NO327238B1 - Metode for den setespesifikke fremstilling av hGRF-PEG konjugater, GRF-PEG-konjugat, anvendelse derav for fremstilling av et medikament og en farmasoytisk sammensetning omfattende samme. - Google Patents
Metode for den setespesifikke fremstilling av hGRF-PEG konjugater, GRF-PEG-konjugat, anvendelse derav for fremstilling av et medikament og en farmasoytisk sammensetning omfattende samme. Download PDFInfo
- Publication number
- NO327238B1 NO327238B1 NO20002664A NO20002664A NO327238B1 NO 327238 B1 NO327238 B1 NO 327238B1 NO 20002664 A NO20002664 A NO 20002664A NO 20002664 A NO20002664 A NO 20002664A NO 327238 B1 NO327238 B1 NO 327238B1
- Authority
- NO
- Norway
- Prior art keywords
- hgrf
- peg
- lys
- stated
- conjugates
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 37
- 238000002360 preparation method Methods 0.000 title claims description 26
- 239000003814 drug Substances 0.000 title claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 72
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- 230000006320 pegylation Effects 0.000 claims description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 102000018997 Growth Hormone Human genes 0.000 claims description 23
- 108010051696 Growth Hormone Proteins 0.000 claims description 23
- 239000000122 growth hormone Substances 0.000 claims description 23
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 14
- 239000000872 buffer Substances 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 238000004587 chromatography analysis Methods 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229960003966 nicotinamide Drugs 0.000 claims description 7
- 235000005152 nicotinamide Nutrition 0.000 claims description 7
- 239000011570 nicotinamide Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 206010056438 Growth hormone deficiency Diseases 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 230000002152 alkylating effect Effects 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 140
- 239000002202 Polyethylene glycol Substances 0.000 description 88
- 239000000562 conjugate Substances 0.000 description 81
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 40
- 229920005989 resin Polymers 0.000 description 31
- 239000011347 resin Substances 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- 241000700159 Rattus Species 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 102100022831 Somatoliberin Human genes 0.000 description 17
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 16
- 101710142969 Somatoliberin Proteins 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 102000004196 processed proteins & peptides Human genes 0.000 description 13
- 229910001868 water Inorganic materials 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000004472 Lysine Substances 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 238000004007 reversed phase HPLC Methods 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- -1 succinimidyl ester Chemical class 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000000099 in vitro assay Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000703463 Homo sapiens Rho GTPase-activating protein 35 Proteins 0.000 description 6
- 102100030676 Rho GTPase-activating protein 35 Human genes 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000003275 alpha amino acid group Chemical group 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 230000021615 conjugation Effects 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000010532 solid phase synthesis reaction Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000003127 radioimmunoassay Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 101000997535 Homo sapiens Growth hormone-releasing hormone receptor Proteins 0.000 description 4
- 101000825742 Homo sapiens Somatoliberin Proteins 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 230000001817 pituitary effect Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000005932 reductive alkylation reaction Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- 108091026890 Coding region Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 229920000361 Poly(styrene)-block-poly(ethylene glycol) Polymers 0.000 description 3
- 101001075370 Rattus norvegicus Gamma-glutamyl hydrolase Proteins 0.000 description 3
- 108090000787 Subtilisin Proteins 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000007385 chemical modification Methods 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000001641 gel filtration chromatography Methods 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000003571 reporter gene assay Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 2
- UHEPSJJJMTWUCP-DHDYTCSHSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-[(1r)-1-hydroxyethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;sulfuric acid Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H]([C@@H](C)O)O2)N)[C@@H](N)C[C@H]1N UHEPSJJJMTWUCP-DHDYTCSHSA-N 0.000 description 2
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 241001415846 Procellariidae Species 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 2
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- DFPOZTRSOAQFIK-UHFFFAOYSA-N S,S-dimethyl-beta-propiothetin Chemical compound C[S+](C)CCC([O-])=O DFPOZTRSOAQFIK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 238000004737 colorimetric analysis Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 239000005549 deoxyribonucleoside Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007515 enzymatic degradation Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 229920001427 mPEG Polymers 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000863 peptide conjugate Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000002342 ribonucleoside Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- WGWPRVFKDLAUQJ-MITYVQBRSA-N sermorelin Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)C1=CC=C(O)C=C1 WGWPRVFKDLAUQJ-MITYVQBRSA-N 0.000 description 2
- 229960002758 sermorelin Drugs 0.000 description 2
- PCMORTLOPMLEFB-ONEGZZNKSA-N sinapic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-ONEGZZNKSA-N 0.000 description 2
- PCMORTLOPMLEFB-UHFFFAOYSA-N sinapinic acid Natural products COC1=CC(C=CC(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-UHFFFAOYSA-N 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AFVLVVWMAFSXCK-UHFFFAOYSA-N α-cyano-4-hydroxycinnamic acid Chemical compound OC(=O)C(C#N)=CC1=CC=C(O)C=C1 AFVLVVWMAFSXCK-UHFFFAOYSA-N 0.000 description 2
- OJBNDXHENJDCBA-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-(prop-2-enoxycarbonylamino)hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 OJBNDXHENJDCBA-QFIPXVFZSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- LZKGFGLOQNSMBS-UHFFFAOYSA-N 4,5,6-trichlorotriazine Chemical compound ClC1=NN=NC(Cl)=C1Cl LZKGFGLOQNSMBS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 239000012901 Milli-Q water Substances 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229920002375 Peptide(-Tyr) Polymers 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002538 Polyethylene Glycol 20000 Polymers 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000012435 analytical chromatography Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical group N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000013310 pig model Methods 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- JAHCMOSSKRAPEL-IBFVROBCSA-N somatorelin Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(N)=O)C1=CC=C(O)C=C1 JAHCMOSSKRAPEL-IBFVROBCSA-N 0.000 description 1
- 229960002090 somatorelin Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 239000006163 transport media Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Birds (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97121264A EP0922446A1 (en) | 1997-12-03 | 1997-12-03 | Solution-phase site-specific preparation of GRF-PEG conjugates |
PCT/EP1998/007748 WO1999027897A1 (en) | 1997-12-03 | 1998-12-01 | Site-specific preparation of polyethylene glycol-grf conjugates |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20002664D0 NO20002664D0 (no) | 2000-05-24 |
NO20002664L NO20002664L (no) | 2000-07-13 |
NO327238B1 true NO327238B1 (no) | 2009-05-18 |
Family
ID=8227732
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20002664A NO327238B1 (no) | 1997-12-03 | 2000-05-24 | Metode for den setespesifikke fremstilling av hGRF-PEG konjugater, GRF-PEG-konjugat, anvendelse derav for fremstilling av et medikament og en farmasoytisk sammensetning omfattende samme. |
Country Status (30)
Country | Link |
---|---|
US (3) | US6528485B1 (ru) |
EP (2) | EP0922446A1 (ru) |
JP (2) | JP2001524505A (ru) |
KR (1) | KR100561768B1 (ru) |
CN (1) | CN1149967C (ru) |
AR (1) | AR017780A1 (ru) |
AT (1) | ATE236607T1 (ru) |
AU (1) | AU755285B2 (ru) |
BG (1) | BG64815B1 (ru) |
BR (1) | BR9815159A (ru) |
CA (1) | CA2312004C (ru) |
DE (1) | DE69813291T2 (ru) |
DK (1) | DK1037587T3 (ru) |
EA (1) | EA004269B1 (ru) |
EE (1) | EE200000319A (ru) |
ES (1) | ES2194376T3 (ru) |
HK (1) | HK1034203A1 (ru) |
HU (1) | HUP0100507A3 (ru) |
IL (2) | IL136551A0 (ru) |
NO (1) | NO327238B1 (ru) |
NZ (1) | NZ504570A (ru) |
PL (1) | PL192082B1 (ru) |
PT (1) | PT1037587E (ru) |
SI (1) | SI1037587T1 (ru) |
SK (1) | SK8242000A3 (ru) |
TR (1) | TR200001615T2 (ru) |
TW (1) | TWI254641B (ru) |
UA (1) | UA73716C2 (ru) |
WO (1) | WO1999027897A1 (ru) |
ZA (1) | ZA9811068B (ru) |
Families Citing this family (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010055581A1 (en) | 1994-03-18 | 2001-12-27 | Lawrence Tamarkin | Composition and method for delivery of biologically-active factors |
US7229841B2 (en) * | 2001-04-30 | 2007-06-12 | Cytimmune Sciences, Inc. | Colloidal metal compositions and methods |
US6407218B1 (en) * | 1997-11-10 | 2002-06-18 | Cytimmune Sciences, Inc. | Method and compositions for enhancing immune response and for the production of in vitro mabs |
WO2002028437A1 (en) * | 2000-10-05 | 2002-04-11 | Ares Trading S.A. | Regioselective liquid phase pegylation |
EP1234583A1 (en) | 2001-02-23 | 2002-08-28 | F. Hoffmann-La Roche Ag | PEG-conjugates of HGF-NK4 |
US20030171285A1 (en) * | 2001-11-20 | 2003-09-11 | Finn Rory F. | Chemically-modified human growth hormone conjugates |
ATE371680T1 (de) | 2002-01-16 | 2007-09-15 | Biocompatibles Uk Ltd | Polymerkonjugate |
US7998705B2 (en) * | 2002-08-06 | 2011-08-16 | FUJIFILM Diosynth Biotechnologies U.S.A., Inc | Increased dynamic binding capacity in ion exchange chromatography by addition of polyethylene glycol |
CA2496687A1 (en) * | 2002-09-18 | 2004-04-01 | Centre Hospitalier De L'universite De Montreal (Chum) | Ghrh analogues |
GB0301014D0 (en) * | 2003-01-16 | 2003-02-19 | Biocompatibles Ltd | Conjugation reactions |
US7662915B2 (en) * | 2003-01-18 | 2010-02-16 | Pegsphere Co., Ltd. | Peptides having protected amines of untargeted sites, methods for production thereof and of specifically conjugated PEG peptides using the same |
US20050058658A1 (en) * | 2003-07-15 | 2005-03-17 | Barros Research Institute | Compositions and methods for immunotherapy of human immunodeficiency virus (HIV) |
US7393534B2 (en) * | 2003-07-15 | 2008-07-01 | Barros Research Institute | Compositions and methods for immunotherapy of cancer and infectious diseases |
JP2008504216A (ja) * | 2003-12-02 | 2008-02-14 | サイトイミューン サイエンシズ インコーポレイテッド | モノクローナル抗体の生成のための方法および組成物 |
JP4833862B2 (ja) * | 2004-01-28 | 2011-12-07 | サイトイミューン サイエンシズ インコーポレイテッド | 官能化コロイド金属組成物および方法 |
CN100355784C (zh) * | 2004-02-12 | 2007-12-19 | 江苏恒瑞医药股份有限公司 | 聚乙二醇修饰α-干扰素1b的制备方法 |
US20050261475A1 (en) * | 2004-02-13 | 2005-11-24 | Harvard Medical School | Solid-phase capture-release-tag methods for phosphoproteomic analyses |
US6986264B1 (en) * | 2004-07-15 | 2006-01-17 | Carrier Corporation | Economized dehumidification system |
SI3130601T1 (sl) | 2004-11-12 | 2020-11-30 | Bayer Healthcare Llc | Usmerjena modifikacija FVIII |
WO2007016105A2 (en) * | 2005-07-26 | 2007-02-08 | Rhodia Inc. | Polymers with pendant poly(alkyleneoxy) substituent groups and their use in personal care applications |
US20070238656A1 (en) * | 2006-04-10 | 2007-10-11 | Eastman Kodak Company | Functionalized poly(ethylene glycol) |
US20080096819A1 (en) | 2006-05-02 | 2008-04-24 | Allozyne, Inc. | Amino acid substituted molecules |
EP2581450B1 (en) | 2006-05-02 | 2018-08-15 | MedImmune Limited | Non-natural amino acid substituted polypeptides |
CA2659990C (en) * | 2006-08-04 | 2016-03-22 | Prolong Pharmaceuticals, Inc. | Polyethylene glycol erythropoietin conjugates |
US20080083154A1 (en) * | 2006-10-05 | 2008-04-10 | Timothy M Gregory | Bait retention fish hook |
CA2707840A1 (en) | 2007-08-20 | 2009-02-26 | Allozyne, Inc. | Amino acid substituted molecules |
CN102203002A (zh) * | 2007-09-21 | 2011-09-28 | 细胞免疫科学公司 | 纳米治疗性胶态金属组合物和方法 |
US20110014118A1 (en) * | 2007-09-21 | 2011-01-20 | Lawrence Tamarkin | Nanotherapeutic colloidal metal compositions and methods |
US7960145B2 (en) * | 2007-11-08 | 2011-06-14 | Cytimmune Sciences, Inc. | Compositions and methods for generating antibodies |
US10040838B2 (en) * | 2008-11-04 | 2018-08-07 | Janssen Pharmaceutica Nv | CRHR2 peptide agonists and uses thereof |
RU2495881C2 (ru) | 2009-03-20 | 2013-10-20 | Ханми Холдингс Ко., Лтд. | Способ регулирования условий для сайт-специфического связывания полипептида и непептидильного полимера |
US20100267636A1 (en) * | 2009-04-20 | 2010-10-21 | Theratechnologies Inc. | Use of cytochrome p450-metabolized drugs and grf molecules in combination therapy |
EP2421547A1 (en) * | 2009-04-20 | 2012-02-29 | Theratechnologies Inc. | Use of (hexenoyl trans-3)hgrf(1-44)nh2 and ritonavir in combination therapy |
BRPI1015424B1 (pt) | 2009-06-22 | 2022-01-18 | Burnham Institute For Medical Research | Composição compreendendo um elemento cendr e uma co-composição e composição para uso no reforço da internalização, penetração, ou ambas, de uma co-composição |
MX2012005262A (es) | 2009-11-04 | 2012-09-28 | Janssen Pharmaceutica Nv | Metodo para tratar la insuficiencia cardiaca con petidos tipo estrescopina. |
WO2012118778A1 (en) | 2011-02-28 | 2012-09-07 | Sanford-Burnham Medical Research Institute | Truncated car peptides and methods and compositions using truncated car peptides |
MX2013012259A (es) | 2011-04-21 | 2013-11-22 | Theratechnologies Inc | Analogos del factor de liberacion de la hormona de crecimiento (grf) y usos de estos. |
CA2837588A1 (en) | 2011-05-31 | 2012-12-06 | Airware, Inc. | Re-calibration of ab ndir gas sensors |
US10179801B2 (en) | 2011-08-26 | 2019-01-15 | Sanford-Burnham Medical Research Institute | Truncated LYP-1 peptides and methods and compositions using truncated LYP-1 peptides |
WO2013190520A2 (en) | 2012-06-22 | 2013-12-27 | The General Hospital Corporation | Gh-releasing agents in the treatment of vascular stenosis and associated conditions |
US10064940B2 (en) | 2013-12-11 | 2018-09-04 | Siva Therapeutics Inc. | Multifunctional radiation delivery apparatus and method |
CA2986927C (en) | 2015-05-28 | 2023-12-19 | Institut National De La Recherche Scientifique | Inhibitors of prototypic galectin dimerization and uses thereof |
CA3021231A1 (en) * | 2016-04-19 | 2017-10-26 | Griffon Pharmaceuticals Inc. | Pegylated bioactive peptides and uses thereof |
CN110317826B (zh) * | 2019-05-22 | 2020-11-10 | 中国农业大学 | 调控PvGRF9含量或活性的物质在调控植物茎生长发育中的应用 |
WO2021133407A1 (en) | 2019-12-27 | 2021-07-01 | Compagnie Generale Des Etablissements Michelin | Rubber mix with high specific surface area and high structure acetylene carbon black |
CA3206260A1 (en) | 2021-01-28 | 2022-08-04 | Ilse Roodink | Anti-sars-cov-2 spike glycoprotein antibodies and the therapeutic use thereof |
WO2024081918A1 (en) | 2022-10-14 | 2024-04-18 | Talem Therapeutics Llc | Anti-trkb/cd3 antibodies and uses thereof |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4563352A (en) * | 1982-10-04 | 1986-01-07 | The Salk Institute For Biological Studies | Human pancreatic GRF |
ES2085297T3 (es) * | 1989-05-27 | 1996-06-01 | Sumitomo Pharma | Procedimiento para preparar derivados de poli(etilenglicol) y proteina modificada. |
JPH06500311A (ja) * | 1990-06-29 | 1994-01-13 | エフ・ホフマン―ラ ロシュ アーゲー | ヒスチジン置換されたヒト成長ホルモン放出因子類縁体 |
JP3051145B2 (ja) * | 1990-08-28 | 2000-06-12 | 住友製薬株式会社 | 新規なポリエチレングリコール誘導体修飾ペプチド |
WO1992018531A1 (en) * | 1991-04-09 | 1992-10-29 | F. Hoffmann-La Roche Ag | Growth hormone releasing factor analogs |
EP0518295A3 (en) * | 1991-06-14 | 1993-09-01 | Millipore Corporation | Allyl side chain protection in peptide synthesis |
FR2687681B1 (fr) * | 1992-02-20 | 1995-10-13 | Transgene Sa | Conjugues polyethyleneglycol-hirudine, leur procede de preparation et leur emploi pour le traitement des thromboses. |
US5932462A (en) * | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
WO1997017367A1 (en) * | 1995-11-03 | 1997-05-15 | Theratechnologies Inc. | Method of grf peptides synthesis |
-
1997
- 1997-12-03 EP EP97121264A patent/EP0922446A1/en not_active Withdrawn
-
1998
- 1998-01-12 UA UA2000063885A patent/UA73716C2/uk unknown
- 1998-12-01 BR BR9815159-2A patent/BR9815159A/pt not_active Application Discontinuation
- 1998-12-01 EP EP98959898A patent/EP1037587B1/en not_active Expired - Lifetime
- 1998-12-01 WO PCT/EP1998/007748 patent/WO1999027897A1/en active IP Right Grant
- 1998-12-01 IL IL13655198A patent/IL136551A0/xx unknown
- 1998-12-01 PL PL341139A patent/PL192082B1/pl not_active IP Right Cessation
- 1998-12-01 CN CNB988117592A patent/CN1149967C/zh not_active Expired - Fee Related
- 1998-12-01 ES ES98959898T patent/ES2194376T3/es not_active Expired - Lifetime
- 1998-12-01 DE DE69813291T patent/DE69813291T2/de not_active Expired - Lifetime
- 1998-12-01 SK SK824-2000A patent/SK8242000A3/sk unknown
- 1998-12-01 KR KR1020007005736A patent/KR100561768B1/ko not_active IP Right Cessation
- 1998-12-01 DK DK98959898T patent/DK1037587T3/da active
- 1998-12-01 EE EEP200000319A patent/EE200000319A/xx unknown
- 1998-12-01 AT AT98959898T patent/ATE236607T1/de active
- 1998-12-01 TR TR2000/01615T patent/TR200001615T2/xx unknown
- 1998-12-01 JP JP2000522885A patent/JP2001524505A/ja active Pending
- 1998-12-01 EA EA200000601A patent/EA004269B1/ru not_active IP Right Cessation
- 1998-12-01 CA CA002312004A patent/CA2312004C/en not_active Expired - Lifetime
- 1998-12-01 PT PT98959898T patent/PT1037587E/pt unknown
- 1998-12-01 HU HU0100507A patent/HUP0100507A3/hu unknown
- 1998-12-01 AU AU15633/99A patent/AU755285B2/en not_active Expired
- 1998-12-01 SI SI9830400T patent/SI1037587T1/xx unknown
- 1998-12-01 NZ NZ504570A patent/NZ504570A/en unknown
- 1998-12-02 AR ARP980106098A patent/AR017780A1/es active IP Right Grant
- 1998-12-03 ZA ZA9811068A patent/ZA9811068B/xx unknown
-
1999
- 1999-01-26 TW TW088101139A patent/TWI254641B/zh not_active IP Right Cessation
-
2000
- 2000-05-24 NO NO20002664A patent/NO327238B1/no not_active IP Right Cessation
- 2000-05-29 BG BG10448A patent/BG64815B1/bg unknown
- 2000-06-04 IL IL136551A patent/IL136551A/en not_active IP Right Cessation
- 2000-06-05 US US09/587,460 patent/US6528485B1/en not_active Expired - Lifetime
-
2001
- 2001-07-16 HK HK01104960A patent/HK1034203A1/xx not_active IP Right Cessation
-
2002
- 2002-11-20 US US10/299,790 patent/US6869932B2/en not_active Expired - Lifetime
-
2004
- 2004-12-15 US US11/011,617 patent/US7317002B2/en not_active Expired - Fee Related
-
2009
- 2009-10-30 JP JP2009251100A patent/JP5431874B2/ja not_active Expired - Lifetime
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6869932B2 (en) | Site-specific preparation of polyethlene glycol-GRF conjugates | |
US20220362345A1 (en) | Peptide pharmaceuticals for insulin resistance | |
JP4805911B2 (ja) | Hiv侵入阻害剤のポリマー系組成物及び複合体 | |
CA2737040C (en) | Polymer conjugates of therapeutic peptides | |
US7256258B2 (en) | Regioselective liquid phase pegylation | |
US7595294B2 (en) | Vasoactive intestinal polypeptide pharmaceuticals | |
AU2001295589A1 (en) | Regioselective liquid phase pegylation | |
EP1608680A2 (en) | Glp-2 derivatives | |
MXPA00005138A (en) | Site-specific preparation of polyethylene glycol-grf conjugates | |
CZ20002055A3 (cs) | Způsob selektivní přípravy specifických konjugátů polyethylenglykol - GRF | |
EP2334333A1 (en) | Polymer conjugates of v681-like peptides |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
CREP | Change of representative |
Representative=s name: ONSAGERS AS, POSTBOKS 6963 ST OLAVS PLASS, 0130 OS |
|
MK1K | Patent expired |