JP5981151B2 - α−ガラクトシダーゼA欠損症の治療 - Google Patents
α−ガラクトシダーゼA欠損症の治療 Download PDFInfo
- Publication number
- JP5981151B2 JP5981151B2 JP2012010796A JP2012010796A JP5981151B2 JP 5981151 B2 JP5981151 B2 JP 5981151B2 JP 2012010796 A JP2012010796 A JP 2012010796A JP 2012010796 A JP2012010796 A JP 2012010796A JP 5981151 B2 JP5981151 B2 JP 5981151B2
- Authority
- JP
- Japan
- Prior art keywords
- gal
- cells
- preparation
- human
- glycans
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 208000024720 Fabry Disease Diseases 0.000 title claims abstract description 29
- 238000011282 treatment Methods 0.000 title description 19
- 101000718525 Homo sapiens Alpha-galactosidase A Proteins 0.000 claims abstract description 55
- 102000043404 human GLA Human genes 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 55
- NNISLDGFPWIBDF-MPRBLYSKSA-N alpha-D-Gal-(1->3)-beta-D-Gal-(1->4)-D-GlcNAc Chemical compound O[C@@H]1[C@@H](NC(=O)C)C(O)O[C@H](CO)[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](CO)O2)O)[C@@H](O)[C@@H](CO)O1 NNISLDGFPWIBDF-MPRBLYSKSA-N 0.000 claims description 338
- 101000718529 Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2) Alpha-galactosidase Proteins 0.000 claims description 327
- 238000002360 preparation method Methods 0.000 claims description 230
- 210000004027 cell Anatomy 0.000 claims description 142
- 150000004676 glycans Chemical class 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 44
- 150000001720 carbohydrates Chemical class 0.000 claims description 28
- 230000001434 glomerular Effects 0.000 claims description 16
- 210000002889 endothelial cell Anatomy 0.000 claims description 9
- 210000002919 epithelial cell Anatomy 0.000 claims description 9
- 210000004748 cultured cell Anatomy 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000010171 animal model Methods 0.000 claims description 6
- 210000005265 lung cell Anatomy 0.000 claims description 6
- 210000003556 vascular endothelial cell Anatomy 0.000 claims description 6
- 210000003292 kidney cell Anatomy 0.000 claims description 5
- 230000000747 cardiac effect Effects 0.000 claims description 4
- 210000002450 kidney nerve cell Anatomy 0.000 claims description 4
- 210000002569 neuron Anatomy 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000002552 dosage form Substances 0.000 abstract 1
- 108010049936 agalsidase alfa Proteins 0.000 description 88
- 108090000623 proteins and genes Proteins 0.000 description 60
- 210000005260 human cell Anatomy 0.000 description 54
- 210000002966 serum Anatomy 0.000 description 42
- 230000037396 body weight Effects 0.000 description 40
- 108010056760 agalsidase beta Proteins 0.000 description 37
- 229940014516 fabrazyme Drugs 0.000 description 37
- 102000004190 Enzymes Human genes 0.000 description 33
- 108090000790 Enzymes Proteins 0.000 description 33
- 229940088598 enzyme Drugs 0.000 description 33
- 210000001519 tissue Anatomy 0.000 description 33
- 235000018102 proteins Nutrition 0.000 description 31
- 102000004169 proteins and genes Human genes 0.000 description 31
- 230000007935 neutral effect Effects 0.000 description 30
- 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 28
- 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 27
- 235000014633 carbohydrates Nutrition 0.000 description 24
- 230000013595 glycosylation Effects 0.000 description 24
- 238000006206 glycosylation reaction Methods 0.000 description 24
- 210000004185 liver Anatomy 0.000 description 23
- 239000000523 sample Substances 0.000 description 23
- 210000004369 blood Anatomy 0.000 description 20
- 239000008280 blood Substances 0.000 description 20
- 229910019142 PO4 Inorganic materials 0.000 description 19
- 238000009472 formulation Methods 0.000 description 19
- 239000010452 phosphate Substances 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- 102000005962 receptors Human genes 0.000 description 19
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 18
- 210000002950 fibroblast Anatomy 0.000 description 18
- 235000000346 sugar Nutrition 0.000 description 18
- NBSCHQHZLSJFNQ-QTVWNMPRSA-N D-Mannose-6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@@H]1O NBSCHQHZLSJFNQ-QTVWNMPRSA-N 0.000 description 17
- 239000000872 buffer Substances 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 230000008685 targeting Effects 0.000 description 16
- 230000007812 deficiency Effects 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 108091026890 Coding region Proteins 0.000 description 14
- 108090000288 Glycoproteins Proteins 0.000 description 14
- 102000003886 Glycoproteins Human genes 0.000 description 14
- 230000026731 phosphorylation Effects 0.000 description 14
- 238000006366 phosphorylation reaction Methods 0.000 description 14
- 108020004414 DNA Proteins 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000011068 loading method Methods 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 102000051366 Glycosyltransferases Human genes 0.000 description 12
- 108700023372 Glycosyltransferases Proteins 0.000 description 12
- 230000004913 activation Effects 0.000 description 12
- 239000011347 resin Substances 0.000 description 12
- 229920005989 resin Polymers 0.000 description 12
- 108010076504 Protein Sorting Signals Proteins 0.000 description 11
- 230000004700 cellular uptake Effects 0.000 description 11
- 230000004048 modification Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 11
- 229920002684 Sepharose Polymers 0.000 description 10
- 230000004071 biological effect Effects 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000001802 infusion Methods 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 230000001404 mediated effect Effects 0.000 description 10
- 230000009450 sialylation Effects 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000013459 approach Methods 0.000 description 9
- 238000009826 distribution Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 150000002482 oligosaccharides Polymers 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 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 8
- 241000282412 Homo Species 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 8
- 238000002641 enzyme replacement therapy Methods 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 7
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 7
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 102000005348 Neuraminidase Human genes 0.000 description 7
- 108010006232 Neuraminidase Proteins 0.000 description 7
- 108090000141 Sialyltransferases Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 108700014210 glycosyltransferase activity proteins Proteins 0.000 description 7
- 238000002744 homologous recombination Methods 0.000 description 7
- 230000006801 homologous recombination Effects 0.000 description 7
- 230000003907 kidney function Effects 0.000 description 7
- 229960000485 methotrexate Drugs 0.000 description 7
- 238000007634 remodeling Methods 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 102000003838 Sialyltransferases Human genes 0.000 description 6
- 102000005840 alpha-Galactosidase Human genes 0.000 description 6
- 108010030291 alpha-Galactosidase Proteins 0.000 description 6
- 102000005936 beta-Galactosidase Human genes 0.000 description 6
- 108010005774 beta-Galactosidase Proteins 0.000 description 6
- 239000002299 complementary DNA Substances 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000006167 equilibration buffer Substances 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 238000010353 genetic engineering Methods 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 238000001542 size-exclusion chromatography Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 210000003494 hepatocyte Anatomy 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 210000000557 podocyte Anatomy 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 102000002464 Galactosidases Human genes 0.000 description 4
- 108010093031 Galactosidases Proteins 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000004413 cardiac myocyte Anatomy 0.000 description 4
- 230000004087 circulation Effects 0.000 description 4
- 229960003624 creatine Drugs 0.000 description 4
- 239000006046 creatine Substances 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 238000004520 electroporation Methods 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 238000004255 ion exchange chromatography Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 229920001542 oligosaccharide Polymers 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000011144 upstream manufacturing Methods 0.000 description 4
- 230000002861 ventricular Effects 0.000 description 4
- 239000012619 Butyl Sepharose® Substances 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- YINZYTTZHLPWBO-UHFFFAOYSA-N Kifunensine Natural products COC1C(O)C(O)C(O)C2NC(=O)C(=O)N12 YINZYTTZHLPWBO-UHFFFAOYSA-N 0.000 description 3
- 241000282567 Macaca fascicularis Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102000019218 Mannose-6-phosphate receptors Human genes 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 230000004988 N-glycosylation Effects 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 3
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 239000012505 Superdex™ Substances 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 210000001043 capillary endothelial cell Anatomy 0.000 description 3
- 238000013184 cardiac magnetic resonance imaging Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000011210 chromatographic step Methods 0.000 description 3
- 230000010405 clearance mechanism Effects 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000002716 delivery method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 150000008195 galaktosides Chemical group 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000007913 intrathecal administration Methods 0.000 description 3
- OIURYJWYVIAOCW-VFUOTHLCSA-N kifunensine Chemical compound OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H]2NC(=O)C(=O)N12 OIURYJWYVIAOCW-VFUOTHLCSA-N 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000002132 lysosomal effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 108091027963 non-coding RNA Proteins 0.000 description 3
- 102000042567 non-coding RNA Human genes 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000005629 sialic acid group Chemical group 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 3
- -1 thereby For example Proteins 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 description 2
- 208000004652 Cardiovascular Abnormalities Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 238000011537 Coomassie blue staining Methods 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 101150074155 DHFR gene Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 102000001390 Fructose-Bisphosphate Aldolase Human genes 0.000 description 2
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108010007979 Glycocholic Acid Proteins 0.000 description 2
- 229930186217 Glycolipid Natural products 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 108050006616 Mannose-6-phosphate receptors Proteins 0.000 description 2
- 101100278853 Mus musculus Dhfr gene Proteins 0.000 description 2
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 2
- 241001045988 Neogene Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 210000001766 X chromosome Anatomy 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 108010006523 asialoglycoprotein receptor Proteins 0.000 description 2
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 2
- 108010085377 beta-N-Acetylhexosaminidases Proteins 0.000 description 2
- 102000007478 beta-N-Acetylhexosaminidases Human genes 0.000 description 2
- 229920000249 biocompatible polymer Polymers 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000007248 cellular mechanism Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 230000004186 co-expression Effects 0.000 description 2
- 238000003271 compound fluorescence assay Methods 0.000 description 2
- 239000003636 conditioned culture medium Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 210000003953 foreskin Anatomy 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 238000012239 gene modification Methods 0.000 description 2
- 230000005017 genetic modification Effects 0.000 description 2
- 235000013617 genetically modified food Nutrition 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 2
- 229940099347 glycocholic acid Drugs 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000001155 isoelectric focusing Methods 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 238000012317 liver biopsy Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 101150091879 neo gene Proteins 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- IDOQDZANRZQBTP-UHFFFAOYSA-N 2-[2-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=CC=C1OCCO IDOQDZANRZQBTP-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- CIHKVMHPDDJIIP-UHFFFAOYSA-N 2-methylperoxybenzoic acid Chemical compound COOC1=CC=CC=C1C(O)=O CIHKVMHPDDJIIP-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- VZEZONWRBFJJMZ-UHFFFAOYSA-N 3-allyl-2-[2-(diethylamino)ethoxy]benzaldehyde Chemical compound CCN(CC)CCOC1=C(CC=C)C=CC=C1C=O VZEZONWRBFJJMZ-UHFFFAOYSA-N 0.000 description 1
- YUDPTGPSBJVHCN-CHUNWDLHSA-N 4-methylumbelliferyl alpha-D-galactoside Chemical compound C1=CC=2C(C)=CC(=O)OC=2C=C1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O YUDPTGPSBJVHCN-CHUNWDLHSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- TXCIAUNLDRJGJZ-UHFFFAOYSA-N CMP-N-acetyl neuraminic acid Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(N=C(N)C=C2)=O)O1 TXCIAUNLDRJGJZ-UHFFFAOYSA-N 0.000 description 1
- TXCIAUNLDRJGJZ-BILDWYJOSA-N CMP-N-acetyl-beta-neuraminic acid Chemical compound O1[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](O)C[C@]1(C(O)=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(N=C(N)C=C2)=O)O1 TXCIAUNLDRJGJZ-BILDWYJOSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 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
- 229920002271 DEAE-Sepharose Polymers 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 108700034637 EC 3.2.-.- Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors 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
- 229940121672 Glycosylation inhibitor Drugs 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
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108010031792 IGF Type 2 Receptor Proteins 0.000 description 1
- 108091092195 Intron Proteins 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 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
- 208000034693 Laceration Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 208000015439 Lysosomal storage disease Diseases 0.000 description 1
- 206010027727 Mitral valve incompetence Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 1
- 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 1
- 102100039267 N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase Human genes 0.000 description 1
- 108010040066 N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 208000027032 Renal vascular disease Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 239000012506 Sephacryl® Substances 0.000 description 1
- 241000287219 Serinus canaria Species 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 229920004929 Triton X-114 Polymers 0.000 description 1
- LFTYTUAZOPRMMI-CFRASDGPSA-N UDP-N-acetyl-alpha-D-glucosamine Chemical compound O1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](NC(=O)C)[C@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-CFRASDGPSA-N 0.000 description 1
- 108010044965 UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase Proteins 0.000 description 1
- LFTYTUAZOPRMMI-UHFFFAOYSA-N UNPD164450 Natural products O1C(CO)C(O)C(O)C(NC(=O)C)C1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-UHFFFAOYSA-N 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 108700029631 X-Linked Genes Proteins 0.000 description 1
- 208000028247 X-linked inheritance Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000069 breast epithelial cell Anatomy 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
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000011098 chromatofocusing Methods 0.000 description 1
- 239000012539 chromatography resin Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229940081104 fibrinogen / thrombin Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004927 fusion Effects 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
- 238000010363 gene targeting Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 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 1
- 229920001427 mPEG Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 108010009689 mannosyl-oligosaccharide 1,2-alpha-mannosidase Proteins 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 230000007030 peptide scission Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920000111 poly(butyric acid) Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 208000015670 renal artery disease Diseases 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012609 strong anion exchange resin Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- FXUAIOOAOAVCGD-FKSUSPILSA-N swainsonine Chemical compound C1CC[C@H](O)[C@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-FKSUSPILSA-N 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01022—Alpha-galactosidase (3.2.1.22)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
- G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Obesity (AREA)
- General Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Cardiology (AREA)
- Toxicology (AREA)
Description
本出願は、2002年4月25日提出の米国特許仮出願第60/375,584号(その内容全体が参照として本明細書に組み入れられる)の優先権を主張する。
本発明は、ファブリー病を含むα-ガラクトシダーゼA欠損症の治療のための改良されたα-ガラクトシダーゼA組成物に関する。
ファブリー病は、重篤な腎障害、被角血管種、および/または心血管の異常(心室拡大および僧帽弁閉鎖不全を含む)によって特徴付けられるX連鎖遺伝性リソソーム蓄積症である。ファブリー病はまた、末梢神経系に影響を与え、苦悶エピソード(episodes of agonizing)、先端(extremities)の灼熱痛を引き起こす。
ヒトα-Gal Aの薬物動態学および修飾プロフィール(例えば、炭水化物、リン酸、またはシアル酸化修飾)の理解により、本発明者らは、α-Gal Aの新規の薬学的組成物、α-Gal A欠損症の治療用キット、患者のためのα-Gal Aの適切な用量を選択する方法、およびこのような組成物を使用したα-Gal A欠損症の治療方法を開発した。α-Gal A調製物、試料、バッチなどの評価方法(例えば、本明細書に記載のα-Gal A組成物に関する生物学的等価物の品質管理方法および決定方法)もまた提供する。
mg α-Gal A/肝臓=2.1mg(1-e-用量/4.7)
(式中、用量は、典型的な75kgの患者に投与した総用量(mg)である)。変動係数(CV)は、例えば、約0.40であり得る(したがって、用量および量は患者の大小によって調整する)。
序文
α-Gal A欠損症の酵素代替療法に望ましい薬物動態学的性質を有するヒトα-Gal A調製物が得られる修飾(例えば、炭水化物の構造(例えば、グリカン、リン酸、またはシアル酸の修飾))をヒトα-Gal Aに行うことができることが発見された。例えば、ヒトα-Gal Aが産生されるように遺伝子操作されたヒト細胞から産生されたヒトα-Gal Aの調製物は、ヒトにおける循環血中からのクリアランスについての対比スケール式Y=a(BW)b(式中、Yはα-Gal Aのクリアランス速度(ml/分)であり、「a」は非特異的定数であり、BWは体重である)の指数「b」(少なくとも0.85)(好ましくは0.92まで)を有する。本明細書に記載のこのようなα-Gal A調製物を、主にM6P受容体によって取り込むことができ、非ヒト細胞(例えば、CHO細胞)で産生されたヒトα-Gal Aと比較して血清クリアランスはあまり迅速ではない。したがって、本明細書に記載のα-Gal A欠損症の治療のための薬学的組成物およびキットは、実質的に当技術分野において現在使用されているよりも少量の単位用量で投与するこのようなα-Gal A調製物を含む。例えば、いくつかの態様では、本明細書に記載のα-Gal A調製物を、0.05mg/kg体重〜2.0mg/kg体重(mg/kg)の間、好ましくは0.05mg/kg〜5mg/kgの間、より好ましくは0.05mg/kg〜0.3mg/kgの間(例えば、約0.1、0.2、0.25、0.3、0.4、または0.5mg/kg)の単位用量で投与する。単位用量は、例えば、0.1×106U/kg〜10×106U/kgの間であり得る。いくつかの態様では、α-Gal A調製物の単位用量は、0.1×106U/kg〜5×106U/kgの間、好ましくは約0.1×106U/kg〜3×106U/kgの間である。他の態様では、本明細書に記載のα-Gal A調製物を、7日毎(例えば、10日毎、14日毎、または21日毎、4週間毎、5週間毎、6週間毎、7週間毎、または8週間毎に1回だけ投与する。患者によっては、さらに低い頻度(例えば、9、10、11、12週、またはそれ以上に1回)での投与が可能であり得る。
精製ヒトα-Gal Aを、培養細胞、好ましくは遺伝子操作細胞(例えば、遺伝子操作ヒト細胞)または他の哺乳動物細胞(例えば、CHO細胞)から得ることができる。昆虫細胞を使用することもできる。
本明細書に記載のデータは、α-Gal A欠損症の酵素代替療法に望ましい酵素の薬物動態学的性質が得られる修飾(例えば、炭水化物、リン酸、またはシアル酸の修飾)をヒトα-Gal Aに行うことができることを示す。このようなヒトα-Gal A調製物の1つの作製方法は、ヒト細胞からヒトα-Gal Aを産生することである。
糖タンパク質修飾(例えば、非ヒト細胞中でα-Gal Aが産生される場合)により、肝臓およびマクロファージ以外の特定の組織中での酵素取り込みを増大させることができる(例えば、毛細血管/血管内皮細胞、腎糸球体上皮細胞(有足細胞)、糸球体間膜細胞、腎内皮細胞、肺細胞、腎細胞、神経細胞、または心筋細胞中の取り込みを増加させることができる)。糖タンパク質修飾法を使用して、35%〜85%の間、好ましくは少なくとも50%のオリゴ糖が負荷されたヒトグリコシル化α-Gal A調製物を得ることができる。
シアル酸化は、タンパク質の循環半減期および生体分布に影響を与える。タンパク質上の露呈されたガラクトース残基による肝細胞上のアシアロ糖タンパク質受容体(Ashwell受容体)によって最小のシアル酸を含むか全く含まないタンパク質が容易に内在化される。ガラクトース末端化α-Gal Aの循環半減期を、(1)α-Gal Aをノイラミニダーゼ(シアリダーゼ)と接触させて露呈した末端ガラクトシダーゼ部分を遊離することによるシアル酸の除去および(2)脱シアル酸化α-Gal Aのβ-ガラクトシダーゼとの接触による末端ガラクトシダーゼ残基の除去を連続的に行うことによって変化させることができる。得られたα-Gal A調製物は、ノイラミニダーゼおよびβ-ガラクトシダーゼに連続的に接触させていないα-Gal A調製物と比較して、オリゴ糖鎖上の末端シアル酸および/または末端ガラクトシド残基の数が減少する。または、ガラクトース末端化α-Gal Aの循環半減期を、脱シアル酸化α-Gal Aのβ-ガラクトシダーゼとの接触による末端ガラクトシド残基の除去のみによって増大させることができる。得られたα-Gal A調製物は、β-ガラクトシダーゼに接触させていないα-Gal A調製物と比較して、オリゴ糖鎖上の末端ガラクトシド残基数が減少した。好ましい態様では、ノイラミニダーゼおよびβ-ガラクトシダーゼとの連続接触後、得られたα-Gal A調製物にβ-ヘキソサミニダーゼと連続的に接触させることにより、オリゴ糖をトリマンノースコアに切断する。
本明細書に記載のα-Gal A調製物のリン酸化の変化により、循環半減期および調製物の所望の組織への細胞取り込みを変化させることができる。好ましい態様では、α-Gal A調製物は、45%未満のリン酸化グリカンを有する。例えば、調製物は、約35%、30%、25%、または20%未満のリン酸化グリカンを有する。α-Gal A調製物中の所望のシアル酸:マンノース-6-リン酸比(モル/モルベース)は、1.5:1超、好ましくは2:1超、より好ましくは3:1超、最も好ましくは3.5:1超またはそれ以上である。
他の態様では、ヒトα-Gal A調製物の循環半減期を、α-Gal Aのポリエチレングリコール(PEG)での複合体化によって増強する。好ましい態様では、テシルモノメトキシPEG(TMPEG)を使用してα-Gal A調製物を複合体化し、PEG化α-Gal Aを形成する。次いで、PEG化α-Gal Aを精製して単離されたPEG化α-Gal A調製物を得る。α-Gal AのPEG化により、タンパク質の循環半減期、細胞取り込み、および/または組織分布が増加する。
培養細胞株および/または酵素を産生させるために安定にトランスフェクトされた培養細胞株の馴化培地からα-Gal Aをほぼ均一に精製することができる。クロマトグラフィ段階を使用して、培地を含むα-Gal Aからα-Gal Aを単離することができる。例えば、1つまたは複数(例えば、2、3、4、5、またはそれ以上)のクロマトグラフィ段階を使用することができる。異なるクロマトグラフィ段階は、夾雑物質からα-Gal Aを分離するための酵素の異なる物理的性質を活用する種々の分離原理を使用する。例えば、段階には、ブチルSepharoseによる疎水性相互作用クロマトグラフィ、ハイドロキシアパタイトによるイオン相互作用、Q Sepharoseによる陰イオン交換クロマトグラフィ、およびSuperdex 200によるサイズ排除クロマトグラフィが含まれ得る。サイズ排除クロマトグラフィは、精製タンパク質を処方物適合緩衝液に交換するために有効な手段として役立ち得る。
本明細書に記載のα-Gal A調製物は、例えば、毛細血管内皮細胞、腎糸球体上皮細胞(有足細胞)、糸球体間膜細胞、および/または心筋細胞に対して所望の循環半減期および組織分布を示す。このような調製物を、比較的低い投薬量で投与することができる。例えば、投与単位用量は、0.05〜2.0mg/kg体重(mg/kg)であり得る。例えば、単位用量は、0.05mg/kg〜1.0mg/kgの間、0.5mg/kg〜0.5mg/kgの間、または0.5mg/kg〜0.3mg/kgの間であり得る。0.05mg/kg〜0.29mg/kgの間の単位用量が好ましい(例えば、約0.05、0.1、0.15、0.2、0.25mg/kgの単位用量)。α-Gal A調製物の比活性を2×106U/mg〜4.5×106U/mgの間と仮定すれば、これらの値は、約0.1×106U/kg〜1.3×106U/kgに相当する。好ましい単位用量により、α-Gal Aの肝臓取り込みが飽和する。
本明細書に記載のα-Gal A調製物は、実質的に、非α-Gal Aタンパク質(アルブミンなど)、宿主細胞によって産生された非α-Gal Aタンパク質、または動物組織もしくは流動物から単離したタンパク質を含まない。調製物は、水性または生理学的に適合可能な懸濁液または溶液の一部を含むことが好ましい。患者への所望の調製物の送達に加えて、患者の電解質および/または体積のバランスに悪影響を与えないようにキャリアまたは賦形剤は生理学的に適合可能である。非経口投与に有用な溶液を、薬学分野において任意の周知の方法によって調製することができる(例えば、REMINGTON'S PHARMACEUTICAL SCIENCES Gennaro,A.,ed.,Mack Pub.,1990を参照のこと)。
本明細書に記載のα-Gal A調製物を、α-Gal A調製物に適合可能な任意の経路で投与することができる。精製α-Gal A調製物を、α-Gal Aタンパク質の産生が不十分であるか欠損した個体またはα-Gal A療法から利益を得ることができる個体に投与することができる。本発明の治療調製物を、任意の適切な手段によって個体に直接(例えば、局所的、注射、移植、または組織軌跡(locus)への局所投与)または全身(例えば、経口または非経口)に提供することができる。
実施例1:α-Gal Aを送達および発現するようにデザインされた構築物の調製および使用
1.1:遺伝子活性化α-Gal A(GA-GAL)の調製
本質的に米国特許第5,733,761号(参考として本明細書に組み入れられる)に記載のGAテクノロジーを使用したヒトα-Gal Aコード配列上流の調節配列および構造DNA配列の挿入によって遺伝子活性化α-Gal A(GA-GAL)を産生した。トランスフェクトしたDNAフラグメント上に存在するDNAとヒト細胞中のα-Gal A遺伝子座上流のゲノムDNA配列との間の相同組換えの結果として、遺伝子活性化配列が正確に挿入される。遺伝子活性化配列自体は、シグナルペプチド切断部位(限定されない)までのα-Gal Aコード配列を含む。活性化α-Gal A遺伝子座を含む細胞を単離し、薬物選択に供してGA-GAL産生が増大した細胞を単離した。
2つの他の発現プラスミドpXAG-16およびpXAG-28を構築した。これらのプラスミドは、α-Gal A酵素の398アミノ酸(α-Gal Aシグナルペプチドを含まない)をコードするヒトα-Gal A cDNA、hGH遺伝子の第1のイントロンによって妨害されるヒト成長ホルモン(hon-none)(hGH)シグナルペプチドゲノムDNA配列、およびポリアデニル化シグナルを含むhGH遺伝子の非翻訳配列(UTS)を含む。プラスミドpXAG-16は、ヒトサイトメガロウイルス最初期(CMV IE)プロモーターおよび第1のイントロン(非コードエクソン配列に隣接)を有し、pXAG-28はコラーゲンIα2プロモーターおよびエクソン1によって駆動し、β-アクチン遺伝子の第1のイントロンを含むβ-アクチン遺伝子の5’UTSも含む。
この実施例は、Replagal(商標)(ヒト細胞中で産生されたα-Gal A調製物)とFabrazyme(商標)(CHO細胞中で産生されたα-Gal A調製物)の構造を比較する。調製物を、等電点、分子量、ならびに炭水化物、リン酸化、およびシアル酸化プロフィールに関して比較した。
Replagal(商標)およびFabrazyme(商標)を、変性等電点電気泳動(5%ゲル、pH範囲3〜7、6M尿素)およびその後のウェスタンブロッティングによって分析した。調製物を、未変性等電点電気泳動(Novex5%ゲル、pH範囲3〜7)およびその後のクーマシーブルー染色によっても分析した。2つの調製物の全pI範囲は類似しているが、結合パターンの相対強度は異なっていた。これは、各調製物に存在する糖形態の電荷分布が異なることを示し、Fabrazyme(商標)はReplagal(商標)よりもより低いpI(より高い負電荷)の糖形態の比率が高い。
Replagal(商標)およびFabrazyme(商標)を、SDS-PAGE(8〜16%ポリアクリルアミドゲル、還元試料)およびその後のクーマシーブルー染色によって分析した。調製物の分子量は類似していた。しかし、Fabrazyme(商標)の低い方の分子(約45kD)糖形態バンドはReplagal(商標)のそれとより異なり、Replagal(商標)はより広いサイズ分布を示す。
正常なヒト線維芽細胞を、Replagal(商標)またはFabrazyme(商標)の非存在下(対照、示さず)または存在下で6時間多ウェル培養プレートにてインキュベートした。この内在化は、マンノース-6-リン酸で阻害可能であり、内在化は主にマンノース-6-リン酸受容体を介することを示す。結果は、Replagal(商標)およびFabrazyme(商標)は線維芽細胞によって同等に内在化されないことを示す。Fabrazyme(商標)は、マンノース-6-リン酸受容体媒介内在化によってReplagal(商標)より容易に内在化される(図5を参照のこと)。
図7は、Replagal(商標)(下)およびFabrazyme(商標)(上)から放出されたグリカンの負荷プロフィールを示す。グリカンを、蛍光プローブで誘導体化し、GlycoSep(商標)Cカラムでのイオン交換クロマトグラフィによって比較した。結果は、Replagal(商標)は中性および一負荷グリカンの比率が高く、Fabrazyme(商標)は三負荷グリカンの比率が高いことを示す。
本実施例の目的は、動物モデルとヒトの薬物動態学的結果由来の薬物動態学パラメーターを比較することであった。
本評価の主な目的は、男性および女性のファブリー病患者におけるReplagal(商標)の薬物動態学特性を比較することであった。第2の目的は、Replagal(商標)およびFabrazyme(商標)で治療された患者間の薬物動態学特性を比較することであった。
式:Y=a(BW)b
Chappell and Mordenti(1991)Extrapolation of Toxicological and Pharmacological Data from Animals to Humans.In B.Testa(ed.)Advances in Drug Research,Vol.20,pp.1-116
*Mordentiら(1991)Interspecies Scaling of Clearance and Volume Distribution Data for Five Therapeutic Proteins.Pharmaceutical Research 8:1351-1359
M6P受容体のKdは2×10-9Mである(Kornfeld Ann Rev Biochem 61:307-330,1992)。
α-ガラクトシダーゼAの半減期:
ファブリー線維芽細胞で4日間(Mayesら、Am J Hum Genet 34:602-610,1982)
マウス肝臓で2日間(Ioannouら、Am J Hum Genet 68:14-25,2001)
*ベースライン値が約15U/mLの男性患者1人を除く
1単位(U)を、37℃で1時間あたりの1ナノモルの4-メチルウンベリフェリル-α-D-ガラクトピラノシド加水分解と定義する。
( )標準偏差
NA=適用せず
NS=有意でない
Tlast=最後の検出可能なReplagal酵素活性の時間
標準化AUCは(分*U/mL)/(U/kg)の単位を有する。
( )標準偏差
N=Replagalの第1の投与後の薬物動態学パラメーターについて評価した患者数
*GFR=Replagalの第1の投与の2〜3週間前に測定した糸球体濾過速度
†女性で測定したクレアチンクリアランス
*Engら(2001)A Phase I/II Clinical Trial of Enzyme Replacement in Fabry Disease.Am J Hum Genet 68:711-722
†飽和血清クリアランス
当業者は、日常的な実験のみを使用して、本明細書に記載の本発明の特定の態様の多数の等価物を認識するか確認することができる。このような等価物は、以下の特許請求の範囲に含まれることが意図される。
Claims (6)
- ヒトα-Gal A調製物を生産する方法であって、
培養細胞から採取した第1のヒトα-Gal A調製物を得るまたは提供する段階と、
該α-Gal A調製物が、以下の特徴:
(1)35%未満のトリおよびテトラシアル酸化グリカンの組み合わせを有する、
(2)50%を超えるグリカン複合体を有する、
(3)45%未満のリン酸化グリカンを有する、および
(4)シアル酸化グリカンのリン酸化グリカンに対する比が1を超える、
を有するか否かを決定する段階と、
該決定に基づいてα-Gal A調製物をさらに処理する段階と、
を含み、ここで、
前記特徴(1)〜(4)を有するヒトα-Gal A調製物が、要求される薬物動態学的パラメーターを有すると予測され、それによりヒトα-Gal A調製物を生産する、方法。 - 次のパラメーター:
該調製物が動物モデルにおける毛細血管/血管内皮細胞、腎糸球体上皮細胞、糸球体間膜細胞、腎内皮細胞、肺細胞、腎細胞、神経細胞、または心臓ミオサイテシンに優先的にターゲティングするか否か、
を決定する段階をさらに含む、請求項1記載の方法。 - 製剤化されたヒトα-Gal A調製物を生産する方法であって、
培養細胞から採取した第1のヒトα-Gal A調製物を得るまたは提供する段階と、
該α-Gal A調製物が、以下の特徴:
(1)35%未満のトリおよびテトラシアル酸化グリカンの組み合わせを有する、
(2)50%を超えるグリカン複合体を有する、
(3)45%未満のリン酸化グリカンを有する、および
(4)シアル酸化グリカンのリン酸化グリカンに対する比が1を超える、
を有するか否かを決定する段階と、
該決定に基づいてα-Gal A調製物を製剤化する段階と、
を含み、ここで、
前記特徴(1)〜(4)を有するヒトα-Gal A調製物が、要求される薬物動態学的パラメーターを有すると予測され、それによりヒトα-Gal A調製物を生産する、方法。 - 次のパラメーター:
該調製物が動物モデルにおける毛細血管/血管内皮細胞、腎糸球体上皮細胞、糸球体間膜細胞、腎内皮細胞、肺細胞、腎細胞、神経細胞、または心臓ミオサイテシンに優先的にターゲティングするか否か、
を決定する段階をさらに含む、請求項3記載の方法。 - 必要な被験体においてファブリー病を治療するのに用いるための、薬学的に許容されるキャリアおよびα-Gal A調製物を含む組成物であって、該α-Gal A調製物が、以下の特徴:
(1)35%未満のトリおよびテトラシアル酸化グリカンの組み合わせを有する、
(2)50%を超えるグリカン複合体を有する、
(3)45%未満のリン酸化グリカンを有する、および
(4)シアル酸化グリカンのリン酸化グリカンに対する比が1を超える、
に適合する炭水化物特性を有する組成物。 - 前記α-Gal A調製物が、次のパラメーター:
該調製物が動物モデルにおける毛細血管/血管内皮細胞、腎糸球体上皮細胞、糸球体間膜細胞、腎内皮細胞、肺細胞、腎細胞、神経細胞、または心臓ミオサイテシンに優先的にターゲティングするか否か、
を有する、請求項5記載の組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37558402P | 2002-04-25 | 2002-04-25 | |
US60/375,584 | 2002-04-25 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003587334A Division JP5570677B2 (ja) | 2002-04-25 | 2003-04-25 | α−ガラクトシダーゼA欠損症の治療 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014139236A Division JP2014196343A (ja) | 2002-04-25 | 2014-07-07 | α−ガラクトシダーゼA欠損症の治療 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2012140431A JP2012140431A (ja) | 2012-07-26 |
JP2012140431A5 JP2012140431A5 (ja) | 2013-04-11 |
JP5981151B2 true JP5981151B2 (ja) | 2016-08-31 |
Family
ID=29270665
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003587334A Expired - Lifetime JP5570677B2 (ja) | 2002-04-25 | 2003-04-25 | α−ガラクトシダーゼA欠損症の治療 |
JP2012010796A Expired - Lifetime JP5981151B2 (ja) | 2002-04-25 | 2012-01-23 | α−ガラクトシダーゼA欠損症の治療 |
JP2014139236A Withdrawn JP2014196343A (ja) | 2002-04-25 | 2014-07-07 | α−ガラクトシダーゼA欠損症の治療 |
JP2016135614A Expired - Lifetime JP6225224B2 (ja) | 2002-04-25 | 2016-07-08 | α−ガラクトシダーゼA欠損症の治療 |
JP2017170109A Expired - Lifetime JP6492139B2 (ja) | 2002-04-25 | 2017-09-05 | α−ガラクトシダーゼA欠損症の治療 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003587334A Expired - Lifetime JP5570677B2 (ja) | 2002-04-25 | 2003-04-25 | α−ガラクトシダーゼA欠損症の治療 |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014139236A Withdrawn JP2014196343A (ja) | 2002-04-25 | 2014-07-07 | α−ガラクトシダーゼA欠損症の治療 |
JP2016135614A Expired - Lifetime JP6225224B2 (ja) | 2002-04-25 | 2016-07-08 | α−ガラクトシダーゼA欠損症の治療 |
JP2017170109A Expired - Lifetime JP6492139B2 (ja) | 2002-04-25 | 2017-09-05 | α−ガラクトシダーゼA欠損症の治療 |
Country Status (13)
Country | Link |
---|---|
US (6) | US20040071686A1 (ja) |
EP (2) | EP1503788B1 (ja) |
JP (5) | JP5570677B2 (ja) |
AT (1) | ATE514430T1 (ja) |
AU (2) | AU2003228722B2 (ja) |
BR (2) | BRPI0309665B8 (ja) |
CA (1) | CA2483270C (ja) |
DK (1) | DK1503788T3 (ja) |
ES (1) | ES2367257T3 (ja) |
HK (1) | HK1073608A1 (ja) |
IL (4) | IL164757A0 (ja) |
NZ (1) | NZ536361A (ja) |
WO (1) | WO2003090695A2 (ja) |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003090695A2 (en) * | 2002-04-25 | 2003-11-06 | Transkaryotic Therapies, Inc. | TREATMENT OF α-GALACTOSIDASE A DEFICIENCY |
US7442372B2 (en) | 2003-08-29 | 2008-10-28 | Biomarin Pharmaceutical Inc. | Delivery of therapeutic compounds to the brain and other tissues |
AU2005282449B2 (en) | 2004-09-07 | 2011-07-14 | Velico Medical, Inc. | Apparatus for prolonging survival of platelets |
ATE495667T1 (de) * | 2004-10-15 | 2011-02-15 | Velico Medical Inc | Zusammensetzungen und verfahren für die verlängerung der überlebensdauer von blutplättchen |
WO2007097934A2 (en) * | 2006-02-17 | 2007-08-30 | Elusys Therapeutics, Inc. | Methods and compositions for using erythrocytes as carriers for delivery of drugs |
US20100144008A1 (en) * | 2006-12-21 | 2010-06-10 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Treatment of fabry disease |
EP2192924B1 (en) | 2007-08-20 | 2017-10-11 | Protalix Ltd. | Saccharide-containing protein conjugates and uses thereof |
EP2185187A1 (en) * | 2007-08-29 | 2010-05-19 | Shire Human Genetic Therapies, Inc. | Subcutaneous administration of alpha-galatosidase a |
US9194011B2 (en) | 2009-11-17 | 2015-11-24 | Protalix Ltd. | Stabilized alpha-galactosidase and uses thereof |
US20120230974A1 (en) * | 2009-11-17 | 2012-09-13 | Protalix Ltd | Alkaline alpha galactosidase for the treatment of fabry disease |
CN103179980B (zh) | 2010-06-25 | 2016-09-28 | 夏尔人类遗传性治疗公司 | 艾杜糖醛酸-2-硫酸酯酶的cns递送的方法和组合物 |
HRP20211520T1 (hr) | 2010-06-25 | 2021-12-24 | Shire Human Genetic Therapies, Inc. | Postupci i pripravci za dostavu iduronat-2-sulfataze u središnji živčani sustav |
CN103260637B (zh) | 2010-06-25 | 2016-04-06 | 夏尔人类遗传性治疗公司 | 乙酰肝素n-硫酸酯酶cns递送的方法和组合物 |
CN103282046B (zh) | 2010-06-25 | 2015-05-13 | 夏尔人类遗传性治疗公司 | 芳基硫酸酯酶 a cns 递送的方法和组合物 |
UA115648C2 (uk) * | 2010-06-25 | 2017-12-11 | Шае Хюмен Дженетік Терапіс, Інк. | Доставка терапевтичних агентів до цнс |
EP2661307A4 (en) | 2011-01-03 | 2014-08-06 | Univ California | HIGH-DENSITY EPIDURAL STIMULATION TO FACILITATE MOVEMENTS, ATTACHMENTS, ARBITRARY MOVEMENTS AND RECOVERY OF AUTONOMIC, SEXUAL, VASOMOTORIC AND COGNITIVE FUNCTIONS AFTER NEUROLOGICAL INJURIES |
ES2774190T3 (es) | 2011-01-20 | 2020-07-17 | Protalix Ltd | Composiciones de alfa-galactosidasa |
AU2012285696B2 (en) * | 2011-07-14 | 2015-12-10 | Grifols, S.A. | Rapid and accurate analysis of protein sialylation |
BR112014011409A2 (pt) | 2011-11-11 | 2017-05-02 | Neuroenabling Tech Inc | dispositivo de neuromodulação não invasivo para permitir a recuperação de função motora, sensorial, autonômica, sexual, vasomotora e cohnitiva |
US20140377244A1 (en) | 2011-12-23 | 2014-12-25 | Shire Human Genetic Therapies, Inc. | Stable formulations for cns delivery of arylsulfatase a |
US10155027B2 (en) | 2012-07-17 | 2018-12-18 | Amicus Therapeutics, Inc. | Alpha-galactosidase A and 1-deoxygalactonojirimycin co-formulation for the treatment of fabry disease |
US9694056B2 (en) | 2012-07-17 | 2017-07-04 | Amicus Therapeutics, Inc. | α-galactosidase A and 1-deoxygalactonojirimycin co-formulation |
AU2014342232B2 (en) * | 2013-10-31 | 2017-12-21 | Amgen Inc. | Use of monensin to regulate glycosylation of recombinant proteins |
HUE062016T2 (hu) * | 2014-12-22 | 2023-09-28 | Codexis Inc | Humán alfa-galaktozidáz variánsok |
US9981021B1 (en) | 2015-04-09 | 2018-05-29 | Kinetiq, Inc. | Subcutaneous therapeutic enzyme formulations, uses, and methods for generating thereof |
GB201508025D0 (en) | 2015-05-11 | 2015-06-24 | Ucl Business Plc | Fabry disease gene therapy |
JP6996676B2 (ja) * | 2016-03-30 | 2022-02-04 | 国立研究開発法人農業・食品産業技術総合研究機構 | マンノース-6-リン酸基含有糖蛋白質の製造方法、及び蛍光基結合型マンノース-6-リン酸基含有糖蛋白質の細胞内分布を検出する方法 |
MX2019008076A (es) * | 2017-01-05 | 2019-08-29 | Protalix Ltd | Regimen terapeutico para el tratamiento de fabry usando alfa-galactosidasa estabilizada. |
TW201829770A (zh) * | 2017-01-10 | 2018-08-16 | 美商阿米庫斯醫療股份有限公司 | 用於治療fabry氏病之重組α-半乳糖苷酶A |
EP3421081B1 (en) | 2017-06-30 | 2020-04-15 | GTX medical B.V. | A system for neuromodulation |
US20200206323A1 (en) * | 2017-09-08 | 2020-07-02 | The Nemours Foundation | An agent, a device and a blood-circulation system for treating lysosomal storage diseases, and a method for treating lysosomal storage diseases |
WO2019110400A1 (en) | 2017-12-05 | 2019-06-13 | Ecole Polytechnique Federale De Lausanne (Epfl) | A system for planning and/or providing neuromodulation |
DE18205821T1 (de) | 2018-11-13 | 2020-12-24 | Gtx Medical B.V. | Steuerungssystem zur bewegungsrekonstruktion und/oder wiederherstellung für einen patienten |
EA202191735A1 (ru) | 2018-12-20 | 2021-11-24 | Кодексис, Инк. | Варианты альфа-галактозидазы человека |
EP3695878B1 (en) | 2019-02-12 | 2023-04-19 | ONWARD Medical N.V. | A system for neuromodulation |
EP3827871A1 (en) | 2019-11-27 | 2021-06-02 | ONWARD Medical B.V. | Neuromodulation system |
JP2023516301A (ja) * | 2020-02-28 | 2023-04-19 | コデクシス, インコーポレイテッド | ヒトアルファ-ガラクトシダーゼ変異体 |
Family Cites Families (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US658567A (en) * | 1899-10-14 | 1900-09-25 | Elmer G Howard | Threshing-machine attachment. |
US4407957A (en) | 1981-03-13 | 1983-10-04 | Damon Corporation | Reversible microencapsulation of a core material |
EP0159604B1 (en) | 1984-04-09 | 1990-11-07 | Toyo Boseki Kabushiki Kaisha | Sustained-release preparation applicable to mucous membrane in oral cavity |
US4764376A (en) * | 1984-06-18 | 1988-08-16 | Eli Lilly And Company | Method of inhibiting aromatase |
GB8530631D0 (en) * | 1985-12-12 | 1986-01-22 | Ciba Geigy Ag | Thrombin inhibitors |
US4764378A (en) | 1986-02-10 | 1988-08-16 | Zetachron, Inc. | Buccal drug dosage form |
US5272066A (en) * | 1986-03-07 | 1993-12-21 | Massachusetts Institute Of Technology | Synthetic method for enhancing glycoprotein stability |
US6048729A (en) | 1987-05-01 | 2000-04-11 | Transkaryotic Therapies, Inc. | In vivo protein production and delivery system for gene therapy |
FR2619719B1 (fr) | 1987-09-01 | 1991-05-10 | Sanofi Sa | Procede d'obtention d'interleukine-2 a partir de cellules eucaryotes, vecteurs necessaires a sa mise en oeuvre et lignees cellulaires hautement productrices |
WO1990011353A1 (en) | 1989-03-24 | 1990-10-04 | Research Corporation Technologies, Inc. | Recombinant alpha-galactosidase, a therapy for fabry disease |
US5179023A (en) * | 1989-03-24 | 1993-01-12 | Research Corporation Technologies, Inc. | Recombinant α-galactosidase a therapy for Fabry disease |
US5382518A (en) * | 1989-07-13 | 1995-01-17 | Sanofi | Urate oxidase activity protein, recombinant gene coding therefor, expression vector, micro-organisms and transformed cells |
NZ234453A (en) | 1989-07-13 | 1993-01-27 | Sanofi Sa | Recombinant dna encoding urate oxidase, and vector, host, protein and pharmaceutical compositions associated therewith |
JPH04502108A (ja) * | 1989-09-05 | 1992-04-16 | バイオテクノロジー オーストラリア ピーティーワイ リミテッド | 組替え生産物 |
JP2688854B2 (ja) | 1989-10-27 | 1997-12-10 | 株式会社ホーネンコーポレーション | 糖転移活性の強いα―ガラクトシダーゼの製造法 |
US5697901A (en) * | 1989-12-14 | 1997-12-16 | Elof Eriksson | Gene delivery by microneedle injection |
US5661132A (en) * | 1989-12-14 | 1997-08-26 | Auragen, Inc. | Wound healing |
CA2092823A1 (en) | 1990-09-28 | 1992-03-29 | Barry D. Greenberg | Transgenic animals with alzheimer's amyloid precursor gene |
US5401650A (en) | 1990-10-24 | 1995-03-28 | The Mount Sinai School Of Medicine Of The City University Of New York | Cloning and expression of biologically active α-galactosidase A |
US5356804A (en) | 1990-10-24 | 1994-10-18 | Mount Sinai School Of Medicine Of The City Of New York | Cloning and expression of biologically active human α-galactosidase A |
WO1992013067A1 (en) | 1991-01-21 | 1992-08-06 | Genzyme Corporation | Production of enzymatically active glucocerebrosidase from recombinant cells |
DK0585368T3 (da) * | 1991-04-25 | 1998-03-16 | Univ Brown Res Found | Implanterbart biokompatibelt immunisolatorisk vehikel til afgivelse af udvalgte terapeutiske produkter |
ATE359842T1 (de) | 1991-07-02 | 2007-05-15 | Nektar Therapeutics | Abgabevorrichtung für nebelförmige medikamente |
US5750376A (en) * | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
WO1993008292A1 (en) | 1991-10-16 | 1993-04-29 | Agracetus, Inc. | Particle-mediated transformation of animal somatic cells |
US6270989B1 (en) | 1991-11-05 | 2001-08-07 | Transkaryotic Therapies, Inc. | Protein production and delivery |
PT101031B (pt) | 1991-11-05 | 2002-07-31 | Transkaryotic Therapies Inc | Processo para o fornecimento de proteinas por terapia genetica |
US6063630A (en) | 1991-11-05 | 2000-05-16 | Transkaryotic Therapies, Inc. | Targeted introduction of DNA into primary or secondary cells and their use for gene therapy |
US5641670A (en) | 1991-11-05 | 1997-06-24 | Transkaryotic Therapies, Inc. | Protein production and protein delivery |
US5733761A (en) * | 1991-11-05 | 1998-03-31 | Transkaryotic Therapies, Inc. | Protein production and protein delivery |
US5858751A (en) * | 1992-03-09 | 1999-01-12 | The Regents Of The University Of California | Compositions and methods for producing sialyltransferases |
ES2105262T3 (es) | 1992-05-18 | 1997-10-16 | Minnesota Mining & Mfg | Dispositivo de suministro de farmaco a traves de las mucosas. |
US5785049A (en) | 1994-09-21 | 1998-07-28 | Inhale Therapeutic Systems | Method and apparatus for dispersion of dry powder medicaments |
US5383851A (en) | 1992-07-24 | 1995-01-24 | Bioject Inc. | Needleless hypodermic injection device |
US5804413A (en) * | 1992-07-31 | 1998-09-08 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Herpes simplex virus strains for gene transfer |
US5569189A (en) | 1992-09-28 | 1996-10-29 | Equidyne Systems, Inc. | hypodermic jet injector |
KR100291620B1 (ko) | 1992-09-29 | 2001-10-24 | 추후제출 | 부갑상선호르몬의활성단편의폐를통한전달방법 |
US6329191B1 (en) | 1993-08-30 | 2001-12-11 | Hawaii Biotechnology Group, Inc. | DNA encoding recombinant coffee bean alpha-galactosidase |
EP0726964A4 (en) * | 1993-09-23 | 1999-01-13 | New England Biolabs Inc | INSULATION AND COMPOSITION OF NEW GLYCOSIDASES |
DE4339605A1 (de) | 1993-11-20 | 1995-05-24 | Beiersdorf Ag | Desodorierende Wirkstoffkombinationen auf der Basis von alpha, omega-Alkandicarbonsäuren und Fettsäurepartialglyceriden |
US5843015A (en) | 1993-12-28 | 1998-12-01 | Becton Dickinson And Company | Molecules for iontophoretic delivery |
US5789247A (en) * | 1994-04-01 | 1998-08-04 | Ballay; Annick | Expression in non-tumoral human lymphoblastoid lines with an integrative vector |
FR2718357B1 (fr) | 1994-04-06 | 1997-10-03 | Defarges Alain Moreau | Perfectionnements apportés à un dispositif d'injection par jet sans aiguille. |
US5834251A (en) * | 1994-12-30 | 1998-11-10 | Alko Group Ltd. | Methods of modifying carbohydrate moieties |
US5599302A (en) | 1995-01-09 | 1997-02-04 | Medi-Ject Corporation | Medical injection system and method, gas spring thereof and launching device using gas spring |
US5780014A (en) | 1995-04-14 | 1998-07-14 | Inhale Therapeutic Systems | Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin |
US5654007A (en) | 1995-06-07 | 1997-08-05 | Inhale Therapeutic Systems | Methods and system for processing dispersible fine powders |
US6566089B1 (en) * | 1996-09-04 | 2003-05-20 | Tularik Inc. | Cell-based drug screens for regulators of gene expression |
US6458574B1 (en) | 1996-09-12 | 2002-10-01 | Transkaryotic Therapies, Inc. | Treatment of a α-galactosidase a deficiency |
US6083725A (en) * | 1996-09-13 | 2000-07-04 | Transkaryotic Therapies, Inc. | Tranfected human cells expressing human α-galactosidase A protein |
RU2179034C2 (ru) | 1996-09-13 | 2002-02-10 | Транскариотик Терапиз, Инк. | ЛЕЧЕНИЕ В СЛУЧАЕ ДЕФИЦИТА α-ГАЛАКТОЗИДАЗЫ А |
WO1999057263A1 (en) | 1998-05-07 | 1999-11-11 | Transkaryotic Therapies, Inc. | Modifying the expression of the fsh beta gene by homologous recombination |
US6242218B1 (en) | 1998-05-07 | 2001-06-05 | Transkaryotic Therapies Inc. | Genomic sequences for protein production and delivery |
IL125423A (en) * | 1998-07-20 | 2004-08-31 | Israel State | Alkaline alpha-galactosidase having broad substrate specificity |
US6749851B2 (en) * | 2001-08-31 | 2004-06-15 | Clearant, Inc. | Methods for sterilizing preparations of digestive enzymes |
WO2003090695A2 (en) * | 2002-04-25 | 2003-11-06 | Transkaryotic Therapies, Inc. | TREATMENT OF α-GALACTOSIDASE A DEFICIENCY |
-
2003
- 2003-04-25 WO PCT/US2003/013063 patent/WO2003090695A2/en active Application Filing
- 2003-04-25 EP EP03726489A patent/EP1503788B1/en not_active Expired - Lifetime
- 2003-04-25 AT AT03726489T patent/ATE514430T1/de active
- 2003-04-25 AU AU2003228722A patent/AU2003228722B2/en not_active Expired
- 2003-04-25 ES ES03726489T patent/ES2367257T3/es not_active Expired - Lifetime
- 2003-04-25 EP EP11151977A patent/EP2361631A1/en not_active Withdrawn
- 2003-04-25 DK DK03726489.2T patent/DK1503788T3/da active
- 2003-04-25 CA CA2483270A patent/CA2483270C/en not_active Expired - Lifetime
- 2003-04-25 BR BRPI0309665A patent/BRPI0309665B8/pt not_active IP Right Cessation
- 2003-04-25 NZ NZ536361A patent/NZ536361A/en not_active IP Right Cessation
- 2003-04-25 US US10/423,225 patent/US20040071686A1/en not_active Abandoned
- 2003-04-25 JP JP2003587334A patent/JP5570677B2/ja not_active Expired - Lifetime
- 2003-04-25 BR BR122017016940A patent/BR122017016940B8/pt not_active IP Right Cessation
-
2004
- 2004-10-21 IL IL16475704A patent/IL164757A0/xx active IP Right Grant
-
2005
- 2005-08-03 HK HK05106677.2A patent/HK1073608A1/xx not_active IP Right Cessation
-
2006
- 2006-04-13 US US11/403,618 patent/US7833742B2/en not_active Expired - Lifetime
-
2009
- 2009-09-22 AU AU2009217430A patent/AU2009217430B2/en not_active Expired
-
2010
- 2010-04-15 US US12/761,287 patent/US9267166B2/en not_active Expired - Fee Related
-
2012
- 2012-01-23 JP JP2012010796A patent/JP5981151B2/ja not_active Expired - Lifetime
- 2012-05-29 IL IL220043A patent/IL220043B/en active IP Right Grant
-
2014
- 2014-07-07 JP JP2014139236A patent/JP2014196343A/ja not_active Withdrawn
-
2016
- 2016-01-14 US US14/995,540 patent/US9523113B2/en not_active Expired - Lifetime
- 2016-07-08 JP JP2016135614A patent/JP6225224B2/ja not_active Expired - Lifetime
- 2016-11-14 US US15/350,785 patent/US10245304B2/en not_active Expired - Lifetime
-
2017
- 2017-09-05 JP JP2017170109A patent/JP6492139B2/ja not_active Expired - Lifetime
-
2018
- 2018-01-21 IL IL257056A patent/IL257056B/en active IP Right Grant
-
2019
- 2019-02-14 US US16/276,039 patent/US11116823B2/en not_active Expired - Lifetime
-
2021
- 2021-02-11 IL IL280818A patent/IL280818B/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6492139B2 (ja) | α−ガラクトシダーゼA欠損症の治療 | |
EP1163349B1 (en) | Medical preparations for the treatment of alpha-galactosidase a deficiency | |
KR20240017127A (ko) | Gla 유전자에 돌연변이를 갖는 환자에서 파브리 질병을 치료하는 방법 | |
AU2012241170B2 (en) | Treatment of alpha-Galactosidase A deficiency | |
AU2016250357A1 (en) | Treatment of alpha-Galactosidase A deficiency |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130214 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130515 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130814 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130819 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130823 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20140305 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140707 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20140707 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20140822 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20150529 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151225 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160205 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160304 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160325 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160728 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5981151 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
EXPY | Cancellation because of completion of term |