) | JP5199073B2 (ja) |
AT (2) | ATE517917T1 (ja) |
AU (1) | AU2006254103B2 (ja) |
CA (1) | CA2609060C (ja) |
CY (2) | CY1111969T1 (ja) |
DK (2) | DK1885753T3 (ja) |
ES (2) | ES2370417T3 (ja) |
IL (1) | IL187838A (ja) |
NO (1) | NO342802B1 (ja) |
PL (2) | PL1885753T3 (ja) |
PT (2) | PT2267024E (ja) |
SI (2) | SI2267024T1 (ja) |
WO (1) | WO2006128908A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016536332A (ja) * | 2013-09-05 | 2016-11-24 | エイビー2 バイオ ソシエテアノニム | 炎症性疾患におけるil−18結合タンパク質(il−18bp) |
JP2018532791A (ja) * | 2015-11-05 | 2018-11-08 | ジェネクシン・インコーポレイテッドGenexine, Inc. | 遺伝子組み換えヒト甲状腺刺激ホルモンを含む組成物および遺伝子組み換えヒト甲状腺刺激ホルモンを生産する方法 |
US10882905B2 (en) | 2015-03-05 | 2021-01-05 | Ab2 Bio Sa | IL-18 binding protein (IL-18BP) and antibodies in inflammatory diseases |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001236807A1 (en) * | 2000-02-10 | 2001-08-20 | Abbott Laboratories | Antibodies that bind human interleukin-18 and methods of making and using |
AU2004219917B2 (en) * | 2003-03-11 | 2008-01-31 | Merck Serono Sa | Expression vectors comprising the mCMV IE2 promoter |
CA2524403C (en) * | 2003-05-13 | 2013-07-09 | Applied Research Systems Ars Holding N.V. | Active variants of the il-18 binding protein and medical uses thereof |
DE602004029598D1 (de) | 2003-10-21 | 2010-11-25 | Merck Serono Sa | Minimale dna sequenz, die als chromatin-isolator wirkt, und deren verwendung für die protein-expression |
WO2005049649A1 (en) * | 2003-11-05 | 2005-06-02 | Ares Trading S.A. | Process for the purification of il-18 binding protein |
US7968684B2 (en) | 2003-11-12 | 2011-06-28 | Abbott Laboratories | IL-18 binding proteins |
WO2005083058A1 (en) | 2004-03-01 | 2005-09-09 | Ares Trading S.A. | Use of a serum-free cell culture medium for the production of il-18bp in mammalian cells |
US7439336B2 (en) | 2004-06-29 | 2008-10-21 | Ares Trading S.A. | Process for the purification of IL-18 binding protein |
SI1891088T1 (sl) | 2005-06-10 | 2012-02-29 | Ares Trading Sa | Postopek za äśiĺ äśenje il-18 vezavnega proteina |
US20160145589A1 (en) | 2011-06-24 | 2016-05-26 | Green Cross Corporation | Composition and formulation comprising recombinant human iduronate-2-sulfatase and preparation method thereof |
KR101857380B1 (ko) * | 2011-07-01 | 2018-05-11 | 암젠 인크 | 포유동물 세포 배양 |
US9150841B2 (en) | 2012-06-29 | 2015-10-06 | Shire Human Genetic Therapies, Inc. | Cells for producing recombinant iduronate-2-sulfatase |
KR101380740B1 (ko) | 2012-06-29 | 2014-04-11 | 쉐어 휴먼 제네텍 세러피스, 인코포레이티드 | 이듀로네이트-2-설파타제의 정제 |
US20140004097A1 (en) * | 2012-06-29 | 2014-01-02 | Shire Human Genetic Therapies, Inc. | Method of producing recombinant iduronate-2-sulfatase |
US9217168B2 (en) | 2013-03-14 | 2015-12-22 | Momenta Pharmaceuticals, Inc. | Methods of cell culture |
US9677105B2 (en) * | 2013-03-14 | 2017-06-13 | Momenta Pharmaceuticals, Inc. | Methods of cell culture |
US8956830B2 (en) | 2013-03-14 | 2015-02-17 | Momenta Pharmaceuticals, Inc. | Methods of cell culture |
EP3391942A1 (en) * | 2013-03-26 | 2018-10-24 | Coherus Biosciences, Inc. | Protein production method |
USD759075S1 (en) * | 2014-04-11 | 2016-06-14 | Nutonian, Inc. | Display screen with graphical user interface |
USD759076S1 (en) * | 2014-04-18 | 2016-06-14 | Nutonian, Inc. | Display screen with graphical user interface |
KR102694992B1 (ko) | 2017-10-16 | 2024-08-14 | 리제너론 파아마슈티컬스, 인크. | 관류 바이오리액터 및 관련 사용 방법 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0975077A (ja) * | 1995-09-19 | 1997-03-25 | Suntory Ltd | 動物細胞の新規培養方法 |
JP2004516830A (ja) * | 2000-12-05 | 2004-06-10 | アプライド・リサーチ・システムズ・エイアールエス・ホールディング・ナムローゼ・フェンノートシャップ | 哺乳動物系における組換えタンパク質の均質性および分泌の改良 |
WO2004058800A2 (en) * | 2002-12-23 | 2004-07-15 | Bristol-Myers Squibb Company | Mammalian cell culture processes for protein production |
WO2005049649A1 (en) * | 2003-11-05 | 2005-06-02 | Ares Trading S.A. | Process for the purification of il-18 binding protein |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4737462A (en) | 1982-10-19 | 1988-04-12 | Cetus Corporation | Structural genes, plasmids and transformed cells for producing cysteine depleted muteins of interferon-β |
US4588585A (en) | 1982-10-19 | 1986-05-13 | Cetus Corporation | Human recombinant cysteine depleted interferon-β muteins |
US4959314A (en) | 1984-11-09 | 1990-09-25 | Cetus Corporation | Cysteine-depleted muteins of biologically active proteins |
US5116943A (en) | 1985-01-18 | 1992-05-26 | Cetus Corporation | Oxidation-resistant muteins of Il-2 and other protein |
US5266476A (en) | 1985-06-18 | 1993-11-30 | Yeda Research & Development Co., Ltd. | Fibrous matrix for in vitro cell cultivation |
US5017691A (en) | 1986-07-03 | 1991-05-21 | Schering Corporation | Mammalian interleukin-4 |
US4879111A (en) | 1986-04-17 | 1989-11-07 | Cetus Corporation | Treatment of infections with lymphokines |
US4965195A (en) | 1987-10-26 | 1990-10-23 | Immunex Corp. | Interleukin-7 |
US4904584A (en) | 1987-12-23 | 1990-02-27 | Genetics Institute, Inc. | Site-specific homogeneous modification of polypeptides |
AU1235692A (en) | 1991-01-18 | 1992-08-27 | Synergen, Inc. | Methods for treating tumor necrosis factor mediated diseases |
WO1997030161A1 (en) | 1996-02-20 | 1997-08-21 | Applied Research Systems Ars Holding N.V. | Hybrid proteins which form heterodimers |
NZ333325A (en) | 1996-07-12 | 2000-06-23 | Genentech Inc | Recombinant chimeric heteromultimer adhesins comprising extracellular domains of ErbB receptors |
IL121860A0 (en) * | 1997-08-14 | 1998-02-22 | Yeda Res & Dev | Interleukin-18 binding proteins their preparation and use |
WO2001000814A2 (en) | 1999-06-25 | 2001-01-04 | Universität Zürich | Hetero-associating coiled-coil peptides and screenign method therefor |
ES2317843T3 (es) | 1999-07-13 | 2009-05-01 | Bolder Biotechnology, Inc. | Proteinas de fusion de eritropoyetina-inmunoglobulina. |
IL131047A0 (en) | 1999-07-22 | 2001-01-28 | Yeda Res & Dev | Use of il-18 inhibitors |
UA74557C2 (en) * | 1999-09-03 | 2006-01-16 | Applied Research Systems | A method for producing a heterologous secreted protein from chinese hamster ovaries cells grown on microcarriers |
KR20020086540A (ko) | 2000-02-21 | 2002-11-18 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Il-18 저해물질의 용도 |
JP5122053B2 (ja) | 2000-05-05 | 2013-01-16 | メルク セロノ ソシエテ アノニム | アテローム性動脈硬化症の治療および/または予防のためのil−18阻害剤の用途 |
ZA200305439B (en) | 2001-01-29 | 2004-07-15 | Applied Research Systems | Use of IL-18 inhibitors for the treatment and/or prevention of heat disease. |
EA005769B1 (ru) | 2001-03-08 | 2005-06-30 | Арес Трейдинг С.А. | Мутанты интерлейкина-18, их продуцирование и применение |
CN100556450C (zh) | 2001-05-16 | 2009-11-04 | 耶达研究发展有限公司 | Il-18抑制剂在治疗或预防脓毒症中的应用 |
BR0210007A (pt) | 2001-05-25 | 2004-08-10 | Ares Trading Sa | Uso de inibidores de il-18 para tratamento ou prevenção de lesões do sistema nervoso central |
UA78516C2 (en) | 2001-08-10 | 2007-04-10 | Applied Research Systems | Use of inhibitors of il-18 for treatment and/or prevention of hypersensitivity disorders, and in particular of delayed-type hypersensitivity |
ATE414556T1 (de) | 2002-03-22 | 2008-12-15 | Serono Lab | Verwendung von il-18-inhibitoren zur behandlung und/oder prävention von peripheren gefässkrankheiten |
CN1726283A (zh) | 2002-08-14 | 2006-01-25 | 阿维迪斯公司 | 利用c4bp支架制备多聚体融合蛋白 |
WO2004033486A2 (en) | 2002-10-11 | 2004-04-22 | Zymogenetics, Inc. | Production of homotrimeric fusion proteins |
AU2004219917B2 (en) | 2003-03-11 | 2008-01-31 | Merck Serono Sa | Expression vectors comprising the mCMV IE2 promoter |
CA2524403C (en) | 2003-05-13 | 2013-07-09 | Applied Research Systems Ars Holding N.V. | Active variants of the il-18 binding protein and medical uses thereof |
DE602004029598D1 (de) * | 2003-10-21 | 2010-11-25 | Merck Serono Sa | Minimale dna sequenz, die als chromatin-isolator wirkt, und deren verwendung für die protein-expression |
WO2005083058A1 (en) | 2004-03-01 | 2005-09-09 | Ares Trading S.A. | Use of a serum-free cell culture medium for the production of il-18bp in mammalian cells |
US7439336B2 (en) * | 2004-06-29 | 2008-10-21 | Ares Trading S.A. | Process for the purification of IL-18 binding protein |
SI1891088T1 (sl) | 2005-06-10 | 2012-02-29 | Ares Trading Sa | Postopek za äśiĺ äśenje il-18 vezavnega proteina |
-
2006
- 2006-06-01 EP EP06763472A patent/EP1885753B1/en active Active
- 2006-06-01 WO PCT/EP2006/062851 patent/WO2006128908A1/en not_active Application Discontinuation
- 2006-06-01 PT PT10184728T patent/PT2267024E/pt unknown
- 2006-06-01 DK DK06763472.5T patent/DK1885753T3/da active
- 2006-06-01 US US11/915,453 patent/US7691611B2/en active Active
- 2006-06-01 DK DK10184728.3T patent/DK2267024T3/da active
- 2006-06-01 PL PL06763472T patent/PL1885753T3/pl unknown
- 2006-06-01 AT AT06763472T patent/ATE517917T1/de active
- 2006-06-01 JP JP2008514112A patent/JP5199073B2/ja active Active
- 2006-06-01 ES ES06763472T patent/ES2370417T3/es active Active
- 2006-06-01 PT PT06763472T patent/PT1885753E/pt unknown
- 2006-06-01 CA CA2609060A patent/CA2609060C/en active Active
- 2006-06-01 ES ES10184728T patent/ES2385639T3/es active Active
- 2006-06-01 AU AU2006254103A patent/AU2006254103B2/en active Active
- 2006-06-01 PL PL10184728T patent/PL2267024T3/pl unknown
- 2006-06-01 SI SI200631379T patent/SI2267024T1/sl unknown
- 2006-06-01 EP EP10184728A patent/EP2267024B1/en active Active
- 2006-06-01 AT AT10184728T patent/ATE557038T1/de active
- 2006-06-01 SI SI200631144T patent/SI1885753T1/sl unknown
-
2007
- 2007-12-03 IL IL187838A patent/IL187838A/en active IP Right Grant
- 2007-12-27 NO NO20076672A patent/NO342802B1/no unknown
-
2010
- 2010-02-15 US US12/705,773 patent/US20100137195A1/en not_active Abandoned
-
2011
- 2011-10-27 CY CY20111101026T patent/CY1111969T1/el unknown
-
2012
- 2012-06-29 CY CY20121100583T patent/CY1113056T1/el unknown
- 2012-11-09 JP JP2012247547A patent/JP5837476B2/ja active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0975077A (ja) * | 1995-09-19 | 1997-03-25 | Suntory Ltd | 動物細胞の新規培養方法 |
JP2004516830A (ja) * | 2000-12-05 | 2004-06-10 | アプライド・リサーチ・システムズ・エイアールエス・ホールディング・ナムローゼ・フェンノートシャップ | 哺乳動物系における組換えタンパク質の均質性および分泌の改良 |
WO2004058800A2 (en) * | 2002-12-23 | 2004-07-15 | Bristol-Myers Squibb Company | Mammalian cell culture processes for protein production |
WO2005049649A1 (en) * | 2003-11-05 | 2005-06-02 | Ares Trading S.A. | Process for the purification of il-18 binding protein |
Non-Patent Citations (4)
Title |
---|
JPN6011013643; Bioetchnol. Bioeng. vol.82, no.3, 2003, pp.289-298 * |
JPN6011013644; Bioetchnol. Bioeng. vol.84, no.4, 2003, pp.433-438 * |
JPN6011013645; Bioetchnol. Bioeng. vol.85, no.2, 2004, pp.177-184 * |
JPN6011064292; Biotechnol. Bioeng. vol.77, no.7, 2002, pp.838-842 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016536332A (ja) * | 2013-09-05 | 2016-11-24 | エイビー2 バイオ ソシエテアノニム | 炎症性疾患におけるil−18結合タンパク質(il−18bp) |
US10858426B2 (en) | 2013-09-05 | 2020-12-08 | Ab2 Bio Sa | IL-18 binding protein (IL-18BP) in inflammatory diseases |
US10882905B2 (en) | 2015-03-05 | 2021-01-05 | Ab2 Bio Sa | IL-18 binding protein (IL-18BP) and antibodies in inflammatory diseases |
US11820817B2 (en) | 2015-03-05 | 2023-11-21 | Ab2 Bio Sa | IL-18 binding protein (IL-18BP) and antibodies in inflammatory diseases |
US11926663B2 (en) | 2015-03-05 | 2024-03-12 | Ab2 Bio Sa | IL-18 binding protein (IL-18BP) and antibodies in inflammatory diseases |
JP2018532791A (ja) * | 2015-11-05 | 2018-11-08 | ジェネクシン・インコーポレイテッドGenexine, Inc. | 遺伝子組み換えヒト甲状腺刺激ホルモンを含む組成物および遺伝子組み換えヒト甲状腺刺激ホルモンを生産する方法 |
Also Published As
Publication number | Publication date |
---|---|
IL187838A0 (en) | 2008-03-20 |
DK2267024T3 (da) | 2012-06-25 |
SI2267024T1 (sl) | 2012-09-28 |
EP2267024A1 (en) | 2010-12-29 |
NO342802B1 (no) | 2018-08-06 |
NO20076672L (no) | 2008-02-22 |
WO2006128908A1 (en) | 2006-12-07 |
AU2006254103B2 (en) | 2012-09-06 |
DK1885753T3 (da) | 2011-10-03 |
PL1885753T3 (pl) | 2011-12-30 |
AU2006254103A1 (en) | 2006-12-07 |
ES2385639T3 (es) | 2012-07-27 |
ATE557038T1 (de) | 2012-05-15 |
ES2370417T3 (es) | 2011-12-15 |
EP1885753B1 (en) | 2011-07-27 |
CA2609060C (en) | 2014-07-15 |
EP1885753A1 (en) | 2008-02-13 |
EP2267024B1 (en) | 2012-05-09 |
PL2267024T3 (pl) | 2012-10-31 |
JP2013048633A (ja) | 2013-03-14 |
JP5837476B2 (ja) | 2015-12-24 |
JP5199073B2 (ja) | 2013-05-15 |
PT1885753E (pt) | 2011-10-06 |
IL187838A (en) | 2011-07-31 |
SI1885753T1 (sl) | 2011-12-30 |
CA2609060A1 (en) | 2006-12-07 |
US7691611B2 (en) | 2010-04-06 |
US20100137195A1 (en) | 2010-06-03 |
CY1113056T1 (el) | 2016-04-13 |
ATE517917T1 (de) | 2011-08-15 |
PT2267024E (pt) | 2012-06-01 |
US20080199913A1 (en) | 2008-08-21 |
CY1111969T1 (el) | 2015-11-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5837476B2 (ja) | 組換えil−18結合タンパク質の生産 | |
EP1699821B1 (en) | Fc-ERYTHROPOIETIN FUSION PROTEIN WITH IMPROVED PHARMACOKINETICS | |
TW516962B (en) | A human TNFR1-IgG1 preparation | |
TWI403519B (zh) | Fgf21突變體及其用途 | |
DK1917276T3 (en) | Process for Preparation of Glycosylated Interferon Beta | |
JP2010529833A5 (ja) | ||
WO2005083058A1 (en) | Use of a serum-free cell culture medium for the production of il-18bp in mammalian cells | |
JP2021535153A (ja) | Enpp1ポリペプチドおよびその使用方法 | |
RU2698671C2 (ru) | КОЛИЧЕСТВЕННАЯ ОЦЕНКА НЕПРАВИЛЬНО СВЕРНУТОГО TNFR2:Fc | |
CN106459900B (zh) | 包含尿苷和n-乙酰基-d-甘露糖胺的培养基 | |
CN112111475B (zh) | 一种经上皮细胞转运能力增强的TNK-tPA融合蛋白及其应用 | |
RU2805879C1 (ru) | Штамм линии клеток яичника китайского хомячка | |
EP3241908B1 (en) | Method for regulating glycosylation of recombinant glycoprotein | |
WO2022254319A1 (en) | Cell culture method for producing sfgfr3 polypeptide | |
NZ733430A (en) | A method for controlling glycosylation of recombinant glycoprotein |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090529 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20111206 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120305 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120312 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120323 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20120710 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121109 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20121113 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20121204 |
|
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: 20130108 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130207 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160215 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5199073 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 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 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |