CN113710277B - 一种负载双毒素的抗体药物偶联物及其应用 - Google Patents
一种负载双毒素的抗体药物偶联物及其应用 Download PDFInfo
- Publication number
- CN113710277B CN113710277B CN202180002141.5A CN202180002141A CN113710277B CN 113710277 B CN113710277 B CN 113710277B CN 202180002141 A CN202180002141 A CN 202180002141A CN 113710277 B CN113710277 B CN 113710277B
- Authority
- CN
- China
- Prior art keywords
- lysine
- phenylalanine
- valine
- antibody
- phe
- 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
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims abstract description 43
- 239000000611 antibody drug conjugate Substances 0.000 title claims abstract description 42
- 239000003053 toxin Substances 0.000 title abstract description 15
- 231100000765 toxin Toxicity 0.000 title abstract description 15
- 108700012359 toxins Proteins 0.000 title abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 29
- 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 claims abstract description 25
- 230000027455 binding Effects 0.000 claims abstract description 20
- 239000004472 Lysine Substances 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 45
- 239000000427 antigen Substances 0.000 claims description 40
- 108091007433 antigens Proteins 0.000 claims description 40
- 102000036639 antigens Human genes 0.000 claims description 40
- 150000001413 amino acids Chemical group 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 34
- 241000282414 Homo sapiens Species 0.000 claims description 31
- 239000012634 fragment Substances 0.000 claims description 24
- -1 monomethoxy trityl Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 241001529936 Murinae Species 0.000 claims description 14
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000003776 cleavage reaction Methods 0.000 claims description 10
- 230000007017 scission Effects 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims description 2
- 239000007821 HATU Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000036961 partial effect Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 230000002195 synergetic effect Effects 0.000 abstract description 4
- 230000002147 killing effect Effects 0.000 abstract description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 abstract description 2
- 235000018417 cysteine Nutrition 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 34
- 235000001014 amino acid Nutrition 0.000 description 30
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 25
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 25
- 125000003275 alpha amino acid group Chemical group 0.000 description 22
- 108090000623 proteins and genes Proteins 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 229960001602 ceritinib Drugs 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 231100000433 cytotoxic Toxicity 0.000 description 8
- 230000001472 cytotoxic effect Effects 0.000 description 8
- 210000004408 hybridoma Anatomy 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 6
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 108010024636 Glutathione Proteins 0.000 description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 229960003180 glutathione Drugs 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 229930185603 trichostatin Natural products 0.000 description 5
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 208000035473 Communicable disease Diseases 0.000 description 4
- 206010010144 Completed suicide Diseases 0.000 description 4
- 239000012623 DNA damaging agent Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000012661 PARP inhibitor Substances 0.000 description 4
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 4
- 108010087230 Sincalide Proteins 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 108010044540 auristatin Proteins 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 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 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 239000002254 cytotoxic agent Substances 0.000 description 4
- 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 4
- 229950009429 exatecan Drugs 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- 239000003744 tubulin modulator Substances 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 3
- 101150029707 ERBB2 gene Proteins 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 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 compound 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 description 3
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 3
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 229960005558 mertansine Drugs 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 2
- 108010066676 Abrin Proteins 0.000 description 2
- XWIYFDMXXLINPU-UHFFFAOYSA-N Aflatoxin G Chemical class O=C1OCCC2=C1C(=O)OC1=C2C(OC)=CC2=C1C1C=COC1O2 XWIYFDMXXLINPU-UHFFFAOYSA-N 0.000 description 2
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 102100032937 CD40 ligand Human genes 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 2
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000014429 Insulin-like growth factor Human genes 0.000 description 2
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 244000302512 Momordica charantia Species 0.000 description 2
- 235000009811 Momordica charantia Nutrition 0.000 description 2
- 102100034256 Mucin-1 Human genes 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102100035194 Placenta growth factor Human genes 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 108010039491 Ricin Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007640 basal medium Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 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
- 229960005501 duocarmycin Drugs 0.000 description 2
- 229930184221 duocarmycin Natural products 0.000 description 2
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- SRNFODIJXVPXHO-FSJWMSIRSA-N (4r,4ar,5'r,7r,8r,8as)-5'-(furan-3-yl)-4,7-dimethylspiro[1,3,4,4a,5,6,7,8a-octahydronaphthalene-8,3'-oxolane]-2,2'-dione Chemical compound C=1([C@H]2C[C@@]3(C(O2)=O)[C@H](C)CC[C@H]2[C@@H]3CC(=O)C[C@H]2C)C=COC=1 SRNFODIJXVPXHO-FSJWMSIRSA-N 0.000 description 1
- OTLLEIBWKHEHGU-UHFFFAOYSA-N 2-[5-[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COC1C(CO)OC(OC(C(O)C(OP(O)(O)=O)C(O)C(O)=O)C(O)=O)C(O)C1O OTLLEIBWKHEHGU-UHFFFAOYSA-N 0.000 description 1
- HRGUSFBJBOKSML-UHFFFAOYSA-N 3',5'-di-O-methyltricetin Chemical compound COC1=C(O)C(OC)=CC(C=2OC3=CC(O)=CC(O)=C3C(=O)C=2)=C1 HRGUSFBJBOKSML-UHFFFAOYSA-N 0.000 description 1
- VNEOHNUYPRAJMX-UHFFFAOYSA-N 3-[[2-[[2-amino-3-(1h-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-4-[[1-(butoxycarbonylamino)-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid Chemical compound C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(CC(C)C)C(=O)NC(CC(O)=O)C(=O)NC(C(=O)NC(=O)OCCCC)CC1=CC=CC=C1 VNEOHNUYPRAJMX-UHFFFAOYSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 241000545417 Aleurites Species 0.000 description 1
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 102100032412 Basigin Human genes 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 208000033386 Buerger disease Diseases 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 101710098275 C-X-C motif chemokine 10 Proteins 0.000 description 1
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 1
- 108700012439 CA9 Proteins 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 1
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 102100022002 CD59 glycoprotein Human genes 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 102100035793 CD83 antigen Human genes 0.000 description 1
- 101100504320 Caenorhabditis elegans mcp-1 gene Proteins 0.000 description 1
- 101710158575 Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase Proteins 0.000 description 1
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 1
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 206010068051 Chimerism Diseases 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 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
- SRNFODIJXVPXHO-UHFFFAOYSA-N Crotonin Natural products CC1CC(=O)CC2C1CCC(C)C2(C(O1)=O)CC1C=1C=COC=1 SRNFODIJXVPXHO-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 240000006497 Dianthus caryophyllus Species 0.000 description 1
- 235000009355 Dianthus caryophyllus Nutrition 0.000 description 1
- 240000003421 Dianthus chinensis Species 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 206010015226 Erythema nodosum Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000714165 Feline leukemia virus Species 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018372 Glomerulonephritis membranous Diseases 0.000 description 1
- 206010051920 Glomerulonephropathy Diseases 0.000 description 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 1
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000798441 Homo sapiens Basigin Proteins 0.000 description 1
- 101000868215 Homo sapiens CD40 ligand 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
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 1
- 101100061856 Homo sapiens CXCL2 gene Proteins 0.000 description 1
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 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
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 description 1
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 1
- 101000606465 Homo sapiens Inactive tyrosine-protein kinase 7 Proteins 0.000 description 1
- 101001046683 Homo sapiens Integrin alpha-L Proteins 0.000 description 1
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 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
- 101000853002 Homo sapiens Interleukin-25 Proteins 0.000 description 1
- 101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 1
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000961414 Homo sapiens Membrane cofactor protein Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 description 1
- 101000972284 Homo sapiens Mucin-3A Proteins 0.000 description 1
- 101000972286 Homo sapiens Mucin-4 Proteins 0.000 description 1
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 description 1
- 101000972276 Homo sapiens Mucin-5B Proteins 0.000 description 1
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 1
- 101001128431 Homo sapiens Myeloid-derived growth factor Proteins 0.000 description 1
- 101000610551 Homo sapiens Prominin-1 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 1
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 description 1
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100039813 Inactive tyrosine-protein kinase 7 Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100022339 Integrin alpha-L Human genes 0.000 description 1
- 102100025304 Integrin beta-1 Human genes 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102100020793 Interleukin-13 receptor subunit alpha-2 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 108010002350 Interleukin-2 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
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108010048043 Macrophage Migration-Inhibitory Factors Proteins 0.000 description 1
- 102100037791 Macrophage migration inhibitory factor Human genes 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 102100039373 Membrane cofactor protein Human genes 0.000 description 1
- 101100162020 Mesorhizobium japonicum (strain LMG 29417 / CECT 9101 / MAFF 303099) adc3 gene Proteins 0.000 description 1
- 108090000015 Mesothelin Proteins 0.000 description 1
- 102000003735 Mesothelin Human genes 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 235000009812 Momordica cochinchinensis Nutrition 0.000 description 1
- 235000018365 Momordica dioica Nutrition 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 102100034263 Mucin-2 Human genes 0.000 description 1
- 102100022497 Mucin-3A Human genes 0.000 description 1
- 102100022693 Mucin-4 Human genes 0.000 description 1
- 102100022494 Mucin-5B Human genes 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- KUIFHYPNNRVEKZ-VIJRYAKMSA-N O-(N-acetyl-alpha-D-galactosaminyl)-L-threonine Chemical compound OC(=O)[C@@H](N)[C@@H](C)O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O KUIFHYPNNRVEKZ-VIJRYAKMSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 240000007643 Phytolacca americana Species 0.000 description 1
- 235000009074 Phytolacca americana Nutrition 0.000 description 1
- 101100413173 Phytolacca americana PAP2 gene Proteins 0.000 description 1
- IDDMFNIRSJVBHE-UHFFFAOYSA-N Piscigenin Natural products COC1=C(O)C(OC)=CC(C=2C(C3=C(O)C=C(O)C=C3OC=2)=O)=C1 IDDMFNIRSJVBHE-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 102100040120 Prominin-1 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108091006576 SLC34A2 Proteins 0.000 description 1
- 101100434411 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ADH1 gene Proteins 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 241000219287 Saponaria Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 102100038437 Sodium-dependent phosphate transport protein 2B Human genes 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 102100035721 Syndecan-1 Human genes 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 1
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 1
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 1
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 102100038126 Tenascin Human genes 0.000 description 1
- 108010008125 Tenascin Proteins 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 241000711975 Vesicular stomatitis virus Species 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 101150102866 adc1 gene Proteins 0.000 description 1
- 101150042711 adc2 gene Proteins 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 101150061829 bre-3 gene Proteins 0.000 description 1
- 229960000455 brentuximab vedotin Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 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 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 231100000776 exotoxin Toxicity 0.000 description 1
- 239000002095 exotoxin Substances 0.000 description 1
- 102000006815 folate receptor Human genes 0.000 description 1
- 108020005243 folate receptor Proteins 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940045808 haemophilus influenzae type b Drugs 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 108040003607 interleukin-13 receptor activity proteins Proteins 0.000 description 1
- 108040002039 interleukin-15 receptor activity proteins Proteins 0.000 description 1
- 102000008616 interleukin-15 receptor activity proteins Human genes 0.000 description 1
- 108040001304 interleukin-17 receptor activity proteins Proteins 0.000 description 1
- 102000053460 interleukin-17 receptor activity proteins Human genes 0.000 description 1
- 108040002014 interleukin-18 receptor activity proteins Proteins 0.000 description 1
- 102000008625 interleukin-18 receptor activity proteins Human genes 0.000 description 1
- 108040006849 interleukin-2 receptor activity proteins Proteins 0.000 description 1
- 108040006852 interleukin-4 receptor activity proteins Proteins 0.000 description 1
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000008350 membranous glomerulonephritis Diseases 0.000 description 1
- 231100000855 membranous nephropathy Toxicity 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 108010010621 modeccin Proteins 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229950011068 niraparib Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- BMCJATLPEJCACU-UHFFFAOYSA-N tricin Natural products COc1cc(OC)c(O)c(c1)C2=CC(=O)c3c(O)cc(O)cc3O2 BMCJATLPEJCACU-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K47/6801—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
-
- 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
- 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
-
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—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
- A61K47/54—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 organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- 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
-
- 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
- A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
-
- 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
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明提供了一种负载双毒素的抗体药物偶联物,通过抗体上半胱氨酸结合位点上将MMAF与另外一种药物单元串联,二者可以发挥显著的协同效应,从而有效的提升杀伤肿瘤细胞的效果,这为开发高效低毒的ADC提供了新方案。
Description
技术领域
本发明涉及抗体药物偶联物领域,具体涉及一种通过一个抗体负载双毒素的抗体药物偶联物。
背景技术
抗体药物偶联物(antibody-drug conjugate,ADC),是指通过化学连接子(Linker)将具有生物活性的药物(Drug)和抗体(Antibody)连接起来的一类生物药。ADC就像是精确制导武器体系,其中具有生物活性的药物作为杀伤性弹药,在抗体的指引下,精准打击病变细胞。因此,ADC结合了细胞毒药物分子的高效能和抗体高靶向性的双重优点。
截止到2021年3月,全球仅批准了11种抗体偶联药物(如表1所示),他们均为一个靶点抗体偶联一种毒素分子的ADC分子。由于肿瘤细胞表面上抗原数量有限,有效的ADC活性所需的抗原表达水平根据不同抗原特性而变化。ADC需要至少104个抗原/细胞,以确保能够递送致死数量的细胞毒性药物。理想情况下,ADC的抗体部分所针对的抗原应在肿瘤细胞表面均匀表达且拷贝数较高(>105/细胞)。而现实情况为肿瘤细胞表面通常只有有限数量的抗原(大约5000到106个抗原/细胞),并且ADC理想的平均DAR值为3.5-4(如Brentuximabvedotin的平均DAR值为4、Trastuzumab emtansine的平均DAR值为3.5),输送到肿瘤细胞的药物量很低,因此对于肿瘤细胞的药效较低,这也被认为是ADC临床失败的主要原因之一。
表1已上市抗体药物偶联物
注:Mylotarg于2000年获批上市后在2010年撤市,后于2017年重新获批上市。
发明内容
为了解决上述问题,本发明提供了一种能够负载双毒素的抗体药物偶联物。具体而言,本发明提供了一种包含下式结构的抗体药物偶联物:
其中:
Ab为抗体或抗原结合片段;
S为所述Ab上的链间二硫键打开后形成的巯基残基中的硫原子;
Aa为包含一个或多个氨基酸的氨基酸单元;
G为可选择的裂解单元;
D1为MMAF;
D2是不同于MMAF的第二活性药物单元;
p为选自1、2、3、4、5、6、7、8的整数。
抗体或抗原结合片段Ab与癌症、感染性疾病或自身免疫性疾病相关的抗原或所述抗原的表位具有反应性;可选的,Ab为鼠、嵌合、灵长类动物化、人化、或人单克隆抗体的完整、片段(如Fab、Fab’、F(ab)2、F(ab’)2等)或亚片段(如单链构建体等)形式,所述抗体包括双特异性抗体、或多特异性抗体。可选的,Ab为鼠、嵌合、灵长类动物化、人化、或人单克隆抗体的完整形式,且所述的Ab具有人IgG1或者人IgG4抗体的Fc结构域和铰链区结构域或其部分氨基酸突变、替换、缺失形式。
第一活性药物单元D1为选自奥瑞他汀(auristatin)类细胞毒性剂;优选的,所述的第一活性药物单元D1含有游离的羧基。
在一些优选的实施例中,第一活性药物单元D1选自以下结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其药学上可接受的盐或溶剂化物:
第二活性药物单元D2为选自细胞毒性分子、免疫增强剂和放射性同位素,所述细胞毒性分子包括但不限于微管蛋白抑制剂、DNA损伤剂、拓扑异构酶抑制剂、ALK抑制剂、PARP抑制剂;进一步优选的,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;所述拓扑异构酶抑制剂包括喜树碱(camptothecins)及喜树碱类衍生物;进一步优选的,所述奥瑞他汀(auristatin)类细胞素分子包括但不限于MMAE或MMAF或它们的洐生物,所述美登素类细胞毒分子包括但不限于DM1、DM4或它们的洐生物。
在一些优选的实施例中,第二活性药物单元D2选自ALK抑制剂、PARP抑制剂、拓扑异构酶抑制剂。
在一些更优选的实施例中,第二活性药物单元D2选自以下结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其药学上可接受的盐或溶剂化物:
在一些优选的实施例中,第一活性药物单元D1和第二活性药物单元D2分别是MMAF和SN38。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和MK4827。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和Ceritinib。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和Dxd。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和Exatecan。
氨基酸单元Aa可以包含一个氨基酸,可选自:-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的AA选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-。
氨基酸单元Aa可以包含两个氨基酸,且二者可以相同,也可以不同,它们均独立的选自-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的氨基酸选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-。
氨基酸单元Aa可以包含三个氨基酸,且三者可以相同,也可以不同,它们均独立的选自-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的氨基酸选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-。
氨基酸单元Aa可以包含四个氨基酸,且四者可以相同,也可以不同,它们均独立的选自-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的氨基酸选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-;n为选自0、1的整数,当n为0时,AA4和D2直接共价连接。
在一些优选的实施例中,所述的氨基酸单元Aa选自-缬氨酸-瓜氨酸-(-Val-Cit-)、-缬氨酸-丙氨酸-(-Val-Ala-)、-缬氨酸-赖氨酸-(-Val-Lys-)、-缬氨酸-赖氨酸(三苯甲基)-(-Val-Lys(Trt)-)、-缬氨酸-赖氨酸(单甲氧基三苯甲基)-(-Val-Lys(Mmt)-)、-缬氨酸-赖氨酸(芴氧羰基)-(-Val-Lys(Fmoc)-)、-缬氨酸-精氨酸-(-Val-Arg-)、-苯丙氨酸-瓜氨酸-(-Phe-Cit-)、-苯丙氨酸-赖氨酸-(-Phe-Lys-)、-苯丙氨酸-赖氨酸(三苯甲基)-(-Phe-Lys(Trt)-)、-苯丙氨酸-赖氨酸(单甲氧基三苯甲基)-(-Phe-Lys(Mmt)-)、-苯丙氨酸-赖氨酸(芴氧羰基)-(-Phe-Lys(Fmoc)-)、-亮氨酸-瓜氨酸-(-Leu-Cit-)、-异亮氨酸-瓜氨酸-(-Ile-Cit-)、-苯丙氨酸-精氨酸-(-Phe-Arg-);
在另一些优选的实施例中,所述的氨基酸单元Aa为-苯丙氨酸-精氨酸-精氨酸-(-Ala-Arg-Arg-);
在另一些优选的实施例中,所述的氨基酸单元Aa选自-甘氨酸-甘氨酸-苯丙氨酸-甘氨酸-(-Gly-Gly-Phe-Gly-)、-甘氨酸-苯丙氨酸-亮氨酸-甘氨酸-(-Gly-Phe-Leu-Gly-),-丙氨酸-亮氨酸-丙氨酸-亮氨酸(-Ala-Leu-Ala-Leu-)。
可选的,所述的氨基酸单元Aa的结构可选自如下:
在一些具体的实施例中,所述的自裂解单元G为空或选自如下结构: 其中所述的R1、R2为任一取代基团,优选的,所述的R1和R2独立地选自H或者C1至C10的烷基或为:
当自裂解单元G为空时,氨基酸单元Aa中最后一个氨基酸基团和第二活性药物单元D2共价连接。
可选的,所述的自裂解单元G选自如下结构:
在一些具体的实施例中,所述的抗体药物偶联物选自如下结构,其中p为选自1、2、3、4、5、6、7、8的整数:
本发明还涉及前述任一项所述的抗体药物偶联物在制备用于治疗或预防癌症、感染性疾病或自身免疫性疾病的药物中的应用。
所述的癌症指造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤,例如非限制性地选自:乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤和白血病等实体瘤或血液肿瘤。
所述的自身免疫性疾病是指身体产生针对其自身组织的免疫应答导致的病症,诸如包括但不限于:免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈病、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性肝硬变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、纤维化肺泡炎和青少年糖尿病及新发生的疾病。
所述的感染性疾病主要指的是病原性生物感染,包括但不限于如下:人免疫缺陷病毒(HIV)、结核分支杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫、克氏锥虫、罗德西亚锥虫、布氏锥虫、曼森血吸虫、日本血吸虫、牛巴贝虫、柔嫩艾美球虫、盘尾丝虫、热带利什曼原虫、旋毛线虫、小泰累尔梨浆虫、水泡绦虫、羊绦虫、牛肉绦虫、细粒棘球绦虫、科特氏中殖孔绦虫、关节炎支原体、猪鼻支原体、口腔支原体、精氨酸支原体、莱氏无胆甾原体、唾液支原体和肺炎支原体及新发生的疾病。
本发明还提供了一种中间体化合物,其结构如下式所示:
其中:
Aa为包含一个或多个氨基酸的氨基酸单元;
G为可选择的裂解单元;
D1为MMAF;
D2是不同于MMAF的第二活性药物单元。
第一活性药物单元D1为选自奥瑞他汀(auristatin)类细胞毒性剂;优选的,所述的第一活性药物单元D1含有游离的羧基。
在一些优选的实施例中,第一活性药物单元D1选自以下结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其药学上可接受的盐或溶剂化物:
第二活性药物单元D2为选自细胞毒性分子、免疫增强剂和放射性同位素,所述细胞毒性分子包括但不限于微管蛋白抑制剂、DNA损伤剂、拓扑异构酶抑制剂、ALK抑制剂、PARP抑制剂;进一步优选的,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;所述拓扑异构酶抑制剂包括喜树碱(camptothecins)及喜树碱类衍生物;进一步优选的,所述奥瑞他汀(auristatin)类细胞素分子包括但不限于MMAE或MMAF或它们的洐生物,所述美登素类细胞毒分子包括但不限于DM1、DM4或它们的洐生物。
在一些优选的实施例中,第二活性药物单元D2选自ALK抑制剂、PARP抑制剂、拓扑异构酶抑制剂。
在一些更优选的实施例中,第二活性药物单元D2选自以下结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其药学上可接受的盐或溶剂化物:
/>
在一些优选的实施例中,第一活性药物单元D1和第二活性药物单元D2分别是MMAF和SN38。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和MK4827。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和Ceritinib。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和Dxd。
在一些优选的实施例中,所述的第一活性药物单元D1和第二活性药物单元D2分别是MMAF和Exatecan。
氨基酸单元Aa可以包含一个氨基酸,可选自:-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的AA选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-。
氨基酸单元Aa可以包含两个氨基酸,且二者可以相同,也可以不同,它们均独立的选自-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的氨基酸选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-。
氨基酸单元Aa可以包含三个氨基酸,且三者可以相同,也可以不同,它们均独立的选自-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的氨基酸选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-。
氨基酸单元Aa可以包含四个氨基酸,且四者可以相同,也可以不同,它们均独立的选自-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;优选的,所述的氨基酸选自-缬氨酸-、-瓜氨酸-、-丙氨酸-、-赖氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-、-精氨酸-、-苯丙氨酸-、-甘氨酸-、-亮氨酸-、-异亮氨酸-;n为选自0、1的整数,当n为0时,AA4和D2直接共价连接。
在一些优选的实施例中,所述的氨基酸单元Aa选自-缬氨酸-瓜氨酸-(-Val-Cit-)、-缬氨酸-丙氨酸-(-Val-Ala-)、-缬氨酸-赖氨酸-(-Val-Lys-)、-缬氨酸-赖氨酸(三苯甲基)-(-Val-Lys(Trt)-)、-缬氨酸-赖氨酸(单甲氧基三苯甲基)-(-Val-Lys(Mmt)-)、-缬氨酸-赖氨酸(芴氧羰基)-(-Val-Lys(Fmoc)-)、-缬氨酸-精氨酸-(-Val-Arg-)、-苯丙氨酸-瓜氨酸-(-Phe-Cit-)、-苯丙氨酸-赖氨酸-(-Phe-Lys-)、-苯丙氨酸-赖氨酸(三苯甲基)-(-Phe-Lys(Trt)-)、-苯丙氨酸-赖氨酸(单甲氧基三苯甲基)-(-Phe-Lys(Mmt)-)、-苯丙氨酸-赖氨酸(芴氧羰基)-(-Phe-Lys(Fmoc)-)、-亮氨酸-瓜氨酸-(-Leu-Cit-)、-异亮氨酸-瓜氨酸-(-Ile-Cit-)、-苯丙氨酸-精氨酸-(-Phe-Arg-);
在另一些优选的实施例中,所述的氨基酸单元Aa为-苯丙氨酸-精氨酸-精氨酸-(-Ala-Arg-Arg-);
在另一些优选的实施例中,所述的氨基酸单元Aa选自-甘氨酸-甘氨酸-苯丙氨酸-甘氨酸-(-Gly-Gly-Phe-Gly-)、-甘氨酸-苯丙氨酸-亮氨酸-甘氨酸-(-Gly-Phe-Leu-Gly-),-丙氨酸-亮氨酸-丙氨酸-亮氨酸(-Ala-Leu-Ala-Leu-)。
可选的,所述的氨基酸单元Aa的结构可选自如下:
/>
/>
在一些具体的实施例中,所述的自裂解单元G为空或选自如下结构: 其中所述的R1、R2为任一取代基团,优选的,所述的R1和R2独立地选自H或者C1至C10的烷基或为:
当自裂解单元G为空时,氨基酸单元Aa中最后一个氨基酸基团和第二活性药物单元D2共价连接。
可选的,所述的自裂解单元G选自如下结构:
在一些具体的实施例中,所述的化合物选自如下结构:
本发明还提供了上述任一项所述的化合物在制备用于治疗或预防癌症、感染性疾病或自身免疫性疾病的药物中的应用。
本发明还提供了上述所述的中间体化合物的合成方法,其特征在于,所述方法的合成路线为:
所述方法包括如下步骤:
步骤1:将化合物Fmoc-Aa-G、第二活性药物单元D2、有机碱1溶于适量有机溶剂1中,使其接触反应,得化合物Fmoc-Aa-G-D2;
步骤2:将化合物Fmoc-Aa-G-D2脱除Fmoc基团保护,得化合物Aa-G-D2;
步骤3:将化合物Aa-G-D2、化合物Mc-D1、缩合剂1溶于适量有机溶剂2中,使其接触反应,得化合物Mc-D1-Aa-G-D2;
其中,所述的有机碱1选自N,N二异丙基乙胺、三乙胺、吡啶的一种或几种;所述的有机溶剂1和有机溶剂2分别独立的选自DMF、DMA的一种或两种;所述的缩合剂1选自TSTU、HATU、HBTU、HCTU、PyBop、CDMT、T3P中的一种或几种。
在一些具体的实施例中,本发明还提供了利用上述提供的合成方法,其特征在于制备特定中间体化合物的合成路线,所述的合成路线选自如下:
/>
/>
本发明惊奇地发现在抗体中一个半胱氨酸结合位点上通过连接子将MMAF与另外一种药物单元串联,二者可以发挥显著的协同效应,从而有效的提升杀伤肿瘤细胞的效果,这为开发高效低毒的ADC提供了新方案。
具体实施方式
除非另有限定,本文所用的所有技术和科学术语均与本发明所属领域普通技术人员的通常理解一致。虽然也可采用与本文所述相似或等同的任何方法和材料实施或测试本发明,但本文描述了优选的方法和材料。描述和要求保护本发明时,依据以下定义使用下列术语。
当本发明中使用商品名时,申请人旨在包括该商品名产品的制剂、该商品名产品的非专利药和活性药物部分。
除非有相反陈述,在说明书和权利要求书中使用的术语具有相同的下述含义。
本发明所使用的术语“抗体药物偶联物(即Antibody drug conjugate,ADC)”表示抗体或抗原结合片段、连接单元、活性药物单元经过化学反应连接在一起的化合物,其结构通常由三部分组成:抗体或抗体类配体、药物部分(即活性药物单元)、以及将抗体或抗体类配体及药物部分偶联起来的连接单元(linker)。
本发明所使用的术语“抗体”是指能识别和结合目标细胞相关的抗原或受体的大分子化合物,抗体的作用是将药物呈递给与抗体结合的目标细胞群,这些抗体包括但不限于蛋白类激素、凝集素、生长因子、抗体或其他能与细胞结合的分子。在一些特定的实施例中,所述的抗体结合于包括但不限于以下组成的组的抗原:碳酸酐酶IX、B7、CCCL19、CCCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、HLA-DR、CD66a-d、MAGE、McRP、McP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PSMA二聚物、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5、和致癌基因产物。在一些具体的实施例中,所述的抗体包括但不限于如下:抗EGFRvIII抗体、抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗IntegrinAv抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体及新发现的靶点抗体。
本发明的抗体包括鼠源抗体、嵌合抗体、灵长类动物化、人源化抗体(即人化)和全人源抗体(即人),优选人源化抗体和全人源抗体。
术语“鼠源抗体”在本公开中为根据本领域知识和技能用鼠制备抗体。制备时用特定抗原注射试验对象,然后分离表达具有所需序列或功能特性的抗体的杂交
术语“嵌合抗体(chimeric antibody)”,是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体,可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体,要先建立分泌鼠源性特异性单抗的杂交瘤,然后从鼠杂交瘤细胞中克隆可变区基因,再根据需要克隆人抗体的恒定区基因,将鼠可变区基因与人恒定区基因连接成嵌合基因后插入表达载体中,最后在真核系统或原核系统中表达嵌合抗体分子。
术语“人源化抗体(humanized antibody)”也称为CDR移植抗体(CDR-graftedantibody),是指将鼠的CDR序列移植到人的抗体可变区框架,即不同类型的人种系抗体框架序列中产生的抗体。可以克服嵌合抗体由于携带大量鼠蛋白成分,从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com/ac.uk/vbase可获得),以及在Kabat,E.A.等人,1991Sequences ofProteins of Immunological Interest,第5版中找到。为避免免疫原性下降的同时,引起的活性下降,可对所述的人抗体可变区框架序列进行最少反向突变或回复突变,以保持活性。本发明的人源化抗体也包括进一步由噬菌体展示对CDR进行亲和力成熟后的人源化抗体。进一步描述参与人源化可使用小鼠抗体的方法的文献包括,例如Queen等,Proc.,Natl.Acad.Sci.USA,88,2869,1991和Winter及其同事的方法[Jones.,Nature,321,522,(1986)],Riechmann,等[Nature,332,323-327,1988),Verhoeyen,等,Science,239,1534(1988)]。
术语“全人源抗体”、“全人抗体”或“完全人源抗体”、“人抗体”,也称“全人源单克隆抗体”、,其抗体的可变区和恒定区都是人源的,去除免疫原性和毒副作用。单克隆抗体的发展经历了四个阶段,分别为:鼠源性单克隆抗体、嵌合性单克隆抗体、人源化单克隆抗体和全人源单克隆抗体。本发明为全人源单克隆抗体。全人抗体制备的相关技术主要有:人杂交瘤技术、EBV转化B淋巴细胞技术、噬菌体显示技术(phage display)、转基因小鼠抗体制备技术(transgenic mouse)和单个B细胞抗体制备技术等。
本发明所使用的术语“抗原结合片段”是指抗体的保持特异性结合抗原的能力的一个或多个片段。“抗原结合片段”中包含的结合片段的实例包括(i)Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')2片段,包含通过铰链区上的二硫桥连接的两个Fab片段的二价片段,(iii)由VH和CH1结构域组成的Fd片段;(iv)由抗体的单臂的VH和VL结构域组成的Fv片段;(v)单结构域或dAb片段(Ward等人,(1989)Nature341:544-546),其由VH结构域组成;和(vi)分离的互补决定区(CDR)或(vii)可任选地通过合成的接头连接的两个或更多个分离的CDR的组合。此外,虽然Fv片段的两个结构域VL和VH由分开的基因编码,但可使用重组方法,通过合成的接头连接它们,从而使得其能够产生为其中VL和VH区配对形成单价分子的单个蛋白质链(称为单链Fv(scFv);参见,例如,Bird等人(1988)Science242:423-426和Huston等人(1988)Proc.NatL.Acad.Sci.USA85:5879-5883)。此类单链抗体也意欲包括在术语抗体的“抗原结合片段”中。使用本领域技术人员己知的常规技术获得此类抗体片段,并且以与对于完整抗体的方式相同的方式就功用性筛选片段。可通过重组DNA技术或通过酶促或化学断裂完整免疫球蛋白来产生抗原结合部分。抗体可以是不同同种型的抗体,例如,IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或lgM抗体。
术语Fab是通过用蛋白酶木瓜蛋白酶(切割H链的224位的氨基酸残基)处理IgG抗体分子所获得的片段中的具有约50,000的分子量并具有抗原结合活性的抗体片段,其中H链N端侧的约一半和整个L链通过二硫键结合在一起。
术语F(ab')2是通过用酶胃蛋白酶消化IgG铰链区中两个二硫键的下方部分而获得的分子量为约100,000并具有抗原结合活性并包含在铰链位置相连的两个Fab区的抗体片段。
术语Fab'是通过切割上述F(ab')2的铰链区的二硫键而获得的分子量为约50,000并具有抗原结合活性的抗体片段。此外,可以通过将编码抗体的Fab'片段的DNA插入到原核生物表达载体或真核生物表达载体中并将载体导入到原核生物或真核生物中以表达Fab'来生产所述Fab'。
术语“单链构建体”包括但不限于“单链抗体”、“单链Fv”或“scFv”,意指包含通过接头连接的抗体重链可变结构域或区域(即VH)和抗体轻链可变结构域或区域(即VL)的分子。此类scFv分子可具有一般结构:NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成,例如使用1-4个重复的变体(Holliger等人(1993),proc.Natl.Acad.Sci.USA90:6444-6448)。可用于本发明的其他接头由Alfthan等人(1995),Protein Eng.8:725-731,Choi等人(2001),Eur.J.Immuno 1.31:94-106,Hu等人(1996),Cancer Res.56:3055-3061,Kipriyanov等人(1999),J.Mol.Biol.293:41-56和Roovers等人(2001),Cancer Immunol.描述。
用于制备针对实际上任何靶抗原的抗体或其抗原结合片段的技术是本领域公知的。例如,参见Kohler和Milstein,Nature256:495(1975),以及Coligan等(编),CURRENTPROTOCOLS IN IMMUNOLOGY(免疫学最新实验方案),第1卷,第2.5.1-2.6.7页(JohnWiley&Sons,1991)。简言之,单克隆抗体可如下获得:即用包括抗原的组合物注射小鼠,取出脾脏以获得B淋巴细胞,使所述B淋巴细胞与骨髓瘤细胞融合以产生杂交瘤,克隆所述杂交瘤,选择产生针对所述抗原的抗体的阳性克隆,培养产生针对所述抗原的抗体的所述克隆,并从所述杂交瘤培养物中分离所述抗体。可通过许多充分建立的技术从杂交瘤培养物中分离和纯化。此类分离技术包括蛋白A或蛋白G琼脂糖亲和层析、大小排阻层析以及离子交换层析。例如,参见Coligan第2.7.1-2.7.12页及第2.9.1-2.9.3页。也参见Baines等,“Purification of ImmunoglobulinG(IgG)(免疫球蛋白G(IgG)的纯化)”,于METHODS INMOLECULARBIOLOGY(分子生物学方法),第10卷,第79-104页(The Humana Press,Inc.1992)。在初次引起针对免疫原的抗体后,可对抗体进行测序并随后通过重组技术制备。鼠源抗体和抗体片段的人化和嵌合是本领域技术人员众所周知的。
术语“连接单元”是指一端与抗体/抗原结合片段连接而另一端与药物相连的化学结构片段或键,因此做为一种“桥梁”将抗体/抗原结合片段与药物分子连接起来。它可以包括连接头、间隔物和氨基酸单元,可以通过本领域己知方法合成,诸如US2005-0238649A1中所记载的。如本文所用,“连接单元”可被分为两类:不可断裂连接子和可断裂连接子。
不可断裂连接子是一种相对比较稳定的连接子,其结构很难在体内环境下降解断裂。对于含有不可断裂连接子的抗体药物偶联物,其药物释放机制为:偶联物与抗原结合并被细胞内吞后,抗体在溶酶体中被酶解,释放出由药物,连接子,和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性,但由于活性分子是带电荷的(氨基酸残基),从而导致其不能渗入邻近细胞。因此,此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应,bystander effect)(Bioconjugate Chem.2010,21,5-13)。常见的连接子例如Mc连接子和Mcc连接子等,如下结构所示。
可断裂连接子,顾名思义,可以在目标细胞内断裂并释放出活性药物(小分子药物本身)。可断裂连接子可分为两个主要的类别:化学不稳定连接子和酶不稳定连接子。
化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括pH值,谷胱甘肽浓度等。
对pH值敏感的连接子,通常又称为酸断裂连接子。这样的连接子在血液的中性环境下相对稳定(pH7.3-7.5),但是在弱酸性的内涵体(pH5.0-6.5)和溶酶体(pH4.5-5.0)内将会被水解。第一代的抗体药物偶联物大多应用这类连接子,例如腙,碳酸酯,缩醛,缩酮类。由于酸断裂连接子有限的血浆稳定性,基于此类连接子的抗体药物偶联物通常具有较短的半衰期(2-3天)。这种较短的半衰期在一定程度上限制了pH敏感连接子在新一代抗体药物偶联物中的应用。
对于谷胱甘肽敏感的连接子,又称二硫键连接子。药物释放是基于细胞内谷胱甘肽的高浓度(毫摩尔范围)与血液中相对较低的谷胱甘肽浓度(微摩尔范围)差异引起的。对于肿瘤细胞而言尤其如此,其低含氧量导致还原酶的活性增强,因而导致更高的谷胱甘肽浓度。二硫键具有热力学稳定性,因此在血浆中具有较好的稳定性。
酶不稳定连接子,如肽连接子,能够更好地控制药物释放。肽连接子能够被溶酶体内蛋白酶,如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加)有效地切断。这种肽连接被认为在血浆循环中非常稳定,这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常在细胞外不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性,酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。
自杀式连接子一般嵌合在可断裂连接子与活性药物之间,或者本身就是可断裂连接子的一部分。自杀式连接子的作用机制是:当可断裂连接子在合宜的条件下断裂后,自杀式连接子能够自发地进行结构重排,进而释放与之连接的活性药物。常见的自杀式连接子如对氨基苄醇类(PAB)等。
本发明所使用的术语“毒素”、“药物”以及“药物部分”、“药物单元”泛指同一结构,可以在本发明中以任一名称使用。它们泛指任何具有期望的生物活性,并具有反应性官能团以便制备本发明所述偶联物的化合物。期望的生物活性包括诊断、治愈、缓解、治疗、预防人或其它动物的疾病。随着新型药物不断被发现和发展,这些新药也应纳入本发明所述的药物中。它能够对细胞的生长或增殖产生有害效果的任何物质,可以是来自细菌、真菌、植物或动物的小分子毒素及其衍生物,包括喜树碱类衍生物如伊沙替康,美登木素生物碱及其衍生物(CN101573384)如DM1、DM3、DM4,auristatinF(AF)及其衍生物,如MMAF、MMAE、3024(WO2016/127790A1),白喉毒素、外毒素、蓖麻毒蛋白(ricin)A链、相思豆毒蛋白(abrin)A链、modeccin、α-帚曲霉素(sarcin)、油桐(Aleutitesfordii)毒蛋白、香石竹(dianthin)毒蛋白、美洲商陆(Phytolaca americana)毒蛋白(PAPI、PAPII和PAP-S)、苦瓜(Momordicacharantia)抑制物、麻疯树毒蛋白(curcin)、巴豆毒蛋白(crotin)、肥皂草(sapaonariaofficinalis)抑制物、白树毒蛋白(gelonin)、丝林霉素(mitogellin)局限曲霉素(restrictocin)、酚霉素(phenomycin)、依诺霉素(enomycin)和单端孢菌素(trichothecenes)。
术语“氨基酸”的三字母代码和单字母代码如J.biol.Chem,1968,243,3558.中所述。包括单不限于“酸性氨基酸”、“天然氨基酸”、“非天然氨基酸”。“酸性氨基酸”指氨基酸的等电点小于7,酸性氨基酸分子中往往带有1个或多个羧基等酸性基团,在结构中可有效电离为负离子形式而增加亲水性。酸性氨基酸可以为天然的,也可为非天然的氨基酸。“天然氨基酸”指由生物合成的氨基酸。天然氨基酸一般情况下是L-型的,但也有少数例外,比如甘氨酸,包括天然的和生物体合成的。“非天然氨基酸”指通过合成手段所获得的氨基酸。
最重要的是,本领域技术人员将认识到,本发明所要求保护的化合物和方法可利用本领域已知的多种抗体的任一种抗体。使用的抗体可以从多种已知来源商购买获得或者通过本领域技术人员公知技术制备。另外,本发明所要求保护的化合物和方法可利用本领域已知的多种连接单元,使用的连接单元可以从多种已知来源商购买获得或者用于本领域技术人员公知技术制备。因此,抗体和连接单元的选择不应当视为本发明所要求的保护的化合物和方法的限制。
实施例1化合物L-D(即连接基团-双毒素基团化合物)的制备
①化合物LD-1(即Mc-MMAF-VC-PAB-Ceritinib)的制备
取Fmoc-VC-PAB-PNP 75.6mg和Ceritinib(即色瑞替尼)50.0mg,加入5mLN,N-二甲基甲酰胺和49μLN,N-二异丙基乙胺,室温至反应结束,旋干溶剂,Flash法纯化后得到Fmoc-VC-PAB-Ceritinib粗品80.0mg。LC-MS:[M+H]+:1185.2;[M-H]-:1183.7。
向Fmoc-VC-PAB-Ceritinib粗品中加入8mLN,N-二甲基甲酰胺和2mLN,N-二异丙基乙胺,室温至反应结束,旋干溶剂,制备液相法纯化后得到VC-PAB-Ceritinib纯品50.0mg。LC-MS:[M+H]+:963.4,[M-H]-:961.6。
取Mc-MMAF 20.0mg和TSTU 9.8mg,加入14.2μL N,N-二异丙基乙胺和18.8mg VC-PAB-Ceritinib,室温至反应结束,旋干溶剂,制备液相法纯化,得Mc-MMAF-VC-PAB-Ceritinib纯品12.0mg。LC-MS:[M+H]+:=1869.8,[M-H]-:=1868.2。
②化合物LD-2(即Mc-MMAF-VC-PAB-MK4827)的制备
取Fmoc-VC-PAB-PNP 131.7mg和MK4827(即Niraparib)50.0mg,加入5mL N,N-二甲基甲酰胺和78μL N,N-二异丙基乙胺,室温至反应结束,旋干溶剂,Flash法纯化后得Fmoc-VC-PAB-MK4827粗品98.0mg。LC-MS:[M+H]+:947.5;[M-H+HCOOH]-:992.4。
向上述Fmoc-VC-PAB-MK4827粗品中加入8mL N,N-二甲基甲酰胺和2mL N,N-二异丙基乙胺,室温至反应结束,旋干溶剂,制备液相法纯化,得VC-PAB-MK4827纯品60.0mg。LC-MS:[M+H]+:725.4,[M-H+HCOOH]-:770.0。
取Mc-MMAF 20.0mg和TSTU 9.8mg,加入14.2μL N,N-二异丙基乙胺和VC-PAB-MK4827 18.8mg,室温至反应结束16h,旋干溶剂,制备液相法纯化,得Mc-MMAF-VC-PAB-MK4827纯品7.0mg。LC-MS:[M+H]+:m/z=1632.6,[M-H+HCOOH]-:m/z=1677.5。
③其他化合物的制备
参照化合物1和化合物2的制备方法,制备出化合物LD-3(即Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38),化合物LD-4(即Mc-MMAF-VC-PAB-Exatecan)和化合物LD-5(即Mc-MMAF-GGFG-Dxd)。
实施例2抗体药物偶联物的制备
抗体药物偶联物(ADC)的制备采用通用的偶联方法:用纯化水分别配制还原剂和保护剂如下:1~20mM TCEP(Tris-2-carboxyethyl-phosphine)、1~20mM DTPA(Diethylene triaminepentacetate acid)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(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1h。TCEP还原后的抗体可直接进行偶联。
配制一定浓度(5mM)连接子-活性药物单元化合物溶于25%的DMSO(dimethylsulfoxide,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1-4h。反应结束后,用PBS缓冲液离心超滤3次,纯化去除残余未反应药物以及DMSO等游离小分子,并且利用SDS-PAGE电泳和疏水高效液相(HIC-HPLC)法检测偶联情况。
通过本实施例提供的方法,分别制备了ADC1(即Ab-Mc-MMAF-VC-PAB-Ceritinib)、ADC2(即Ab-Mc-MMAF-VC-PAB-MK4827)、ADC3(即Ab-Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38)、ADC4(即Ab-Mc-MMAF-VC-PAB-Exatecan)、ADC5(即Ab-Mc-MMAF-GGFG-Dxd)。其中,p为选自1、2、3、4、5、6、7、8的任一整数,其中所用的Ab为HER2抗体。
实施例3体外细胞活性评价
①乳腺癌细胞SK-BR-3活性评价
本实施例采用细胞增殖抑制法对Her2单抗-Mc-MMAF-VC-PAB-MK4827及Her2单抗-Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38对乳腺癌细胞SK-BR-3的细胞活性进行评价。
将SK-BR-3细胞胰酶消化后调整细胞密度为50000个/ml,100μL/孔加入细胞培养板中,37℃,5%CO2培养箱中孵育14-20h。用基础培养基对供试品(样品组和对照组见表2)进行梯度稀释,以100μl/孔转入铺有细胞的细胞培养板中;37℃,5%CO2培养箱中孵育70-74h。用培养基将CCK-8稀释10倍,将96孔板中的旧培养基吸出,每孔加入100μL稀释的CCK-8溶液,5%CO2条件下显色2-4h,离心去气泡后在酶标仪上选择测定波长450nm/655nm进行读数。
表2供试样品
表3的结果表明,HER2单抗-Mc-MMAF-VC-PAB-MK4827对SK-BR-3细胞的抑制作用优于HER2单抗-Mc-MMAF、HER2单抗-Mc-VC-PAB-MK4827、HER2单抗-Mc-MMAF和HER2单抗-Mc-VC-PAB-MK4827的混合物、HER2裸抗体;HER2单抗-Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38对SK-BR-3细胞的抑制作用优于HER2单抗-Mc-MMAF、HER2单抗-Mc-VC-PAB-DMEDA-PEG(N3)-SN38、HER2单抗-Mc-MMAF和HER2单抗-Mc-VC-PAB-DMEDA-PEG(N3)-SN38的混合物、HER2裸抗体。并且双毒素串联组的两组毒素产生了协同效应。
表3对SK-BR-3细胞的抑制作用
/>
②胃癌细胞NCI-N87活性评价
本实施例采用细胞增殖抑制法对Her2单抗-Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38对胃癌细胞NCI-N87的细胞活性进行评价。
将NCI-N87细胞胰酶消化后调整细胞密度为50000个/ml,100μL/孔加入细胞培养板中,37℃,5%CO2培养箱中孵育14-20h。用基础培养基对供试品(样品组和对照组见表4)进行梯度稀释,以100μL/孔转入铺有细胞的细胞培养板中;37℃,5%CO2培养箱中孵育70-74h。用培养基将CCK-8稀释10倍,将96孔板中的旧培养基吸出,每孔加入100μL稀释的CCK-8溶液,5%CO2条件下显色2-4h,离心去气泡后在酶标仪上选择测定波长450nm/655nm进行读数。
表4供试样品
序号 | 供试品 |
样品3 | HER2单抗-Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38 |
对照3-1 | HER2单抗-Mc-MMAF |
对照3-2 | HER2单抗-Mc-VC-PAB-DMEDA-PEG(N3)-SN38 |
对照3-3 | HER2单抗-Mc-MMAF和HER2单抗-Mc-VC-PAB-DMEDA-PEG(N3)-SN38,质量浓度1:1混合 |
对照3-4 | HER2裸抗体 |
表5的结果表明,HER2单抗-Mc-MMAF-VC-PAB-DMEDA-PEG(N3)-SN38对NCI-N87细胞的抑制作用优于HER2单抗-Mc-MMAF和HER2单抗-Mc-VC-PAB-DMEDA-PEG(N3)-SN38的混合物、HER2裸抗体。并且双毒素串联组的两组毒素产生了显著的协同效应。
表5对NCI-N87细胞的抑制作用
本发明已通过各个具体实施例作了举例说明。但是,本领域普通技术人员能够理解,本发明并不限于各个具体实施方式,普通技术人员在本发明的范围内可以作出各种改动或变型,并且在本说明书中各处提及的各个技术特征可以相互组合,而仍不背离本发明的精神和范围。这样的改动和变型均在本发明的范围之内。
Claims (17)
1.一种具有以下结构式的抗体药物偶联物或其药学上可接受的盐,
其中:
Ab为抗体或抗原结合片段;
S为所述Ab上的链间二硫键打开后形成的巯基残基中的硫原子;
Aa为包含一个或多个氨基酸的氨基酸单元;
G为可选择的裂解单元,且所述的裂解单元G选自如下结构:
D1为MMAF;
D2是不同于MMAF的第二活性药物单元,且所述的第二活性药物单元D2选自MK4827、SN38;
p为选自1、2、3、4、5、6、7、8的整数。
2.根据权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述Ab为鼠、嵌合、人源化、或全人抗体的完整或抗原结合片段。
3.根据权利要求2所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述抗原结合片段包括Fab、Fab’、F(ab)2、F(ab’)2;所述抗体包括双特异性抗体、或多特异性抗体。
4.根据权利要求3所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述Ab具有人IgG1或者人IgG4抗体的Fc结构域和/或铰链区结构域或其部分氨基酸突变、替换、缺失形式。
5.根据权利要求1-4任一项所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述的第一活性药物单元D1选自以下结构或其药学上可接受的盐:
6.根据权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述的第二活性药物单元D2选自MK4827,SN38或其药学上可接受的盐。
7.根据权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述的氨基酸单元Aa选自:-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;缬氨酸-瓜氨酸-(-Val-Cit-)、-缬氨酸-丙氨酸-(-Val-Ala-)、-缬氨酸-赖氨酸-(-Val-Lys-)、-缬氨酸-赖氨酸(三苯甲基)-(-Val-Lys(Trt)-)、-缬氨酸-赖氨酸(单甲氧基三苯甲基)-(-Val-Lys(Mmt)-)、-缬氨酸-赖氨酸(芴氧羰基)-(-Val-Lys(Fmoc)-)、-缬氨酸-精氨酸-(-Val-Arg-)、-苯丙氨酸-瓜氨酸-(-Phe-Cit-)、-苯丙氨酸-赖氨酸-(-Phe-Lys-)、-苯丙氨酸-赖氨酸(三苯甲基)-(-Phe-Lys(Trt)-)、-苯丙氨酸-赖氨酸(单甲氧基三苯甲基)-(-Phe-Lys(Mmt)-)、-苯丙氨酸-赖氨酸(芴氧羰基)-(-Phe-Lys(Fmoc)-)、亮氨酸-瓜氨酸-(-Leu-Cit-)、-异亮氨酸-瓜氨酸-(-Ile-Cit-)、-苯丙氨酸-精氨酸-(-Phe-Arg-);-苯丙氨酸-精氨酸-精氨酸-(-Ala-Arg-Arg-);-甘氨酸-甘氨酸-苯丙氨酸-甘氨酸-(-Gly-Gly-Phe-Gly-)、-甘氨酸-苯丙氨酸-亮氨酸-甘氨酸-(-Gly-Phe-Leu-Gly-)、-丙氨酸-亮氨酸-丙氨酸-亮氨酸(-Ala-Leu-Ala-Leu-)。
8.根据权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述的抗体药物偶联物选自如下结构,其中p为选自1、2、3、4、5、6、7、8的整数:
9.权利要求1-8中任一项所述的抗体药物偶联物或其药学上可接受的盐在制备用于治疗或预防癌症的药物中的应用。
10.一种中间体化合物,其结构如下式所示:
其中:
Aa为包含一个或多个氨基酸的氨基酸单元;
G为可选择的裂解单元,且所述的裂解单元G选自如下结构:
D1为MMAF;
D2是不同于MMAF的第二活性药物单元,且所述的第二活性药物单元D2选自MK4827、SN38。
11.根据权利要求10所述的化合物,其特征在于,所述的第一活性药物单元D1选自以下结构或其药学上可接受的盐:
12.根据权利要求10所述的化合物,其特征在于,所述的第二活性药物单元D2选自MK4827,SN38或其药学上可接受的盐。
13.根据权利要求10-12中任一项所述的化合物,其特征在于,所述的氨基酸单元Aa选自:-甘氨酸-、-丙氨酸-、-缬氨酸-、-亮氨酸-、-异亮氨酸-、-脯氨酸-、-苯丙氨酸-、-色氨酸-、-蛋氨酸-、-酪氨酸-、-丝氨酸-、-苏氨酸-、-半胱氨酸-、-天冬酰胺-、-谷氨酰胺-、-天冬氨酸-、-谷氨酸-、-赖氨酸-、-精氨酸-、-组氨酸-、-瓜氨酸-、-赖氨酸(三苯甲基)-、-赖氨酸(单甲氧基三苯甲基)-、-赖氨酸(芴氧羰基)-;-缬氨酸-瓜氨酸-(-Val-Cit-)、-缬氨酸-丙氨酸-(-Val-Ala-)、-缬氨酸-赖氨酸-(-Val-Lys-)、-缬氨酸-赖氨酸(三苯甲基)-(-Val-Lys(Trt)-)、-缬氨酸-赖氨酸(单甲氧基三苯甲基)-(-Val-Lys(Mmt)-)、-缬氨酸-赖氨酸(芴氧羰基)-(-Val-Lys(Fmoc)-)、-缬氨酸-精氨酸-(-Val-Arg-)、-苯丙氨酸-瓜氨酸-(-Phe-Cit-)、-苯丙氨酸-赖氨酸-(-Phe-Lys-)、-苯丙氨酸-赖氨酸(三苯甲基)-(-Phe-Lys(Trt)-)、-苯丙氨酸-赖氨酸(单甲氧基三苯甲基)-(-Phe-Lys(Mmt)-)、-苯丙氨酸-赖氨酸(芴氧羰基)-(-Phe-Lys(Fmoc)-)、-亮氨酸-瓜氨酸-(-Leu-Cit-)、-异亮氨酸-瓜氨酸-(-Ile-Cit-)、-苯丙氨酸-精氨酸-(-Phe-Arg-);-苯丙氨酸-精氨酸-精氨酸-(-Ala-Arg-Arg-);-甘氨酸-甘氨酸-苯丙氨酸-甘氨酸-(-Gly-Gly-Phe-Gly-)、-甘氨酸-苯丙氨酸-亮氨酸-甘氨酸-(-Gly-Phe-Leu-Gly-)、-丙氨酸-亮氨酸-丙氨酸-亮氨酸(-Ala-Leu-Ala-Leu-)。
14.根据权利要求10所述的化合物,其特征在于,所述的化合物选自如下结构:
15.权利要求10-14任一项所述的化合物在制备用于治疗或预防癌症的药物中的应用。
16.一种如权利要求10所述的化合物的合成方法,其特征在于,所述方法的合成路线为:
所述方法包括如下步骤:
步骤1:将化合物Fmoc-Aa-G、第二活性药物单元D2、有机碱1溶于适量有机溶剂1中,使其接触反应,得化合物Fmoc-Aa-G-D2;
步骤2:将化合物Fmoc-Aa-G-D2脱除Fmoc基团保护,得化合物Aa-G-D2;
步骤3:将化合物Aa-G-D2、化合物Mc-D1、缩合剂1溶于适量有机溶剂2中,使其接触反应,得化合物Mc-D1-Aa-G-D2;
其中,所述的有机碱1选自N,N二异丙基乙胺、三乙胺、吡啶的一种或几种;所述的有机溶剂1和有机溶剂2分别独立的选自DMF、DMA的一种或两种;所述的缩合剂1选自TSTU、HATU、HBTU、HCTU、PyBop、CDMT、T3P中的一种或几种。
17.一种如权利要求16所述的合成方法,其特征在于,所述的化合物选自权利要求14所示的结构,所述的合成路线选自如下:
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2021/107079 WO2023000131A1 (zh) | 2021-07-19 | 2021-07-19 | 一种负载双毒素的抗体药物偶联物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113710277A CN113710277A (zh) | 2021-11-26 |
CN113710277B true CN113710277B (zh) | 2023-09-01 |
Family
ID=78647596
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180002141.5A Active CN113710277B (zh) | 2021-07-19 | 2021-07-19 | 一种负载双毒素的抗体药物偶联物及其应用 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20230270874A1 (zh) |
EP (1) | EP4144376A4 (zh) |
JP (1) | JP7451677B2 (zh) |
KR (1) | KR20230015301A (zh) |
CN (1) | CN113710277B (zh) |
AU (1) | AU2021225125B9 (zh) |
CA (1) | CA3129419C (zh) |
WO (1) | WO2023000131A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023078230A1 (zh) * | 2021-11-02 | 2023-05-11 | 烟台迈百瑞国际生物医药股份有限公司 | 一种包含sn38的抗体药物偶联物中间体及其制备方法 |
WO2023180489A1 (en) | 2022-03-23 | 2023-09-28 | Synaffix B.V. | Antibody-conjugates for targeting of tumours expressing carcinoembyronic antigen |
WO2023180484A1 (en) | 2022-03-23 | 2023-09-28 | Synaffix B.V. | Antibody-conjugates for targeting of tumours expressing ptk7 |
WO2023180490A1 (en) | 2022-03-23 | 2023-09-28 | Synaffix B.V. | Antibody-conjugates for targeting of tumours expressing nectin-4 |
WO2023180485A1 (en) | 2022-03-23 | 2023-09-28 | Synaffix B.V. | Antibody-conjugates for targeting of tumours expressing trop-2 |
US20240108744A1 (en) * | 2022-07-27 | 2024-04-04 | Mediboston Limited | Auristatin derivatives and conjugates thereof |
CN116444672B (zh) * | 2023-06-13 | 2023-11-03 | 上海偌妥生物科技有限公司 | 人表皮生长因子3的抗体、其制备方法及其应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101573384A (zh) * | 2006-10-27 | 2009-11-04 | 健泰科生物技术公司 | 抗体和免疫偶联物及其用途 |
CN106132431A (zh) * | 2013-10-15 | 2016-11-16 | 索伦托治疗有限公司 | 具有靶向分子和两种不同药物的药物偶联物 |
CN108653746A (zh) * | 2017-03-29 | 2018-10-16 | 北京键凯科技股份有限公司 | 一种多载药点、高载药配基药物偶联物 |
CN108743966A (zh) * | 2018-04-24 | 2018-11-06 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物 |
CN110997010A (zh) * | 2019-08-07 | 2020-04-10 | 烟台迈百瑞国际生物医药有限公司 | 一种抗体药物偶联物及其应用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107213469A (zh) * | 2003-11-06 | 2017-09-29 | 西雅图基因公司 | 能够与配体偶联的单甲基缬氨酸化合物 |
JP5394246B2 (ja) | 2007-03-30 | 2014-01-22 | ジェネンテック, インコーポレイテッド | 抗体及びイムノコンジュゲートとこれらの使用方法 |
NZ717668A (en) * | 2013-10-15 | 2024-03-22 | Seagen Inc | Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics |
US10973920B2 (en) * | 2014-06-30 | 2021-04-13 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
US20180177890A1 (en) | 2015-02-15 | 2018-06-28 | Jiangsu Hengrui Medicine Co., Ltd. | Ligand-cytotoxic drug conjugate, preparation method thereof, and use thereof |
CN107778372B (zh) * | 2016-08-22 | 2019-11-26 | 中国科学院上海药物研究所 | 一种寡糖连接子以及利用该寡糖连接子制备的定点连接的抗体-药物偶联物 |
JP7244987B2 (ja) | 2016-12-14 | 2023-03-23 | シージェン インコーポレイテッド | 多剤抗体薬物コンジュゲート |
KR20220024829A (ko) * | 2019-06-24 | 2022-03-03 | 유니버시티 오브 죠지아 리서치 파운데이션, 인코포레이티드 | 이중 약물 항체-약물 접합체 |
-
2021
- 2021-07-19 CN CN202180002141.5A patent/CN113710277B/zh active Active
- 2021-07-19 JP JP2022503434A patent/JP7451677B2/ja active Active
- 2021-07-19 US US17/434,796 patent/US20230270874A1/en active Pending
- 2021-07-19 KR KR1020227003469A patent/KR20230015301A/ko unknown
- 2021-07-19 EP EP21838960.9A patent/EP4144376A4/en active Pending
- 2021-07-19 AU AU2021225125A patent/AU2021225125B9/en active Active
- 2021-07-19 CA CA3129419A patent/CA3129419C/en active Active
- 2021-07-19 WO PCT/CN2021/107079 patent/WO2023000131A1/zh unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101573384A (zh) * | 2006-10-27 | 2009-11-04 | 健泰科生物技术公司 | 抗体和免疫偶联物及其用途 |
CN106132431A (zh) * | 2013-10-15 | 2016-11-16 | 索伦托治疗有限公司 | 具有靶向分子和两种不同药物的药物偶联物 |
CN108653746A (zh) * | 2017-03-29 | 2018-10-16 | 北京键凯科技股份有限公司 | 一种多载药点、高载药配基药物偶联物 |
CN108743966A (zh) * | 2018-04-24 | 2018-11-06 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物 |
CN110997010A (zh) * | 2019-08-07 | 2020-04-10 | 烟台迈百瑞国际生物医药有限公司 | 一种抗体药物偶联物及其应用 |
CN112569368A (zh) * | 2019-08-07 | 2021-03-30 | 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及其应用 |
Non-Patent Citations (1)
Title |
---|
高华."抗癌药物喜树碱及其衍生物的研究概况".《河北医药》.2008,第30卷(第11期),第1786-1788页. * |
Also Published As
Publication number | Publication date |
---|---|
EP4144376A4 (en) | 2023-09-20 |
WO2023000131A1 (zh) | 2023-01-26 |
EP4144376A1 (en) | 2023-03-08 |
JP2023532380A (ja) | 2023-07-28 |
US20230270874A1 (en) | 2023-08-31 |
CA3129419C (en) | 2023-02-28 |
AU2021225125B1 (en) | 2023-01-05 |
CA3129419A1 (en) | 2022-01-14 |
JP7451677B2 (ja) | 2024-03-18 |
AU2021225125B9 (en) | 2023-02-02 |
CN113710277A (zh) | 2021-11-26 |
KR20230015301A (ko) | 2023-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113710277B (zh) | 一种负载双毒素的抗体药物偶联物及其应用 | |
JP6828950B2 (ja) | Cl2aリンカーを有する抗体−sn−38免疫抱合体 | |
AU2007230822B2 (en) | Camptothecin-binding moiety conjugates | |
AU2009212436B2 (en) | Camptothecin-binding moiety conjugates | |
JP6427789B2 (ja) | Cl2aリンカーを有する抗体−sn−38免疫複合体 | |
CN112125915A (zh) | 一种喜树碱衍生物及其偶联物 | |
CN110869393A (zh) | 靶向cd73的抗体及抗体-药物偶联物、其制备方法和用途 | |
CN107735093A (zh) | Cd123抗体和其结合物 | |
JP6982070B2 (ja) | 長期作用型多重特異性分子および関連した方法 | |
US20230295346A1 (en) | Prodruggable antibodies, prodrugs thereof, and methods of use and making | |
JP2021530436A (ja) | Axlを標的とする抗体および抗体−薬物複合体ならびにその製造方法と使用 | |
TW202116808A (zh) | 用於偶聯的多肽複合物及其應用 | |
WO2021143741A1 (zh) | 靶向多肽-药物缀合物及其用途 | |
CN113121639A (zh) | 澳瑞他汀类似物及其偶联物、其制备方法及其应用 | |
RU2795148C2 (ru) | Конъюгат антитело-лекарственное средство, нагруженный бинарными токсинами, и его применение | |
WO2022228563A1 (zh) | 靶向Nectin-4的抗体药物偶联物及其制备方法和用途 | |
CN109562172B (zh) | 抗HLA-DR抗体药物缀合物IMMU-140(hL243-CL2A-SN-38)在HLA-DR阳性癌症中的功效 | |
WO2022268050A1 (zh) | 一种药物组合及其用途 | |
WO2023151679A1 (en) | Pegylated antibody hydroxyl-bearing drug conjugate | |
JPWO2020219775A5 (zh) | ||
JP2023552733A (ja) | 抗クローディン-18.2抗体及びその抗体薬物複合体 | |
CN117460540A (zh) | 艾日布林衍生物的药物偶联物 | |
CN117430708A (zh) | 一种抗Claudin18.2抗体 | |
JPWO2020219778A5 (zh) | ||
JPWO2020219774A5 (zh) |
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 |