JP2023083504A - 1段階の工程によるマイタンシノイド-抗体複合体の調製 - Google Patents
1段階の工程によるマイタンシノイド-抗体複合体の調製 Download PDFInfo
- Publication number
- JP2023083504A JP2023083504A JP2023070124A JP2023070124A JP2023083504A JP 2023083504 A JP2023083504 A JP 2023083504A JP 2023070124 A JP2023070124 A JP 2023070124A JP 2023070124 A JP2023070124 A JP 2023070124A JP 2023083504 A JP2023083504 A JP 2023083504A
- Authority
- JP
- Japan
- Prior art keywords
- cell
- cytotoxic agent
- binding agent
- antibody
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 103
- 230000008569 process Effects 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title description 3
- 229940127121 immunoconjugate Drugs 0.000 title 1
- 229940127089 cytotoxic agent Drugs 0.000 claims abstract description 177
- 239000002254 cytotoxic agent Substances 0.000 claims abstract description 177
- 231100000599 cytotoxic agent Toxicity 0.000 claims abstract description 137
- 239000011230 binding agent Substances 0.000 claims abstract description 112
- 239000000203 mixture Substances 0.000 claims abstract description 75
- 230000027455 binding Effects 0.000 claims abstract description 65
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 60
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000006227 byproduct Substances 0.000 claims abstract description 9
- -1 piperazine-1,4-bis-(2-hydroxy-propane-sulfonic acid) anhydride Chemical class 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 29
- 239000000126 substance Substances 0.000 claims description 21
- 238000010791 quenching Methods 0.000 claims description 20
- OWXMKDGYPWMGEB-UHFFFAOYSA-N HEPPS Chemical compound OCCN1CCN(CCCS(O)(=O)=O)CC1 OWXMKDGYPWMGEB-UHFFFAOYSA-N 0.000 claims description 16
- 230000000171 quenching effect Effects 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 238000009295 crossflow filtration Methods 0.000 claims description 15
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 claims description 12
- 230000000274 adsorptive effect Effects 0.000 claims description 11
- 239000000872 buffer Substances 0.000 claims description 11
- 238000004587 chromatography analysis Methods 0.000 claims description 9
- GTBCXYYVWHFQRS-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(pyridin-2-yldisulfanyl)pentanoate Chemical compound C=1C=CC=NC=1SSC(C)CCC(=O)ON1C(=O)CCC1=O GTBCXYYVWHFQRS-UHFFFAOYSA-N 0.000 claims description 6
- 230000003432 anti-folate effect Effects 0.000 claims description 6
- 229940127074 antifolate Drugs 0.000 claims description 6
- 150000002148 esters Chemical group 0.000 claims description 6
- 239000004052 folic acid antagonist Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- JSHOVKSMJRQOGY-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(pyridin-2-yldisulfanyl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCSSC1=CC=CC=N1 JSHOVKSMJRQOGY-UHFFFAOYSA-N 0.000 claims description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 4
- 108090000371 Esterases Proteins 0.000 claims description 4
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 4
- 102000035195 Peptidases Human genes 0.000 claims description 4
- 108091005804 Peptidases Proteins 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 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 4
- 102000006495 integrins Human genes 0.000 claims description 4
- 108010044426 integrins Proteins 0.000 claims description 4
- 235000019833 protease Nutrition 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229960000575 trastuzumab Drugs 0.000 claims description 4
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 claims description 3
- IUTPJBLLJJNPAJ-UHFFFAOYSA-N 3-(2,5-dioxopyrrol-1-yl)propanoic acid Chemical compound OC(=O)CCN1C(=O)C=CC1=O IUTPJBLLJJNPAJ-UHFFFAOYSA-N 0.000 claims description 3
- NCPQROHLJFARLL-UHFFFAOYSA-N 4-(2,5-dioxopyrrol-1-yl)butanoic acid Chemical compound OC(=O)CCCN1C(=O)C=CC1=O NCPQROHLJFARLL-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 125000005179 haloacetyl group Chemical group 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 229960004641 rituximab Drugs 0.000 claims description 3
- 229950008684 sibrotuzumab Drugs 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- QPPUSXURIGJCFQ-UHFFFAOYSA-N 2-[(2-iodoacetyl)amino]propanoic acid Chemical compound OC(=O)C(C)NC(=O)CI QPPUSXURIGJCFQ-UHFFFAOYSA-N 0.000 claims description 2
- LVQFQZZGTZFUNF-UHFFFAOYSA-N 2-hydroxy-3-[4-(2-hydroxy-3-sulfonatopropyl)piperazine-1,4-diium-1-yl]propane-1-sulfonate Chemical compound OS(=O)(=O)CC(O)CN1CCN(CC(O)CS(O)(=O)=O)CC1 LVQFQZZGTZFUNF-UHFFFAOYSA-N 0.000 claims description 2
- 239000007995 HEPES buffer Substances 0.000 claims description 2
- 239000007996 HEPPS buffer Substances 0.000 claims description 2
- GIZQLVPDAOBAFN-UHFFFAOYSA-N HEPPSO Chemical compound OCCN1CCN(CC(O)CS(O)(=O)=O)CC1 GIZQLVPDAOBAFN-UHFFFAOYSA-N 0.000 claims description 2
- 101100369076 Mus musculus Tdgf1 gene Proteins 0.000 claims description 2
- GHAZCVNUKKZTLG-UHFFFAOYSA-N N-ethyl-succinimide Natural products CCN1C(=O)CCC1=O GHAZCVNUKKZTLG-UHFFFAOYSA-N 0.000 claims description 2
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000008351 acetate buffer Substances 0.000 claims description 2
- 229950002903 bivatuzumab Drugs 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 claims description 2
- YCLWMUYXEGEIGD-UHFFFAOYSA-M sodium;2-hydroxy-3-[4-(2-hydroxyethyl)piperazin-1-yl]propane-1-sulfonate Chemical compound [Na+].OCCN1CCN(CC(O)CS([O-])(=O)=O)CC1 YCLWMUYXEGEIGD-UHFFFAOYSA-M 0.000 claims description 2
- 239000008362 succinate buffer Substances 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- FUHCFUVCWLZEDQ-UHFFFAOYSA-N 1-(2,5-dioxopyrrolidin-1-yl)oxy-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2-sulfonic acid Chemical compound O=C1CCC(=O)N1OC(=O)C(S(=O)(=O)O)CCSSC1=CC=CC=N1 FUHCFUVCWLZEDQ-UHFFFAOYSA-N 0.000 claims 1
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 claims 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 claims 1
- 102100031013 Transgelin Human genes 0.000 claims 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 24
- 210000004027 cell Anatomy 0.000 description 173
- 239000000562 conjugate Substances 0.000 description 88
- 125000005647 linker group Chemical group 0.000 description 68
- 125000004432 carbon atom Chemical group C* 0.000 description 39
- 239000011347 resin Substances 0.000 description 34
- 229920005989 resin Polymers 0.000 description 34
- 125000003342 alkenyl group Chemical group 0.000 description 33
- 239000000427 antigen Substances 0.000 description 31
- 102000036639 antigens Human genes 0.000 description 30
- 108091007433 antigens Proteins 0.000 description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 16
- 239000012634 fragment Substances 0.000 description 16
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 16
- 241000894007 species Species 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 239000000178 monomer Substances 0.000 description 13
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 12
- 231100000433 cytotoxic Toxicity 0.000 description 12
- 230000001472 cytotoxic effect Effects 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 11
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 10
- 241001529936 Murinae Species 0.000 description 10
- 229920005654 Sephadex Polymers 0.000 description 9
- 239000012507 Sephadex™ Substances 0.000 description 9
- 229920002684 Sepharose Polymers 0.000 description 9
- 229960005558 mertansine Drugs 0.000 description 9
- 229940123237 Taxane Drugs 0.000 description 8
- 210000004408 hybridoma Anatomy 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 229940074404 sodium succinate Drugs 0.000 description 7
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 7
- 150000003573 thiols Chemical class 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000006011 modification reaction Methods 0.000 description 5
- 238000005580 one pot reaction Methods 0.000 description 5
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 4
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 125000002228 disulfide group Chemical group 0.000 description 4
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 4
- 238000001597 immobilized metal affinity chromatography Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- FPKVOQKZMBDBKP-UHFFFAOYSA-N 1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 FPKVOQKZMBDBKP-UHFFFAOYSA-N 0.000 description 3
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 102100037241 Endoglin Human genes 0.000 description 3
- 101800003838 Epidermal growth factor Proteins 0.000 description 3
- 102400001368 Epidermal growth factor Human genes 0.000 description 3
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 3
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 3
- 101001023230 Homo sapiens Folate receptor alpha Proteins 0.000 description 3
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 3
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 3
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 description 3
- 101000834948 Homo sapiens Tomoregulin-2 Proteins 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 3
- 239000000637 Melanocyte-Stimulating Hormone Substances 0.000 description 3
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 3
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 description 3
- 102000007072 Nerve Growth Factors Human genes 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- 102000005157 Somatostatin Human genes 0.000 description 3
- 108010056088 Somatostatin Proteins 0.000 description 3
- 241000187747 Streptomyces Species 0.000 description 3
- 102100026160 Tomoregulin-2 Human genes 0.000 description 3
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 3
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000003636 chemical group Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012539 chromatography resin Substances 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229940116977 epidermal growth factor Drugs 0.000 description 3
- 102000006815 folate receptor Human genes 0.000 description 3
- 108020005243 folate receptor Proteins 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 239000011724 folic acid Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 229940047124 interferons Drugs 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- SVVGCFZPFZGWRG-OTKBOCOUSA-N maytansinoid dm4 Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)C(C)(C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 SVVGCFZPFZGWRG-OTKBOCOUSA-N 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 3
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 3
- 229960000553 somatostatin Drugs 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- NKUZQMZWTZAPSN-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-bromoacetate Chemical compound BrCC(=O)ON1C(=O)CCC1=O NKUZQMZWTZAPSN-UHFFFAOYSA-N 0.000 description 2
- VRDGQQTWSGDXCU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-iodoacetate Chemical compound ICC(=O)ON1C(=O)CCC1=O VRDGQQTWSGDXCU-UHFFFAOYSA-N 0.000 description 2
- LLXVXPPXELIDGQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)benzoate Chemical compound C=1C=CC(N2C(C=CC2=O)=O)=CC=1C(=O)ON1C(=O)CCC1=O LLXVXPPXELIDGQ-UHFFFAOYSA-N 0.000 description 2
- WGMMKWFUXPMTRW-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[(2-bromoacetyl)amino]propanoate Chemical compound BrCC(=O)NCCC(=O)ON1C(=O)CCC1=O WGMMKWFUXPMTRW-UHFFFAOYSA-N 0.000 description 2
- PVGATNRYUYNBHO-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(2,5-dioxopyrrol-1-yl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O PVGATNRYUYNBHO-UHFFFAOYSA-N 0.000 description 2
- PMJWDPGOWBRILU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCC(C=C1)=CC=C1N1C(=O)C=CC1=O PMJWDPGOWBRILU-UHFFFAOYSA-N 0.000 description 2
- WCMOHMXWOOBVMZ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCNC(=O)CCN1C(=O)C=CC1=O WCMOHMXWOOBVMZ-UHFFFAOYSA-N 0.000 description 2
- RVRLFABOQXZUJX-UHFFFAOYSA-N 1-[1-(2,5-dioxopyrrol-1-yl)ethyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(C)N1C(=O)C=CC1=O RVRLFABOQXZUJX-UHFFFAOYSA-N 0.000 description 2
- AASYSXRGODIQGY-UHFFFAOYSA-N 1-[1-(2,5-dioxopyrrol-1-yl)hexyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(CCCCC)N1C(=O)C=CC1=O AASYSXRGODIQGY-UHFFFAOYSA-N 0.000 description 2
- SGVWDRVQIYUSRA-UHFFFAOYSA-N 1-[2-[2-(2,5-dioxopyrrol-1-yl)ethyldisulfanyl]ethyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CCSSCCN1C(=O)C=CC1=O SGVWDRVQIYUSRA-UHFFFAOYSA-N 0.000 description 2
- DIYPCWKHSODVAP-UHFFFAOYSA-N 1-[3-(2,5-dioxopyrrol-1-yl)benzoyl]oxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)C1=CC=CC(N2C(C=CC2=O)=O)=C1 DIYPCWKHSODVAP-UHFFFAOYSA-N 0.000 description 2
- VHYRLCJMMJQUBY-UHFFFAOYSA-N 1-[4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoyloxy]-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)CCCC1=CC=C(N2C(C=CC2=O)=O)C=C1 VHYRLCJMMJQUBY-UHFFFAOYSA-N 0.000 description 2
- ZMRMMAOBSFSXLN-UHFFFAOYSA-N 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanehydrazide Chemical compound C1=CC(CCCC(=O)NN)=CC=C1N1C(=O)C=CC1=O ZMRMMAOBSFSXLN-UHFFFAOYSA-N 0.000 description 2
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 102100025221 CD70 antigen Human genes 0.000 description 2
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 108010036395 Endoglin Proteins 0.000 description 2
- 102000050554 Eph Family Receptors Human genes 0.000 description 2
- 108091008815 Eph receptors Proteins 0.000 description 2
- 108010055196 EphA2 Receptor Proteins 0.000 description 2
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 101150021185 FGF gene Proteins 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 description 2
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 2
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 2
- 101000721757 Homo sapiens Olfactory receptor 51E2 Proteins 0.000 description 2
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000003996 Interferon-beta Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- XNSAINXGIQZQOO-UHFFFAOYSA-N L-pyroglutamyl-L-histidyl-L-proline amide Natural products NC(=O)C1CCCN1C(=O)C(NC(=O)C1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-UHFFFAOYSA-N 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 2
- 102000008072 Lymphokines Human genes 0.000 description 2
- 108010074338 Lymphokines Proteins 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 102100025128 Olfactory receptor 51E2 Human genes 0.000 description 2
- 101710160107 Outer membrane protein A Proteins 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 102100035721 Syndecan-1 Human genes 0.000 description 2
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 239000000627 Thyrotropin-Releasing Hormone Substances 0.000 description 2
- 102400000336 Thyrotropin-releasing hormone Human genes 0.000 description 2
- 101800004623 Thyrotropin-releasing hormone Proteins 0.000 description 2
- 102100030859 Tissue factor Human genes 0.000 description 2
- 102100033571 Tissue-type plasminogen activator Human genes 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 201000011186 acute T cell leukemia Diseases 0.000 description 2
- 238000005377 adsorption chromatography Methods 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- DGBBXVWXOHSLTG-UMDRASRXSA-N ansamitocin p 2 Chemical compound C([C@@H]([C@@]1(O[C@H]1[C@@H]1C)C)OC(=O)CC)C(=O)N(C)C(C(=C(OC)C=2)Cl)=CC=2C\C(C)=C\C=C\[C@@H](OC)[C@]2(O)NC(=O)O[C@H]1C2 DGBBXVWXOHSLTG-UMDRASRXSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 229940047120 colony stimulating factors Drugs 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000001268 conjugating effect Effects 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229930188854 dolastatin Natural products 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 229940014144 folate Drugs 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 102000053180 human FOLR1 Human genes 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 210000000066 myeloid cell Anatomy 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 230000000955 neuroendocrine Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- HHSGWIABCIVPJT-UHFFFAOYSA-M sodium;1-[4-[(2-iodoacetyl)amino]benzoyl]oxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)C1=CC=C(NC(=O)CI)C=C1 HHSGWIABCIVPJT-UHFFFAOYSA-M 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 229940034199 thyrotropin-releasing hormone Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- TYKASZBHFXBROF-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-(2,5-dioxopyrrol-1-yl)acetate Chemical compound O=C1CCC(=O)N1OC(=O)CN1C(=O)C=CC1=O TYKASZBHFXBROF-UHFFFAOYSA-N 0.000 description 1
- ULZJAHZPCLFGHQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 5-(2,5-dioxopyrrol-1-yl)pentanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCN1C(=O)C=CC1=O ULZJAHZPCLFGHQ-UHFFFAOYSA-N 0.000 description 1
- LTDQGCFMTVHZKP-UHFFFAOYSA-N (4-bromophenyl)-(4,6-dimethoxy-3-methyl-1-benzofuran-2-yl)methanone Chemical compound O1C2=CC(OC)=CC(OC)=C2C(C)=C1C(=O)C1=CC=C(Br)C=C1 LTDQGCFMTVHZKP-UHFFFAOYSA-N 0.000 description 1
- OJQSISYVGFJJBY-UHFFFAOYSA-N 1-(4-isocyanatophenyl)pyrrole-2,5-dione Chemical compound C1=CC(N=C=O)=CC=C1N1C(=O)C=CC1=O OJQSISYVGFJJBY-UHFFFAOYSA-N 0.000 description 1
- VNJBTKQBKFMEHH-UHFFFAOYSA-N 1-[4-(2,5-dioxopyrrol-1-yl)-2,3-dihydroxybutyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC(O)C(O)CN1C(=O)C=CC1=O VNJBTKQBKFMEHH-UHFFFAOYSA-N 0.000 description 1
- WXXSHAKLDCERGU-UHFFFAOYSA-N 1-[4-(2,5-dioxopyrrol-1-yl)butyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CCCCN1C(=O)C=CC1=O WXXSHAKLDCERGU-UHFFFAOYSA-N 0.000 description 1
- FYKCKCYYMXDNHZ-UHFFFAOYSA-N 2-sulfobutanoic acid Chemical compound CCC(C(O)=O)S(O)(=O)=O FYKCKCYYMXDNHZ-UHFFFAOYSA-N 0.000 description 1
- KTLUMOZOWZSJFC-UHFFFAOYSA-N 3-azatetracyclo[7.5.0.02,6.012,14]tetradeca-1,3,5,7,9,11,13-heptaene Chemical group C1=C2C=CN=C2C2=C3C=C3C=CC2=C1 KTLUMOZOWZSJFC-UHFFFAOYSA-N 0.000 description 1
- GUPXYSSGJWIURR-UHFFFAOYSA-N 3-octoxypropane-1,2-diol Chemical compound CCCCCCCCOCC(O)CO GUPXYSSGJWIURR-UHFFFAOYSA-N 0.000 description 1
- QXZBMSIDSOZZHK-DOPDSADYSA-N 31362-50-2 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CNC=N1 QXZBMSIDSOZZHK-DOPDSADYSA-N 0.000 description 1
- 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 description 1
- HBEDKBRARKFPIC-UHFFFAOYSA-N 6-(2,5-dioxopyrrol-1-yl)hexanoic acid;1-hydroxypyrrolidine-2,5-dione Chemical compound ON1C(=O)CCC1=O.OC(=O)CCCCCN1C(=O)C=CC1=O HBEDKBRARKFPIC-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 108010059616 Activins Proteins 0.000 description 1
- 102000005606 Activins Human genes 0.000 description 1
- 102100036526 Anoctamin-7 Human genes 0.000 description 1
- DGBBXVWXOHSLTG-UHFFFAOYSA-N Ansamitocin P2 Natural products CC1C2OC2(C)C(OC(=O)CC)CC(=O)N(C)C(C(=C(OC)C=2)Cl)=CC=2CC(C)=CC=CC(OC)C2(O)NC(=O)OC1C2 DGBBXVWXOHSLTG-UHFFFAOYSA-N 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 239000012619 Butyl Sepharose® Substances 0.000 description 1
- 102100031092 C-C motif chemokine 3 Human genes 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 108010046080 CD27 Ligand Proteins 0.000 description 1
- 102000049320 CD36 Human genes 0.000 description 1
- 108010045374 CD36 Antigens Proteins 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 102100022002 CD59 glycoprotein Human genes 0.000 description 1
- 102100027221 CD81 antigen Human genes 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 102100025680 Complement decay-accelerating factor Human genes 0.000 description 1
- 102100032768 Complement receptor type 2 Human genes 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 101710181478 Envelope glycoprotein GP350 Proteins 0.000 description 1
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 1
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 102100031517 Fc receptor-like protein 1 Human genes 0.000 description 1
- 102100031511 Fc receptor-like protein 2 Human genes 0.000 description 1
- 102100031512 Fc receptor-like protein 3 Human genes 0.000 description 1
- 102100031513 Fc receptor-like protein 4 Human genes 0.000 description 1
- 102100031507 Fc receptor-like protein 5 Human genes 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102100035139 Folate receptor alpha Human genes 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 1
- 241001622557 Hesperia Species 0.000 description 1
- 101000928370 Homo sapiens Anoctamin-7 Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 101000914479 Homo sapiens CD81 antigen Proteins 0.000 description 1
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 1
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 1
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 description 1
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000846913 Homo sapiens Fc receptor-like protein 1 Proteins 0.000 description 1
- 101000846911 Homo sapiens Fc receptor-like protein 2 Proteins 0.000 description 1
- 101000846910 Homo sapiens Fc receptor-like protein 3 Proteins 0.000 description 1
- 101000846909 Homo sapiens Fc receptor-like protein 4 Proteins 0.000 description 1
- 101000846908 Homo sapiens Fc receptor-like protein 5 Proteins 0.000 description 1
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001063456 Homo sapiens Leucine-rich repeat-containing G-protein coupled receptor 5 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 1
- 101001099381 Homo sapiens Peroxisomal biogenesis factor 19 Proteins 0.000 description 1
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 102100031036 Leucine-rich repeat-containing G-protein coupled receptor 5 Human genes 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 240000001427 Mallotus nudiflorus Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000003735 Mesothelin Human genes 0.000 description 1
- 108090000015 Mesothelin Proteins 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 102100023123 Mucin-16 Human genes 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 102100023616 Neural cell adhesion molecule L1-like protein Human genes 0.000 description 1
- 102100029268 Neurotrophin-3 Human genes 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 108091033411 PCA3 Proteins 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102100038883 Peroxisomal biogenesis factor 19 Human genes 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 description 1
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 239000012614 Q-Sepharose Substances 0.000 description 1
- JQYMGXZJTCOARG-UHFFFAOYSA-N Reactive blue 2 Chemical compound C1=2C(=O)C3=CC=CC=C3C(=O)C=2C(N)=C(S(O)(=O)=O)C=C1NC(C=C1S(O)(=O)=O)=CC=C1NC(N=1)=NC(Cl)=NC=1NC1=CC=CC(S(O)(=O)=O)=C1 JQYMGXZJTCOARG-UHFFFAOYSA-N 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 102400000834 Relaxin A chain Human genes 0.000 description 1
- 101800000074 Relaxin A chain Proteins 0.000 description 1
- 102400000610 Relaxin B chain Human genes 0.000 description 1
- 101710109558 Relaxin B chain Proteins 0.000 description 1
- 102100036546 Salivary acidic proline-rich phosphoprotein 1/2 Human genes 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 108010029180 Sialic Acid Binding Ig-like Lectin 3 Proteins 0.000 description 1
- 102000001555 Sialic Acid Binding Ig-like Lectin 3 Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100022831 Somatoliberin Human genes 0.000 description 1
- 101710142969 Somatoliberin Proteins 0.000 description 1
- 108010017622 Somatomedin Receptors Proteins 0.000 description 1
- 102000004584 Somatomedin Receptors Human genes 0.000 description 1
- 231100000632 Spindle poison Toxicity 0.000 description 1
- 241000133426 Streptomyces zelensis Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 108050006955 Tissue-type plasminogen activator Proteins 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 102000011117 Transforming Growth Factor beta2 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- 101800000304 Transforming growth factor beta-2 Proteins 0.000 description 1
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 description 1
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 102220589754 YjeF N-terminal domain-containing protein 3_G25F_mutation Human genes 0.000 description 1
- 239000000488 activin Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000012615 aggregate Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 229940094957 androgens and estrogen Drugs 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000013602 bacteriophage vector Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 108700001680 des-(1-3)- insulin-like growth factor 1 Proteins 0.000 description 1
- 125000001142 dicarboxylic acid group Chemical group 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000005414 dithiopyridyl group Chemical group 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 239000003687 estradiol congener Substances 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229910052587 fluorapatite Inorganic materials 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000013415 human tumor xenograft model Methods 0.000 description 1
- 210000004754 hybrid cell Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 102000028416 insulin-like growth factor binding Human genes 0.000 description 1
- 108091022911 insulin-like growth factor binding Proteins 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100000187 late toxicity Toxicity 0.000 description 1
- 108010034897 lentil lectin Proteins 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000003580 lung surfactant Substances 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000012516 mab select resin Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 229920000889 poly(m-phenylene isophthalamide) Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 108010087851 prorelaxin Proteins 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- ZCOSUVZGFDGWFV-UHFFFAOYSA-N pyrrolo[2,3-e]indole Chemical compound C1=CC2=NC=CC2=C2N=CC=C21 ZCOSUVZGFDGWFV-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- MKNJJMHQBYVHRS-UHFFFAOYSA-M sodium;1-[11-(2,5-dioxopyrrol-1-yl)undecanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCCCCCCCCCN1C(=O)C=CC1=O MKNJJMHQBYVHRS-UHFFFAOYSA-M 0.000 description 1
- ULARYIUTHAWJMU-UHFFFAOYSA-M sodium;1-[4-(2,5-dioxopyrrol-1-yl)butanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O ULARYIUTHAWJMU-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 230000034005 thiol-disulfide exchange Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 108010042974 transforming growth factor beta4 Proteins 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6819—Plant toxins
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6867—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
-
- 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
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Cell Biology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Toxicology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Botany (AREA)
- Analytical Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本出願は、2011年3月29日に出願された米国特許仮出願第61/468,997号の利益を主張するものであり、上記出願は参照により本明細書に組み込まれるものとする。
(電子提出された物件の参照による援用)
以下:
9,233バイトのASCII(テキスト)ファイル1件(名称「710088SequenceListing.TXT」、2013年4月3日作成)、
と特定される、コンピューターで可読なヌクレオチド/アミノ酸の配列表が、本明細書中、参照によりその全体が援用される。
物質を細胞結合物質と接触させて、細胞結合物質と細胞毒性物質とを含む混合物を形成した後に、混合物を二官能性架橋試薬と接触させることが不可欠である。
階a)の一定時間後(例えば、約1時間、約2時間、約3時間またはそれ以上後)に行う。別の実施形態では、段階c)を行う前に段階b)を複数回(例えば、1、2、3、4回またはそれ以上)繰り返してもよい。追加の段階b)は最初の段階b)の一定時間後(例えば、約1時間、約2時間、約3時間または後)に行ってもよい。
または約25℃)で行う。
抑えるものでもある。極性のある荷電チオール反応停止試薬(4-マレイミド酪酸または3-マレイミドプロピオン酸など)による反応停止の際には、過剰な未反応の細胞毒性物質が、精製段階で共有結合した複合体から容易に分離することが可能な極性のある荷電水溶性付加物に変換される。このほか非極性および中性のチオール反応停止試薬を使用することができる。
最初に選択的沈殿、吸着ろ過、吸着クロマトグラフィーまたは非吸着クロマトグラフィーにより複合体を精製し、次いでTFFにより精製する。当業者は、細胞結合物質-細胞毒性物質複合体の精製により、細胞毒性物質と化学的に結合した細胞結合物質を含む安定な複合体の単離が可能であることを理解するであろう。
、室温(例えば、約20℃~約30℃または約20℃~約25℃)または高温(例えば、約30℃~約37℃)に維持することを含む。一実施形態では、保持段階は、溶液を約16℃~約24℃の温度(例えば、約15℃、約16℃、約17℃、約18℃、約19℃、約20℃、約21℃、約22℃、約23℃、約24℃または約25℃)に維持することを含む。別の実施形態では、保持段階は、溶液を約2℃~約8℃の温度(例えば、約0℃、約1℃、約2℃、約3℃、約4℃、約5℃、約6℃、約7℃、約8℃、約9℃または約10℃)に維持することを含む。別の実施形態では、保持段階は、溶液を約37℃の温度(例えば、約34℃、約35℃、約36℃、約37℃、約38℃、約39℃または約40℃)に維持することを含む。
以下、6%以下、5%以下、4%以下、3%以下、2%以下、1%以下または0%)である(総リンカーに対して)、(c)複合体種の10%未満(例えば、約9%以下、8%以下、7%以下、6%以下、5%以下、4%以下、3%以下、2%以下、1%以下または0%)が架橋されている、(d)複合体調製物中の遊離の細胞毒性物質レベルが約2%未満(例えば、約1.5%以下、1.4%以下、1.3%以下、1.2%以下、1.1%以下、1.0%以下、0.9%以下、0.8%以下、0.7%以下、0.6%以下、0.5%以下、0.4%以下、0.3%以下、0.2%以下、0.1%以下または0%)(総細胞毒性物質に対するmol/mol)であるおよび/または(e)保管時(例えば、約1週間後、約2週間後、約3週間後、約1か月後、約2か月後、約3か月後、約4か月後、約5か月後、約6か月後、約1年後、約2年後、約3年後、約4年後または約5年後)に遊離の細胞毒性物質レベルの実質的な増加がみられない。遊離の細胞毒性物質レベルの「実質的な増加」は、特定の保管期間(例えば、約1週間、約2週間、約3週間、約1か月、約2か月、約3か月、約4か月、約5か月、約6か月、約1年、約2年、約3年、約4年または約5年)の後に遊離の細胞毒性物質レベルの増加が約0.1%未満、約0.2%未満、約0.3%未満、約0.4%未満、約0.5%未満、約0.6%未満、約0.7%未満、約0.8%未満、約0.9%未満、約1.0%未満、約1.1%未満、約1.2%未満、約1.3%未満、約1.4%未満、約1.5%未満、約1.6%未満、約1.7%未満、約1.8%未満、約1.9%未満、約2.0%未満、約2.2%未満、約2.5%未満、約2.7%未満、約3.0%未満、約3.2%未満、約3.5%未満、約3.7%未満または約4.0%未満であることを意味する。
1984))など、栄養素輸送分子(例えば、トランスフェリン)、ビタミン(例えば、葉酸塩)ならびに細胞表面の標的分子と特異的に結合する他の任意の物質または分子が挙げられる。
GEP、PSMA、PSCA、TMEFF2およびSTEAP1など;LGR5、B7H4ならびに任意の上記ポリペプチドのフラグメントなどの分子が挙げられる。
としては、例えば、酵素結合免疫吸着測定法(ELISA)、ウエスタンブロット分析およびラジオイムノアッセイが挙げられる。ハイブリドーマの集団をスクリーニングして、それぞれが抗原に対する単一の抗体種を分泌する個々のクローンを単離する。各ハイブリドーマは単一のB細胞との融合に由来するクローンであるため、それが産生する抗体分子はすべて、その抗原結合部位およびアイソタイプを含めた構造が同一である。またモノクローナル抗体を、EBV-ハイブリドーマ技術(例えば、HaskardおよびArcher,J.Immunol.Methods,74(2):361-67(1984)ならびにRoderら,Methods Enzymol.,121:140-67(1986)を参照)、バクテリオファージベクター発現システム(例えば、Huseら,Science,246:1275-81(1989)を参照)またはFabおよびscFv(一本鎖可変領域)などの抗体フラグメントを含むファージディスプレイライブラリー(例えば、米国特許第5,885,793号および同第5,969,108号ならびに国際公開第92/01047号および同第99/06587号を参照)を含めた他の適切な技術を用いて作製してもよい。
ークとヒト抗体のフレームワークが類似していることから、この方法により、抗原性がヒト抗体と同一であるが、CDR配列が由来するマウスモノクローナル抗体と同じ抗原と結合するモノクローナル抗体が作製されることが当該技術分野において一般に認められている。ヒト化抗体を作製する方法は当該技術分野で公知であり、例えば、Janewayら(上記)、米国特許第5,225,539号、同第5,585,089号および同第5,693,761号、欧州特許第0239400B1号ならびに英国特許第2188638号に詳細に記載されている。また、米国特許第5,639,641号およびPedersenら,J.Mol.Biol.,235:959-973(1994)に記載されている抗体リサーフィシング(resurfacing)技術を用いてヒト化抗体を作製してもよい。本発明の組成物の複合体で使用する抗体は、最も好ましくはヒト化モノクローナル抗体であるが、上記のようなヒトモノクローナル抗体およびマウスモノクローナル抗体も本発明の範囲内にある。
(2004)を参照)などであってもよい。
願公開第2010/0111979号、同第2009/0240038号、同第2009/0175887号、同第2009/0156790号および同第2009/0155282号に記載されている。また米国特許第7,982,024号に記載されているようなインスリン様成長因子受容体と結合する抗IGF-IR抗体も複合体に使用することができる。またCD27L、Cripto、CD138、CD38、EphA2、インテグリン、CD37、葉酸塩、CD20、PSGR、NGEP、PSCA、TMEFF2、STEAP1、エンドグリンおよびHer3と結合する抗体も複合体に使用することができる。
1、RASNLEA(配列番号5)を含む軽鎖CDR2およびQQSREYPYT(配列番号6)を含む軽鎖CDR3とを含み、式中、Xaa1はK、Q、HおよびRから選択され、Xaa2はQ、H、NおよびRから選択され、Xaa3はG、E、T、S、AおよびVから選択される。好ましくは、重鎖CDR2配列はRIHPYDGDTFYNQKFQG(配列番号7)を含む。
QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号8)
を有する重鎖を含む。
QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSS(配列番号9)
と少なくとも約90%、95%、99%または100%同一である重鎖可変ドメインと、DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLNISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKR(配列番号10);または
DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKR(配列番号11)と少なくとも約90%、95%、99%または100%同一である軽鎖可変ドメインとを含む、ヒト化抗体またはその抗原結合フラグメントである。
Today,5:155-158(1984)を参照)、ソマトスタチンおよびトランスフェリン(例えば、O’Keefeら,J.Biol.Chem.,260:932-
937(1985)を参照)が挙げられる。例えば、GM-CSFは骨髄性細胞と結合し、急性骨髄性白血病細胞を標的とする細胞結合物質として使用することができる。さらに、IL-2は活性化T細胞と結合し、移植片拒絶反応の予防、移植片対宿主病の治療および予防ならびに急性T細胞白血病の治療に使用することができる。上皮成長因子(EGF)は肺癌および頭頸部癌などの扁平上皮癌を標的とするのに使用することができる。ソマトスタチンは神経芽腫細胞その他の腫瘍細胞型を標的とするのに使用することができる。
個の炭素原子を有する環状アルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、さらに、置換基の1つがHであってよく、アシル基が、カルボニル官能基と硫黄原子との間に少なくとも炭素原子3個の直鎖長を有するアシル化アミノ酸側鎖とを有する、マイタンシノイドである。
Y’は(CR7R8)l(CR9=CR10)p(C≡C)qAo(CR5R6)mDu(CR11=CR12)r(C≡C)sBt(CR3R4)nCR1R2SZを表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく,
A、B、Dは、3~10個の炭素原子を有するシクロアルキルもしくはシクロアルケニル、単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
R3、R4、R5、R6、R7、R8、R9、R10、R11およびR12は、それぞれ独立してH、CH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、m、n、o、p、q、r、sおよびtは、それぞれ独立してゼロまたは1~5の整数であり、ただし、l、m、n、o、p、q、r、sおよびtのうちの少なくとも2つは同時にゼロになることがなく、
ZはH、SRまたはCORであり、式中、Rは1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルである。
であり、R2がメチルであり、Zが-SCH3である、ならびに(d)R1およびR2がメチルであり、Zが-SCH3である、式(III)の化合物が挙げられる。
Yは(CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZを表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく、
R3、R4、R5、R6、R7およびR8は、それぞれ独立してH、CH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、mおよびnは、それぞれ独立して1~5の整数であり、さらにnはゼロであってもよく、
Zは、H、SRまたはCORであり、式中、Rは、1~10個の炭素原子を有する直鎖もしくは分岐のアルキルもしくはアルケニル、3~10個の炭素原子を有する環状アルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
Mayは、C-3、C-14ヒドロキシメチル、C-15ヒドロキシまたはC-20デスメチルに側鎖を有するマイタンシノイドを表す。
Yは(CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZを表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく、
R3、R4、R5、R6、R7およびR8は、それぞれ独立してH、CH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、mおよびnは、それぞれ独立して1~5の整数であり、さらにnはゼロであってもよく、
Zは、H、SRまたはCORであり、式中、Rは、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルである。
Y2は(CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ2を表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく、
R3、R4、R5、R6、R7およびR8は、それぞれ独立してH、CH3、C2H5、1~10個の炭素原子を有する直鎖環状アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、mおよびnは、それぞれ独立して1~5の整数であり、さらにnはゼロであってもよく、
Z2は、SRまたはCORであり、式中、Rは、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、または単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
Mayは、マイタンシノイドの大環状構造である。
Y2’は(CR7R8)l(CR9=CR10)p(C≡C)qAo(CR5R6)mD
u(CR11=CR12)r(C≡C)sBt(CR3R4)nCR1R2SZ2を表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1~10個の炭素原子を有する直鎖分岐もしくはアルキルもしくはアルケニル、3~10個の炭素原子を有する環状アルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、さらにR2はHであってもよく、
A、BおよびDは、それぞれ独立して3~10個の炭素原子を有するシクロアルキルもしくはシクロアルケニル、単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
R3、R4、R5、R6、R7、R8、R9、R10、R11およびR12は、それぞれ独立してH、CH3、C2H5、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、m、n、o、p、q、r、sおよびtは、それぞれ独立してゼロまたは1~5の整数であり、ただし、l、m、n、o、p、q、r、sおよびtのうちの少なくとも2つは同時にゼロになることがなく、
Z2は、SRまたは-CORであり、式中、Rは、1~10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3~10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルである。
物(例えば、米国特許第6,630,579号を参照)も細胞毒性物質として使用することができる。
IAB)、N-スクシンイミジル-ヨードアセタート(SIA)、N-スクシンイミジル-ブロモアセタート(SBA)およびN-スクシンイミジル-3-(ブロモアセトアミド)プロピオナート(SBAP)、ビス-マレイミドポリエチレングリコール(BMPEO)、BM(PEO)2、BM(PEO)3、N-(β-マレイミドプロピルオキシ)スクシンイミドエステル(BMPS)、5-マレイミド吉草酸NHS、HBVS、4-(4-N-マレイミドフェニル)-酪酸ヒドラジド・HCl(MPBH)、スクシンイミジル-(4-ビニルスルホニル)ベンゾアート(SVSB),ジチオビス-マレイミドエタン(DTME)、1,4-ビス-マレイミドブタン(BMB)、1,4-ビスマレイミジル-2,3-ジヒドロキシブタン(BMDB)、ビス-マレイミドヘキサン(BMH)、ビス-マレイミドエタン(BMOE)、スルホスクシンイミジル-4-(N-マレイミド-メチル)シクロヘキサン-1-カルボキシラート(スルホ-SMCC)、スルホスクシンイミジル(4-ヨード-アセチル)アミノベンゾアート(スルホ-SIAB)、m-マレイミドベンゾイル-N-ヒドロキシスルホスクシンイミドエステル(スルホ-MBS)、N-(γ-マレイミドブトリルオキシ)スルホスクシンイミドエステル(スルホ-GMBS)、N-(ε-マレイミドカプロイルオキシ)スルホスクシミド(sulfosuccimido)エステル(スルホ-EMCS)、N-(κ-マレイミドウンデカノイルオキシ)スルホスクシンイミドエステル(スルホ-KMUS)、スルホスクシンイミジル-4-(p-マレイミドフェニル)ブチラート(スルホ-SMPB)CX1-1、スルホ-MalおよびPEGn-Malが挙げられる。好ましくは、二官能性架橋試薬はSMCCである。
可能なリンカーは穏やかな条件下、すなわち、細胞毒性物質の活性が影響を受けない細胞内条件下で切断される。
一般式(IX):
HOOC-Xl-Yn-Zm-COOH
(IX)
のα,ω-ジカルボン酸が挙げられ、上式中、Xは、2~20個の炭素原子を有する直鎖または分岐のアルキル、アルケニルまたはアルキニル基であり、Yは、3~10個の炭素原子を有するシクロアルキルまたはシクロアルケニル基であり、Zは、6~10個の炭素原子を有する置換もしくは非置換芳香族基またはヘテロ原子がN、OもしくはSから選択される置換もしくは非置換複素環基であり、l、mおよびnは、それぞれ0または1であり、ただし、l、mおよびnは同時にすべてがゼロになることはない。
これまでに記載されている工程(例えば、米国特許第5,208,020号)および本出願の対象である1段階の工程を用いて、ヒト化CD37-3抗体をヘテロ二官能性架橋試薬SMCCおよびマイタンシノイドDM1と反応させた。
H6.9)中、16℃で90分間実施した。1M酢酸塩で反応を停止させてpHを4.5に調整し、修飾抗体を、平衡化したSephadex G-25F樹脂のカラムを用いて精製し、2mM EDTAを含有する20mM酢酸ナトリウム(pH4.5)で溶出させた。精製後、修飾抗体(5mg/mL)をマイタンシノイドDM1(抗体量に対して6.8倍モル過剰;測定された抗体上のリンカー量に対して1.3倍過剰)と反応させて、コンジュゲート抗体を形成した。コンジュゲーション反応を、2mM EDTAと5%DMAとを含有する20mM酢酸ナトリウム緩衝液(pH5.0)中、20℃で約20時間実施した。次いで反応混合物を、平衡化したSephadex G-25F樹脂のカラムを用いて精製し、10mMコハク酸ナトリウム(pH5.0)で溶出させた。
これまでに記載されている2つの工程および本出願の対象である改善された工程を用いて、ヒト化葉酸受容体抗体huMov19(米国特許出願公開第2012/0009181号を参照)をヘテロ二官能性架橋試薬スルホ-SPDBおよびマイタンシノイドDM4と反応させた。
この実施例は、本明細書に記載の1段階の工程を用いて、各種のリンカーおよびマイタンシノイド細胞毒性物質から出発して複合体を製造し得ることを示すものである。
Claims (27)
- 細胞結合物質-細胞毒性物質複合体を調製する工程であって、
(a)細胞結合物質を細胞毒性物質と接触させて、前記細胞結合物質と前記細胞毒性物質とを含む第一の混合物を形成し、次いで、前記第一の混合物をpHが約4~約9の溶液中でリンカーを含む二官能性架橋試薬と接触させて、(i)前記細胞結合物質が前記リンカーを介して前記細胞毒性物質と化学的に結合している前記細胞結合物質-細胞毒性物質複合体と、(ii)遊離の細胞毒性物質と、(iii)反応副生成物とを含む第二の混合物を得る段階
を含む工程。 - (b)前記細胞結合物質-細胞毒性物質複合体を含む前記第二の混合物を精製して、精製された細胞結合物質-細胞毒性物質複合体を得る段階をさらに含む、請求項1に記載の工程。
- 前記第二の混合物をタンジェンシャルフローろ過、選択的沈殿、吸着ろ過、吸着クロマトグラフィー、非吸着クロマトグラフィーまたはその組合せに供することにより精製して、前記細胞結合物質-細胞毒性物質複合体を前記遊離の細胞毒性物質および前記反応副生成物から精製する、請求項2に記載の工程。
- 前記第二の混合物をタンジェンシャルフローろ過に供することにより精製する、請求項3に記載の工程。
- 前記段階(a)の接触が、前記細胞結合物質を反応容器中に準備し、前記反応容器に前記細胞毒性物質を加えて、前記細胞結合物質と前記細胞毒性物質とを含む前記第一の混合物を形成し、次いで、前記二官能性架橋試薬を前記第一の混合物に加えることにより行われる、請求項1~4のいずれか1項に記載の工程。
- 前記第二の混合物を段階(a)と段階(b)の間で保持して、不安定に結合したリンカーを前記細胞結合物質から解離させることをさらに含む、請求項2~5のいずれか1項に記載の工程。
- 前記第二の混合物を約2℃~約8℃の温度で約20時間保持する、請求項6に記載の工程。
- 前記第二の混合物の反応を段階(a)と段階(b)の間で停止させて、任意の未反応の細胞毒性物質および/または未反応の二官能性架橋試薬の反応を停止させることをさらに含む、請求項2~7のいずれか1項に記載の工程。
- 前記第二の混合物を前記遊離の細胞毒性物質と反応する反応停止試薬と接触させることにより、前記混合物の反応を停止させる、請求項8に記載の工程。
- 前記反応停止試薬が、4-マレイミド酪酸、3-マレイミドプロピオン酸、N-エチルマレイミド、ヨードアセトアミドおよびヨードアセトアミドプロピオン酸からなる群より選択される、請求項9に記載の工程。
- 前記段階(a)の接触が、pHが約7~約9の溶液中で行われる、請求項1~10のいずれか1項に記載の工程。
- 前記段階(a)の接触が約16℃~約24℃の温度で行われる、請求項1~11のいず
れか1項に記載の工程。 - 前記段階(a)の接触が約0℃~約15℃の温度で行われる、請求項1~11のいずれか1項に記載の工程。
- 前記細胞結合物質が抗体である、請求項1~13のいずれか1項に記載の工程。
- 前記抗体がモノクローナル抗体である、請求項14に記載の工程。
- 前記抗体がヒト化モノクローナル抗体である、請求項15に記載の工程。
- 前記抗体が、huN901、huMy9-6、huB4、huC242、トラスツズマブ、ビバツズマブ、シブロツズマブ、CNTO95、huDS6、リツキシマブ、抗Her2、抗EGFR、抗CD27L、抗EGFRvIII、Cripto、抗CD138、抗CD38、抗EphA2、インテグリン標的抗体、抗CD37、抗葉酸、抗Her3および抗IGFIRからなる群より選択される、請求項14~16のいずれか1項に記載の工程。
- 前記細胞毒性物質がマイタンシノイドである、請求項1~17のいずれか1項に記載の工程。
- 前記マイタンシノイドがチオール基を含む、請求項18に記載の工程。
- 前記マイタンシノイドがN2’-デアセチル-N2’-(3-メルカプト-1-オキソプロピル)-マイタンシン(DM1)である、請求項19に記載の工程。
- 前記マイタンシノイドがN2’-デアセチル-N2’-(4-メチル-4-メルカプト-1-オキソペンチル)-マイタンシン(DM4)である、請求項19に記載の工程。
- 前記細胞結合物質が、ジスルフィド結合、酸に不安定な結合、光に不安定な結合、ペプチダーゼに不安定な結合、チオエーテル結合およびエステラーゼに不安定な結合からなる群より選択される化学結合を介して前記細胞毒性物質と化学的に結合している、請求項1~21のいずれか1項に記載の工程。
- 前記二官能性架橋試薬が、N-スクシンイミジルエステル部分、N-スルホスクシンイミジルエステル部分、マレイミド系部分またはハロアセチル系部分を含む、請求項1~22のいずれか1項に記載の工程。
- 前記二官能性架橋試薬が、SPDP、SPP、SPDB、スルホ-SPDB、SMCC、PEG-mal、スルホ-MalおよびCX1-1からなる群より選択される、請求項23に記載の工程。
- 前記段階(a)の溶液がスクロースを含む、請求項1~24のいずれか1項に記載の工程。
- 前記段階(a)の溶液が、クエン酸緩衝剤、酢酸緩衝剤、コハク酸緩衝剤およびリン酸緩衝剤からなる群より選択される緩衝剤を含む、請求項1~25のいずれか1項に記載の工程。
- 前記段階(a)の溶液が、HEPPSO(N-(2-ヒドロキシエチル)ピペラジン-
N’-(2-ヒドロキシプロパンスルホン酸))、POPSO(ピペラジン-1,4-ビス-(2-ヒドロキシ-プロパン-スルホン酸)無水物)、HEPES(4-(2-ヒドロキシエチル)ピペラジン-1-エタンスルホン酸)、HEPPS(EPPS)(4-(2-ヒドロキシエチル)ピペラジン-1-プロパンスルホン酸)、TES(N-[トリス(ヒドロキシメチル)メチル]-2-アミノエタンスルホン酸)およびその組合せからなる群より選択される緩衝剤を含む、請求項1~25のいずれか1項に記載の工程。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161468997P | 2011-03-29 | 2011-03-29 | |
US61/468,997 | 2011-03-29 | ||
JP2020191507A JP7269210B2 (ja) | 2011-03-29 | 2020-11-18 | 1段階の工程によるマイタンシノイド-抗体複合体の調製 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020191507A Division JP7269210B2 (ja) | 2011-03-29 | 2020-11-18 | 1段階の工程によるマイタンシノイド-抗体複合体の調製 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2023083504A true JP2023083504A (ja) | 2023-06-15 |
Family
ID=46928080
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014502803A Active JP6000329B2 (ja) | 2011-03-29 | 2012-03-29 | 1段階の工程によるマイタンシノイド−抗体複合体の調製 |
JP2016167618A Active JP6456885B2 (ja) | 2011-03-29 | 2016-08-30 | 1段階の工程によるマイタンシノイド−抗体複合体の調製 |
JP2018236944A Active JP6797885B2 (ja) | 2011-03-29 | 2018-12-19 | 1段階の工程によるマイタンシノイド−抗体複合体の調製 |
JP2020191507A Active JP7269210B2 (ja) | 2011-03-29 | 2020-11-18 | 1段階の工程によるマイタンシノイド-抗体複合体の調製 |
JP2023070124A Pending JP2023083504A (ja) | 2011-03-29 | 2023-04-21 | 1段階の工程によるマイタンシノイド-抗体複合体の調製 |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014502803A Active JP6000329B2 (ja) | 2011-03-29 | 2012-03-29 | 1段階の工程によるマイタンシノイド−抗体複合体の調製 |
JP2016167618A Active JP6456885B2 (ja) | 2011-03-29 | 2016-08-30 | 1段階の工程によるマイタンシノイド−抗体複合体の調製 |
JP2018236944A Active JP6797885B2 (ja) | 2011-03-29 | 2018-12-19 | 1段階の工程によるマイタンシノイド−抗体複合体の調製 |
JP2020191507A Active JP7269210B2 (ja) | 2011-03-29 | 2020-11-18 | 1段階の工程によるマイタンシノイド-抗体複合体の調製 |
Country Status (25)
Country | Link |
---|---|
US (7) | US8795673B2 (ja) |
EP (2) | EP3545977A1 (ja) |
JP (5) | JP6000329B2 (ja) |
KR (6) | KR102351886B1 (ja) |
CN (2) | CN103717262B (ja) |
AU (5) | AU2012236398B2 (ja) |
CA (1) | CA2831467C (ja) |
CY (1) | CY1121321T1 (ja) |
DK (1) | DK2691155T3 (ja) |
EA (2) | EA201991268A3 (ja) |
ES (1) | ES2709577T3 (ja) |
HR (1) | HRP20190243T1 (ja) |
HU (1) | HUE041384T2 (ja) |
IL (3) | IL228559A (ja) |
LT (1) | LT2691155T (ja) |
ME (1) | ME03353B (ja) |
MX (2) | MX339927B (ja) |
NZ (1) | NZ726386A (ja) |
PL (1) | PL2691155T3 (ja) |
PT (1) | PT2691155T (ja) |
RS (1) | RS58367B1 (ja) |
SI (1) | SI2691155T1 (ja) |
TR (1) | TR201902180T4 (ja) |
UA (1) | UA116524C2 (ja) |
ZA (1) | ZA201605918B (ja) |
Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8288557B2 (en) | 2004-07-23 | 2012-10-16 | Endocyte, Inc. | Bivalent linkers and conjugates thereof |
US20110166319A1 (en) * | 2005-02-11 | 2011-07-07 | Immunogen, Inc. | Process for preparing purified drug conjugates |
CA2794554C (en) | 2005-08-24 | 2015-09-22 | Immunogen, Inc. | Process for preparing antibody maytansinoid conjugates |
CA2680535C (en) | 2007-03-14 | 2016-09-20 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
ES2732879T3 (es) | 2007-06-25 | 2019-11-26 | Endocyte Inc | Conjugados que contienen enlazantes espaciadores hidrófilos |
US9877965B2 (en) | 2007-06-25 | 2018-01-30 | Endocyte, Inc. | Vitamin receptor drug delivery conjugates for treating inflammation |
SG10201810743WA (en) | 2009-06-03 | 2018-12-28 | Immunogen Inc | Conjugation methods |
SG10201501342UA (en) | 2010-02-24 | 2015-04-29 | Immunogen Inc | Folate receptor 1 antibodies and immunoconjugates and uses thereof |
AR080513A1 (es) | 2010-03-12 | 2012-04-11 | Inmunogen Inc | Moleculas de union cd37 y sus inmunoconjugados |
PL2691155T3 (pl) | 2011-03-29 | 2019-06-28 | Immunogen, Inc. | Otrzymywanie koniugatu majtansynoidu przeciwciała jednoetapowym sposobem |
KR20200039843A (ko) * | 2011-04-01 | 2020-04-16 | 이뮤노젠 아이엔씨 | Folr1 암 치료의 효능을 증가시키기 위한 방법 |
WO2013126797A1 (en) | 2012-02-24 | 2013-08-29 | Purdue Research Foundation | Cholecystokinin b receptor targeting for imaging and therapy |
US20140080175A1 (en) | 2012-03-29 | 2014-03-20 | Endocyte, Inc. | Processes for preparing tubulysin derivatives and conjugates thereof |
NZ630433A (en) | 2012-08-31 | 2017-10-27 | Immunogen Inc | Antibodies and uses thereof to detect folate receptor 1 |
RU2018122734A (ru) | 2012-10-04 | 2018-07-24 | Иммуноджен, Инк. | Использование пвдф-мембраны для очистки конъюгатов клеточно-связывающий агент-цитотоксический агент |
WO2014055842A1 (en) * | 2012-10-04 | 2014-04-10 | Immunogen, Inc. | Process for preparing stable antibody maytansinoid conjugates |
WO2014055893A1 (en) * | 2012-10-04 | 2014-04-10 | Immunogen, Inc. | Use of an ion exchange membrane to remove impurities from cell-binding agent cytotoxic agent conjugates |
MX2015004757A (es) | 2012-10-16 | 2015-07-17 | Endocyte Inc | Conjugados de suministro de farmacos que contienen aminoacidos no naturales y metodo para usarlos. |
US8769557B1 (en) | 2012-12-27 | 2014-07-01 | The Nielsen Company (Us), Llc | Methods and apparatus to determine engagement levels of audience members |
US9999680B2 (en) | 2013-02-28 | 2018-06-19 | Immunogen, Inc. | Conjugates comprising cell-binding agents and maytansinoids as cytotoxic agents |
EP2961435B1 (en) | 2013-02-28 | 2019-05-01 | ImmunoGen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
ES2701051T3 (es) | 2013-03-15 | 2019-02-20 | Novartis Ag | Conjugados de anticuerpo-fármaco |
WO2014194030A2 (en) | 2013-05-31 | 2014-12-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
SI3038650T1 (sl) | 2013-08-30 | 2021-11-30 | Immunogen, Inc. | Protitelesa in preiskave za odkrivanje folatnega receptorja 1 |
TWI541022B (zh) * | 2013-12-18 | 2016-07-11 | 應克隆公司 | 針對纖維母細胞生長因子受體-3(fgfr3)之化合物及治療方法 |
MA39313B1 (fr) | 2014-03-11 | 2018-12-31 | Regeneron Pharma | Anticorps anti-egfrviii et leurs utilisations dans le traitement de divers cancers |
US10973920B2 (en) | 2014-06-30 | 2021-04-13 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
TN2016000577A1 (en) | 2014-08-12 | 2018-04-04 | Novartis Ag | Anti-cdh6 antibody drug conjugates |
MA40968A (fr) * | 2014-10-31 | 2017-10-04 | Formation Biologics Inc | Polythérapie à base d'anticorps anti-egfr |
CN106267225B (zh) * | 2015-05-29 | 2020-03-06 | 上海新理念生物医药科技有限公司 | 三马来酰亚胺型连接子及其应用 |
TW201711702A (zh) | 2015-06-04 | 2017-04-01 | 應克隆公司 | 使用針對纖維母細胞生長因子受體3(fgfr3)之化合物的療法 |
JP6979877B2 (ja) | 2015-06-08 | 2021-12-15 | デビオファーム インターナショナル, エス. アー. | 抗cd37イムノコンジュゲートおよび抗cd20抗体の組み合わせ |
EP3310813A1 (en) | 2015-06-17 | 2018-04-25 | Novartis AG | Antibody drug conjugates |
MX2018002467A (es) * | 2015-08-28 | 2018-06-15 | Debiopharm Int Sa | Anticuerpos y ensayos para deteccion del antigeno leucocitico (cd37). |
EP3349796A4 (en) | 2015-09-17 | 2019-05-29 | ImmunoGen, Inc. | THERAPEUTIC COMBINATIONS COMPRISING ANTI-FOLR1 IMMUNOCONJUGATES |
DK3380525T3 (da) | 2015-11-25 | 2024-01-29 | Immunogen Inc | Farmaceutiske formuleringer og fremgangsmåder til anvendelse deraf |
CN108601848A (zh) * | 2016-02-05 | 2018-09-28 | 伊缪诺金公司 | 用于制备细胞结合剂-细胞毒性剂缀合物的有效方法 |
CN108421048B (zh) * | 2016-09-28 | 2021-04-20 | 首都医科大学附属北京世纪坛医院 | 纳米活性碳靶向药物递送系统、制备方法及其用途 |
US11278629B2 (en) | 2016-11-02 | 2022-03-22 | Debiopharm International, S.A. | Methods for improving anti-CD37 immunoconjugate therapy |
US10864279B2 (en) | 2016-12-16 | 2020-12-15 | Industrial Technology Research Institute | Linker-drug and antibody-drug conjugate (ADC) employing the same |
JOP20190187A1 (ar) | 2017-02-03 | 2019-08-01 | Novartis Ag | مترافقات عقار جسم مضاد لـ ccr7 |
KR20240110082A (ko) * | 2017-02-28 | 2024-07-12 | 이뮤노젠 아이엔씨 | 자기희생적 펩티드 링커 및 이들의 접합체를 갖는 메이탄시노이드 유도체 |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
CN111867621A (zh) * | 2018-01-18 | 2020-10-30 | 美真达治疗公司 | 用于耗尽cd134+细胞的组合物和方法 |
EP3552631A1 (en) | 2018-04-10 | 2019-10-16 | Inatherys | Antibody-drug conjugates and their uses for the treatment of cancer |
CN111620927B (zh) * | 2019-05-20 | 2022-11-11 | 烟台迈百瑞国际生物医药股份有限公司 | 一种抗体药物偶联物中间体的一锅法制备工艺 |
CN114096279A (zh) * | 2019-06-25 | 2022-02-25 | 塔弗达治疗有限公司 | Sstr靶向缀合物及其制剂 |
PE20220485A1 (es) | 2019-07-10 | 2022-04-04 | Cybrexa 3 Inc | Conjugados peptidicos de agentes dirigidos a microtubulos como terapeuticos |
WO2021007435A1 (en) | 2019-07-10 | 2021-01-14 | Cybrexa 2, Inc. | Peptide conjugates of cytotoxins as therapeutics |
US20230181756A1 (en) | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
AU2022441090A1 (en) | 2022-02-17 | 2024-08-22 | Novelty Nobility Inc. | Antibody-drug conjugate. |
Family Cites Families (166)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1043543A (en) | 1912-02-15 | 1912-11-05 | Robert H Shaw | Poultry-house door. |
SE430062B (sv) | 1977-03-04 | 1983-10-17 | Pharmacia Fine Chemicals Ab | Kopplings- eller tioleringsreagens |
US4137230A (en) * | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4563304A (en) | 1981-02-27 | 1986-01-07 | Pharmacia Fine Chemicals Ab | Pyridine compounds modifying proteins, polypeptides or polysaccharides |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4664911A (en) | 1983-06-21 | 1987-05-12 | Board Of Regents, University Of Texas System | Immunotoxin conjugates employing toxin B chain moieties |
DE3584012D1 (de) | 1985-01-22 | 1991-10-10 | Saint Gobain Vitrage | Verfahren zur herstellung eines pulvers auf basis von indium-formiat zur herstellung einer duennen beschichtung auf einem substrat, insbesondere auf glas. |
GB8600582D0 (en) | 1986-01-10 | 1986-02-19 | Ca Minister Nat Defence | Purifying biological materials |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US4859449A (en) | 1987-09-14 | 1989-08-22 | Center For Molecular Medicine And Immunology | Modified antibodies for enhanced hepatocyte clearance |
US5241078A (en) | 1988-06-14 | 1993-08-31 | Cetus Oncology | Coupling agents and sterically hindered disulfide linked conjugates prepared therefrom |
US5024834A (en) | 1988-07-12 | 1991-06-18 | Cetus Corporation | Thioether linked immunotoxin conjugates |
CA2006408A1 (en) | 1988-12-27 | 1990-06-27 | Susumu Iwasa | Bispecific monoclonal antibody, its production and use |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5714149A (en) | 1989-02-10 | 1998-02-03 | Celltech Therapeutics Limited | Crosslinked antibodies and processes for their preparation |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
CA2026147C (en) | 1989-10-25 | 2006-02-07 | Ravi J. Chari | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US6316003B1 (en) | 1989-12-21 | 2001-11-13 | Whitehead Institute For Biomedical Research | Tat-derived transport polypeptides |
US5137877B1 (en) | 1990-05-14 | 1996-01-30 | Bristol Myers Squibb Co | Bifunctional linking compounds conjugates and methods for their production |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
ATE300615T1 (de) | 1990-08-29 | 2005-08-15 | Genpharm Int | Transgene mäuse fähig zur produktion heterologer antikörper |
CA2048078A1 (en) | 1990-11-15 | 1992-05-16 | Wolfgang A. Wrasidlo | Chemical modification of antibodies for creation of immunoconjugates |
US5252714A (en) * | 1990-11-28 | 1993-10-12 | The University Of Alabama In Huntsville | Preparation and use of polyethylene glycol propionaldehyde |
SE9102074D0 (sv) | 1991-07-03 | 1991-07-03 | Kabi Pharmacia Ab | Tomour antigen specific antibody |
SE470006B (sv) * | 1991-09-26 | 1993-10-25 | Corline Systems Ab | Nytt konjugat, dess framställning och användning samt substrat preparerat med konjugatet |
DK1024191T3 (da) | 1991-12-02 | 2008-12-08 | Medical Res Council | Fremstilling af autoantistoffer fremvist på fag-overflader ud fra antistofsegmentbiblioteker |
CA2076465C (en) | 1992-03-25 | 2002-11-26 | Ravi V. J. Chari | Cell binding agent conjugates of analogues and derivatives of cc-1065 |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US5556623A (en) * | 1993-03-30 | 1996-09-17 | Eli Lilly And Company | Antibody-drug conjugates |
IL111748A0 (en) | 1993-12-03 | 1995-01-24 | Zeneca Ltd | Proteins |
US5747446A (en) | 1994-03-22 | 1998-05-05 | Beth Israel Deaconess Medical Center | Modified polypeptides with increased biological activity |
US5580853A (en) | 1994-03-22 | 1996-12-03 | New England Deaconess Hospital | Modified polypeptides with increased biological activity |
US5919758A (en) | 1994-03-22 | 1999-07-06 | Beth Israel Deaconess Medical Center | Modified polypeptides with altered biological activity |
US5612474A (en) | 1994-06-30 | 1997-03-18 | Eli Lilly And Company | Acid labile immunoconjugate intermediates |
AU5908296A (en) * | 1995-05-31 | 1996-12-24 | Fred Hutchinson Cancer Research Center | Compositions and methods for targeted delivery of effector m olecules |
US6265150B1 (en) | 1995-06-07 | 2001-07-24 | Becton Dickinson & Company | Phage antibodies |
US5714352A (en) | 1996-03-20 | 1998-02-03 | Xenotech Incorporated | Directed switch-mediated DNA recombination |
US5958872A (en) | 1996-04-01 | 1999-09-28 | Apoptosis Technology, Inc. | Active survival domains of IGF-IR and methods of use |
WO1998026747A2 (en) | 1996-12-17 | 1998-06-25 | Terman David S | Superantigen based methods and compositions for treatment of diseases |
US6462070B1 (en) * | 1997-03-06 | 2002-10-08 | The General Hospital Corporation | Photosensitizer conjugates for pathogen targeting |
US6371975B2 (en) * | 1998-11-06 | 2002-04-16 | Neomend, Inc. | Compositions, systems, and methods for creating in situ, chemically cross-linked, mechanical barriers |
ES2231991T3 (es) * | 1997-06-11 | 2005-05-16 | Borean Pharma A/S | Modulo de trimerizacion. |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US5958677A (en) | 1997-07-28 | 1999-09-28 | The New York Blood Center, Inc. | Method for purifying viral nucleic acids |
JP2002501721A (ja) | 1997-08-01 | 2002-01-22 | モルフォシス・アクチェンゲゼルシャフト | 多量体(ポリ)ペプチドコンプレックスのメンバーをコードする核酸配列を同定するための新規方法およびファージ |
US5965714A (en) | 1997-10-02 | 1999-10-12 | Connaught Laboratories, Inc. | Method for the covalent attachment of polysaccharides to protein molecules |
IL135148A0 (en) * | 1997-10-03 | 2001-05-20 | Galenica Pharmaceuticals Inc | A polysaccharide conjugate and pharmaceutical compositions containing the same |
US6121236A (en) * | 1998-03-24 | 2000-09-19 | The Children's Medical Center Corporation | Multivalent ligands which modulate angiogenesis |
EP1073667A2 (en) * | 1998-04-28 | 2001-02-07 | Galenica Pharmaceuticals, Inc. | Polysaccharide-antigen conjugates |
US5981564A (en) * | 1998-07-01 | 1999-11-09 | Universite Laval | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
ES2188202T3 (es) | 1998-07-13 | 2003-06-16 | Univ Texas | Metodos de tratamiento para el cancer usando conjugados terapeuticos que se enlazan con aminofosfolipidos. |
TW593241B (en) | 1999-04-20 | 2004-06-21 | Hoffmann La Roche | Carbamic acid derivatives |
AUPQ014799A0 (en) * | 1999-05-04 | 1999-05-27 | Access Pharmaceuticals Australia Pty Limited | Amplification of folate-mediated targeting to tumor cells using polymers |
WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
DK1242401T3 (da) | 1999-11-24 | 2007-05-07 | Immunogen Inc | Cytotoksiske midler, der omfatter taxaner, og den terapeutiske anvendelse deraf |
DE60031793T2 (de) | 1999-12-29 | 2007-08-23 | Immunogen Inc., Cambridge | Doxorubicin- und daunorubicin-enthaltende, zytotoxische mittel und deren therapeutische anwendung |
WO2001058479A1 (en) | 2000-02-08 | 2001-08-16 | The Penn State Research Foundation | Immunotherapy using interleukin 13 receptor subunit alpha 2 |
US7097840B2 (en) * | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
US6632979B2 (en) | 2000-03-16 | 2003-10-14 | Genentech, Inc. | Rodent HER2 tumor model |
US6596503B1 (en) | 2000-08-18 | 2003-07-22 | East Carolina University | Monoclonal antibody DS6, tumor-associated antigen CA6, and methods of use thereof |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US20060062786A1 (en) | 2000-11-08 | 2006-03-23 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to TRAIL receptors |
AU2002231368C1 (en) | 2001-01-05 | 2018-08-16 | Amgen Fremont Inc. | Antibodies to insulin-like growth factor I receptor |
EA007388B1 (ru) | 2001-01-29 | 2006-10-27 | Идек Фармасьютикалз Корпорейшн | Модифицированные антитела и способы применения |
ATE337011T1 (de) * | 2001-02-07 | 2006-09-15 | Beth Israel Hospital | Modifizierte psma-liganden und deren verwendung |
US20020197261A1 (en) | 2001-04-26 | 2002-12-26 | Chun Li | Therapeutic agent/ligand conjugate compositions, their methods of synthesis and use |
KR100863624B1 (ko) | 2001-05-11 | 2008-10-15 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | Cd26을 발현하는 세포와 연관된 질환의 치료제로사용되는 항-cd26 단클론항체 |
EP1258255A1 (en) | 2001-05-18 | 2002-11-20 | Boehringer Ingelheim International GmbH | Conjugates of an antibody to CD44 and a maytansinoid |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
WO2002098897A2 (en) | 2001-06-01 | 2002-12-12 | Cornell Research Foundation, Inc. | Modified antibodies to prostate-specific membrane antigen and uses thereof |
TW593239B (en) | 2001-06-04 | 2004-06-21 | Kevin Dale Allen | One-step production of 1,3-propanediol from ethylene oxide and syngas with a catalyst with a phospholanoalkane ligand |
JP2005532415A (ja) | 2001-12-11 | 2005-10-27 | メルク エンド カムパニー インコーポレーテッド | スタフィロコッカス・アウレウスエキソポリサッカライド及び方法 |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
AU2003201824A1 (en) | 2002-01-03 | 2003-07-24 | Smithkline Beecham Corporation | Methods for preparing immunoconjugates |
US8877901B2 (en) | 2002-12-13 | 2014-11-04 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US7591994B2 (en) * | 2002-12-13 | 2009-09-22 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US6534660B1 (en) | 2002-04-05 | 2003-03-18 | Immunogen, Inc. | CC-1065 analog synthesis |
US6756397B2 (en) | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
JP4319979B2 (ja) | 2002-04-26 | 2009-08-26 | ジェネンテック・インコーポレーテッド | タンパク質の非アフィニティ精製 |
HUE030806T2 (hu) | 2002-05-02 | 2017-05-29 | Wyeth Holdings Llc | Calicheamicin származék-hordozó konjugátumok |
US20090068178A1 (en) | 2002-05-08 | 2009-03-12 | Genentech, Inc. | Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin |
US6596757B1 (en) | 2002-05-14 | 2003-07-22 | Immunogen Inc. | Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use |
JP2005530845A (ja) | 2002-06-21 | 2005-10-13 | アイデック ファーマシューティカルズ コーポレイション | 抗体を濃縮するための緩衝化処方物およびその使用方法 |
US7390898B2 (en) | 2002-08-02 | 2008-06-24 | Immunogen Inc. | Cytotoxic agents containing novel potent taxanes and their therapeutic use |
WO2004016801A2 (en) | 2002-08-16 | 2004-02-26 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
AU2003273413A1 (en) * | 2002-10-08 | 2004-05-04 | Fresenius Kabi Deutschland Gmbh | Pharmaceutically active oligosaccharide conjugates |
DK2348125T3 (en) * | 2002-10-30 | 2017-10-02 | Nuevolution As | Process for the synthesis of a bifunctional complex |
CA2504818C (en) | 2002-11-07 | 2013-04-23 | Immunogen, Inc. | Anti-cd33 antibodies and method for treatment of acute myeloid leukemia using the same |
EA009285B1 (ru) | 2003-05-14 | 2007-12-28 | Иммуноджен, Инк. | Композиция конъюгированного лекарственного средства |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
US7276497B2 (en) * | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
PT3524611T (pt) | 2003-05-20 | 2021-04-01 | Immunogen Inc | Agentes citotóxicos melhorados compreendendo novos maitansinóides |
KR101435167B1 (ko) | 2003-06-27 | 2014-11-04 | 암젠 프레몬트 인코포레이티드 | 상피 성장 인자 수용체의 결실 돌연변이체 지향 항체 및 그용도 |
US20050074425A1 (en) * | 2003-07-02 | 2005-04-07 | Polycord, Inc. | Method for delivering polymerized therapeutic agent compositions and compositions thereof |
CA2542886A1 (en) * | 2003-11-05 | 2005-05-19 | Neelima M. Bhat | Enhanced b cell cytotoxicity of cdim binding antibody |
US20050175619A1 (en) | 2004-02-05 | 2005-08-11 | Robert Duffy | Methods of producing antibody conjugates |
US20110064754A1 (en) | 2005-03-03 | 2011-03-17 | Center For Molecular Medicine And Immunology | Immunoconjugates Comprising Poxvirus-Derived Peptides and Antibodies Against Antigen-Presenting Cells for Subunit-Based Poxvirus Vaccines |
WO2005094882A1 (en) | 2004-03-03 | 2005-10-13 | Millennium Pharmaceuticals, Inc. | Modified antibodies to prostate-specific membrane antigen and uses thereof |
WO2005115477A2 (en) | 2004-04-13 | 2005-12-08 | Quintessence Biosciences, Inc. | Non-natural ribonuclease conjugates as cytotoxic agents |
US20060073528A1 (en) * | 2004-05-14 | 2006-04-06 | Jean-Michel Lecerf | Measurement methods |
MXPA06013413A (es) | 2004-05-19 | 2007-01-23 | Medarex Inc | Enlazadores quimicos y conjugados de los mismos. |
RU2402548C2 (ru) | 2004-05-19 | 2010-10-27 | Медарекс, Инк. | Химические линкеры и их конъюгаты |
NZ579482A (en) | 2004-06-01 | 2011-02-25 | Genentech Inc | Antibody drug conjugates and methods |
AU2004224925C1 (en) | 2004-08-30 | 2011-07-21 | Biotest Ag | Immunoconjugates targeting syndecan-1 expressing cells and use thereof |
AR052774A1 (es) | 2004-10-08 | 2007-04-04 | Wyeth Corp | Inmunoterapia para trastornos autoinmunes |
AU2005316844A1 (en) | 2004-11-29 | 2006-06-22 | Seattle Genetics, Inc. | Engineered antibodies and immunoconjugates |
CA2591148A1 (en) | 2004-12-09 | 2006-06-15 | Centocor, Inc. | Anti-integrin immunoconjugates, methods and uses |
US7408030B2 (en) | 2005-01-13 | 2008-08-05 | North Carolina State University | Purification of immunoglobulins using affinity chromatography and peptide ligands |
US20110166319A1 (en) * | 2005-02-11 | 2011-07-07 | Immunogen, Inc. | Process for preparing purified drug conjugates |
EP1853322B1 (en) | 2005-02-11 | 2014-06-25 | ImmunoGen, Inc. | Process for preparing maytansinoid antibody conjugates |
US7678371B2 (en) | 2005-03-04 | 2010-03-16 | Biogen Idec Ma Inc. | Methods of humanizing immunoglobulin variable regions through rational modification of complementarity determining residues |
CA2618721A1 (en) | 2005-04-15 | 2006-10-26 | Immunogen, Inc. | Elimination of heterogeneous or mixed cell population in tumors |
GB2427360A (en) * | 2005-06-22 | 2006-12-27 | Complex Biosystems Gmbh | Aliphatic prodrug linker |
BRPI0613005A8 (pt) | 2005-07-15 | 2017-12-26 | Angiochem Inc | uso de polipeptídeos de aprotinina como veículos em conjugados farmacêuticos. |
CA2615122A1 (en) * | 2005-08-03 | 2007-02-15 | Immunogen, Inc. | Immunoconjugate formulations |
JP2009506302A (ja) * | 2005-08-04 | 2009-02-12 | イェシバ・ユニバーシティ | Ablによるタウのリン酸化 |
CA2794554C (en) * | 2005-08-24 | 2015-09-22 | Immunogen, Inc. | Process for preparing antibody maytansinoid conjugates |
JP2009508938A (ja) * | 2005-09-22 | 2009-03-05 | ハダシット メディカル リサーチ サーヴィスィズ アンド ディベロップメント リミテッド | 治療上活性な化合物の結合体 |
NZ566982A (en) | 2005-09-26 | 2011-06-30 | Medarex Inc | Duocarmycin drug conjugates |
WO2007059195A1 (en) | 2005-11-14 | 2007-05-24 | University Of Southern California | Integrin-binding small molecules |
US7964415B2 (en) * | 2006-04-26 | 2011-06-21 | Cardiogenics Inc. | Stable water-soluble polyethylenimine conjugates and methods of use thereof |
MX2008015132A (es) | 2006-05-30 | 2008-12-10 | Genentech Inc | Anticuerpos e inmunoconjugados y sus usos. |
KR101528939B1 (ko) | 2006-07-18 | 2015-06-15 | 사노피 | 암 치료를 위한 epha2에 대한 길항제 항체 |
US20080213349A1 (en) * | 2006-09-11 | 2008-09-04 | Deepak Ramesh Thakker | Liposome Complexes Containing Pharmaceutical Agents and Methods |
WO2008057683A2 (en) | 2006-10-03 | 2008-05-15 | Novo Nordisk A/S | Methods for the purification of polypeptide conjugates |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
PL2019104T3 (pl) | 2007-07-19 | 2014-03-31 | Sanofi Sa | Środki cytotoksyczne obejmujące nowe pochodne tomaymycyny i ich zastosowanie terapeutyczne |
RU2487877C2 (ru) | 2008-04-30 | 2013-07-20 | Иммьюноджен, Инк. | Высокоэффективные конъюгаты и гидрофильные сшивающие агенты (линкеры) |
NO2281006T3 (ja) * | 2008-04-30 | 2017-12-30 | ||
GB0811743D0 (en) * | 2008-06-26 | 2008-07-30 | Hemosol Biopharma Inc | Composition |
JP2012509273A (ja) * | 2008-11-17 | 2012-04-19 | エンゾン ファーマシューティカルズ,インコーポレーテッド | 核酸送達系のための放出可能融合性脂質 |
RU2545080C2 (ru) | 2009-02-05 | 2015-03-27 | Иммьюноджен, Инк. | Новые производные бензодиазепина |
AR076284A1 (es) | 2009-04-29 | 2011-06-01 | Bayer Schering Pharma Ag | Inmunoconjugados de antimesotelina y usos de los mismos |
SG10201810743WA (en) | 2009-06-03 | 2018-12-28 | Immunogen Inc | Conjugation methods |
FR2947269B1 (fr) | 2009-06-29 | 2013-01-18 | Sanofi Aventis | Nouveaux composes anticancereux |
TW201117814A (en) | 2009-10-02 | 2011-06-01 | Sanofi Aventis | New maytansinoids and the use of said maytansinoids to prepare conjugates with an antibody |
AR078470A1 (es) | 2009-10-02 | 2011-11-09 | Sanofi Aventis | Anticuerpos que se unen especificamente al receptor epha2 |
SG10201501342UA (en) | 2010-02-24 | 2015-04-29 | Immunogen Inc | Folate receptor 1 antibodies and immunoconjugates and uses thereof |
KR20110103182A (ko) | 2010-03-12 | 2011-09-20 | 삼성전자주식회사 | 입체 영상 표시 장치 |
AR080513A1 (es) | 2010-03-12 | 2012-04-11 | Inmunogen Inc | Moleculas de union cd37 y sus inmunoconjugados |
WO2012019024A2 (en) | 2010-08-04 | 2012-02-09 | Immunogen, Inc. | Her3-binding molecules and immunoconjugates thereof |
US20120149732A1 (en) * | 2010-12-14 | 2012-06-14 | Alexander Chucholowski | Multifunctional linkers and methods for the use thereof |
EP2675481A1 (en) * | 2011-02-15 | 2013-12-25 | ImmunoGen, Inc. | Cytotoxic benzodiazepine derivatives and methods of preparation |
US20120259100A1 (en) | 2011-03-29 | 2012-10-11 | Immunogen, Inc. | Process for manufacturing conjugates of improved homogeneity |
SG193997A1 (en) | 2011-03-29 | 2013-11-29 | Immunogen Inc | Process for manufacturing conjugates of improved homogeneity |
PL2691155T3 (pl) | 2011-03-29 | 2019-06-28 | Immunogen, Inc. | Otrzymywanie koniugatu majtansynoidu przeciwciała jednoetapowym sposobem |
KR20200039843A (ko) | 2011-04-01 | 2020-04-16 | 이뮤노젠 아이엔씨 | Folr1 암 치료의 효능을 증가시키기 위한 방법 |
US20130071482A1 (en) * | 2011-09-20 | 2013-03-21 | The University Of Kentucky Research Foundation | Block copolymer cross-linked nanoassemblies as modular delivery vehicles |
SG10201604747WA (en) | 2011-12-13 | 2016-08-30 | Immunogen Inc | Use of n-hydroxysuccinimide to improve conjugate stability |
WO2014055842A1 (en) | 2012-10-04 | 2014-04-10 | Immunogen, Inc. | Process for preparing stable antibody maytansinoid conjugates |
WO2014055893A1 (en) | 2012-10-04 | 2014-04-10 | Immunogen, Inc. | Use of an ion exchange membrane to remove impurities from cell-binding agent cytotoxic agent conjugates |
RU2018122734A (ru) | 2012-10-04 | 2018-07-24 | Иммуноджен, Инк. | Использование пвдф-мембраны для очистки конъюгатов клеточно-связывающий агент-цитотоксический агент |
TR201905612T4 (tr) * | 2012-12-05 | 2019-05-21 | Univ Heidelberg Ruprecht Karls | Proteinlerin ve çok değerlikli, hücreye nüfuz eden peptitlerin konjugatları ve bunların kullanımları. |
-
2012
- 2012-03-29 PL PL12714160T patent/PL2691155T3/pl unknown
- 2012-03-29 DK DK12714160.4T patent/DK2691155T3/en active
- 2012-03-29 KR KR1020217019701A patent/KR102351886B1/ko active IP Right Grant
- 2012-03-29 CN CN201280016107.4A patent/CN103717262B/zh active Active
- 2012-03-29 US US13/434,451 patent/US8795673B2/en active Active
- 2012-03-29 NZ NZ726386A patent/NZ726386A/en unknown
- 2012-03-29 RS RS20190189A patent/RS58367B1/sr unknown
- 2012-03-29 EA EA201991268A patent/EA201991268A3/ru unknown
- 2012-03-29 EP EP18199729.7A patent/EP3545977A1/en not_active Withdrawn
- 2012-03-29 MX MX2013011215A patent/MX339927B/es active IP Right Grant
- 2012-03-29 CA CA2831467A patent/CA2831467C/en active Active
- 2012-03-29 ES ES12714160T patent/ES2709577T3/es active Active
- 2012-03-29 CN CN201710705089.5A patent/CN107537040A/zh active Pending
- 2012-03-29 PT PT12714160T patent/PT2691155T/pt unknown
- 2012-03-29 LT LTEP12714160.4T patent/LT2691155T/lt unknown
- 2012-03-29 JP JP2014502803A patent/JP6000329B2/ja active Active
- 2012-03-29 HU HUE12714160A patent/HUE041384T2/hu unknown
- 2012-03-29 EA EA201391398A patent/EA033468B1/ru unknown
- 2012-03-29 AU AU2012236398A patent/AU2012236398B2/en active Active
- 2012-03-29 KR KR1020137028135A patent/KR102103302B1/ko active IP Right Grant
- 2012-03-29 TR TR2019/02180T patent/TR201902180T4/tr unknown
- 2012-03-29 KR KR1020207010853A patent/KR102272828B1/ko active IP Right Grant
- 2012-03-29 KR KR1020227000970A patent/KR20220009505A/ko not_active Application Discontinuation
- 2012-03-29 MX MX2016007829A patent/MX369659B/es unknown
- 2012-03-29 KR KR1020237029015A patent/KR20230128583A/ko not_active Application Discontinuation
- 2012-03-29 ME MEP-2019-34A patent/ME03353B/me unknown
- 2012-03-29 KR KR1020227028603A patent/KR20220123130A/ko not_active Application Discontinuation
- 2012-03-29 UA UAA201312640A patent/UA116524C2/uk unknown
- 2012-03-29 EP EP12714160.4A patent/EP2691155B1/en active Active
- 2012-03-29 SI SI201231538T patent/SI2691155T1/sl unknown
-
2013
- 2013-09-29 IL IL228559A patent/IL228559A/en active IP Right Grant
-
2014
- 2014-06-24 US US14/313,868 patent/US9428543B2/en active Active
-
2016
- 2016-05-03 AU AU2016202832A patent/AU2016202832B2/en active Active
- 2016-07-21 US US15/215,857 patent/US9914748B2/en active Active
- 2016-08-25 ZA ZA2016/05918A patent/ZA201605918B/en unknown
- 2016-08-30 JP JP2016167618A patent/JP6456885B2/ja active Active
-
2017
- 2017-02-22 IL IL250723A patent/IL250723B/en active IP Right Grant
-
2018
- 2018-02-01 US US15/886,495 patent/US10435432B2/en active Active
- 2018-04-25 IL IL258929A patent/IL258929B/en active IP Right Grant
- 2018-08-03 AU AU2018211331A patent/AU2018211331B2/en active Active
- 2018-12-19 JP JP2018236944A patent/JP6797885B2/ja active Active
-
2019
- 2019-02-05 HR HRP20190243TT patent/HRP20190243T1/hr unknown
- 2019-02-07 CY CY20191100166T patent/CY1121321T1/el unknown
-
2020
- 2020-02-11 US US16/787,942 patent/US11090390B2/en active Active
- 2020-08-10 AU AU2020217301A patent/AU2020217301B2/en active Active
- 2020-11-18 JP JP2020191507A patent/JP7269210B2/ja active Active
-
2021
- 2021-07-09 US US17/371,151 patent/US11744900B2/en active Active
-
2023
- 2023-04-21 JP JP2023070124A patent/JP2023083504A/ja active Pending
- 2023-07-14 US US18/352,362 patent/US20240156976A1/en active Pending
-
2024
- 2024-01-09 AU AU2024200123A patent/AU2024200123A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7269210B2 (ja) | 1段階の工程によるマイタンシノイド-抗体複合体の調製 | |
JP2014510757A (ja) | 均質性が改善された複合体を製造する工程 | |
WO2012135517A2 (en) | Preparation of maytansinoid antibody conjugates by a one-step process | |
NZ712414B2 (en) | Preparation of antibody maytansinoid conjugates | |
NZ616509B2 (en) | Preparation of maytansinoid antibody conjugates by a one-step process |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230519 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20230519 |
|
RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20230522 |
|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20230522 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230522 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240507 |