CN111655295B - 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 - Google Patents
抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 Download PDFInfo
- Publication number
- CN111655295B CN111655295B CN201980002467.0A CN201980002467A CN111655295B CN 111655295 B CN111655295 B CN 111655295B CN 201980002467 A CN201980002467 A CN 201980002467A CN 111655295 B CN111655295 B CN 111655295B
- Authority
- CN
- China
- Prior art keywords
- antibody
- urothelial cancer
- use according
- her2
- medicament
- 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.)
- Active
Links
- 206010044412 transitional cell carcinoma Diseases 0.000 title claims abstract description 61
- 238000011282 treatment Methods 0.000 title claims abstract description 45
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims abstract description 27
- 239000000611 antibody drug conjugate Substances 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 38
- 206010061289 metastatic neoplasm Diseases 0.000 claims abstract description 20
- 230000001394 metastastic effect Effects 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000012634 fragment Substances 0.000 claims description 26
- 210000004408 hybridoma Anatomy 0.000 claims description 15
- 231100000433 cytotoxic Toxicity 0.000 claims description 12
- 230000001472 cytotoxic effect Effects 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical group CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 7
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 7
- 230000036961 partial effect Effects 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 241001529936 Murinae Species 0.000 claims description 6
- 239000003223 protective agent Substances 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- -1 protectants Substances 0.000 claims description 4
- 238000002271 resection Methods 0.000 claims description 4
- 238000009629 microbiological culture Methods 0.000 claims description 3
- 108010093470 monomethyl auristatin E Proteins 0.000 claims description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 238000010521 absorption reaction Methods 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003623 enhancer Substances 0.000 claims 1
- 239000012669 liquid formulation Substances 0.000 claims 1
- 239000012931 lyophilized formulation Substances 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 238000011105 stabilization Methods 0.000 claims 1
- 230000004083 survival effect Effects 0.000 abstract description 17
- 230000027455 binding Effects 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
- 206010028980 Neoplasm Diseases 0.000 description 23
- 229940079593 drug Drugs 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 16
- 229940022353 herceptin Drugs 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 238000002965 ELISA Methods 0.000 description 13
- 229960003852 atezolizumab Drugs 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 12
- 210000003932 urinary bladder Anatomy 0.000 description 12
- 206010027476 Metastases Diseases 0.000 description 11
- 230000009401 metastasis Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 238000001356 surgical procedure Methods 0.000 description 10
- 230000003321 amplification Effects 0.000 description 9
- 238000003199 nucleic acid amplification method Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 150000001413 amino acids Chemical group 0.000 description 8
- 239000000427 antigen Substances 0.000 description 8
- 102000036639 antigens Human genes 0.000 description 8
- 108091007433 antigens Proteins 0.000 description 8
- 238000000137 annealing Methods 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 238000004925 denaturation Methods 0.000 description 7
- 230000036425 denaturation Effects 0.000 description 7
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000003364 immunohistochemistry Methods 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 6
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 6
- 206010005003 Bladder cancer Diseases 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 241000283707 Capra Species 0.000 description 5
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 5
- 108091008794 FGF receptors Proteins 0.000 description 5
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 5
- 208000007433 Lymphatic Metastasis Diseases 0.000 description 5
- 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 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 229960003668 docetaxel Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229960003301 nivolumab Drugs 0.000 description 5
- 210000000626 ureter Anatomy 0.000 description 5
- 201000005112 urinary bladder cancer Diseases 0.000 description 5
- 208000023747 urothelial carcinoma Diseases 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- 102000008096 B7-H1 Antigen Human genes 0.000 description 4
- 108010074708 B7-H1 Antigen Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 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
- 241000699670 Mus sp. Species 0.000 description 4
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 4
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 4
- 238000012300 Sequence Analysis Methods 0.000 description 4
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 210000000244 kidney pelvis Anatomy 0.000 description 4
- 230000036210 malignancy Effects 0.000 description 4
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000010839 reverse transcription Methods 0.000 description 4
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 3
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 3
- 229940123237 Taxane Drugs 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 108010044540 auristatin Proteins 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 239000003433 contraceptive agent Substances 0.000 description 3
- 230000002254 contraceptive effect Effects 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 229950004444 erdafitinib Drugs 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- OLAHOMJCDNXHFI-UHFFFAOYSA-N n'-(3,5-dimethoxyphenyl)-n'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylethane-1,2-diamine Chemical compound COC1=CC(OC)=CC(N(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 OLAHOMJCDNXHFI-UHFFFAOYSA-N 0.000 description 3
- 238000007857 nested PCR Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000003708 urethra Anatomy 0.000 description 3
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 2
- LGNCNVVZCUVPOT-FUVGGWJZSA-N (2s)-2-[[(2r,3r)-3-[(2s)-1-[(3r,4s,5s)-4-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-methoxy-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 LGNCNVVZCUVPOT-FUVGGWJZSA-N 0.000 description 2
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 2
- 229930190007 Baccatin Natural products 0.000 description 2
- 239000012623 DNA damaging agent Substances 0.000 description 2
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 2
- 101150081124 FGFR gene Proteins 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 206010027458 Metastases to lung Diseases 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000012197 amplification kit Methods 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 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 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 229930188854 dolastatin Natural products 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229960005501 duocarmycin Drugs 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
- 229930184221 duocarmycin Natural products 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- 238000002509 fluorescent in situ hybridization Methods 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 230000001024 immunotherapeutic effect Effects 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 208000020984 malignant renal pelvis neoplasm Diseases 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical class CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 2
- 210000005015 mediastinal lymph node Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 108010059074 monomethylauristatin F Proteins 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000011518 platinum-based chemotherapy Methods 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000012257 pre-denaturation Methods 0.000 description 2
- 238000007639 printing Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000011521 systemic chemotherapy Methods 0.000 description 2
- 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 2
- 238000012360 testing method Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 239000003744 tubulin modulator Substances 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 210000003741 urothelium Anatomy 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 2
- 229960000922 vinflunine Drugs 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- XWIYFDMXXLINPU-UHFFFAOYSA-N Aflatoxin G Chemical class O=C1OCCC2=C1C(=O)OC1=C2C(OC)=CC2=C1C1C=COC1O2 XWIYFDMXXLINPU-UHFFFAOYSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- 108010027164 Amanitins Proteins 0.000 description 1
- PSUXEQYPYZLNER-QXEWZRGKSA-N Arg-Val-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PSUXEQYPYZLNER-QXEWZRGKSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- ALMIMUZAWTUNIO-BZSNNMDCSA-N Asp-Tyr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ALMIMUZAWTUNIO-BZSNNMDCSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- AUJXLBOHYWTPFV-BLWRDSOESA-N CS[C@H]1SC[C@H]2N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C(=O)[C@@H]1N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C2=O)NC(=O)c1cnc2ccccc2n1)NC(=O)c1cnc2ccccc2n1 Chemical compound CS[C@H]1SC[C@H]2N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C(=O)[C@@H]1N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C2=O)NC(=O)c1cnc2ccccc2n1)NC(=O)c1cnc2ccccc2n1 AUJXLBOHYWTPFV-BLWRDSOESA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 241000255749 Coccinellidae Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 238000011537 Coomassie blue staining Methods 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 108010009858 Echinomycin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- ILKYYKRAULNYMS-JYJNAYRXSA-N Gln-Lys-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ILKYYKRAULNYMS-JYJNAYRXSA-N 0.000 description 1
- LCNXZQROPKFGQK-WHFBIAKZSA-N Gly-Asp-Ser Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O LCNXZQROPKFGQK-WHFBIAKZSA-N 0.000 description 1
- FLYSHWAAHYNKRT-JYJNAYRXSA-N His-Gln-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FLYSHWAAHYNKRT-JYJNAYRXSA-N 0.000 description 1
- 206010048612 Hydrothorax Diseases 0.000 description 1
- 208000004044 Hypesthesia Diseases 0.000 description 1
- LVQDUPQUJZWKSU-PYJNHQTQSA-N Ile-Arg-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N LVQDUPQUJZWKSU-PYJNHQTQSA-N 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 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 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 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 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- KIGGUSRFHJCIEJ-DCAQKATOSA-N Pro-Asp-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O KIGGUSRFHJCIEJ-DCAQKATOSA-N 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010041101 Small intestinal obstruction Diseases 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- YJQCOFNZVFGCAF-UHFFFAOYSA-N Tunicamycin II Natural products O1C(CC(O)C2C(C(O)C(O2)N2C(NC(=O)C=C2)=O)O)C(O)C(O)C(NC(=O)C=CCCCCCCCCC(C)C)C1OC1OC(CO)C(O)C(O)C1NC(C)=O YJQCOFNZVFGCAF-UHFFFAOYSA-N 0.000 description 1
- GZWPQZDVTBZVEP-BZSNNMDCSA-N Tyr-Tyr-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O GZWPQZDVTBZVEP-BZSNNMDCSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- RUDNHCHNENLLKM-UHFFFAOYSA-N ac1mj1v6 Chemical compound O=C1NC(CC(O)=O)C(=O)N2CC(O)CC2C(=O)NC(C(C)C(O)CO)C(=O)NC(C2)C(=O)NCC(=O)NC(C(C)CC)C(=O)NCC(=O)NC1CSC1=C2C2=CC=C(O)C=C2N1 RUDNHCHNENLLKM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000036981 active tuberculosis Diseases 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 150000004814 combretastatins Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000011985 exploratory data analysis Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000008134 glucuronides Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 208000034783 hypoesthesia Diseases 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000001114 myogenic effect Effects 0.000 description 1
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical compound CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 210000002097 psoas muscle Anatomy 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 1
- AUJXLBOHYWTPFV-UHFFFAOYSA-N quinomycin A Natural products CN1C(=O)C(C)NC(=O)C(NC(=O)C=2N=C3C=CC=CC3=NC=2)COC(=O)C(C(C)C)N(C)C(=O)C2N(C)C(=O)C(C)NC(=O)C(NC(=O)C=3N=C4C=CC=CC4=NC=3)COC(=O)C(C(C)C)N(C)C(=O)C1CSC2SC AUJXLBOHYWTPFV-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229930185156 spinosyn Natural products 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 108010042747 stallimycin Proteins 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940066453 tecentriq Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 229930184737 tubulysin Natural products 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- ZHSGGJXRNHWHRS-VIDYELAYSA-N tunicamycin Chemical compound O([C@H]1[C@@H]([C@H]([C@@H](O)[C@@H](CC(O)[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C(NC(=O)C=C2)=O)O)O1)O)NC(=O)/C=C/CC(C)C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O ZHSGGJXRNHWHRS-VIDYELAYSA-N 0.000 description 1
- MEYZYGMYMLNUHJ-UHFFFAOYSA-N tunicamycin Natural products CC(C)CCCCCCCCCC=CC(=O)NC1C(O)C(O)C(CC(O)C2OC(C(O)C2O)N3C=CC(=O)NC3=O)OC1OC4OC(CO)C(O)C(O)C4NC(=O)C MEYZYGMYMLNUHJ-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 210000001113 umbilicus Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
-
- 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
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- 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
-
- 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
- A61K47/6847—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 hormone or a hormone-releasing or -inhibiting factor
-
- 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
- A61K47/6855—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 breast cancer cell
-
- 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
- A61K47/6861—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 kidney or bladder cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Otolaryngology (AREA)
- Toxicology (AREA)
- Hematology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及抗HER2抗体药物偶联物(ADC)在制备用于治疗尿路上皮癌的药物中的用途。本发明所述的药物对于尿路上皮癌特别是局部晚期或转移性尿路上皮癌患者安全有效,能有效延长患者生存期。
Description
技术领域
本发明涉及一种抗HER2(人类表皮生长因子受体2,human epidermal growthfactor receptor 2)抗体药物偶联物在治疗尿路上皮癌中的用途。
背景技术
尿路上皮细胞癌(Urothelial carcinoma,UC;或称移行细胞癌,Transitionalcell carcinoma,TCC)是一种癌症类型,其通常存在于泌尿系统:肾、膀胱和附属器官中。其为膀胱癌和输尿管、尿道和脐尿管癌症的最常见类型。其为第二最常见的肾癌类型,占所有原发性肾脏恶性肿瘤的5-10%。
尿路上皮(也称为过渡性上皮)是膀胱,输尿管和尿道内侧以及肾盂(尿液收集的肾脏部分)内衬。它由尿路上皮细胞或过渡细胞组成。这些细胞可以变成癌细胞,即称为尿路上皮癌(或移行细胞癌)。
根据癌变细胞的侵入性,尿路上皮癌可以是非侵入性的(仅在膀胱的衬里中)或侵入性的(生长到膀胱壁的其他层中)。其中,非侵入性尿路上皮癌仅在膀胱内膜中并且未在膀胱壁中更深地生长。在诊断时,50%-60%的尿路上皮癌患者的肿瘤为非侵入性的。非侵入性尿路上皮癌的类型包括:非侵袭性扁平尿路上皮癌(也称为原位癌);非侵袭性乳头状尿路上皮癌,高级别;非侵袭性乳头状尿路上皮癌,低度恶性;具有低恶性潜能的非侵袭性乳头状尿路上皮肿瘤发展成侵袭性癌症的可能性很小。
相比之下,侵入性尿路上皮癌从膀胱内膜生长到膀胱壁的较深层,例如结缔组织(称为固有层)和肌肉层(称为肌层)。在诊断时,40%-50%的尿路上皮癌患者的肿瘤为侵袭性的。
理论上,尿路上皮癌可以从泌尿道的任何部位开始,包括但不限于肾盂、输尿管、膀胱或尿道。
当相关肿瘤细胞未转移时,手术切除治疗为首选的治疗方案,对于肿瘤已经转移的患者,一般需要采取抗癌药物治疗,目前的一线疗法是:吉西他滨和顺铂的联合疗法;而放射疗法针对尿路上皮癌的效果并不理想,一般用作辅助治疗的手段;当治疗肾盂/输尿管上皮中的癌时,可以使用BCG注射疗法(导管注射牛结核杆菌)。
尿路上皮癌具有多中心,易复发的特点,对于肿瘤累及肌层的患者首选膀胱全切,且术后还需严格规律复查,因此,治疗难度大,复发率高。(李学松,王刚,张骞编.泌尿外科病例精粹,北京大学医学出版社,2017)。在术后早期(24小时内)作为一次性剂量或在外科手术后几周作为六剂量方案将丝裂霉素(一种化疗药物)给予至膀胱中也是部分患者可选择的治疗方案。目前基于顺铂的化疗仍然是转移性UC患者的治疗金标准,基于顺铂的化疗的总体反应率(ORR)为60-70%,总生存期(OS)为14-15个月,5年生存率为13-15%,复发后的患者基于铂的化疗,ORR约为15%,中位OS约为7个月。
在欧洲已批准长春氟宁用于治疗泌尿上皮晚期或转移性TCC(Bellmunt,J.等人,JClin Oncol.27(27):4454-4461(2009))。经单一药剂疗法测试,若干药剂已显示适中活性,且中值存活期为5至10个月(Yafi,F.A.等人,Current Oncol.18(1):e25-e34(2011))。在转移性情况中,多西他赛(Docetaxel)作为缓解性选择向移行细胞癌患者投与(NCCN 2014),且美国及加拿大(Canada)医学界基于来自2期研究的证据认可多西他赛治疗晚期疾病的方案(WO2016/064649A1)。
近年来,治疗尿路上皮癌的新药主要有:1.罗氏的Atezolizumab是2016年批准上市的首个抗PD-L1癌症免疫治疗药物,根据最新的Atezolizumab治疗局部晚期或转移性尿道膀胱癌三期临床试验(IMvigor211)试验结果表明:Atezolizumab未满足III期IMvigor211试验的主要临床终点,即改善局部晚期或转移性尿路上皮癌(mUC)患者二线治疗的总生存期(OS),在共234例患者(atezolizumab组116例,化疗组118例)中,atezolizumab组的中位总生存期为11.1个月,化疗组为10.6个月;该人群中可评估患者的确诊客观反应率分别为23%和22%,中位反应持续时间为15.9个月对8.3个月。
该人群的中位无进展生存期为2.4个月(对照为4.2个月),在意向治疗人群的探索性分析中,12个月的总生存率数据:atezolizumab为39.2%,化疗为32.4%;atezolizumab的中位总生存期为8.3个月,紫杉烷为7.5个月,长春氟宁为9.2个月。(The ASCO Post,IMvigor211Trial:Atezolizumab vs Chemotherapy in Platinum-Treated AdvancedUrothelial Carcinoma,Matthew Stenger,9/17/2018)
此外,由于美国数据监测委员会观测到使用Atezolizumab单一疗法与基于铂的化疗疗法相比,发现了PD-L1的低表达肿瘤患者的存活率下降的问题,因此在2018年6月,美国FDA发出了限制Atezolizumab(Tecentriq)在适合含顺铂化疗的局部晚期或转移性尿路上皮癌患者中使用的要求。要求在使用Atezolizumab前需先行检测PD-L1表达水平。这进一步表明了Atezolizumab应用于治疗尿路上皮癌的局限性。
2.百时美施贵宝公司的Nivolumab于2017年被FDA批准用于局部晚期或转移性尿路上皮癌患者,Nivolumab是一种抗PD-1单克隆抗体,临床数据显示,Nivolumab的客观缓解率(ORR)为19.6%,中位数总生存率为8.7个月,最常见严重不良事件包括:尿路感染,败血症,腹泻,小肠梗阻,以及总体健康状况退化。最常见的不良反应包括疲劳,肌与骨骼疼痛,恶心,以及食欲减退。17%患者因不良反应停止Nivolumab治疗,46%患者因不良反应延迟给药。在临床开展中,出现了3例患者由于肺炎或心血管衰竭导致与治疗相关的死亡。
综合以上内容来看,目前临床阶段的PD-L1/PD-1免疫治疗药物的主要问题是治疗效果不佳,主要体现在客观缓解率(ORR)和中位数总生存期等治疗数据方面不理想,另一个主要问题是严重不良反应占比相对较高,例如:Nivolumab在相关临床试验中造成3例死亡病例。
3.强生公司旗下的杨森公司的erdafitinib在2018年被FDA授予突破性药物资格,用于治疗接受化疗后病情进展且肿瘤中存在特定成纤维细胞生长因子(FGFR)基因改变的局部晚期或转移性尿路上皮癌患者的治疗,该药物属于一种成纤维细胞生长因子受体(FGFR)酪氨酸激酶抑制剂;其二期临床研究(BLC2001,NCT02365597)的结果显示,erdafitinib治疗的总缓解率为40%(完全缓解率3%,部分缓解率37%),中位无进展生存期为5.5个月,中位总生存期13.8个月,在总计99例患者中,7例患者因治疗相关不良事件停止治疗(https://www.j nj.com/media-center/press-releases/erdafitinib-phase-2-study-results-show-promise-in-the-treatment-of-metastatic-urothelial-cancer)。由于该药的治疗靶点是FGFR,因此,其仅适用于具有某些FGFR基因突变的尿路上皮癌患者,而FGFR仅在15%至20%的转移性尿路上皮癌和40%至70%的非肌层浸润性膀胱癌过表达(2018 ASCO Annual Meeting,Responses Found in Advanced Urothelial CarcinomaWith FGFR Inhibitor)。
从目前的治疗来看,晚期尿路上皮癌恶性程度高,预后差,特别是常规化疗失败后,治疗手段有限,免疫治疗仅能使部分患者获益,而且可用的免疫治疗抑制剂数量也极为有限,客观缓解率不高,治疗副作用较大,或者使用存在特定基因要求;目前患者能够选择的治疗药物并不多,因此,仍需要开发治疗效果更为显著、适用更广的药物,以满足临床的迫切需求。
发明内容
本发明公开了一种治疗尿路上皮癌的方法,所述方法包括向患者注射有效量的抗体药物偶联物(ADC),所述ADC为抗HER2抗体偶联细胞毒分子。所述细胞毒分子包括但不限于微管蛋白抑制剂或DNA损伤剂。所述微管蛋白抑制剂包括但不限于海兔毒素(dolastatin)及奥瑞他汀(auristatin)类细胞毒分子,美登素(maytansine)类细胞毒分子;所述DNA损伤剂包括但不限于卡奇霉素(calicheamicin)类、倍癌霉素(duocarmycin)类、安曲霉素类衍生物PBD(pyrrolobenzodiazepine,吡咯并苯并二氮杂)、喜树碱类衍生物SN-38。所述奥瑞他汀(auristatin)类细胞素分子包括但不限于单甲基澳瑞他汀E(monomethyl auristatin E;MMAE)、单甲基澳瑞他汀F(monomethyl auristatin F;MMAF)、和澳瑞他汀F(auristatin F;AF)或它们的衍生物,所述美登素类细胞毒分子包括但不限于DM1、DM3、DM4或它们的衍生物(抗体药物偶联物的弹头分子研究进展,胡馨月等,中国医药生物技术,2017年12月,第12卷第6期)(美登素类抗体药物偶联物研究进展,周磊等,中国新药杂志2016年第25卷第22期,第2521-2530页)。所述细胞毒分子还可以是瓢菌素(amanitins)、蒽环类物(anthracyclines)、浆果赤霉素(baccatins)、喜树碱(camptothecins)、西马多丁(cemadotins)、秋水仙碱(colchicines)、秋水仙胺(colcimids)、考布他汀(combretastatins)、隐菲辛(cryptophycins)、圆皮海绵内酯(discodermolides)、多烯紫杉醇(docetaxel)、阿霉素(doxorubicin)、棘霉素(echinomycins)、艾榴塞洛素(eleutherobins)、埃博霉素(epothilones)、雌莫司汀(estramustines)、偏端霉素(lexitropsins)、美登素(maytansines)、氨甲蝶呤(methotrexate)、纺锤菌素(netropsins)、嘌呤霉素(puromycins)、根瘤菌素(rhizoxins)、紫杉烷(taxanes)、微管蛋白裂解素(tubulysins)、或长春花生物碱(vinca alkaloids)。所述细胞毒分子不限于上述类别,包括所有可用于ADC的药物。
本发明的另一个方面是提供了一种抗体药物偶联物(ADC)在制备用于治疗膀胱癌的药物中的用途;所述抗体药物偶联物包含结合HER2的抗体或其功能性片段,其中所述抗体包含重链可变区和轻链可变区,其中(i)所述重链可变区包含三个CDR区,其中所述CDR区的氨基酸序列分别具有如SEQ ID NO:1、2和3所示的氨基酸序列;和(ii)所述轻链可变区包含三个CDR区,其中所述CDR区的氨基酸序列分别具有如SEQ ID NO:4、5和6所示的氨基酸序列。所述抗体还可以是与上述CDR限定的抗体竞争性结合相同或相近表位的抗体。
本发明中,术语“抗体”可以包括全长抗体或与HER2结合、反应性相关、或复合的抗体片段。抗体可以是任何蛋白质、类蛋白质分子、或多肽,其与寻求治疗性修饰的细胞群的一部分结合、复合、或反应。所述抗体可为嵌合抗体或其功能活性片段、人源化抗体或其功能活性片段、人类抗体或其功能活性片段。亦可为上述物种以外的其他物种的抗体或其其功能活性片段,例如:小鼠抗体或其功能活性片段、大鼠抗体或其功能活性片段、羊抗体或其功能活性片段、兔子抗体或其功能活性片段。抗体可为多克隆抗体或单克隆抗体。于一些实施例中,抗体可为双特异性抗体。此外,抗体也可为功能性活性片段、抗体的衍生物或类似物。“功能性”代表所述片段、衍生物或类似物可辨认相同的抗原,辨认衍生自抗原的片段、衍生物或类似物的抗体,例如但不限于:F(ab’)2、Fab、Fab’、Fv片段及抗体的重链及轻链二聚体、或其任何最小片段像是Fvs或单链抗体(SCAs)。此外,抗体可为抗体的融合蛋白。抗体也可包括经修饰或未经修饰(亦即,通过任何分子的共价连接)的类似物和衍生物,只要这样的共价连接允许抗体保留其抗原结合免疫特异性。例如但不限于:抗体的类似物和衍生物,包括经过进一步修饰,例如:糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知的保护/阻隔基衍生化、蛋白酶切割、连接至细胞抗体单元或其他蛋白质等。可利用已知技术实现任何大量的化学修饰,包括但不限于特异性化学切割、乙酰化、甲酰化、衣霉素存在下的代谢合成等。此外,类似物或衍生物可包括一种或多种非天然氨基酸。在一些实施例中,抗体可在与Fc受体作用的氨基酸残基中具有修饰(例如:取代、删除、或增加)。另一方面,所述抗体药物偶联物具有通式Ab-(L-U)n的结构,其中Ab表示所述的抗体或其功能性片段,L表示接头;U表示偶联的细胞毒分子,n为1至8的整数,代表每一抗体上结合的治疗剂的分子数量。
另一方面,所述接头与所述抗体或其功能性片段通过巯基和/或氨基连接,所述细胞毒分子定点或非定点偶联所述抗体。本发明的接头可以选自以下列表中的接头:
本发明的接头优选马来酰亚胺基-己酰基-缬氨酸-瓜氨酸-p-氨基苄氧基(Maleimido-Caproyl-Valine-Citrulline-p-Aminobenzyloxy,mc-vc-pAB)和马来酰亚胺基己酰基(Maleimidocaproyl,mc)。
本发明的接头也可选择三甘氨酸肽接头(triglycyl peptide linker),该接头是近年来开发的用于ADC药物偶联物的新接头。(Rajeeva Singh et al,A New TriglycylPeptide Linker for Antibody-Drug Conjugates(ADCs)with Improved TargetedKilling of Cancer Cells,MCT-16-002,Published June 2016.),此外,也可以选择葡萄糖醛酸接头(glucuronide-tubulysin)(Patrick J.Burke et al,Glucuronide-linkedantibody-tubulysin conjugates display activity in MDR+and heterogeneous tumormodels,Molecular Cancer Therapeutics,2018)。
另一方面,其中所述抗体或其功能性片段衍生自在2013年08月22日以保藏编号CGMCC No.8102保藏于中国微生物菌种保藏管理委员会普通微生物中心的杂交瘤所分泌的抗体;地址:北京市朝阳区北辰西路1号院3号;另一方面,其中所述抗体是人源化抗体,优选地所述抗体是在2013年11月06日以保藏编号CCTCC C2013170保藏于中国典型培养物保藏中心的CHO细胞所分泌的抗体。地址:湖北武汉武汉大学
在一个实施例中,所使用的抗体药物偶联物名称为RC48-mc-vc-pAB-MMAE,符合通式Ab-(L-U)n的结构,RC48(一种人源化的抗HER2单克隆抗体)通过连接子mc-vc-pAB偶联MMAE,偶联数量为1-8个不等,包括偶联1个,2个,3个,4个,5个,6个,7个,8个或为偶联1-8个MMAE数量不等的抗体药物偶联物的组合。
本发明中,所述尿路上皮癌为无法接受手术切除的局部进展尿路上皮癌、局部晚期或转移性尿路上皮癌、HER2(人类表皮生长因子受体2,也称之为ErbB-2、c-erbB2或HER2/neu)阳性尿路上皮癌、HER2阳性局部晚期或转移性尿路上皮癌。
本发明中所述药物可通过鼻内、皮下、皮内、肌内或静脉内施用。
所述药物还包括药学上可接受的载体;所述药物优选为冻干剂或液体制剂;所述载体包括稳定剂、保护剂、缓冲液、冻干保护剂、活性保护剂、表面活性剂、吸附载体、吸收促进剂中的一种或多种。
附图说明
图1:纯化人重组蛋白HER2-ECD的SDS-PAGE图,经考马斯亮蓝染色。每孔上样量为10μg。
图2:表示cRC48(嵌合抗体),RC48(人源化抗体)的SDS-PAGE分析图,抗体每孔上样量为2μg。
图3:显示了通过ELISA实验测定的人源化抗体RC48的HER2-ECD的结合亲和力,并计算出结合亲和力常数Kd。本实验中Herceptin和cRC48作为对照。
图4A:表示用流式细胞术分析抗HER2人源化抗体RC48结合HER2+细胞SK-BR3,BT474,HER2-细胞MDA-MB468的能力。
图4B:显示流式细胞术分析不同抗体浓度下抗HER2抗体结合BT474细胞表面抗原的能力。抗HER2抗体包括Herceptin,cRC48,RC48。共分析了5×104个细胞。
图5:表示RC48只对HER2表现出特异性结合亲和力,而对EGFR,HER3,HER4没有结合。
图6.受试者编号01001疗效示意图
患者基本情况:女,57岁,右肾盂癌术后,多发肺转移。病理诊断尿路上皮癌,HER2IHC 3+;
图7.受试者编号01003疗效示意图
患者基本情况:女,45岁,右肾盂癌术后,腹腔淋巴结转移。病理诊断尿路上皮癌,HER2IHC 3+。
图8.受试者编号01007疗效示意图
患者基本情况:男,63岁,膀胱癌术后,右肾盂癌术后,肺转移,肝转移,颈部淋巴结转移,纵隔转移,多发骨转移。病理诊断尿路上皮癌,,HER2IHC 3+;
具体实施方式
实施例1.鼠源单克隆抗体mRC48的制备与序列分析
1、HER2抗原的表达和纯化
编码HER2-ECD(氨基酸Thr23至Thr652,GenBank登录号为M11730)的cDNA片段通过PCR克隆到pcDNA3(Invitrogen公司)表达载体上。
具体方法为:通过RT-PCR方法从HER2+SKBR3细胞株(ATCC号:HTB-30)中获得HER2-ECD编码区的cDNA(试剂盒采用Promega公司的ImProm-IITM Reverse TranscriptionSystem逆转录系统)。
引物为:P1:5’CGGGATCCTGCCACCAGCTGTGCGCC(SEQ ID NO:7),P2:5’GCTCTAGATCAGTTGATGGGGCAAGGCT(SEQ ID NO:8),下划线序列分别为引入的BamHI、XbaI酶切位点,以反转录的HER2-ECD的cDNA为模板用上述引物进行PCR扩增,扩增条件是:94℃变性30s,60℃退火30s,72℃延伸1分钟,循环30次,最后72℃延伸10分钟。然后将PCR片段回收,用BamHI和XbaI酶(NEB)进行酶切,与pcDNA3载体连接。HER2-ECD的C末端加入了一个多聚组氨酸标签以方便纯化。用构建的DNA表达载体转染HEK293细胞(美国ATCC),利用Ni-NTA亲和层析(Qiagen)从细胞培养液中纯化His-标记的可溶性蛋白HER2-ECD。SDS-PAGE及考马斯亮蓝染色表明纯化的HER2-ECD蛋白具有95%以上的同质性,结果见图1。可溶性的HER2-ECD以单体形式出现,相对分子量约为75kDa,比计算的分子量(71kDa)稍大,表明蛋白在HEK293细胞中进行了糖基化。将纯化得到的HER2-ECD蛋白进一步浓缩,并转移到无菌pH7.4的PBS缓冲液中,用于随后的体内和体外分析。
2、杂交瘤细胞的生产与筛选
使用上述制备的HER2-ECD作为抗原免疫小鼠,制备单克隆抗体。免疫反应、杂交瘤细胞融合和初筛都按照标准步骤(参考文献:WHO Technical Report Series,No.822,1992Annex 3)进行。0.25ml HER2-ECD蛋白(50-100μg)和0.25ml弗氏完全佐剂(Difco Lab)等体积混合均匀后免疫4只Balb/c小鼠(购自上海斯莱克实验动物有限责任公司),间隔2周后进行第2次注射,用弗氏不完全佐剂(Difco Lab),抗原量为25-50μg/0.5ml/只小鼠,间隔3周后进行第3次注射,注射剂量同第2次,第3次注射后10天取血。用酶联免疫吸附试验(ELISA)检测小鼠的血清,将血清中抗HER2抗体滴度最大的2只小鼠的脾脏取出,然后与骨髓瘤细胞P3X63Ag8(ATCC CRL-1580)融合。将融合细胞稀释到10块96孔板上,根据与HER2-ECD的结合能力用ELISA方法进行初筛。在典型的ELISA实验中,用HER2-ECD(0.2-1μg/ml)包被Nunc Maxisorb 96孔板,然后用梯度稀释的小鼠血清或杂交瘤上清液(100μL)孵育。鼠源的抗HER2抗体用辣根过氧化物酶偶联的山羊F(ab′)2抗鼠IgG Fc特异的二抗(Invitrogen公司)进行检测。
用ELISA法对400个杂交瘤细胞株的上清液进行筛选,其中36个表现出强的HER2-ECD结合力。选择HER2结合能力最强的十株杂交瘤细胞,通过有限稀释方法筛选亚克隆杂交瘤细胞株。通过悬浮亚克隆杂交瘤细胞株培养,蛋白纯化,用ELISA确定HER2的结合亲和力,用流式细胞仪(BD FACS Calibur)来进一步测试上述抗体对自然表达在人乳腺癌细胞株表面的HER2的结合能力(更详细的描述见实施例4)。最终通过序列分析确定了一株杂交瘤细胞系mRC48(鼠源IgG1k),它具有强的HER2结合能力。所述杂交瘤细胞mRC48在2013年08月22日以保藏编号No.8102保藏于中国微生物菌种保藏管理委员会普通微生物中心(转为按照布达佩斯条约之保藏的日期为2013年10月29日)。
3、抗HER2杂交瘤细胞克隆mRC48的序列分析
上述杂交瘤细胞克隆mRC48重链和轻链的可变区根据说明书利用商业试剂盒SMARTTM RACE cDNA Amplification Kit(Clontech公司)快速扩增5’末端进行测序。
用RNApure Tissue Kit(北京康威世纪生物科技有限公司)从杂交瘤细胞中提取总RNA,使用SMARTTM RACE cDNA Amplification Kit进行总RNA的反转录,以总RNA为模板,利用试剂盒中的引物,加入反转录酶SMARTScribeTM Reverse Transcriptase,按照试剂盒提供的步骤进行反转录获得RACE-Ready第一链cDNA,然后进行两轮PCR,第一轮PCR以获得的cDNA为模板,试剂盒中提供的UPM为5’端引物,3’端引物为mRC48-VL-1/mRC48-VH-1。PCR反应条件为:94℃预变性5min;25个扩增循环(94℃变性30s,68℃退火30s,72℃延伸2min);最后72℃延伸10min。
第二轮PCR,以第一轮PCR的产物为模板,以试剂盒中提供的NUP为5’端引物,3’端引物为mRC48-VL-2/mRC48-VH-2,PCR反应条件为:94℃预变性5min;25个扩增循环(94℃变性30s,68℃退火30s,72℃延伸2min);72℃延伸10min。这样既获得上述杂交瘤细胞克隆mRC48重链和轻链的可变区。
具体引物序列如下:
mRC48-VL-1:5’-GTTGGTGCAGCATCAGCCCGTT-3’(SEQ ID NO.9)
mRC48-VL-2:5’-GTTCACTGCCATCAATCTTCCAC-3’(SEQ ID NO.10)
mRC48-VH-1:5’-GCCAGTGGATAGACAGATGG-3’(SEQ ID NO.11)
mRC48-VH-2:5’-AGGTCACTGTCACTGGCTCAG-3’(SEQ ID NO.12)
PCR产物通过琼脂糖凝胶电泳进行纯化,并亚克隆到pCR2.1TOPO克隆载体上(Invitrogen公司)。通过PCR,获得10个独立克隆的质粒DNA,进而用M13正向和反向引物测序。DNA序列分析表明,这10个克隆都具有编码相同VH或VL多肽的cDNA。互补决定区(CDR)的氨基酸序列通过Kabat编码表定义,并在表1中列出。序列比较分析表明,抗HER2mRC48的CDR与已知的HER2抗体包括Herceptin(曲妥珠单抗)有显著区别。
表1.抗HER2单克隆抗体mRC48CDR的氨基酸序列
重链(VH) | 轻链(VL) | |
CDR1 | DYYIH(SEQ ID NO.1) | KASQDVGTAVA(SEQ ID NO.4) |
CDR2 | RVNPDHGDSYYNQKFKD(SEQ ID NO.2) | WASIRHT(SEQ ID NO.5) |
CDR3 | ARNYLFDHW(SEQ ID NO.3) | HQFATYT(SEQ ID NO.6) |
实施例2.抗HER2单克隆抗体mRC48的人源化(源引自CN105008398A中相应方法)
通过移植轻链或重链CDR到人的IgG1K框架区来人源化鼠抗HER2单克隆抗体mRC48。
设计了人源化RC48抗体的轻链可变区(RC48-VL),以及人源化RC48抗体的重链可变区(RC48-VH),从而组合成为人源化抗HER2抗体:RC48。RC48-VH的整体序列与人IgG1VH基因的相似性分别84%。RC48抗体包含轻链可变区RC48-VL和重链可变区RC48-VH。
人源化抗HER2单克隆抗体RC48通过CDR移植的方法获得,重链或轻链可变区是由南京金斯瑞生物科技有限公司直接合成,合成的可变区包括Kozak共有序列、起始密码子,重链或轻链信号肽,人源框架区和鼠源CDR,可变区与人IgG1k恒定区是通过重叠延伸PCR的方法连接成完整片段。
重叠延伸PCR的引物是:
重链VH1:5 CGCGGATCC GCCGCCACCATGGGATGGAGCT3′(SEQ ID NO:13)
VH2:5GATGGGCCCTTGGTGCTAGCGGAGCTCACTGTCACCAG TGTT3(SEQ ID NO:14)
CH1:5 GCTAGCACCAAGGGCCCATC 3(SEQ ID NO:15)
CH2:5 CCGGAATTCTTTACCGGGAGACAGGGAGA 3(SEQ ID NO:16)
轻链:VL1:5 CGCGGATCC GCCGCCACCATGGACATGAGGGT 3(SEQ ID NO:17)
VL2:5 GATGGTGCAGCCACAGTACGCTTTATCTCAACTTTTG T 3
AC3(SEQ ID NO:18)
CL1:5 CGTACTGTGGCTGCACCAT 3(SEQ ID NO:19)
CL2:5 CCGGAATTCACACTCTCCCCTGTTGAAGC 3(SEQ ID NO:20)
对于重链的扩增,首先以合成的可变区为模板,以VH1和VH2为引物,人IgG1K重链恒定区为模板,以CH1和CH2为引物,分别扩增重链的可变区、恒定区,扩增条件均是:94℃变性30s,60℃退火30s,72℃延伸1分钟,循环30次,最后72℃延伸10分钟。再以两次的PCR产物为模板,VH1和CH2为引物,扩增RC48的重链序列。扩增条件均是:94℃变性30s,60℃退火30s,72℃延伸2分钟,循环30次,最后72℃延伸10分钟。
对于轻链的扩增,首先以合成的可变区为模板,以VL1和VL2为引物,以人IgG1K轻链恒定区为模板,以CL1和CL2为引物,分别扩增轻链的可变区、恒定区,扩增条件均是:94℃变性30s,60℃退火30s,72℃延伸1分钟,循环30次,最后72℃延伸10分钟。再以两次的PCR产物为模板,VL1和CL2为引物,扩增轻链序列。扩增条件均是:94℃变性30s,60℃退火30s,72℃延伸2分钟,循环30次,最后72℃延伸10分钟。
因此,得到了人源化抗HER2单克隆抗体RC48,其中RC48包含人IgG1K重链恒定区和重链可变区RC48-VH,以及人IgG1K轻链恒定区和轻链可变区RC48-VL。
人-鼠嵌合抗体cRC48也是通过相同的方法获得,将鼠的可变区和人IgG1k恒定区通过重叠延伸PCR的方法连接成完整片段。
将上述扩增得到的各片段分别亚克隆到表达载体pcDNA3.0上。将构建的不同质粒转染到悬浮CHO细胞(Invitrogen)中,以产生不同的重组抗体,并利用Protein A进行纯化和后续的特征分析。嵌合的抗-HER2 RC48(被称为cRC48)是由鼠-人嵌合cRC48重链和轻链组成。RC48包括人源化重链RC48-VH和人源化轻链RC48-VL。cRC48和RC48都能够表达,从CHO细胞上清液中收集所述抗体,经Protein A进行纯化,在还原与非还原条件下用SDS-PAGE分析(见图2)。如上所述分泌RC48抗体的CHO细胞(即转染了人IgG1K重链恒定区和重链可变区RC48-VH,以及人IgG1K轻链恒定区和轻链可变区RC48-VL的CHO细胞)在2013年11月06日以保藏编号C2013170保藏于中国典型培养物保藏中心。
实施例3.抗HER2RC48抗体的表征分析
用ELISA法测定cRC48(嵌合抗体)和RC48抗体(人源化抗体)的HER2-结合亲和力常数(Kd),具体方法可见实施例1,即以可溶性HER2-ECD蛋白包被96孔板,之后与稀释的抗体(Herceptin和嵌合cRC48作为对照)一起孵育,对于与HER2-ECD相关的抗体(所有形式的人IgG1K)用HRP-偶联的羊F(ab’)2抗-人IgG Fc-特异性二抗进行检测(invitrogen)。绘制结合曲线并进一步用单一位点特异性结合非线性方程(Journal of ImmunologicalMethods,270:155-162,2002),为每一个抗HER2抗体计算表面结合亲和力常数(Kd)值(图3中展示的是由3次独立的ELISA实验得出的一条典型HER2-结合曲线)。ELISA试验结果见图3。
从3次独立的测定试验可知,与cRC48(平均亲和常数77pM)和Herceptin(平均亲和常数97pM)相比,RC48(人源化抗体)有显著提高的HER2-ECD结合亲和力,平均亲和常数为44pM,结果见表2。
表2.本发明的抗体与Herceptin的平均亲和常数比较
样品 | 平均亲和常数 |
Herceptin | 97pM |
cRC48 | 77pM |
RC48 | 44pM |
实施例4.RC48(人源化抗体)与HER2的结合力
1)RC48抗体与HER2的结合亲和力试验
利用流式细胞仪来检测人乳腺癌细胞内源表达的HER2与人源化抗HER2抗体RC48的结合力,结果见图3。用6μg对照组人IgG、Herceptin、cRC48、RC48分别与两种HER2+细胞系人乳腺癌细胞SK-BR-3、BT474以及HER2-细胞MDA-MB468(2×107个细胞)共同孵育,冰上孵育30-45分钟。用4ml冷的PBS充分洗涤2次之后,细胞表面结合的抗体通过偶联R-PE的山羊抗人IgG Fc(15μl,25μg/mL)特异性二抗检测,然后利用流式细胞仪(BDFACSCalibur)进行分析。对照组人IgG1没有检测出与上述三种癌症细胞的结合。相比而言,Herceptin、cRC48、RC48与两种HER2阳性细胞强烈结合,但与HER2阴性细胞不结合,这说明这种结合是HER2特异性的(如图4A所示)。通过比较同种对照组的平均荧光强度发现,与Herceptin和cRC48相比,RC48表现出更高的结合亲和力。通过滴定抗HER2抗体的浓度,以及流式细胞术中分析的细胞数目,得出基于细胞的抗HER2的抗体与细胞表面HER2的结合曲线,结果见图4B。人源化的抗HER2抗体RC48表现出明显的结合亲和力,与BT474细胞表面HER2结合亲和力Kd为4nM,Herceptin、cRC48分别为10nM和5nM,结果见表3:
样品 | 结合亲和力Kd |
Herceptin | 10nM |
cRC48 | 5nM |
RC48 | 4nM |
2)抗原结合特异性试验
用ELISA方法测定Herceptin、cRC48、RC48结合不同的表面抗原EGFR、HER2、HER3、HER4的能力。ELISA方法见实施例1。分别用抗原EGFR、HER2、HER3、HER4包被96孔板,每孔上样量为20ng,用不同的抗HER2抗体进行孵育,即Herceptin、cRC48、RC48抗体,然后用辣根过氧化物酶偶联的羊F(ab′)2抗鼠IgG Fc特异的二抗(Invitrogen公司)进行检测。结果见图5,结果表明Herceptin、cRC48、RC48抗体与EGFR、HER3、HER4几乎无结合力,而与HER2有强的结合力,说明Herceptin、RC48对HER2的结合有高度的特异性。
实施例5.抗体偶联物的制备
1)单克隆抗体RC48的纯化
经Protein A从CHO细胞培养液中捕获得到RC48的单克隆抗体,SDS-PAGE电泳及SEC分析纯度达到95%以上。用30KD膜包将所获抗体蛋白超滤透析到PBS缓冲液中,浓缩,用紫外吸光光度计标定浓度,用于后续的偶联反应。
2)单克隆抗体RC48与药物分子的偶联
用PBS缓冲液分别配制还原剂和保护剂如下:1~20mmol/L TCEP(Tris-2-carboxyethyl-phosphine)、1~20mmol/L DTPA(Diethylene triamine pentacetateacid)母液,还原剂用量根据所需偶联率不同可在一定浓度范围内添加,与一定浓度单克隆抗体(如:5~30mg/ml)按照一定体积比(如1∶1)混合,TCEP与抗体的终浓度摩尔比0.5~6.0∶1,于25℃搅拌反应2h。用DTNB法于412nm检测自由巯基浓度,与抗体的摩尔比计算自由巯基个数。TCEP还原可重复性好,还原后自由巯基数可以达到1.0-8.0。
TCEP还原后抗体可直接进行后续偶联。配制一定浓度(10mM)药物(vc-MMAE、vc-MMAF、mc-MMAF)(购自上海皓元化学科技有限公司)溶于25%的DMSO(dimethyl sulfoxide,二甲亚砜),按照药物与巯基的摩尔比0.3~2.8∶1缓慢加药,于25℃搅拌反应2h。用DTNB法于412nm检测自由巯基浓度(接近0),Sephadex G-25纯化除去残余未反应药物以及DMSO等游离小分子,SDS-PAGE电泳、反相高效液相(R-HPLC)疏水高效液相(HIC-HPLC)法检测偶联情况。
实施例6.抗体药物偶联物亲和力的测定
ELISA法测亲和力
用重组蛋白HER2-ECD(浓度为0.5mg/ml)包被ELISA板,2℃-8℃过夜。洗板机洗板3次。3%BSA-PBST溶液封闭,37度2h。洗板机洗板3次。加样:用PBST溶液稀释标线从1000ng/ml起梯度稀释11个点,100μl/孔,37度2h。洗板机洗板3次。用PBST溶液稀释二抗(山羊抗人IgG-Fc-HRP)5000倍。加入TMB显色液显色,室温避光显色8-10分钟。用2M H2SO4终止试验,酶标仪450/655nm处读数。结果见表4。
表4.抗体药物偶联物与T-DM1亲和力比较(VC为mc-vc-pAB缩写)
由结果可知,RC48-VC-MMAE(即RC48-mc-vc-pAB-MMAE)、RC48-VC-MMAF、RC48-MC-MMAF的HER2-ECD亲和力与T-DM1相当。
实施例7.单药治疗HER2阳性局部晚期或转移性尿路上皮癌的有效性和安全性实验
本实验的目的是评价单药治疗HER2阳性局部晚期或转移性尿路上皮癌的有效性和安全性。所使用的抗体药物偶联物为RC48-mc-vc-pAB-MMAE,RC48通过连接子mc-vc-pAB偶联MMAE,偶联数量为1-8个不等。
其中对于受试者的选择标准为:
年龄:18岁(最小年龄)至80岁(最大年龄)
其中入选标准为:
1.自愿同意参与研究并签署知情同意书;
2.男性或女性,年龄大于等于18岁且小于60岁;
3.预期生存期大于等于12周;
4.具有病理学确诊的无法接受手术完全切除的局部进展或转移性膀胱尿路上皮癌;
5.受试者确诊为无法手术切除的局部进展或转移性疾病后接受过至少一线全身化疗后出现疾病进展或不能耐受;
6.至少具有RECIST 1.1标准规定的可测量病灶;
7.中心实验室确认的HER2表达阳性;
8.ECOG体力状况0或1分;
9.足够的心、骨髓、肝、肾功能;
10.对于女性受试者:应为手术绝育、绝经后的患者,或同意在研究治疗期间和研究治疗期结束后6个月内至少采用一种经医学认可的避孕措施(如宫内节育器,避孕药或避孕套);男性受试者应同意在研究治疗期间和研究治疗期结束后6个月内至少采用一种经医学认可的避孕措施(如避孕套、禁欲等);
11.愿意且能够遵从试验和随访程序安排。
同时,排除标准为:
1.已知对重组人源化抗HER2单抗-MMAE偶联剂药物及其组分过敏者;
2.研究治疗开始前4周内接受过其他抗肿瘤治疗;
3.既往接受过重组人源化抗HER2单抗-MMAE偶联剂药物;
4.研究给药开始前4周内进行过大型手术且未完全恢复;
5.研究给药开始前4周内接种过活疫苗或计划在研究期间接受任何疫苗;
6.其他可能影响方案依从性或干扰结果解释的严重的、无法控制的伴随疾病;
7.研究给药开始前5年内患有其他恶性肿瘤;
8.患有中枢神经系统转移和/或癌性脑膜炎;
9.有在过去2年内需要系统治疗的活动性自身免疫性疾病;
10.既往接受过异体造血干细胞移植或实体器官移植;
11.伴有临床症状或需要对症处理的大量胸水或腹水;
12.妊娠或哺乳期妇女;
13.HIV检测结果阳性;
14.活动性乙型肝炎或丙型肝炎患者;
15.活动性结核病史;
16.患有任何其它疾病,代谢异常,体格检查异常或实验室检查异常,根据研究者判断,有理由怀疑患者具有不适合使用研究药物的某种疾病或状态,或者将会影响研究结果的解读,或者使患者处于高风险的情况;
17.估计患者参加本临床研究的依从性不足。
具体实验方法:
本研究将纳入既往接受过至少一线全身化疗失败或不能耐受的局部晚期或转移性尿路上皮癌受试者,且具有可测量病灶,一般情况及器官功能良好。所有受试者送检肿瘤组织病理切片至中心实验室检测确认HER2表达阳性,其阳性定义为免疫组化(IHC)为2+或3+(无论荧光原位杂交[FISH]检测结果)。
本研究中HER2免疫组化(IHC)的结果判定依据中国《乳腺癌HER2检测指南(2014版)》中的HER2判读标准。具体如表5所示。
表5中国《乳腺癌HER2检测指南(2014版)》中的HER2判读标准。
符合所有研究人群标准的受试者接受RC48-ADC治疗(2.0mg/kg,静脉滴注,每2周一次),每6周进行疗效评价,直至发生疾病进展、不可耐受毒性或主动退出。研究的主要终点指标为独立评估的客观缓解率(ORR),次要研究终点为无进展生存期、总生存期以及治疗的安全性。
研究结果:
该研究于2017年12月启动,截至2018年7月31日,共入组18例受试者接受治疗,其中男性15例,女性3例,中位年龄63岁。原发病灶包括膀胱(50.0%)、肾盂(27.8%)和输尿管(22.2%),主要的转移部位为肺、肝以及淋巴结转移。16例(88.9%)既往接受过一线铂类治疗。受试者肿瘤HER2表达经中心实验室确认的免疫组化(IHC)结果为11例(61.1%)IHC2+,7例(38.9%)IHC3+。
18例受试者中有13例受试者进行了疗效评估,部分缓解(PR)10例(4例已确认PR(连续两次评效为PR称为确认PR)。根据RECIST标准“当每一个受试者符合部分或者完全缓解标准而且在随后的时间点(一般是四周后)再次做疗效确认后才能认为是完全或者部分缓解”,即受试者连续两次评效为PR,称为确认PR。其他6例还未到再次疗效确认时间点,目前仅完成一次确认),客观缓解率(ORR)为76.9%(10/13),疾病控制率(DCR)(13例疗效评估者中10例PR,2例疾病稳定(SD))为92.3%(12/13)。目前受试者最长治疗时间超过7个月。获得疾病缓解的受试者中,7例(53.8%)接受过紫杉类药物治疗,4例(30.8%)接受过PD-1/PD-L1治疗。
18例受试者中,有16例接受了安全性评估,安全性评估中最常见的治疗相关不良反应(TRAEs)为ALT升高(50.0%,1-2级)、感觉减退(50.0%,1-2级)和白细胞计数降低(50.0%,1-2级);≥3级的TRAE为中性粒细胞计数下降(12.5%,3级)。无药物相关严重不良事件(SAE)发生。
下方为部分病例直观治疗效果描述:
1.患者01001:女,57岁,右肾盂癌术后,多发肺转移。病理诊断尿路上皮癌,HER2IHC 3+;
根据图6可以看出:经过长达12周的治疗,其位于右肺下叶的肿瘤病灶经过6周、12周的治疗后,肿瘤病灶从54×31mm缩小到37×23mm,缩小了49%。
2.患者01003,女,45岁,右肾盂癌术后,腹腔淋巴结转移。病理诊断尿路上皮癌,HER2IHC 3+;
根据图7可以看出:通过6周的治疗,其位于右腰大肌旁的肿瘤病灶从56×48mm缩小到33×22mm,缩小了72.9%。
3.患者01007,男,63岁,膀胱癌术后,右肾盂癌术后,肺转移,肝转移,颈部淋巴结转移,纵隔转移,多发骨转移。病理诊断尿路上皮癌,,HER2IHC 3+;
根据图8可以看出:位于左上肺叶、肝转移、纵隔淋巴结的肿瘤病灶经过为期6周的治疗,病灶处的肿瘤面积均有明显的缩小。左上肺叶从45×36mm缩小到28×22mm,减少61.9%,肝转移处从38×32mm缩小到25×21mm,减少56.8%,纵隔淋巴结从29×15mm缩小到18×7mm,减少71.03%。
以上临床数据及直观病理检测均表明本发明的抗HER2单抗-MMAE偶联剂药物具有非常显著的治疗效果;通过与目前的上市药物对比,也可以看出:其明显优于目前已经被欧盟和美国批准的同类药物,例如:罗氏的Atezolizumab三期临床数据显示ORR仅为23%,百时美施贵宝公司的Nivolumab的ORR仅为19.6%,而杨森公司的erdafitinib仅针对具有某些FGFR基因突变的尿路上皮癌患者,反观本发明的重组人源化抗HER2单抗-MMAE偶联剂药物的ORR为76.9%,疾病控制率(DCR)为92.3%,明显优于目前上市的同类药物,并且副作用也明显小于同类药物,未发生任何严重不良反应(SAE),针对的患者更为广泛,为急需治疗的尿路上皮癌患者提供了另一种选择;由此可见,本发明的抗HER2抗体偶联物在治疗尿路上皮癌中有着极佳的应用前景,能够有效改善,甚至逆转患者的疾病发展进程,取得了预料不到的技术效果。
PCT
打印件(原件为电子形式)
由受理局填写
PCT
打印件(原件为电子形式)
由国际局填写
SEQUENCE LISTING
<110> 荣昌生物制药(烟台)有限公司
<120> 抗HER2抗体药物偶联物在治疗尿路上皮癌中的用途
<130> 1
<160> 20
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<400> 1
Asp Tyr Tyr Ile His
1 5
<210> 2
<211> 16
<212> PRT
<213> 人工序列
<400> 2
Arg Val Asn Pro Asp His Gly Asp Ser Tyr Tyr Asn Gln Lys Phe Lys
1 5 10 15
<210> 3
<211> 9
<212> PRT
<213> 人工序列
<400> 3
Ala Arg Asn Tyr Leu Phe Asp His Trp
1 5
<210> 4
<211> 11
<212> PRT
<213> 人工序列
<400> 4
Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<400> 5
Trp Ala Ser Ile Arg His Thr
1 5
<210> 6
<211> 7
<212> PRT
<213> 人工序列
<400> 6
His Gln Phe Ala Thr Tyr Thr
1 5
<210> 7
<211> 26
<212> DNA
<213> 人工序列
<400> 7
cgggatcctg ccaccagctg tgcgcc 26
<210> 8
<211> 28
<212> DNA
<213> 人工序列
<400> 8
gctctagatc agttgatggg gcaaggct 28
<210> 9
<211> 22
<212> DNA
<213> 人工序列
<400> 9
gttggtgcag catcagcccg tt 22
<210> 10
<211> 23
<212> DNA
<213> ˹
<400> 10
gttcactgcc atcaatcttc cac 23
<210> 11
<211> 20
<212> DNA
<213> 人工序列
<400> 11
gccagtggat agacagatgg 20
<210> 12
<211> 21
<212> DNA
<213> 人工序列
<400> 12
aggtcactgt cactggctca g 21
<210> 13
<211> 31
<212> DNA
<213> 人工序列
<400> 13
cgcggatccg ccgccaccat gggatggagc t 31
<210> 14
<211> 42
<212> DNA
<213> 人工序列
<400> 14
gatgggccct tggtgctagc ggagctcact gtcaccagtg tt 42
<210> 15
<211> 20
<212> DNA
<213> 人工序列
<400> 15
gctagcacca agggcccatc 20
<210> 16
<211> 29
<212> DNA
<213> 人工序列
<400> 16
ccggaattct ttaccgggag acagggaga 29
<210> 17
<211> 32
<212> DNA
<213> 人工序列
<400> 17
cgcggatccg ccgccaccat ggacatgagg gt 32
<210> 18
<211> 40
<212> DNA
<213> 人工序列
<400> 18
gatggtgcag ccacagtacg ctttatctca acttttgtac 40
<210> 19
<211> 19
<212> DNA
<213> 人工序列
<400> 19
cgtactgtgg ctgcaccat 19
<210> 20
<211> 29
<212> DNA
<213> 人工序列
<400> 20
ccggaattca cactctcccc tgttgaagc 29
Claims (16)
1.一种抗体药物偶联物在制备用于治疗尿路上皮癌的药物中的用途,所述抗体药物偶联物为抗HER2抗体或其功能性片段偶联细胞毒分子,
其中所述尿路上皮癌是HER2阳性尿路上皮癌,
其中所述抗体药物偶联物由通式Ab-(L-U)n表示,其中Ab是抗体或其功能性片段、L是接头、U是偶联的细胞毒分子,并且n是1至8的整数,其代表结合至抗体的治疗剂分子数量,
其中所述抗体包含通过CDR序列限定的重链可变区和轻链可变区,其中
(i)重链可变区包含三个CDR,其中所述CDR的氨基酸序列分别如SEQ ID NO:1、2和3所示;并且
(ii)轻链可变区包含三个CDR,其中所述CDR的氨基酸序列分别如SEQ ID NO:4、5和6所示,
其中所述接头是马来酰亚胺基-己酰基-缬氨酸-瓜氨酸-p-氨基苄氧基接头,以及
其中所述细胞毒分子是单甲基澳瑞他汀E。
2.根据权利要求1所述的用途,所述接头与所述抗体或其功能性片段通过巯基和/或氨基连接。
3.根据权利要求1或2所述的用途,所述细胞毒分子定点或非定点偶联所述抗体。
4.根据权利要求1或2所述的用途,其中所述抗体或其功能性片段为鼠源、嵌合或人源化的。
5.根据权利要求1或2所述的用途,其中所述抗体或其功能性片段衍生自在2013年08月22日以保藏编号CGMCC No.8102保藏于中国微生物菌种保藏管理委员会普通微生物中心的杂交瘤所分泌的抗体。
6.根据权利要求4所述的用途,其中所述抗体是人源化抗体。
7.根据权利要求6所述的用途,其中所述抗体是由在2013年11月06日以保藏编号CCTCCC2013170保藏于中国典型培养物保藏中心的CHO细胞所分泌的。
8.根据权利要求1或2所述的用途,所述尿路上皮癌为无法接受手术切除的局部进展尿路上皮癌、和局部晚期或转移性尿路上皮癌。
9.根据权利要求1或2所述的用途,所述药物还包括药学上可接受的载体。
10.根据权利要求9所述的用途,其中所述载体选自由稳定剂、保护剂、缓冲液、表面活性剂、吸附载体和吸收促进剂组成的组的一种或多种。
11.根据权利要求1或2所述的用途,其中所述药物是冻干制剂或液体制剂。
12.根据权利要求1或2所述的用途,所述药物可通过鼻内、皮下、皮内、肌内或静脉内施用。
13.根据权利要求1或2所述的用途,其中向有需要的受试者施用药物导致部分缓解或疾病稳定。
14.根据权利要求13所述的用途,其中向有需要的受试者施用药物导致部分缓解。
15.根据权利要求1或2所述的用途,其中向有需要的受试者施用药物不会导致严重不良事件。
16.根据权利要求10所述的用途,其中所述保护剂选自由冻干保护剂和活性保护剂组成的组的一种或多种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410581446.1A CN118557749A (zh) | 2018-08-29 | 2019-08-19 | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018109980554 | 2018-08-29 | ||
CN201810998055 | 2018-08-29 | ||
PCT/CN2019/101283 WO2020042941A1 (zh) | 2018-08-29 | 2019-08-19 | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410581446.1A Division CN118557749A (zh) | 2018-08-29 | 2019-08-19 | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111655295A CN111655295A (zh) | 2020-09-11 |
CN111655295B true CN111655295B (zh) | 2024-05-28 |
Family
ID=69643195
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410581446.1A Pending CN118557749A (zh) | 2018-08-29 | 2019-08-19 | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 |
CN201980002467.0A Active CN111655295B (zh) | 2018-08-29 | 2019-08-19 | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410581446.1A Pending CN118557749A (zh) | 2018-08-29 | 2019-08-19 | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20200289663A1 (zh) |
EP (1) | EP3845252A4 (zh) |
JP (3) | JP7105304B2 (zh) |
KR (2) | KR20230051318A (zh) |
CN (2) | CN118557749A (zh) |
AU (2) | AU2019330680A1 (zh) |
BR (1) | BR112020010856A8 (zh) |
CA (1) | CA3077260C (zh) |
RU (1) | RU2750817C1 (zh) |
SG (1) | SG11202009130XA (zh) |
TW (2) | TWI767139B (zh) |
WO (1) | WO2020042941A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3077260C (en) * | 2018-08-29 | 2023-03-07 | Remegen, Ltd. | Use of anti-her2 antibody-drug conjugate in treating urothelial carcinoma |
BR112023023398A2 (pt) * | 2021-05-21 | 2024-01-23 | Remegen Co Ltd | Usos de um conjugado anticorpo-droga em combinação com um inibidor de checkpoint imune e de uma quantidade eficaz de conjugado anticorpo-droga e um inibidor de checkpoint imune, método para tratar um paciente com câncer urotelial, e, composição farmacêutica |
EP4346908A1 (en) * | 2021-05-24 | 2024-04-10 | RemeGen Co., Ltd. | Use of her2-targeting antibody-drug conjugate in treatment of her2-low expressing breast cancer |
CN115925954A (zh) * | 2022-12-28 | 2023-04-07 | 广州誉衡生物科技有限公司 | 抗-pd-1抗体及其在制备治疗尿路上皮癌患者的药物中的用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105008398A (zh) * | 2013-11-19 | 2015-10-28 | 烟台荣昌生物工程有限公司 | 抗her2抗体及其缀合物 |
CN106456794A (zh) * | 2014-05-22 | 2017-02-22 | 斯索恩生物制药有限公司 | 接头药物与抗体的位点特异性缀合以及所得adc |
CN107532217A (zh) * | 2015-05-29 | 2018-01-02 | 豪夫迈·罗氏有限公司 | 用于癌症的治疗和诊断方法 |
CN107789631A (zh) * | 2017-11-03 | 2018-03-13 | 合肥瀚科迈博生物技术有限公司 | 抗人ErbB2双表位抗体‑药物偶联物及其应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3170821B1 (en) * | 2011-05-27 | 2021-09-15 | Ambrx, Inc. | Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives |
CN103319599B (zh) * | 2013-05-27 | 2015-02-18 | 上海交联药物研发有限公司 | 一种抗人ErbB2抗体—美登木素偶联物及其应用 |
TW201625304A (zh) | 2014-10-24 | 2016-07-16 | 美國禮來大藥廠 | 泌尿上皮癌之療法 |
US10195175B2 (en) * | 2015-06-25 | 2019-02-05 | Immunomedics, Inc. | Synergistic effect of anti-Trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or PARP inhibitors |
CN107029244B (zh) * | 2016-02-04 | 2021-04-27 | 浙江昭华生物医药有限公司 | 抗her2抗体-药物偶联物及其应用 |
TW201825118A (zh) * | 2016-11-30 | 2018-07-16 | 美商艾堤爾製藥公司 | 抗-hrs抗體及用於治療癌症之組合療法 |
CA3077260C (en) | 2018-08-29 | 2023-03-07 | Remegen, Ltd. | Use of anti-her2 antibody-drug conjugate in treating urothelial carcinoma |
-
2019
- 2019-08-19 CA CA3077260A patent/CA3077260C/en active Active
- 2019-08-19 BR BR112020010856A patent/BR112020010856A8/pt unknown
- 2019-08-19 JP JP2020529589A patent/JP7105304B2/ja active Active
- 2019-08-19 KR KR1020237012001A patent/KR20230051318A/ko active IP Right Grant
- 2019-08-19 CN CN202410581446.1A patent/CN118557749A/zh active Pending
- 2019-08-19 WO PCT/CN2019/101283 patent/WO2020042941A1/zh unknown
- 2019-08-19 SG SG11202009130XA patent/SG11202009130XA/en unknown
- 2019-08-19 EP EP19855043.6A patent/EP3845252A4/en active Pending
- 2019-08-19 CN CN201980002467.0A patent/CN111655295B/zh active Active
- 2019-08-19 AU AU2019330680A patent/AU2019330680A1/en not_active Abandoned
- 2019-08-19 RU RU2020117761A patent/RU2750817C1/ru active
- 2019-08-19 US US16/652,413 patent/US20200289663A1/en active Pending
- 2019-08-19 KR KR1020207029858A patent/KR102520974B1/ko active IP Right Grant
- 2019-08-28 TW TW108130782A patent/TWI767139B/zh active
- 2019-08-28 TW TW111119136A patent/TWI843105B/zh active
-
2022
- 2022-07-11 JP JP2022111260A patent/JP7470154B2/ja active Active
- 2022-10-11 AU AU2022252734A patent/AU2022252734A1/en active Pending
-
2024
- 2024-04-05 JP JP2024061325A patent/JP2024086799A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105008398A (zh) * | 2013-11-19 | 2015-10-28 | 烟台荣昌生物工程有限公司 | 抗her2抗体及其缀合物 |
CN106456794A (zh) * | 2014-05-22 | 2017-02-22 | 斯索恩生物制药有限公司 | 接头药物与抗体的位点特异性缀合以及所得adc |
CN107532217A (zh) * | 2015-05-29 | 2018-01-02 | 豪夫迈·罗氏有限公司 | 用于癌症的治疗和诊断方法 |
CN107789631A (zh) * | 2017-11-03 | 2018-03-13 | 合肥瀚科迈博生物技术有限公司 | 抗人ErbB2双表位抗体‑药物偶联物及其应用 |
Non-Patent Citations (1)
Title |
---|
Vlachostergios, P.J.等.Antibody-Drug Conjugates in Bladder Cancer.Bladder Cancer.2018,第4卷(第3期),第247-259页,尤其是第252页. * |
Also Published As
Publication number | Publication date |
---|---|
WO2020042941A1 (zh) | 2020-03-05 |
JP7105304B2 (ja) | 2022-07-22 |
KR20240033092A (ko) | 2024-03-12 |
JP7470154B2 (ja) | 2024-04-17 |
KR20200134268A (ko) | 2020-12-01 |
JP2024086799A (ja) | 2024-06-28 |
AU2019330680A1 (en) | 2020-04-23 |
TWI767139B (zh) | 2022-06-11 |
TW202023626A (zh) | 2020-07-01 |
TW202310877A (zh) | 2023-03-16 |
KR102520974B1 (ko) | 2023-04-17 |
BR112020010856A8 (pt) | 2023-03-07 |
BR112020010856A2 (pt) | 2021-03-09 |
KR20230051318A (ko) | 2023-04-17 |
US20200289663A1 (en) | 2020-09-17 |
SG11202009130XA (en) | 2020-10-29 |
CA3077260C (en) | 2023-03-07 |
CN118557749A (zh) | 2024-08-30 |
CN111655295A (zh) | 2020-09-11 |
RU2750817C1 (ru) | 2021-07-05 |
AU2022252734A1 (en) | 2022-11-03 |
TWI843105B (zh) | 2024-05-21 |
CA3077260A1 (en) | 2020-03-05 |
JP2021504427A (ja) | 2021-02-15 |
EP3845252A4 (en) | 2022-06-15 |
JP2022130744A (ja) | 2022-09-06 |
EP3845252A1 (en) | 2021-07-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111655295B (zh) | 抗her2抗体药物偶联物在治疗尿路上皮癌中的用途 | |
JP6728264B2 (ja) | 抗her2抗体及びその結合体 | |
EP4096717A1 (en) | Treatment of cancer | |
KR102710423B1 (ko) | 요로상피 암종의 치료에서 항―her2 항체―약물 접합체의 용도 | |
CN110152014B (zh) | 抗trailr2抗体-毒素-偶联物及其在抗肿瘤治疗中的药物用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |