WO2021118321A1 - 안정한 항-pd-1 항체 약제학적 제제 - Google Patents
안정한 항-pd-1 항체 약제학적 제제 Download PDFInfo
- Publication number
- WO2021118321A1 WO2021118321A1 PCT/KR2020/018247 KR2020018247W WO2021118321A1 WO 2021118321 A1 WO2021118321 A1 WO 2021118321A1 KR 2020018247 W KR2020018247 W KR 2020018247W WO 2021118321 A1 WO2021118321 A1 WO 2021118321A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical formulation
- buffer
- formulation
- antibody
- amino acid
- Prior art date
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 7
- 239000000872 buffer Substances 0.000 claims abstract description 111
- 239000012634 fragment Substances 0.000 claims abstract description 38
- 239000003381 stabilizer Substances 0.000 claims abstract description 38
- 239000000427 antigen Substances 0.000 claims abstract description 36
- 102000036639 antigens Human genes 0.000 claims abstract description 36
- 108091007433 antigens Proteins 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims description 172
- 238000009472 formulation Methods 0.000 claims description 127
- 239000008194 pharmaceutical composition Substances 0.000 claims description 103
- 229960002621 pembrolizumab Drugs 0.000 claims description 68
- 229930006000 Sucrose Natural products 0.000 claims description 53
- 239000005720 sucrose Substances 0.000 claims description 53
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 51
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 44
- 150000001413 amino acids Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 29
- 239000004094 surface-active agent Substances 0.000 claims description 29
- 239000003963 antioxidant agent Substances 0.000 claims description 28
- 230000003078 antioxidant effect Effects 0.000 claims description 24
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 22
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 20
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 13
- 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 claims description 13
- 229920005862 polyol Polymers 0.000 claims description 13
- 150000003077 polyols Chemical group 0.000 claims description 13
- 239000000600 sorbitol Substances 0.000 claims description 13
- 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 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000004475 Arginine Substances 0.000 claims description 12
- 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 claims description 12
- 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 claims description 12
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 12
- 239000004472 Lysine Substances 0.000 claims description 10
- 239000004471 Glycine Substances 0.000 claims description 9
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 229930182817 methionine Natural products 0.000 claims description 9
- 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 claims description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 8
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 8
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 8
- 150000005846 sugar alcohols Chemical class 0.000 claims description 7
- 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 claims description 6
- 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 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000008177 pharmaceutical agent Substances 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 5
- 229920000136 polysorbate Polymers 0.000 claims description 5
- 229950008882 polysorbate Drugs 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- -1 sorbitan ester Chemical class 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 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 claims description 3
- 238000010253 intravenous injection Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000010254 subcutaneous injection Methods 0.000 claims description 3
- 239000007929 subcutaneous injection Substances 0.000 claims description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims 1
- 239000013628 high molecular weight specie Substances 0.000 description 59
- 235000006708 antioxidants Nutrition 0.000 description 26
- 230000008859 change Effects 0.000 description 26
- 239000002253 acid Substances 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 238000001542 size-exclusion chromatography Methods 0.000 description 14
- 238000012506 imaged capillary isoelectric focusing Methods 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- 229940074410 trehalose Drugs 0.000 description 10
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 8
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 8
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 239000013627 low molecular weight specie Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000002296 dynamic light scattering Methods 0.000 description 7
- 238000000691 measurement method Methods 0.000 description 7
- 238000010586 diagram Methods 0.000 description 6
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 6
- 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 5
- 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 5
- 229940079593 drug Drugs 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 229930091371 Fructose Natural products 0.000 description 4
- 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 4
- 239000005715 Fructose Substances 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 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 4
- 229960000106 biosimilars Drugs 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229930182830 galactose Natural products 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 238000011105 stabilization Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- 239000011123 type I (borosilicate glass) Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 208000013056 classic Hodgkin lymphoma Diseases 0.000 description 3
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 3
- 239000003398 denaturant Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068977 polysorbate 20 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 208000032818 Microsatellite Instability Diseases 0.000 description 2
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000000533 capillary isoelectric focusing Methods 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 229960004198 guanidine Drugs 0.000 description 2
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000000670 ligand binding assay Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 208000003747 lymphoid leukemia Diseases 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000033607 mismatch repair Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 125000000185 sucrose group Chemical group 0.000 description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- DPVHGFAJLZWDOC-PVXXTIHASA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol;dihydrate Chemical compound O.O.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 DPVHGFAJLZWDOC-PVXXTIHASA-N 0.000 description 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-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
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018338 Glioma Diseases 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
- 108010024636 Glutathione Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 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
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 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
- 229940125385 biologic drug Drugs 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000003508 chemical denaturation Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 238000007796 conventional method Methods 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
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000003168 generic drug Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000000050 ionisation spectroscopy Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 208000037843 metastatic solid tumor Diseases 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000007281 self degradation Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000017572 squamous cell neoplasm Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- GZGWEDQFRVOWFA-UHFFFAOYSA-N sulfo methanesulfonate Chemical compound CS(=O)(=O)OS(O)(=O)=O GZGWEDQFRVOWFA-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- 229940074409 trehalose dihydrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000023747 urothelial carcinoma Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K47/16—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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Definitions
- the present invention relates to a stable anti-PD-1 antibody pharmaceutical formulation and a method for preparing the same.
- the need to develop a stable anti-PD-1 antibody pharmaceutical formulation to enhance drug stability is emerging.
- the anti-PD-1 antibody pharmaceutical formulation contains a buffer, a stabilizer, and a surfactant for drug stability.
- One aspect is (a) an anti-PD-1 antibody or antigen-binding fragment thereof; and (b) a stabilizer, no buffer, and a stable anti-PD-1 antibody pharmaceutical formulation having from about pH 4.5 to about pH 6.5.
- Another aspect is to provide a method of treating cancer in a subject, comprising administering to the subject the pharmaceutical agent as described above.
- Another aspect is to provide a method for preparing the pharmaceutical formulation.
- an anti-PD-1 antibody or antigen-binding fragment thereof comprising (a) an anti-PD-1 antibody or antigen-binding fragment thereof; and (b) a stabilizer, no buffer, and a stable anti-PD-1 antibody pharmaceutical formulation having from about pH 4.5 to about pH 6.5.
- the pharmaceutical preparations do not contain a buffer, but preferably pH 4.5 to pH 6.5 as an environment for preservation of anti-PD-1 antibody, and more preferably about pH 5.0 to pH 5.0 A pH of about 5.5 can be maintained.
- the pH of the pharmaceutical formulation is, for example, pH 4.5 to 6.3, pH 4.8 to 6.3, pH 5 to 6.3, pH 5.2 to 6.3, pH 4.5 to 6.0, pH 4.8 to 6.0, pH 5.0 to 6.0, pH 5.2 to 6.0 , pH 4.5-5.8, pH 4.8-5.8, pH 5.0-5.8, pH 5.2-5.8, pH 4.5-5.6, pH 4.8-5.6, pH 5.0-5.6, pH 5.2-5.6, pH 4.9-5.5, pH 4.9, pH 5.0, pH 5.1, pH 5.2, pH 5.3, pH 5.4, or pH 5.5.
- the pH of the pharmaceutical formulation may be about pH 4.5 to about pH 5.5.
- the pH of the pharmaceutical formulation may be about pH 5.0 to about pH 5.5.
- the pH of the pharmaceutical preparation can be adjusted according to a conventional method known in the art.
- the pH of the pharmaceutical formulation may be adjusted by addition of an acid (eg, HCl) or a base (eg, NaOH), but is not limited thereto.
- antibody refers to any form of antibody that has the activity of specifically binding to PD-1.
- Such antibodies include monoclonal antibodies, polyclonal antibodies, humanized antibodies, human antibodies and chimeric antibodies.
- the antibody may be pembrolizumab.
- antigen-binding fragment refers to a fragment capable of binding to a PD-1 antigen in an anti-PD-1 antibody, including, for example, a Fab fragment, F(ab′) 2 fragment, Fc fragment, or scFv fragment. It is not limited thereto.
- "Pembrolizumab antibody” is a humanized antibody used in cancer immunotherapy, sold under the name KEYDTRUDA ® under one of several trade names.
- Pembrolizumab is indicated for melanoma, lung cancer including non-small cell lung cancer (NSCLC), head and neck cancer including head and neck squamous cell cancer (HNSCC), classic Hodgkin's lymphoma Hodgkin's lymphoma, including classical Hodgkin Lymphoma (cHL), urothelial carcinoma, renal cell carcinoma, gastric cancer, microsatellite instability-high cancer (MSI-H), mismatch repair deficient; dMMR) can be used to treat solid cancer, cervical cancer, liver cancer, Merkel cell carcinoma (MCC), and the like.
- the pembrolizumab may also include a biosimilar or biobetter of the active pembrolizumab present in commercially available Keytruda.
- Pembrolizumab is to include a heavy chain variable region comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 3, and a light chain variable region comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 4 to 6 can
- Pembrolizumab is a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 1 (NYYMY), a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 2 (GINPSNGGTNFNEKFK), and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 3 (RDYRFDMGFDY), and SEQ ID NO: It may include a light chain CDR1 having an amino acid sequence of 4 (RASKGVSTSGYSYLH), a light chain CDR2 having an amino acid sequence of SEQ ID NO: 5 (LASYLES), and a light chain CDR3 having an amino acid sequence of SEQ ID NO: 6 (QHSRDLPLT).
- Pembeu Raleigh jumap may be one that comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 8 light chain variable region having the amino acid sequence of (VQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTL
- biosimilar is also referred to as a biosimilar. Since biopharmaceuticals are produced through cells rather than synthesized chemical products, the same product as an original drug cannot be copied like a generic. Therefore, a generic drug for a biopharmaceutical is called a biosimilar in the sense that it is similar to, but not identical to, the original drug.
- biobetter is a drug that has improved efficacy, safety, and convenience based on an original biologic drug. It is called biobetter, meaning that it is better than existing biopharmaceuticals. Biobetters can be manufactured using biotechnology such as genetic recombination technology and cell culture technology.
- Pembrolizumab targets the programmed cell death protein 1 (PD-1) receptor on lymphocytes.
- Pembrolizumab is an IgG 4 isotype antibody that blocks the protective mechanism of cancer cells, allowing the immune system to destroy cancer cells.
- Pembrolizumab was approved for medicinal use in the United States in 2014.
- pembrolizumab was approved in 2017 for unresectable or metastatic solid tumors with certain genetic anomalies, such as mismatch repair deficiency or microsalterite instability. .
- pembrolizumab may be used alone or in combination with other chemotherapeutic agents.
- Pembrolizumab may be administered by intravenous or subcutaneous injection.
- Pembrolizumab can be produced by a general method known in the art. For example, US 9,834,605 and WO 2008/156712A1 describe methods that one of ordinary skill in the art can use to prepare pembrolizumab. For example, pembrolizumab can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell.
- the anti-PD-1 antibody eg, pembrolizumab or antigen-binding fragment thereof, has a buffering function against pH in aqueous solution.
- the concentration of the anti-PD-1 antibody for example, pembrolizumab or an antigen-binding fragment thereof, may be an amount suitable to provide a buffering function corresponding to pH 4.5 to pH 6.5.
- the concentration of the anti-PD-1 antibody for example, pembrolizumab or an antigen-binding fragment thereof, may be an amount effective for the treatment of cancer.
- the concentration of the anti-PD-1 antibody, for example, pembrolizumab or an antigen-binding fragment thereof may be selected in consideration of stability, viscosity, and the like of the pharmaceutical formulation.
- the concentration of the anti-PD-1 antibody is, for example, 5-300 mg/mL, 5-250 mg/mL, 5-200 mg/mL, 10- 200 mg/mL, 10-165 mg/mL, 15-160 mg/mL, 5-45 mg/mL, 10-40 mg/mL, 15-35 mg/mL, 20-30 mg/mL, 130-250 mg/mL, 135-200 mg/mL, 135-170 mg/mL, 140-160 mg/mL, 145-155 mg/mL, about 25 mg/mL, about 150 mg/mL, about 200 mg/mL, or about 250 mg/mL.
- the anti-PD-1 antibody for example, pembrolizumab or an antigen-binding fragment thereof, may contribute to the stability of the pharmaceutical formulation at the concentration, and the maintenance of viscosity and pH of the pharmaceutical formulation suitable for administration.
- stabilizer refers to a substance added to prevent state change or chemical change when the substance is left or preserved.
- the stabilizer may be at least one selected from the group consisting of polyols, amino acids, and metal salts.
- polyol refers to an excipient having a plurality of hydroxyl groups.
- the polyol may include a sugar, a sugar alcohol, and a sugar acid.
- the sugar represents a soluble carbohydrate.
- the sugar may be a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide.
- the sugar alcohol is an organic compound derived from sugar, and each carbon atom has one hydroxyl group.
- the sugar acid refers to a sugar having a carboxyl group on one or both sides of the chain.
- the polyol may be one or more selected from glucose, fructose, mannose, galactose, sucrose, lactose, maltose, trehalose, mannitol, sorbitol, and polyethylene glycol.
- the polyol may be sorbitol, sucrose, trehalose, mannose, maltose, mannitol, or a mixture thereof.
- the polyol includes an anhydride of a polyol.
- trehalose may include trehalose as well as trehalose dihydrate.
- the concentration of the polyol can be freely adjusted within a range desirable for maintaining the stability of the anti-PD-1 antibody, for example, pembrolizumab or an antigen-binding fragment thereof, and the viscosity of the liquid pharmaceutical formulation in the pharmaceutical formulation, , may vary individually for each specific polyol, sugar alcohol or sugar acid.
- the sugar concentration is 1.0 to 15.0% (w / v), 3.0 to 15.0% (w / v), 5.0 to 15.0% (w / v), 7.0 to 15.0% (w / v), 1.0 to 10.0% (w) /v), 3.0 to 10.0% (w/v), 4.0 to 10.0% (w/v), 5.0 to 10.0% (w/v), 7.0 to 10.0% (w/v), 1.0 to 7.0% (w) /v), 2.0 to 7.0% (w/v), 3.0 to 7.0% (w/v), 4.0 to 7.0% (w/v), 1.0 to 5.0% (w/v), 2.0 to 5.0% (w) /v), 3.0-5.0% (w/v), 4.0-5.0% (w/v), 4.5-5.0% (w/v) (eg, about 4.7% (w/v)), 6.5-8.5% (w/v) (eg, about 6.8% (w/v), about 7.0% (w/v), about 7.2% (w/v)) or 7.8 to 8.2% (w
- the sugar may be, for example, sucrose, glucose, galactose, maltose, fructose, trehalose, or a mixture thereof.
- the sugar is 1.0 to 15.0% (w/v), 4.0 to 10.0% (w/v), 6.0 to 8.0% (w/v), or about 7.0% (w/v) sucrose can be
- the sugar is 1.0 to 15.0% (w/v), 4.0 to 10.0% (w/v), 7.0 to 8.0% (w/v), or about 7.6% (w/v) trehaloseyl can
- the concentration of the sugar alcohol is 1.0 to 20.0% (w / v), for example, 1.0 to 15.0% (w / v), 1.0 to 10.0% (w / v), 2.5 to 10.0% (w / v), 3.0 to 10.0% (w/v), 3.5 to 10.0% (w/v), 4.0 to 10.0% (w/v), 1.0 to 8.0% (w/v), 2.5 to 8.0% (w/v), 3.0 to 8.0% (w/v), 3.5 to 8.0% (w/v), 4.0 to 8.0% (w/v), 1.0 to 6.0% (w/v), 2.5 to 6.0% (w/v), 3.0 to 6.0% (w/v), 3.5 to 6.0% (w/v), 4.0 to 6.0% (w/v), 4.0 to 5.5% (w/v), or 4.0 to 5.0% (w/v) can be
- the sugar alcohol may be, for example, sorbitol, mannitol, a hydrate thereof, or a mixture thereof. In one embodiment, the sugar alcohol may be about
- the amino acids are glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, pharmaceuticals thereof It may be a scientifically acceptable salt, or a mixture thereof.
- the amino acid may be, for example, glycine, proline, phenylalanine, tyrosine, tryptophan, lysine, arginine, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the amino acid may be arginine, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the amino acid may be proline, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the amino acid may be lysine, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the amino acid may be arginine, lysine, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the concentration of the amino acid as the stabilizer is 0.1 to 300.0 mM, 0.5 to 300.0 mM, 1.0 to 300.0 mM, 5.0 to 300.0 mM, 10.0 to 300.0 mM, 25.0 to 300.0 mM, 30.0 to 300.0 mM, 50.0 to 300.0 mM, 80.0 to 300.0 mM, 100.0 to 300.0 mM, 120.0 to 300.0 mM, 0.1 to 250.0 mM, 0.5 to 250.0 mM, 1.0 to 250.0 mM, 5.0 to 250.0 mM, 10.0 to 250.0 mM, 25.0 to 250.0 mM, 30.0 to 250.0 mM, 50.0 to 250.0 mM, 80.0 to 250.0 mM, 100.0 to 250.0 mM, 120.0 to 250.0 mM, 0.1 to 200.0 mM, 0.5 to 200.0 mM, 1.0 to 200.0 mM, 5.0 to 200.0 mM, 10.0 to 200.0 mM,
- the amino acid is 1.0 to 10.0 mM, 1.0 to 5.0 mM, 2.0 to 10.0 mM, 2.0 to 5.0 mM, 2.0 to 4.0 mM, or about 3.3 mM arginine, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. It may be a mixture. In another embodiment, the amino acid may be 24-29 mM glycine, a pharmaceutically acceptable salt thereof, or a mixture thereof. The concentration of the amino acid is freely adjusted within a range that does not affect the desired pH of the pharmaceutical formulation and does not affect the stability of the anti-PD-1 antibody, for example, pembrolizumab or an antigen-binding fragment thereof. and may vary individually for each specific amino acid.
- the metal salt may be NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4 , NaSCN, CaCl 2 , MgCl 2 , or K 2 SO 4 .
- the metal salt may be, for example, NaCl or Na 2 SO 4 .
- the concentration of the metal salt is 1.0 to 300.0 mM, 5.0 to 150.0 mM, 10.0 to 150.0 mM, 30.0 to 150.0 mM, 50.0 to 150.0 mM, 80.0 to 150.0 mM, 100.0 to 150.0 mM, 120.0 to 150.0 mM, 5.0 to 125.0 mM, 10.0 to 125.0 mM, 30.0 to 125.0 mM, 50.0 to 125.0 mM, 80.0 to 125.0 mM, 100.0 to 125.0 mM, 120.0 to 125.0 mM, 5.0 to 100.0 mM, 10.0 to 100.0 mM, 30.0 to 100.0 mM, 50.0 to 100.0 mM, 80.0 to 100.0 mM, 5 to 80.0 mM, 10.0 to 80.0 mM, 30.0 to 80.0 mM, or 50.0 to 80.0 mM.
- the metal salt may be 5.0 to 150.0 mM, 20.0 to 140.0 mM, or about 100.0 mM sodium chloride.
- concentration of the metal salt in the pharmaceutical formulation of the present invention can be freely adjusted within the range of maintaining the stability of the anti-PD-1 antibody, for example, pembrolizumab or an antigen-binding fragment thereof, and not precipitating it, and each specific It may vary individually depending on the metal salt.
- the stabilizer may be a mixture of polyols and amino acids. When a mixture of a polyol and an amino acid is used, the amino acid may act as one or more of a stabilizer and a viscosity reducing agent.
- a pharmaceutical formulation provided herein is 'free of component A' may mean that the pharmaceutical formulation is free or substantially free of component A.
- 'Substantially free of component A' means no component A at all, or even if component A is present, is present in a trace amount that does not substantially affect the properties of the pharmaceutical formulation, or is detected. It may be construed as including the case where it is present in an impossible amount.
- the pharmaceutical formulation does not contain a separate buffer other than an anti-PD-1 antibody, eg, pembrolizumab or an antigen-binding fragment thereof.
- buffer refers to a composition to which a pharmaceutical agent is added to resist pH change.
- the buffer can maintain the pH of the formulation within an acceptable range.
- the buffer generally renders the agent resistant to changes in pH by the action of its acid-base conjugate component.
- concentration of a buffer when referred to, the stated concentration refers to the molar concentration of the free acid or free base form of the buffer.
- buffer-free indicates that the pharmaceutical formulation does not contain a buffer to such an extent that it resists changes in pH.
- the buffer may be histidine, phosphoric acid (sodium phosphate or potassium phosphate), maleic acid, tartaric acid, succinic acid (succinate), citric acid (citrate), acetic acid (acetate), carbonic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the buffer may be histidine, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the buffer may be phosphoric acid, a pharmaceutically acceptable salt thereof, or a mixture thereof.
- the pharmaceutical formulation may not include a surfactant or may further include a surfactant.
- the surfactant may be a nonionic surfactant.
- the nonionic surfactant may be a polysorbate, a poloxamer, a sorbitan ester of another fatty acid, or a mixture thereof.
- the polysorbate may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof.
- the poloxamer may be poloxamer 188.
- the concentration of the surfactant is 0.001 to 1% (w/v), 0.001 to 0.5% (w) based on the total volume of the pharmaceutical formulation or the reconstituted formulation.
- the pharmaceutical formulation comprises 0.02 to 0.04% (w/v) of polysorbate 20, or polysorbate 80.
- the pharmaceutical formulation may further include an antioxidant.
- the term “antioxidant” means a substance that prevents oxidation.
- the antioxidant may be an amino acid, vitamin, coenzyme, glutathione, methylsulfonyl sulfate, or a mixture thereof.
- the amino acid as the antioxidant may be methionine, L-cysteine, L-carnitine, or a mixture thereof.
- the vitamin as the antioxidant may be vitamin A, vitamin C, vitamin E, or a mixture thereof.
- the coenzyme may be coenzyme Q10. In one embodiment, the antioxidant may be methionine.
- the concentration of the antioxidant can be freely adjusted within a range desired for maintaining the stability of the anti-PD-1 antibody, for example, pembrolizumab or an antigen-binding fragment thereof, in the pharmaceutical formulation, and each specific antioxidant It may vary individually depending on the type.
- the concentration of the antioxidant is 1 to 70 mM, 1 to 50 mM, 1 to 30 mM, 5 to 50 mM, 5 to 30 mM, 1 to 20 mM, 1 to 15 mM, 1-10 mM, 1-5 mM, 3-20 mM, 3-15 mM, 3-10 mM, 3-7 mM, 20-60 mM, 30-50 mM, about 5 mM, about 20 mM , about 30 mM, about 40 mM, or about 50 mM.
- the pharmaceutical formulation comprises about 5 mM methionine.
- the pharmaceutical formulation comprises about 30 mM methionine.
- the pharmaceutical formulation comprises about 50
- the pharmaceutical formulation may be a liquid.
- the pharmaceutical formulation may be for subcutaneous injection or intravenous injection.
- the pharmaceutical formulation may further comprise an aqueous carrier suitable for injection.
- the aqueous carrier is pharmaceutically acceptable, which is safe and non-toxic when administered to humans, and may be, for example, water, saline solution, Ringer's solution, dextrose, or a mixture thereof.
- the pharmaceutical formulation may have an osmotic pressure in an appropriate range when injected subcutaneously or intravenously.
- the osmotic pressure is, for example, 200 to 400 mOsm/kg, 200 to 350 mOsm/kg, 250 to 300 mOsm/kg, 250 to 290 mOsm/kg, 270 to 328 mOsm/kg, 250 to 269 mOsm/kg, or 328 to 350 mOsm/kg.
- the osmotic pressure may be appropriately adjusted to minimize pain that may occur during administration.
- the pharmaceutical formulation may have a viscosity in an appropriate range when injected subcutaneously or intravenously.
- the viscosity is, for example, 0.5 to 100 cp, 0.5 to 90 cp, 0.5 to 80 cp, 0.5 to 70 cp, 0.5 to 60 cp, 0.5 to 50 cp, 0.5 to when measured at room temperature of 25 °C ⁇ 3 °C. 40 cp, 0.5 to 30 cp, 0.5 to 20 cp, 0.5 to 15 cp, or 0.5 to 10 cp.
- the viscosity may be appropriately adjusted to minimize pain that may occur during administration.
- the concentration of the anti-PD-1 antibody, for example, pembrolizumab or an antigen-binding fragment thereof, in the pharmaceutical formulation is 5-300 mg/mL, 5-250 mg/mL, 5-200 mg/mL, 15-30 mg/mL, or 150-250 mg/mL, wherein the stabilizer is sucrose, glucose, galactose, maltose, fructose, trehalose, sorbitol, mannitol, arginine, lysine, proline, glycine, phenylalanine , tyrosine, tryptophan, a hydrate thereof, a pharmaceutically acceptable salt thereof, a mixture thereof, or a metal salt, and the pH of the pharmaceutical preparation may be pH 4.5 to pH 6.5, pH 5.0 to pH 5.5.
- the stabilizer is sucrose, glucose, galactose, maltose, fructose, trehalose, a hydrate thereof, or a mixture thereof, and the concentration of the stabilizer is 1.0 to 15.0% (w/v), 3.0 to 15.0% (w/v), 5.0 to 15.0% (w/v), 7.0 to 15.0% (w/v), 1.0 to 10.0% (w/v), 3.0 to 10.0% (w/v), 5.0 to 10.0% (w/v), 7.0 to 10.0% (w/v), 1.0 to 7.0% (w/v), 2.0 to 7.0% (w/v), 3.0 to 7.0% (w/v), 4.0 to 7.0% (w/v), 1.0-5.0% (w/v), .02-5.0% (w/v), 3.0-5.0% (w/v), 4.0-5.0% (w/v), 4.5 to 5.0% (w/v) (eg, about 4.7% (w/v)), or 7.8 to 8.2% (w/v) (eg, about 7.8%
- the stabilizer is sorbitol, mannitol, a hydrate thereof, or a mixture thereof, and the concentration of the stabilizer is 1.0 to 20.0% (w/v), for example, 1.0 to 15.0% (w/v), 1.0 to 10.0%.
- the stabilizer is arginine, lysine, proline, glycine, phenylalanine, tyrosine, tryptophan, a hydrate thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, and the concentration of the stabilizer is 0.1 to 300.0 mM, 0.5 to 300.0 mM , 1.0-300.0 mM, 5.0-300.0 mM, 10.0-300.0 mM, 25.0-300.0 mM, 30.0-300.0 mM, 50.0-300.0 mM, 80.0-300.0 mM, 100.0-300.0 mM, 120.0-300.0 mM, 0.1-250.0 mM , 0.5 to 250.0 mM, 1.0 to 250.0 mM, 5.0 to 250.0 mM, 10.0 to 250.0 mM, 25.0 to 250.0 mM, 30.0 to 250.0 mM, 50.0 to 250.0 mM, 80.0 to 250.0 mM, 100.0 to 250.0 mM, 120.0 to 250.0
- the stabilizer is from about 1.0 to about 15.0% (w/v) sucrose, trehalose, a hydrate thereof, or a mixture thereof; and about 0.1 to about 300.0 mM of arginine, lysine, proline, glycine, phenylalanine, tyrosine, tryptophan, a pharmaceutically acceptable salt thereof, or a mixture thereof;
- the stabilizer is from about 1.0 to about 20.0% (w/v) of sorbitol, mannitol, a hydrate thereof, or a mixture thereof; and about 0.1 to about 300.0 mM of arginine, lysine, proline, glycine, phenylalanine, tyrosine, tryptophan, a pharmaceutically acceptable salt thereof, or a mixture thereof;
- the pharmaceutical formulation may further include a surfactant.
- the surfactant may be a polysorbate or a poloxamer.
- the polysorbate may be polysorbate 20 or polysorbate 80.
- the concentration of surfactant is 0.001 to 1% (w / v), 0.001 to 0.5% (w / v), 0.001 to 0.1% (w / v), 0.001 to 0.05% (w / v), 0.001 to 0.02% ( w/v), 0.005 to 1% (w/v), 0.005 to 0.5% (w/v), 0.005 to 0.1% (w/v), 0.005 to 0.05% (w/v), 0.005 to 0.02% ( w/v), 0.008 to 1% (w/v), 0.008 to 0.5% (w/v), 0.008 to 0.1% (w/v), 0.008 to 0.05% (w/v), 0.008 to 0.1% (w/v), 0.008 to 0.05% (w/v), 0.00
- the pharmaceutical formulation may further include an antioxidant.
- the antioxidant may be methionine.
- the concentration of methionine is 1 to 70 mM, 1 to 50 mM, 1 to 30 mM, 5 to 50 mM, 5 to 30 mM, 1 to 20 mM, 1 to 15 mM, 1 to 10 mM, 1 to 5 mM, 3 to 20 mM, 3 to 15 mM, 3 to 10 mM, 3 to 7 mM, 20 to 60 mM, 30 to 50 mM, about 5 mM, about 20 mM, about 30 mM, about 40 mM, or about 50 mM can
- the anti-PD-1 antibody for example, pembrolizumab or an antigen-binding fragment thereof may be stabilized.
- stabilization means that the anti-PD-1 antibody, e.g., pembrolizumab or an antigen-binding fragment thereof, is subjected to its physical stability, chemical stability and / or substantially retaining biological activity. Physical stability, chemical stability and/or biological activity can be evaluated by commonly known methods.
- the stability of the anti-PD-1 antibody or antigen-binding fragment thereof may satisfy one or more of the following.
- Stability may be measured at a selected temperature and for a selected period of time.
- a stable formulation is a formulation in which no significant change is observed for 12 months or longer at 2-8°C.
- a stable formulation is a formulation in which no significant change is observed for 18 months or longer at 2-8°C.
- a stable formulation is a formulation in which no significant change is observed for 3 months or more at 23-27°C.
- a stable formulation is a formulation in which no significant change is observed for 6 months or longer at 23-27°C.
- a stable formulation is a formulation in which no significant change is observed for 12 months or longer at 23-27°C.
- a stable formulation is a formulation in which no significant change is observed for 18 months or longer at 23-27°C.
- the stability criteria for antibody formulations are as follows. As determined by SE-HPLC, 10% or less, eg, 5% or less, or 2.5% or less of the antibody monomer is degraded. Antibody potency is within 60-140%, or 80-120% of a control or standard antibody. For example, when the low molecular weight species (LMW) is measured by SE-HPLC, the antibody may have a change of 10% or less, 5% or less, or 2.5% or less. For example, when the high molecular weight species (HMW) is measured by SE-HPLC, the antibody may have a change of 10% or less, 5% or less, or 2.5% or less. In addition, the concentration and pH of the formulation may have a change of ⁇ 10% or less, ⁇ 5% or less, or ⁇ 2.5% or less.
- HMW or pH within the range of 10% or less, 5% or less, or 2.5% or less it will change
- the pharmaceutical formulation is placed in a 2cc vial made of type I glass (Schott) by 0.3 to 1mL, the vial is mounted on a stirrer (Heidolph) and stirred at room temperature at 400 rpm for 72 hours, 10% or less , 5% or less, or 2.5% or less HMW or pH change.
- a stirrer Heidolph
- the pembrolizumab or antigen-binding fragment thereof retains chemical stability in the pharmaceutical formulation if it is chemically stable for a given period of time that appears to still retain biological activity. Chemical stability can be assessed by detecting and quantifying the chemically modified form of pembrolizumab.
- Chemical modifications include size modifications or charge changes. The charge change may be, for example, a charge change that occurs as a result of deamidation.
- the size modification was performed by size exclusion chromatography (SE-HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary electrophoresis-sodium dodecyl sulfate (CE-SDS).
- PD-1 ligand binding assay may be performed by enzyme-linked immuonsorbent assay (ELISA). The ELISA assay measures the percentage (%) binding of pembrolizumab to PD-1 ligand. After reacting the pembrolizumab sample with the PD-1 ligand on the ELISA substrate, the degree of binding can be obtained by measuring the absorbance at 450 nm to obtain a relative binding rate.
- the anti-PD-1 antibody eg, pembrolizumab or antigen-binding fragment thereof, retains biological activity in the pharmaceutical formulation.
- the biological activity is, for example, within about 30%, about 20%, or about 10% of the biological activity of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical formulation at the time of manufacture of the pharmaceutical formulation. (or within assay error) retains biological activity.
- the biological activity can be determined, for example, in an antigen binding assay.
- Stabilization is determined by temperature stress, e.g., 1 to 4 weeks at 40 °C, freeze-thaw stress, e.g., 5 repetitions of a cycle of -70 °C freezing and thawing at room temperature, or stirring stress, e.g. , by measuring %HMW, % monomer and/or %LMW using size-exclusion-high-speed liquid chromatography (Size-Exclusion HPLC, SE-HPLC) by applying 400 rpm rotational force for 72 hours on a stirrer.
- the pharmaceutical formulation of the present invention may have equal or less ⁇ %HMW, ⁇ %LMW, or ⁇ %monomer values compared to Keytruda ®.
- Stabilization can also be assessed by measuring the % Acidic change using image capillary isoelectric focusing (icIEF) by applying temperature stress, freeze-thaw stress, or stirring stress.
- icIEF image capillary isoelectric focusing
- the pharmaceutical formulation of the present invention may have a ⁇ % acidity value equal to or less than that of Keytruda ®.
- the amount of change in %HMW measured by conventional SEC that is, the %HMW value of %HMW-0 weeks after 4 weeks, may be 10.0% or less, 5.0% or less, or 2.5%.
- the stable pharmaceutical formulation provided herein has an antibody content of 25 mg/ml (pH 5.5 or pH 5.0)
- the formulation is placed in a polypropylene microtube, stored at 40° C. for 4 weeks, and using icIEF
- the measured change in % acidity that is, the % acidity value of 0 weeks after 4 weeks, may be 20.0% or less, 15.0% or less, or 10.0% or less.
- the pharmaceutical agent comprises (i) an anti-PD-1 antibody or antigen-binding fragment thereof; (ii) a stabilizer, and (iii) a buffer excluding histidine, and having a pH of about 4.5 to about 6.5.
- the buffer other than histidine may be succinate, citrate, acetate, phosphate, or a combination thereof.
- Another aspect provides a method of treating cancer with the pharmaceutical agent described above.
- the pharmaceutical formulation is the same as described above.
- the method of treating cancer may include administering to the subject a pharmaceutical agent in an amount effective to treat the cancer.
- the subject may be a human.
- cancer refers to or describes a pathological condition in a mammal that is typically characterized by upregulated cell growth.
- cancers include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma.
- Said cancer is, for example, squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, gastrointestinal or gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic Leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer , colon carcinoma, Merkel cell cancer, high frequency microsatellite instability cancer, esophageal cancer, urothelial cancer, primary mediastinal giant B-cell lymphoma, and head and neck cancer.
- squamous cell carcinoma myeloma
- small cell lung cancer non
- Another aspect is to prepare a mixed solution by adding a stabilizer to the solvent; and adding an anti-PD-1 antibody or antigen-binding fragment thereof to the mixed solution; or adding an anti-PD-1 antibody or antigen-binding fragment thereof to a solvent to prepare a solution of the anti-PD-1 antibody or antigen-binding fragment thereof; and adding a stabilizing agent to the solution; as a method for preparing a stable pharmaceutical formulation comprising a, wherein the manufacturing step provides a method that is performed without adding a buffer.
- the solvent may be an aqueous solvent, for example, water or saline.
- the method may further include adding a surfactant to the mixed solution to which the anti-PD-1 antibody or antigen-binding fragment thereof is added.
- the method may further include adding an antioxidant to the mixed solution to which the anti-PD-1 antibody or antigen-binding fragment thereof is added.
- the method may further comprise adjusting the pH of the formulation to about pH 4.5 to about pH 5.5, about pH 5.5, or about pH 5.0.
- the anti-PD-1 antibody may be stably maintained without including a buffer.
- cancer can be effectively treated in an individual.
- 1 is a diagram showing ⁇ %HMW of a formulation after 4 weeks of temperature stress applied to a formulation with a different buffer.
- T agg values for formulations with different buffer-free or histidine buffer and surfactant contents.
- 3 is a diagram showing the ratio (348/332) according to the change in denaturant concentration measured for the buffer-free and 20 mM histidine-containing formulation.
- 4 is a diagram showing ⁇ %HMW of the formulation after 4 weeks of temperature stress for formulations with different buffer and PS80 contents.
- the purity of the samples was checked by size exclusion chromatography.
- size exclusion chromatography the percentages of antibody monomers, high molecular weight species (HMW), and low molecular weight species (LMW) are determined.
- LMW elutes later than HMW. The presence of HMW indicates protein aggregate and the presence of LMW indicates protein fragments.
- each sample was diluted with each buffer and loaded into the wells of a 96-well plate.
- the plate was loaded into a DynoPro ® Plate Reader TM II (Wyatt Technology) instrument.
- the size of the sample was measured through dynamic light scattering (DLS) for aggregates in the pharmaceutical formulation while raising the temperature in the range of 25 to 70° C. at a rate of 0.15° C./min.
- DLS dynamic light scattering
- the HUNKY device (HUNKY, Unchained Labs.) is a device that can check protein stability through chemical denaturation, and the device can check C 1/2 , ⁇ G, AggPath, and ⁇ G trend values using a denaturant and a sample. .
- C 1/2 ranks stability.
- ⁇ G quantifies stability.
- AggPath predicts aggregation.
- the ⁇ G trend details the aggregation.
- the % acidic value of the sample was measured using icIEF. Specifically, each sample was placed in a 1.5 mL microtube made of polypropylene, and the tube was exposed to a temperature stress condition of 40° C. in a stability thermostat for 4 weeks. The sample was injected into the iCE3 system (Protein Simple, USA), and the charge shift value of the protein was measured using the iCE CFR software. The % acidity represents the charge shift value of the protein. Measuring them identifies a charge variant of the protein. When a protein changes under stress, aggregation occurs or the charge changes. Therefore, the charge variation of a protein can be one factor confirming its stability.
- a buffer solution was prepared by adding a buffer and a stabilizer except for pembrolizumab and a surfactant to sterile distilled water in the composition of each pharmaceutical formulation described in Table 1.
- a dialysis cassette Slide-A-Lyzer cassette, Thermo Fisher Scientific
- the surfactant PS80 in the prepared buffer solution was added to the pembrolizumab solution at a concentration of 1x. Thereafter, each solution was used to adjust the concentration of pembrolizumab to a final 25 mg/mL.
- composition 1A 1 Buffer free
- 7% sucrose, pH 5.5 1B Buffer Free, 7% Sucrose, 0.02% PS80 pH 5.5 1C Buffer Free, 7% Sucrose, 0.10% PS80, pH 5.5 1D Buffer Free, 7% Sucrose, 0.20% PS80, pH 5.5 2A 2 (histidine buffer) 20 mM histidine, 7% sucrose, pH 5.5 2B 20 mM histidine, 7% sucrose, 0.02% PS80, pH 5.5 2C 20 mM histidine, 7% sucrose, 0.10% PS80, pH 5.5 2D 20 mM histidine, 7% sucrose, 0.20% PS80, pH 5.5 2E 40 mM histidine, 7% sucrose, pH 5.5 2F 40 mM histidine, 7% sucrose, 0.02% PS80, pH 5.5 2G 40 mM histidine, 7% sucrose, 0.10% PS80, pH 5.5 2H 40 mM histidine, 7%
- the effect of the buffer on the stability of the pharmaceutical formulation containing pembrolizumab was confirmed. Specifically, after temperature stress was applied to formulations 1A, 2I, 3A, 4A, and 5A, the purity of the samples was measured.
- 0.3 mL of each of the formulations was placed in a 2cc vial made of type I glass, and the vial was exposed to a temperature stress condition of 40° C. in a stability thermostat for 4 weeks. Specifically, the vial was placed in the stability thermostat and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 4 weeks. SEC analysis was performed as described above for formulations stored for 4 weeks.
- Table 2 is a table showing the purity of the formulations with different buffers and the formulations subjected to temperature stress for 4 weeks as HMW content.
- 1 is a diagram showing ⁇ %HMW of the formulation after 4 weeks of temperature stress for formulations with different buffers.
- the average ⁇ %HMW value of the formulation containing the buffer and the ⁇ %HMW value of the formulation without the buffer at 4 weeks were 0.64% and 0.39%, respectively, and the formulation without the buffer was It was more stable than the formulation containing buffer.
- Example 2 Effect of buffer and surfactant content on stability of pembrolizumab-containing pharmaceutical formulation
- T agg values were measured by DLS measurement.
- Table 3 is a table showing the composition of formulations with different buffer-free or histidine buffer and surfactant PS80 contents and T agg measurements thereof.
- 2 is a diagram showing T agg values for formulations with different buffer-free or histidine buffer and surfactant contents.
- the T agg value of the formulation without or containing 0.02% of the surfactant PS80 was higher than the T agg value of the formulation containing 0.10% or 0.20% of the surfactant PS80.
- formulations containing a low content of PS80 of less than 0.10% i.e., 1A, 1B, 2A, 2B, 2E, and 2F
- the HUNKY measurement method measures the stability to chemical stress through guanidine-HCl (Guanidine-HCl, Gdn-HCl). Specifically, the HUNKY measurement method measures the absorbance intensity ratio, that is, the ratio (348/332) at 348 nm and 332 nm in a concentration gradient of 0 to 5.5 M Gdn-HCl. This ratio increases as the protein denatures.
- Table 4 is a table showing the composition of the buffer-free and 20 mM histidine-containing formulations and the ⁇ G values measured therefor.
- 3 is a view showing the ratio (348/332) according to the change in the concentration of the denaturant measured for the buffer-free and 20 mM histidine-containing formulations.
- the effect of the buffer and surfactant content on the stability of the pharmaceutical formulation containing pembrolizumab was confirmed. Specifically, after temperature stress was applied to the formulations 1A, 1B, 1C, 1D, 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2H, the purity of the sample was measured by SEC.
- 0.3 mL of each of the formulations was placed in a 2cc vial made of type I glass, and the vial was exposed to a temperature stress condition of 40° C. in a stability thermostat for 4 weeks. Specifically, the vial was placed in the stability thermostat and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 4 weeks. SEC analysis was performed as described above for formulations stored for 4 weeks.
- Table 5 is a table showing the composition of the formulation with different buffer and PS80 contents and the purity of the formulation subjected to temperature stress for 4 weeks as HMW content.
- 4 is a diagram showing ⁇ %HMW of the formulation after 4 weeks of temperature stress for formulations with different buffer and PS80 contents.
- the average ⁇ %HMW value of the formulation containing 20 mM histidine buffer and the ⁇ %HMW value of the formulation without the buffer at 4 weeks were 0.51% and 0.42%, respectively, without buffer.
- the untreated formulation was more stable than the formulation containing 20 mM histidine buffer.
- the average ⁇ %HMW value of the formulation containing 40 mM histidine buffer was 0.80%, showing the lowest stability.
- the ⁇ %HMW value of the formulation without PS80 i.e., 2A
- the ⁇ %HMW value of the formulation without PS80 was the lowest compared to the ⁇ %HMW values of the formulations containing PS80, i.e., 2B, 2C, and 2D.
- the ⁇ %HMW value of the formulation without PS80 that is, 3A
- the ⁇ %HMW value of the formulation without PS80 was the lowest compared to the ⁇ %HMW values of the formulations containing PS80, ie, 3B, 3C, and 3D. This indicates that the formulation containing the buffer and PS80 free is more stable compared to the formulation containing the buffer and PS80.
- Table 6 is a table showing the results of measuring the pH of the samples left for 4 weeks under 40 °C temperature stress conditions.
- each pharmaceutical formulation listed in Table 7 was prepared in the same manner as above.
- Pembrolizumab buffer stabilizer Surfactants pH 2I 25 mg/ml 10 mM histidine 7% sucrose 0.02% PS80 5.5 6A 25 mg/ml - 7% sucrose 0.02% PS80 5.5 6B 25 mg/ml 10 mM histidine 7% sucrose 0.02% PS80 5.0 6C 25 mg/ml - 7% sucrose 0.02% PS80 5.0
- Table 8 is a table showing the presence or absence of a buffer and the purity of the formulation with different pH as HMW content.
- the buffer-free formulation had a lower %HMW value compared to the buffer-containing formulation.
- the pH 5.0 formulation had a lower %HMW value compared to the pH 5.5 formulation.
- the formulation at pH 5.0 without buffer had the lowest %HMW value. Therefore, it was confirmed that the buffer-free formulation was more stable than the buffer-containing formulation, the pH 5.0 formulation was more stable than the pH 5.5 formulation, and the pH 5.0 formulation without the buffer had the best stability.
- Table 9 is a table showing the % acidity values of formulations with different pH and presence of buffers.
- the buffer-free formulation had a lower % acidity value than the buffer-containing formulation.
- the pH 5.0 formulation had a lower % acidity value compared to the pH 5.5 formulation.
- the formulation at pH 5.0 without buffer had the lowest % acidity value. Therefore, it was confirmed that the buffer-free formulation was more stable than the buffer-containing formulation, the pH 5.0 formulation was more stable than the pH 5.5 formulation, and the pH 5.0 formulation without the buffer had the best stability.
- each pharmaceutical formulation listed in Table 10 was prepared in the same manner as above.
- Pembrolizumab buffer stabilizer Surfactants antioxidant pH 7A 25 mg/ml - 7% sucrose 3.3 mM Arg 0.02% PS80 5.0 mM Met 5.0 7B 25 mg/ml - 4% sorbitol 3.3 mM Arg 0.02% PS80 5.0 mM Met 5.0 7C 25 mg/ml - 7.6% Trehalose 3.3 mM Arg 0.02% PS80 5.0 mM Met 5.0 6A 25 mg/ml 10 mM histidine 7% sucrose - 0.02% PS80 - 5.5
- Table 11 is a table showing the purity of the formulations with different types of stabilizers and added antioxidants as HMW content.
- the formulations without buffer and with antioxidant added and pH 5.0 i.e., 7A, 7B, and 7C, were prepared with buffer and without antioxidants and pH 5.5, i.e., 6A.
- the ⁇ %HMW value was low. That is, the formulation without the buffer and with the addition of the antioxidant and having a pH of 5.0 was more stable than the formulation with the buffer and without the antioxidant and having a pH of 5.5.
- the formulation without adding an antioxidant without a buffer and having a pH of 5.0 exhibited excellent stability even when the type of stabilization was variously changed, such as sucrose, sorbitol, trehalose, arginine, or a combination thereof.
- Table 12 is a table showing the % acidity value of formulations with different types of stabilizers and added antioxidants.
- each pharmaceutical formulation listed in Table 13 was prepared in the same manner as above.
- Pembrolizumab buffer stabilizer Surfactants pH 8A 25 mg/ml 10 mM acetate 128 mM Arg-HCl 0.02% PS80 5.5 8B 25 mg/ml 10 mM acetate 0.7% NaCl 0.02% PS80 5.5 8C 25 mg/ml 10 mM histidine 128 mM Arg-HCl 0.02% PS80 5.5 8D 25 mg/ml 10 mM histidine 0.7% NaCl 0.02% PS80 5.5 8E 25 mg/ml 10 mM citrate 128 mM Arg-HCl 0.02% PS80 5.5 8F 25 mg/ml 10 mM citrate 0.7% NaCl 0.02% PS80 5.5 8G 25 mg/ml 10 mM succinate 128 mM Arg-HCl 0.02% PS80 5.5 8H 25 mg/ml 10 mM succinate 0.7% NaCl 0.02% PS80 5.5
- Table 14 is a table showing the purity of the formulations with different types of buffer as HMW content.
- the formulations containing histidine ie, 8C and 8D, had higher ⁇ %HMW values compared to the formulations containing other buffers. Therefore, it was confirmed that the formulation containing histidine as a buffer had lower stability than the formulation containing other types of buffers.
- each pharmaceutical formulation listed in Table 15 was prepared in the same manner as above.
- Pembrolizumab buffer stabilizer Surfactants antioxidant pH 9A 150 mg/ml - 7% sucrose 10 mM Arg 50 mM Lys 0.02% PS80 30 mM Met 5.5 9B 150 mg/ml - 1% sucrose 50 mM Arg 50 mM Lys 0.02% PS80 30 mM Met 5.5 9C 150 mg/ml - 7% sucrose 50 mM Arg - 0.02% PS80 30 mM Met 5.5 9D 150 mg/ml - 7% sucrose 20 mM Arg - 0.02% PS80 30 mM Met 5.0 9E 150 mg/ml - - 20 mM Arg - 0.02% PS80 - 5.0 9F 150 mg/ml - 5% sucrose 60 mM Arg - 0.02% PS80 30 mM Met 5.0 9G 150 mg/ml - 7% sucrose 30 mM Pro - 0.02% PS80 30 mM Met 5.0 9H 150 mg/ml
- formulations 9A to 9D containing a high concentration of 150 mg/ml of pembrolizumab but without a buffer exhibited better stability than formulation 9K containing the buffer.
- formulations 9A to 9J containing a high concentration of 150 mg/ml of pembrolizumab but without a buffer exhibited better stability than formulation 9K containing the buffer.
- each pharmaceutical formulation described in Table 18 was prepared in the same manner as above.
- Pembrolizumab buffer stabilizer Surfactants antioxidant pH 10A 200 mg/ml - 5% sucrose 80 mM Arg - 0.02% PS80 30 mM Met 5.0 10B 200 mg/ml - 7% sucrose 40 mM Lys - 0.02% PS80 30 mM Met 5.0 10C 200 mg/ml - 7% sucrose 26.4 mM Arg - 0.02% PS80 40 mM Met 5.0 10D 200 mg/ml - 7% sucrose 13.2 mM Arg 13.2 mM Lys 0.02% PS80 40 mM Met 5.0 10E 200 mg/ml - 4% sorbitol 13.2 mM Arg 13.2 mM Lys 0.02% PS80 40 mM Met 5.0 10F 250 mg/ml - 7% sucrose 33.3 mM Arg - 0.02% PS80 50 mM Met 5.0 10G 250 mg/ml - 7% sucrose 33.3 mM Lys - 0.02%
- formulations 10A to 10I containing a high concentration of 200 mg/ml or 250 mg/ml of pembrolizumab but no buffer showed superior stability than formulation 9K containing the buffer.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
명칭 | 그룹 | 제제 조성 |
1A | 1(버퍼 프리) | 버퍼 프리, 7% 수크로스, pH 5.5 |
1B | 버퍼 프리, 7% 수크로스, 0.02% PS80, pH 5.5 | |
1C | 버퍼 프리, 7% 수크로스, 0.10% PS80, pH 5.5 | |
1D | 버퍼 프리, 7% 수크로스, 0.20% PS80, pH 5.5 | |
2A | 2(히스티딘 버퍼) | 20 mM 히스티딘, 7% 수크로스, pH 5.5 |
2B | 20 mM 히스티딘, 7% 수크로스, 0.02% PS80, pH 5.5 | |
2C | 20 mM 히스티딘, 7% 수크로스, 0.10% PS80, pH 5.5 | |
2D | 20 mM 히스티딘, 7% 수크로스, 0.20% PS80, pH 5.5 | |
2E | 40 mM 히스티딘, 7% 수크로스, pH 5.5 | |
2F | 40 mM 히스티딘, 7% 수크로스, 0.02% PS80, pH 5.5 | |
2G | 40 mM 히스티딘, 7% 수크로스, 0.10% PS80, pH 5.5 | |
2H | 40 mM 히스티딘, 7% 수크로스, 0.20% PS80, pH 5.5 | |
2I | 10 mM 히스티딘, 7% 수크로스, 0.02% PS80, pH 5.5 (키트루다 제제) |
|
3A | 3(아세트산 버퍼) | 10 mM 아세트산, 7% 수크로스, 0.20% PS80, pH 5.5 |
4A | 4(숙신산 버퍼) | 10 mM 숙신산, 7% 수크로스, 0.20% PS80, pH 5.5 |
5A | 5(시트르산 버퍼) | 10 mM 시트르산, 7% 수크로스, 0.20% PS80, pH 5.5 |
명칭 | 0주 | 4주 | |
%HMW | %HMW | Δ%HMW | |
1B | 0.20 | 0.59 | 0.39 |
2I | 0.21 | 0.63 | 0.42 |
3A | 0.22 | 0.73 | 0.51 |
4A | 0.24 | 0.98 | 0.74 |
5A | 0.25 | 1.13 | 0.88 |
명칭 | Tagg (℃) |
1A | 61.01 |
1B | 61.71 |
1C | 56.06 |
1D | 50.80 |
2A | 62.26 |
2B | 61.97 |
2C | 57.41 |
2D | 53.28 |
2E | 60.99 |
2F | 62.51 |
2G | 59.36 |
2H | 59.35 |
명칭 | ΔG1(kcal/mol) |
1B | 4.26 |
2B | 4.50 |
명칭 | 0주 | 4주 | |
%HMW | %HMW | Δ%HMW | |
1A | 0.19 | 0.50 | 0.31 |
1B | 0.20 | 0.59 | 0.39 |
1C | 0.28 | 0.75 | 0.47 |
1D | 0.41 | 0.90 | 0.49 |
2A | 0.18 | 0.48 | 0.30 |
2B | 0.18 | 0.62 | 0.44 |
2C | 0.25 | 0.87 | 0.62 |
2D | 0.39 | 1.05 | 0.66 |
2E | 0.18 | 0.60 | 0.42 |
2F | 0.19 | 0.84 | 0.65 |
2G | 0.27 | 1.20 | 0.93 |
2H | 0.41 | 1.59 | 1.18 |
명칭 | pH | |
40℃/0주 | 40℃/4주 | |
1A | 5.50 | 5.57 |
1B | 5.47 | 5.60 |
1C | 5.46 | 5.53 |
1D | 5.49 | 5.55 |
2A | 5.59 | 5.55 |
2B | 5.57 | 5.53 |
2C | 5.58 | 5.54 |
2D | 5.64 | 5.52 |
2E | 5.56 | 5.52 |
2F | 5.54 | 5.51 |
2G | 5.55 | 5.50 |
2H | 5.53 | 5.51 |
명칭 | 펨브롤리주맙 | 버퍼 | 안정화제 | 계면활성제 | pH |
2I | 25 mg/ml | 10 mM 히스티딘 | 7% 수크로스 | 0.02% PS80 | 5.5 |
6A | 25 mg/ml | - | 7% 수크로스 | 0.02% PS80 | 5.5 |
6B | 25 mg/ml | 10 mM 히스티딘 | 7% 수크로스 | 0.02% PS80 | 5.0 |
6C | 25 mg/ml | - | 7% 수크로스 | 0.02% PS80 | 5.0 |
명칭 | 조성 | 0주 |
%HMW | ||
2I | 10 mM 히스티딘, 7% 수크로스, 0.02% PS80, pH 5.5 | 0.34 |
6A | 버퍼 프리, 7% 수크로스, 0.02% PS80, pH 5.5 | 0.18 |
6B | 10 mM 히스티딘, 7% 수크로스, 0.02% PS80, pH 5.0 | 0.16 |
6C | 버퍼 프리, 7% 수크로스, 0.02% PS80, pH 5.0 | 0.14 |
명칭 | 온도 스트레스(40℃): icIEF |
0주 | |
%산성 | |
2I | 23.90 |
6A | 20.51 |
6B | 20.38 |
6C | 20.41 |
명칭 | 펨브롤리주맙 | 버퍼 | 안정화제 | 계면활성제 | 항산화제 | pH | |
7A | 25 mg/ml | - | 7% 수크로스 | 3.3 mM Arg | 0.02% PS80 | 5.0 mM Met | 5.0 |
7B | 25 mg/ml | - | 4% 소르비톨 | 3.3 mM Arg | 0.02% PS80 | 5.0 mM Met | 5.0 |
7C | 25 mg/ml | - | 7.6% 트레할로스 | 3.3 mM Arg | 0.02% PS80 | 5.0 mM Met | 5.0 |
6A | 25 mg/ml | 10 mM 히스티딘 | 7% 수크로스 | - | 0.02% PS80 | - | 5.5 |
명칭 | 0주 | 1주 | 2주 | ||
%HMW | %HMW | Δ%HMW | %HMW | Δ%HMW | |
7A | 0.32 | ND | ND | 0.64 | 0.32 |
7B | 0.17 | 0.43 | 0.26 | 0.55 | 0.38 |
7C | 0.19 | 0.40 | 0.21 | 0.54 | 0.35 |
6A | 0.36 | ND | ND | 0.76 | 0.40 |
명칭 | 온도 스트레스(40℃): icIEF | ||||||
0주 | 1주 | 2주 | 4주 | ||||
%산성 | %산성 | Δ%산성 | %산성 | Δ%산성 | %산성 | Δ%산성 | |
7A | 22.48 | ND | ND | 24.58 | 2.10 | 29.42 | 6.95 |
7B | 20.57 | 21.95 | 1.38 | 24.08 | 3.51 | ND | ND |
7C | 20.97 | 21.95 | 0.98 | 24.05 | 3.08 | ND | ND |
6A | 22.34 | ND | ND | 24.92 | 2.58 | 30.78 | 8.44 |
명칭 | 펨브롤리주맙 | 버퍼 | 안정화제 | 계면활성제 | pH |
8A | 25 mg/ml | 10 mM 아세테이트 | 128 mM Arg-HCl | 0.02% PS80 | 5.5 |
8B | 25 mg/ml | 10 mM 아세테이트 | 0.7% NaCl | 0.02% PS80 | 5.5 |
8C | 25 mg/ml | 10 mM 히스티딘 | 128 mM Arg-HCl | 0.02% PS80 | 5.5 |
8D | 25 mg/ml | 10 mM 히스티딘 | 0.7% NaCl | 0.02% PS80 | 5.5 |
8E | 25 mg/ml | 10 mM 시트레이트 | 128 mM Arg-HCl | 0.02% PS80 | 5.5 |
8F | 25 mg/ml | 10 mM 시트레이트 | 0.7% NaCl | 0.02% PS80 | 5.5 |
8G | 25 mg/ml | 10 mM 숙시네이트 | 128 mM Arg-HCl | 0.02% PS80 | 5.5 |
8H | 25 mg/ml | 10 mM 숙시네이트 | 0.7% NaCl | 0.02% PS80 | 5.5 |
명칭 | 0주 | 1주 | 2주 | 4주 | |||
%HMW | %HMW | Δ%HMW | %HMW | Δ%HMW | %HMW | Δ%HMW | |
8A | 0.25 | 0.85 | 0.60 | 1.23 | 0.98 | 1.90 | 1.65 |
8B | 0.27 | 0.90 | 0.63 | 1.27 | 1.00 | 1.93 | 1.66 |
8C | 0.25 | 0.90 | 0.65 | 1.32 | 1.07 | 2.02 | 1.77 |
8D | 0.26 | 0.83 | 0.57 | 1.21 | 0.95 | 1.86 | 1.60 |
8E | 0.24 | 0.75 | 0.51 | 1.07 | 0.83 | 1.71 | 1.47 |
8F | 0.28 | 0.82 | 0.54 | 1.11 | 0.83 | 1.65 | 1.37 |
8G | 0.26 | 0.73 | 0.47 | 1.05 | 0.79 | 1.76 | 1.50 |
8H | 0.28 | 0.77 | 0.49 | 1.10 | 0.82 | 1.71 | 1.43 |
명칭 | 펨브롤리주맙 | 버퍼 | 안정화제 | 계면활성제 | 항산화제 | pH | ||
9A | 150 mg/ml | - | 7% 수크로스 | 10 mM Arg | 50 mM Lys | 0.02% PS80 | 30 mM Met | 5.5 |
9B | 150 mg/ml | - | 1% 수크로스 | 50 mM Arg | 50 mM Lys | 0.02% PS80 | 30 mM Met | 5.5 |
9C | 150 mg/ml | - | 7% 수크로스 | 50 mM Arg | - | 0.02% PS80 | 30 mM Met | 5.5 |
9D | 150 mg/ml | - | 7% 수크로스 | 20 mM Arg | - | 0.02% PS80 | 30 mM Met | 5.0 |
9E | 150 mg/ml | - | - | 20 mM Arg | - | 0.02% PS80 | - | 5.0 |
9F | 150 mg/ml | - | 5% 수크로스 | 60 mM Arg | - | 0.02% PS80 | 30 mM Met | 5.0 |
9G | 150 mg/ml | - | 7% 수크로스 | 30 mM Pro | - | 0.02% PS80 | 30 mM Met | 5.0 |
9H | 150 mg/ml | - | 7% 수크로스 | 20 mM Lys | - | 0.02% PS80 | 30 mM Met | 5.0 |
9I | 150 mg/ml | - | 7% 수크로스 | 20 mM Arg | - | 0.02% PS80 | 30 mM Met | 5.0 |
9J | 150 mg/ml | - | 7% 수크로스 | 20 mM Lys | - | 0.02% PS80 | 30 mM Met | 5.0 |
9K | 150 mg/ml | 10 mM 히스티딘 | 7% 수크로스 | - | - | 0.02% PS80 | - | 5.5 |
명칭 | 0주 | 1주 | 2주 | ||
%HMW | %HMW | Δ%HMW | %HMW | Δ%HMW | |
9A | 0.50 | 1.35 | 0.85 | 1.70 | 1.20 |
9B | 0.44 | 1.58 | 1.14 | 2.03 | 1.59 |
9C | 0.49 | 1.35 | 0.86 | 1.70 | 1.21 |
9D | 0.43 | 1.63 | 1.20 | 2.13 | 1.70 |
9K | 0.64 | ND | ND | 2.35 | 1.71 |
명칭 | 온도 스트레스(40℃): icIEF | ||||||
0주 | 1주 | 2주 | 4주 | ||||
%산성 | %산성 | Δ%산성 | %산성 | Δ%산성 | %산성 | Δ%산성 | |
9A | 20.74 | 21.93 | 1.19 | 23.84 | 3.10 | ND | ND |
9B | 20.72 | 21.87 | 1.15 | 23.68 | 2.96 | ND | ND |
9C | 20.42 | 21.76 | 1.34 | 23.61 | 3.19 | ND | ND |
9D | 20.96 | 22.05 | 1.09 | 24.29 | 3.33 | ND | ND |
9E | 22.86 | 23.34 | 0.48 | 24.89 | 2.03 | 28.86 | 6.00 |
9F | 22.44 | 23.26 | 0.82 | 25.00 | 2.56 | 28.41 | 5.97 |
9G | 22.80 | 23.86 | 1.06 | 25.64 | 2.84 | 29.99 | 7.19 |
9H | 22.92 | 23.34 | 0.42 | 25.16 | 2.24 | 28.00 | 5.08 |
9I | 20.02 | 21.52 | 1.50 | 24.19 | 4.17 | 28.86 | 8.84 |
9J | 20.21 | 20.55 | 0.34 | 23.83 | 3.62 | 28.86 | 8.65 |
9K | 24.6 | ND | ND | 28.9 | 4.3 | 36.69 | 12.09 |
명칭 | 펨브롤리주맙 | 버퍼 | 안정화제 | 계면활성제 | 항산화제 | pH | ||
10A | 200 mg/ml | - | 5% 수크로스 | 80 mM Arg | - | 0.02% PS80 | 30 mM Met | 5.0 |
10B | 200 mg/ml | - | 7% 수크로스 | 40 mM Lys | - | 0.02% PS80 | 30 mM Met | 5.0 |
10C | 200 mg/ml | - | 7% 수크로스 | 26.4 mM Arg | - | 0.02% PS80 | 40 mM Met | 5.0 |
10D | 200 mg/ml | - | 7% 수크로스 | 13.2mM Arg | 13.2 mM Lys | 0.02% PS80 | 40 mM Met | 5.0 |
10E | 200 mg/ml | - | 4% 소르비톨 | 13.2mM Arg | 13.2 mM Lys | 0.02% PS80 | 40 mM Met | 5.0 |
10F | 250 mg/ml | - | 7% 수크로스 | 33.3 mM Arg | - | 0.02% PS80 | 50 mM Met | 5.0 |
10G | 250 mg/ml | - | 7% 수크로스 | 33.3 mM Lys | - | 0.02% PS80 | 50 mM Met | 5.0 |
10H | 250 mg/ml | - | 7% 수크로스 | 16.7 mM Arg | 16.7 mM Lys | 0.02% PS80 | 50 mM Met | 5.0 |
10I | 250 mg/ml | - | 4% 소르비톨 | 16.7 mM Arg | 16.7 mM Lys | 0.02% PS80 | 50 mM Met | 5.0 |
명칭 | 0주 | 4주 | |
%산성 | %산성 | Δ%산성 | |
10A | 22.19 | 28.73 | 6.54 |
10B | 22.66 | 28.86 | 6.20 |
10C | 19.72 | 28.86 | 9.14 |
10D | 19.41 | 28.86 | 9.45 |
10E | 20.01 | 28.86 | 8.85 |
10F | 19.76 | 28.86 | 9.10 |
10G | 19.56 | 28.86 | 9.30 |
10H | 19.76 | 28.86 | 9.10 |
10I | 19.92 | 28.86 | 8.94 |
Claims (19)
- (a) 항-PD-1 항체 또는 이의 항원 결합 단편; 및(b) 안정화제를 포함하고,버퍼를 포함하지 않고, 약 pH 4.5 내지 약 pH 6.5를 갖는 안정한 항-PD-1 항체 약제학적 제제.
- 청구항 1에 있어서, 상기 제제는 약 pH 5.0 내지 약 pH 5.5를 갖는 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 항-PD-1 항체는 서열번호 1의 아미노산 서열을 갖는 중쇄 CDR1, 서열번호 2의 아미노산 서열을 갖는 중쇄 CDR2, 및 서열번호 3의 아미노산 서열을 갖는 중쇄 CDR3; 및 서열번호 4의 아미노산 서열을 갖는 경쇄 CDR1, 서열번호 5의 아미노산 서열을 갖는 경쇄 CDR2, 및 서열번호 6의 아미노산 서열을 갖는 경쇄 CDR3을 포함하는 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 항-PD-1 항체는 펨브롤리주맙인 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 항-PD-1 항체 또는 이의 항원 결합 단편의 농도는 약 5 내지 약 200 mg/ml인 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 안정화제는 폴리올, 아미노산 또는 이의 약제학적으로 허용가능한 염, 또는 이들의 혼합물인 것인 약제학적 제제.
- 청구항 6에 있어서, 상기 폴리올은 소르비톨, 수크로스, 트레할로스, 만노스, 말토스, 만니톨, 또는 이들의 혼합물인 것인 약제학적 제제.
- 청구항 6에 있어서, 상기 아미노산은 글리신, 프롤린, 페닐알라닌, 티로신, 트립토판, 라이신, 아르기닌, 이의 약제학적으로 허용가능한 염, 또는 이의 혼합물 인 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 안정화제는 약 1.0 내지 약 15.0%(w/v)의 당, 약 1.0 내지 약 20.0%(w/v)의 당 알코올, 약 0.1 내지 약 300.0 mM의 아미노산, 또는 약 1.0 내지 약 300.0 mM의 금속염인 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 안정화제는 약 1.0 내지 약 15.0%(w/v)의 당 및 약 0.1 내지 약 300.0 mM의 아미노산인 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 버퍼는 히스티딘, 인산, 구연산, 말레인산, 타르타르산, 숙신산, 시트르산, 아세트산, 탄산, 이의 약제학적으로 허용가능한 염, 또는 이들의 혼합물인 것인 약제학적 제제.
- 청구항 1에 있어서, 계면활성제를 포함하지 않는 것, 또는 계면활성제를 더 포함하는 것인 약제학적 제제.
- 청구항 12에 있어서, 상기 계면활성제는 폴리소르베이트, 폴록사머, 다른 지방산의 소르비탄 에스테르 또는 이들의 혼합물인 것인 약제학적 제제.
- 청구항 1에 있어서, 항산화제를 더 포함하는 것인 약제학적 제제.
- 청구항 14에 있어서, 상기 항산화제는 메티오닌인 것인 약제학적 제제.
- 청구항 1에 있어서, 상기 약제학적 제제는 피하 주사 또는 정맥 주사용인 것 인 약제학적 제제.
- 청구항 1에 있어서,상기 항-PD-1 항체 또는 이의 항원 결합 단편의 농도는 약 5 내지 약 200 mg/mL이고,상기 안정화제는 약 1.0 내지 약 15.0%(w/v)의 수크로스, 트레할로스, 이의 수화물, 또는 이의 혼합물; 약 1.0 내지 약 20.0 %(w/v)의 소르비톨, 만니톨, 이의 수화물, 또는 이의 혼합물; 약 0.1 내지 약 300.0 mM의 아르기닌, 라이신, 프롤린, 글리신, 페닐알라닌, 티로신, 트립토판, 이의 약제학적으로 허용가능한 염, 또는 이의 혼합물; 또는 이들의 2종 이상의 혼합물인 것인 약제학적 제제.
- 암을 치료하기에 효과적인 양의 청구항 1에 따른 약제학적 제제를 개체에 투 여하는 단계를 포함하는 개체에서 암을 치료하는 방법.
- 용매에 안정화제를 첨가하여 혼합 용액을 제조하는 단계; 및상기 혼합 용액에 펨브롤리주맙 또는 이의 항원 결합 단편을 첨가하는 단계; 또는용매에 펨브롤리주맙 또는 이의 항원 결합 단편을 첨가하여 펨브롤리주맙 또는 이의 항원 결합 단편 용액을 제조하는 단계; 및상기 용액에 안정화제를 첨가하는 단계;를 포함하는 안정한 약제학적 제제를 제조하는 방법으로서, 상기 제조 단계는 버퍼를 첨가하지 않고 수행되는 것인 방법.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2020402369A AU2020402369A1 (en) | 2019-12-13 | 2020-12-14 | Stable anti-PD-1 antibody pharmaceutical preparation |
JP2022535787A JP2023506629A (ja) | 2019-12-13 | 2020-12-14 | 安定した抗pd-1抗体の薬剤学的製剤 |
KR1020227023258A KR20220115803A (ko) | 2019-12-13 | 2020-12-14 | 안정한 항-pd-1 항체 약제학적 제제 |
EP20899757.7A EP4074338A4 (en) | 2019-12-13 | 2020-12-14 | STABLE PHARMACEUTICAL ANTI-PD-1 ANTIBODY PREPARATION |
US17/784,251 US20230054413A1 (en) | 2019-12-13 | 2020-12-14 | Stable anti-pd1 antibody pharmaceutical formulations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20190167147 | 2019-12-13 | ||
KR10-2019-0167147 | 2019-12-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021118321A1 true WO2021118321A1 (ko) | 2021-06-17 |
Family
ID=76330229
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2020/018247 WO2021118321A1 (ko) | 2019-12-13 | 2020-12-14 | 안정한 항-pd-1 항체 약제학적 제제 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20230054413A1 (ko) |
EP (1) | EP4074338A4 (ko) |
JP (1) | JP2023506629A (ko) |
KR (1) | KR20220115803A (ko) |
AU (1) | AU2020402369A1 (ko) |
TW (1) | TW202138006A (ko) |
WO (1) | WO2021118321A1 (ko) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022268887A1 (en) | 2021-06-23 | 2022-12-29 | Formycon Ag | Formulations of anti-pd1 antibodies |
WO2024006981A1 (en) * | 2022-07-01 | 2024-01-04 | Amgen Inc. | Anti-pd-1 antibody formulations |
WO2024133625A1 (en) | 2022-12-21 | 2024-06-27 | Formycon Ag | Formulations of anti-pd1 antibodies |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20210097882A (ko) * | 2020-01-30 | 2021-08-10 | 삼성바이오에피스 주식회사 | 안정한 항-pd-1 항체 약제학적 제제 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008156712A1 (en) | 2007-06-18 | 2008-12-24 | N. V. Organon | Antibodies to human programmed death receptor pd-1 |
KR20170138477A (ko) * | 2015-04-17 | 2017-12-15 | 브리스톨-마이어스 스큅 컴퍼니 | 항-pd-1 항체 및 또 다른 항체의 조합물을 포함하는 조성물 |
KR20180027576A (ko) * | 2015-07-14 | 2018-03-14 | 브리스톨-마이어스 스큅 컴퍼니 | 면역 체크포인트 억제제를 사용하여 암을 치료하는 방법 |
KR20180085801A (ko) * | 2015-12-07 | 2018-07-27 | 메르크 파텐트 게엠베하 | 항-pd-1 항체 아벨루맙을 포함하는 수성 약학 제형 |
WO2018204368A1 (en) * | 2017-05-02 | 2018-11-08 | Merck Sharp & Dohme Corp. | Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof |
KR20190120792A (ko) * | 2017-02-21 | 2019-10-24 | 리제너론 파아마슈티컬스, 인크. | 폐암의 치료를 위한 항-pd-1 항체 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109971724B (zh) * | 2017-12-28 | 2023-10-31 | 上海细胞治疗研究院 | 靶向ErbB受体家族且自表达PD-1抗体的CAR-T细胞及其用途 |
-
2020
- 2020-12-14 KR KR1020227023258A patent/KR20220115803A/ko unknown
- 2020-12-14 JP JP2022535787A patent/JP2023506629A/ja active Pending
- 2020-12-14 EP EP20899757.7A patent/EP4074338A4/en active Pending
- 2020-12-14 AU AU2020402369A patent/AU2020402369A1/en active Pending
- 2020-12-14 WO PCT/KR2020/018247 patent/WO2021118321A1/ko unknown
- 2020-12-14 US US17/784,251 patent/US20230054413A1/en active Pending
- 2020-12-14 TW TW109144142A patent/TW202138006A/zh unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008156712A1 (en) | 2007-06-18 | 2008-12-24 | N. V. Organon | Antibodies to human programmed death receptor pd-1 |
US9834605B2 (en) | 2007-06-18 | 2017-12-05 | Merck Sharpe & Dohme B.V. | Antibodies to human programmed death receptor PD-1 |
KR20170138477A (ko) * | 2015-04-17 | 2017-12-15 | 브리스톨-마이어스 스큅 컴퍼니 | 항-pd-1 항체 및 또 다른 항체의 조합물을 포함하는 조성물 |
KR20180027576A (ko) * | 2015-07-14 | 2018-03-14 | 브리스톨-마이어스 스큅 컴퍼니 | 면역 체크포인트 억제제를 사용하여 암을 치료하는 방법 |
KR20180085801A (ko) * | 2015-12-07 | 2018-07-27 | 메르크 파텐트 게엠베하 | 항-pd-1 항체 아벨루맙을 포함하는 수성 약학 제형 |
KR20190120792A (ko) * | 2017-02-21 | 2019-10-24 | 리제너론 파아마슈티컬스, 인크. | 폐암의 치료를 위한 항-pd-1 항체 |
WO2018204368A1 (en) * | 2017-05-02 | 2018-11-08 | Merck Sharp & Dohme Corp. | Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof |
Non-Patent Citations (2)
Title |
---|
See also references of EP4074338A4 |
SVEN BAHRENBURG, ANNE R. KAROW, PATRICK GARIDEL: "Buffer-free therapeutic antibody preparations provide a viable alternative to conventionally buffered solutions: From protein buffer capacity prediction to bioprocess applications", BIOTECHNOLOGY JOURNAL, vol. 10, no. 4, 30 January 2015 (2015-01-30), pages 610 - 622, XP055669725, ISSN: 1860-6768, DOI: 10.1002/biot.201400531 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022268887A1 (en) | 2021-06-23 | 2022-12-29 | Formycon Ag | Formulations of anti-pd1 antibodies |
WO2024006981A1 (en) * | 2022-07-01 | 2024-01-04 | Amgen Inc. | Anti-pd-1 antibody formulations |
WO2024133625A1 (en) | 2022-12-21 | 2024-06-27 | Formycon Ag | Formulations of anti-pd1 antibodies |
Also Published As
Publication number | Publication date |
---|---|
EP4074338A4 (en) | 2024-03-06 |
EP4074338A1 (en) | 2022-10-19 |
AU2020402369A1 (en) | 2022-07-14 |
US20230054413A1 (en) | 2023-02-23 |
JP2023506629A (ja) | 2023-02-17 |
TW202138006A (zh) | 2021-10-16 |
KR20220115803A (ko) | 2022-08-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2021118321A1 (ko) | 안정한 항-pd-1 항체 약제학적 제제 | |
US20210100903A1 (en) | Aqueous pharmaceutical formulation comprising anti-pd-l1 antibody avelumab | |
JP7382232B2 (ja) | 抗lag3抗体の製剤および抗lag3抗体と抗pd-1抗体との共製剤 | |
US20110158987A1 (en) | Novel antibody formulation | |
JP7503056B6 (ja) | 抗lag3抗体および抗pd-1抗体の共-製剤 | |
JP2021178862A (ja) | タンパク質製剤 | |
CN114632150B (zh) | 一种抗pd-l1人源化单克隆抗体的药物组合物 | |
WO2018131893A1 (ko) | 안정한 액체 제제 | |
EP2167127A1 (en) | Novel formulation | |
WO2020060192A1 (ko) | 고농도의 계면활성제를 포함하는 트라스투주맙 안정화 액체 제제 | |
WO2013147559A1 (en) | A liquid formulation of highly concentrated long-acting human growth hormone conjugate | |
WO2018169348A1 (ko) | 항-tnf 알파 항체의 액상 제제 | |
WO2021154027A1 (ko) | 안정한 항-pd-1 항체 약제학적 제제 | |
WO2021125852A1 (ko) | 신규 주사제 제형 | |
WO2022019721A1 (ko) | 안과용 액상 조성물 | |
WO2020101452A1 (ko) | 단백질을 포함하는 안정한 액상 조성물 | |
WO2020071876A1 (ko) | 점도가 감소된 고농도 트라스투주맙 또는 이의 항원 결합 단편 안정화 제제 | |
WO2021071326A1 (ko) | 안정한 액상 조성물과 이의 제조방법 및 이를 포함하는 제제 | |
CN114007648B (zh) | 包含抗lag-3抗体的制剂、其制备方法及其用途 | |
WO2023096475A1 (ko) | Hgh 융합단백질의 고농도 투여 제형 | |
WO2020060179A1 (ko) | 완충화제를 포함하지 않는 트라스투주맙 항체 안정화 제제 | |
WO2021187897A1 (ko) | Il-2 단백질 및 cd80 단백질을 포함하는 융합단백질 제제 | |
WO2018080196A2 (ko) | 안정한 약제학적 제제 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20899757 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2022535787 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20227023258 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2020402369 Country of ref document: AU Date of ref document: 20201214 Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2020899757 Country of ref document: EP Effective date: 20220713 |