US20200061015A1 - Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations - Google Patents
Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations Download PDFInfo
- Publication number
- US20200061015A1 US20200061015A1 US16/547,237 US201916547237A US2020061015A1 US 20200061015 A1 US20200061015 A1 US 20200061015A1 US 201916547237 A US201916547237 A US 201916547237A US 2020061015 A1 US2020061015 A1 US 2020061015A1
- Authority
- US
- United States
- Prior art keywords
- months
- formulation
- pfa
- pharmaceutical formulation
- surfactants
- 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
- 239000004094 surface-active agent Substances 0.000 title claims abstract description 132
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 107
- 108090001060 Lipase Proteins 0.000 title claims abstract description 58
- 102000004882 Lipase Human genes 0.000 title claims abstract description 58
- 239000004367 Lipase Substances 0.000 title claims abstract description 58
- 235000019421 lipase Nutrition 0.000 title claims abstract description 58
- 230000015556 catabolic process Effects 0.000 title claims abstract description 21
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 21
- 239000000203 mixture Substances 0.000 title claims description 244
- 238000009472 formulation Methods 0.000 title claims description 198
- 150000002605 large molecules Chemical class 0.000 title description 8
- 229920002521 macromolecule Polymers 0.000 title description 8
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 125
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 125
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 103
- 238000000034 method Methods 0.000 claims abstract description 85
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 34
- 150000002191 fatty alcohols Chemical class 0.000 claims abstract description 17
- 229920000136 polysorbate Polymers 0.000 claims description 54
- 229950008882 polysorbate Drugs 0.000 claims description 48
- -1 polyoxyethylene Polymers 0.000 claims description 43
- 108090000371 Esterases Proteins 0.000 claims description 42
- 210000004027 cell Anatomy 0.000 claims description 40
- 235000019626 lipase activity Nutrition 0.000 claims description 38
- 239000002245 particle Substances 0.000 claims description 36
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 18
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 claims description 10
- 239000000427 antigen Substances 0.000 claims description 9
- 102000036639 antigens Human genes 0.000 claims description 9
- 108091007433 antigens Proteins 0.000 claims description 9
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 claims description 7
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 claims description 5
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 claims description 5
- 150000001720 carbohydrates Chemical class 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 210000002966 serum Anatomy 0.000 claims description 5
- 230000004845 protein aggregation Effects 0.000 claims description 4
- 241000699802 Cricetulus griseus Species 0.000 claims description 3
- 239000000611 antibody drug conjugate Substances 0.000 claims description 3
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 3
- 235000019846 buffering salt Nutrition 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 abstract description 6
- 235000018102 proteins Nutrition 0.000 description 110
- 238000003860 storage Methods 0.000 description 44
- 101000968511 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Triacylglycerol lipase Proteins 0.000 description 31
- 230000035882 stress Effects 0.000 description 17
- 238000002296 dynamic light scattering Methods 0.000 description 15
- 238000001542 size-exclusion chromatography Methods 0.000 description 15
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 13
- 229920000053 polysorbate 80 Polymers 0.000 description 13
- 229940068968 polysorbate 80 Drugs 0.000 description 13
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 229920001213 Polysorbate 20 Polymers 0.000 description 11
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 11
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 11
- 229940068977 polysorbate 20 Drugs 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 229920011301 perfluoro alkoxyl alkane Polymers 0.000 description 10
- 101150060820 Pfas gene Proteins 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 230000009255 platelet function activity Effects 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 230000008646 thermal stress Effects 0.000 description 9
- 239000000178 monomer Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 6
- 230000001627 detrimental effect Effects 0.000 description 6
- 229940068965 polysorbates Drugs 0.000 description 6
- 230000001681 protective effect Effects 0.000 description 6
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- DTPCFIHYWYONMD-UHFFFAOYSA-N decaethylene glycol Polymers OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO DTPCFIHYWYONMD-UHFFFAOYSA-N 0.000 description 5
- 239000012537 formulation buffer Substances 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 102000008100 Human Serum Albumin Human genes 0.000 description 4
- 108091006905 Human Serum Albumin Proteins 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical class OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 229940126587 biotherapeutics Drugs 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000008380 degradant Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 238000010525 oxidative degradation reaction Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000013618 particulate matter Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 2
- 229940031826 phenolate Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 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
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- KOMQWDINDMFMPD-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO KOMQWDINDMFMPD-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 1
- LXEKPEMOWBOYRF-QDBORUFSSA-N AAPH Chemical compound Cl.Cl.NC(=N)C(C)(C)\N=N\C(C)(C)C(N)=N LXEKPEMOWBOYRF-QDBORUFSSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 108010077360 CNTO 530 Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Chemical class OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 108091006020 Fc-tagged proteins Proteins 0.000 description 1
- 102000002090 Fibronectin type III Human genes 0.000 description 1
- 108050009401 Fibronectin type III Proteins 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-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
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- LXEKPEMOWBOYRF-UHFFFAOYSA-N [2-[(1-azaniumyl-1-imino-2-methylpropan-2-yl)diazenyl]-2-methylpropanimidoyl]azanium;dichloride Chemical compound Cl.Cl.NC(=N)C(C)(C)N=NC(C)(C)C(N)=N LXEKPEMOWBOYRF-UHFFFAOYSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 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
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229940008421 amivantamab Drugs 0.000 description 1
- 210000001776 amniocyte Anatomy 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000011668 ascorbic acid Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical class O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 238000000533 capillary isoelectric focusing Methods 0.000 description 1
- 238000005515 capillary zone electrophoresis Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 108091006116 chimeric peptides Proteins 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960002204 daratumumab Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Chemical class 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229950010864 guselkumab Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012538 light obscuration Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000007793 ph indicator Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000004844 protein turnover Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000006950 reactive oxygen species formation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012055 resonant mass measurement Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940071598 stelara Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 229940073585 tromethamine hydrochloride Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/01—Carboxylic ester hydrolases (3.1.1)
- C12Y301/01001—Carboxylesterase (3.1.1.1)
Definitions
- the present invention is directed to pharmaceutical formulations of therapeutic proteins that comprise one or more lipase resistant surfactants.
- the present invention is also directed to methods of reducing aggregate and/or particulate formation in pharmaceutical formulations comprising therapeutic proteins and extending the shelf-life of such pharmaceutical formulations.
- surfactants in large molecule formulations are commonly used strategy for stabilizing the biological molecules, preventing adherence to surfaces, avoiding turnover at the air-water interface, protecting against surface-induced denaturation, and limiting self-association events that would otherwise lead to aggregation. Protein aggregation can occur during drug processing, long term storage, shipment, and during administration.
- a surfactant has been shown to minimize interfacial interactions that may stress proteins during filtration, agitation, freeze-thaw, lyophilization, reconstitution, administration, and storage.
- the dominant surfactants used by the pharmaceutical industry in large molecule commercial formulations are polysorbates, e.g., polysorbate 20 (PS20) and polysorbate 80 (PS80).
- Each of these surfactants has their advantages, e.g., they decrease protein self-association at an interface and prevent protein aggregation.
- a primary disadvantage of their use relates to their oxidative degradation (Kerwin B A, “Polysorbates 20 and 80 Used in the Formulation of Protein Biotherapeutics: Structure and Degradation Pathways,” J. Pharm. Sci. 97(8): 2924-35 (2008), which is hereby incorporated by reference in its entirety) and catalytic degradation (LaBrenz S R, “Ester Hydrolysis of Polysorbate 80 in mAb Drug Product: Evidence in Support of the Hypothesized Risk After the Observation of Visible Particulate in mAb Formulations,” J. Pharm. Sci., 103:2268-2277 (2014), which is hereby incorporated by reference in its entirety), which, in turn, negatively impacts the stability and shelf-life of large molecule formulations.
- Oxidative degradation of polysorbates can be mitigated in protein formulations by co-formulating with antioxidants (e.g., methionine) or with tryptophan (see, e.g., U.S. Patent Application Publication No. 2014/0322203 to Alavattam et al.).
- antioxidants e.g., methionine
- tryptophan see, e.g., U.S. Patent Application Publication No. 2014/0322203 to Alavattam et al.
- the enzymatic degradation of polysorbates which has been attributed to the presence of host cell lipases and esterases (LaBrenz S R, “Ester Hydrolysis of Polysorbate 80 in mAb Drug Product: Evidence in Support of the Hypothesized Risk After the Observation of Visible Particulate in mAb Formulations,” J. Pharm. Sci., 103:2268-2277 (2014)) remains a significant challenge to biopharmaceutical development.
- HCPs host cell proteins
- lipases trace quantities of certain host cell proteins, including some lipases, are typically retained in biopharmaceutical products (Chiu et al., “Knockout of a Difficult-to-Remove CHO Host Cell Protein, Lipoprotein Lipase, for Improved Polysorbate Stability in Monoclonal Antibody Formulations,” Biotech. Bioeng. 114(5): 1006-1015 (2017)).
- the present invention is directed at overcoming the deficiencies in the art related to host cell protein mediated degradation of surfactants in large molecule formulations.
- a first aspect of the present invention is directed to a pharmaceutical formulation.
- the pharmaceutical formulation of the present invention comprises about 20 mg/mL to about 200 mg/mL of a therapeutic protein, a pharmaceutically acceptable carrier, and one or more polyethoxylated fatty alcohol (PFA) surfactants, where the one or more PFA surfactants is resistant to lipase degradation
- PFA polyethoxylated fatty alcohol
- Another aspect of the present invention is directed to a method of reducing aggregate and/or particulate formation in a pharmaceutical formulation that comprises a biological composition.
- This method involves providing a biological composition, where the biological composition comprises about 20 mg/mL to about 200 mg/mL of therapeutic protein and incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the biological composition as a replacement for a polysorbate surfactant.
- PFA polyethoxylated fatty alcohol
- Another aspect of the present invention is directed to a method of extending the shelf life of a pharmaceutical formulation that comprises a biological composition.
- This method involves providing a biological composition, where the biological composition comprises about 20 mg/mL to about 200 mg/mL of therapeutic protein, and incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the biological composition as a replacement for a polysorbate surfactant.
- PFA polyethoxylated fatty alcohol
- Another aspect of the present invention is directed to a method of producing a pharmaceutically acceptable therapeutic protein formulation comprising a stable surfactant concentration.
- This method involves providing a pharmaceutically acceptable therapeutic protein composition and incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the therapeutic protein composition, thereby producing a pharmaceutically acceptable therapeutic formulation comprising a surfactant concentration that remains stable over the shelf life of the formulation.
- PFA polyethoxylated fatty alcohol
- Polysorbates are currently the standard surfactant used by the pharmaceutical industry.
- degradation of polysorbate can occur in large molecule formulations as a result of residual host cell protein impurities, namely lipases.
- the decrease of intact polysorbate levels over time, together with the formation of polysorbate degradant particles (e.g., free fatty acids) and large molecule destabilizing polysorbate degradants lead to formulation instability, reduced drug product shelf life, longer development timelines, and more frequent manufacturing campaigns, all of which reduce patient access to therapeutic molecules.
- polyethoxylated fatty alcohol (PFA) surfactants function to stabilize biotherapeutics the same as, and in some cases better than, their counterpart polysorbate surfactants, e.g., polysorbate 20 and polysorbate 80.
- PFAs are resistant to degradation by host cell lipases; therefore, the concentration of the PFA surfactant remains stable in the formulation overtime and able to protect the therapeutic molecule of the formulation from aggregation and particulate formation.
- the stability of the therapeutic molecule formulation is significantly improved as compared to a corresponding therapeutic molecule formulation containing polysorbate surfactant when the surfactants are exposed to lipases.
- FIGS. 1A-1C are graphs showing the protective effect of polysorbate surfactants (i.e., polysorbate 20 (PS20) and polysorbate 80 (PS80)) and polyethoxylated fatty alcohol (PFA) surfactants (i.e., Brij® O20 and Brij® L23) on antibody stability after exposure to shaking or thermal stress as measured by size exclusion chromatography (SEC).
- the graphs show percent monomer present in each formulation at time zero (T0; white bar), after shaking stress (72 hours of shaking at 250 RPM at ambient temperature; grey bars), and after thermal stress (3 month incubation at 25° C., followed by shaking stress of 72 h at 250 RPM; black bars).
- Three different antibody formulations were tested including bispecific mAb A ( FIG. 1A ), bispecific mAb B ( FIG. 1B ), and IgG4 mAb C ( FIG. 1C ). Details of antibody formulations are described herein in the Examples.
- FIG. 2 is a graph showing surfactant level (% w/v) in stock solutions exposed to lipases immobilized on beads over the course of 18 days.
- FIGS. 3A-3C are graphs showing the protective effects of polysorbate and PFA surfactants in three different antibody formulations following lipase exposure of the surfactants as assessed by SEC.
- Antibody stability was assessed based on percent monomer present in each formulation at T0 (white bars), after shaking stress (72 hours of shaking at 250 RPM at ambient temperature) (grey bars), and after thermal stress (3 month incubation at 25° C., followed by shaking stress of 72 h at 250 RPM) (black bars).
- the three antibody formulations that were tested include bispecific mAb A ( FIG. 3A ), bispecific mAb B ( FIG. 3B ), and IgG4 mAb C ( FIG. 3C ).
- FIGS. 4A-4C are graphs showing the protective effects of polysorbate and PFA surfactants in three different antibody formulations following lipase exposure of the surfactants as assessed by dynamic light scattering (DLS).
- DLS analysis was used to measure particle size distribution in each antibody formulation after thermal stress (3 months at 25° C. and shaking 72 hours at 250 RPM). Particles binning to peak 1 (2-8 nm) represent monomers, while particles in peaks 2 to peak 4 represent larger particulate ranging from 8 nm to 10,000 nm, which are indicative of aggregates.
- FIG. 4A shows the DLS results for bispecific mAb A
- FIG. 4B shows the DLS results for bispecific mAb B
- FIG. 4C shows the DLS results for IgG4 mAb C.
- FIG. 5 is a graph showing esterase/lipase activity in mAb D formulations with concentrations of 90 mg/ml and 5 mg/ml. Controls for the assay included, NaOH, HCl, porcine esterase (Sigma Product No.: E2884-5KU), water, and formulation buffer without protein.
- a first aspect of the present invention is directed to a pharmaceutical formulation.
- the pharmaceutical formulation of the present invention comprises about 20 mg/mL to about 200 mg/mL of a therapeutic protein, a pharmaceutically acceptable carrier, and one or more polyethoxylated fatty alcohol (PFA) surfactants, where the one or more PFA surfactants is resistant to lipase degradation.
- PFA polyethoxylated fatty alcohol
- the “pharmaceutical formulation” of the present invention is a preparation which is in a form that permits the biological activity of the active ingredient to be effective, and which contains no additional components that are unacceptably toxic to a subject to which the formulation is administered.
- the pharmaceutical formulation is a biopharmaceutical formulation comprising a therapeutic protein.
- a “therapeutic protein” as used herein encompasses any therapeutic product made of two or more coupled amino acids.
- Therapeutic proteins include non-recombinant, serum isolated proteins and peptide or polypeptide fragments thereof, recombinant proteins and peptide or polypeptide fragments thereof, antibodies and antigen binding portions thereof, and antibody mimetics.
- Therapeutic proteins also include recombinant and non-recombinant fusion proteins and peptides, chimeric proteins and peptides, and protein and peptide conjugates, and well as antibody and antibody fragment fusions (e.g., Fc fusion protein), chimeras, and conjugates.
- Therapeutic proteins also include engineered protein scaffolds, e.g., fibronectin type III domain scaffold binding proteins or monobodies.
- the therapeutic protein is an antibody.
- Antibodies include both full length antibodies, antigen binding fragments thereof, and antibody derivatives. Suitable antibodies include polyclonal and monoclonal antibodies of any class (e.g., IgG, IgE, IgM, IgD, and IgA), and any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).
- the antibody can be a humanized antibody, a human antibody, a chimeric antibody, a CDR-grafted antibody, a multispecific antibody (e.g., bi-specific or tri-specific antibodies).
- Suitable antibody fragments include, without limitation, any molecule containing an antigen binding region or antigen binding domain of a full antibody, e.g., single domain antibodies comprising the heavy chain variable region (V H ) or the light chain variable region (V L ).
- the antibody fragment comprises a single-chain polypeptide containing a portion of the light-chain variable domain (e.g., one, two or three of the complementary determining regions (CDRs)), or a single-chain polypeptide containing a portion of the heavy chain variable domain.
- CDRs complementary determining regions
- Other suitable antibody fragments encompassed by the present invention include antigen-binding (F(ab)) fragments and F(ab′) 2 fragments.
- the therapeutic protein is an antibody derivative.
- Antibody derivatives include, for example and without limitation, single-chain antibodies (scFv), tandem scFvs, diabodies, triabodies, or linear antibodies.
- Exemplary therapeutic antibodies of the pharmaceutical formulation as described herein include, without limitation, the anti-TNF- ⁇ /IL-17A duobody CNTO 9762 (U.S. Patent Application Publication No. 20170218092 to Chiu et al., which is hereby incorporated by reference in its entirety); the anti-CD38 antibody Daratumumab (U.S. Patent Application Publication No. 20160367663 to Doshi et al., which is hereby incorporated by reference in its entirety); the anti-thrombin antibody Ichorcumab (U.S. Pat.
- the concentration of the therapeutic protein in the pharmaceutical formulation will vary depending upon numerous factors including, without limitation, the activity of the therapeutic protein, the condition being treated, the age of the intended recipient population, route of administration, among other things.
- the pharmaceutical formulation of the present invention comprises a concentration of a therapeutic protein in the range from about 10 mg/mL to about 250 mg/mL or any range between these values. In some embodiments, the therapeutic protein is at a concentration greater than about 250 mg/mL.
- the therapeutic protein is at a concentration in the range from any one of about 10 mg/mL to 250 mg/mL, 50 mg/mL to 250 mg/mL, 100 mg/mL to 250 mg/mL, 150 mg/mL to 250 mg/mL, 200 mg/mL to 250 mg/mL, 10 mg/mL to 200 mg/mL, 20 mg/mL to 200 mg/mL, 50 mg/mL to 200 mg/mL, 100 mg/mL to 200 mg/mL, 150 mg/mL to 200 mg/mL, 10 mg/mL to 150 mg/mL, 50 mg/mL to 150 mg/mL, 100 mg/mL to 150 mg/mL, 10 mg/mL to 100 mg/mL, 50 mg/mL to 100 mg/mL, 10 mg/mL to 50 mg/mL or any range between these ranges.
- the therapeutic protein of the pharmaceutical formulation is one that is produced from a biological source, e.g., a primary population of cells or an immortalized cell line.
- the therapeutic protein is produced in a mammalian cell line.
- Suitable mammalian cell lines include hamster cell lines such as Chinese Hamster Ovary (CHO) cell lines CHODG44 and DUXB11 (Gibco, Gaithersburg, Md.), CHO-K1 (American Type Culture Collection (ATCC) #CCL-61), CHO-S (Gibco), Freestyle CHO-S (Invitrogen, Carlsbad, Calif.),CHO-T (Acyte, Brisbane, Australia), and CHO3E7 (National Research Council of Canada (CNRC) # L-11992).
- CHO Chinese Hamster Ovary
- CHODG44 and DUXB11 Gibco, Gaithersburg, Md.
- CHO-K1 American Type Culture Collection (ATCC) #CCL-61
- CHO-S Gibco
- Freestyle CHO-S Invitrogen, Carlsbad, Calif.
- CHO-T Acyte, Brisbane, Australia
- CHO3E7 National Research Council of Canada
- Suitable mammalian cell lines also include mouse cell lines, e.g., the mouse myeloma NS0 cell line (European Collection of Authenticated Cell Cultures (ECACC) #85110503) and mouse myeloma cell line Sp2/0 (ATCC-CRL-1581).
- mouse myeloma NS0 cell line European Collection of Authenticated Cell Cultures (ECACC) #85110503
- mouse myeloma cell line Sp2/0 ATCC-CRL-1581
- Suitable mammalian cells also include human cell lines such as human amniocyte, e.g., CAP cells and CAP-T cells (Cevec, Koln, Germany), human retina cells, e.g., PER.C6 cells (Crucell, Leiden, Netherlands), or human embryonic kidney cells, e.g., Freestyle HEK2930F cells (Invitrogen), HEK 293 6E (CNRC #L-11266), HEK 293 T (ATCC #CRL-11268).
- human amniocyte e.g., CAP cells and CAP-T cells (Cevec, Koln, Germany)
- human retina cells e.g., PER.C6 cells (Crucell, Leiden, Netherlands)
- human embryonic kidney cells e.g., Freestyle HEK2930F cells (Invitrogen), HEK 293 6E (CNRC #L-11266), HEK 293 T (ATCC #CRL-11268).
- the lipase or esterase activity in the pharmaceutical formulation as described herein will vary depending upon numerous factors including, without limitation, the concentration of the therapeutic protein, the biological source of the therapeutic protein, and methods of therapeutic protein purification employed.
- the lipase activity in the pharmaceutical formulation is >1 unit/mL of purified porcine esterase or equivalent thereof, where one “unit” of lipase/esterase activity hydrolyzes 1.0 ⁇ mole of ethyl butyrate to butyric acid and ethanol per minute at pH 8.0 at 25° C.
- the pharmaceutical formulation of the present invention also comprises one or more polyethoxylated fatty alcohol (PFA) surfactants.
- PFA polyethoxylated fatty alcohol
- the incorporation of one or more PFA surfactants is particularly advantageous in pharmaceutical formulations containing a therapeutic protein that was produced in a biological system, like a cell, because PFAs are resistant to degradation by residual host cell proteins that are carried over to the formulation.
- PFAs are resistant to host cell lipases that cannot be adequately removed from the therapeutic protein preparation, and which are highly active at very low concentrations.
- PFAs also referred to as alcohol ethoxylates encompass a class of non-ionic surfactants that contain a hydrophobic alkyl chain attached via an ether linkage to a hydrophilic ethylene oxide (EO) chain.
- This class of surfactants is defined by a general structure of Formula I.
- the alkyl chain, R, of the PFA varies in length and degree of linearity, but is typically between 8 and 18 carbons in length, in some embodiments, between 11-15 carbons in length.
- the length of the EO chain i.e., n of formula I
- the PFA of the pharmaceutical formulation of the present invention comprises a PFA having an ethylene oxide chain comprising about 5 to about 40 ethylene oxide units (i.e., 5, 6, 7, 8, 9, 10, 11, 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, or 40 EO units).
- PFAs are surfactants that are used primarily in laundry detergents and other household products
- PFAs have not been used in pharmaceutical formulations of biologic molecules, in particular, pharmaceutical formulations comprising therapeutic proteins, such as antibodies.
- this class of surfactants function the same as, and in some cases better than polysorbate surfactants, e.g., polysorbate 20 and polysorbate 80, which are the predominant surfactants utilized by the pharmaceutical industry in large molecule commercial formulations.
- polysorbate surfactants e.g., polysorbate 20 and polysorbate 80
- PFAs are resistant to degradation by host cell lipases; therefore, the concentration of the PFA surfactant remains stable in the formulation overtime and able to protect the therapeutic protein of the formulation from aggregation and particulate formation.
- the stability of the therapeutic protein formulation is significantly improved as compared to a corresponding therapeutic protein formulation containing polysorbate surfactant when the surfactants are exposed to lipases.
- the pharmaceutical formulation of the present invention comprises a polyoxyethylene lauryl ether (CAS No. 9002-92-0).
- exemplary polyoxyethylene lauryl ethers include, without limitation, polyoxyethylene (23) lauryl ether (also known by the tradenames Brij® L23 and Brij® 35); polyoxyethylene (4) lauryl ether (also known as polyethylene glycol dodecyl ether and Brij® L4); and polyoxyethylene (10) lauryl ether (also known as decaethylene glycol monododecyl ether).
- the pharmaceutical formulation of the present invention comprises a polyoxyethylene oleyl ether (CAS No. 9004-98-2).
- exemplary polyoxyethylene oleyl ethers include, without limitation, polyoxyethylene (20) oleyl ether (also know by the tradenames Brij® 98, Brij® 99, and Brij® O20); polyoxyethylene (10) oleyl ether (also know by the tradenames Brij® O10 and Brij® 97); and polyoxyethylene (2) oleyl ether (also know by the tradenames Brij® 93 and polyethylene glycol oleyl ether).
- the pharmaceutical formulation of the present invention comprises a polyoxyethylene stearyl ether (Cas No. 9005-00-9).
- Exemplary polyoxyethylene stearyl ethers include, without limitation, polyoxyethylene (20) stearyl ether (also know by the tradename Brij® S20); polyoxyethylene (100) stearyl ether (also known by the tradename Brij® S100); polyoxyethylene (10) stearyl ether (also known by the tradenames Brij® S10 and polyethylene glycol octadecyl ether); and polyoxyethylene (2) stearyl ether (also known by the tradename Brij® S2).
- the pharmaceutical formulation of the present invention comprises a polyoxyethylene cetyl ether (Cas No. 9004-95-9).
- exemplary polyoxyethylene cetyl ethers include, without limitation, polyoxyethylene (20) cetyl ether (also known by the tradenames Brij® 58 and polyethylene glycol hexadecyl ether); polyoxyethylene (2) cetyl ether (also known by the tradename Brij® 52); and polyoxyethylene (10) cetyl ether (also known by the tradename Brij® C10).
- the pharmaceutical formulation of the present invention comprises about 0.001% to about 0.4% (w/v) of PFA surfactant. In one embodiment, the pharmaceutical formulation comprises about 0.005% to about 0.2% (w/v) of the PFA surfactant. In one embodiment, the pharmaceutical formulation comprises about 0.01% to about 0.1% (w/v) of PFA surfactant (i.e., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%). In another embodiment, the pharmaceutical formulation comprises about 0.01% to about 0.09% (w/v) of PFA surfactant. In another embodiment, the pharmaceutical formulation comprises about 0.01% to about 0.06% (w/v) of PFA surfactant. In another embodiment, the pharmaceutical formulation comprises about 0.01% to about 0.04% (w/v) of PFA surfactant.
- the pharmaceutical formulation of the present invention is a stable formulation.
- 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.
- the formulation essentially retains its physical and chemical stability, as well as its biological activity upon storage.
- Steady levels of PFA surfactant during processing and storage contribute to the stability of the formulations describe herein.
- the formulation retains 70% of its starting level of PFA under appropriate storage conditions.
- the formulation retains 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of its starting level of PFA surfactant under appropriate storage conditions.
- >90% of the PFA remains intact after the formulation is stored at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- >95% of the PFA remains intact in the formulation after the formulation is stored at about 1° C. to about 10° C. for at least about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- >90% of the PFA remains intact after the formulation is stored at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- >95% of the PFA remains intact after the formulation is stored at about 22° C. to about 28° C.
- >90% of the PFA remains intact after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- >95% of the PFA remains intact after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C.
- Stability can be measured at a selected amount of light exposure and/or temperature for a selected time period. Stability can be evaluated qualitatively and/or quantitatively in a variety of different ways, including evaluation of aggregate formation. Aggregate formation can be evaluated by, for example and without limitation, size exclusion chromatography, turbidity, and/or by visual inspection. Stability can also be evaluated based on particulate and sub-visible particulate formation, which can be assessed using, for example and without limitation, dynamic light scattering, nanoparticle tracking analysis, resonant mass measurement, light obscuration, and flow imaging.
- stability is measured by evaluation of ROS formation, using for example and without limitation, a light stress assay or a 2,2′-Azobis(2-Amidinopropane) Dihydrochloride (AAPH) stress assay.
- stability is assessed based on the oxidation of specific amino acid residues of the protein. This analysis can be carried out using antibody detection. For example, detection of a Trp residue and/or a Met residue by monoclonal antibody detection.
- stability is evaluated by assessing charge heterogeneity using cation exchange chromatography, image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis.
- Other measures of stability include, without limitation, amino-terminal or carboxy-terminal sequence analysis; mass spectrometric analysis; SDS-PAGE or capillary electrophoresis SDS analysis to compare reduced and intact antibody; peptide map (for example tryptic or LYS-C) analysis; and evaluating biological activity or target binding function of the protein (e.g., antigen binding function of an antibody.
- the pharmaceutical formulation of the present invention has enhanced stability as compared to pharmaceutical formulations comprising the same therapeutic protein but formulated with a polysorbate surfactant.
- the stability of the pharmaceutical formulation of the present invention is characterized by the percentage of therapeutic protein in the formulation that maintains its desired monomeric state (vs. a dimer or trimer aggregated state). Accordingly, in one embodiment, >90% of the therapeutic protein in the pharmaceutical formulation comprising a PFA surfactant as described herein is in a monomeric state for its shelf-life. In another embodiment, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the therapeutic protein in the pharmaceutical formulation is in the desired monomeric state for the entirety of its shelf-life.
- >90% of the therapeutic protein is in a monomeric state after the formulation is stored at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- >95% of the therapeutic protein is in a monomeric state after the formulation is stored at about 22° C. to about 28° C.
- >90% of the therapeutic protein is in a monomeric state after the formulation is stored at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- >95% of the therapeutic protein is in a monomeric state after the formulation is stored at about 1° C. to about 10° C. for at least about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- >90% of the therapeutic protein is in a monomeric state after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- >95% of the therapeutic protein is in a monomeric state after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C.
- the formulation of the present invention is a stable formulation, as shown by its resistance to sub-visible particulate formation.
- the formulations as described herein contain ⁇ 6000 particles ( ⁇ 10 ⁇ m in size) per container (e.g., 1 mL to 50 mL vial or 0.25 mL to 2 mL syringe) and ⁇ 600 particles ( ⁇ 25 ⁇ m in size) per container after storage at about 22° C. to about 28° C.
- the therapeutic protein pharmaceutical formulations described herein are resistance to sub-visible particulate formation during cold storage.
- the formulations as described herein contain ⁇ 6000 particles ( ⁇ 10 ⁇ m in size) per container and ⁇ 600 particles ( ⁇ 25 ⁇ m in size) per container after storage at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the therapeutic protein pharmaceutical formulations described herein are resistance to sub-visible particulate formation during long-term cold storage.
- the formulations as described herein contain ⁇ 6000 particles ( ⁇ 10 ⁇ m in size) per container and ⁇ 600 particles ( ⁇ 25 ⁇ m in size) per container after storage at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the therapeutic protein pharmaceutical formulations described herein are stable formulations as demonstrated by their resistance to visible particulate formation.
- the formulations as described herein contain ⁇ 80 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- the formulations as described herein contain ⁇ 10 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 22° C. to about 28° C.
- the stable therapeutic protein pharmaceutical formulations as described herein are resistant to visible particulate formation during cold storage.
- the formulations as described herein contain ⁇ 80 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the formulations as described herein contain ⁇ 10 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 1° C. to about 10° C. for at least about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the therapeutic protein pharmaceutical formulations described herein are resistant to visible particulate formation during long-term cold storage.
- the formulations as described herein contain ⁇ 80 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the formulations as described herein contain ⁇ 10 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about ⁇ 15° C. to about ⁇ 90° C.
- the stable formulations of the present invention have low turbidity.
- the turbidity of the formulations as described herein is ⁇ 18.0 NTU (Nephelometric Turbidity Unit) after storage at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- NTU Nephelometric Turbidity Unit
- the stable therapeutic protein pharmaceutical formulations have low turbidity during cold storage.
- the turbidity of the formulations as described herein is ⁇ 18.0 NTU after storage at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the stable therapeutic protein pharmaceutical formulations have low turbidity during cold storage.
- the turbidity of the formulations as described herein is ⁇ 18.0 NTU after storage at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the pharmaceutical formulation of the present invention can further comprise at least one of any suitable auxiliary agents, such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants or the like.
- suitable auxiliary agents such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants or the like.
- suitable auxiliary agents such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants or the like.
- compositions include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars, such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume.
- Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like.
- amino acid/antibody components which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.
- Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myoinositol and the like.
- the carbohydrate excipient comprises from about 0.5% to about 15% w/v of the pharmaceutical formulation described herein.
- the formulation of the present invention can also include a buffer or a pH-adjusting agent.
- the buffer is a salt prepared from an organic acid or base.
- Representative buffers include organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
- the buffering salts are typically present in pharmaceutical formulations of the present invention at a concentration of about 5 mM to about 50 mM.
- the pH of the formulations can range from about pH 4 to about pH 10, from about pH 5 to about pH 9, or from about pH 6 to about pH 8. In one embodiment, the formulations of the present invention have a pH between about pH 6.8 and about pH 7.8.
- Preferred buffers include phosphate buffers and sodium phosphate buffers, e.g., phosphate buffered saline (PBS).
- the pharmaceutical formulation of the present invention can include polymeric excipients/additives, such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2 -hydroxypropyl- ⁇ -cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).
- polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2 -hydroxypropyl- ⁇ -cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids (e.
- the pharmaceutical formulation of the present invention may further comprise one or more pharmaceutically acceptable carriers.
- a “pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic protein is formulated with.
- Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration).
- the pharmaceutical formulation described herein may also contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating and coloring agents, etc.
- concentration of the therapeutic protein in such pharmaceutical formulations may vary, from less than about 0.5%, usually to at least about 1%, to as much as 15%, 20%, 25%, 30%, or >30% by weight and may be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the particular mode of administration selected.
- Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21 st Edition, (2006), which is hereby incorporated by reference in its entirety.
- Another aspect of the present invention is directed to a method of reducing aggregate and/or particulate formation in a pharmaceutical formulation that comprises a biological composition.
- This method involves providing a biological composition, where the biological composition comprises about 20 mg/mL to about 200 mg/mL of therapeutic protein, and incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the biological composition as a replacement for a polysorbate surfactant.
- PFA polyethoxylated fatty alcohol
- Another aspect of the present invention is directed to a method of extending the shelf life of a pharmaceutical formulation that comprises a biological composition.
- This method involves providing a biological composition, where the biological composition comprises about 20 mg/mL to about 200 mg/mL of therapeutic protein, and incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the biological composition as a replacement for a polysorbate surfactant.
- PFA polyethoxylated fatty alcohol
- Another aspect of the present invention is directed to a method of producing a pharmaceutically acceptable therapeutic protein formulation comprising a stable surfactant concentration.
- This method involves providing a pharmaceutically acceptable therapeutic protein composition and incorporating one or more lipase resistant polyethoxylated fatty alcohol (PFA) surfactants in the therapeutic protein composition thereby, producing a pharmaceutically acceptable therapeutic formulation comprising a surfactant concentration that remains stable over the shelf life of the formulation.
- PFA polyethoxylated fatty alcohol
- the methods as described herein are particularly suitable for biological compositions having a lipase/esterase activity that is ⁇ 1 unit/mL of purified porcine esterase or equivalent thereof, where one “unit” of activity hydrolyzes 1.0 ⁇ mole of ethyl butyrate to butyric acid and ethanol per minute at pH 8.0 at 25° C. It is this level of lipase activity in a biological composition that is sufficient to cause polysorbate degradation, subsequently jeopardizing the stability of the biological composition.
- the methods as described herein involve providing a pharmaceutical formulation of a biological composition, where the biological composition has a lipase/esterase activity of ⁇ 1 units/mL of purified porcine esterase or equivalent thereof.
- the methods as described herein provide a pharmaceutical formulation of a biological composition with one or more lipase resistance PFA surfactants, wherein the biological composition has a lipase/esterase activity of ⁇ 1 units/mL of purified porcine esterase or equivalent thereof.
- the methods as described herein provide a pharmaceutical formulation of a biological composition with one or more lipase resistance PFA surfactants, wherein the biological composition has a lipase/esterase activity of ⁇ 1, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, ⁇ 0.1 units/mL of purified porcine esterase or equivalent thereof.
- the methods as described herein provide a pharmaceutical formulation of a biological composition with one or more lipase resistance PFA surfactants, wherein the biological composition has a lipase/esterase activity of ⁇ 0.1 units/mL of purified porcine esterase or equivalent thereof.
- the methods of the present invention further involve measuring lipase activity of the biological composition prior to incorporating the one or more lipase resistant PFA surfactants.
- Suitable methods of measuring lipase activity in a biological sample are known in the art, see, e.g., Hernandez-Garcia et al., “An Improved Method to Measure Lipase Activity in Aqueous Media,” Anal. Biochem. 530:104-106 (2017), Tietz and Repique, “Proposed Standard Method for Measuring Lipase Activity in Serum by a Continuous Sampling Technique,” Clin. Chem.
- a suitable method of measuring lipase activity of the biological sample involves measuring the conversion of 4-nitrophenyl acetate to 4-nitrophenol by the esterase/lipase present in the sample. This conversion can be monitored, detected, and quantified using spectrophotometric methods. For example, at pH>6.0 the conversion the 4-nitrophenol is colored yellow and its production can be monitored at 400 nm.
- a lipase resistant PFA surfactant is incorporated into biological compositions comprising a lipase/esterase activity of ⁇ 1 unit/mL of purified porcine esterase or equivalent thereof.
- compositions comprising any of the therapeutic proteins described supra, including, without limitation, non-recombinant, serum isolated proteins and peptides thereof, recombinant proteins or peptides thereof, an antibody or an antigen binding portion thereof, antibody derivatives, and/or antibody-drug conjugate.
- the pharmaceutical formulation comprises a therapeutic protein that is derived from a biological source, i.e., a population of cells or a cell line.
- a biological source i.e., a population of cells or a cell line.
- Cell lines from which the therapeutic protein may be obtained from include, without limitation, mammalian CHO cell lines, PER.C6 cell lines, and Sp2/0 cell lines as described supra.
- the concentration of the therapeutic protein in the formulation ranges from about 10 mg/mL to about 250 mg/mL or any range between these values as described supra. In some embodiments, the therapeutic protein is at a concentration greater than about 250 mg/mL.
- the therapeutic protein is at a concentration in the range from any one of about 10 mg/mL to 250 mg/mL, 50 mg/mL to 250 mg/mL, 100 mg/mL to 250 mg/mL, 150 mg/mL to 250 mg/mL, 200 mg/mL to 250 mg/mL, 10 mg/mL to 200 mg/mL, 50 mg/mL to 200 mg/mL, 100 mg/mL to 200 mg/mL, 150 mg/mL to 200 mg/mL, 10 mg/mL to 150 mg/mL, 50 mg/mL to 150 mg/mL, 100 mg/mL to 150 mg/mL, 10 mg/mL to 100 mg/mL, 50 mg/mL to 100 mg/mL, 10 mg/mL to 50 mg/mL or any range between these ranges.
- the incorporation of one or more PFA surfactants in a pharmaceutical formulation containing a therapeutic protein that was produced in a biological system, like a cell is particularly advantageous, because PFAs are resistant to degradation by residual host cell proteins that are carried over to the formulation.
- PFAs are resistant to host cell lipases that are not, and cannot be, adequately removed from the therapeutic protein preparation, and which are highly active at very low concentrations ( ⁇ 1 unit/mL of purified porcine esterase or equivalent thereof).
- suitable PFA surfactants have the general structure of Formula I.
- the length of the hydrophilic ethylene oxide chain comprises about 1 to about 40 units. In one embodiment, the length of the ethylene oxide chain comprises about 5 to about 40 ethylene oxide units.
- a polyoxyethylene lauryl ether e.g., polyoxyethylene (23) lauryl ether (also known by the tradenames Brij® L23 and Brij® 35)
- a polyoxyethylene oleyl ether e.g., polyoxyethylene (20) oleyl ether (also know by the tradenames Brij® 98 and Brij® 99) or polyoxyethylene (10) oleyl ether (also know by the tradenames Brij® O10 and Brij® 97)
- a polyoxyethylene lauryl ether e.g., polyoxyethylene (23) lauryl ether (also known by the tradenames Brij® L23 and Brij® 35)
- a polyoxyethylene oleyl ether e.g., polyoxyethylene (20) oleyl ether (also know by the tradenames Brij® 98 and Brij® 99) or polyoxyethylene (10) oleyl ether (also know by the tradenames Brij® O10 and Brij® 97)
- a polyoxyethylene cetyl ether e.g., polyoxyethylene (20) cetyl ether (also known by the tradename Brij® 58)
- a polyoxyethylene stearyl ether e.g., polyoxyethylene (20) stearyl ether (also know by the tradename Brij® S20)
- a polyoxyethylene stearyl ether e.g., polyoxyethylene (20) stearyl ether
- the one or more PFA surfactants are incorporated into the pharmaceutical formulation such that the composition comprises 0.001% to about 0.4% (w/v) of PFA surfactant.
- the method produces a pharmaceutical formulation comprising about 0.005% to about 0.2% (w/v) of PFA surfactant.
- the method produces a pharmaceutical formulation comprising about 0.01% to about 0.1% (w/v) of PFA surfactant.
- the method produces a pharmaceutical formulation comprising about 0.01% to about 0.09% (w/v) of PFA surfactant.
- the method produces a pharmaceutical formulation comprising about 0.01% to about 0.06% (w/v) of PFA surfactant.
- the method produces a pharmaceutical formulation comprising about 0.01% to about 0.04% (w/v) of PFA surfactant.
- the methods of the present invention produce therapeutic protein pharmaceutical formulations having a stable surfactant concentration.
- >90% of the PFA remains intact in the formulation after the formulation is stored at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods of the present invention produce formulations where >95% of the PFA remains intact in the formulation after the formulation is stored at about 1° C. to about 10° C. for at least about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods of the present invention produce formulations where >90% of the PFA remains intact after the formulation is stored at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- the methods of the present invention produce formulations where >95% of the PFA remains intact after the formulation is stored at about 22° C. to about 28° C.
- the methods of the present invention produce formulations where >90% of the PFA remains intact after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the methods of the present invention produce formulations where >95% of the PFA remains intact after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C.
- the methods of the present invention produce stable therapeutic protein formulations where >90% of the therapeutic protein (e.g., antibody) is in a monomeric state after the formulation is stored at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- the methods of the present invention produce formulations where >95% of the therapeutic protein in the formulation is in a monomeric state after the formulation is stored at about 22° C. to about 28° C.
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations where >90% of the therapeutic protein (e.g., antibody) is in a monomeric state after the formulation is stored at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods described herein produce therapeutic protein formulations where >95% of the therapeutic protein is in a monomeric state after the formulation is stored at about 1° C. to about 10° C. for at least about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods of the present invention produce formulations where >90% of the therapeutic protein (e.g., antibody) is in a monomeric state after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the methods of the present invention produce formulations where >95% of the therapeutic protein is in a monomeric state after the formulation is stored at about ⁇ 15° C. to about ⁇ 90° C.
- the methods of the present invention produce stable formulations resistant to sub-visible particulate formation.
- the formulations as described herein contain ⁇ 6000 particles ( ⁇ 10 ⁇ m in size) per container and ⁇ 600 particles ( ⁇ 25 ⁇ m in size) per container after storage at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations resistance to sub-visible particulate formation during cold storage.
- the methods produce formulations containing ⁇ 6000 particles ( ⁇ 10 ⁇ m in size) per container and ⁇ 600 particles ( ⁇ 25 ⁇ m in size) per container after storage at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations resistance to sub-visible particulate formation during long-term cold storage.
- the methods described herein produce formulations containing ⁇ 6000 particles ( ⁇ 10 ⁇ m in size) per container and ⁇ 600 particles ( ⁇ 25 ⁇ m in size) per container after storage at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the methods of the present invention produce stable formulations resistant to visible particulate formation.
- the methods produce formulations containing ⁇ 80 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- the methods described herein produce formulations containing ⁇ 10 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 22° C. to about 28° C.
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations resistance to visible particulate formation during cold storage.
- the methods described herein produce formulations containing ⁇ 80 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods described herein produce formulations containing ⁇ 10 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about 1° C. to about 10° C. for at least about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations resistance to visible particulate formation during long-term cold storage.
- the methods described herein produce formulations containing ⁇ 80 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the methods described herein produce formulations containing ⁇ 10 particles ( ⁇ 70 ⁇ m in size) per milliliter after storage at about ⁇ 15° C.
- the methods of the present invention produce stable formulations with low turbidity.
- the methods described herein produce formulations having ⁇ 18.0 NTU (Nephelometric Turbidity Unit) after storage at about 22° C. to about 28° C. for at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months.
- NTU Nephelometric Turbidity Unit
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations with low turbidity during cold storage.
- the methods described herein produce formulations having ⁇ 18.0 NTU after storage at about 1° C. to about 10° C. for about six months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months.
- the methods of the present invention produce stable therapeutic protein pharmaceutical formulations having low turbidity during cold storage.
- the turbidity of the formulations as described herein is ⁇ 18.0 NTU after storage at about ⁇ 15° C. to about ⁇ 90° C. for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, or at least about 72 months.
- the methods of the present invention produce pharmaceutical formulations where the shelf life of the formulation is extended at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months beyond the shelf life of a corresponding formulation containing a polysorbate surfactant.
- the soluble aggregation quality attribute of the investigated formulations was evaluated using size exclusion ultra performance liquid chromatography (SE-UPLC).
- SE-UPLC size exclusion ultra performance liquid chromatography
- Particulate formation was assessed using dynamic light scattering.
- the assay measures the conversion of 4-Nitrophenyl Acetate to 4-Nitrophenol by esterase/lipase.
- the 4-Nitrophenol is deprotonated (phenolate) and is colored yellow.
- the presence of phenolate is monitored at 400 nm and the intensity of the color is pH dependent from 6.0 to 8.0.
- Example 1 PFA Surfactants Protect mAbs from Shaking and Thermal Stability Stresses
- mAbs A and B are bispecific antibodies, and mAb C is an IgG4 monoclonal antibody.
- the formulations for mAbs A and B comprised 10 mM histidine, 8.5% (w/v) sucrose, at pH 5.7.
- the mAb C formulation consisted of 10 mM sodium phosphate, 8.5% (w/v) sucrose, 10 ppm EDTA, at pH 7.1. All three mAbs were at a 50 mg/mL concentration in their respective formulations.
- FIGS. 1A-1C are graphs showing the percentage of each formulation that is in the desired monomeric state as assessed by SEC.
- the comparison of polysorbate and PFA containing formulations reveals similar percent monomer results when formulations are exposed to shaking and thermal stresses.
- SEC results indicate that PFA (Brij O20 and Brij L23) formulations retain higher percent monomer content than polysorbate (PS20 and PS80) formulations for the stressed condition of 3-month storage at 25° C. following by shaking stress (Student's t-test, p ⁇ 0.01).
- Example 2 PFA Sock Solutions Exposed to Lipases Immobilized on Beads Exhibit Significant Resistance to Degradation.
- Example 3 mAb Stability is Maintained in Formulations Containing PFA Surfactant Exposed to Lipase
- the orthogonal DLS assay complements SEC results and demonstrates that PFA formulations outperform polysorbate formulations in their ability to protect the mAb from soluble aggregation and insoluble particulate formation in conditions where lipases can degrade ester bond containing surfactants.
- esterase/lipase activity was determined in formulations containing different concentrations of purified therapeutic proteins (antibodies).
- a representative example is shown in FIG. 5 , with analysis of esterase/lipase activity in mAb D formulations with concentrations of 90 mg/ml and 5 mg/ml.
- mAb D formulations containing 5 mg/mL total protein exhibited a lower level of esterase/lipase activity (see last bar in graph of FIG. 5 ).
- esterase/lipase activity below this level of activity could be acceptable with regard to polysorbate degradation and stability of a therapeutic protein.
- esterase/lipase activity below what is present in the 5 mg/mL sample of mAb D was determined to be an acceptable esterase/lipase activity level.
- a more prudent cutoff for an acceptable level of esterase/lipase activity would be activity that is ⁇ 10% of the activity present in the 5 mg/mL sample of mAb D.
- esterase/lipase activity in the 5 mg/mL mAb D sample represented 1% of the esterase control (porcine esterase; Sigma PN E2884-5KU, CAS#9016-18-6, EC3.1.1.1) having 125 U/mL activity. Based on that analysis, an acceptable level of esterase/lipase activity in the mAb D formulation corresponds to ⁇ 1.25 Units/mL of porcine esterase. Rounding to the correct number of significant figures, an acceptable level of esterase/lipase activity in the mAb D formulation corresponds to ⁇ 1 Units/mL of porcine esterase.
- an acceptable level of esterase/lipase activity in the mAb D formulation corresponds to ⁇ 1, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1 Units/mL of porcine esterase. In certain embodiments, an acceptable level of esterase/lipase activity in the mAb D formulation corresponds to ⁇ 0.1 Units/mL of porcine esterase. Thus, an esterase/lipase activity level corresponding to ⁇ 1 Units/mL of porcine esterase is considered to be detrimental to a therapeutic protein formulation.
- esterase/lipase activity level corresponding to ⁇ 1, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1 Units/mL of porcine esterase is considered to be detrimental to a therapeutic protein formulation.
- esterase/lipase activity level corresponding to ⁇ 0.1 Units/mL of porcine esterase is considered to be detrimental to a therapeutic protein formulation.
- a polysorbate surfactant may not be the best choice for a formulation with an esterase/lipase activity level corresponding to ⁇ 1 Units/mL of porcine esterase.
- a polysorbate surfactant may not be the best choice for a formulation with an esterase/lipase activity level corresponding to ⁇ 1, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1 Units/mL of porcine. Rather, the data suggests that polysorbate surfactants should be avoided in formulations with an esterase/lipase activity level corresponding to ⁇ 1 Units/mL of porcine esterase.
- polysorbate surfactants should be avoided in formulations with an esterase/lipase activity level corresponding to ⁇ 1, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1 Units/mL of porcine esterase.
- polysorbate surfactants should be avoided in formulations with an esterase/lipase activity level corresponding to ⁇ 0.1 Units/mL of porcine esterase.
- a polyethoxylated fatty alcohol surfactant as described herein should be used in a formulation with an esterase/lipase activity level corresponding to ⁇ 1 Units/mL of porcine esterase.
- a polyethoxylated fatty alcohol surfactant as described herein should be used in a formulation with an esterase/lipase activity level corresponding to ⁇ 1, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, or ⁇ 0.1 Units/mL of porcine esterase.
- a polyethoxylated fatty alcohol surfactant as described herein should be used in a formulation with an esterase/lipase activity level corresponding to ⁇ 0.1 Units/mL of porcine esterase.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/547,237 US20200061015A1 (en) | 2018-08-23 | 2019-08-21 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
US17/734,523 US20220265596A1 (en) | 2018-08-23 | 2022-05-02 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862721884P | 2018-08-23 | 2018-08-23 | |
US16/547,237 US20200061015A1 (en) | 2018-08-23 | 2019-08-21 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/734,523 Continuation US20220265596A1 (en) | 2018-08-23 | 2022-05-02 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
US20200061015A1 true US20200061015A1 (en) | 2020-02-27 |
Family
ID=69587008
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/547,237 Abandoned US20200061015A1 (en) | 2018-08-23 | 2019-08-21 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
US17/734,523 Pending US20220265596A1 (en) | 2018-08-23 | 2022-05-02 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/734,523 Pending US20220265596A1 (en) | 2018-08-23 | 2022-05-02 | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations |
Country Status (8)
Country | Link |
---|---|
US (2) | US20200061015A1 (zh) |
EP (2) | EP4371568A3 (zh) |
KR (1) | KR20210049842A (zh) |
CN (1) | CN112601518A (zh) |
ES (1) | ES2977866T3 (zh) |
IL (1) | IL280862A (zh) |
MA (1) | MA53447A (zh) |
WO (1) | WO2020039384A1 (zh) |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3300624C2 (de) * | 1983-01-11 | 1984-11-15 | Danfoss A/S, Nordborg | Ventil mit Voreinstellung der Durchflußmenge |
US5770198A (en) | 1988-05-18 | 1998-06-23 | The Research Foundation Of The State Of New York | Platelet-specific chimeric 7E3 immunoglobulin |
US5656272A (en) | 1991-03-18 | 1997-08-12 | New York University Medical Center | Methods of treating TNF-α-mediated Crohn's disease using chimeric anti-TNF antibodies |
US6902734B2 (en) | 2000-08-07 | 2005-06-07 | Centocor, Inc. | Anti-IL-12 antibodies and compositions thereof |
EP1575499A2 (en) | 2002-06-28 | 2005-09-21 | Centocor, Inc. | Mammalian epo mimetic ch1 deleted mimetibodies, compositions, methods and uses |
US20060142234A1 (en) * | 2004-12-23 | 2006-06-29 | Guohua Chen | Injectable non-aqueous suspension |
ES2622602T3 (es) | 2005-12-29 | 2017-07-06 | Janssen Biotech, Inc. | Anticuerpos anti-IL-23 humanos, composiciones, procedimientos y usos |
US20110223208A1 (en) * | 2010-03-09 | 2011-09-15 | Beth Hill | Non-Aqueous High Concentration Reduced Viscosity Suspension Formulations |
US9518128B2 (en) | 2011-12-14 | 2016-12-13 | Janssen Pharmaceuticals, Inc. | Thrombin-binding antibody molecules |
CA2885862A1 (en) * | 2012-10-25 | 2014-05-01 | Medimmune, Llc | Stable, low viscosity antibody formulation |
CA3182876A1 (en) | 2012-11-21 | 2014-05-30 | Janssen Biotech, Inc. | Bispecific egfr/c-met antibodies |
US10653779B2 (en) | 2013-03-13 | 2020-05-19 | Genentech, Inc. | Formulations with reduced oxidation |
WO2016209921A1 (en) | 2015-06-22 | 2016-12-29 | Janssen Biotech, Inc. | Combination therapies for heme malignancies with anti-cd38 antibodies and survivin inhibitors |
RS64263B1 (sr) * | 2015-08-19 | 2023-07-31 | Astrazeneca Ab | Stabilna anti-ifnar1 formulacija |
US20170218092A1 (en) | 2016-01-28 | 2017-08-03 | Janssen Biotech, Inc. | Bispecific Anti-TNF-Alpha/IL17A Antibodies and Anti-TNF-Alpha Antibodies and Methods of Their Use |
WO2018096445A1 (en) * | 2016-11-22 | 2018-05-31 | Biocon Limited | Stable formulation of recombinant humanized monoclonal antibody |
-
2019
- 2019-08-21 US US16/547,237 patent/US20200061015A1/en not_active Abandoned
- 2019-08-22 EP EP24167511.5A patent/EP4371568A3/en active Pending
- 2019-08-22 ES ES19852009T patent/ES2977866T3/es active Active
- 2019-08-22 MA MA053447A patent/MA53447A/fr unknown
- 2019-08-22 EP EP19852009.0A patent/EP3840726B1/en active Active
- 2019-08-22 CN CN201980055399.4A patent/CN112601518A/zh active Pending
- 2019-08-22 KR KR1020217008045A patent/KR20210049842A/ko unknown
- 2019-08-22 WO PCT/IB2019/057079 patent/WO2020039384A1/en unknown
-
2021
- 2021-02-14 IL IL280862A patent/IL280862A/en unknown
-
2022
- 2022-05-02 US US17/734,523 patent/US20220265596A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
KR20210049842A (ko) | 2021-05-06 |
MA53447A (fr) | 2021-09-15 |
EP3840726A4 (en) | 2022-06-08 |
ES2977866T3 (es) | 2024-09-02 |
IL280862A (en) | 2021-04-29 |
EP4371568A2 (en) | 2024-05-22 |
WO2020039384A1 (en) | 2020-02-27 |
EP3840726A1 (en) | 2021-06-30 |
CN112601518A (zh) | 2021-04-02 |
US20220265596A1 (en) | 2022-08-25 |
EP4371568A3 (en) | 2024-09-11 |
EP3840726B1 (en) | 2024-04-03 |
EP3840726C0 (en) | 2024-04-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2731418C2 (ru) | Стабильный фармацевтический препарат на основе антитела к pd-1 и его применение в медицине | |
US9844594B2 (en) | Liquid formulations for an anti-TNF α antibody | |
CA2910065C (en) | Purification of recombinantly produced polypeptides | |
AU2018336623B2 (en) | Methods of reducing particle formation and compositions formed thereby | |
US20220265596A1 (en) | Lipase Degradation Resistant Surfactants for Use in Large Molecule Therapeutic Formulations | |
US20240199688A1 (en) | Methods for reducing lipase activity | |
US11833206B2 (en) | Polysorbate mixtures having modified fatty acid ester distribution | |
Floyd et al. | The Development of a Novel Aflibercept Formulation for Ocular Delivery | |
Roy et al. | A comparison of Polysorbates and Alternative Surfactants for Interfacial Stress Protection and Mitigation of Fatty Acid Particle Formation in the Presence of an Esterase | |
CN117323430A (zh) | 抗pcsk9抗体的制剂及其应用 | |
CN116528906A (zh) | 具有改性脂肪酸酯分布的聚山梨醇酯混合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |