US20050053598A1 - Immunoglobulin formulation and method of preparation thereof - Google Patents
Immunoglobulin formulation and method of preparation thereof Download PDFInfo
- Publication number
- US20050053598A1 US20050053598A1 US10/773,406 US77340604A US2005053598A1 US 20050053598 A1 US20050053598 A1 US 20050053598A1 US 77340604 A US77340604 A US 77340604A US 2005053598 A1 US2005053598 A1 US 2005053598A1
- Authority
- US
- United States
- Prior art keywords
- formulation
- polysorbate
- amount
- present
- antibody
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 167
- 238000009472 formulation Methods 0.000 title claims abstract description 146
- 238000000034 method Methods 0.000 title claims abstract description 40
- 108060003951 Immunoglobulin Proteins 0.000 title claims description 40
- 102000018358 immunoglobulin Human genes 0.000 title claims description 40
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims abstract description 85
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 85
- 229940068968 polysorbate 80 Drugs 0.000 claims abstract description 85
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 85
- 229920000136 polysorbate Polymers 0.000 claims abstract description 24
- 229950008882 polysorbate Drugs 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 66
- 108090000623 proteins and genes Proteins 0.000 claims description 66
- 102000004169 proteins and genes Human genes 0.000 claims description 66
- 229960005027 natalizumab Drugs 0.000 claims description 64
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 33
- 239000011780 sodium chloride Substances 0.000 claims description 33
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 24
- 239000001488 sodium phosphate Substances 0.000 claims description 16
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 16
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 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 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 108010041012 Integrin alpha4 Proteins 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 239000000872 buffer Substances 0.000 abstract description 16
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 2
- 229960002885 histidine Drugs 0.000 description 32
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 30
- 239000012535 impurity Substances 0.000 description 24
- 239000000902 placebo Substances 0.000 description 19
- 229940068196 placebo Drugs 0.000 description 19
- 238000011282 treatment Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 14
- 238000003860 storage Methods 0.000 description 14
- 229910019142 PO4 Inorganic materials 0.000 description 13
- 238000011049 filling Methods 0.000 description 13
- 239000010452 phosphate Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 230000002776 aggregation Effects 0.000 description 12
- 238000004220 aggregation Methods 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 12
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 150000001413 amino acids Chemical group 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 9
- 230000004071 biological effect Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 8
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 8
- 239000000427 antigen Substances 0.000 description 8
- 102000036639 antigens Human genes 0.000 description 8
- 108091007433 antigens Proteins 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 229940126534 drug product Drugs 0.000 description 8
- 229940072221 immunoglobulins Drugs 0.000 description 8
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- -1 aromatic alcohols Chemical class 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000004743 Polypropylene Substances 0.000 description 5
- 229920005549 butyl rubber Polymers 0.000 description 5
- 230000006240 deamidation Effects 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 229920001155 polypropylene Polymers 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000011026 diafiltration Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000006920 protein precipitation Effects 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 229920002271 DEAE-Sepharose Polymers 0.000 description 3
- 239000012506 Sephacryl® Substances 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004925 denaturation Methods 0.000 description 3
- 230000036425 denaturation Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 238000001641 gel filtration chromatography Methods 0.000 description 3
- 238000003306 harvesting Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000002054 inoculum Substances 0.000 description 3
- 108010044426 integrins Proteins 0.000 description 3
- 102000006495 integrins Human genes 0.000 description 3
- 238000001155 isoelectric focusing Methods 0.000 description 3
- 239000012669 liquid formulation Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000012146 running buffer Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920002545 silicone oil Polymers 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 238000012371 Aseptic Filling Methods 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 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 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000005349 anion exchange Methods 0.000 description 2
- 238000006701 autoxidation reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 150000002411 histidines Chemical class 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000013627 low molecular weight specie Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940068965 polysorbates Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000012429 release testing Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000011100 viral filtration Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- KNDAEDDIIQYRHY-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(piperazin-1-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCNCC1 KNDAEDDIIQYRHY-UHFFFAOYSA-N 0.000 description 1
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 1
- QRDAGKVHMGNVHB-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;3,5-diamino-6-chloro-n-(diaminomethylidene)pyrazine-2-carboxamide;hydrochloride Chemical compound Cl.NC(N)=NC(=O)C1=NC(Cl)=C(N)N=C1N.C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O QRDAGKVHMGNVHB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 238000011111 UV-scan method Methods 0.000 description 1
- 239000011358 absorbing material Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000012556 adjustment buffer Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- HUTDDBSSHVOYJR-UHFFFAOYSA-H bis[(2-oxo-1,3,2$l^{5},4$l^{2}-dioxaphosphaplumbetan-2-yl)oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O HUTDDBSSHVOYJR-UHFFFAOYSA-H 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 229940126600 bulk drug product Drugs 0.000 description 1
- 239000012512 bulk drug substance Substances 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011082 depyrogenation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000035611 feeding Effects 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012537 formulation buffer Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000005351 kimble Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000012514 protein characterization Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012421 spiking Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000011123 type I (borosilicate glass) Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07K16/2839—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 integrin superfamily
-
- 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
-
- 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
- A61K47/26—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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 invention is directed to stable, concentrated formulations of proteins or antibodies, such as natalizumab, wherein the activity of the antibody is retained and also can be administered in a small volume and can be administered to a subject of variable weight in need thereof.
- Antibody and protein formulations are known in the art.
- preparing protein formulations, such as antibody formulations, which are chemically and biologically stable are fraught with challenges.
- Preparing formulations which are also not only stable but can maintain a small volume (i.e., allowing for a small volume injection) even with an increased concentration of protein, such as antibody also is problematic.
- the need for such formulations exist.
- concentrated amounts of protein in a fixed volume that is also stable would be especially beneficial to patients of variable weight.
- Administration of fluids to patients of variable weights may, for example, have an adverse reaction. Development of such formulations has been hindered by the proteins or the antibodies themselves, which have a high tendency to aggregate and precipitate.
- One aspect of the invention provides for a stable, aqueous pharmaceutical formulation comprising an immunoglobulin (or other protein), a phosphate buffer, a polysorbate, and sodium chloride.
- the polysorbate is polysorbate 80, and preferably in the amount of about 0.001% to about 2.0% (w/v). Most preferably the polysorbate is present in the amount of about 0.02%.
- the immunoglobulin or other protein is present in the formulation in an amount of about 0.1 mg/mL to about 200 mg/mL.
- the formulation is buffered to a pH between about 3.0 and about 7.0 and most preferably is about 6.0 ⁇ 0.5.
- the formulation is preferably isotonic.
- the formulation may further comprise histidine.
- the histidine is L-histidine.
- the immunoglobulin of the above formulation is an anti-alpha-4 integrin antibody, such as natalizumab or another humanized antibody or monoclonal antibody.
- This antibody can be present in a standard amount or in a concentrated amount, e.g., about 15 mg/mL or more.
- the natalizumab is present in an amount from about 20 mg/mL to about 150 mg/mL. In instances wherein the formulation is present in a concentration of about 15 mg/mL or more, this formulation is maintained in a fixed volume, for example, of about 125 mL.
- It is a further object of the invention to provide a method of treating a patient with variable weight for a condition with a therapeutic amount of an immunoglobulin comprising administering a formulation as described above and herein, wherein the condition is treated by administration of the formulation.
- the condition be one that is mediated by alpha-4 integrin, and in such conditions the immunoglobulin is one which recognizes and binds to alpha-4 integrin, such as natalizumab.
- a further aspect of the invention provides for a composition
- a composition comprising a sodium phosphate, a polysorbate, a protein and NaCl with a pH of 6.0 ⁇ 0.5, wherein the composition is stable when stored at 5° C. to 8° C. for a long period of time.
- Another aspect of the invention provides for a method of preparing a stable protein containing formulation comprising admixing sodium phosphate, sodium chloride, a polysorbate and a protein and adjusting the pH of the mixture with phosphoric acid to about pH 6.0 ⁇ 0.5.
- the protein may be lyophilized in the formulation of the present invention.
- the polysorbate is preferably polysorbate 80 k, present in an amount of about 0.02% (w/v), and the protein is preferably natalizumab.
- the formulation may further comprise histidine.
- the protein is lyophilized in a solution comprising 5 mM histidine, 20 mg/mL sucrose and 0.02% polysorbate 80 at a pH 6, and the protein is natalizumab at a concentration of 20 mg/mL.
- Another aspect of the invention provides for a method for treating a patient with variable weight for a condition, comprising simultaneously or sequentially administering to the patient a therapeutically effective combination of a formulation described above and herein and a compound or therapy effective against the condition.
- This medicament may further comprise a second compound or therapy to treat the condition.
- protein is meant to include but is not limited to immunoglobulins, enzymes, receptor, and fragments thereof. Although discussion of the formulation is provided mainly in reference to an antibody or immunoglobulin, other proteins are contemplated as interchangeable in the formulations disclosed.
- immunoglobulin is meant to include but is not limited to an antibody and antibody fragment (such as scFv, Fab, Fc, F(ab′) 2 ), and other genetically engineered portions of antibodies.
- antibody and antibody fragment such as scFv, Fab, Fc, F(ab′) 2
- immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM. Several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, and IgG4; IgA1 and IgA2.
- the heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ), and mu ( ⁇ ), respectively.
- the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
- the immunoglobulin recognizes and binds to alpha-4 integrin.
- antibody is used in the broadest sense and specifically covers monoclonal antibodies (including agonist and antagonist antibodies), antibody compositions with polyepitopic specificity, and antibody fragments (e.g., Fab, F(ab′) 2 , scFv and Fv), so long as they exhibit the desired biological activity. “Antibody” is meant to include polyclonal antibodies, monoclonal antibodies, humanized antibodies, human antibodies, primatized® antibodies and other antibodies produced via genetic engineering.
- the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by mammalian cell expression systems or transgenic technology, uncontaminated by other immunoglobulins.
- the monoclonal antibodies to be used in accordance with the present invention may be expressed in goats, as described by Behboodi, et al. (2002) Transgenic cloned goats and the production of therapeutic proteins . In Principles of Cloning . Elsevier Science (USA); and Meade et al. (1999). Expression of recombinant proteins in the milk of transgenic animals in Gene expression systems: using nature for the art of expression . J. M. Fernandez and J. P. Hoeffler ed., Academic Press.
- the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the methods described by Shepherd et al., Monoclonal Antibodies: A Practical Approach (Oxford University Press, 2000).
- monoclonal antibodies also includes “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity. For example, the ability to bind to alpha-4 integrin.
- “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described for example in Clackson et al., 1991 Nature 352: 624-628 and Marks et al., 1991 J. Mol. Biol., 222: 581-597.
- “Humanized” forms of non-human (e.g., murine, rabbit, bovine, equine, porcine, and the like) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′) 2 or other antigen-binding subsequences of antibodies), which contain minimal sequence derived from non-human immunoglobulin.
- humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
- CDR complementary determining region
- donor antibody non-human species
- Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
- humanized antibody may comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
- the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
- the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
- linear antibodies are also included by the general term “antibody” and are a pair of tandem Fd segments (VH-CH1-VH -CH1), which form a pair of antigen binding regions. Linear antibodies can be bispecific or monospecific.
- a “variant antibody” (also included by the generic term “antibody”) is a molecule which differs in amino acid sequence from a “parent” antibody's amino acid sequence by virtue of addition, deletion and/or substitution of one or more amino acid residue(s) in the parent antibody sequence.
- the variant comprises one or more amino acid substitution(s) in one or more hypervariable region(s) of the parent antibody.
- the variant may comprise at least one substitution, e.g., from about one to about ten, and preferably from about two to about five, in one or more hypervariable regions of the parent antibody.
- the variant will have an amino acid sequence having at least 75% amino acid sequence identity with the parent antibody heavy or light chain variable domain sequences, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%.
- Identity or homology with respect to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the parent antibody residues, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. None of the N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence should be construed as affecting sequence identity or homology.
- the variant antibody of particular interest is one which displays at least about 10 fold, preferably at least about 20 fold, and most preferably at least about 50 fold, enhancement in biological activity when compared to the parent antibody.
- the “parent” antibody is one which is encoded by an amino acid sequence used for the preparation of the variant.
- the parent antibody has a human framework region and has human antibody constant region(s).
- the parent antibody may be a humanized or a human antibody.
- an “isolated antibody” is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
- the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain.
- Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
- Antibody fragments comprise a portion of an intact antibody, generally the antigen binding or variable region of the intact antibody.
- antibody fragments include Fab, Fab′, F(ab′) 2 , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
- Single-chain Fv or “sFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain.
- the Fv polypeptide further comprises a polypeptide linker between the VH and VH domains which enables the sFv to form the desired structure for antigen binding.
- diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL).
- VH heavy chain variable domain
- VL light chain variable domain
- the route of antibody administration is in accord with known methods and are well known, and may include, for example, injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, or intralesional routes, or by sustained release systems.
- the antibody can be administered continuously by infusion or by bolus injection.
- Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
- “Pharmaceutically acceptable” excipients e.g., vehicles, additives
- a “stable” formulation is one in which the protein therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage.
- stable is also meant a formulation which exhibits little or no signs of instability, including aggregation and/or deamidation.
- the formulations provided by the present invention may remain stable for at least two years, when stored as indicated at a temperature of 5-8° C.
- Stability can be measured at a selected temperature for a selected time period as exemplified by the provided examples. Storage of stable formulations if preferably for at least 6 months, more preferably 12 months, more preferably 12-18 months, and more preferably for 2 or more years.
- a protein such as an antibody or fragment thereof, “retains its physical stability” in a pharmaceutical formulation if it shows no signs of aggregation, precipitation, deamidation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography.
- a protein “retains its chemical stability” in a pharmaceutical formulation if the chemical stability at a given time is such that the protein is considered to still retain its biological activity.
- Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein.
- Chemical alteration may involve size modification (e.g., clipping), which can be evaluated using size exclusion chromatography, SDS-PAGE and/or matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS), for examples.
- Other types of chemical alteration include charge alteration (e.g., occurring as a result of deamidation), which can be evaluated by ion-exchange chromatography, for example.
- An antibody “retains its biological activity” in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within about 10% (within the errors of the assay) of the biological activity exhibited at the time the pharmaceutical formulation was prepared as determined in an antigen binding assay, for example.
- isotonic is meant that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to 350 mOsm. Isotonicity can be measured using a vapor pressure or ice-freezing type osmometer, for example.
- buffer refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components.
- the buffer of this invention has a pH in the range from about 3.0 to about 7.5; preferably from about pH 4.0 to about 7.0; more preferably from about pH 5.0 to about 6.5; and most preferably has a pH of about 6.0 ⁇ 0.5.
- a pH of any point in between the above ranges is also contemplated.
- a “therapeutically effective amount” of an antibody refers to an amount effective in the prevention or treatment of a disorder for the treatment of which the antibody is effective.
- a “disorder” is any condition that would benefit from treatment with the antibody or protein. This includes chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question.
- Treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented.
- a “preservative” is a compound which can be included in the formulation to essentially reduce bacterial action therein, thus facilitating the production of a multi-use formulation, for example.
- potential preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), and benzethonium chloride.
- preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.
- patient or “subject” is meant to include any mammal.
- a “mammal,” for purposes of treatment, refers to any animal classified as a mammal, including but not limited to humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like.
- the mammal is human.
- natalizumab is a recombinant, humanized anti-alpha-4 integrin antibody.
- the disease or condition being treated in the mammal is one which is modulated when a therapeutically effective dose of natalizumab is administered.
- stable is meant a formulation which exhibits little or no signs of instability, including aggregation and/or deamidation.
- stable may also refer to a formulation which does not exhibit any signs of instability for greater than or equal to two years, when stored as indicated at
- formulations for stable antibody formulations are disclosed. Certain stable formulations disclosed have high concentrations of antibody but maintain a fixed volume, wherein the antibodies in these formulations are stable and the antibody does not precipitate out of solution or aggregate. Proteins other than antibodies are also contemplated for the high concentration formulations.
- Antibodies are typically administered to a subject (e.g., a human) at a concentration of about 0.01 mg/mL to about 200 mg/mL. More typically, antibodies range in concentration from about 0.1 mg/mL to about 150 mg/mL. However, instances exist when greater concentrations are required to be administered to a patient, e.g., about 15 to about 200 mg/mL, more preferably about 15 mg/mL to 150 mg/mL, more preferably about 20 to about 50 mg/mL, and most preferably about 20 mg/mL and any integer value in between.
- the antibody formulation may be administered to a mammal in need of treatment with the protein, in accordance with known methods. These methods may include, but are not limited to intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. In preferred embodiments, the antibody formulation is administered to the mammal by intravenous administration.
- the appropriate dosage of the protein will depend, for example, on the condition to be treated, the severity and course of the condition, whether the protein is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the protein, the type of protein used, and the discretion of the attending physician.
- the protein is suitably administered to the patient at one time or over a series of treatments and may be administered to the patient at any time from diagnosis onwards.
- the protein may be administered as the sole treatment or in conjunction with other drugs or therapies useful in treating the condition in question.
- two (or more) agents are said to be administered in combination when the two agents are administered simultaneously or are administered independently in a fashion such that the agents will act contemporaneously.
- the compounds of this invention may be used alone or in combination, or in combination with other therapeutic agents.
- the compounds of this invention may be co-administered along with other compounds typically prescribed for these conditions according to generally accepted medical practice.
- the formulations of this invention can be administered in combination with other therapeutic agents or physical therapies for the treatment of rheumatoid arthritis, multiple schlerosis and Crohn's Disease.
- the process can be altered as would be known to the skilled artisan, but generally would follow a procedure such as the following.
- Prepare the inoculum. Culture or ferment the cells with additional feedings as is necessary.
- Harvest/clarify the cells by centrifugation and/or filtration. This can be done for example by concentrating the cells 10 fold by spiral wound filtration. Filter by a 0.2 ⁇ m intermediate filtration followed by purification by protein A Sepharose Fast Flow® (i.e., affinity chromatography) and reverse elution.
- the antibody containing composition then receives a treatment at pH 3.6-3.7.
- the mixture receives a viral filtration followed by a concentration/diafiltration step.
- the composition can then be purified by DEAE Sepharose Fast Flow® (anion exchange). This step can be performed multiple times. From this point, the composition is then further concentrated followed by a purification step using Sephacryl S300HR® (i.e., gel filtration chromatography) system, wherein the running buffer used is phosphate/NaCl.
- the antibody containing composition can be further concentrated for the high concentration formulations (e.g., 20 mg/mL or more) if so desired.
- the antibody containing composition is then further buffered and the concentration adjusted by adding 0.02% (w/v) polysorbate 80. This composition then receives a final filtration using a 0.2 ⁇ m filter and can be dispensed at this point into 100 mL to 10 L polypropylene bottles.
- the antibody or immunoglobulin so obtained can then be QC tested and QA released.
- an immunoglobulin is formulated in concentrations of about 1.7, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0 or 50.0 mg/mL in 10 mM sodium phosphate, 140 mM NaCl (pH 6.0 ⁇ 0.5) and 0.02% polysorbate 80. If necessary, the pH is adjusted to 6.0 ⁇ 0.5 with phosphoric acid.
- any of the above formulations are optimally vialed in an aseptic vial.
- These vials can be, for example, Type I EP neutral glass vials (e.g., 5.0 or 20 mL fill vials) with Helvoet Pharma V9145/FM 157/1 gray butyl rubber stoppers with aluminum seals.
- Other suitable aseptic vials are also contemplated.
- the formulations can be bottled as follows: BOTTLING Compounding of phosphate/sodium chloride/polysorbate 80 buffer, if needed ⁇ Sterilization of vials, stoppers and manufacturing equipment ⁇ Dilution with phosphate/sodium chloride/polysorbate 80 buffer antibody to 1.7 or 50 mg/mL, as required ⁇ Sterile filtration ⁇ Aseptic filling and stoppering of vials Capping ⁇ Release Testing
- natalizumab obtained for example by the procedures discussed above can be bottled as follows.
- Natalizumab 200 L and 2000 L drug product can be filled on a fully automated filling line equipped with a vial washing, sterilization and depyrogenation tunnel. Stoppers, seals and filling equipment are washed and sterilized prior to use. This process allows for large scale tilling operations consistent with the volumes produced from the 2000 L fermentation.
- the formulation buffer about 10 mM phosphate, about 140 mM NaCl, pH 6.0 ⁇ 0.5, about 0.02% polysorbate 80, can be compounded in a Class 10,000 suite and used to dilute the bulk drug product to the final concentration. In-process specifications of concentration, pH and density are preferably reached prior to filtration.
- the formulated natalizumab or other immunoglobulin can be sterile filtered through a 0.2 ⁇ m Millipak filter into a stainless steel surge tank inside the sterile core. Filling, stoppering and capping of natalizumab is fully automated. In-process samples for bulk sterility are collected; fill weight and headspace testing is conducted throughout the filling operation. Filled drug product is stored under refrigeration at about 2-8° C.
- Filling occurs within a fully validated Class 100 sterile core.
- the filling line is validated to provide fill volumes within expected tolerances for the 5.0 mL and 20 mL fill volumes.
- Comprehensive environmental monitoring is conducted throughout the filling operation and reviewed to verify continual compliance with this standard.
- Media fills are conducted on a quarterly basis to support aseptic filling operations.
- the 200 L drug substance material produced can be bottled pursuant to the following example. Vials, filling needles, the filtration assembly and tubing are prepared and sterilized prior to use. Stoppers can be prepared by the supplier. The stoppers are then sterilized prior to filling.
- Natalizumab drug product or other protein is filled on a semi-automatic filling line, with batch preparation of components, automated filling, immediate stoppering, and a subsequent capping operation. This operation is appropriate for small batch scale operations.
- the final bulk solution is then sterile filtered through a 0.2 ⁇ m Millipak filter into a sterile glass receiving vessel within a Class 100 environment. Regular calibration and in-process checks ensure that the filling tolerance remains within ⁇ 2%. Vials are stoppered and capped immediately. Filled drug product is preferably stored refrigerated at 2-8° C.
- the glass receiving vessel can be any number of vials, but can for example be a 5.0 or 20 mL neutral glass vial Type I (EP) supplied by, for example, Epsom Glass or AMILCO or a 5.0 mL or 20 mL USP Type I borosilicate glass vial, supplied by, for example Kimble or Wheaton.
- EP neutral glass vial Type I
- Vial closures include, but are not limited to a 13 mm Helvoet Pharma V9145/FM 157/1 grey butyl rubber stopper or a 13 mm and 20 mm Helvoet Pharma V9145/FM 157/1 grey butyl rubber stopper or a 13 mm or 20 mm West 4432/50 gray butyl rubber stopper.
- the rubber-stoppered bottled is then sealed most typically using an aluminum seal, such as that manufactured by West.
- the typical method of administering natalizumab is intravenous. Intravenous administration requires the final formulation to be isotonic.
- a formulation of AN100226 (natalizumab), 5 mg/mL in 50 mM L-histidine, 150 mM NaCl, pH 6.0 was initially chosen (Formulation #1).
- Polysorbate 80 was introduced into the formulation (Formulation #2) to resolve the observed protein precipitation.
- the polysorbate for use with the present invention is low in peroxide, i.e., polysorbate from Sigma, Product number P6479, Lot Number 071K7283.
- the two factors that have been shown to accelerate the precipitation of the AN100226 antibody are the presence of trace levels of silicone oil and denaturation at the air-liquid interface.
- the silicone oil was introduced into the product upon use of standard lubricated polypropylene syringes equipped with siliconized rubber stoppers. The introduction of the silicone oil is sufficient to cause discernible antibody precipitation in Formulation # 1 upon gentle agitation and room temperature storage.
- the aggregation, deamidation and subsequent precipitation caused by denaturation at the air-liquid interface has become more discernable problematic with the drug being shipped to more clinical sites. Both causes of protein precipitation have been resolved by the addition of polysorbate 80 at a concentration of 0.02% (w/v).
- Formulation #2 shows comparable stability to the histidine/NaCl formulation (Formulation #1) in all protein characterization assays, while providing increased stability during product shipping and handling in the clinical setting.
- polysorbate 80 to the formulation also overcomes the problem of precipitating or aggregating antibody when preparing formulations with higher protein content.
- Initial work focused on agitation-induced aggregation at high protein concentrations, including 50 mg/mL.
- SEC-HPLC size exclusion-high performance liquid chromatography
- the size exclusion HPLC method used to monitor antibody aggregation was modified to increase sensitivity for detection of the trace impurities by increasing the column load 5-fold to 100 ⁇ L, and the sample is applied undiluted rather than 10-fold diluted.
- the absorbency is monitored at 260 nm to reflect the absorbency maximum of the impurities. The method provides a tool to evaluate the presence of these trace impurities in both placebo and product, as the antibody emerges much earlier in the elution profile.
- Placebo and natalizumab final drug product formulated in Formulations #1 and #2 were analyzed by the SEC-HPLC method described above. Analysis of the placebo in Formulation #1 spiked with polysorbate 80 to 0.02% (w/v) was performed just prior to chromatography. This shows the UV absorbency of polysorbate 80, histidine, and salt in the absence of the trace impurities. The broad peak at 16 minutes is associated with polysorbate 80 while the peaks at approximately 26-27 minutes are attributed to histidine and salt. The histidine/NaCl/0.02% (w/v) polysorbate 80 placebo (Formulation #2) stored at 5° C. for two months shows a marked increase in the late eluting peaks which implicates polysorbate 80 in the production of these impurities. In addition, the eluting at 16 minutes disappeared, indicating that the polysorbate 80 has been degraded.
- AN100226 stored as bulk drug substance for approximately 5 months at 5° C. in Formulation #1 was analyzed after spiking with polysorbate 80 to 0.02% (w/v) just prior to chromatography. The antibody elutes at 16-18 minutes using these overload conditions. The remainder of the profile resembles the placebo with polysorbate 80 spike.
- the two-month stability samples for natalizumab lot #AN100226-0004 were also analyzed by this method.
- the elution profile for the 5° C. natalizumab sample indicates the absence of any additional peaks and comparable levels of the histidine/salt peaks at 26-27 minutes.
- the trace impurities are detected at two months for the 25° C. sample, and elevated levels are present for the two month 40° C. sample. Thus, these impurities have not been detected in the clinical supplies, which are stored at 5° C. The appearance of these trace impurities is occurring much more rapidly in placebo than in natalizumab.
- histidine was replaced with inorganic buffering components in the placebo formulation.
- the placebo product for the clinical trials is a sterile isotonic phosphate buffered solution with 0.02% (w/v) polysorbate 80 at pH 6.0.
- the substitution of histidine with phosphate was demonstrated to significantly reduce the rate of polysorbate 80 degradation.
- 100 ⁇ L of the phosphate/NaCl/0.02% (w/v) polysorbate 80 placebo formulation was analyzed by size exclusion HPLC monitored at 260 nm both at time zero and after 3 days at 60° C. Little change is seen in the SEC-HPLC profile as a result of this incubation.
- the SEC-HPLC profile for the histidine/NaCl/0.02% (w/v) polysorbate 80 formulation following only two days at 60° C. shows significant levels of trace impurities related to the degradation of polysorbate 80.
- the SEC-HPLC profiles for 100 ⁇ L injections of samples used in the mouse single-dose limit test were determined.
- the natalizumab sample in Formulation #1 spiked with polysorbate 80 prior to analysis has little 260 nm absorbing material eluting after 20 minutes. The peak eluting at 34 minutes was found in this lot of natalizumab without polysorbate 80 addition and therefore does not indicate polysorbate 80 degradation.
- the placebo in Formulation #2 stored at 40° C. for six weeks showed complete degradation, as the total area under the curve was 12.8 million ⁇ V.seconds.
- the natalizumab sample in Formulation #2 and stored at 40° C. for six weeks had less complete degradation.
- the analysis confirms that the samples stored at 40° C. and tested in the mouse single-dose limit test are laden with degraded polysorbate 80.
- Formulation #2 was heated to 60° C. for 3 days in the presence of a needle to convert all the polysorbate 80 to the maximum levels of impurities. The reaction was confirmed to have degraded all the polysorbate 80 by both SEC and reverse phase HPLC. This material was diluted one-to-one with a 10 mg/mL solution of AN100226 in Formulation #2 resulting in a solution containing 0.01% (w/v) polysorbate 80 and 50% of the maximum level of degraded polysorbate 80. These antibody solutions were exposed to both shaking and siliconized syringes for several hours; aggregation of the antibody was prevented. The control samples exposed to the same conditions but without polysorbate 80 showed significant precipitation.
- IEF isoelectric focusing
- a preliminary limit for these trace impurities in natalizumab has been established based on the mouse single-dose limit test, the antibody solubility data with 50% degraded polysorbate 80, and estimates of the extent of the polysorbate 80 degradation. The method has been included in the ongoing stability program and a limit has been established. If additional lots are manufactured with histidine buffer, these limits will be applied at time of release as well.
- Adjust pH to 6.0 ⁇ 0.5 with phosphoric acid Optimally store formulation at about 5° C. to about 8° C.
- Additional liquid formulations of antibody at high concentration may consist of phosphate or other suitable buffer (such as histidine, citrate, acetate or succinate) in the concentration range of 2 to 50 mM, to provide buffering in the pH range of 3.0 to 7.0. Most preferably, the pH is 6.0, ⁇ 0.5.
- phosphate or other suitable buffer such as histidine, citrate, acetate or succinate
- the pH is 6.0, ⁇ 0.5.
- polyols such as sorbitol and mannitol
- disaccharides such as sucrose or trehalose
- amino acids such as glycine
- surfactants such but not limited to the polysorbates, add stability when used in the range of 0.001 to 2%.
- natalizumab was concentrated to 65 mg/mL in 10 mM sodium phosphate, 140 mM sodium chloride, pH 6, with about 0.06% polysorbate 80.
- the resulting solution was slightly opalescent but without particulates.
- the sample contained greater than 99% monomer with no high molecular weight aggregate or low molecular weight species by SEC.
- a stable lyophilized pharmaceutical formulation is provided. Because phosphate buffer undergoes a pH change during freezing, it is necessary to replace the phosphate with a different buffer.
- This buffer may be comprised of histidine, citrate or succinate,with the ability to buffer effectively in the pH range of 3.0 to 7.0, most preferably in the range of 6.0 ⁇ 0.5.
- polyols such as mannitol
- sugars such as sucrose
- polyols may be used alone or in a combination to provide for stability and adjustment of the tonicity.
- amino acids such as glycine
- at levels of 10-1000 mM may be used to prevent aggregation.
- Surfactants such as polysorbates or poloxamers, may be used at levels from 0.001% to 2.0% to provide for stability before lyophilization and after reconstitution and to provide for more rapid reconstitution times.
- the protein following the final purification step, may be formulated using ultrafiltration for concentration and diafiltration for buffer exchange.
- the protein may also be formulated using column chromatography for buffer exchange. Some combination of these techniques may also be used.
- the final desired protein concentration may be obtained by filling at a protein and excipient concentration lower than desired and reconstitution at a smaller volume.
- a 2.5 mL fill volume of a 40 mg/mL solution may be used, followed by reconstitution with 1 mL to obtain a 100 mg/mL solution.
- natalizumab at a concentration of 20 mg/mL, was lyophilized in a solution containing 5 mM histidine, 20 mg/mL sucrose and 0.02% polysorbate 80, pH 6.
- the solution was filled at 5mL per vial into 10 mL borosilicate glass vials and fitted with gray butyl rubber lyophilization stoppers. Lyophilization was done using a Virtis Gensis model lyophilizer.
- the product was frozen at a shelf temperature of ⁇ 60° C. for 10 hours and then the shelf temperature was raised to ⁇ 40°.
- Primary drying was performed at a shelf temperature of ⁇ 10° C. and a chamber pressure of 100 mTorr for 20 hours. Secondary drying was achieved at a shelf temperature of 25° C. with a chamber pressure of 100 mTorr for 10 hours.
- the vials were stoppered under vacuum.
- the vials were then reconstituted using 1 mL of sterile WFI to give a formulation containing 100 mg/mL natalizumab.
- the samples were analyzed immediately after lyophilization and after 2 wks of storage in the lyophilized form at 40 deg. In both cases reconstitution times were immediate.
- the reconstituted solutions were clear and colorless with an absence of particulate material.
- the samples contained greater than 99% monomer by SEC, with no high molecular weight aggregate, or low molecular weight species. After 2 weeks storage at 40 deg, the sample showed 94% potency relative to reference (specification 80-125%).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Rheumatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Nutrition Science (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/773,406 US20050053598A1 (en) | 2003-02-10 | 2004-02-09 | Immunoglobulin formulation and method of preparation thereof |
US12/572,978 US8349321B2 (en) | 2003-02-10 | 2009-10-02 | Immunoglobulin formulation and method of preparation thereof |
US13/605,590 US8900577B2 (en) | 2003-02-10 | 2012-09-06 | Immunoglobulin formulation and method of preparation thereof |
US13/676,866 US8815236B2 (en) | 2003-02-10 | 2012-11-14 | Method for treating multiple sclerosis and crohn's disease |
US14/524,687 US20150044206A1 (en) | 2003-02-10 | 2014-10-27 | Immunoglobulin formulation and method of preparation thereof |
US15/914,980 US10954303B2 (en) | 2003-02-10 | 2018-03-07 | Immunoglobulin formulation and method of preparation thereof |
US17/191,589 US20210292419A1 (en) | 2003-02-10 | 2021-03-03 | Immunoglobulin formulation and method of preparation thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44581803P | 2003-02-10 | 2003-02-10 | |
US10/773,406 US20050053598A1 (en) | 2003-02-10 | 2004-02-09 | Immunoglobulin formulation and method of preparation thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/572,978 Continuation US8349321B2 (en) | 2003-02-10 | 2009-10-02 | Immunoglobulin formulation and method of preparation thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050053598A1 true US20050053598A1 (en) | 2005-03-10 |
Family
ID=32869424
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/773,406 Abandoned US20050053598A1 (en) | 2003-02-10 | 2004-02-09 | Immunoglobulin formulation and method of preparation thereof |
US12/572,978 Expired - Lifetime US8349321B2 (en) | 2003-02-10 | 2009-10-02 | Immunoglobulin formulation and method of preparation thereof |
US13/605,590 Expired - Lifetime US8900577B2 (en) | 2003-02-10 | 2012-09-06 | Immunoglobulin formulation and method of preparation thereof |
US13/676,866 Expired - Lifetime US8815236B2 (en) | 2003-02-10 | 2012-11-14 | Method for treating multiple sclerosis and crohn's disease |
US14/524,687 Abandoned US20150044206A1 (en) | 2003-02-10 | 2014-10-27 | Immunoglobulin formulation and method of preparation thereof |
US15/914,980 Expired - Lifetime US10954303B2 (en) | 2003-02-10 | 2018-03-07 | Immunoglobulin formulation and method of preparation thereof |
US17/191,589 Pending US20210292419A1 (en) | 2003-02-10 | 2021-03-03 | Immunoglobulin formulation and method of preparation thereof |
Family Applications After (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/572,978 Expired - Lifetime US8349321B2 (en) | 2003-02-10 | 2009-10-02 | Immunoglobulin formulation and method of preparation thereof |
US13/605,590 Expired - Lifetime US8900577B2 (en) | 2003-02-10 | 2012-09-06 | Immunoglobulin formulation and method of preparation thereof |
US13/676,866 Expired - Lifetime US8815236B2 (en) | 2003-02-10 | 2012-11-14 | Method for treating multiple sclerosis and crohn's disease |
US14/524,687 Abandoned US20150044206A1 (en) | 2003-02-10 | 2014-10-27 | Immunoglobulin formulation and method of preparation thereof |
US15/914,980 Expired - Lifetime US10954303B2 (en) | 2003-02-10 | 2018-03-07 | Immunoglobulin formulation and method of preparation thereof |
US17/191,589 Pending US20210292419A1 (en) | 2003-02-10 | 2021-03-03 | Immunoglobulin formulation and method of preparation thereof |
Country Status (29)
Country | Link |
---|---|
US (7) | US20050053598A1 (fr) |
EP (4) | EP3777880A1 (fr) |
JP (3) | JP4728948B2 (fr) |
KR (1) | KR20050110628A (fr) |
CN (2) | CN103040732B (fr) |
AR (1) | AR043144A1 (fr) |
AU (2) | AU2004210679A1 (fr) |
CA (1) | CA2515444C (fr) |
CL (1) | CL2004000224A1 (fr) |
CY (2) | CY1120574T1 (fr) |
DK (2) | DK2236154T3 (fr) |
ES (1) | ES2819011T3 (fr) |
HK (1) | HK1182021A1 (fr) |
HU (1) | HUE051878T2 (fr) |
IL (1) | IL170008A (fr) |
MX (1) | MXPA05008409A (fr) |
MY (1) | MY162623A (fr) |
NO (1) | NO346070B1 (fr) |
PE (1) | PE20050190A1 (fr) |
PT (2) | PT2236154T (fr) |
RU (1) | RU2358763C2 (fr) |
SI (2) | SI3417875T1 (fr) |
SK (1) | SK50672005A3 (fr) |
TR (1) | TR201808801T4 (fr) |
TW (1) | TWI367766B (fr) |
UA (1) | UA82685C2 (fr) |
UY (1) | UY28184A1 (fr) |
WO (1) | WO2004071439A2 (fr) |
ZA (1) | ZA200506159B (fr) |
Cited By (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040115194A1 (en) * | 2002-09-06 | 2004-06-17 | Yi Wang | Method of treatment of asthma using antibodies to complement component C5 |
US20050271660A1 (en) * | 2002-09-06 | 2005-12-08 | Alexion Pharmaceuticals, Inc. | Nebulization of monoclonal antibodies for treating pulmonary diseases |
US20060269543A1 (en) * | 2005-05-19 | 2006-11-30 | Amgen Inc. | Compositions and methods for increasing the stability of antibodies |
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 |
US20080254026A1 (en) * | 2003-11-04 | 2008-10-16 | Novartis Vaccines And Diagnostics, Inc. | Antagonist anti-cd40 monoclonal antibodies and methods for their use |
US20080260728A1 (en) * | 2004-08-20 | 2008-10-23 | Biogen Idec Ma Inc. | Treatment of Severe Multiple Sclerosis |
WO2008157409A1 (fr) * | 2007-06-14 | 2008-12-24 | Elan Pharmaceutical, Inc. | Formulations d'immunoglobuline lyophilisées et procédés de préparation |
WO2009003010A2 (fr) * | 2007-06-25 | 2008-12-31 | Becton, Dickinson And Company | Procédés d'évaluation de l'agrégation d'une protéine dans une suspension comprenant un organopolysiloxane, et articles médicaux enrobés d'organopolysiloxane contenant une solution de protéines |
US20090060906A1 (en) * | 2007-01-09 | 2009-03-05 | Wyeth | Anti-IL-13 antibody formulations and uses thereof |
US20090202527A1 (en) * | 2004-11-19 | 2009-08-13 | Biogen Idec Ma Inc. | Treatment for multiple sclerosis |
US20100098700A1 (en) * | 2008-04-05 | 2010-04-22 | Sabbadini Roger A | Pharmaceutical compositions for binding sphingosine-1-phosphate |
US20100172862A1 (en) * | 2008-11-28 | 2010-07-08 | Abbott Laboratories | Stable antibody compositions and methods of stabilizing same |
US20100266587A1 (en) * | 2009-04-17 | 2010-10-21 | Biogen Idec Ma Inc. | Compositions and Methods to Treat Acute Myelogenous Leukemia |
US20100278822A1 (en) * | 2009-05-04 | 2010-11-04 | Abbott Biotechnology, Ltd. | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
US20110066111A1 (en) * | 2009-09-17 | 2011-03-17 | Wolfgang Teschner | Stable co-formulation of hyaluronidase and immunoglobulin, and methods of use thereof |
US20110106044A1 (en) * | 2007-06-25 | 2011-05-05 | Becton, Dickinson And Company | Methods for evaluating the aggregation of a protein in a suspension including organopolysiloxane and medical articles coated with organopolysiloxane containing a protein solution |
US20110263481A1 (en) * | 2008-12-29 | 2011-10-27 | Samyang Corporation | Pharmaceutical Composition of Lyophilized Formulation and Preparation Method of the Same |
US20110318332A1 (en) * | 2008-12-30 | 2011-12-29 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Immunoglobulin g composition |
US20120134989A1 (en) * | 2007-06-14 | 2012-05-31 | Biogen Idec Ma Inc. | Antibody formulations |
US20120230982A1 (en) * | 2002-09-06 | 2012-09-13 | Alexion Pharmaceuticals, Inc. | High concentration antibody formulations |
US20130028907A1 (en) * | 2010-02-26 | 2013-01-31 | Novo Nordisk A/S | Stable Antibody Containing Compositions |
US20130186797A1 (en) * | 2012-01-23 | 2013-07-25 | Regeneron Pharmaceuticals, Inc. | Stabilized Formulations Containing Anti-Ang2 Antibodies |
US8821865B2 (en) | 2010-11-11 | 2014-09-02 | Abbvie Biotechnology Ltd. | High concentration anti-TNFα antibody liquid formulations |
US8828396B2 (en) | 2010-11-15 | 2014-09-09 | Novartis Ag | Silent Fc variants of anti-CD40 antibodies |
US8883979B2 (en) | 2012-08-31 | 2014-11-11 | Bayer Healthcare Llc | Anti-prolactin receptor antibody formulations |
US8883146B2 (en) | 2007-11-30 | 2014-11-11 | Abbvie Inc. | Protein formulations and methods of making same |
US20160237151A1 (en) * | 2005-12-29 | 2016-08-18 | Janssen Biotech, Inc. | Human Anti-IL-23 Antibodies, Compositions, Methods and Uses |
WO2017015198A1 (fr) * | 2015-07-17 | 2017-01-26 | Coherus Biosciences, Inc. | Formulations aqueuses stables de natalizumab |
US9725501B2 (en) | 2008-04-15 | 2017-08-08 | Grifols Therapeutics Inc. | Two-stage ultrafiltration/diafiltration |
US10111958B2 (en) | 2012-05-04 | 2018-10-30 | Novartis Ag | Anti-CD40 antibody formulation |
US10301376B2 (en) | 2008-03-17 | 2019-05-28 | Baxalta GmbH | Combinations and methods for subcutaneous administration of immune globulin and hyaluronidase |
US20190194277A1 (en) * | 2017-12-08 | 2019-06-27 | Argenx Bvba | Use of fcrn antagonists for treatment of generalized myasthenia gravis |
US10335485B2 (en) | 2010-04-16 | 2019-07-02 | Biogen Ma Inc. | Anti-VLA-4 antibodies |
US10588983B2 (en) | 2005-02-23 | 2020-03-17 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US20200268675A1 (en) * | 2017-09-20 | 2020-08-27 | Tillotts Pharma Ag | Method for preparing a solid dosage form comprising antibodies by wet granulation, extrusion and spheronization |
US10835602B2 (en) | 2010-05-28 | 2020-11-17 | Novo Nordisk A/S | Stable multi-dose compositions comprising an antibody and a preservative |
US10914720B2 (en) | 2016-02-10 | 2021-02-09 | Becton Dickinson France | Method to evaluate the stability of a protein-based formulation |
CN114126647A (zh) * | 2019-06-07 | 2022-03-01 | 阿尔金克斯有限公司 | 适用于皮下施用的FcRn抑制剂的药物制剂 |
US11548941B2 (en) | 2018-11-20 | 2023-01-10 | Janssen Biotech, Inc. | Safe and effective method of treating psoriasis with anti-IL-23 specific antibody |
US11738068B2 (en) | 2018-06-25 | 2023-08-29 | Jcr Pharmaceuticals Co., Ltd. | Protein-containing aqueous liquid formulation |
US11780911B2 (en) | 2019-05-23 | 2023-10-10 | Janssen Biotech, Inc. | Method of treating inflammatory bowel disease with a combination therapy of antibodies to IL-23 and TNF alpha |
US12037398B2 (en) | 2018-06-04 | 2024-07-16 | Biogen Ma Inc. | Anti-VLA-4 antibodies having reduced effector function |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1485127E (pt) * | 2002-02-25 | 2011-09-07 | Elan Pharm Inc | Administração de agentes para o tratamento de inflamação |
EP3777880A1 (fr) | 2003-02-10 | 2021-02-17 | Biogen MA Inc. | Formulation d'immunoglobuline et son procédé de préparation |
HUE040595T2 (hu) * | 2004-04-02 | 2019-03-28 | Swedish Orphan Biovitrum Ab Publ | Eljárás IL-1ra aggregációjának csökkentésére |
JO3000B1 (ar) * | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
EP1871806A2 (fr) * | 2005-03-08 | 2008-01-02 | Pharmacia & Upjohn Company LLC | Compositions d'anticorps anti-madcam |
EA014025B1 (ru) * | 2005-09-12 | 2010-08-30 | Новиммун С.А. | Композиции антитела против cd3 |
US9309316B2 (en) | 2005-12-20 | 2016-04-12 | Bristol-Myers Squibb Company | Stable subcutaneous protein formulations and uses thereof |
AU2007225044C1 (en) | 2006-03-15 | 2018-03-29 | Alexion Pharmaceuticals, Inc. | Treatment of paroxysmal nocturnal hemoglobinuria patients by an inhibitor of complement |
TW200806315A (en) * | 2006-04-26 | 2008-02-01 | Wyeth Corp | Novel formulations which stabilize and inhibit precipitation of immunogenic compositions |
JP2010504361A (ja) * | 2006-09-25 | 2010-02-12 | メディミューン,エルエルシー | 安定した抗体製剤およびその使用 |
CN101674734A (zh) * | 2007-02-12 | 2010-03-17 | 拉萨德·布杰贝尔 | 不含防腐剂的无菌三氯蔗糖溶液 |
MX2011002159A (es) | 2008-08-27 | 2011-03-29 | Schering Corp | Formulaciones liofilizadas de anticuerpos anti-interleucina-23p19 construidos por ingenieria. |
TWI445716B (zh) * | 2008-09-12 | 2014-07-21 | Rinat Neuroscience Corp | Pcsk9拮抗劑類 |
US8765432B2 (en) | 2009-12-18 | 2014-07-01 | Oligasis, Llc | Targeted drug phosphorylcholine polymer conjugates |
AU2011262346B2 (en) | 2010-06-04 | 2014-12-11 | Wyeth Llc | Streptococcus pneumoniae vaccine formulations |
WO2012019168A2 (fr) | 2010-08-06 | 2012-02-09 | Moderna Therapeutics, Inc. | Acides nucléiques modifiés et leurs procédés d'utilisation |
CN103282042B (zh) * | 2010-09-17 | 2014-12-10 | 巴克斯特国际公司 | 通过具有组氨酸的水性制剂在弱酸性至中性pH稳定的免疫球蛋白 |
CA2821992A1 (fr) | 2010-10-01 | 2012-04-05 | Moderna Therapeutics, Inc. | Synthese d'acides nucleiques et methodes d'utilisation associees |
WO2012061074A1 (fr) | 2010-10-25 | 2012-05-10 | Elan Pharmaceuticals, Inc. | Procédés de détermination de différences dans l'activité alpha-4 intégrine par la corrélation de différences des taux de svcam et/ou de smadcam |
CA2831613A1 (fr) | 2011-03-31 | 2012-10-04 | Moderna Therapeutics, Inc. | Administration et formulation d'acides nucleiques genetiquement modifies |
KR102289394B1 (ko) | 2011-03-31 | 2021-08-13 | 머크 샤프 앤드 돔 코포레이션 | 인간 프로그램화된 사멸 수용체 pd-1에 대한 항체의 안정한 제제 및 관련된 치료 |
EA201391515A1 (ru) * | 2011-05-26 | 2014-05-30 | Глаксосмитклайн Байлоджикалс С.А. | Инактивированная вакцина вируса денге |
JP6463968B2 (ja) | 2011-07-01 | 2019-02-06 | バイオジェン・エムエイ・インコーポレイテッドBiogen MA Inc. | アルギニンを含まない腫瘍壊死因子受容体:fc融合ポリペプチド組成物およびその使用方法 |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
ES2911677T3 (es) | 2011-10-03 | 2022-05-20 | Modernatx Inc | Nucleósidos, nucleótidos y ácidos nucleicos modificados, y sus usos |
DE12858350T1 (de) | 2011-12-16 | 2021-10-07 | Modernatx, Inc. | Modifizierte mrna zusammensetzungen |
BR122019026701B1 (pt) * | 2012-03-26 | 2023-01-24 | Sanofi | Formulações de agentes de ligação à base de igg4 estáveis, kit, e dispositivo ou recipiente pré-cheios |
US9592289B2 (en) | 2012-03-26 | 2017-03-14 | Sanofi | Stable IgG4 based binding agent formulations |
US10501512B2 (en) | 2012-04-02 | 2019-12-10 | Modernatx, Inc. | Modified polynucleotides |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
EP3501550A1 (fr) | 2012-04-02 | 2019-06-26 | Moderna Therapeutics, Inc. | Polynucléotides modifiés pour la production de protéines associées à une maladie humaine |
AR091902A1 (es) | 2012-07-25 | 2015-03-11 | Hanmi Pharm Ind Co Ltd | Formulacion liquida de un conjugado de insulina de accion prolongada |
EP2727602A1 (fr) * | 2012-10-31 | 2014-05-07 | Takeda GmbH | Procédé de préparation d'une formulation liquide à concentration élevée d'un anticorps |
US9597380B2 (en) | 2012-11-26 | 2017-03-21 | Modernatx, Inc. | Terminally modified RNA |
UA117466C2 (uk) | 2012-12-13 | 2018-08-10 | Мерк Шарп Енд Доме Корп. | СТАБІЛЬНИЙ СКЛАД У ВИГЛЯДІ РОЗЧИНУ АНТИТІЛА ДО IL-23p19 |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
SI3041513T1 (sl) | 2013-09-08 | 2020-11-30 | Kodiak Sciences Inc. | Zwitterionski polimerni konjugati faktorja VIII |
US10023626B2 (en) | 2013-09-30 | 2018-07-17 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
EP3052521A1 (fr) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucléotides codant pour un récepteur de lipoprotéines de faible densité |
WO2015075201A1 (fr) | 2013-11-21 | 2015-05-28 | Genmab A/S | Formulation lyophilisée de conjugués anticorps-médicaments |
WO2015095568A1 (fr) | 2013-12-18 | 2015-06-25 | Kelvin Lee | Réduction de l'activité d'une lipase dans des formulations de produits |
US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
JP6849590B2 (ja) | 2014-10-17 | 2021-03-24 | コディアック サイエンシーズ インコーポレイテッドKodiak Sciences Inc. | ブチリルコリンエステラーゼ両性イオン性ポリマーコンジュゲート |
AR104847A1 (es) | 2015-06-17 | 2017-08-16 | Lilly Co Eli | Formulación de anticuerpo anti-cgrp |
US10484453B2 (en) * | 2015-07-29 | 2019-11-19 | Xerox Corporation | System and method for printing documents using print hardware and automatic context inference |
CN108712911A (zh) | 2015-12-30 | 2018-10-26 | 科达制药股份有限公司 | 抗体及其缀合物 |
BR112018014277A2 (pt) | 2016-01-13 | 2018-12-18 | Genmab As | formulação, e, método de preparação de uma solução injetável de um axl-adc |
EP3541413A2 (fr) | 2016-11-21 | 2019-09-25 | Polpharma Biologics S.A. | Formulations pharmaceutiques aqueuses |
RU2019138507A (ru) | 2017-05-02 | 2021-06-02 | Мерк Шарп И Доум Корп. | Составы антител против lag3 и совместные составы антител против lag3 и антител против pd-1 |
JOP20190260A1 (ar) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | صيغ ثابتة لأجسام مضادة لمستقبل الموت المبرمج 1 (pd-1) وطرق استخدامها |
JP7369123B2 (ja) | 2017-12-06 | 2023-10-25 | メルク・シャープ・アンド・ドーム・エルエルシー | 肺炎球菌多糖類-タンパク質コンジュゲートを含む組成物およびその使用方法 |
WO2019147824A1 (fr) | 2018-01-26 | 2019-08-01 | Progenity, Inc. | Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur de pde4 |
US11426446B2 (en) | 2018-03-08 | 2022-08-30 | Coherus Biosciences, Inc. | Stable aqueous formulations of aflibercept |
WO2019173767A1 (fr) | 2018-03-08 | 2019-09-12 | Coherus Biosciences Inc. | Formulations aqueuses stables d'aflibercept |
AU2019253070A1 (en) * | 2018-04-10 | 2020-11-26 | Dr. Reddy's Laboratories Limited | Antibody formulation |
CN112243379A (zh) * | 2018-04-10 | 2021-01-19 | 雷迪博士实验室有限公司 | 稳定的抗体制剂 |
WO2019246455A1 (fr) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Traitement d'une maladie du tractus gastro-intestinal par un inhibiteur de l'intégrine |
US20230009902A1 (en) | 2018-06-20 | 2023-01-12 | Progenity, Inc. | Treatment of a disease or condition in a tissue orginating from the endoderm |
EP3810095A1 (fr) | 2018-06-20 | 2021-04-28 | Progenity, Inc. | Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur du tnf |
EP3810094A1 (fr) | 2018-06-20 | 2021-04-28 | Progenity, Inc. | Traitement d'une maladie du tractus gastro-intestinal avec un jak ou un autre inhibiteur de kinase |
US20230041197A1 (en) | 2018-06-20 | 2023-02-09 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immunomodulator |
EP3810268A1 (fr) | 2018-06-20 | 2021-04-28 | Progenity, Inc. | Traitement d'une maladie du tractus gastro-intestinal avec un inhibiteur d'il-12/il-23 |
MA54533A (fr) | 2018-12-19 | 2022-03-30 | Merck Sharp & Dohme | Compositions comprenant des conjugués polysaccharide-protéine de streptococcus pneumoniae et leurs méthodes d'utilisation |
US20220088188A1 (en) * | 2018-12-24 | 2022-03-24 | Grand Theravac Life Science (Nanjing) Co., Ltd. | Pharmaceutical preparation for treating hepatitis b, preparation method therefor and use thereof |
JP2022536646A (ja) * | 2019-06-11 | 2022-08-18 | マクロジェニクス,インコーポレーテッド | 二重特異性ダイアボディの医薬製剤及びその使用 |
WO2021050687A1 (fr) | 2019-09-10 | 2021-03-18 | Coherus Biosciences, Inc. | Formulations aqueuses stables d'aflibercept |
JP2022553640A (ja) | 2019-10-10 | 2022-12-26 | コディアック サイエンシーズ インコーポレイテッド | 眼障害を処置する方法 |
WO2021124793A1 (fr) * | 2019-12-16 | 2021-06-24 | ニプロ株式会社 | Agent inhibiteur d'agrégation, et composition médicale et dispositif médical le comprenant |
WO2021146336A1 (fr) * | 2020-01-13 | 2021-07-22 | Aptevo Research And Development Llc | Procédés et compositions pour empêcher l'adsorption de protéines thérapeutiques sur des composants d'un système d'administration de médicament |
CN115023276A (zh) * | 2020-01-29 | 2022-09-06 | 默沙东有限公司 | 从抗-lag3抗体生产中分离宿主细胞脂肪酶的方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945098A (en) * | 1990-02-01 | 1999-08-31 | Baxter International Inc. | Stable intravenously-administrable immune globulin preparation |
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 (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2508132C3 (de) * | 1974-03-08 | 1980-10-16 | Teijin Ltd., Osaka (Japan) | Verfahren zur Herstellung von Humanimmunglobulin-Derivaten und parenteral applizierbare Lösung hiervon |
US4362661A (en) * | 1979-08-09 | 1982-12-07 | Teijin Limited | Immunoglobulin composition having a high monomer content, and process for production thereof |
US4597966A (en) | 1985-01-09 | 1986-07-01 | Ortho Diagnostic Systems, Inc. | Histidine stabilized immunoglobulin and method of preparation |
US5981485A (en) | 1997-07-14 | 1999-11-09 | Genentech, Inc. | Human growth hormone aqueous formulation |
WO1989011298A1 (fr) * | 1988-05-27 | 1989-11-30 | Centocor, Inc. | Formule de reactifs contenant des anticorps |
US5840299A (en) | 1994-01-25 | 1998-11-24 | Athena Neurosciences, Inc. | Humanized antibodies against leukocyte adhesion molecule VLA-4 |
US7435802B2 (en) | 1994-01-25 | 2008-10-14 | Elan Pharaceuticals, Inc. | Humanized anti-VLA4 immunoglobulins |
CN102416176A (zh) * | 1995-07-27 | 2012-04-18 | 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 |
EP0999853B1 (fr) | 1997-06-13 | 2003-01-02 | Genentech, Inc. | Formulation stabilisee renfermant un anticorps |
DE19912637A1 (de) | 1999-03-20 | 2000-09-21 | Aventis Cropscience Gmbh | 2,4-Diamino-1,3,5-triazine, Verfahren zur Herstellung und Verwendung als Herbizide und Pflanzenwachstumsregulatoren |
CZ303725B6 (cs) | 1999-03-25 | 2013-04-03 | Abbott Gmbh & Co. Kg | Lidské protilátky, které se vází na lidský IL-12 a zpusoby jejich produkce |
DE10013029A1 (de) | 2000-03-17 | 2001-09-20 | Roehm Gmbh | Mehrschichtige Arzneiform für die Colonfreigabe |
US7288390B2 (en) * | 2000-08-07 | 2007-10-30 | Centocor, Inc. | Anti-dual integrin antibodies, compositions, methods and uses |
EP1248599B1 (fr) * | 2001-01-31 | 2007-12-05 | Evonik Röhm GmbH | Forme galenique multiparticulaire contenant au moins deux formes de pellets enrobes de differentes manieres |
DE10133394A1 (de) | 2001-07-13 | 2003-01-30 | Merck Patent Gmbh | Flüssige Formulierung enthaltend Cetuximab |
CA2454587C (fr) | 2001-07-25 | 2012-11-13 | Protein Design Labs, Inc. | Formulation pharmaceutique lyophilisee stable d'anticorps igg |
EP2311489A3 (fr) * | 2002-02-14 | 2013-08-21 | Chugai Seiyaku Kabushiki Kaisha | Formulation des solutions contenant des anti-corps comportant un sucre comme stabilisateur |
PT1485127E (pt) * | 2002-02-25 | 2011-09-07 | Elan Pharm Inc | Administração de agentes para o tratamento de inflamação |
US20040033228A1 (en) * | 2002-08-16 | 2004-02-19 | Hans-Juergen Krause | Formulation of human antibodies for treating TNF-alpha associated disorders |
EP3777880A1 (fr) * | 2003-02-10 | 2021-02-17 | Biogen MA Inc. | Formulation d'immunoglobuline et son procédé de préparation |
US7807187B2 (en) | 2003-05-13 | 2010-10-05 | The University Of Massachusetts | Endogenous adjuvant molecules and uses thereof |
CA2555365A1 (fr) | 2004-02-06 | 2005-08-25 | Elan Pharmaceuticals, Inc. | Methodes et compositions de traitement de tumeurs et de maladie metastatique |
MY162179A (en) | 2004-04-01 | 2017-05-31 | Elan Pharm Inc | Steroid sparing agents and methods of using same |
EP3461500A1 (fr) | 2007-06-14 | 2019-04-03 | Biogen MA Inc. | Formulations d'anticorps natalizumab |
-
2004
- 2004-02-09 EP EP20180019.0A patent/EP3777880A1/fr active Pending
- 2004-02-09 SK SK5067-2005A patent/SK50672005A3/sk not_active Application Discontinuation
- 2004-02-09 NO NO20054164A patent/NO346070B1/no unknown
- 2004-02-09 WO PCT/US2004/003873 patent/WO2004071439A2/fr active Application Filing
- 2004-02-09 ZA ZA200506159A patent/ZA200506159B/en unknown
- 2004-02-09 SI SI200432502T patent/SI3417875T1/sl unknown
- 2004-02-09 SI SI200432441T patent/SI2236154T1/en unknown
- 2004-02-09 MX MXPA05008409A patent/MXPA05008409A/es active IP Right Grant
- 2004-02-09 EP EP04709508A patent/EP1592440A4/fr not_active Withdrawn
- 2004-02-09 RU RU2005128280/15A patent/RU2358763C2/ru active IP Right Revival
- 2004-02-09 CL CL200400224A patent/CL2004000224A1/es unknown
- 2004-02-09 DK DK10005235.6T patent/DK2236154T3/en active
- 2004-02-09 PT PT100052356T patent/PT2236154T/pt unknown
- 2004-02-09 EP EP18174115.8A patent/EP3417875B1/fr not_active Expired - Lifetime
- 2004-02-09 HU HUE18174115A patent/HUE051878T2/hu unknown
- 2004-02-09 CN CN201210292453.7A patent/CN103040732B/zh not_active Expired - Lifetime
- 2004-02-09 MY MYPI20040377A patent/MY162623A/en unknown
- 2004-02-09 CN CN2004800094412A patent/CN1771053B/zh not_active Expired - Lifetime
- 2004-02-09 PT PT181741158T patent/PT3417875T/pt unknown
- 2004-02-09 CA CA2515444A patent/CA2515444C/fr not_active Expired - Lifetime
- 2004-02-09 KR KR1020057014654A patent/KR20050110628A/ko active Search and Examination
- 2004-02-09 AU AU2004210679A patent/AU2004210679A1/en not_active Abandoned
- 2004-02-09 EP EP10005235.6A patent/EP2236154B1/fr not_active Expired - Lifetime
- 2004-02-09 JP JP2006503453A patent/JP4728948B2/ja not_active Expired - Lifetime
- 2004-02-09 DK DK18174115.8T patent/DK3417875T3/da active
- 2004-02-09 US US10/773,406 patent/US20050053598A1/en not_active Abandoned
- 2004-02-09 TR TR2018/08801T patent/TR201808801T4/tr unknown
- 2004-02-09 ES ES18174115T patent/ES2819011T3/es not_active Expired - Lifetime
- 2004-02-10 UY UY28184A patent/UY28184A1/es not_active Application Discontinuation
- 2004-02-10 TW TW093103043A patent/TWI367766B/zh not_active IP Right Cessation
- 2004-02-10 AR ARP040100411A patent/AR043144A1/es unknown
- 2004-02-10 PE PE2004000149A patent/PE20050190A1/es active IP Right Grant
- 2004-09-02 UA UAA200508632A patent/UA82685C2/uk unknown
-
2005
- 2005-08-01 IL IL170008A patent/IL170008A/en active IP Right Grant
-
2009
- 2009-10-02 US US12/572,978 patent/US8349321B2/en not_active Expired - Lifetime
-
2010
- 2010-06-01 AU AU2010202254A patent/AU2010202254B2/en not_active Expired
- 2010-12-13 JP JP2010277365A patent/JP2011088913A/ja active Pending
-
2012
- 2012-09-06 US US13/605,590 patent/US8900577B2/en not_active Expired - Lifetime
- 2012-11-14 US US13/676,866 patent/US8815236B2/en not_active Expired - Lifetime
-
2013
- 2013-08-12 HK HK13109421.5A patent/HK1182021A1/xx not_active IP Right Cessation
- 2013-09-17 JP JP2013192276A patent/JP2014028831A/ja not_active Withdrawn
-
2014
- 2014-10-27 US US14/524,687 patent/US20150044206A1/en not_active Abandoned
-
2018
- 2018-03-07 US US15/914,980 patent/US10954303B2/en not_active Expired - Lifetime
- 2018-06-29 CY CY20181100682T patent/CY1120574T1/el unknown
-
2020
- 2020-09-15 CY CY20201100869T patent/CY1123667T1/el unknown
-
2021
- 2021-03-03 US US17/191,589 patent/US20210292419A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5945098A (en) * | 1990-02-01 | 1999-08-31 | Baxter International Inc. | Stable intravenously-administrable immune globulin preparation |
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 (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050271660A1 (en) * | 2002-09-06 | 2005-12-08 | Alexion Pharmaceuticals, Inc. | Nebulization of monoclonal antibodies for treating pulmonary diseases |
US9352035B2 (en) | 2002-09-06 | 2016-05-31 | Alexion Pharmaceuticals, Inc. | High concentration antibody formulations |
US20120230982A1 (en) * | 2002-09-06 | 2012-09-13 | Alexion Pharmaceuticals, Inc. | High concentration antibody formulations |
US9415102B2 (en) * | 2002-09-06 | 2016-08-16 | Alexion Pharmaceuticals, Inc. | High concentration formulations of anti-C5 antibodies |
US20040115194A1 (en) * | 2002-09-06 | 2004-06-17 | Yi Wang | Method of treatment of asthma using antibodies to complement component C5 |
US8277810B2 (en) * | 2003-11-04 | 2012-10-02 | Novartis Vaccines & Diagnostics, Inc. | Antagonist anti-CD40 antibodies |
US8637032B2 (en) | 2003-11-04 | 2014-01-28 | Novartis Vaccines And Diagnostics, Inc. | Antagonist anti-CD40 monoclonal antibodies and methods for their use |
US20080254026A1 (en) * | 2003-11-04 | 2008-10-16 | Novartis Vaccines And Diagnostics, Inc. | Antagonist anti-cd40 monoclonal antibodies and methods for their use |
US20080260728A1 (en) * | 2004-08-20 | 2008-10-23 | Biogen Idec Ma Inc. | Treatment of Severe Multiple Sclerosis |
US20090202527A1 (en) * | 2004-11-19 | 2009-08-13 | Biogen Idec Ma Inc. | Treatment for multiple sclerosis |
US10588983B2 (en) | 2005-02-23 | 2020-03-17 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US10125191B2 (en) | 2005-05-11 | 2018-11-13 | Alexion Pharmaceutiacls, Inc. | Compositions comprising an anti-C5 antibody |
US10479828B2 (en) | 2005-05-11 | 2019-11-19 | Alexion Pharmaceuticals, Inc. | Compositions comprising an anti-C5 antibody |
US10927166B2 (en) | 2005-05-11 | 2021-02-23 | Alexion Pharmaceuticals, Inc. | Compositions comprising an anti-C5 antibody |
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 |
US9783607B2 (en) * | 2005-12-29 | 2017-10-10 | Janssen Biotech, Inc. | Human anti-IL-23 antibodies, compositions, methods and uses |
US20160237151A1 (en) * | 2005-12-29 | 2016-08-18 | Janssen Biotech, Inc. | Human Anti-IL-23 Antibodies, Compositions, Methods and Uses |
US10954297B2 (en) | 2005-12-29 | 2021-03-23 | Janssen Biotech, Inc. | Methods of treatment using human anti-IL-23 antibodies |
US10030070B2 (en) | 2005-12-29 | 2018-07-24 | Janssen Biotech, Inc. | Human anti-IL-23 antibodies, compositions, methods and uses |
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 |
US20100158908A1 (en) * | 2006-10-20 | 2010-06-24 | Amgen Inc. | Stable Polypeptide 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 |
US20090060906A1 (en) * | 2007-01-09 | 2009-03-05 | Wyeth | Anti-IL-13 antibody formulations and uses thereof |
US20090208492A1 (en) * | 2007-06-14 | 2009-08-20 | Elan Pharmaceuticals, Inc. | Lyophilized Immunoglobulin Formulations and Methods of Preparation |
US20120134989A1 (en) * | 2007-06-14 | 2012-05-31 | Biogen Idec Ma Inc. | Antibody formulations |
WO2008157409A1 (fr) * | 2007-06-14 | 2008-12-24 | Elan Pharmaceutical, Inc. | Formulations d'immunoglobuline lyophilisées et procédés de préparation |
JP2010530003A (ja) * | 2007-06-14 | 2010-09-02 | エラン ファーマシューティカルズ,インコーポレイテッド | 凍結乾燥免疫グロブリン製剤および調製方法 |
US9533044B2 (en) | 2007-06-14 | 2017-01-03 | Biogen Ma Inc. | Methods of treating inflammatory disorders using high concentration natalizumab compositions |
EP3461500A1 (fr) | 2007-06-14 | 2019-04-03 | Biogen MA Inc. | Formulations d'anticorps natalizumab |
US20110106044A1 (en) * | 2007-06-25 | 2011-05-05 | Becton, Dickinson And Company | Methods for evaluating the aggregation of a protein in a suspension including organopolysiloxane and medical articles coated with organopolysiloxane containing a protein solution |
WO2009003010A2 (fr) * | 2007-06-25 | 2008-12-31 | Becton, Dickinson And Company | Procédés d'évaluation de l'agrégation d'une protéine dans une suspension comprenant un organopolysiloxane, et articles médicaux enrobés d'organopolysiloxane contenant une solution de protéines |
WO2009003010A3 (fr) * | 2007-06-25 | 2009-02-12 | Becton Dickinson Co | Procédés d'évaluation de l'agrégation d'une protéine dans une suspension comprenant un organopolysiloxane, et articles médicaux enrobés d'organopolysiloxane contenant une solution de protéines |
US8633034B2 (en) | 2007-06-25 | 2014-01-21 | Becton, Dickinson And Company | Methods for evaluating the aggregation of a protein in a suspension including organopolysiloxane and medical articles coated with organopolysiloxane containing a protein solution |
US8883146B2 (en) | 2007-11-30 | 2014-11-11 | Abbvie Inc. | Protein formulations and methods of making same |
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 |
US11191834B2 (en) | 2007-11-30 | 2021-12-07 | Abbvie Biotechnology Ltd | Protein formulations and methods of making same |
US10301376B2 (en) | 2008-03-17 | 2019-05-28 | Baxalta GmbH | Combinations and methods for subcutaneous administration of immune globulin and hyaluronidase |
USRE49967E1 (en) | 2008-03-17 | 2024-05-14 | Takeda Pharmaceutical Company Limited | Combinations and methods for subcutaneous administration of immune globulin and hyaluronidase |
US9181331B2 (en) * | 2008-04-05 | 2015-11-10 | Lpath, Inc. | Pharmaceutical compositions for binding sphingosine-1-phosphate |
US20100098700A1 (en) * | 2008-04-05 | 2010-04-22 | Sabbadini Roger A | Pharmaceutical compositions for binding sphingosine-1-phosphate |
US9725501B2 (en) | 2008-04-15 | 2017-08-08 | Grifols Therapeutics Inc. | Two-stage ultrafiltration/diafiltration |
US20100172862A1 (en) * | 2008-11-28 | 2010-07-08 | Abbott Laboratories | Stable antibody compositions and methods of stabilizing same |
US20110263481A1 (en) * | 2008-12-29 | 2011-10-27 | Samyang Corporation | Pharmaceutical Composition of Lyophilized Formulation and Preparation Method of the Same |
US20110318332A1 (en) * | 2008-12-30 | 2011-12-29 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Immunoglobulin g composition |
US20100266587A1 (en) * | 2009-04-17 | 2010-10-21 | Biogen Idec Ma Inc. | Compositions and Methods to Treat Acute Myelogenous Leukemia |
US20100278822A1 (en) * | 2009-05-04 | 2010-11-04 | Abbott Biotechnology, Ltd. | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
US20110066111A1 (en) * | 2009-09-17 | 2011-03-17 | Wolfgang Teschner | Stable co-formulation of hyaluronidase and immunoglobulin, and methods of use thereof |
US9084743B2 (en) * | 2009-09-17 | 2015-07-21 | Baxter International Inc. | Stable co-formulation of hyaluronidase and immunoglobulin, and methods of use thereof |
US10709782B2 (en) | 2010-02-26 | 2020-07-14 | Novo Nordisk A/S | Stable antibody containing compositions |
US9795674B2 (en) * | 2010-02-26 | 2017-10-24 | Novo Nordisk A/S | Stable antibody containing compositions |
US20130028907A1 (en) * | 2010-02-26 | 2013-01-31 | Novo Nordisk A/S | Stable Antibody Containing Compositions |
US10335485B2 (en) | 2010-04-16 | 2019-07-02 | Biogen Ma Inc. | Anti-VLA-4 antibodies |
US11083791B2 (en) | 2010-04-16 | 2021-08-10 | Biogen Ma Inc. | Anti-VLA-4 antibodies |
US11571477B2 (en) | 2010-04-16 | 2023-02-07 | Biogen Ma Inc. | Anti-VLA-4 antibodies |
US10835602B2 (en) | 2010-05-28 | 2020-11-17 | Novo Nordisk A/S | Stable multi-dose compositions comprising an antibody and a preservative |
US8821865B2 (en) | 2010-11-11 | 2014-09-02 | Abbvie Biotechnology Ltd. | High concentration anti-TNFα antibody liquid formulations |
US10323096B2 (en) | 2010-11-15 | 2019-06-18 | Novartis Ag | Nucleic acids encoding silent Fc variants of anti-CD40 antibodies |
US8828396B2 (en) | 2010-11-15 | 2014-09-09 | Novartis Ag | Silent Fc variants of anti-CD40 antibodies |
US11124578B2 (en) | 2010-11-15 | 2021-09-21 | Novartis Ag | Method of treating transplant rejection with silent Fc variants of anti-CD40 antibodies |
US9688768B2 (en) | 2010-11-15 | 2017-06-27 | Novartis Ag | Silent Fc variants of anti-CD40 antibodies |
US9828433B2 (en) | 2010-11-15 | 2017-11-28 | Novartis Ag | Nucleic acids encoding silent Fc variants of anti-CD40 antibodies |
US9221913B2 (en) | 2010-11-15 | 2015-12-29 | Novartis Ag | Silent Fc variants of anti-CD40 antibodies |
US9925262B2 (en) | 2011-03-08 | 2018-03-27 | Alexion Pharmaceuticals, Inc. | Kits comprising formulations of anti-C5 antibodies |
US9556263B2 (en) | 2011-03-08 | 2017-01-31 | Alexion Pharmaceuticals, Inc. | Methods for treating atypical hemolytic uremic syndrome with high concentration formulations of anti-C5 antibodies |
US9409980B1 (en) | 2011-03-08 | 2016-08-09 | Alexion Pharmaceuticals, Inc. | Methods for treating patients with complement-associated disorders with high concentration formulations of anti-C5 antibodies |
US20130186797A1 (en) * | 2012-01-23 | 2013-07-25 | Regeneron Pharmaceuticals, Inc. | Stabilized Formulations Containing Anti-Ang2 Antibodies |
US9402898B2 (en) * | 2012-01-23 | 2016-08-02 | Regeneron Pharmaceuticals, Inc. | Stabilized formulations containing anti-Ang2 antibodies |
US10588976B2 (en) | 2012-05-04 | 2020-03-17 | Novartis Ag | Anti-CD40 antibody formulation |
US11612659B2 (en) | 2012-05-04 | 2023-03-28 | Novartis Ag | Anti-CD40 antibody formulation delivery device |
US10111958B2 (en) | 2012-05-04 | 2018-10-30 | Novartis Ag | Anti-CD40 antibody formulation |
US8883979B2 (en) | 2012-08-31 | 2014-11-11 | Bayer Healthcare Llc | Anti-prolactin receptor antibody formulations |
WO2017015198A1 (fr) * | 2015-07-17 | 2017-01-26 | Coherus Biosciences, Inc. | Formulations aqueuses stables de natalizumab |
US10914720B2 (en) | 2016-02-10 | 2021-02-09 | Becton Dickinson France | Method to evaluate the stability of a protein-based formulation |
US20200268675A1 (en) * | 2017-09-20 | 2020-08-27 | Tillotts Pharma Ag | Method for preparing a solid dosage form comprising antibodies by wet granulation, extrusion and spheronization |
AU2018380979B2 (en) * | 2017-12-08 | 2023-07-20 | Argenx Bvba | Use of FcRn antagonists for treatment of generalized myasthenia gravis |
US20190194277A1 (en) * | 2017-12-08 | 2019-06-27 | Argenx Bvba | Use of fcrn antagonists for treatment of generalized myasthenia gravis |
US12037398B2 (en) | 2018-06-04 | 2024-07-16 | Biogen Ma Inc. | Anti-VLA-4 antibodies having reduced effector function |
US11738068B2 (en) | 2018-06-25 | 2023-08-29 | Jcr Pharmaceuticals Co., Ltd. | Protein-containing aqueous liquid formulation |
US11548941B2 (en) | 2018-11-20 | 2023-01-10 | Janssen Biotech, Inc. | Safe and effective method of treating psoriasis with anti-IL-23 specific antibody |
US11780911B2 (en) | 2019-05-23 | 2023-10-10 | Janssen Biotech, Inc. | Method of treating inflammatory bowel disease with a combination therapy of antibodies to IL-23 and TNF alpha |
CN114126647A (zh) * | 2019-06-07 | 2022-03-01 | 阿尔金克斯有限公司 | 适用于皮下施用的FcRn抑制剂的药物制剂 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210292419A1 (en) | Immunoglobulin formulation and method of preparation thereof | |
ES2676544T3 (es) | Formulación de inmunoglobulina y procedimiento de preparación de la misma | |
US20090208492A1 (en) | Lyophilized Immunoglobulin Formulations and Methods of Preparation | |
IL275038B2 (en) | Formulation for anti-antibody alpha 4 in cell 7 | |
AU2012202845B2 (en) | Immunoglobulin formulation and method of preparation thereof | |
TW200909005A (en) | Lyophilized immunoglobulin formulations and methods of preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: BIOGEN IDEC INTERNATIONAL HOLDING LTD., BERMUDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ELAN PHARMA INTERNATIONAL LIMITED;REEL/FRAME:030155/0822 Effective date: 20130402 |
|
AS | Assignment |
Owner name: BIOGEN IDEC MA INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIOGEN IDEC INTERNATIONAL HOLDING LTD.;REEL/FRAME:031214/0500 Effective date: 20130819 Owner name: BIOGEN IDEC INTERNATIONAL HOLDING LTD., BERMUDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ELAN PHARMACEUTICALS, INC.;REEL/FRAME:031214/0424 Effective date: 20130724 |