US20030138417A1 - Stable liquid pharmaceutical formulation of IgG antibodies - Google Patents
Stable liquid pharmaceutical formulation of IgG antibodies Download PDFInfo
- Publication number
- US20030138417A1 US20030138417A1 US10/291,528 US29152802A US2003138417A1 US 20030138417 A1 US20030138417 A1 US 20030138417A1 US 29152802 A US29152802 A US 29152802A US 2003138417 A1 US2003138417 A1 US 2003138417A1
- Authority
- US
- United States
- Prior art keywords
- clear
- antibody
- formulation
- buffer
- succinate
- 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.)
- Abandoned
Links
- 239000007788 liquid Substances 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 97
- 238000009472 formulation Methods 0.000 claims abstract description 86
- 239000000872 buffer Substances 0.000 claims abstract description 50
- 229960002806 daclizumab Drugs 0.000 claims abstract description 28
- 239000008362 succinate buffer Substances 0.000 claims abstract description 26
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229920000136 polysorbate Polymers 0.000 claims abstract description 16
- 239000008181 tonicity modifier Substances 0.000 claims abstract description 10
- 229950008882 polysorbate Drugs 0.000 claims abstract description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 66
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 48
- 239000011780 sodium chloride Substances 0.000 claims description 33
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 24
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 23
- 102000003800 Selectins Human genes 0.000 abstract description 11
- 108090000184 Selectins Proteins 0.000 abstract description 11
- 102000005962 receptors Human genes 0.000 abstract description 11
- 108020003175 receptors Proteins 0.000 abstract description 11
- AAEVYOVXGOFMJO-UHFFFAOYSA-N prometryn Chemical compound CSC1=NC(NC(C)C)=NC(NC(C)C)=N1 AAEVYOVXGOFMJO-UHFFFAOYSA-N 0.000 abstract description 9
- 238000010254 subcutaneous injection Methods 0.000 abstract description 8
- 239000007929 subcutaneous injection Substances 0.000 abstract description 8
- 239000012669 liquid formulation Substances 0.000 abstract description 7
- 229940044627 gamma-interferon Drugs 0.000 abstract description 4
- 102000004169 proteins and genes Human genes 0.000 description 37
- 235000018102 proteins Nutrition 0.000 description 36
- 108090000623 proteins and genes Proteins 0.000 description 36
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 28
- 239000000546 pharmaceutical excipient Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 24
- 229920000053 polysorbate 80 Polymers 0.000 description 24
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 21
- 239000000178 monomer Substances 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 18
- 239000000427 antigen Substances 0.000 description 16
- 108091007433 antigens Proteins 0.000 description 16
- 102000036639 antigens Human genes 0.000 description 16
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 15
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 15
- 239000004471 Glycine Substances 0.000 description 14
- 238000011534 incubation Methods 0.000 description 14
- 239000008363 phosphate buffer Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 13
- 229930182817 methionine Natural products 0.000 description 13
- 229960004452 methionine Drugs 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 229940074404 sodium succinate Drugs 0.000 description 13
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 13
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 12
- 239000004472 Lysine Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 238000000533 capillary isoelectric focusing Methods 0.000 description 11
- 229920001213 Polysorbate 20 Polymers 0.000 description 10
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 10
- 238000006731 degradation reaction Methods 0.000 description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 10
- 229910019142 PO4 Inorganic materials 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- -1 sodium succinate) Chemical compound 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 7
- 102000008070 Interferon-gamma Human genes 0.000 description 7
- 108010074328 Interferon-gamma Proteins 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 102000018358 immunoglobulin Human genes 0.000 description 7
- 239000010452 phosphate Substances 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 6
- 238000002296 dynamic light scattering Methods 0.000 description 6
- 229960003130 interferon gamma Drugs 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- 108010029485 Protein Isoforms Proteins 0.000 description 5
- 102000001708 Protein Isoforms Human genes 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 238000001542 size-exclusion chromatography Methods 0.000 description 5
- 238000012430 stability testing Methods 0.000 description 5
- 230000000087 stabilizing effect Effects 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- 102100029268 Neurotrophin-3 Human genes 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229960005261 aspartic acid Drugs 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000006240 deamidation Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 229940072221 immunoglobulins Drugs 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 3
- 108010092694 L-Selectin Proteins 0.000 description 3
- 102100033467 L-selectin Human genes 0.000 description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 description 3
- 108090000099 Neurotrophin-4 Proteins 0.000 description 3
- 102100033857 Neurotrophin-4 Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000036425 denaturation Effects 0.000 description 3
- 238000004925 denaturation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 210000002443 helper t lymphocyte Anatomy 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 238000012510 peptide mapping method Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 229940068977 polysorbate 20 Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 2
- XKJBIJTYIQAFAQ-UHFFFAOYSA-N C(CCC(=O)O)(=O)O.C(CCC(=O)O)(=O)O.C(CCC(=O)O)(=O)O.P(=O)(O)(O)O.P(=O)(O)(O)O.P(=O)(O)(O)O Chemical compound C(CCC(=O)O)(=O)O.C(CCC(=O)O)(=O)O.C(CCC(=O)O)(=O)O.P(=O)(O)(O)O.P(=O)(O)(O)O.P(=O)(O)(O)O XKJBIJTYIQAFAQ-UHFFFAOYSA-N 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 108010024212 E-Selectin Proteins 0.000 description 2
- 102100023471 E-selectin Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 2
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108090000742 Neurotrophin 3 Proteins 0.000 description 2
- 108010035766 P-Selectin Proteins 0.000 description 2
- 102100023472 P-selectin Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- ZJUKTBDSGOFHSH-WFMPWKQPSA-N S-Adenosylhomocysteine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSCC[C@H](N)C(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZJUKTBDSGOFHSH-WFMPWKQPSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 210000000447 Th1 cell Anatomy 0.000 description 2
- 102100033571 Tissue-type plasminogen activator Human genes 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 229940112869 bone morphogenetic protein Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- OVYQSRKFHNKIBM-UHFFFAOYSA-N butanedioic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)CCC(O)=O OVYQSRKFHNKIBM-UHFFFAOYSA-N 0.000 description 2
- 238000005251 capillar electrophoresis Methods 0.000 description 2
- 230000006652 catabolic pathway Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 229940047120 colony stimulating factors Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000001506 fluorescence spectroscopy Methods 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 239000003900 neurotrophic factor Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229940068965 polysorbates Drugs 0.000 description 2
- 235000013930 proline Nutrition 0.000 description 2
- 230000004845 protein aggregation Effects 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007974 sodium acetate buffer Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 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 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-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
- 208000030507 AIDS Diseases 0.000 description 1
- 108010059616 Activins Proteins 0.000 description 1
- 102000005606 Activins Human genes 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 1
- 102400001282 Atrial natriuretic peptide Human genes 0.000 description 1
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 102100031092 C-C motif chemokine 3 Human genes 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 1
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 1
- 108010009575 CD55 Antigens Proteins 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 102400000113 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 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
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000622123 Homo sapiens E-selectin Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 1
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 102100030173 Muellerian-inhibiting factor Human genes 0.000 description 1
- 101710122877 Muellerian-inhibiting factor Proteins 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 108090000095 Neurotrophin-6 Proteins 0.000 description 1
- 102000008212 P-Selectin Human genes 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102400000834 Relaxin A chain Human genes 0.000 description 1
- 101800000074 Relaxin A chain Proteins 0.000 description 1
- 102400000610 Relaxin B chain Human genes 0.000 description 1
- 101710109558 Relaxin B chain Proteins 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 102400000827 Saposin-D Human genes 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100022831 Somatoliberin Human genes 0.000 description 1
- 101710142969 Somatoliberin Proteins 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 1
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 108050006955 Tissue-type plasminogen activator Proteins 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000488 activin Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001455 anti-clotting effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000003164 beta-aspartyl group Chemical group 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 238000013357 binding ELISA Methods 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011098 chromatofocusing Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013499 data model Methods 0.000 description 1
- 108700001680 des-(1-3)- insulin-like growth factor 1 Proteins 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000055277 human IL2 Human genes 0.000 description 1
- 102000051210 human SELE Human genes 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 238000012872 hydroxylapatite chromatography Methods 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 239000000893 inhibin Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 102000028416 insulin-like growth factor binding Human genes 0.000 description 1
- 108091022911 insulin-like growth factor binding Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000014828 interferon-gamma production Effects 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229940066294 lung surfactant Drugs 0.000 description 1
- 239000003580 lung surfactant Substances 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 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
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 229940032018 neurotrophin 3 Drugs 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- 229940127126 plasminogen activator Drugs 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
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010087851 prorelaxin Proteins 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/249—Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
- C07K16/246—IL-2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
- C07K16/2854—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72 against selectins, e.g. CD62
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Definitions
- the present invention relates generally to the field of pharmaceutical formulation of antibodies. Specifically, the present invention relates to a stable, liquid, high concentration antibody formulation.
- This invention is exemplified by a stabilized liquid formulation of Daclizumab, an anti-IL2 receptor antibody; HAIL-12, a humanized anti-IL-12 monoclonal antibody; and HuEP5C7, a humanized anti-L selectin monoclonal antibody.
- Immunoglobulins are recognized as possessing characteristics that tend to form aggregates and particulates in solution, and as such, may require filtration before use for intravenous or subcutaneous injection.
- the formation of protein aggregates and particulates has long been a problem in the development of parenteral immunoglobulin products, especially when the immunoglobulins are formulated at high concentrations.
- SynagisTM (MedImmune) is a humanized monoclonal IgG1 antibody produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the T protein of respiratory syncytial virus (RSV).
- SynagisTM is a composite of human (90%) and murine (10%) antibody sequences.
- SynagisTM is supplied as a sterile lyophilized product for reconstruction with sterile water for injection. Reconstituted SynagisTM is to be administered by intramuscular injection only. Upon reconstitution, SynagisTM contains the following excipients: 47 mM histidine, 3.0 mM glycine, 5.6% mannitol, and the active ingredient, IgG1 antibody, at a concentration of 100 milligrams per vial. The reconstituted SynagisTM is to be administered within 6 hours of reconstitution.
- WO 89/11297 discloses a lyophilized monoclonal antibody formulation comprising a lyophilized formulation of 1-25 mg/ml IgG monoclonal antibody, 2-10% maltose, and sodium acetate, phosphate, or citrate buffer having a pH between 3.0 to 6.0.
- WO 97/45140 discloses an aqueous preparation of anti-CD4 antibody concentrated to approximately 100 mg/ml in 100 mM sodium citrate, 0.05 mM EDTA, pH 6.0.
- the application discloses a slight rise in turbidity after concentration of the antibody, which likely reflects protein aggregation. Removing this aggregation requires addition of Polysorbate 80 and sterile filtration.
- WO 90/11091 discloses injectable aqueous compositions comprising about 5 mg/ml of IgM, 2.5-5% (w/v) human serum albumin, in 8-20 mM phosphate buffer, 270 mM sodium chloride, pH 6.8-7.4.
- U.S. Pat. No. 6,171,586 discloses a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, an acetate buffer from about pH 4.8 to about 5.5, a surfactant, and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride.
- U.S. Patent Application Publication No. US 2001/0014326A1 discloses a pre-lyophilized antibody formulation containing 25 mg/ml anti-IgE antibody, 5 mM histidine, pH 6.0, 85 mM sucrose, and 0.01% polysorbate 20.
- U.S. Pat. No. 5,744,132 discloses a composition comprising 1-1000 ⁇ g/ml IL-12 antibody, 2% sucrose, 4.15% mannitol, 10 mM sodium succinate, and about 0.02% Tween® 20, having a pH of about 5.6.
- U.S. Pat. No. 6,165,467 discloses a process for stabilizing a human monoclonal antibody composition produced by hybridoma cell line having accession number HB8307, which comprises dialyzing the human monoclonal antibody in a phosphate salt stabilized buffer solution having a pH from 7.2 to 7.4, said solution comprising 1-20 mg of D-mannitol per mg of said monoclonal antibody, 0.005-0.2 millimole of glycine per mg of said monoclonal antibody, and an amount of pH stabilizing phosphate salt to stabilize the pH of said solution.
- This invention is directed to a stable liquid pharmaceutical formulation comprising a high concentration, e.g., greater than 50 mg/ml, of an antibody in 20-60 mM succinate buffer or 30-70 mM histidine buffer (pH from about pH 5.5 to about pH 6.5), a tonicity modifier, and about 0.01-0.1% polysorbate.
- This formulation retains the physical, chemical, and biological stability of antibody and prevents the immunoglobulins intended for administration to human subjects from forming aggregates and particulates in the final product.
- Preferred antibodies of this invention include Daclizumab, a humanized anti-1L-2 receptor monoclonal antibody; HAIL-12, a humanized anti-IL-12 monoclonal antibody; and HuEP5C7, a humanized anti-L selectin monoclonal antibody; and Flintozumab, a humanized anti-gamma interferon monoclonal antibody.
- the liquid antibody formulation is stable at refrigerated temperature (2-8° C.) for at least 1 year and preferably 2 years. This liquid formulation is also stable at room temperature (23-27° C.) for at least six months. This liquid formulation is suitable for subcutaneous injection.
- FIG. 1A shows the percent clips formation
- FIG. 1B shows the percent aggregates, at various pH levels following a four-week incubation of the sample at 45° C., as assessed by SEC-HPLC.
- FIG. 2 shows the percent of degradation obtained at various pH levels as assessed by cIEF following a four-week incubation of the sample at 45° C.
- FIG. 3 shows the percent of iso-aspartic acid formed at various pH levels as assessed by the Promega IsoQuant kit following a four-week incubation of the sample at 45° C.
- FIG. 4 shows the effect of different buffers over time on potency following incubation at 37° C.
- buffer encompasses those agents which maintain the solution pH in an acceptable range and may include succinate (sodium), histidine, phosphate (sodium or potassium), Tris (tris (hydroxymethyl) aminomethane), diethanolamine, and the like.
- the buffer of this invention has a pH in the range from about 5.5 to about 6.5; and preferably has a pH of about 6.0.
- Examples of buffers that will control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate phospate and other organic acid buffers.
- “Pharmaceutically acceptable excipients” are those inert substances that can reasonably be administered to a subject mammal and provide an effective dose of the active ingredient employed. These substances are added to a formulation to stabilize the physical, chemical and biological structure of the antibody. The term also refers to additives that may be needed to attain an isotonic formulation, suitable for the intended mode of administration.
- pharmaceutical formulation refers to preparations which are in such form as to permit the biological activity of the active ingredients to be unequivocally effective, and which contain no additional components which are toxic to the subjects to which the formulation would be administered.
- a “stable” formulation is one in which the protein therein essentially retains its physical stability, chemical stability, and biological activity upon storage.
- Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time period.
- a “stable” liquid antibody formulation is a liquid antibody formulation with no significant changes observed at a refrigerated temperature (2-8° C.) for at least 12 months, preferably 2 years, and more preferably 3 years; or at room temperature (23-27° C.) for at least 3 months, preferably 6 months, and more preferably 1 year.
- the criteria for stability are as follows. No more than 10%, preferably 5%, of antibody monomer is degraded as measured by SEC-HPLC. The solution is colorless, or clear to slightly opalescent by visual analysis. The concentration, pH and osmolality of the formulation have no more than +/ ⁇ 10% change. Potency is within 70-130%, preferably 80-120% of the control. No more than 10%, preferably 5% of clipping (hydrolysis) is observed. No more than 10%, preferably 5% of aggregation is formed.
- An antibody “retains its physical stability” in a pharmaceutical formulation if it shows no significant increase of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering, size exclusion chromatography (SEC-HPLC) and dynamic light scattering.
- SEC-HPLC size exclusion chromatography
- dynamic light scattering the protein conformation is not altered.
- the changes of protein conformation can be evaluated by fluorescence spectroscopy, which determines the protein tertiary structure, and by FTIR spectroscopy, which determines the protein secondary structure.
- An antibody “retains its biological activity” in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared.
- the biological activity of an antibody can be determined, for example, by an antigen binding ELISA assay.
- isotonic means that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 270-328 mOsm. Slightly hypotonic osmotic pressure is 250-269 and slightly hypertonic osmotic pressure is 328-350 mOsm. Osmotic pressure can be measured, for example, using a vapor pressure or ice-freezing type osmometer.
- Tonicity modifiers are those pharmaceutically acceptable inert substances that can be added to the formulation to provide an isotonity of the formulation.
- Tonicity modifiers suitable for this invention include salts and amino acids.
- the antibody formulation contains pharmaceutically acceptable excipients.
- the antibody formulation is formulated such that the antibody retains its physical, chemical and biological activity.
- the formulation is preferably stable for at least 1 year at refrigerated temperature (2-8° C.) and 6 months at room temperature (23-27° C.).
- the analytical methods for evaluating the product stability include size exclusion chromatography (SEC-HPLC), dynamic light scattering test (DLS), differential scanning calorimetery (DSC), iso-asp quantification, potency, UV at 340 nm, and UV spectroscopy.
- SEC J. Pharm. Scien., 83:1645-1650, (1994); Pharm. Res., 11:485 (1994); J. Pharm. Bio. Anal., 15:1928 (1997); J. Pharm. Bio. Anal., 14:1133-1140 (1986)
- DSC Pharm. Res., 15:200 (1998); Pharm.
- the iso-Asp content in the samples is measured using the Isoquant Isoaspartate Detection kit (Promega).
- the kit uses the enzyme Protein Isoaspartyl Methyltransferase (PIMT) to specifically detect the presence of isoaspartic acid residues in a target protein.
- PIMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to isoaspartic acid at the ⁇ -carboxyl position, generating S-adenosyl-L-homocysteine (SAH) in the process.
- SAH S-adenosyl-L-homocysteine
- the potency or bioactivity of an antibody can be measured by its ability to bind to its antigen.
- the specific binding of an antibody to its antigen can be quantitated by any method known to those skilled in the art, for example, an immunoassay, such as ELISA (enzyme-linked immunosorbant assay).
- the invention herein relates to a stable aqueous formulation comprising an antibody.
- the antibody in the formulation is prepared using techniques available in the art for generating antibodies, exemplary methods of which are described in more detail in the following sections.
- the antibody is directed against an antigen of interest.
- the antigen is a biologically important polypeptide and administration of the antibody to a mammal may prevent or treat a disorder.
- antibodies directed against nonpolypeptide antigens are also contemplated.
- the antigen is a polypeptide, it may be a transmembrane molecule (e.g. receptor) or ligand such as a growth factor.
- exemplary antigens include molecules such as renin; a growth hormone, including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoproteins; alpha-1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as factor VIIIC, factor IX, tissue factor, and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and
- the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed cells, is removed, for example, by centrifugation or ultrafiltration. Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.
- a protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.
- the matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose.
- the antibody comprises a C H3 domain
- the Bakerbond ABXTM resin J. T. Baker, Phillipsburg, N.J. is useful for purification.
- Daclizumab USAN, United States Adopted Names
- Daclizumab is currently being marketed as Zenapax® for the prevention of organ rejection after renal transplantation and is administered through the intravenous route.
- Daclizumab is also useful for treating psoriasis, for which, the subcutaneous delivery is the preferred route of administration.
- high concentration of antibody is preferred.
- Daclizumab is a recombinant humanized monoclonal antibody, subclass IgG1. The molecule is composed of two identical heavy chain and two identical light chain subunits. Disulfide bridges link the four chains.
- Daclizumab monomer is approximately 150,000 daltons in molecular weight. Daclizumab binds to the p55 subunit of the IL-2 receptor expressed on activated T cells. The antigen target is designated CD25. Daclizumab is produced from a GS-NSO cell line containing the heavy and light chain genes by fed-batch fermentation culture. Bioreactor harvests are processed to remove cells and debris and purified using a combination of ion-exchange and gel filtration chromatography and a series of ultrafiltration and filtration techniques to produce drug substance containing greater than 95% monomeric species.
- IL-12 anti-interleukin 12
- IL-12 is a cytokine synthesized by antigen presenting cells. It is composed of two subunits (p35 and p40), both must be present for functional activity. Functional IL-12 is also called IL-12p70.
- This cytokine preferentially acts on T helper cell type 1 (Th1) lymphocytes and natural killer cells by increasing their proliferative rate.
- Th1 T helper cell type 1
- IFNg interferon gamma
- 16G2 (Hoffman La Roche) is a murine antibody raised against IL-12p70. 16G2 has been shown to act in near stoichiometric amounts to IL-12 in a functional assay-the inhibition of proliferation of activated T cells from human peripheral blood (PBMC). This is an important characteristic because p40 dimers of IL-12 exist in serum and antibodies raised to the p40 subunit need to be used in excess amounts to neutralize the proliferative capacity of a given amount of IL-12. 16G2 was humanized at Protein Design Labs. (Fremont, Calif.) to give rise to HAIL-12 (humanized anti-IL-12, an IgG1 antibody).
- Another preferred antibody is anti-L selectin antibody.
- Selectins such as L, E, and P-selectin have been found to be associated with tissue damage during the course of ischemia and reperfusion. Neutrophils play an important role in this connection. It is assumed that selectin is required for the recruitment of neutrophils. L-selectin is important for the complete development of damage in skeletal muscle as well as in the lung (Seekamp, et al., Am. J. Pathol. 11:592-598 (1994). Mulligan, et al., J, Immunol. 151:832-840 (1994).
- Flintozumab an anti-gamma interferon antibody.
- Flintozumab is an IgG1 humanized monoclonal antibody developed by Protein Design Labs, Inc. for the treatment of immune disorders mediated by interferon-gamma (IFN-g), a proinflammatory cytokine.
- IFN-g induces the expression of major histocompatibility complex (MHC) class I and/or class II (HLA-DR) antigens, enhances the cytolytic activity of natural killer cells, activates macrophages, and modulates the immunoglobulin isotype profile of the humoral response.
- MHC major histocompatibility complex
- HLA-DR class II
- IFN-g As a lymphokine, IFN-g also enhances the development of T helper cell type 1 (Th1), while suppressing the development of T helper cell type 2 (Th2) cells. Aberrations in the Th1/Th2 ratio have been implicated in a variety of autoimmune conditions.
- a pharmaceutical formulation comprising the antibody is prepared.
- the formulation development approach is as follows: selecting the optimum solution pH, selecting buffer type and concentration, evaluating the effect of various excipients of the liquid stability, and optimizing the concentration of the screened excipients using an I-optimal experimental design (Statistics for Experimenters: An Introduction to Design, Data Analysis, and Model Building, Box, George E. P. et al., John Wiley and Sons, Inc., 1978).
- compositions of this invention minimize the formation of antibody aggregates and particulates and insure that the antibody maintains its bioactivity over time.
- the composition is a pharmaceutically acceptable liquid formulation containing a high concentration of an antibody in a buffer having a neutral or slightly acidic pH (pH 5.5-6.5), a surfactant, and a tonicity modifier.
- the antibody in the composition is a high concentration of 50 mg/ml or greater, preferably 100 mg/ml or greater.
- a preferred composition of this invention contains Daclizumab, a humanized anti-IL2 receptor antibody; HAIL12, a humanized anti-IL-12 antibody; HaEP5C7, a humanized anti-L selectin antibody; and Flintozumab, a humanized anti-gamma interferon antibody.
- a buffer of pH 5.5-6.5 is used in the composition.
- a buffer of pH 6.0-6.5 is preferred.
- buffers that control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate, phosphate, and other organic acid buffers.
- Succinate pKa 5.63 is a preferred buffer for subcutaneous injection.
- Histidine PK 5.97 is less preferred because of its susceptibility to oxidization, although such oxidation can be retarded by replacing the vial headspace with N 2 or adding an antioxidant.
- Citrate and phosphate buffers are much less preferred because it causes a painful reaction when injected subcutaneously.
- a preferred buffer contains about 20-60 mM sodium succinate.
- Another preferred buffer is 30-70 mM histidine buffer overlaid with N 2 .
- a surfactant is also added to the antibody formulation.
- exemplary surfactants include nonionic surfactants such as polysorbates (e.g. polysorbates 20, 80, such as Tween® 20, Tween® 80) or poloxamers (e.g. poloxamer 188).
- the amount of surfactant added is such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption.
- the surfactant may be present in the formulation in an amount from about 0.005% to about 0.5%, preferably from about 0.01% to about 0.1%, more preferably from about 0.01% to about 0.05%, and most preferably from about 0.02% to about 0.04%.
- a tonicity modifier which contributes to the isotonicity of the formulations, is added to the present composition.
- the tonicity modifier useful for the present invention includes salts and amino acids. Salts that are pharmaceutically acceptable and suitable for this invention include sodium chloride, sodium succinate, sodium sulfate, potassuim chloride, magnesium chloride, magnesium sulfate, and calcium chloride. Preferred salts for this invention are NaCl and MgCl 2 . MgCl 2 may also improve the antibody stability by protecting the protein from deamidation. A preferred concentration of NaCl is about 75-150 mM. A preferred concentration of MgCl 2 is about 1-100 mM.
- Amino acids that are pharmaceutically acceptable and suitable for this invention include proline, alanine, L-arginine, asparagine, L-aspartic acid, glycine, serine, lysine, and histidine.
- a preferred amino acid for this invention is proline.
- a preferred concentration of proline is than 200 mM.
- EDTA which is commonly used to stabilize a protein formulation, may also be included in the formulation.
- EDTA as a chelating agent, may inhibit the metal-catalyzed oxidation of the sulfhydryl groups, thus reducing the formation of disulfide-linked aggregates.
- a preferred concentration of EDTA is 0.01-0.2%.
- Exemplary liquid compositions are formulations comprising antibody at about 100 mg/ml or greater, about 20-60 mM sodium succinate (pH 6), about 0.01-0.1% polysorbate 20 or 80, and about 75-150 mM NaCl. This formulation retains the stability of biological activity of the monoclonal antibody, and prevents the immunoglobulins intended for administration to human subjects from physical, chemical and biological degradation in the final product.
- the liquid antibody formulation of this invention is suitable for parenteral administration such as intravenous, intramuscular, intraperitoneal, or subcutaneous injection; particularly suitable for subcutaneous injection.
- Sample formulations contained 5.0 mg/ml anti-IL2 receptor antibody (Daclizumab) in one of three buffers: 50 mM sodium acetate buffer at pH 4.0 or 5.0, 50 mM histidine at pH 5.5, 6.0, or 6.5, or 50 mM sodium phosphate buffer at pH 7.0 or 8. 5. Independent formulations were incubated at either 5° C. or 45° C. with 100 RPM shaking for 4 weeks.
- Daclizumab anti-IL2 receptor antibody
- the physical and chemical stability of each sample was assessed at 0 and 4 weeks by analytical methods including: pH and visual analysis, UV spectroscopy at 340 nm, size exclusion chromatography (SEC-HPLC), fluorescence spectroscopy, dynamic light scattering (DLS), differential scanning calorimetry (DSC), Promega IsoQuant Assay, capillary isoelectric focusing (cIEF), SDS-PAGE (reduced and non-reduced), and bioactivity assessments (ELISA).
- pH and visual analysis UV spectroscopy at 340 nm
- SEC-HPLC size exclusion chromatography
- fluorescence spectroscopy fluorescence spectroscopy
- DLS dynamic light scattering
- DSC differential scanning calorimetry
- Promega IsoQuant Assay capillary isoelectric focusing (cIEF), SDS-PAGE (reduced and non-reduced), and bioactivity assessments (ELISA).
- FIG. 2 shows the percent of degradation obtained at various pH levels as assessed by cIEF following a four-week incubation of the sample at 45° C. Minimal degradation was obtained at a pH value of about 5.5.
- FIG. 3 shows the percent of iso-aspartic acid formed at various pH levels as assessed by the Promega IsoQuant kit following a four-week incubation of the sample at 45° C. Iso-aspartic acid formation (deamidation) was minimized at pH values of 6 and 6.5, and increased sharply at pH 8.0.
- FIG. 4 shows the effect of different buffers over time on potency following incubation at 37° C. Highest stability of the antibody formulation was achieved through 8 weeks with 50 mM sodium succinate buffer at pH 6.0. Formulations in histidine alone rapidly (less than 8 weeks) lost their potency as the buffer oxidized. Potency of the formulation remained greater than 80% for at least 12 weeks in either sodium succinate buffer or histidine buffer gassed with N 2 to prevent oxidation.
- surfactants Teween 80® and Tween 20®
- salts NaCl and MgCl 2
- antioxidants EDTA and methionine
- amino acids glycine, lysine, serine and proline
- co-solvents glycerol and ethanol.
- Various analytical techniques clarity, pH, SEC-HPLC, UV-Vis, and cIEF were used to characterize the excipient-containing formulations.
- the Daclizumab antibody was in a 67 mM sodium phosphate formulation (without Tween® 80) at a concentration of 6.6 mg/mL. This material was concentrated to about 30 mg/mL in the Pellicon II (Millipore) unit, and subsequently, buffer exchanged into two selected buffers (50 mM sodium phosphate pH 6.5, and 50 mM sodium succinate pH 6.0) using the 50 mL amicon stir cell (Millipore). During the third and final buffer exchange step, the material was also concentrated to a final concentration of 125 mg/mL. Finally, the antibody was filtered through 0.8 ⁇ m membrane (Uniflo). The post filtration protein concentration was determined to be approximately 100 mg/mL for the phosphate buffer sample and 97 mg/mL for the succinate buffer sample.
- the target concentration of the excipients at which they were screened is shown in Table 1.
- the formulations were prepared by either weighing the required amount of the excipients directly into the vial (e.g. all amino acids) or by preparing concentrated stock solutions of the excipients.
- the excipients were added to 0.5 mL of the appropriate buffer solution and the pH adjusted to the desired value with either 1N HCl or 10% NaOH. Subsequently, 0.5 mL of the concentrated antibody solution in the appropriate buffer ( ⁇ 100 mg/mL) was added to attain the target concentration of 50 mg/mL. This procedure was adopted to prevent protein degradation due to direct contact with concentrated excipients.
- the 1 mL solution was split into two vials with 0.5 mL fill each.
- the samples were analyzed using various analytical techniques. Solution clarity was visually examined by holding the sample vials up against a black background under fluorescent lighting. The solution was inspected for insoluble species and color changes were recorded. Size exclusion chromatography was performed using a Perkin Elmer HPLC unit with diode array detection and two Tosohaas columns connected in series. The samples were diluted approximately 5 fold with the corresponding buffer to bring the concentration to about 1 mg/mL and 100 ⁇ L of the sample was injected onto the column. The sample concentration was measured by UV spectroscopy using the Perkin Elmer Lambda Bio 40 spectrophotometer.
- Results of SEC-HPLC are tabulated in Table 3(A-C).
- Table 3B lists the % aggregate formation in all samples being investigated in this study. It is clear from these results that the increase in aggregate formation during the 3-week duration is minimal for all samples at 5° C. in both buffers. After 3 weeks of incubation at 45° C., samples in the phosphate buffer showed an increase in % aggregate ranging from 0.40% (EDTA) to 2.40% (glycine). In the succinate buffer, the aggregate formation was slightly lower; ranging from 0.7% (methionine) to 1.09% (glycine) after the 3 week incubation period.
- EDTA EDTA
- succinate buffer the aggregate formation was slightly lower; ranging from 0.7% (methionine) to 1.09% (glycine) after the 3 week incubation period.
- One of the hypotheses that supports these results is that if aggregate formation is due to oxidation, it may be slowed down in the succinate buffer due to the metal chelating properties of the succinate buffer.
- Table 3C lists the % clip formation in all samples being investigated in this study.
- the % clipping ranged from ⁇ 0.2-0.4% in all samples. For all samples incubated at 5° C., the % increase in clips was insignificant over the 3-week period. At 45° C., a significant increase in the rate of clip formation was observed. For samples formulated in the phosphate buffer, the % clipping varied from 4.74 (methionine) to 1.5% (proline, glycerol and ethanol), while in the succinate buffer, the range was 1.48%(Tween-80) to 3.44 (methionine). In general, an increase in the clip formation was observed in the amino acid containing formulations. Further, the rate of clip formation appears to be higher in the phosphate buffer.
- the stability of formulation was higher in the Na-succinate buffer at pH 6.0, compared with the Na-phosphate buffer at pH 6.5. This is primarily due to base-catalyzed hydrolysis that is accelerated at the higher pH of 6.5, causing an increase in the rate of clip formation.
- the Na-succinate buffer at pH 6.0 is the selected buffer for all future studies.
- Results of this study also clearly indicated that in both buffers, the amino acids (glycine, lysine, serine, proline, and methionine) did not have a stabilizing effect on the protein stability. As shown by the data on sample clarity, all amino acid containing formulations indicated the formation of insoluble aggregates at 45° C.
- the excipient MgCl 2 was selected in this study based on the hypothesis that it might protect the protein against dimidiation. While MgCl 2 precipitated in the Na-phosphate buffer; in the Na-succinate buffer, based on the cIEF data, MgCl 2 has a stabilizing effect on the protein. Ethanol was also included as an excipient to test if it stabilized the protein against deamidation by lowering the dielectric constant of the solution. The results, however, do not support this hypothesis. Finally, Tween-80, EDTA, and NaCl, the excipients most commonly used to stabilize protein formulations, did not show any destabilizing effect on the protein in either buffer.
- MgCl 2 in the concentration range of 0-50 mM also could have a favorable effect.
- the results also indicate that the excipient concentrations for the most stable formulation are: 150 mM NaCl, 0.05% Tween 80, 0.03-0.04% EDTA and 60-70 mM MgCl 2 , however, these conditions are not practical because they do not provide isotonic conditions.
- Formulation 1 100 mg/ml Daclizumab antibody, 30 mM sodium succinate (pH 6.0) 100 mM NaC 1 and 0.03% Tween ⁇ 80.
- Formulation 2 same as Formulation 1, plus 0.05% EDTA.
- Formulation 3 100 mg/ml Daclizumab antibody, 50 mM histidine (pH 6.0), 115 mM NaCl, 0.03% Tween®-80, purged with nitrogen.
- Formulation 4 same as Formulation 3, plus 0.05% EDTA.
- a liquid antibody formulation of 100 mg/ml Daclizumab in 30 mM sodium succinate, pH 6, 100 mM NaCl, and 0.03% Tween® 80 was incubated at 5° C. (2-8° C.) and tested for stability at different time points. The stability results indicate that the formulation is stable for at least 18 months at refrigerated temperature (Table 8). TABLE 8 Stability Results of Daclizumab at 5° C. Time (Month) % Monomer % Aggregate 0 99.0 N/A 3 99.1 0.2% 6 99.1 0.2% 9 98.8 0.2% 12 98.9 0.2% 18 98.6 0.2%
- HuEP5C7 (anti-L selectin antibody, 50 and 100 mg/mL) was formulated in 50 mM histidine buffer, 125 mM sodium chloride, 0.01% Tween 80, pH 6.0.
- the on-going stability testing indicates that the formulation is stable for three months at 25° C. and 45° C. and for at least 9 months at 5° C.
- the results of the 9-month stability testing at 5° C. is shown in Table 12.
- the results of the 3-month accelerated stability testing is shown in Table 13. TABLE 12 Stability Results of HuEP5C7 at 5° C.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Mycology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Transplantation (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/291,528 US20030138417A1 (en) | 2001-11-08 | 2002-11-08 | Stable liquid pharmaceutical formulation of IgG antibodies |
US12/954,512 US20110070231A1 (en) | 2001-11-08 | 2010-11-24 | Stable liquid pharmaceutical formulation of igg antibodies |
US13/226,372 US8465739B2 (en) | 2001-11-08 | 2011-09-06 | Stable aqueous pharmaceutical formulations of daclizumab antibodies |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33750901P | 2001-11-08 | 2001-11-08 | |
US10/291,528 US20030138417A1 (en) | 2001-11-08 | 2002-11-08 | Stable liquid pharmaceutical formulation of IgG antibodies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/954,512 Continuation US20110070231A1 (en) | 2001-11-08 | 2010-11-24 | Stable liquid pharmaceutical formulation of igg antibodies |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030138417A1 true US20030138417A1 (en) | 2003-07-24 |
Family
ID=23320826
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/291,528 Abandoned US20030138417A1 (en) | 2001-11-08 | 2002-11-08 | Stable liquid pharmaceutical formulation of IgG antibodies |
US12/954,512 Abandoned US20110070231A1 (en) | 2001-11-08 | 2010-11-24 | Stable liquid pharmaceutical formulation of igg antibodies |
US13/226,372 Expired - Lifetime US8465739B2 (en) | 2001-11-08 | 2011-09-06 | Stable aqueous pharmaceutical formulations of daclizumab antibodies |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/954,512 Abandoned US20110070231A1 (en) | 2001-11-08 | 2010-11-24 | Stable liquid pharmaceutical formulation of igg antibodies |
US13/226,372 Expired - Lifetime US8465739B2 (en) | 2001-11-08 | 2011-09-06 | Stable aqueous pharmaceutical formulations of daclizumab antibodies |
Country Status (17)
Country | Link |
---|---|
US (3) | US20030138417A1 (fr) |
EP (1) | EP1441589B1 (fr) |
JP (2) | JP5290489B2 (fr) |
KR (1) | KR100913714B1 (fr) |
CN (1) | CN1292655C (fr) |
AT (1) | ATE556591T1 (fr) |
AU (1) | AU2002363339B2 (fr) |
CA (1) | CA2466034C (fr) |
CY (1) | CY2016044I1 (fr) |
DK (1) | DK1441589T3 (fr) |
ES (1) | ES2392073T3 (fr) |
HK (1) | HK1074750A1 (fr) |
IL (2) | IL161677A0 (fr) |
LU (1) | LU93314I2 (fr) |
NZ (1) | NZ532896A (fr) |
PT (1) | PT1441589E (fr) |
WO (1) | WO2003039485A2 (fr) |
Cited By (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030236196A1 (en) * | 2002-06-20 | 2003-12-25 | Amgen Inc. | Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing |
US20040166111A1 (en) * | 2002-10-24 | 2004-08-26 | Zehra Kaymakcalan | Low dose methods for treating disorders in which TNFalpha activity is detrimental |
US20040191243A1 (en) * | 2002-12-13 | 2004-09-30 | Bei Chen | System and method for stabilizing antibodies with histidine |
US20040197324A1 (en) * | 2003-04-04 | 2004-10-07 | Genentech, Inc. | High concentration antibody and protein formulations |
US20040208869A1 (en) * | 2003-01-30 | 2004-10-21 | Medimmune, Inc. | Uses of anti-integrin alphanubeta3 antibody formulations |
US20050158303A1 (en) * | 2003-04-04 | 2005-07-21 | Genentech, Inc. | Methods of treating IgE-mediated disorders comprising the administration of high concentration anti-IgE antibody formulations |
US20050175603A1 (en) * | 2000-10-12 | 2005-08-11 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US20050232917A1 (en) * | 2004-01-09 | 2005-10-20 | Nicholas Pullen | Antibodies to MAdCAM |
US20060008415A1 (en) * | 2004-06-25 | 2006-01-12 | Protein Design Labs, Inc. | Stable liquid and lyophilized formulation of proteins |
US20060153846A1 (en) * | 2002-08-16 | 2006-07-13 | Hans-Juergen Krause | Formulation of human antibodies for treating tnf-alpha associated disorders |
US20060159653A1 (en) * | 2003-02-28 | 2006-07-20 | Chugai Seiyaku Kabushiki Kaisha | Stabilized preparation containing protein |
US20060182740A1 (en) * | 2002-06-21 | 2006-08-17 | Biogen Idec, Inc. | Buffered formulations for concentrating antibodies and methods of use thereof |
WO2006096490A2 (fr) * | 2005-03-08 | 2006-09-14 | Pharmacia & Upjohn Company Llc | Compositions d'anticorps anti-madcam |
US20060269543A1 (en) * | 2005-05-19 | 2006-11-30 | Amgen Inc. | Compositions and methods for increasing the stability of antibodies |
WO2006138181A2 (fr) | 2005-06-14 | 2006-12-28 | Amgen Inc. | Preparations de proteines a tamponnage spontane |
US20070065437A1 (en) * | 2005-09-12 | 2007-03-22 | Greg Elson | Anti-CD3 antibody formulations |
US20070148171A1 (en) * | 2002-09-27 | 2007-06-28 | Xencor, Inc. | Optimized anti-CD30 antibodies |
WO2007089445A2 (fr) | 2006-01-27 | 2007-08-09 | Amgen Inc. | Combinaisons d'inhibiteurs d'ang2 et de vegf |
US20070249529A1 (en) * | 2003-11-28 | 2007-10-25 | Robert Hofmeister | Compositions Comprising Polypeptides |
US20080112953A1 (en) * | 2006-10-06 | 2008-05-15 | Amgen Inc. | Stable formulations |
US20080124326A1 (en) * | 2006-10-20 | 2008-05-29 | Amgen Inc. | Stable polypeptide formulations |
US20080213282A1 (en) * | 2006-12-21 | 2008-09-04 | Jaby Jacob | Formulations |
US20080267976A1 (en) * | 2005-10-06 | 2008-10-30 | Gregory Alan Lazar | Optimized Anti-Cd30 Antibodies |
US20090053238A1 (en) * | 2003-01-30 | 2009-02-26 | Medimmune, Inc. | Stabilized High Concentration Anti-Integrin alphavbeta3 Antibody Formulations |
US20090169544A1 (en) * | 2007-12-28 | 2009-07-02 | Biolnvent International Ab | Formulation |
WO2010031720A2 (fr) | 2008-09-19 | 2010-03-25 | F. Hoffmann-La Roche Ag | Nouvelle formulation d’anticorps |
EP2173163A1 (fr) * | 2007-07-06 | 2010-04-14 | GlaxoSmithKline LLC | Formulations d'anticorps |
US20100172862A1 (en) * | 2008-11-28 | 2010-07-08 | Abbott Laboratories | Stable antibody compositions and methods of stabilizing same |
US20100239567A1 (en) * | 2009-03-06 | 2010-09-23 | Genentech, Inc. | Antibody Formulation |
US20100278822A1 (en) * | 2009-05-04 | 2010-11-04 | Abbott Biotechnology, Ltd. | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
US20100285011A1 (en) * | 2007-12-27 | 2010-11-11 | Chugai Seiyaku Kabushiki Kaish | High concentration antibody-containing liquid formulation |
WO2011026117A1 (fr) | 2009-08-31 | 2011-03-03 | Facet Biotech Corporation | Utilisation d'une population de cellules nk immunorégulatrices pour surveiller l'efficacité d'anticorps anti-il-2r chez des patients atteints d'une sclérose en plaques |
US20110059079A1 (en) * | 2009-09-04 | 2011-03-10 | Xoma Technology Ltd. | Antibody Coformulations |
WO2011028961A2 (fr) * | 2009-09-04 | 2011-03-10 | Xoma Technology Ltd. | Co-formulations d'anticorps anti-botulisme |
WO2011053777A1 (fr) | 2009-10-30 | 2011-05-05 | Abbott Biotherapeutics Corp. | Utilisation de populations de cellules nk immunorégulatrices pour prédire l'efficacité d'anticorps anti-il-2r dans des patients atteints de sclérose en plaques |
US20110236398A1 (en) * | 2008-12-10 | 2011-09-29 | Joachim Momm | Antibody Formulation |
WO2011008770A3 (fr) * | 2009-07-14 | 2011-12-15 | Biogen Idec Ma Inc. | Procédés pour l'inhibition de la formation de couleur jaune et du peroxyde dans une composition |
US20120018338A1 (en) * | 2009-03-30 | 2012-01-26 | Hoffman-La Roche Inc. | Method for avoiding glass fogging |
WO2011089062A3 (fr) * | 2010-01-19 | 2012-03-15 | F. Hoffmann-La Roche Ag | Formulation pharmaceutique de protéines |
US20120201812A1 (en) * | 2009-09-03 | 2012-08-09 | Ablynx N.V. | Stable formulations of polypeptides and uses thereof |
US20130216525A1 (en) * | 2010-03-01 | 2013-08-22 | Cytodyn, Inc. | Concentrated protein formulations and uses thereof |
US8613919B1 (en) | 2012-08-31 | 2013-12-24 | Bayer Healthcare, Llc | High concentration antibody and protein formulations |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
AU2012200203B2 (en) * | 2005-03-08 | 2014-07-03 | Pfizer Products Inc. | Anti-CTLA-4 Antibody Compositions |
US8821865B2 (en) | 2010-11-11 | 2014-09-02 | Abbvie Biotechnology Ltd. | High concentration anti-TNFα antibody liquid formulations |
US8883146B2 (en) | 2007-11-30 | 2014-11-11 | Abbvie Inc. | Protein formulations and methods of making same |
US20150182626A1 (en) * | 2012-09-07 | 2015-07-02 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US9265834B2 (en) | 2009-03-05 | 2016-02-23 | Ablynx N.V. | Stable formulations of polypeptides and uses thereof |
AU2014240252B2 (en) * | 2005-03-08 | 2016-10-06 | Pfizer Products Inc | Anti-CTLA-4 Antibody Compositions |
US9566311B2 (en) | 2010-09-30 | 2017-02-14 | Ferring B.V. | Pharmaceutical composition |
US9592297B2 (en) | 2012-08-31 | 2017-03-14 | Bayer Healthcare Llc | Antibody and protein formulations |
US9605051B2 (en) | 2014-06-20 | 2017-03-28 | Reform Biologics, Llc | Viscosity-reducing excipient compounds for protein formulations |
US20170252436A1 (en) * | 2014-05-07 | 2017-09-07 | Takeda Gmbh | Liquid formulation comprising gm-csf neutralizing compound |
US9855331B2 (en) | 2010-09-17 | 2018-01-02 | Baxalta Incorporated | Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral pH |
US20180134772A1 (en) * | 2015-06-17 | 2018-05-17 | Eli Lilly And Company | Anti-CGRP Antibody Formulation |
US10005830B2 (en) | 2009-03-05 | 2018-06-26 | Ablynx N.V. | Antigen binding dimer-complexes, methods of making/avoiding and uses thereof |
WO2018154320A1 (fr) * | 2017-02-24 | 2018-08-30 | Arecor Limited | Solutions d'anticorps stabilisées |
USRE47150E1 (en) | 2010-03-01 | 2018-12-04 | Bayer Healthcare Llc | Optimized monoclonal antibodies against tissue factor pathway inhibitor (TFPI) |
WO2019050780A1 (fr) | 2017-09-05 | 2019-03-14 | Merck Sharp & Dohme Corp. | Composés pour la réduction de la viscosité de formulations biologiques |
US10307483B2 (en) | 2016-10-21 | 2019-06-04 | Amgen Inc. | Pharmaceutical formulations and methods of making the same |
US10478498B2 (en) | 2014-06-20 | 2019-11-19 | Reform Biologics, Llc | Excipient compounds for biopolymer formulations |
US10689451B2 (en) | 2012-06-12 | 2020-06-23 | Novartis Ag | Anti-BAFFR antibody therapeutic formulations |
US10745475B2 (en) | 2013-08-30 | 2020-08-18 | Takeda Gmbh | Antibodies neutralizing GM-CSF for use in the treatment of rheumatoid arthritis or as analgesics |
US11046785B2 (en) | 2014-03-27 | 2021-06-29 | Takeda Pharmaceutical Company Limited | Compositions and methods for treatment of diabetic macular edema |
US11066458B2 (en) | 2006-06-16 | 2021-07-20 | Regeneron Pharmaceuticals, Inc. | VEGF antagonist formulations suitable for intravitreal administration |
US11071782B2 (en) | 2016-04-20 | 2021-07-27 | Coherus Biosciences, Inc. | Method of filling a container with no headspace |
US11084884B2 (en) | 2014-01-21 | 2021-08-10 | Takeda Pharmaceutical Company Limited | Plasma kallikrein binding proteins and uses thereof in treating hereditary angioedema |
US11103552B2 (en) | 2018-05-10 | 2021-08-31 | Regeneron Pharmaceuticals, Inc. | High concentration VEGF receptor fusion protein containing formulations |
US11142571B2 (en) | 2014-11-07 | 2021-10-12 | Sesen Bio, Inc. | IL-6 antibodies |
US11229702B1 (en) | 2015-10-28 | 2022-01-25 | Coherus Biosciences, Inc. | High concentration formulations of adalimumab |
US11253572B2 (en) | 2011-01-13 | 2022-02-22 | Regeneron Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US11286307B2 (en) | 2015-12-11 | 2022-03-29 | Takeda Pharmaceutical Company Limited | Plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack |
US11299553B2 (en) | 2013-03-15 | 2022-04-12 | Takeda Pharmaceutical Company Limited | Anti-plasma kallikrein antibodies |
US11357857B2 (en) | 2014-06-20 | 2022-06-14 | Comera Life Sciences, Inc. | Excipient compounds for protein processing |
US11401346B2 (en) | 2011-01-06 | 2022-08-02 | Takeda Pharmaceutical Company Limited | Nucleic acids encoding plasma kallikrein binding proteins |
US20220241414A1 (en) * | 2016-02-23 | 2022-08-04 | Sesen Bio, Inc. | Il-6 antagonist formulations and uses thereof |
US11433134B2 (en) * | 2007-11-15 | 2022-09-06 | Amgen Inc. | Aqueous formulation of erythropoiesis stimulating protein stabilised by antioxidants for parenteral administration |
US11505620B2 (en) | 2010-01-06 | 2022-11-22 | Takeda Pharmaceutical Company Limited | Methods of detecting plasma kallikrein |
US11519020B2 (en) | 2018-05-25 | 2022-12-06 | Regeneron Pharmaceuticals, Inc. | Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF |
US11534403B2 (en) | 2017-03-06 | 2022-12-27 | Arecor Limited | Liquid pharmaceutical composition |
US11534402B2 (en) | 2017-03-06 | 2022-12-27 | Arecor Limited | Liquid pharmaceutical composition |
US11608357B2 (en) | 2018-08-28 | 2023-03-21 | Arecor Limited | Stabilized antibody protein solutions |
US11633476B2 (en) | 2017-05-02 | 2023-04-25 | Merck Sharp & Dohme Llc | Stable formulations of programmed death receptor 1 (PD-1) antibodies and methods of use thereof |
EP3996740A4 (fr) * | 2019-07-12 | 2023-07-05 | Contrafect Corporation | Formulations de protéines thérapeutiques comprenant des anticorps et leurs utilisations |
EP4209499A1 (fr) | 2015-08-13 | 2023-07-12 | Amgen Inc. | Filtration sur profondeur chargée de protéines de liaison à l'antigène |
US11769597B2 (en) | 2015-12-03 | 2023-09-26 | Regeneron Pharmaceuticals, Inc. | Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF |
US11802156B2 (en) | 2017-07-14 | 2023-10-31 | Pfizer Inc. | Antibodies to MAdCAM |
US11806398B2 (en) | 2005-03-25 | 2023-11-07 | Regeneron Pharmaceuticals, Inc. | Citrate buffered VEGF antagonist formulations |
US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
Families Citing this family (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7964192B1 (en) | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
TWI239847B (en) | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US7790856B2 (en) | 1998-04-07 | 2010-09-07 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
US20080050367A1 (en) | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US7700751B2 (en) | 2000-12-06 | 2010-04-20 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize β-amyloid peptide |
WO2003039485A2 (fr) * | 2001-11-08 | 2003-05-15 | Protein Design Labs | Formulation pharmaceutique liquide stable d'anticorps igg |
MY139983A (en) | 2002-03-12 | 2009-11-30 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
TWI374893B (en) | 2003-05-30 | 2012-10-21 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
US20050136055A1 (en) * | 2003-12-22 | 2005-06-23 | Pfizer Inc | CD40 antibody formulation and methods |
JO3000B1 (ar) * | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
JP2008523815A (ja) | 2004-12-15 | 2008-07-10 | エラン ファーマ インターナショナル リミテッド | 認知の改善における使用のためのヒト化アミロイドβ抗体 |
GT200600033A (es) * | 2005-01-28 | 2006-10-25 | Formulaciones liquidas estabilizadas de polipeptido | |
GT200600031A (es) * | 2005-01-28 | 2006-08-29 | Formulacion anticuerpo anti a beta | |
WO2007002543A2 (fr) * | 2005-06-23 | 2007-01-04 | Medimmune, Inc. | Formulations d'anticorps possedant des profils d'agregation et de fragmentation optimises |
EP1909838A2 (fr) * | 2005-07-29 | 2008-04-16 | Amgen Inc. | Formulations inhibant l'agregation de proteines |
CA2615122A1 (fr) * | 2005-08-03 | 2007-02-15 | Immunogen, Inc. | Formulations d'immunoconjugue |
KR101105871B1 (ko) * | 2005-09-27 | 2012-01-16 | 주식회사 엘지생명과학 | 인 난포자극호르몬의 안정한 용액 제형 |
CN101378782A (zh) * | 2005-12-21 | 2009-03-04 | 惠氏公司 | 粘度降低的蛋白质制剂及其用途 |
US8569278B2 (en) | 2006-01-25 | 2013-10-29 | Taro Pharmaceuticals North America, Inc. | Anti-histamine compositions and use thereof |
CN102887955A (zh) | 2006-04-05 | 2013-01-23 | 艾博特生物技术有限公司 | 抗体纯化 |
AU2007239679B2 (en) | 2006-04-13 | 2012-10-11 | Chugai Seiyaku Kabushiki Kaisha | Taurine transporter gene |
US8784810B2 (en) | 2006-04-18 | 2014-07-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
KR101317235B1 (ko) | 2006-04-21 | 2013-10-15 | 조마 테크놀로지 리미티드 | 길항제 항-cd40 항체 제약 조성물 |
TW200806315A (en) * | 2006-04-26 | 2008-02-01 | Wyeth Corp | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
AU2016204760A1 (en) * | 2006-04-26 | 2016-07-28 | Wyeth Llc | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
AU2014268186C1 (en) * | 2006-04-26 | 2017-12-07 | Wyeth Llc | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
AU2012200284B2 (en) * | 2006-10-06 | 2014-03-06 | Amgen Inc. | Stable Antibody Formulations |
US20100233759A1 (en) | 2007-03-15 | 2010-09-16 | Chugai Seiyaku Kabushiki Kaisha | Method for production of polypeptide |
US8003097B2 (en) | 2007-04-18 | 2011-08-23 | Janssen Alzheimer Immunotherapy | Treatment of cerebral amyloid angiopathy |
JP5889529B2 (ja) | 2007-07-27 | 2016-03-22 | ヤンセン・サイエンシズ・アイルランド・ユーシー | アミロイド原性疾患の処置 |
JP5337033B2 (ja) | 2007-08-07 | 2013-11-06 | 中外製薬株式会社 | 異種タンパク質の製造方法 |
PE20090711A1 (es) | 2007-09-26 | 2009-07-15 | Chugai Pharmaceutical Co Ltd | Region constante de anticuerpo mutante |
ES2595638T3 (es) | 2007-09-26 | 2017-01-02 | Chugai Seiyaku Kabushiki Kaisha | Método para modificar el punto isoeléctrico de un anticuerpo mediante la sustitución de aminoácidos en una CDR |
WO2009041621A1 (fr) | 2007-09-26 | 2009-04-02 | Chugai Seiyaku Kabushiki Kaisha | Anticorps du récepteur anti-il-6 |
BRPI0818039A2 (pt) | 2007-10-15 | 2014-10-14 | Chugai Pharmaceutical Co Ltd | Método para produzir uma célula capaz de produção de alto rendimento de heteroproteínas. |
JO3076B1 (ar) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | نظم العلاج المناعي المعتمد على حالة apoe |
AU2008314973C1 (en) * | 2007-10-24 | 2014-05-08 | Chugai Seiyaku Kabushiki Kaisha | A cell for use in production of heteroproteins and production method using the same |
WO2010089522A1 (fr) * | 2009-07-16 | 2010-08-12 | Arecor Limited | Formulation stable d'une protéine thérapeutique |
EP2328607A1 (fr) | 2008-07-16 | 2011-06-08 | Arecor Limited | Formulation stable d'une protéine thérapeutique |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
US8741601B2 (en) | 2009-04-22 | 2014-06-03 | Chugai Seiyaku Kabushiki Kaisha | Method for producing a cell capable of high-yield production of heteroproteins |
MX2012007676A (es) * | 2009-12-29 | 2012-08-03 | Hoffmann La Roche | Nueva formulacion de anticuerpo. |
TWI505838B (zh) | 2010-01-20 | 2015-11-01 | Chugai Pharmaceutical Co Ltd | Stabilized antibody solution containing |
DK2575870T3 (en) | 2010-06-04 | 2017-02-13 | Wyeth Llc | vaccine Formulations |
FR2961107B1 (fr) * | 2010-06-15 | 2012-07-27 | Lab Francais Du Fractionnement | Composition d'immunoglobulines humaines stabilisee |
WO2012061448A1 (fr) | 2010-11-04 | 2012-05-10 | Boehringer Ingelheim International Gmbh | Anticorps anti-il-23 |
EP2471554A1 (fr) * | 2010-12-28 | 2012-07-04 | Hexal AG | Formulation pharmaceutique comprenant un médicament biopharmaceutique |
EP2697369B1 (fr) | 2011-03-25 | 2018-06-27 | F.Hoffmann-La Roche Ag | Nouveaux procédés de purification de protéines |
UY34105A (es) * | 2011-06-03 | 2012-07-31 | Lg Life Sciences Ltd | Formulación líquida estable de etanercept |
US20130004484A1 (en) * | 2011-06-30 | 2013-01-03 | Genentech, Inc. | Anti-c-met antibody formulations |
EP4088736A1 (fr) | 2011-10-25 | 2022-11-16 | Prothena Biosciences Limited | Formulations d'anticorps humanisés et amyloid specific et procédés correspondants |
US10316095B2 (en) * | 2012-02-16 | 2019-06-11 | Santarus, Inc. | Antibody formulations |
EP4039275A1 (fr) * | 2012-05-03 | 2022-08-10 | Boehringer Ingelheim International GmbH | Anticorps anti-il-23p19 |
SG10201709555SA (en) * | 2012-05-18 | 2017-12-28 | Genentech Inc | High-concentration monoclonal antibody formulations |
MX2015000337A (es) * | 2012-07-09 | 2015-09-25 | Coherus Biosciences Inc | Formulaciones de etanercept que exhiben reduccion notable en particulas subvisibles. |
FR2994390B1 (fr) | 2012-08-10 | 2014-08-15 | Adocia | Procede d'abaissement de la viscosite de solutions de proteines a concentration elevee |
EP2727602A1 (fr) | 2012-10-31 | 2014-05-07 | Takeda GmbH | Procédé de préparation d'une formulation liquide à concentration élevée d'un anticorps |
UA117466C2 (uk) * | 2012-12-13 | 2018-08-10 | Мерк Шарп Енд Доме Корп. | СТАБІЛЬНИЙ СКЛАД У ВИГЛЯДІ РОЗЧИНУ АНТИТІЛА ДО IL-23p19 |
CA2902289A1 (fr) * | 2013-03-15 | 2014-09-18 | Glaxosmithkline Intellectual Property (No.2) Limited | Formulations d'anticorps a faibles concentrations |
BR112015023084A2 (pt) | 2013-03-15 | 2017-11-21 | Abbvie Biotechnology Ltd | anticorpo anti-cd25 monoclonal ou um fragmento ligante anti-cd25 de um anticorpo monoclonal, conjugado de anticorpo-droga, composição farmacêutica, ácido nucleico, vetor, célula hospedeira procariota e eucariota, método para a produção de um anticorpo anti-cd25 ou fragmento ligante anti-cd25, e, uso de um anticorpo anti-cd25 monoclonal de um conjugado anticorpo-droga ou de uma composição farmacêutica |
WO2014144935A2 (fr) | 2013-03-15 | 2014-09-18 | Abbvie Biotherapeutics Inc. | Anticorps anti-cd25 et leurs utilisations |
CN103217525B (zh) * | 2013-03-21 | 2015-04-29 | 上海执诚生物科技股份有限公司 | 一种含有提高胱抑素c胶乳包被抗体的稳定性的组合物、稳定剂及其制备方法和用途 |
KR20140119396A (ko) | 2013-03-29 | 2014-10-10 | 삼성전자주식회사 | 단백질 약물의 액상 제형 |
KR102372245B1 (ko) | 2013-11-21 | 2022-03-08 | 젠맵 에이/에스 | 항체-약물 접합체 동결건조 제제 |
TWI694836B (zh) * | 2014-05-16 | 2020-06-01 | 英商葛蘭素史克智慧財產管理有限公司 | 抗體調配物 |
WO2015198199A1 (fr) | 2014-06-23 | 2015-12-30 | Novartis Ag | Polypeptide de fusion hsa-gdf-15 et son utilisation |
EP3157942B1 (fr) | 2014-06-23 | 2020-06-17 | Novartis AG | Modifications de protéines spécifiques à un site |
US10588980B2 (en) | 2014-06-23 | 2020-03-17 | Novartis Ag | Fatty acids and their use in conjugation to biomolecules |
US10507241B2 (en) | 2014-07-24 | 2019-12-17 | Boehringer Ingelheim International Gmbh | Biomarkers useful in the treatment of IL-23A related diseases |
TWI711629B (zh) | 2014-09-03 | 2020-12-01 | 德商包林格因蓋爾漢國際股份有限公司 | 靶向IL-23A與TNF-α之化合物及其用途 |
MD20170055A2 (ro) | 2014-10-24 | 2017-09-30 | Merck Sharp & Dohme Corp | Co-agonişti ai receptorilor glucagonului şi GLP-1 |
AR103173A1 (es) | 2014-12-22 | 2017-04-19 | Novarits Ag | Productos farmacéuticos y composiciones líquidas estables de anticuerpos il-17 |
EP3247405B1 (fr) | 2015-01-23 | 2019-07-17 | Novartis AG | Conjugués synthétiques comprenant des acides gras et l'apeline présentant une demi-vie améliorée |
AU2016257023B2 (en) | 2015-05-07 | 2022-06-30 | Swedish Orphan Biovitrum Ag | Methods and compositions for diagnosis and treatment of disorders in patients with elevated levels of CXCL9 and other biomarkers |
US11091543B2 (en) | 2015-05-07 | 2021-08-17 | Swedish Orphan Biovitrum Ag | Methods, compositions and dosing regimens for treating or preventing interferon-gamma related indications |
WO2017096262A1 (fr) | 2015-12-04 | 2017-06-08 | Jomoco, Corp. | Compositions et procédés pour atténuer ou prévenir une réponse immunitaire à une molécule thérapeutique immunogène chez des primates non humains |
EP3393494A1 (fr) | 2015-12-22 | 2018-10-31 | Novartis Ag | Méthodes de traitement ou d'amélioration de troubles métaboliques à l'aide du facteur-15 de croissance et de différenciation (gdf-15) |
BR112018014277A2 (pt) | 2016-01-13 | 2018-12-18 | Genmab As | formulação, e, método de preparação de uma solução injetável de um axl-adc |
WO2018027195A1 (fr) * | 2016-08-05 | 2018-02-08 | Abbvie Biotherapeutics Inc. | Compositions contenant des quantités réduites d'isoformes acides de daclizumab et procédés de préparation associés |
US11236146B2 (en) | 2016-10-28 | 2022-02-01 | Celltrion Inc. | Stable pharmaceutical formulation |
WO2018156180A1 (fr) | 2017-02-24 | 2018-08-30 | Kindred Biosciences, Inc. | Anticorps anti-il31 à usage vétérinaire |
WO2018156367A1 (fr) * | 2017-02-24 | 2018-08-30 | Kindred Biosciences, Inc. | Anticorps anti-il31 à usage vétérinaire |
TW202228779A (zh) * | 2017-03-01 | 2022-08-01 | 英商梅迪繆思有限公司 | 抗rsv單株抗體配製物 |
TWI775827B (zh) * | 2017-03-31 | 2022-09-01 | 日商明治製菓藥業股份有限公司 | 水性製劑及裝入注射器之水性製劑以及抗體蛋白去凝集劑及抗體蛋白去凝集方法 |
WO2018193471A1 (fr) * | 2017-04-18 | 2018-10-25 | Dr. Reddy's Laboratories Limited | Composition pharmaceutique liquide stable |
US11654194B2 (en) * | 2017-05-16 | 2023-05-23 | Jiangsu Hengrui Medicine Co., Ltd. | PD-L1 antibody pharmaceutical composition and use thereof |
WO2019055902A1 (fr) * | 2017-09-18 | 2019-03-21 | Amgen Inc. | Formules de protéines de fusion vegfr-fc |
CN111601613A (zh) | 2017-12-22 | 2020-08-28 | 诺华股份有限公司 | 用fgf21变体治疗代谢障碍的方法 |
EP3887393A1 (fr) | 2018-11-26 | 2021-10-06 | Novartis AG | Polypeptides de fusion de lpl-gpihbp1 |
AU2019388808A1 (en) * | 2018-11-29 | 2021-06-17 | Harbour Biomed Therapeutics Limited | Anti-PD-L1 antibody preparation |
US20220098252A1 (en) | 2019-01-25 | 2022-03-31 | Ospedale San Raffaele S.R.L. | Inhibitor of dux4 and uses thereof |
GB201913697D0 (en) | 2019-09-23 | 2019-11-06 | King S College London | DAP10/DAP12 fusion polypeptides |
JP2023512446A (ja) * | 2020-01-13 | 2023-03-27 | アプティーボ リサーチ アンド デベロップメント エルエルシー | 治療的タンパク質の薬物送達システム構成要素への吸着を防ぐ方法および組成物 |
GB202003277D0 (en) | 2020-03-06 | 2020-04-22 | King S College London | Therapeutic agents |
EP4153130A1 (fr) * | 2020-05-19 | 2023-03-29 | F. Hoffmann-La Roche AG | Utilisation de chélateurs pour la prévention de la formation de particules visibles dans des solutions de protéines parentérales |
GB202007655D0 (en) | 2020-05-22 | 2020-07-08 | King S College London | Chimeric nkg2d protein |
CA3212856A1 (fr) | 2021-03-23 | 2022-09-29 | John Maher | Compositions comprenant des polypeptides de fusion nkg2d, cxcr2 et dap10/dap12 et leurs procedes d'utilisation |
GB202214120D0 (en) | 2022-09-27 | 2022-11-09 | King S College London | Compositions comprising NKG2D, CXCR2, and DAP10/DAP12 fusion polypeptides and methods of use thereof |
EP4389762A1 (fr) | 2022-12-23 | 2024-06-26 | Ospedale San Raffaele S.r.l. | Inhibiteurs de l'activité de dux4 et leur utilisation en thérapie. |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5091178A (en) * | 1986-02-21 | 1992-02-25 | Oncogen | Tumor therapy with biologically active anti-tumor antibodies |
US5744132A (en) * | 1995-02-06 | 1998-04-28 | Genetics Institute, Inc. | Formulations for IL-12 |
US6165467A (en) * | 1991-07-20 | 2000-12-26 | Yoshihide Hagiwara | Stabilized human monoclonal antibody preparation |
US6171586B1 (en) * | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6267958B1 (en) * | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US20010014326A1 (en) * | 1995-07-27 | 2001-08-16 | Genentech, Inc. | Protein formulation |
US6914128B1 (en) * | 1999-03-25 | 2005-07-05 | Abbott Gmbh & Co. Kg | Human antibodies that bind human IL-12 and methods for producing |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989011297A1 (fr) | 1988-05-27 | 1989-11-30 | Centocor, Inc. | Preparation lyophilisee pour la stabilisation de produits a base d'anticorps |
EP0448605A4 (en) * | 1988-12-15 | 1991-11-21 | Invitron Corporation | Use of basic amino acids to solubilize immunoglobulins |
JPH04504253A (ja) | 1989-03-27 | 1992-07-30 | セントカー・インコーポレーテツド | IgM抗体の安定化のための配合物 |
CN100360184C (zh) * | 1995-07-27 | 2008-01-09 | 基因技术股份有限公司 | 稳定等渗的冻干蛋白质制剂 |
GB9610992D0 (en) * | 1996-05-24 | 1996-07-31 | Glaxo Group Ltd | Concentrated antibody preparation |
EP0852951A1 (fr) * | 1996-11-19 | 1998-07-15 | Roche Diagnostics GmbH | Compositions pharmaceutiques stables, lyophilisées d'anticorps monoclonaux ou polyclonaux |
DE69810481T2 (de) * | 1997-06-13 | 2003-09-25 | Genentech Inc | Stabilisierte antikörperformulierung |
JP4841038B2 (ja) | 1999-03-25 | 2011-12-21 | アボット ゲーエムベーハー ウント カンパニー カーゲー | ヒトil−12に結合するヒト抗体およびその産生法 |
IL155002A0 (en) * | 2000-10-12 | 2003-10-31 | Genentech Inc | Reduced-viscosity concentrated protein formulations |
GB0113179D0 (en) * | 2001-05-31 | 2001-07-25 | Novartis Ag | Organic compounds |
WO2003039485A2 (fr) * | 2001-11-08 | 2003-05-15 | Protein Design Labs | Formulation pharmaceutique liquide stable d'anticorps igg |
-
2002
- 2002-11-08 WO PCT/US2002/036093 patent/WO2003039485A2/fr active Application Filing
- 2002-11-08 EP EP02802895A patent/EP1441589B1/fr not_active Expired - Lifetime
- 2002-11-08 JP JP2003541777A patent/JP5290489B2/ja not_active Expired - Fee Related
- 2002-11-08 PT PT02802895T patent/PT1441589E/pt unknown
- 2002-11-08 DK DK02802895.9T patent/DK1441589T3/da active
- 2002-11-08 CA CA2466034A patent/CA2466034C/fr not_active Expired - Lifetime
- 2002-11-08 ES ES02802895T patent/ES2392073T3/es not_active Expired - Lifetime
- 2002-11-08 US US10/291,528 patent/US20030138417A1/en not_active Abandoned
- 2002-11-08 AT AT02802895T patent/ATE556591T1/de active
- 2002-11-08 NZ NZ532896A patent/NZ532896A/en not_active IP Right Cessation
- 2002-11-08 AU AU2002363339A patent/AU2002363339B2/en not_active Ceased
- 2002-11-08 KR KR1020047006962A patent/KR100913714B1/ko active IP Right Grant
- 2002-11-08 CN CNB028267273A patent/CN1292655C/zh not_active Expired - Fee Related
- 2002-11-08 IL IL16167702A patent/IL161677A0/xx unknown
-
2004
- 2004-04-29 IL IL161677A patent/IL161677A/en active IP Right Grant
-
2005
- 2005-08-17 HK HK05107139A patent/HK1074750A1/xx not_active IP Right Cessation
-
2010
- 2010-11-24 US US12/954,512 patent/US20110070231A1/en not_active Abandoned
- 2010-12-10 JP JP2010276222A patent/JP2011068675A/ja active Pending
-
2011
- 2011-09-06 US US13/226,372 patent/US8465739B2/en not_active Expired - Lifetime
-
2016
- 2016-11-17 LU LU93314C patent/LU93314I2/fr unknown
- 2016-12-09 CY CY2016044C patent/CY2016044I1/el unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5091178A (en) * | 1986-02-21 | 1992-02-25 | Oncogen | Tumor therapy with biologically active anti-tumor antibodies |
US6165467A (en) * | 1991-07-20 | 2000-12-26 | Yoshihide Hagiwara | Stabilized human monoclonal antibody preparation |
US5744132A (en) * | 1995-02-06 | 1998-04-28 | Genetics Institute, Inc. | Formulations for IL-12 |
US6267958B1 (en) * | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US20010014326A1 (en) * | 1995-07-27 | 2001-08-16 | Genentech, Inc. | Protein formulation |
US6171586B1 (en) * | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6914128B1 (en) * | 1999-03-25 | 2005-07-05 | Abbott Gmbh & Co. Kg | Human antibodies that bind human IL-12 and methods for producing |
Cited By (241)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070116700A1 (en) * | 2000-10-12 | 2007-05-24 | Genentech, Inc. | Reduced-Viscosity Concentrated Protein Formulations |
US7666413B2 (en) | 2000-10-12 | 2010-02-23 | Genetech, Inc. | Method of reducing viscosity of high concentration protein formulations |
US8142776B2 (en) | 2000-10-12 | 2012-03-27 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US20050175603A1 (en) * | 2000-10-12 | 2005-08-11 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US10166293B2 (en) | 2000-10-12 | 2019-01-01 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
US9340612B2 (en) * | 2001-03-19 | 2016-05-17 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US20150190512A1 (en) * | 2001-03-19 | 2015-07-09 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US20100197751A1 (en) * | 2002-06-20 | 2010-08-05 | Amgen Inc. | Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing |
US20030236196A1 (en) * | 2002-06-20 | 2003-12-25 | Amgen Inc. | Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing |
US7700722B2 (en) | 2002-06-20 | 2010-04-20 | Amgen Inc. | Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing |
US20060182740A1 (en) * | 2002-06-21 | 2006-08-17 | Biogen Idec, Inc. | Buffered formulations for concentrating antibodies and methods of use thereof |
US8795670B2 (en) | 2002-08-16 | 2014-08-05 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-alpha associated disorders |
US9289497B2 (en) | 2002-08-16 | 2016-03-22 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US8916158B2 (en) | 2002-08-16 | 2014-12-23 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US8916157B2 (en) | 2002-08-16 | 2014-12-23 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US8911741B2 (en) | 2002-08-16 | 2014-12-16 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-alpha associated disorders |
US9220781B2 (en) | 2002-08-16 | 2015-12-29 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US9950066B2 (en) | 2002-08-16 | 2018-04-24 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US9272042B2 (en) | 2002-08-16 | 2016-03-01 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US8802100B2 (en) | 2002-08-16 | 2014-08-12 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-alpha associated disorders |
US9750808B2 (en) | 2002-08-16 | 2017-09-05 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-alpha associated disorders |
US8802101B2 (en) | 2002-08-16 | 2014-08-12 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US8802102B2 (en) | 2002-08-16 | 2014-08-12 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US9738714B2 (en) | 2002-08-16 | 2017-08-22 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US8940305B2 (en) | 2002-08-16 | 2015-01-27 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US9732152B2 (en) | 2002-08-16 | 2017-08-15 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US8216583B2 (en) | 2002-08-16 | 2012-07-10 | Abbott Biotechnology, Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US9114166B2 (en) | 2002-08-16 | 2015-08-25 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US9327032B2 (en) | 2002-08-16 | 2016-05-03 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US20060153846A1 (en) * | 2002-08-16 | 2006-07-13 | Hans-Juergen Krause | Formulation of human antibodies for treating tnf-alpha associated disorders |
US9302011B2 (en) | 2002-08-16 | 2016-04-05 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-α associated disorders |
US9272041B2 (en) | 2002-08-16 | 2016-03-01 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US8932591B2 (en) | 2002-08-16 | 2015-01-13 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
US9295725B2 (en) | 2002-08-16 | 2016-03-29 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating TNF-alpha associated disorders |
US20070166309A1 (en) * | 2002-09-27 | 2007-07-19 | Xencor, Inc. | Optimized anti-cd30 antibodies |
US20070148171A1 (en) * | 2002-09-27 | 2007-06-28 | Xencor, Inc. | Optimized anti-CD30 antibodies |
US8846046B2 (en) | 2002-10-24 | 2014-09-30 | Abbvie Biotechnology Ltd. | Low dose methods for treating disorders in which TNFα activity is detrimental |
US20040166111A1 (en) * | 2002-10-24 | 2004-08-26 | Zehra Kaymakcalan | Low dose methods for treating disorders in which TNFalpha activity is detrimental |
US20040191243A1 (en) * | 2002-12-13 | 2004-09-30 | Bei Chen | System and method for stabilizing antibodies with histidine |
US20040208869A1 (en) * | 2003-01-30 | 2004-10-21 | Medimmune, Inc. | Uses of anti-integrin alphanubeta3 antibody formulations |
US20090053238A1 (en) * | 2003-01-30 | 2009-02-26 | Medimmune, Inc. | Stabilized High Concentration Anti-Integrin alphavbeta3 Antibody Formulations |
US8765124B2 (en) * | 2003-02-28 | 2014-07-01 | Chugai Seiyaku Kabushiki Kaisha | Stabilized preparation containing protein |
US20060159653A1 (en) * | 2003-02-28 | 2006-07-20 | Chugai Seiyaku Kabushiki Kaisha | Stabilized preparation containing protein |
US20050158303A1 (en) * | 2003-04-04 | 2005-07-21 | Genentech, Inc. | Methods of treating IgE-mediated disorders comprising the administration of high concentration anti-IgE antibody formulations |
US20070086995A1 (en) * | 2003-04-04 | 2007-04-19 | Genentech, Inc. | Methods of treating IgE-mediated disorders comprising the administration of high concentration anti-IgE antibody formulations |
US20070053900A1 (en) * | 2003-04-04 | 2007-03-08 | Genentech, Inc. | High concentration antibody and protein formulations |
US20040197324A1 (en) * | 2003-04-04 | 2004-10-07 | Genentech, Inc. | High concentration antibody and protein formulations |
US10034940B2 (en) | 2003-04-04 | 2018-07-31 | Genentech, Inc. | High concentration antibody and protein formulations |
US20090280129A1 (en) * | 2003-04-04 | 2009-11-12 | Genentech, Inc. | High concentration antibody and protein formulations |
US8961964B2 (en) | 2003-04-04 | 2015-02-24 | Genentech, Inc. | High concentration antibody and protein formulations |
US20070249529A1 (en) * | 2003-11-28 | 2007-10-25 | Robert Hofmeister | Compositions Comprising Polypeptides |
US10000574B2 (en) * | 2003-11-28 | 2018-06-19 | Amgen Research (Munich) Gmbh | Compositions comprising polypeptides |
US9328169B2 (en) | 2004-01-09 | 2016-05-03 | Pfizer Inc. | Human antibodies that bind human MAdCAM |
US7932372B2 (en) | 2004-01-09 | 2011-04-26 | Amgen Fremont Inc. | Antibodies to MAdCAM |
US20050232917A1 (en) * | 2004-01-09 | 2005-10-20 | Nicholas Pullen | Antibodies to MAdCAM |
US10259872B2 (en) | 2004-01-09 | 2019-04-16 | Pfizer, Inc. | Antibodies to MAdCAM |
USRE45847E1 (en) | 2004-01-09 | 2016-01-19 | Pfizer Inc. | Antibodies to MAdCAM |
US20070166308A1 (en) * | 2004-01-09 | 2007-07-19 | Nicholas Pullen | Antibodies to MAdCAM |
US20080124339A1 (en) * | 2004-01-09 | 2008-05-29 | Nicholas Pullen | Antibodies to MAdCAM |
US20060008415A1 (en) * | 2004-06-25 | 2006-01-12 | Protein Design Labs, Inc. | Stable liquid and lyophilized formulation of proteins |
WO2006004736A3 (fr) * | 2004-06-25 | 2007-06-14 | Pdl Biopharma Inc | Formulations liquides et lyophilisees stables de proteines |
WO2006096491A3 (fr) * | 2005-03-08 | 2007-03-29 | Pharmacia & Upjohn Co Llc | Compositions d'anticorps anti-ctla-4 |
WO2006096490A3 (fr) * | 2005-03-08 | 2006-12-28 | Pharmacia & Upjohn Co Llc | Compositions d'anticorps anti-madcam |
KR100989280B1 (ko) * | 2005-03-08 | 2010-10-20 | 파마시아 앤드 업존 캄파니 엘엘씨 | 항-ctla-4 항체 조성물 |
EP2311491A1 (fr) * | 2005-03-08 | 2011-04-20 | Pharmacia & Upjohn Company LLC | Composition comprenant un anticorps contre le facteur de simulation de colonies de macrophages (M-CSF) et un agent chélatant |
WO2006096490A2 (fr) * | 2005-03-08 | 2006-09-14 | Pharmacia & Upjohn Company Llc | Compositions d'anticorps anti-madcam |
WO2006096491A2 (fr) * | 2005-03-08 | 2006-09-14 | Pharmacia & Upjohn Company Llc | Compositions d'anticorps anti-ctla-4 |
WO2006096488A2 (fr) * | 2005-03-08 | 2006-09-14 | Pharmacia & Upjohn Company Llc | Compositions d'anticorps en plateau |
JP2006249085A (ja) * | 2005-03-08 | 2006-09-21 | Pharmacia & Upjohn Co Llc | プラットホーム抗体組成物 |
US20090238820A1 (en) * | 2005-03-08 | 2009-09-24 | Allan Corey M | ANTI-MAdCAM ANTIBODY COMPOSITIONS |
AU2006220829B2 (en) * | 2005-03-08 | 2011-10-13 | Pfizer Products Inc. | Anti-CTLA-4 antibody compositions |
WO2006096488A3 (fr) * | 2005-03-08 | 2006-11-30 | Pharmacia & Upjohn Co Llc | Compositions d'anticorps en plateau |
US9487581B2 (en) | 2005-03-08 | 2016-11-08 | Pfizer Inc. | Anti-CTLA-4 antibody compositions |
AU2014240252B2 (en) * | 2005-03-08 | 2016-10-06 | Pfizer Products Inc | Anti-CTLA-4 Antibody Compositions |
AU2006220829C1 (en) * | 2005-03-08 | 2024-02-01 | Pfizer Products Inc. | Anti-CTLA-4 antibody compositions |
US20090130119A1 (en) * | 2005-03-08 | 2009-05-21 | Justin Abate | Anti-ctla-4 antibody compositions |
US20090110681A1 (en) * | 2005-03-08 | 2009-04-30 | Pfizer, Inc. | Anti-M-CSF Antibody Compositions |
WO2006096461A3 (fr) * | 2005-03-08 | 2006-12-21 | Pharmacia & Upjohn Co Llc | Compositions d'anticorps contre m-csf |
KR100996801B1 (ko) * | 2005-03-08 | 2010-11-25 | 파마시아 앤드 업존 캄파니 엘엘씨 | 항-MAdCAM 항체 조성물 |
US20080248047A1 (en) * | 2005-03-08 | 2008-10-09 | Tapan Das | Platform Antibody Compositions |
AU2012200203B2 (en) * | 2005-03-08 | 2014-07-03 | Pfizer Products Inc. | Anti-CTLA-4 Antibody Compositions |
US20110027262A1 (en) * | 2005-03-08 | 2011-02-03 | Pharmacia & Upjohn Company Llc | Platform antibody compositions |
EP2620450A3 (fr) * | 2005-03-08 | 2014-01-08 | Pfizer Products Inc. | Compositions d'anticorps anti-CTLA-4 |
US11806398B2 (en) | 2005-03-25 | 2023-11-07 | Regeneron Pharmaceuticals, Inc. | Citrate buffered VEGF antagonist formulations |
US20060269543A1 (en) * | 2005-05-19 | 2006-11-30 | Amgen Inc. | Compositions and methods for increasing the stability of antibodies |
US8858935B2 (en) | 2005-05-19 | 2014-10-14 | Amgen Inc. | Compositions and methods for increasing the stability of antibodies |
WO2006138181A2 (fr) | 2005-06-14 | 2006-12-28 | Amgen Inc. | Preparations de proteines a tamponnage spontane |
US11607451B2 (en) | 2005-06-14 | 2023-03-21 | Amgen Inc. | Self-buffering antibody formulations |
EP3351269A1 (fr) | 2005-06-14 | 2018-07-25 | Amgen Inc. | Formulations de protéine à tamponnage spontané |
EP3673919A1 (fr) | 2005-06-14 | 2020-07-01 | Amgen Inc. | Formulations de protéine à tamponnage spontané |
US20070065437A1 (en) * | 2005-09-12 | 2007-03-22 | Greg Elson | Anti-CD3 antibody formulations |
US7973136B2 (en) | 2005-10-06 | 2011-07-05 | Xencor, Inc. | Optimized anti-CD30 antibodies |
US20080267976A1 (en) * | 2005-10-06 | 2008-10-30 | Gregory Alan Lazar | Optimized Anti-Cd30 Antibodies |
US9574006B2 (en) | 2005-10-06 | 2017-02-21 | Xencor, Inc. | Optimized anti-CD30 antibodies |
WO2007089445A2 (fr) | 2006-01-27 | 2007-08-09 | Amgen Inc. | Combinaisons d'inhibiteurs d'ang2 et de vegf |
US11084865B2 (en) | 2006-06-16 | 2021-08-10 | Regeneron Pharmaceuticals, Inc. | VEGF antagonist formulations suitable for intravitreal administration |
US11732024B2 (en) | 2006-06-16 | 2023-08-22 | Regeneron Pharmaceuticals, Inc. | VEGF antagonist formulations suitable for intravitreal administration |
US11066458B2 (en) | 2006-06-16 | 2021-07-20 | Regeneron Pharmaceuticals, Inc. | VEGF antagonist formulations suitable for intravitreal administration |
US20080112953A1 (en) * | 2006-10-06 | 2008-05-15 | Amgen Inc. | Stable formulations |
US7705132B2 (en) | 2006-10-20 | 2010-04-27 | Amgen Inc. | Stable polypeptide formulations |
US8241632B2 (en) | 2006-10-20 | 2012-08-14 | Amgen Inc. | Stable polypeptide formulations |
US20080124326A1 (en) * | 2006-10-20 | 2008-05-29 | Amgen Inc. | Stable polypeptide formulations |
US20100158908A1 (en) * | 2006-10-20 | 2010-06-24 | Amgen Inc. | Stable Polypeptide Formulations |
US20080213282A1 (en) * | 2006-12-21 | 2008-09-04 | Jaby Jacob | Formulations |
EP2173163A4 (fr) * | 2007-07-06 | 2010-12-08 | Glaxosmithkline Llc | Formulations d'anticorps |
EP2173163A1 (fr) * | 2007-07-06 | 2010-04-14 | GlaxoSmithKline LLC | Formulations d'anticorps |
US11433134B2 (en) * | 2007-11-15 | 2022-09-06 | Amgen Inc. | Aqueous formulation of erythropoiesis stimulating protein stabilised by antioxidants for parenteral administration |
US11167030B2 (en) | 2007-11-30 | 2021-11-09 | Abbvie Biotechnology Ltd | Protein formulations and methods of making same |
US9085619B2 (en) | 2007-11-30 | 2015-07-21 | Abbvie Biotechnology Ltd. | Anti-TNF antibody formulations |
US8883146B2 (en) | 2007-11-30 | 2014-11-11 | Abbvie Inc. | Protein formulations and methods of making same |
US11191834B2 (en) | 2007-11-30 | 2021-12-07 | Abbvie Biotechnology Ltd | Protein formulations and methods of making same |
US20100285011A1 (en) * | 2007-12-27 | 2010-11-11 | Chugai Seiyaku Kabushiki Kaish | High concentration antibody-containing liquid formulation |
US11359026B2 (en) | 2007-12-27 | 2022-06-14 | Chugai Seiyaku Kabushiki Kaisha | High concentration antibody-containing liquid formulation |
US8568720B2 (en) | 2007-12-27 | 2013-10-29 | Chugai Seiyaku Kabushiki Kaisha | High concentration antibody-containing liquid formulation |
US11584798B2 (en) | 2007-12-27 | 2023-02-21 | Hoffmann-La Roche Inc. | High concentration antibody-containing liquid formulation |
US11767363B2 (en) | 2007-12-27 | 2023-09-26 | Chugai Seiyaku Kabushiki Kaisha | High concentration antibody-containing liquid formulation |
US20110014203A1 (en) * | 2007-12-28 | 2011-01-20 | Fredrik Nilsson | Formulation |
US20090169544A1 (en) * | 2007-12-28 | 2009-07-02 | Biolnvent International Ab | Formulation |
US20140093512A1 (en) * | 2008-09-19 | 2014-04-03 | Hoffmann-La Roche Inc. | Pharmaceutical formulation comprising an antibody against p-selectin and a sugar selected from sucrose and trehalose |
WO2010031720A3 (fr) * | 2008-09-19 | 2010-09-23 | F. Hoffmann-La Roche Ag | Nouvelle formulation d’anticorps |
US20100074903A1 (en) * | 2008-09-19 | 2010-03-25 | Ulla Grauschopf | Novel antibody formulation |
WO2010031720A2 (fr) | 2008-09-19 | 2010-03-25 | F. Hoffmann-La Roche Ag | Nouvelle formulation d’anticorps |
US20100172862A1 (en) * | 2008-11-28 | 2010-07-08 | Abbott Laboratories | Stable antibody compositions and methods of stabilizing same |
US8623367B2 (en) | 2008-12-10 | 2014-01-07 | Novartis Ag | Antibody formulation |
US20110236398A1 (en) * | 2008-12-10 | 2011-09-29 | Joachim Momm | Antibody Formulation |
US10919954B2 (en) | 2009-03-05 | 2021-02-16 | Ablynx N.V. | Antigen binding dimer-complexes, methods of making/avoiding and uses thereof |
US9265834B2 (en) | 2009-03-05 | 2016-02-23 | Ablynx N.V. | Stable formulations of polypeptides and uses thereof |
US10005830B2 (en) | 2009-03-05 | 2018-06-26 | Ablynx N.V. | Antigen binding dimer-complexes, methods of making/avoiding and uses thereof |
US8318161B2 (en) | 2009-03-06 | 2012-11-27 | Genentech, Inc. | Anti-oxidized LDL antibody formulation |
US20100239567A1 (en) * | 2009-03-06 | 2010-09-23 | Genentech, Inc. | Antibody Formulation |
US20120018338A1 (en) * | 2009-03-30 | 2012-01-26 | Hoffman-La Roche Inc. | Method for avoiding glass fogging |
US20100278822A1 (en) * | 2009-05-04 | 2010-11-04 | Abbott Biotechnology, Ltd. | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
WO2011008770A3 (fr) * | 2009-07-14 | 2011-12-15 | Biogen Idec Ma Inc. | Procédés pour l'inhibition de la formation de couleur jaune et du peroxyde dans une composition |
WO2011026117A1 (fr) | 2009-08-31 | 2011-03-03 | Facet Biotech Corporation | Utilisation d'une population de cellules nk immunorégulatrices pour surveiller l'efficacité d'anticorps anti-il-2r chez des patients atteints d'une sclérose en plaques |
US9884117B2 (en) * | 2009-09-03 | 2018-02-06 | Ablynx N.V. | Stable formulations of polypeptides and uses thereof |
US20120201812A1 (en) * | 2009-09-03 | 2012-08-09 | Ablynx N.V. | Stable formulations of polypeptides and uses thereof |
US20110059079A1 (en) * | 2009-09-04 | 2011-03-10 | Xoma Technology Ltd. | Antibody Coformulations |
WO2011028961A2 (fr) * | 2009-09-04 | 2011-03-10 | Xoma Technology Ltd. | Co-formulations d'anticorps anti-botulisme |
US8821879B2 (en) | 2009-09-04 | 2014-09-02 | Xoma Technology Ltd. | Anti-botulism antibody coformulations |
WO2011028961A3 (fr) * | 2009-09-04 | 2011-06-23 | Xoma Technology Ltd. | Co-formulations d'anticorps anti-botulisme |
WO2011053777A1 (fr) | 2009-10-30 | 2011-05-05 | Abbott Biotherapeutics Corp. | Utilisation de populations de cellules nk immunorégulatrices pour prédire l'efficacité d'anticorps anti-il-2r dans des patients atteints de sclérose en plaques |
US11505620B2 (en) | 2010-01-06 | 2022-11-22 | Takeda Pharmaceutical Company Limited | Methods of detecting plasma kallikrein |
WO2011089062A3 (fr) * | 2010-01-19 | 2012-03-15 | F. Hoffmann-La Roche Ag | Formulation pharmaceutique de protéines |
US11571383B2 (en) | 2010-03-01 | 2023-02-07 | Cytodyn Inc. | Concentrated protein formulations and uses thereof |
USRE47150E1 (en) | 2010-03-01 | 2018-12-04 | Bayer Healthcare Llc | Optimized monoclonal antibodies against tissue factor pathway inhibitor (TFPI) |
US20130216525A1 (en) * | 2010-03-01 | 2013-08-22 | Cytodyn, Inc. | Concentrated protein formulations and uses thereof |
US9956165B2 (en) * | 2010-03-01 | 2018-05-01 | Cytodyn Inc. | Concentrated protein formulations and uses thereof |
TWI621625B (zh) * | 2010-09-17 | 2018-04-21 | 巴克斯歐塔公司 | 在弱酸性至中性ph中經由具有組胺酸的水性調配物穩定免疫球蛋白 |
US20180250401A1 (en) * | 2010-09-17 | 2018-09-06 | Baxalta Incorporated | Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral ph |
US9855331B2 (en) | 2010-09-17 | 2018-01-02 | Baxalta Incorporated | Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral pH |
US9566311B2 (en) | 2010-09-30 | 2017-02-14 | Ferring B.V. | Pharmaceutical composition |
US8821865B2 (en) | 2010-11-11 | 2014-09-02 | Abbvie Biotechnology Ltd. | High concentration anti-TNFα antibody liquid formulations |
US11401346B2 (en) | 2011-01-06 | 2022-08-02 | Takeda Pharmaceutical Company Limited | Nucleic acids encoding plasma kallikrein binding proteins |
US11253572B2 (en) | 2011-01-13 | 2022-02-22 | Regeneron Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US11707506B2 (en) | 2011-01-13 | 2023-07-25 | Regeneren Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US11730794B2 (en) | 2011-01-13 | 2023-08-22 | Regeneron Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US11975045B2 (en) | 2011-01-13 | 2024-05-07 | Regeneron Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US11559564B2 (en) | 2011-01-13 | 2023-01-24 | Regeneron Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US11986511B2 (en) | 2011-01-13 | 2024-05-21 | Regeneron Pharmaceuticals, Inc. | Use of a VEGF antagonist to treat angiogenic eye disorders |
US10689451B2 (en) | 2012-06-12 | 2020-06-23 | Novartis Ag | Anti-BAFFR antibody therapeutic formulations |
US9592297B2 (en) | 2012-08-31 | 2017-03-14 | Bayer Healthcare Llc | Antibody and protein formulations |
US9849181B2 (en) | 2012-08-31 | 2017-12-26 | Bayer Healthcare Llc | High concentration antibody and protein formulations |
US8613919B1 (en) | 2012-08-31 | 2013-12-24 | Bayer Healthcare, Llc | High concentration antibody and protein formulations |
US10286071B2 (en) | 2012-09-07 | 2019-05-14 | Coherus Biosciences, Inc. | Syringe containing stable aqueous formulations of adalimumab |
US9770507B2 (en) | 2012-09-07 | 2017-09-26 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10159732B2 (en) | 2012-09-07 | 2018-12-25 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10195275B2 (en) | 2012-09-07 | 2019-02-05 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10207000B2 (en) | 2012-09-07 | 2019-02-19 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US20150190513A1 (en) * | 2012-09-07 | 2015-07-09 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US10155039B2 (en) | 2012-09-07 | 2018-12-18 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10286072B2 (en) | 2012-09-07 | 2019-05-14 | Coherus Biosciences, Inc. | Methods of manufacturing stable aqueous formulations of adalimumab |
US20150191538A1 (en) * | 2012-09-07 | 2015-07-09 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US20150182626A1 (en) * | 2012-09-07 | 2015-07-02 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US9340611B2 (en) * | 2012-09-07 | 2016-05-17 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9346880B2 (en) * | 2012-09-07 | 2016-05-24 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10688183B2 (en) | 2012-09-07 | 2020-06-23 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US20160256545A1 (en) * | 2012-09-07 | 2016-09-08 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US20160256547A1 (en) * | 2012-09-07 | 2016-09-08 | Coherus Biosciences, Inc. | Stable Aqueous Formulations of Adalimumab |
US10716853B2 (en) | 2012-09-07 | 2020-07-21 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10716854B2 (en) | 2012-09-07 | 2020-07-21 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10716852B2 (en) | 2012-09-07 | 2020-07-21 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10722579B2 (en) | 2012-09-07 | 2020-07-28 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9682145B2 (en) * | 2012-09-07 | 2017-06-20 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10772960B2 (en) | 2012-09-07 | 2020-09-15 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10772959B2 (en) | 2012-09-07 | 2020-09-15 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10780163B2 (en) | 2012-09-07 | 2020-09-22 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10786566B2 (en) | 2012-09-07 | 2020-09-29 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10799585B2 (en) | 2012-09-07 | 2020-10-13 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9707293B2 (en) | 2012-09-07 | 2017-07-18 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9861695B2 (en) | 2012-09-07 | 2018-01-09 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9724415B2 (en) | 2012-09-07 | 2017-08-08 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9808525B2 (en) | 2012-09-07 | 2017-11-07 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9724414B2 (en) | 2012-09-07 | 2017-08-08 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9731008B2 (en) | 2012-09-07 | 2017-08-15 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9789185B2 (en) * | 2012-09-07 | 2017-10-17 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9731009B2 (en) | 2012-09-07 | 2017-08-15 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9737600B2 (en) | 2012-09-07 | 2017-08-22 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9782479B2 (en) * | 2012-09-07 | 2017-10-10 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9757454B2 (en) | 2012-09-07 | 2017-09-12 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US9782480B2 (en) | 2012-09-07 | 2017-10-10 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US10159733B2 (en) | 2012-09-07 | 2018-12-25 | Coherus Biosciences, Inc. | Stable aqueous formulations of adalimumab |
US11299553B2 (en) | 2013-03-15 | 2022-04-12 | Takeda Pharmaceutical Company Limited | Anti-plasma kallikrein antibodies |
US10745475B2 (en) | 2013-08-30 | 2020-08-18 | Takeda Gmbh | Antibodies neutralizing GM-CSF for use in the treatment of rheumatoid arthritis or as analgesics |
US11795216B2 (en) | 2013-08-30 | 2023-10-24 | Takeda Pharmaceutical Company Limited | Antibodies neutralizing GM-CSF for use in the treatment of rheumatoid arthritis or as analgesics |
US11084884B2 (en) | 2014-01-21 | 2021-08-10 | Takeda Pharmaceutical Company Limited | Plasma kallikrein binding proteins and uses thereof in treating hereditary angioedema |
US11046785B2 (en) | 2014-03-27 | 2021-06-29 | Takeda Pharmaceutical Company Limited | Compositions and methods for treatment of diabetic macular edema |
AU2015257798B2 (en) * | 2014-05-07 | 2020-04-23 | Takeda Pharmaceutical Company Limited | Liquid formulation comprising GM-CSF neutralizing compound |
AU2015257798C1 (en) * | 2014-05-07 | 2020-10-22 | Takeda Pharmaceutical Company Limited | Liquid formulation comprising GM-CSF neutralizing compound |
US11173208B2 (en) * | 2014-05-07 | 2021-11-16 | Takeda Gmbh | Liquid formulation comprising GM-CSF neutralizing compound |
US20170252436A1 (en) * | 2014-05-07 | 2017-09-07 | Takeda Gmbh | Liquid formulation comprising gm-csf neutralizing compound |
US9605051B2 (en) | 2014-06-20 | 2017-03-28 | Reform Biologics, Llc | Viscosity-reducing excipient compounds for protein formulations |
US11696951B2 (en) | 2014-06-20 | 2023-07-11 | Comera Life Sciences, Inc. | Viscosity-reducing compounds for protein formulations |
US10478498B2 (en) | 2014-06-20 | 2019-11-19 | Reform Biologics, Llc | Excipient compounds for biopolymer formulations |
US11672865B2 (en) | 2014-06-20 | 2023-06-13 | Comera Life Sciences, Inc. | Viscosity-reducing excipient compounds for protein formulations |
US11806399B2 (en) | 2014-06-20 | 2023-11-07 | Comera Life Sciences, Inc. | Excipient compounds for biopolymer formulations |
US11660343B2 (en) | 2014-06-20 | 2023-05-30 | Comera Life Sciences, Inc. | Viscosity-reducing excipient compounds for protein formulations |
US11357857B2 (en) | 2014-06-20 | 2022-06-14 | Comera Life Sciences, Inc. | Excipient compounds for protein processing |
US11142571B2 (en) | 2014-11-07 | 2021-10-12 | Sesen Bio, Inc. | IL-6 antibodies |
US11498959B2 (en) | 2015-06-17 | 2022-11-15 | Eli Lilly And Company | Anti-CGRP antibody formulation |
US20180134772A1 (en) * | 2015-06-17 | 2018-05-17 | Eli Lilly And Company | Anti-CGRP Antibody Formulation |
EP4209499A1 (fr) | 2015-08-13 | 2023-07-12 | Amgen Inc. | Filtration sur profondeur chargée de protéines de liaison à l'antigène |
US11229702B1 (en) | 2015-10-28 | 2022-01-25 | Coherus Biosciences, Inc. | High concentration formulations of adalimumab |
US11769597B2 (en) | 2015-12-03 | 2023-09-26 | Regeneron Pharmaceuticals, Inc. | Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF |
US11286307B2 (en) | 2015-12-11 | 2022-03-29 | Takeda Pharmaceutical Company Limited | Plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack |
US20220241414A1 (en) * | 2016-02-23 | 2022-08-04 | Sesen Bio, Inc. | Il-6 antagonist formulations and uses thereof |
US11071782B2 (en) | 2016-04-20 | 2021-07-27 | Coherus Biosciences, Inc. | Method of filling a container with no headspace |
US11576971B2 (en) | 2016-04-20 | 2023-02-14 | Coherus Biosciences, Inc. | Method of filling a container with no headspace |
US10307483B2 (en) | 2016-10-21 | 2019-06-04 | Amgen Inc. | Pharmaceutical formulations and methods of making the same |
US11491223B2 (en) | 2016-10-21 | 2022-11-08 | Amgen Inc. | Pharmaceutical formulations and methods of making the same |
WO2018154320A1 (fr) * | 2017-02-24 | 2018-08-30 | Arecor Limited | Solutions d'anticorps stabilisées |
US11534403B2 (en) | 2017-03-06 | 2022-12-27 | Arecor Limited | Liquid pharmaceutical composition |
US11534402B2 (en) | 2017-03-06 | 2022-12-27 | Arecor Limited | Liquid pharmaceutical composition |
US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
US11633476B2 (en) | 2017-05-02 | 2023-04-25 | Merck Sharp & Dohme Llc | Stable formulations of programmed death receptor 1 (PD-1) antibodies and methods of use thereof |
US11802156B2 (en) | 2017-07-14 | 2023-10-31 | Pfizer Inc. | Antibodies to MAdCAM |
WO2019050780A1 (fr) | 2017-09-05 | 2019-03-14 | Merck Sharp & Dohme Corp. | Composés pour la réduction de la viscosité de formulations biologiques |
US11103552B2 (en) | 2018-05-10 | 2021-08-31 | Regeneron Pharmaceuticals, Inc. | High concentration VEGF receptor fusion protein containing formulations |
US11519020B2 (en) | 2018-05-25 | 2022-12-06 | Regeneron Pharmaceuticals, Inc. | Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF |
US11608357B2 (en) | 2018-08-28 | 2023-03-21 | Arecor Limited | Stabilized antibody protein solutions |
EP3996740A4 (fr) * | 2019-07-12 | 2023-07-05 | Contrafect Corporation | Formulations de protéines thérapeutiques comprenant des anticorps et leurs utilisations |
Also Published As
Publication number | Publication date |
---|---|
EP1441589B1 (fr) | 2012-05-09 |
DK1441589T3 (da) | 2012-08-06 |
IL161677A (en) | 2010-06-16 |
CY2016044I2 (el) | 2017-07-12 |
ES2392073T3 (es) | 2012-12-04 |
US20110318343A1 (en) | 2011-12-29 |
PT1441589E (pt) | 2012-08-13 |
CN1612689A (zh) | 2005-05-04 |
CA2466034A1 (fr) | 2003-05-15 |
LU93314I2 (fr) | 2019-11-20 |
JP5290489B2 (ja) | 2013-09-18 |
CN1292655C (zh) | 2007-01-03 |
WO2003039485A3 (fr) | 2004-02-12 |
WO2003039485A2 (fr) | 2003-05-15 |
KR20050044365A (ko) | 2005-05-12 |
IL161677A0 (en) | 2004-09-27 |
US8465739B2 (en) | 2013-06-18 |
AU2002363339B2 (en) | 2008-02-07 |
ATE556591T1 (de) | 2012-05-15 |
JP2005508981A (ja) | 2005-04-07 |
US20110070231A1 (en) | 2011-03-24 |
KR100913714B1 (ko) | 2009-08-24 |
CA2466034C (fr) | 2012-12-18 |
NZ532896A (en) | 2007-08-31 |
EP1441589A4 (fr) | 2007-07-04 |
JP2011068675A (ja) | 2011-04-07 |
EP1441589A2 (fr) | 2004-08-04 |
HK1074750A1 (en) | 2005-11-25 |
CY2016044I1 (el) | 2017-07-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8465739B2 (en) | Stable aqueous pharmaceutical formulations of daclizumab antibodies | |
AU2002363339A1 (en) | Stable liquid pharmaceutical formulation of IGG antibodies | |
US8298530B2 (en) | Stable lyophilized pharmaceutical formulation of IgG antibodies | |
AU2003211991B2 (en) | Antibody-containing solution formulations | |
RU2701181C2 (ru) | Жидкая композиция, содержащая антитело высокой концентрации | |
WO2004039337A2 (fr) | Formulations pharmaceutiques liquides stables d'anticorps ayant tendance a l'isomerisation | |
US20060182740A1 (en) | Buffered formulations for concentrating antibodies and methods of use thereof | |
KR20100016001A (ko) | 항체 제제 | |
CN110787292B (zh) | 一种细胞程序性死亡受体1抗体制剂及其用途 | |
US20040009168A1 (en) | Multidose antibody formulation | |
MXPA04007562A (es) | Preparacion liofilizada que comprende inmunocitocinas. | |
CN111375057A (zh) | 一种包含抗Her2单克隆抗体的药物配制剂 | |
RU2745814C1 (ru) | Водная фармацевтическая композиция левилимаба и ее применение |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: PROTEIN DESIGN LABS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KAISHEVA, ELIZABET A.;GUPTA, SUPRIYA;DUVUR, SHANTI G.;AND OTHERS;REEL/FRAME:017427/0209 Effective date: 20021106 |
|
AS | Assignment |
Owner name: PDL BIOPHARMA, INC., CALIFORNIA Free format text: CHANGE OF NAME;ASSIGNOR:PROTEIN DESIGN LABS, INC.;REEL/FRAME:017439/0502 Effective date: 20060109 |
|
AS | Assignment |
Owner name: FACET BIOTECH CORPORATION, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PDL BIOPHARMA, INC.;REEL/FRAME:022537/0360 Effective date: 20090309 Owner name: FACET BIOTECH CORPORATION,CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PDL BIOPHARMA, INC.;REEL/FRAME:022537/0360 Effective date: 20090309 |
|
AS | Assignment |
Owner name: ABBOTT BIOTHERAPEUTICS CORP., CALIFORNIA Free format text: CHANGE OF NAME;ASSIGNOR:FACET BIOTECH CORPORATION;REEL/FRAME:025445/0807 Effective date: 20100908 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION |
|
AS | Assignment |
Owner name: ABBVIE BIOTHERAPEUTICS INC., CALIFORNIA Free format text: CHANGE OF NAME;ASSIGNOR:ABBOTT BIOTHERAPEUTICS CORP.;REEL/FRAME:046373/0957 Effective date: 20121128 |