TWI781125B - 具有酶裂解基團之抗體-藥劑結合物 - Google Patents
具有酶裂解基團之抗體-藥劑結合物 Download PDFInfo
- Publication number
- TWI781125B TWI781125B TW106144529A TW106144529A TWI781125B TW I781125 B TWI781125 B TW I781125B TW 106144529 A TW106144529 A TW 106144529A TW 106144529 A TW106144529 A TW 106144529A TW I781125 B TWI781125 B TW I781125B
- Authority
- TW
- Taiwan
- Prior art keywords
- antibody
- seq
- chain variable
- sequence
- heavy chain
- Prior art date
Links
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims description 92
- 239000000611 antibody drug conjugate Substances 0.000 title claims description 91
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 160
- 201000011510 cancer Diseases 0.000 claims abstract description 106
- 239000003814 drug Substances 0.000 claims abstract description 37
- 229940079593 drug Drugs 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 238000009739 binding Methods 0.000 claims description 143
- 230000027455 binding Effects 0.000 claims description 142
- 150000001875 compounds Chemical class 0.000 claims description 120
- 239000000427 antigen Substances 0.000 claims description 116
- 108091007433 antigens Proteins 0.000 claims description 116
- 102000036639 antigens Human genes 0.000 claims description 116
- 239000000562 conjugate Substances 0.000 claims description 107
- 239000003795 chemical substances by application Substances 0.000 claims description 69
- 239000012634 fragment Substances 0.000 claims description 59
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 claims description 57
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 37
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 230000001225 therapeutic effect Effects 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002619 cancer immunotherapy Methods 0.000 claims description 8
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 230000036039 immunity Effects 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 claims 21
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 claims 21
- 239000008194 pharmaceutical composition Substances 0.000 claims 5
- 239000002671 adjuvant Substances 0.000 claims 1
- 230000033115 angiogenesis Effects 0.000 claims 1
- 230000008685 targeting Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 129
- 238000011282 treatment Methods 0.000 abstract description 41
- 239000002207 metabolite Substances 0.000 abstract description 26
- 230000006806 disease prevention Effects 0.000 abstract description 4
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 3
- 230000002491 angiogenic effect Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 159
- 108090000623 proteins and genes Proteins 0.000 description 122
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 119
- 239000002953 phosphate buffered saline Substances 0.000 description 119
- 239000000543 intermediate Substances 0.000 description 102
- 239000000872 buffer Substances 0.000 description 94
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 87
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 84
- -1 HsEg5 Proteins 0.000 description 73
- 239000011230 binding agent Substances 0.000 description 69
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 66
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
- 241000282414 Homo sapiens Species 0.000 description 52
- 239000000203 mixture Substances 0.000 description 52
- 102000004169 proteins and genes Human genes 0.000 description 52
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 51
- 108090000765 processed proteins & peptides Proteins 0.000 description 39
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 38
- 235000018102 proteins Nutrition 0.000 description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 229910052786 argon Inorganic materials 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 31
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- 235000001014 amino acid Nutrition 0.000 description 30
- 239000012071 phase Substances 0.000 description 30
- 239000007821 HATU Substances 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 229920005654 Sephadex Polymers 0.000 description 27
- 239000012507 Sephadex™ Substances 0.000 description 27
- 239000003643 water by type Substances 0.000 description 27
- 229940024606 amino acid Drugs 0.000 description 26
- 150000001413 amino acids Chemical class 0.000 description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 238000005199 ultracentrifugation Methods 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 230000000694 effects Effects 0.000 description 23
- 239000003112 inhibitor Substances 0.000 description 23
- 238000011068 loading method Methods 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- 239000002609 medium Substances 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 21
- 239000000126 substance Substances 0.000 description 21
- 210000001519 tissue Anatomy 0.000 description 21
- 102000004190 Enzymes Human genes 0.000 description 20
- 108090000790 Enzymes Proteins 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 238000003556 assay Methods 0.000 description 20
- 229940088598 enzyme Drugs 0.000 description 20
- 125000005647 linker group Chemical group 0.000 description 20
- 231100000331 toxic Toxicity 0.000 description 20
- 230000002588 toxic effect Effects 0.000 description 20
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 19
- 102100038078 CD276 antigen Human genes 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 235000019253 formic acid Nutrition 0.000 description 19
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 description 18
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 description 18
- 102000005962 receptors Human genes 0.000 description 18
- 108020003175 receptors Proteins 0.000 description 18
- 239000012453 solvate Substances 0.000 description 18
- 108010047041 Complementarity Determining Regions Chemical group 0.000 description 17
- 229910052763 palladium Inorganic materials 0.000 description 16
- 102000004196 processed proteins & peptides Human genes 0.000 description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
- 102000016946 TWEAK Receptor Human genes 0.000 description 14
- 108010014401 TWEAK Receptor Proteins 0.000 description 14
- 230000021615 conjugation Effects 0.000 description 14
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 14
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 14
- 241000894007 species Species 0.000 description 14
- 238000000825 ultraviolet detection Methods 0.000 description 14
- PBVAJRFEEOIAGW-UHFFFAOYSA-N 3-[bis(2-carboxyethyl)phosphanyl]propanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCP(CCC(O)=O)CCC(O)=O PBVAJRFEEOIAGW-UHFFFAOYSA-N 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 13
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 description 13
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 239000002243 precursor Substances 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- 238000005984 hydrogenation reaction Methods 0.000 description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 12
- 125000003275 alpha amino acid group Chemical group 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 231100000433 cytotoxic Toxicity 0.000 description 11
- 230000001472 cytotoxic effect Effects 0.000 description 11
- 229920001184 polypeptide Polymers 0.000 description 11
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 11
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 10
- 102000010638 Kinesin Human genes 0.000 description 10
- 108010063296 Kinesin Proteins 0.000 description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 10
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 10
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 210000004962 mammalian cell Anatomy 0.000 description 10
- 230000035699 permeability Effects 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 9
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 239000012980 RPMI-1640 medium Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 230000010354 integration Effects 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 8
- 229960001230 asparagine Drugs 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 239000013598 vector Substances 0.000 description 8
- 208000026310 Breast neoplasm Diseases 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- 239000004472 Lysine Substances 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 description 7
- 235000018417 cysteine Nutrition 0.000 description 7
- 239000000975 dye Substances 0.000 description 7
- 229940082789 erbitux Drugs 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 6
- 102000014914 Carrier Proteins Human genes 0.000 description 6
- 101150029707 ERBB2 gene Proteins 0.000 description 6
- 101001008953 Homo sapiens Kinesin-like protein KIF11 Proteins 0.000 description 6
- 102100027629 Kinesin-like protein KIF11 Human genes 0.000 description 6
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 6
- 230000005593 dissociations Effects 0.000 description 6
- 238000006911 enzymatic reaction Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 238000003259 recombinant expression Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 239000011592 zinc chloride Substances 0.000 description 6
- 235000005074 zinc chloride Nutrition 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 239000006285 cell suspension Substances 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000007429 general method Methods 0.000 description 5
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 102100025221 CD70 antigen Human genes 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 208000017604 Hodgkin disease Diseases 0.000 description 4
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 4
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 102100035721 Syndecan-1 Human genes 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229960003767 alanine Drugs 0.000 description 4
- 229960000548 alemtuzumab Drugs 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 108091008324 binding proteins Proteins 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000000084 colloidal system Substances 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 4
- 229960000789 guanidine hydrochloride Drugs 0.000 description 4
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 229940127121 immunoconjugate Drugs 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- 230000002132 lysosomal effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- ZXFCRVGOHJHZNF-UHFFFAOYSA-N methyl 4-bromo-1h-pyrrole-2-carboxylate Chemical compound COC(=O)C1=CC(Br)=CN1 ZXFCRVGOHJHZNF-UHFFFAOYSA-N 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 210000002307 prostate Anatomy 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 230000009870 specific binding Effects 0.000 description 4
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 244000063299 Bacillus subtilis Species 0.000 description 3
- 235000014469 Bacillus subtilis Nutrition 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N DessMartin periodinane Substances C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 3
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 3
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 3
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 102100031547 HLA class II histocompatibility antigen, DO alpha chain Human genes 0.000 description 3
- 101100356020 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) recA gene Proteins 0.000 description 3
- 101000866278 Homo sapiens HLA class II histocompatibility antigen, DO alpha chain Proteins 0.000 description 3
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 3
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 description 3
- 101000795169 Homo sapiens Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 description 3
- 101000588476 Homo sapiens [heparan sulfate]-glucosamine N-sulfotransferase NDST3 Proteins 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 238000000134 MTT assay Methods 0.000 description 3
- 231100000002 MTT assay Toxicity 0.000 description 3
- 241000282567 Macaca fascicularis Species 0.000 description 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 3
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 3
- 102000003735 Mesothelin Human genes 0.000 description 3
- 108090000015 Mesothelin Proteins 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 101100042680 Mus musculus Slc7a1 gene Proteins 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 3
- 241000191940 Staphylococcus Species 0.000 description 3
- 108010022394 Threonine synthase Proteins 0.000 description 3
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 3
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 3
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 description 3
- 102100031395 [heparan sulfate]-glucosamine N-sulfotransferase NDST3 Human genes 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 3
- 229960000455 brentuximab vedotin Drugs 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 230000009260 cross reactivity Effects 0.000 description 3
- 238000011033 desalting Methods 0.000 description 3
- 102000004419 dihydrofolate reductase Human genes 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 3
- 230000009036 growth inhibition Effects 0.000 description 3
- 230000003394 haemopoietic effect Effects 0.000 description 3
- 238000003306 harvesting Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000000099 in vitro assay Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 229950008001 matuzumab Drugs 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229950010203 nimotuzumab Drugs 0.000 description 3
- 229960003301 nivolumab Drugs 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 229960002621 pembrolizumab Drugs 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 210000002706 plastid Anatomy 0.000 description 3
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 229960001674 tegafur Drugs 0.000 description 3
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 3
- 229960004066 trametinib Drugs 0.000 description 3
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 2
- FUKOTTQGWQVMQB-UHFFFAOYSA-N (2-bromoacetyl) 2-bromoacetate Chemical compound BrCC(=O)OC(=O)CBr FUKOTTQGWQVMQB-UHFFFAOYSA-N 0.000 description 2
- BPVVDVAIARSLKT-GAOQVRBLSA-N (2S)-2-amino-4-[[(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)pyrrol-2-yl]-2,2-dimethylpropyl]-(2-hydroxyacetyl)amino]-N-methylbutanamide 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CNC(=O)[C@@H](N)CCN([C@@H](c1cc(cn1Cc1ccccc1)-c1cc(F)ccc1F)C(C)(C)C)C(=O)CO BPVVDVAIARSLKT-GAOQVRBLSA-N 0.000 description 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- LOBCDGHHHHGHFA-LBPRGKRZSA-N (S)-monastrol Chemical compound CCOC(=O)C1=C(C)NC(=S)N[C@H]1C1=CC=CC(O)=C1 LOBCDGHHHHGHFA-LBPRGKRZSA-N 0.000 description 2
- MXAFDSRFAXCESM-UHFFFAOYSA-N 1-benzyl-4-(2,5-difluorophenyl)pyrrole-2-carbaldehyde Chemical compound FC1=CC(C2=CN(CC3=CC=CC=C3)C(C=O)=C2)=C(F)C=C1 MXAFDSRFAXCESM-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- IHMXVSZXHFTOFN-UHFFFAOYSA-N 2-ethyloxolane Chemical compound CCC1CCCO1 IHMXVSZXHFTOFN-UHFFFAOYSA-N 0.000 description 2
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 2
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 2
- 208000002109 Argyria Diseases 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 102000015790 Asparaginase Human genes 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 102100022108 Aspartyl/asparaginyl beta-hydroxylase Human genes 0.000 description 2
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 2
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 2
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 description 2
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 108700012439 CA9 Proteins 0.000 description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 2
- 208000016778 CD4+/CD56+ hematodermic neoplasm Diseases 0.000 description 2
- 108010065524 CD52 Antigen Proteins 0.000 description 2
- QUPNERXJBBUABM-QMMMGPOBSA-N COC([C@H](CC(=O)O)NC(=O)OCC[Si](C)(C)C)=O Chemical compound COC([C@H](CC(=O)O)NC(=O)OCC[Si](C)(C)C)=O QUPNERXJBBUABM-QMMMGPOBSA-N 0.000 description 2
- 108050007957 Cadherin Proteins 0.000 description 2
- 102000000905 Cadherin Human genes 0.000 description 2
- 101100016516 Caenorhabditis elegans hbl-1 gene Proteins 0.000 description 2
- 102100025473 Carcinoembryonic antigen-related cell adhesion molecule 6 Human genes 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- 102000005600 Cathepsins Human genes 0.000 description 2
- 108010084457 Cathepsins Proteins 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108700022150 Designed Ankyrin Repeat Proteins Proteins 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 2
- 101150076616 EPHA2 gene Proteins 0.000 description 2
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 2
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 2
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 description 2
- 102100031546 HLA class II histocompatibility antigen, DO beta chain Human genes 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 101000914326 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 6 Proteins 0.000 description 2
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 2
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 description 2
- 101000866281 Homo sapiens HLA class II histocompatibility antigen, DO beta chain Proteins 0.000 description 2
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 2
- 101001037261 Homo sapiens Indoleamine 2,3-dioxygenase 2 Proteins 0.000 description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 2
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 2
- 101001112222 Homo sapiens Neural cell adhesion molecule L1-like protein Proteins 0.000 description 2
- 101000835984 Homo sapiens SLIT and NTRK-like protein 6 Proteins 0.000 description 2
- 101000936922 Homo sapiens Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 Proteins 0.000 description 2
- 101000835745 Homo sapiens Teratocarcinoma-derived growth factor 1 Proteins 0.000 description 2
- 101000648505 Homo sapiens Tumor necrosis factor receptor superfamily member 12A Proteins 0.000 description 2
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 2
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 2
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 102100039813 Inactive tyrosine-protein kinase 7 Human genes 0.000 description 2
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 2
- 102100040062 Indoleamine 2,3-dioxygenase 2 Human genes 0.000 description 2
- 102100022337 Integrin alpha-V Human genes 0.000 description 2
- 108010040765 Integrin alphaV Proteins 0.000 description 2
- 102100034845 KiSS-1 receptor Human genes 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 102000017578 LAG3 Human genes 0.000 description 2
- 101150030213 Lag3 gene Proteins 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 2
- 239000007987 MES buffer Substances 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- 102100034256 Mucin-1 Human genes 0.000 description 2
- 108010008707 Mucin-1 Proteins 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 2
- XFAZZQREFHAALG-UHFFFAOYSA-N N-{1-amino-6-[(5-nitro-2-furoyl)amino]-1-oxohexan-2-yl}-23-(indol-3-yl)-20-oxo-4,7,10,13,16-pentaoxa-19-azatricosan-1-amide Chemical compound C=1NC2=CC=CC=C2C=1CCCC(=O)NCCOCCOCCOCCOCCOCCC(=O)NC(C(=O)N)CCCCNC(=O)C1=CC=C([N+]([O-])=O)O1 XFAZZQREFHAALG-UHFFFAOYSA-N 0.000 description 2
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 2
- 238000011786 NMRI nude mouse Methods 0.000 description 2
- 102100035486 Nectin-4 Human genes 0.000 description 2
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 2
- 102100023616 Neural cell adhesion molecule L1-like protein Human genes 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 101710160107 Outer membrane protein A Proteins 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100029198 SLAM family member 7 Human genes 0.000 description 2
- 108091007561 SLC44A4 Proteins 0.000 description 2
- 102100025504 SLIT and NTRK-like protein 6 Human genes 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 102100027732 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 Human genes 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 108700012457 TACSTD2 Proteins 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 102100026404 Teratocarcinoma-derived growth factor 1 Human genes 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102100028786 Tumor necrosis factor receptor superfamily member 12A Human genes 0.000 description 2
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- XJXKGUZINMNEDK-GPJOBVNKSA-L [(4r,5r)-5-(aminomethyl)-2-propan-2-yl-1,3-dioxolan-4-yl]methanamine;platinum(2+);propanedioate Chemical compound [Pt+2].[O-]C(=O)CC([O-])=O.CC(C)C1O[C@H](CN)[C@@H](CN)O1 XJXKGUZINMNEDK-GPJOBVNKSA-L 0.000 description 2
- 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 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229960003272 asparaginase Drugs 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960003852 atezolizumab Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229960003094 belinostat Drugs 0.000 description 2
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960002938 bexarotene Drugs 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 229950008548 bisantrene Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960000419 catumaxomab Drugs 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 238000003570 cell viability assay Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 230000008045 co-localization Effects 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 210000004292 cytoskeleton Anatomy 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 229960000605 dexrazoxane Drugs 0.000 description 2
- DHQUQYYPAWHGAR-QGZVFWFLSA-N dibenzyl (2r)-2-aminopentanedioate Chemical compound C([C@@H](N)C(=O)OCC=1C=CC=CC=1)CC(=O)OCC1=CC=CC=C1 DHQUQYYPAWHGAR-QGZVFWFLSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229960004242 dronabinol Drugs 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 229950002973 epitiostanol Drugs 0.000 description 2
- 229950006835 eptaplatin Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 239000011536 extraction buffer Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 229960002059 gadoversetamide Drugs 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 108700032141 ganirelix Proteins 0.000 description 2
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 description 2
- 229960003794 ganirelix Drugs 0.000 description 2
- 229960000578 gemtuzumab Drugs 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 102000005396 glutamine synthetase Human genes 0.000 description 2
- 108020002326 glutamine synthetase Proteins 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 201000009277 hairy cell leukemia Diseases 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 108700020746 histrelin Proteins 0.000 description 2
- 229960002193 histrelin Drugs 0.000 description 2
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 2
- 102000048770 human CD276 Human genes 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 229960002751 imiquimod Drugs 0.000 description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- PDWUPXJEEYOOTR-IUAIQHPESA-N iobenguane (123I) Chemical compound NC(N)=NCC1=CC=CC([123I])=C1 PDWUPXJEEYOOTR-IUAIQHPESA-N 0.000 description 2
- 229960003795 iobenguane (123i) Drugs 0.000 description 2
- 229960000780 iomeprol Drugs 0.000 description 2
- NJKDOADNQSYQEV-UHFFFAOYSA-N iomeprol Chemical compound OCC(=O)N(C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NJKDOADNQSYQEV-UHFFFAOYSA-N 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- IFMSQTVHQUWBQE-UHFFFAOYSA-N methyl 1-benzyl-4-(2,5-difluorophenyl)pyrrole-2-carboxylate Chemical compound COC(=O)C=1N(C=C(C=1)C1=C(C=CC(=C1)F)F)CC1=CC=CC=C1 IFMSQTVHQUWBQE-UHFFFAOYSA-N 0.000 description 2
- CNWOUWDBHUWYES-UHFFFAOYSA-N methyl 1-benzyl-4-bromopyrrole-2-carboxylate Chemical compound COC(=O)c1cc(Br)cn1Cc1ccccc1 CNWOUWDBHUWYES-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- DASWEROEPLKSEI-UIJRFTGLSA-N monomethyl auristatin e 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)[C@@H](O)C1=CC=CC=C1 DASWEROEPLKSEI-UIJRFTGLSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229960005343 ondansetron Drugs 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- DRKHJSDSSUXYTE-UHFFFAOYSA-L oxidanium;2-[bis[2-[carboxylatomethyl-[2-(2-methoxyethylamino)-2-oxoethyl]amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [OH3+].[Gd+3].COCCNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NCCOC DRKHJSDSSUXYTE-UHFFFAOYSA-L 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229960005244 oxymetholone Drugs 0.000 description 2
- ICMWWNHDUZJFDW-DHODBPELSA-N oxymetholone Chemical compound C([C@@H]1CC2)C(=O)\C(=C/O)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 ICMWWNHDUZJFDW-DHODBPELSA-N 0.000 description 2
- ICMWWNHDUZJFDW-UHFFFAOYSA-N oxymetholone Natural products C1CC2CC(=O)C(=CO)CC2(C)C2C1C1CCC(C)(O)C1(C)CC2 ICMWWNHDUZJFDW-UHFFFAOYSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229960002131 palonosetron Drugs 0.000 description 2
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 229960003978 pamidronic acid Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960000639 pazopanib Drugs 0.000 description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 238000011477 surgical intervention Methods 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 description 2
- 229960005126 tapentadol Drugs 0.000 description 2
- 229960003102 tasonermin Drugs 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229950001699 teceleukin Drugs 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 229960005026 toremifene Drugs 0.000 description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 2
- 229960000977 trabectedin Drugs 0.000 description 2
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000003151 transfection method Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 2
- 229960000922 vinflunine Drugs 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- QMWFDSIDRQIJQN-NRFANRHFSA-N (1R)-1-[1-benzyl-4-(2,5-difluorophenyl)pyrrol-2-yl]-2,2-dimethylpropan-1-amine Chemical compound CC(C)(C)[C@@H](N)C1=CC(=CN1CC1=CC=CC=C1)C1=C(F)C=CC(F)=C1 QMWFDSIDRQIJQN-NRFANRHFSA-N 0.000 description 1
- KTOJGSDLJNUAEP-UHFFFAOYSA-N (2,5-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC=C1F KTOJGSDLJNUAEP-UHFFFAOYSA-N 0.000 description 1
- TYKASZBHFXBROF-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-(2,5-dioxopyrrol-1-yl)acetate Chemical compound O=C1CCC(=O)N1OC(=O)CN1C(=O)C=CC1=O TYKASZBHFXBROF-UHFFFAOYSA-N 0.000 description 1
- VLARLSIGSPVYHX-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-(2,5-dioxopyrrol-1-yl)hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCN1C(=O)C=CC1=O VLARLSIGSPVYHX-UHFFFAOYSA-N 0.000 description 1
- RWRDJVNMSZYMDV-SIUYXFDKSA-L (223)RaCl2 Chemical compound Cl[223Ra]Cl RWRDJVNMSZYMDV-SIUYXFDKSA-L 0.000 description 1
- DKKGGIHZVKOAPK-RXMQYKEDSA-N (2R)-2-(propanoylamino)pentanedioic acid Chemical compound C(C[C@@H](NC(=O)CC)C(=O)O)C(=O)O DKKGGIHZVKOAPK-RXMQYKEDSA-N 0.000 description 1
- VWOQYHGXSXMQNZ-JEDNCBNOSA-N (2S)-2-amino-4-methylpentanoic acid 2-chloro-2-methylpropane Chemical compound C(C)(C)(C)Cl.N[C@@H](CC(C)C)C(=O)O VWOQYHGXSXMQNZ-JEDNCBNOSA-N 0.000 description 1
- MFZSNESUTRVBQX-XEURHVNRSA-N (2S)-2-amino-6-[4-[[3-[[(2S)-1-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl]oxy]-1-oxopropan-2-yl]-methylamino]-3-oxopropyl]disulfanyl]pentanoylamino]hexanoic acid Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(=O)CCSSC(C)CCC(=O)NCCCC[C@H](N)C(O)=O)[C@]2(C)O[C@H]2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 MFZSNESUTRVBQX-XEURHVNRSA-N 0.000 description 1
- WZSJXLUMWSUPFI-WNQIDUERSA-N (2S)-2-aminopropanoic acid 2-chloro-2-methylpropane Chemical compound CC(C)(C)Cl.C[C@H](N)C(O)=O WZSJXLUMWSUPFI-WNQIDUERSA-N 0.000 description 1
- WLQWSECVILICQG-VDGAXYAQSA-N (2S)-4-amino-4-oxo-2-[[(2S)-4-oxo-4-phenylmethoxy-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]butanoyl]amino]butanoic acid Chemical compound NC(C[C@H](NC([C@@H](NC([C@@H](NC(OCC1=CC=CC=C1)=O)C)=O)CC(=O)OCC1=CC=CC=C1)=O)C(=O)O)=O WLQWSECVILICQG-VDGAXYAQSA-N 0.000 description 1
- CATMPQFFVNKDEY-DGCLKSJQSA-N (2r)-2-amino-5-[[(1r)-1-carboxy-2-(1h-indol-3-yl)ethyl]amino]-5-oxopentanoic acid Chemical compound C1=CC=C2C(C[C@@H](NC(=O)CC[C@@H](N)C(O)=O)C(O)=O)=CNC2=C1 CATMPQFFVNKDEY-DGCLKSJQSA-N 0.000 description 1
- UELYDGOOJPRWGF-SRQXXRKNSA-N (2r,3r)-3-[2-[4-(cyclopropylsulfonimidoyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]oxybutan-2-ol Chemical compound C1=C(C(F)(F)F)C(O[C@H](C)[C@H](O)C)=NC(NC=2C=CC(=CC=2)[S@](=N)(=O)C2CC2)=N1 UELYDGOOJPRWGF-SRQXXRKNSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- BXTJCSYMGFJEID-XMTADJHZSA-N (2s)-2-[[(2r,3r)-3-[(2s)-1-[(3r,4s,5s)-4-[[(2s)-2-[[(2s)-2-[6-[3-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]hexanoyl-methylamino]-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-met Chemical group C([C@H](NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)C[C@H]([C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)CCCCCN1C(C(SC[C@H](N)C(O)=O)CC1=O)=O)C(C)C)OC)C(O)=O)C1=CC=CC=C1 BXTJCSYMGFJEID-XMTADJHZSA-N 0.000 description 1
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 1
- BZNDDHWTEVCBAD-BQBZGAKWSA-N (2s)-2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C BZNDDHWTEVCBAD-BQBZGAKWSA-N 0.000 description 1
- ALBODLTZUXKBGZ-JUUVMNCLSA-N (2s)-2-amino-3-phenylpropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 ALBODLTZUXKBGZ-JUUVMNCLSA-N 0.000 description 1
- CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 description 1
- YPBKTZBXSBLTDK-PKNBQFBNSA-N (3e)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole Chemical compound NS(=O)(=O)NCCNC1=NON\C1=C(N=O)/NC1=CC=C(F)C(Br)=C1 YPBKTZBXSBLTDK-PKNBQFBNSA-N 0.000 description 1
- GDFGTRDCCWFXTG-SCTDSRPQSA-N (3r,4ar,10as)-3-(diethylsulfamoylamino)-6-hydroxy-1-propyl-3,4,4a,5,10,10a-hexahydro-2h-benzo[g]quinoline Chemical compound C1=CC=C2C[C@@H]3N(CCC)C[C@H](NS(=O)(=O)N(CC)CC)C[C@H]3CC2=C1O GDFGTRDCCWFXTG-SCTDSRPQSA-N 0.000 description 1
- SCGWHMHVOQPGLS-DFWYDOINSA-N (3s)-3-amino-4-methoxy-4-oxobutanoic acid;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(O)=O SCGWHMHVOQPGLS-DFWYDOINSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- SSNHGLKFJISNTR-DYSNNVSPSA-N (6ar,10ar)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol;2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol Chemical class OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1.C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 SSNHGLKFJISNTR-DYSNNVSPSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- OFVVDFDGFLGAIQ-NRUKRWIHSA-N (R)-N-[(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)pyrrol-2-yl]-2,2-dimethylpropyl]-2-methylpropane-2-sulfinamide Chemical compound C(C1=CC=CC=C1)N1C(=CC(=C1)C1=C(C=CC(=C1)F)F)[C@@H](C(C)(C)C)N[S@](=O)C(C)(C)C OFVVDFDGFLGAIQ-NRUKRWIHSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- HCFKIOACEVHHKQ-UHFFFAOYSA-N 2-(3-amino-2-oxopropyl)octanoic acid Chemical compound CCCCCCC(C(O)=O)CC(=O)CN HCFKIOACEVHHKQ-UHFFFAOYSA-N 0.000 description 1
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 description 1
- PVFFUHAAOKXVTK-UHFFFAOYSA-N 2-(methylamino)-4-oxopentanoic acid Chemical compound CNC(C(O)=O)CC(C)=O PVFFUHAAOKXVTK-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 1
- CNLWNYCFDMAZCB-HUVROIHYSA-N 2-[2-[[2-[[(2r)-1-[[(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-16-benzyl-4-[[(2r,3r)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phe Chemical compound C([C@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)NC(=O)CN(CCN(CCN(CC(O)=O)CC(O)=O)CC(O)=O)CC(O)=O)C1=CC=CC=C1 CNLWNYCFDMAZCB-HUVROIHYSA-N 0.000 description 1
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- MWYDSXOGIBMAET-UHFFFAOYSA-N 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide Chemical compound NC1=NC=C(C=N1)C(=O)N=C1N=C2C(=C(C=CC2=C2N1CCN2)OCCCN1CCOCC1)OC MWYDSXOGIBMAET-UHFFFAOYSA-N 0.000 description 1
- SRSAMLMFVUJPSR-UHFFFAOYSA-N 2-carboxyethylphosphanium;chloride Chemical compound Cl.OC(=O)CCP SRSAMLMFVUJPSR-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- PAEXAIBDCHBNDC-UHFFFAOYSA-N 2-pyridin-4-ylacetic acid Chemical compound OC(=O)CC1=CC=NC=C1 PAEXAIBDCHBNDC-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- GEVGRLPYQJTKKS-UHFFFAOYSA-N 3-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC(=O)CCNC(=O)OCC1=CC=CC=C1 GEVGRLPYQJTKKS-UHFFFAOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- DKUZHSDZSMQOGQ-UHFFFAOYSA-N 3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]propanoic acid Chemical compound NCCOCCOCCOCCOCCC(O)=O DKUZHSDZSMQOGQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CURYRIVJTBNEGU-UHFFFAOYSA-L 3-bromo-1-[12-(3-bromopropanoyl)-3,12-diaza-6,9-diazoniadispiro[5.2.5^{9}.2^{6}]hexadecan-3-yl]propan-1-one;dichloride Chemical compound [Cl-].[Cl-].C1CN(C(=O)CCBr)CC[N+]21CC[N+]1(CCN(CC1)C(=O)CCBr)CC2 CURYRIVJTBNEGU-UHFFFAOYSA-L 0.000 description 1
- LZENMJMJWQSSNJ-UHFFFAOYSA-N 3H-1,2-dithiole-3-thione Chemical compound S=C1C=CSS1 LZENMJMJWQSSNJ-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- HNLRRJSKGXOYNO-UHFFFAOYSA-N 4-[[4-amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl]piperazin-2-one Chemical compound N12N=CN=C(N)C2=C(C=2SC3=C(OC)C=C(C)C=C3C=2)C(COC)=C1CN1CCNC(=O)C1 HNLRRJSKGXOYNO-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- RYYCJUAHISIHTL-UHFFFAOYSA-N 5-azaorotic acid Chemical compound OC(=O)C1=NC(=O)NC(=O)N1 RYYCJUAHISIHTL-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 102000030431 Asparaginyl endopeptidase Human genes 0.000 description 1
- 101710140787 Aspartyl/asparaginyl beta-hydroxylase Proteins 0.000 description 1
- 241001465318 Aspergillus terreus Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 241000937413 Axia Species 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 1
- 102000016605 B-Cell Activating Factor Human genes 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 101710117995 B-lymphocyte antigen CD19 Proteins 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 239000005711 Benzoic acid Chemical class 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 102100022595 Broad substrate specificity ATP-binding cassette transporter ABCG2 Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- UEGONXVOXLVIOF-NHZFLZHXSA-N C(C1=CC=CC=C1)N1C(=CC(=C1)C1=C(C=CC(=C1)F)F)[C@@H](C(C)(C)C)N(CC[C@@H](C(=O)NCCC(=O)O)NC(=O)OCC[Si](C)(C)C)C(CO)=O Chemical compound C(C1=CC=CC=C1)N1C(=CC(=C1)C1=C(C=CC(=C1)F)F)[C@@H](C(C)(C)C)N(CC[C@@H](C(=O)NCCC(=O)O)NC(=O)OCC[Si](C)(C)C)C(CO)=O UEGONXVOXLVIOF-NHZFLZHXSA-N 0.000 description 1
- VSEIDZLLWQQJGK-CHOZPQDDSA-N CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O Chemical compound CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O VSEIDZLLWQQJGK-CHOZPQDDSA-N 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 108010062802 CD66 antigens Proteins 0.000 description 1
- WZWMULHNMGMDOD-VIFPVBQESA-N COC([C@H](CC=O)NC(=O)OCC[Si](C)(C)C)=O Chemical compound COC([C@H](CC=O)NC(=O)OCC[Si](C)(C)C)=O WZWMULHNMGMDOD-VIFPVBQESA-N 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 102100024153 Cadherin-15 Human genes 0.000 description 1
- 101100463133 Caenorhabditis elegans pdl-1 gene Proteins 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- 102100024533 Carcinoembryonic antigen-related cell adhesion molecule 1 Human genes 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 108091005462 Cation channels Proteins 0.000 description 1
- 102100024045 Cell adhesion molecule 4 Human genes 0.000 description 1
- 101710197438 Cell adhesion molecule 4 Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102100039496 Choline transporter-like protein 4 Human genes 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102100032768 Complement receptor type 2 Human genes 0.000 description 1
- 208000009738 Connective Tissue Neoplasms Diseases 0.000 description 1
- 238000011537 Coomassie blue staining Methods 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 101710095468 Cyclase Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 102100036466 Delta-like protein 3 Human genes 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 101001098806 Dictyostelium discoideum cGMP-specific 3',5'-cGMP phosphodiesterase 3 Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102100020743 Dipeptidase 1 Human genes 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 102100026245 E3 ubiquitin-protein ligase RNF43 Human genes 0.000 description 1
- 102000017930 EDNRB Human genes 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 101150097734 EPHB2 gene Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 102000050554 Eph Family Receptors Human genes 0.000 description 1
- 108091008815 Eph receptors Proteins 0.000 description 1
- 102100031968 Ephrin type-B receptor 2 Human genes 0.000 description 1
- 102100033942 Ephrin-A4 Human genes 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 1
- 102100031517 Fc receptor-like protein 1 Human genes 0.000 description 1
- 102100031507 Fc receptor-like protein 5 Human genes 0.000 description 1
- 101150051800 Fcrl1 gene Proteins 0.000 description 1
- 101150032879 Fcrl5 gene Proteins 0.000 description 1
- 101150032412 Fcrla gene Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102000010451 Folate receptor alpha Human genes 0.000 description 1
- 108050001931 Folate receptor alpha Proteins 0.000 description 1
- 102100035139 Folate receptor alpha Human genes 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010081952 Galanin-Like Peptide Proteins 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- ZPLQIPFOCGIIHV-UHFFFAOYSA-N Gimeracil Chemical compound OC1=CC(=O)C(Cl)=CN1 ZPLQIPFOCGIIHV-UHFFFAOYSA-N 0.000 description 1
- 102100033299 Glia-derived nexin Human genes 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000053187 Glucuronidase Human genes 0.000 description 1
- 108010060309 Glucuronidase Proteins 0.000 description 1
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 description 1
- 108010053070 Glutathione Disulfide Proteins 0.000 description 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102100022662 Guanylyl cyclase C Human genes 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000722210 Homo sapiens ATP-dependent DNA helicase DDX11 Proteins 0.000 description 1
- 101000901030 Homo sapiens Aspartyl/asparaginyl beta-hydroxylase Proteins 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000984546 Homo sapiens Bone morphogenetic protein receptor type-1B Proteins 0.000 description 1
- 101000731086 Homo sapiens Brevican core protein Proteins 0.000 description 1
- 101000823298 Homo sapiens Broad substrate specificity ATP-binding cassette transporter ABCG2 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000762242 Homo sapiens Cadherin-15 Proteins 0.000 description 1
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 1
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 1
- 101000928513 Homo sapiens Delta-like protein 3 Proteins 0.000 description 1
- 101000932213 Homo sapiens Dipeptidase 1 Proteins 0.000 description 1
- 101000692702 Homo sapiens E3 ubiquitin-protein ligase RNF43 Proteins 0.000 description 1
- 101000967299 Homo sapiens Endothelin receptor type B Proteins 0.000 description 1
- 101000925259 Homo sapiens Ephrin-A4 Proteins 0.000 description 1
- 101001023230 Homo sapiens Folate receptor alpha Proteins 0.000 description 1
- 101000997803 Homo sapiens Glia-derived nexin Proteins 0.000 description 1
- 101000899808 Homo sapiens Guanylyl cyclase C Proteins 0.000 description 1
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 1
- 101001010614 Homo sapiens Immunoglobulin-like domain-containing receptor 2 Proteins 0.000 description 1
- 101000606465 Homo sapiens Inactive tyrosine-protein kinase 7 Proteins 0.000 description 1
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 1
- 101001091205 Homo sapiens KiSS-1 receptor Proteins 0.000 description 1
- 101000981639 Homo sapiens LHFPL tetraspan subfamily member 3 protein Proteins 0.000 description 1
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- 101001038505 Homo sapiens Ly6/PLAUR domain-containing protein 1 Proteins 0.000 description 1
- 101001038507 Homo sapiens Ly6/PLAUR domain-containing protein 3 Proteins 0.000 description 1
- 101001065568 Homo sapiens Lymphocyte antigen 6E Proteins 0.000 description 1
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 1
- 101000628535 Homo sapiens Metalloreductase STEAP2 Proteins 0.000 description 1
- 101000588067 Homo sapiens Metaxin-1 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 1
- 101001023705 Homo sapiens Nectin-4 Proteins 0.000 description 1
- 101000897042 Homo sapiens Nucleotide pyrophosphatase Proteins 0.000 description 1
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 description 1
- 101000633786 Homo sapiens SLAM family member 6 Proteins 0.000 description 1
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 1
- 101000618133 Homo sapiens Sperm-associated antigen 5 Proteins 0.000 description 1
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 101000844504 Homo sapiens Transient receptor potential cation channel subfamily M member 4 Proteins 0.000 description 1
- 101000801433 Homo sapiens Trophoblast glycoprotein Proteins 0.000 description 1
- 101000892398 Homo sapiens Tryptophan 2,3-dioxygenase Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 1
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 102100034980 ICOS ligand Human genes 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100030712 Immunoglobulin-like domain-containing receptor 2 Human genes 0.000 description 1
- 101710099452 Inactive tyrosine-protein kinase 7 Proteins 0.000 description 1
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 1
- VDJHFHXMUKFKET-UHFFFAOYSA-N Ingenol mebutate Natural products CC1CC2C(C)(C)C2C2C=C(CO)C(O)C3(O)C(OC(=O)C(C)=CC)C(C)=CC31C2=O VDJHFHXMUKFKET-UHFFFAOYSA-N 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 108010076800 Kisspeptin-1 Receptors Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- GDFAOVXKHJXLEI-UHFFFAOYSA-N L-N-Boc-N-methylalanine Natural products CNC(C)C(O)=O GDFAOVXKHJXLEI-UHFFFAOYSA-N 0.000 description 1
- DEFJQIDDEAULHB-IMJSIDKUSA-N L-alanyl-L-alanine Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(O)=O DEFJQIDDEAULHB-IMJSIDKUSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 102000052922 Large Neutral Amino Acid-Transporter 1 Human genes 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 108010062867 Lenograstim Proteins 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 1
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100040281 Ly6/PLAUR domain-containing protein 3 Human genes 0.000 description 1
- 102100032131 Lymphocyte antigen 6E Human genes 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- 108010009254 Lysosomal-Associated Membrane Protein 1 Proteins 0.000 description 1
- 101710116782 Lysosome-associated membrane glycoprotein 1 Proteins 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- JCYZMTMYPZHVBF-UHFFFAOYSA-N Melarsoprol Chemical compound NC1=NC(N)=NC(NC=2C=CC(=CC=2)[As]2SC(CO)CS2)=N1 JCYZMTMYPZHVBF-UHFFFAOYSA-N 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 1
- 102100026711 Metalloreductase STEAP2 Human genes 0.000 description 1
- 102100031603 Metaxin-1 Human genes 0.000 description 1
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 206010027761 Mixed hepatocellular cholangiocarcinoma Diseases 0.000 description 1
- 102100023123 Mucin-16 Human genes 0.000 description 1
- 101100327308 Mus musculus Cd276 gene Proteins 0.000 description 1
- 101000597780 Mus musculus Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- OUCJPRRBOIHWAV-SANMLTNESA-N N-(3-aminopropyl)-N-[(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)pyrrol-2-yl]-2,2-dimethylpropyl]-2-hydroxyacetamide Chemical compound CC(C)(C)[C@@H](N(CCCN)C(=O)CO)C1=CC(=CN1CC1=CC=CC=C1)C1=C(F)C=CC(F)=C1 OUCJPRRBOIHWAV-SANMLTNESA-N 0.000 description 1
- QJZRFPJCWMNVAV-HHHXNRCGSA-N N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide Chemical compound NCCCN([C@H](C(C)C)C=1N(C(=O)C2=CC=C(Cl)C=C2N=1)CC=1C=CC=CC=1)C(=O)C1=CC=C(C)C=C1 QJZRFPJCWMNVAV-HHHXNRCGSA-N 0.000 description 1
- DEFJQIDDEAULHB-UHFFFAOYSA-N N-D-alanyl-D-alanine Natural products CC(N)C(=O)NC(C)C(O)=O DEFJQIDDEAULHB-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 101710202061 N-acetyltransferase Proteins 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- GDFAOVXKHJXLEI-VKHMYHEASA-N N-methyl-L-alanine Chemical compound C[NH2+][C@@H](C)C([O-])=O GDFAOVXKHJXLEI-VKHMYHEASA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 108060005251 Nectin Proteins 0.000 description 1
- 102000002356 Nectin Human genes 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 102100021969 Nucleotide pyrophosphatase Human genes 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 102100037603 P2X purinoceptor 5 Human genes 0.000 description 1
- 101710189969 P2X purinoceptor 5 Proteins 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091059809 PVRL4 Proteins 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000017414 Precursor T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 101710127913 Proteoglycan 4 Proteins 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 108010009413 Pyrophosphatases Proteins 0.000 description 1
- 102000009609 Pyrophosphatases Human genes 0.000 description 1
- 239000005464 Radotinib Substances 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010029107 Respiratory Tract Neoplasms Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- 102100029197 SLAM family member 6 Human genes 0.000 description 1
- 101710083287 SLAM family member 7 Proteins 0.000 description 1
- 108091006576 SLC34A2 Proteins 0.000 description 1
- 108091006938 SLC39A6 Proteins 0.000 description 1
- 108091006232 SLC7A5 Proteins 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 241001138501 Salmonella enterica Species 0.000 description 1
- 101001049892 Scorpio palmatus Potassium channel toxin alpha-KTx 6.2 Proteins 0.000 description 1
- 108010086019 Secretin Proteins 0.000 description 1
- 102100037505 Secretin Human genes 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- LKAJKIOFIWVMDJ-IYRCEVNGSA-N Stanazolol Chemical compound C([C@@H]1CC[C@H]2[C@@H]3CC[C@@]([C@]3(CC[C@@H]2[C@@]1(C)C1)C)(O)C)C2=C1C=NN2 LKAJKIOFIWVMDJ-IYRCEVNGSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 1
- 108090000058 Syndecan-1 Proteins 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 1
- 102000003618 TRPM4 Human genes 0.000 description 1
- 101150117918 Tacstd2 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 102100034195 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 231100000777 Toxicophore Toxicity 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102100033579 Trophoblast glycoprotein Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 description 1
- 102100035283 Tumor necrosis factor ligand superfamily member 18 Human genes 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 101710165436 Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- PCWZKQSKUXXDDJ-UHFFFAOYSA-N Xanthotoxin Natural products COCc1c2OC(=O)C=Cc2cc3ccoc13 PCWZKQSKUXXDDJ-UHFFFAOYSA-N 0.000 description 1
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 1
- 102100023144 Zinc transporter ZIP6 Human genes 0.000 description 1
- WIQIWPPQGWGVHD-JEDNCBNOSA-N [(2s)-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]azanium;chloride Chemical compound Cl.C[C@H](N)C(=O)OC(C)(C)C WIQIWPPQGWGVHD-JEDNCBNOSA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- LGXRRVXXRJRTHK-CWTMBVSESA-I [OH-].[Cl-].[99Tc+5].[O-]C(=O)CNCCNCC([O-])=O.C[C@@H](O)[C@@H](CO)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)c2ccc(NN)nc2)C(=O)N[C@@H](Cc2ccc([O-])cc2)C(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 Chemical compound [OH-].[Cl-].[99Tc+5].[O-]C(=O)CNCCNCC([O-])=O.C[C@@H](O)[C@@H](CO)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)c2ccc(NN)nc2)C(=O)N[C@@H](Cc2ccc([O-])cc2)C(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 LGXRRVXXRJRTHK-CWTMBVSESA-I 0.000 description 1
- CHKFLBOLYREYDO-SHYZEUOFSA-N [[(2s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)C[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 CHKFLBOLYREYDO-SHYZEUOFSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 108010076089 accutase Proteins 0.000 description 1
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010056243 alanylalanine Proteins 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 229940011037 anethole Drugs 0.000 description 1
- 229950006588 anetumab ravtansine Drugs 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- UVJYAKBJSGRTHA-ZCRGAIPPSA-N arglabin Chemical compound C1C[C@H]2C(=C)C(=O)O[C@@H]2[C@@H]2C(C)=CC[C@]32O[C@]31C UVJYAKBJSGRTHA-ZCRGAIPPSA-N 0.000 description 1
- UVJYAKBJSGRTHA-UHFFFAOYSA-N arglabin Natural products C1CC2C(=C)C(=O)OC2C2C(C)=CCC32OC31C UVJYAKBJSGRTHA-UHFFFAOYSA-N 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 229960002594 arsenic trioxide Drugs 0.000 description 1
- 108010055066 asparaginylendopeptidase Proteins 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
- 229950011276 belotecan Drugs 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- DXBNGOWOMMHJKK-KRWDZBQOSA-N benzyl (2s)-4-oxo-2-(phenylmethoxycarbonylamino)butanoate Chemical compound N([C@@H](CC=O)C(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 DXBNGOWOMMHJKK-KRWDZBQOSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229950010559 besilesomab Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- LNQHREYHFRFJAU-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) pentanedioate Chemical compound O=C1CCC(=O)N1OC(=O)CCCC(=O)ON1C(=O)CCC1=O LNQHREYHFRFJAU-UHFFFAOYSA-N 0.000 description 1
- 101150038738 ble gene Proteins 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 208000015322 bone marrow disease Diseases 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 101150046240 bsd gene Proteins 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229960001573 cabazitaxel Drugs 0.000 description 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- KRPUUUJWTZKSOK-YDALLXLXSA-L calcium (4S)-4-[[4-[(2-amino-4-oxidopteridin-6-yl)methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Ca++].Nc1nc([O-])c2nc(CNc3ccc(cc3)C(=O)N[C@@H](CCC([O-])=O)C(O)=O)cnc2n1 KRPUUUJWTZKSOK-YDALLXLXSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 238000001818 capillary gel electrophoresis Methods 0.000 description 1
- 229950001178 capromab Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229950001357 celmoleukin Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- 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 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- FLASNYPZGWUPSU-SICDJOISSA-N chitosan Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)N)O[C@H]1[C@H](O)[C@H]([C@@H](O[C@@H]1CO)O[C@@H]1[C@H](O[C@@H](O[C@@H]2[C@H](O[C@@H](O)[C@H](N)[C@H]2O)CO)[C@H](N)[C@H]1O)CO)NC(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N FLASNYPZGWUPSU-SICDJOISSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960003996 chlormadinone Drugs 0.000 description 1
- VUHJZBBCZGVNDZ-TTYLFXKOSA-N chlormadinone Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 VUHJZBBCZGVNDZ-TTYLFXKOSA-N 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 description 1
- 229960003315 cinacalcet Drugs 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 229960002271 cobimetinib Drugs 0.000 description 1
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 description 1
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 description 1
- 208000011588 combined hepatocellular carcinoma and cholangiocarcinoma Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 229950002550 copanlisib Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229950006799 crisantaspase Drugs 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000009295 crossflow filtration Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- LRCTTYSATZVTRI-UHFFFAOYSA-L cyclohexane-1,2-diamine;platinum(4+);tetradecanoate Chemical compound [Pt+4].NC1CCCCC1N.CCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCC([O-])=O LRCTTYSATZVTRI-UHFFFAOYSA-L 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 229960002204 daratumumab Drugs 0.000 description 1
- 229950001379 darolutamide Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960002272 degarelix Drugs 0.000 description 1
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 1
- 230000022811 deglycosylation Effects 0.000 description 1
- 229940127276 delta-like ligand 3 Drugs 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 229960001251 denosumab Drugs 0.000 description 1
- 229950010726 depreotide Drugs 0.000 description 1
- XXXSJQLZVNKRKX-YQRDHHIGSA-N depreotide Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CCSCC(=O)NC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(N)=O)C(=O)N(C)[C@@H](CC=2C=CC=CC=2)C(=O)N1)=O)C(C)C)C1=CC=C(O)C=C1 XXXSJQLZVNKRKX-YQRDHHIGSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229950007457 dibrospidium chloride Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- DRFILBXQKYDTFW-JIWRMXRASA-L disodium;2-[[(2r)-2-[[(4s)-4-amino-4-carboxybutanoyl]amino]-3-[[(2r)-2-[[(4s)-4-amino-4-carboxybutanoyl]amino]-3-(carboxylatomethylamino)-3-oxopropyl]disulfanyl]propanoyl]amino]acetate Chemical compound [Na+].[Na+].OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC([O-])=O)CSSC[C@@H](C(=O)NCC([O-])=O)NC(=O)CC[C@H](N)C(O)=O DRFILBXQKYDTFW-JIWRMXRASA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229960001776 edrecolomab Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 230000029578 entry into host Effects 0.000 description 1
- 229960004671 enzalutamide Drugs 0.000 description 1
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 229950006370 epacadostat Drugs 0.000 description 1
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 230000008472 epithelial growth Effects 0.000 description 1
- 108010002601 epoetin beta Proteins 0.000 description 1
- 229960004579 epoetin beta Drugs 0.000 description 1
- 108010030868 epoetin zeta Proteins 0.000 description 1
- 229950005185 epoetin zeta Drugs 0.000 description 1
- 229950009760 epratuzumab Drugs 0.000 description 1
- 229960003649 eribulin Drugs 0.000 description 1
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 229950009569 etaracizumab Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 229960004585 etidronic acid Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 210000003499 exocrine gland Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 229950000133 filanesib Drugs 0.000 description 1
- LLXISKGBWFTGEI-FQEVSTJZSA-N filanesib Chemical compound C1([C@]2(CCCN)SC(=NN2C(=O)N(C)OC)C=2C(=CC=C(F)C=2)F)=CC=CC=C1 LLXISKGBWFTGEI-FQEVSTJZSA-N 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 108020005243 folate receptor Proteins 0.000 description 1
- 102000006815 folate receptor Human genes 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960002891 fosaprepitant Drugs 0.000 description 1
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 239000001530 fumaric acid Chemical class 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960003411 gadobutrol Drugs 0.000 description 1
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 1
- 229960003823 gadoteric acid Drugs 0.000 description 1
- 229960005451 gadoteridol Drugs 0.000 description 1
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 210000001654 germ layer Anatomy 0.000 description 1
- 229950009822 gimeracil Drugs 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229950000918 glembatumumab Drugs 0.000 description 1
- 229960004859 glucarpidase Drugs 0.000 description 1
- 108010049491 glucarpidase Proteins 0.000 description 1
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 1
- 108010068227 glutoxim Proteins 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 210000000224 granular leucocyte Anatomy 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000057748 human SPAG5 Human genes 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 210000003026 hypopharynx Anatomy 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- LWRDQHOZTAOILO-UHFFFAOYSA-N incadronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCCCCC1 LWRDQHOZTAOILO-UHFFFAOYSA-N 0.000 description 1
- 229950006971 incadronic acid Drugs 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- MHNNVDILNTUWNS-XYYAHUGASA-N indisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CN(C[C@@H](C3)N4C)C)=NNC2=C1 MHNNVDILNTUWNS-XYYAHUGASA-N 0.000 description 1
- 229950007467 indisetron Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- VDJHFHXMUKFKET-WDUFCVPESA-N ingenol mebutate Chemical compound C[C@@H]1C[C@H]2C(C)(C)[C@H]2[C@@H]2C=C(CO)[C@@H](O)[C@]3(O)[C@@H](OC(=O)C(\C)=C/C)C(C)=C[C@]31C2=O VDJHFHXMUKFKET-WDUFCVPESA-N 0.000 description 1
- 229960002993 ingenol mebutate Drugs 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 108010093036 interleukin receptors Proteins 0.000 description 1
- 102000002467 interleukin receptors Human genes 0.000 description 1
- 229950001014 intetumumab Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 201000008893 intraocular retinoblastoma Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004108 iobitridol Drugs 0.000 description 1
- YLPBXIKWXNRACS-UHFFFAOYSA-N iobitridol Chemical compound OCC(O)CN(C)C(=O)C1=C(I)C(NC(=O)C(CO)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I YLPBXIKWXNRACS-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229950010939 iratumumab Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229950007344 ispinesib Drugs 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 description 1
- 229960003648 ixazomib Drugs 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960002618 lenograstim Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 238000000670 ligand binding assay Methods 0.000 description 1
- 229950002950 lintuzumab Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 229960004289 lipegfilgrastim Drugs 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 229950003526 lorvotuzumab mertansine Drugs 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940107698 malachite green Drugs 0.000 description 1
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Chemical class 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 239000001630 malic acid Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001728 melarsoprol Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 210000000716 merkel cell Anatomy 0.000 description 1
- 229960004635 mesna Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 229960004469 methoxsalen Drugs 0.000 description 1
- UZCXPYDBYUEZCV-UHFFFAOYSA-N methyl 3-aminopropanoate Chemical compound COC(=O)CCN UZCXPYDBYUEZCV-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229960001980 metirosine Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960005225 mifamurtide Drugs 0.000 description 1
- 108700007621 mifamurtide Proteins 0.000 description 1
- 229950003734 milatuzumab Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229950004962 miriplatin Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229950007699 mogamulizumab Drugs 0.000 description 1
- 229960003063 molgramostim Drugs 0.000 description 1
- 108010032806 molgramostim Proteins 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- QJZRFPJCWMNVAV-MHZLTWQESA-N n-(3-aminopropyl)-n-[(1s)-1-(3-benzyl-7-chloro-4-oxoquinazolin-2-yl)-2-methylpropyl]-4-methylbenzamide Chemical compound NCCCN([C@@H](C(C)C)C=1N(C(=O)C2=CC=C(Cl)C=C2N=1)CC=1C=CC=CC=1)C(=O)C1=CC=C(C)C=C1 QJZRFPJCWMNVAV-MHZLTWQESA-N 0.000 description 1
- BLIJXOOIHRSQRB-PXYINDEMSA-N n-[(2s)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide Chemical compound C([C@H](C)NC(=O)C=1NN=C(C=1)C(C)O)N(N=1)C=CC=1C1=CC=C(C#N)C(Cl)=C1 BLIJXOOIHRSQRB-PXYINDEMSA-N 0.000 description 1
- RDSACQWTXKSHJT-NSHDSACASA-N n-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2s)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide Chemical compound C1CC1(C[C@H](O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-NSHDSACASA-N 0.000 description 1
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 229960002967 nabilone Drugs 0.000 description 1
- GECBBEABIDMGGL-RTBURBONSA-N nabilone Chemical compound C1C(=O)CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 GECBBEABIDMGGL-RTBURBONSA-N 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
- 229960002333 nafarelin Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 108010032539 nartograstim Proteins 0.000 description 1
- 229950010676 nartograstim Drugs 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 229960000513 necitumumab Drugs 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 229960000801 nelarabine Drugs 0.000 description 1
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 1
- 229960005163 netupitant Drugs 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- MDJFHRLTPRPZLY-UHFFFAOYSA-N nimorazole Chemical compound [O-][N+](=O)C1=CN=CN1CCN1CCOCC1 MDJFHRLTPRPZLY-UHFFFAOYSA-N 0.000 description 1
- 229960004918 nimorazole Drugs 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229950008607 nitracrine Drugs 0.000 description 1
- YMVWGSQGCWCDGW-UHFFFAOYSA-N nitracrine Chemical compound C1=CC([N+]([O-])=O)=C2C(NCCCN(C)C)=C(C=CC=C3)C3=NC2=C1 YMVWGSQGCWCDGW-UHFFFAOYSA-N 0.000 description 1
- 210000003458 notochord Anatomy 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229960003347 obinutuzumab Drugs 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229950008516 olaratumab Drugs 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 108010070915 orgotein Proteins 0.000 description 1
- 229960004534 orgotein Drugs 0.000 description 1
- 229950001550 orilotimod Drugs 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229950000193 oteracil Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229950007318 ozogamicin Drugs 0.000 description 1
- 108700025694 p53 Genes Proteins 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-OIOBTWANSA-N palladium-103 Chemical compound [103Pd] KDLHZDBZIXYQEI-OIOBTWANSA-N 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 201000003913 parathyroid carcinoma Diseases 0.000 description 1
- 230000009057 passive transport Effects 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960003465 pentetreotide Drugs 0.000 description 1
- 108700023050 pentetreotide Proteins 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000007030 peptide scission Effects 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 229950003332 perflubutane Drugs 0.000 description 1
- KAVGMUDTWQVPDF-UHFFFAOYSA-N perflubutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F KAVGMUDTWQVPDF-UHFFFAOYSA-N 0.000 description 1
- 229950009351 perfosfamide Drugs 0.000 description 1
- VPAWVRUHMJVRHU-VGDKGRGNSA-N perfosfamide Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229950008282 poliglusam Drugs 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 229940034049 polysaccharide-k Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960000214 pralatrexate Drugs 0.000 description 1
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229950000989 procodazole Drugs 0.000 description 1
- XYWJNTOURDMTPI-UHFFFAOYSA-N procodazole Chemical compound C1=CC=C2NC(CCC(=O)O)=NC2=C1 XYWJNTOURDMTPI-UHFFFAOYSA-N 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229960000924 quinagolide Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 229950011613 racotumomab Drugs 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229950004043 radotinib Drugs 0.000 description 1
- DUPWHXBITIZIKZ-UHFFFAOYSA-N radotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3N=CC=NC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 DUPWHXBITIZIKZ-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 229960000424 rasburicase Drugs 0.000 description 1
- 108010084837 rasburicase Proteins 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 229950008933 refametinib Drugs 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 229960000759 risedronic acid Drugs 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- 229950010624 rogaratinib Drugs 0.000 description 1
- FIVSJYGQAIEMOC-ZGNKEGEESA-N rolapitant Chemical compound C([C@@](NC1)(CO[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=CC=CC=2)C[C@@]21CCC(=O)N2 FIVSJYGQAIEMOC-ZGNKEGEESA-N 0.000 description 1
- 229960001068 rolapitant Drugs 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 229950002433 roniciclib Drugs 0.000 description 1
- HNMATTJJEPZZMM-BPKVFSPJSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-[acetyl(ethyl)amino]-4-methoxyoxan-2-yl]oxy-6-[[(2s,5z,9r,13e)-13-[2-[[4-[(2e)-2-[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazinyl]-2-methyl-4-oxobutan-2-yl]disulfanyl]ethylidene]-9-hydroxy-12-(m Chemical compound C1[C@H](OC)[C@@H](N(CC)C(C)=O)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/CSSC(C)(C)CC(=O)N\N=C(/C)C=3C=CC(OCCCC(N)=O)=CC=3)(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 HNMATTJJEPZZMM-BPKVFSPJSA-N 0.000 description 1
- 229960003021 samarium (153sm) lexidronam Drugs 0.000 description 1
- JSTADIGKFYFAIY-GJNDDOAHSA-F samarium-153(3+);n,n,n',n'-tetrakis(phosphonatomethyl)ethane-1,2-diamine Chemical compound [153Sm+3].[O-]P([O-])(=O)CN(CP([O-])([O-])=O)CCN(CP([O-])([O-])=O)CP([O-])([O-])=O JSTADIGKFYFAIY-GJNDDOAHSA-F 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 229950007308 satumomab Drugs 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 229960002101 secretin Drugs 0.000 description 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229960003323 siltuximab Drugs 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 108060007624 small GTPase Proteins 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- NGIYLSFJGRLEMI-MHTUOZSYSA-M sodium 2-[[(2S)-2-[[(4R)-4-[[(2S)-2-[[(2R)-2-[(2R,3R,4R,5R)-2-acetamido-4,5,6-trihydroxy-1-oxohexan-3-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoyl]amino]propanoyl]amino]ethyl [(2R)-2,3-di(hexadecanoyloxy)propyl] phosphate hydrate Chemical compound O.[Na+].CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)[C@H](C)NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@@H]([C@H](O)[C@H](O)CO)[C@@H](NC(C)=O)C=O)C(N)=O)OC(=O)CCCCCCCCCCCCCCC NGIYLSFJGRLEMI-MHTUOZSYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- FWYUJENICVGSJH-UHFFFAOYSA-M sodium;2-[bis[2-[2-(2-methyl-5-nitroimidazol-1-yl)ethoxy]-2-oxoethyl]amino]acetate Chemical compound [Na+].CC1=NC=C([N+]([O-])=O)N1CCOC(=O)CN(CC([O-])=O)CC(=O)OCCN1C([N+]([O-])=O)=CN=C1C FWYUJENICVGSJH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229960005325 sonidegib Drugs 0.000 description 1
- VZZJRYRQSPEMTK-CALCHBBNSA-N sonidegib Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(N=C1)=CC=C1NC(=O)C1=CC=CC(C=2C=CC(OC(F)(F)F)=CC=2)=C1C VZZJRYRQSPEMTK-CALCHBBNSA-N 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 229960000912 stanozolol Drugs 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940022873 synribo Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229950010924 talaporfin Drugs 0.000 description 1
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 1
- 229950010130 tamibarotene Drugs 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229950000864 technetium (99mtc) nofetumomab merpentan Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229960004113 tetrofosmin Drugs 0.000 description 1
- QCWJONLQSHEGEJ-UHFFFAOYSA-N tetrofosmin Chemical compound CCOCCP(CCOCC)CCP(CCOCC)CCOCC QCWJONLQSHEGEJ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229960002952 tipiracil Drugs 0.000 description 1
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000029584 urinary system neoplasm Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229950009233 zinostatin stimalamer Drugs 0.000 description 1
- FYQZGCBXYVWXSP-STTFAQHVSA-N zinostatin stimalamer Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1OC1C/2=C/C#C[C@H]3O[C@@]3([C@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(C)C=CC2=C(C)C=C(OC)C=C12 FYQZGCBXYVWXSP-STTFAQHVSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
Images
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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Abstract
本發明係關於具有改良性質之新穎結合劑-藥劑結合物(ADCs)、這些ADCs的活性代謝物及其製備方法。此外本發明係關於這些結合物用於治療和/或預防疾病的用途以及這些結合物用於製備治療和/或預防疾病,尤其是過度增生和/或血管生成的病症,例如癌症之藥品的用途。
Description
本發明係關於具有改良性質之新穎結合劑-藥劑結合物(ADCs)、這些ADCs的活性代謝物及其製備方法。此外本發明係關於這些結合物用於治療和/或預防疾病的用途以及這些結合物用於製備治療和/或預防疾病,尤其是過度增生和/或血管生成的病症,例如癌症之藥品的用途。此種治療可依單一療法或與其他醫藥品或另外得醫療測量合併。根據本發明,該結合劑較好是抗體。
癌是最多樣組織之細胞生長失控的結果。在許多案例中新細胞會穿透進入既有組織(侵犯性生長),或其轉移進入相隔很遠的器官。癌發生在廣泛種相異器官中並經常具有組織特定的途徑。因此「癌」一詞作為總稱細說明一大群經定義之相異器官、組織和細胞型式的疾病。
某些腫瘤在早期階段可用手術或放射療法的措施予以移除。轉移性腫瘤依慣例僅能用化學療法權宜性地治療。本發明的目標是要達成增進生活品質和延長壽命之最佳組合。
結合劑蛋白質與一種以上藥劑分子的結合物是已知的,尤其是呈抗體藥物結合物(ADCs)的形式,其中經導向對抗腫瘤相關抗原的內化抗體係經由
一連接體共價連接到一細胞毒性劑。接著將ADC加入該腫瘤細胞並緊接著使結合物分離,該細胞毒性劑本身或從其產生的細胞毒性代謝物在該腫瘤細胞中被釋出且可直接和選擇性地展開其作用。以此方式,與傳統的癌症療法相對比,其對於正常組織的損害包含在顯著較窄的限制範圍內[請參考例如J.M.Lambert,Curr.Opin.Pharmacol.5,543-549(2005);A.M.Wu and P.D.Senter,Nat.Biotechnol.23,1137-1146(2005);P.D.Senter,Curr.Opin.Chem.Biol.13,235-244(2009);L.Ducry and B.Stump,Bioconjugate Chem.21,5-13(2010)]。因此,WO2012/171020說明其中複數個毒簇(toxophore)分子經聚合的連接體連接到一抗體。作為可能的毒簇,WO2012/171020尤其提到SB 743921、SB 715992(Ispinesib)、MK-0371、AZD8477、AZ3146和ARRY-520。
最後被提到的物質是紡錘體驅動蛋白抑制劑。紡錘體驅動蛋白(KSP,亦以Eg5、HsEg5、KNSL1或KIF11為人所知)是對兩極細胞分裂紡錘體運作很重要的類似動力素(kinesin)之驅動蛋白。抑制KSP會導致有絲分裂被遏止且過了相當長期間導致細胞凋亡(Tao et al.,Cancer Cell 2005 Jul8(1),39-59)。在發現第一種穿透細胞的KSP抑制劑莫納醇(Monastrol)之後,KSP抑制劑本身已建立成一類新穎的化療劑(Mayer et al.,Science 286:971-974,1999),並且其為一些專利申請案之主題(例如WO2006/044825;WO2006/002236;WO2005/051922;WO2006/060737;WO03/060064;WO03/040979;和WO03/049527)。然而,因為KSP僅在有絲分裂期之相當短的期間裡具有活性,因此KSP抑制劑必須在此期間裡以足夠高的濃度存在。WO2014/151030揭示包含某種KSP抑制劑的ADCs。然而,具有KSP抑制劑且亦包含酵素可裂解連接劑而卻沒有最佳活性數據的ADC已被揭示在專利申請案WO2015/096982和WO2016/096610之中。
列格曼酵素(Legumain)是一與腫瘤相關的天冬醯胺基胜肽內切酶(S.
Ishii,Methods Enzymol.1994,244,604;J.M.Chen et al.J.Biol.Chem.1997,272,8090)且已被應用在小的細胞毒性分子前藥之加工,例如其中包括柔多比星[阿黴素[doxorubicin]]和依托泊苷[etoposide]衍生物(W.Wu et al.Cancer Res.2006,66,970;L.Stern et al.Bioconjugate Chem.2009,20,500;K.M.Bajjuri et al.ChemMedChem 2011,6,54)。
其他溶酶體酵素為例如糖苷酶,例如β-葡糖苷酸酶已被用在藉酵素裂解前要來釋放活性化合物。在體內可用酵素切割的基團尤為2-8-寡肽基或糖苷類。胜肽切割部位揭示在Bioconjugate Chem.2002,13,855-869和Bioorganic & Medicinal Chemistry Letters 8(1998)3341-3346 and also Bioconjugate Chem.1998,9,618-626。這些包括例如纈胺酸-丙胺酸、纈胺酸-離胺酸、纈胺酸-瓜胺酸、丙胺酸-離胺酸和苯丙胺酸-離胺酸(視需要戴有另外的醯胺基)。
先前技藝揭示各種具有酵素可切連接體之抗體-藥劑結合物,然而卻沒有最佳活性的數據,例如關於其在不同細胞中的廣泛活性。因此本發明之一目標是提供更多有效化合物,其在施用較低濃度後展現持久的的細胞凋亡作用且因而具有癌症治療的利益。在本發明另一方面,從ADCs細胞間釋出的代謝物數據扮演著一項重要的角色。經常,從ADCs形成的代謝物是輸出幫浦的受質且/或具有高度細胞膜滲透性。兩種現象均促成短暫駐留時間並從而促成腫瘤細胞中次佳的細胞凋亡作用。
因此本發明提供具有特定毒簇-連接體組成物的結合劑-藥劑結合物(ADCs),其與抗體連接尤具效力和活性光譜方面之有趣的活性數據。為了更增進ADCs及其代謝物的腫瘤選擇性,結合劑結合物已與胜肽連接體一併被提供,該連接體可藉溶酶體之腫瘤相關酵素如列格曼酵素或卡西普辛
酵素[半胱胺酸蛋白酶[Cathepsin]]釋出。因此腫瘤選擇性不僅尤選擇抗體來決定,另外還由胜肽衍生物的切割,例如被腫瘤關聯的酵素如列格曼酵素所決定。
此外,由根據本發明之結合劑-藥劑結合物(ADCs)在腫瘤細胞中釋出的代謝物係藉由一尤其有趣的性質數據來區分。其展現低度外流出腫瘤細胞並導致高的活性化合物暴露在腫瘤中。因此,在腫瘤細胞中達成高活性,但是因為低滲透性,因此僅有低的全身細胞毒性,產生較低之偏離標靶毒性。
依照本發明所使用的紡錘體驅動蛋白抑制劑具有對此作用很重要的一個胺基酸基團。藉著用胜肽衍生物對此胺基酸進行修飾,與該紡錘體驅動蛋白相關的作用就被阻斷且因而也抑制了細胞毒性作用的產生。這些胜肽衍生物亦可為連接體連到抗體的成分。然而,若此胜肽殘基或胜肽連接體可藉腫瘤關聯的酵素如列格曼酵素或卡西普辛酵素而從活性化合物釋出,則該作用能已受控制的方式再被建立於腫瘤組織中。該項腫瘤中形成之代謝物的特殊性質數據經過進一步修改紡錘體驅動蛋白抑制劑之相異於該分子中之胺基的位置,但並未負向影響對該標靶的高度藥效被確認。
此外,對某些實施例而言,根據本發明之ADCs結構容許高度裝載抗體(稱為DAR,藥物對抗體的比率)者,令人驚訝地對於ADCs的生理化學和藥物動力學表現沒有負面的影響。
令人驚奇地,目前吾人已發現式(I)的結合劑-藥劑結合物
其中X1 代表N,X2 代表N以及X3 代表C;或X1 代表N,X2 代表C以及X3 代表N;或X1 代表CH或CF,X2 代表C以及
X3 代表N;或X1 代表NH,X2 代表C以及X3 代表C;或X1 代表CH,X2 代表N以及X3 代表C,R1 代表氫或甲基,R2 代表甲基、乙基、-CH2-CH(CH3)2、-CH2-C(=O)OH或異丙基,R3 代表甲基、乙基、-CH2-CH(CH3)2或-CH2-C(=O)-NH2,M 代表以下基團#-C(=O)-CH(CH3)-NH-C(=O)-CH2-NH-C(=O)-CH2-CH(##)-COOH,#-C(=O)-CH(CH3)-NH-C(=O)-CH2-NH-C(=O)-CH(##)-CH2-COOH,#-C(=O)-CH(CH3)-NH-C(=O)-CH2-W,#-C(=O)-CH2-NH-C(=O)-CH2-CH(##)-COOH,#-C(=O)-CH2-NH-C(=O)-CH(##)-CH2-COOH,#-C(=O)-CH2-W,#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)2-8-C(=O)-###,#-C(=O)-(CH2)3-C(=O)-###,#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)5-W,#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)-##或#-C(=O)-CH(CH3)-NH-C(=O)-(CH2-CH2-O)1-8-(CH2)2-NH-C(=O)-
CH2-##,W 代表基團
n 代表從1到50的數,AK 代表一結合劑或其衍生物,較佳是一抗體或一與抗原結合的片段,# 代表結合至該化合物的鍵,## 代表結合至該結合劑之半胱胺酸側鏈硫原子的鍵,### 代表結合至該結合劑之離胺酸側鏈氮原子的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽,與已知的結合物相較具有勝出的性質。
較佳者當屬那些結合劑-藥劑結合物,其中X1 代表CH,X2 代表C,X3 代表N,R1 代表氫或甲基,R2 代表甲基,-CH2-CH(CH3)2,-CH2-C(=O)OH或異丙基,R3 代表甲基,-CH2-CH(CH3)2或-CH2-C(=O)-NH2,M 代表以下基團#-C(=O)-CH(CH3)-NH-C(=O)-CH2-NH-C(=O)-CH2-CH(##)-COOH,#-C(=O)-CH(CH3)-NH-C(=O)-CH2-NH-C(=O)-CH(##)-CH2-COOH,#-C(=O)-CH(CH3)-NH-C(=O)-CH2-W,#-C(=O)-CH2-NH-C(=O)-CH2-CH(##)-COOH,
#-C(=O)-CH2-NH-C(=O)-CH(##)-CH2-COOH,#-C(=O)-CH2-W,#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,#-C(=O)-(CH2)3-C(=O)-###,#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)5-W,#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)-##或#-C(=O)-CH(CH3)-NH-C(=O)-(CH2-CH2-O)4-(CH2)2-NH-C(=O)-CH2-##,W 代表基團
n 代表從1到50的數,AK 代表一結合劑或其衍生物,較佳是一抗體或一與抗原結合的片段,# 代表結合至該化合物的鍵,## 代表結合至該結合劑之半胱胺酸側鏈硫原子的鍵,### 代表結合至該結合劑之離胺酸側鏈氮原子的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽。
尤佳者當屬那些結合劑-藥劑結合物,其中R1 代表氫或甲基,R2 代表甲基或異丙基,R3 代表甲基或-CH2-C(=O)-NH2,
M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表從1到50的數,AK 代表一結合劑或其衍生物,較佳是一抗體或一與抗原結合的片段,# 代表結合至該化合物的鍵,### 代表結合至該結合劑之離胺酸側鏈氮原子的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽。
非常尤佳者當屬那些結合劑-藥劑結合物,其中R1 代表甲基,R2 代表甲基,R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表從1到50的數,AK 代表一結合劑或其衍生物,較佳是一抗體或一與抗原結合的片段,# 代表結合至該化合物的鍵,### 代表結合至該結合劑之離胺酸側鏈氮原子的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽。
特別較佳者當屬那些結合劑-藥劑結合物,其中R1 代表甲基,R2 代表甲基,R3 代表-CH2-C(=O)-NH2,M 代表基團
#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表一個1到20的數,AK 代表一結合劑或其衍生物,較佳是一抗體或一與抗原結合的片段,# 代表結合至該化合物的鍵,### 代表結合至該結合劑之離胺酸側鏈氮原子的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽。
經挑選者是那些結合劑-藥劑結合物,其中R1 代表甲基,R2 代表甲基,R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表一個1到20的數以及AK 代表一抗-CD123抗體、一抗-CXCR5抗體、一抗-B7H3抗體、一抗-TWEAKR抗體、一抗-Her2抗體或一抗-EGFR抗體或代表這些抗體與抗原結合的抗體片段,# 代表結合至該化合物的鍵,### 代表與抗體(AK)或其結合抗原之抗體片段中離胺酸側鏈之氮原子相連的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽。
經挑選者尤為那些結合劑-藥劑結合物,其中R1 代表甲基,R2 代表甲基,
R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表一個1到20的數以及AK 代表一選自TPP-9476、TPP-8988、TPP-8987和TPP-6013組成群組之抗-CD123抗體,代表一選自TPP-9574和TPP-9580組成群組之抗-CXCR5抗體,代表一抗-B7H3抗體TPP-8382,代表一選自TPP-7006和TPP-7007組成群組之抗-TWEAKR抗體,代表一抗-Her2抗體TPP-1015或代表一抗-EGFR抗體TPP-981或代表這些抗體與抗原結合的抗體片段,# 代表結合至該化合物的鍵,### 代表與抗體(AK)或其結合抗原之抗體片段中離胺酸側鏈之氮原子相連的鍵,及其鹽、溶劑化物及這些溶劑化物的鹽。
較佳者當屬以上提到化學式之結合劑-藥劑結合物,其中AK代表一特定結合至細胞外癌症標靶分子的結合劑。在一項較佳實施例中,該結合劑在與其標靶細胞上的細胞外標靶分子結合之後,透過結合被該標靶細胞內化。較好是該結合劑為一抗體或一與抗原結合的片段。
在本發明之較佳試驗品中,該細胞外癌症標靶分子係選自癌症標靶分子EGFR、CD123、HER2、B7H3、TWEAKR和CXCR5的群組;尤佳者當屬CD123、CXCR5和B7H3。
在本發明之較佳試驗品中,該結合劑AK是一抗CD123抗體、一抗-CXCR5抗體、一抗-B7H3抗體、一抗-TWEAKR抗體、一抗-Her2抗體或一抗-EGFR抗體,或這些抗體之與抗原結合的抗體片段。
特別較佳者是以上提到化學式之結合劑-藥劑結合物,其中AK(AK1、
AK2)代表一選自TPP-8382(抗-B7H3)、TPP-6013(抗-CD123)、TPP-8987(抗-CD123)、TPP-8988(抗-CD123)、TPP-9476(抗-CD123)、TPP-9574(抗-CXCR5)和TPP-9580(抗-CXCR5)之群組的抗體,或這些抗體與抗原結合的片段。在本說明書中,較佳者當屬抗體TPP-6013、TPP-8987、TPP-8988和TPP-9476(在每一案例中之抗-CD123)。這些抗體的確切結構(序列)可參考下表:抗體的蛋白質序列,此表後的文字內容以及列示的序列。
特別較佳者為其中AK代表一選自TPP-8382(抗-B7H3)、TPP-6013(抗-CD123)、TPP-8987(抗-CD123)、TPP-8988(抗-CD123)、TPP 9476(抗-CD123)、TPP-9574(抗-CXCR5)和TPP 9580(抗-CXCR5)群組之抗體的結合劑-藥劑結合物。在本說明書中,較佳者當屬抗體(AK)TPP-6013、TPP-8987、TPP-8988和TPP-9476(在每一案例中之抗-CD123)。
圖1:用作結合劑-藥劑結合物之較佳抗體的被標註的序列。此圖中顯示的是IgG的重鏈和輕鏈的蛋白質序列,以及這些抗體的VH和VL區域。在該序列之下,重要的區域是被標註的(IgG中的VH和VL區域,以及CDR區域(H-CDR1、H-CDR2、H-CDR3、L-CDR1、L-CDR2、L-CDR3))。
圖2:用作結合劑-藥劑結合物之較佳抗體之序列以及標靶蛋白質序列的序列列表
本發明提供一結合劑或其衍生物與一種以上藥物分子的結合物,該藥物
分子為紡錘體驅動蛋白抑制劑(KSP抑制劑)。
根據本發明之可使用結合劑、其可根據本發明使用的KSP抑制劑和可根據本發明使用的連接體,可不受任何限制組合用者說明如下。尤其,在每一案例中較佳或尤佳代表的結合劑可與每一案例中較佳或尤佳代表的KSP抑制劑合併,視需要與每一案例中較佳或尤佳代表的連接體合併被採用。
尤佳的KSP-抑制劑結合物(結合劑-藥劑結合物)
根據本發明由佳者當屬以下的KSP抑制劑結合物,其中AK(AK1、AK2)代表結合劑或其衍生物(較好是抗體),且n代表一個1到20的數,較好是1到8而更好是4到8。AK1較好是代表一藉由半胱胺酸殘基與KSP抑制劑抗體結合的抗體;AK2較好是代表一藉由離胺酸殘基與KSP抑制劑抗體結合的抗體。本發明所使用之結合劑或抗體較好是在說明內容中說明較佳之結合劑和抗體。
較佳者當屬以上提到化學式之結合劑-藥劑結合物,其中AK(AK1、AK2)代表一特定結合至一細胞外癌症標靶分子的結合劑。在一項較佳實施例中,該結合劑在與其標靶細胞上的細胞外標靶分子結合之後,透過結合被該標靶細胞內化。
在本發明之較佳試驗品中,該細胞外癌症標靶分子係選自癌症標靶分子EGFR、CD123、Her2、B7H3、TWEAKR和CXCR5的群組,尤其是CD123、CXCR5和B7H3。
在本發明之較佳試驗品中,結合劑AK(AK1、AK2)是一抗CD123抗體、一抗-CXCR5抗體、一抗-B7H3抗體、一抗-TWEAKR抗體、一抗-Her2抗體或一抗-EGFR抗體,或一這些抗體之與抗原結合的抗體片段。
特別較佳者是以上提到化學式之結合劑-藥劑結合物,其中AK(AK1、AK2)代表一選自TPP-8382(抗-B7H3)、TPP-6013(抗-CD123)、TPP-8987(抗-CD123)、TPP-8988(抗-CD123)、TPP-9476(抗-CD123)、TPP-9574(抗-CXCR5)和TPP-9580(抗-CXCR5)群組的抗體,或這些抗體與抗原結合的片段。在本說明書中,較佳者當屬抗體TPP-6013、TPP-8987、TPP-8988和TPP-9476(在每一案例中之抗-CD123)。這些抗體的確切結構(序列)可參考下表:抗體的蛋白質序列,此表後的文字內容以及列示的序列。
KSP抑制劑-連接體-中間體以及該結合物的製備
根據本發明的合物係藉著一開始提供其低分子量之KSP抑制劑和一連接體。然後將以此方式所得到的中間體與結合劑(較好是抗體)反應來製備。
在以上反應流程圖中,X1、X2、X3、R1、R2、R3和AK2具有式(I)所給的意義且本說明書中R4代表甲基且n代表0或1。
組塊A的合成已說明在WO2015/096982。胜肽衍生物B和C係藉著傳統的胜肽化學方法製備。室溫下利用HATU溶於DMF在N,N-二異丙基乙胺存在下結合中間體C和D。緊接著,將苄氧基羰基保護基和苄酯兩者均用10%活性碳鈀氫解方式移除掉。然後將完全脫除保護的中間體與1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮於DMF中在N,N-二異丙基乙胺存在下於室溫下反應產生ADC前驅體分子E。然後將此活化的酯與對應的抗體如B-5章說明的方式結合。
在以上反應流程圖中,X1、X2、X3、R1、R2、R3和AK1具有式(I)所給的意義且本說明書中R4代表甲基且n代表0或1。
利用相似的方法,亦可製備其中n代表0的化合物。
組塊A的合成已說明在WO2015/096982。胜肽衍生物B和C係藉著傳統的胜肽化學方法製備。室溫下利用HATU溶於DMF在N,N-二異丙基乙胺存在下結合中間體C和D。緊接著,將苄氧基羰基保護基和苄酯兩者均用10%活性碳鈀氫解方式移除掉。然後將完全脫除保護的中間體與1-{6-[(2,5-二酮基吡咯啶-1-基)氧基]-6-酮基己基}-1H-吡咯-2,5-二酮於DMF中在N,N-二異丙基乙胺存在下於室溫下反應產生ADC前驅體分子E。然後將此順丁烯二醯亞胺衍生物與對應的抗體如B-4章說明的方法結合。
視連接體而定,琥珀醯亞胺-連接的ADCs在軛合之後可轉變成開鏈的琥珀醯胺,其具備有利的穩定性之數據輪廓。
此反應(開環)可在pH 7.5到9,較好是在pH 8,於25℃至37℃的溫度下,例如以攪拌方式進行。較佳的攪拌時間為8到30小時。
在以上反應流程圖中,X1、X2、X3、R1、R2、R3和AK1具有式(I)所給的意義且本說明書中R4代表甲基且n代表0或1。
組塊A的合成已說明在WO2015/096982.胜肽衍生物B和C係藉著傳
統的胜肽化學方法製備。室溫下利用HATU溶於DMF在N,N-二異丙基乙胺存在下結合中間體C和D。緊接著,將苄氧基羰基保護基和苄酯兩者均用10%活性碳鈀氫解方式移除掉。然後將完全脫除保護的中間體與1-{2-[(2,5-二酮基吡咯啶-1-基)氧基]-2-酮基乙基}-1H-吡咯-2,5-二酮於N,N-二異丙基乙胺存在下於室溫下反應產生ADC前驅體分子E。然後將此順丁烯二醯亞胺衍生物與對應的抗體如B-4章說明的方法在小型規模或中型規模下結合。
結合劑
廣義而言,「結合劑」一詞被瞭解為意指一與存在於某種標靶細胞群之標靶分子結合的分子,被稱為結合劑-藥劑結合物。結合劑一詞應以其最廣義被瞭解且一包含:例如,凝集素、能與某糖鏈結合的蛋白質。此種結合劑包括:例如,高分子量的蛋白質(結合蛋白質)、多肽或胜肽(結合胜肽)、非胜肽的(例如適體[aptamers](US5,270,163)Keefe AD.,et al.,Nat.Rev.Drug Discov.2010;9:537-550,或維生素)以及所有其他的細胞結合分子或物質。結合蛋白質為:例如,抗體和抗體片段或抗體模仿物,例如:親合體、阿奈亭(adnectins,一類新型類抗體藥物)、抗嘉林[anticalins]、DARPins、高親和性多聚體[avimers]或奈米抗體(Gebauer M.et al.,Curr.Opinion in Chem.Biol.2009;13:245-255;Nuttall S.D.et al.,Curr.Opinion in Pharmacology 2008;8:608-617)。結合胜肽為:例如,配體/受體配對中之配體,例如配體/受體配對VEGF/KDR中之VEGF,如配體/受體配對轉移素/轉移素受體中之轉移素,如配體/受體配對TNFα/TNFα受體中之TNFα。
該結合劑可為一結合蛋白質。結合劑之較佳實施例為一抗體、一與抗原結合的抗體片段、一多重專一性抗體或一抗體模仿物。
該文獻亦揭示各種將有機分子共價結合(軛合)至結合劑且尤其是抗體之
選項。根據本發明的優先選項當屬藉一個以上抗體所屬半胱胺酸殘基之硫原子和/或經一個以上抗體所屬離胺酸殘基之NH基將毒簇軛合到抗體。然而,吾人亦可藉自由羧基或藉抗體的糖類殘基將毒簇結合至抗體。
「標靶分子」廣義而言被瞭解為意指存在於標靶細胞群的分子且為一蛋白質(例如一生長因子受體)或一非胜肽分子(例如一糖或一磷之類)。其較好為一受體或一抗原。
「細胞外的」標靶分子一詞係說明位在細胞的外側連結細胞的標靶分子,或位在細胞外側之標靶分子的部分,意即一結合劑可結合至一完整細胞上之細胞外標靶分子。一細胞外標靶分子可固定在細胞膜中或為細胞膜之成分。熟習本技藝者知道鑑認細胞外標靶分子的方法。對蛋白質而言,可藉測定穿透細胞的區位以及該膜中蛋白質的方向來達成。這些數據通常寄存在蛋白質資料庫中(例如SwissProt)。
「癌症標靶分子」一詞說明一標靶分子,其在一種以上癌細胞上的存在量要比同種組織型的非癌細胞更大。較好是與同一組織型式的非癌細胞相比,該癌症標靶分子選擇性地出現在一個以上癌細胞上,其中選擇性地係說明與同一組織型式的非癌細胞相比至少有兩倍增強的結果發生在癌細胞上(「選擇性的」癌症標靶分子)。癌症標靶分子的用途容許使用根據本發明的結合物選擇性地治療癌細胞。
該結合劑可藉一化學鍵連接到連接體。該結合劑可利用其一雜原子連接。該結合劑之根據本發明可用於連接的雜原子是硫(在一實施例中,經由該結合劑之一個硫氫根)、氧(根據本發明利用該結合劑的羧基或羥基)和氮(在一實施例中,經由該結合劑之一個一級或二級胺基或醯胺基)。這些雜原子可存在於天然結合劑或藉化學法或分子生物學法導入。根據本發明,將該結合劑連接到毒簇對於該結合劑對標靶分子的結合活性僅有微小的影響。在一項較佳實施例中,該項連接對於該結合劑對標靶分子的結合活性不具
影響。
依照本發明,「抗體」可以其廣義被瞭解且包含免疫球蛋白分子,例如:完整或經修飾的單株抗體、多株抗體或多重專一性抗體(例如雙重專一性抗體)。一免疫球蛋白分子較好包含一具有四個多肽鏈-兩個重鏈(H鏈)和兩個輕鏈(L鏈)的分子,典型上以二硫化物橋接。每一種鏈包含一個重鏈可變區位(縮寫為VH)和一個重鏈的固定區位。該重鏈的固定區位可包含例如三個區位CH1、CH2和CH3。每一輕鏈包含一個可變區位(縮寫為VL)和一個固定區位。該輕鏈的固定區位包含一個區位(縮寫為CL)。該VH和VL區位可進一步次分成具有高度變異性的區域,亦稱為互補決定區(縮寫為CDR)以及具有低度序列變異性的區域(架構區,縮寫為FR)。典型上,每一VH和VL區是由三個CDRs和高達四個FRs構成的。例如從胺基端到羧基端以下列順序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。抗體可得自任何適當的物種,例如:兔、大羊駝、駱駝、小鼠或大鼠。在一實施例中,該抗體是人類或鼠科來源的。抗體可為例如人類的、或人類化的、或嵌合的。
「單株」抗體一詞是指得自一大群基本上均質的抗體,亦即該群之個別抗體除了可能有少數天然發生的突變以外,其完全相同。單株抗體以高度專一性辨認單一的抗原結合區位。單株抗體一詞非指特殊的製備方法。
「完整的」抗體一詞係指包含輕鏈與重鏈的抗原決定區和固定區的抗體。固定區可為天然區位或其具有數個經修改的胺基酸位置之變異體,且亦可經去糖基化。
「經修改的完整」抗體一詞是指利用共價鍵(例如胜肽鍵)將其胺基端或羧基端與另一非源自抗體之多肽或蛋白質融合的完整抗體。此外,抗體可為經修改的,如在定義的位置上導入具反應活性的半胱胺酸以輔助其結合到毒簇(請參考Junutula et al.Nat Biotechnol.2008 Aug;26(8):925-32)。
在本說明書中「胺基酸修改」或「突變」意指在一多肽序列中胺基酸之
取代、插入和/或刪除。本說明書中較佳的胺基酸修改是取代。在本說明書中「胺基酸取代」或「取代」意指在一蛋白質序列的某一位置上用一胺基酸交換另一胺基酸。例如,Y50W的取代是說明一母多肽中位置50的酪胺酸已被交換成一色胺酸。多肽的「變異體」係說明具有基本上和參考用多肽之胺基酸序列完全相同的多肽,該參考多肽典型上是天然的或是「親代的」多肽。該多肽變異體可具有一個以上的胺基酸交換、刪除和/或插入在該天然胺基酸序列的某位置上。
「人類」抗體一詞係指可得自人類的抗體或是人工合成的人類抗體。「合成的」人類抗體是部分或完全由電腦模擬從根據人類抗體序列分析之合成序列獲得的抗體。人類抗體可由例如從人類來源的抗體序列庫分離出的核酸編碼。此抗體的實例可在Söderlind et al.,Nature Biotech.2000,18:853-856找到。此種「人類的」和「合成的」抗體也包括去糖基化的變異體,其係經PNGaseF去糖基化或藉著把重鏈的N297(Kabat編碼)突變成其他胺基酸所產生。
「人類化的」或「嵌合的」抗體一詞係說明由一非人類和一人類的序列部分所組成的抗體。在這些抗體中,人類免疫球蛋白(接受者)的部分序列被非人類免疫球蛋白(捐給者)的序列部分置換。在許多情形中,該捐給者是一鼠科的免疫球蛋白。在人類化抗體的情形中,接受者的CDR之胺基酸被該捐給者的胺基酸所置換。有時候,架構的胺基酸也被捐給者之對應胺基酸置換。在某些情形中,人類化抗體包含既不存在於接受者也不存在於捐給者的胺基酸,其係在最佳化抗體的期間被導入的。在嵌合抗體的情形中,捐給者免疫球蛋白的可變區位與人類抗體的固定區融合。此種「人類化的」和「嵌合的」抗體也包括去糖基化變異體,其係經PNGaseF去糖基化或藉著把重鏈的N297(Kabat編碼)突變成其他胺基酸所產生。
互補決定區(CDR)一詞用在本說明書中係指結合到抗原所需的可變抗
體區位。典型上,每一可變區位具有三個CDR區,稱為CDR1、CDR2和CDR3。每一CDR區可包含根據Kabat定義的胺基酸和/或根據Chotia定義之高度變異的環圈胺基酸。根據Kabat的定義包含,例如從大約胺基酸位置在輕鏈可變區(VL)之24-34(CDR1)、50-56(CDR2)和89-97(CDR3)區以及重鏈可變區(VH)之31-35(CDR1)、50-65(CDR2)和95-102(CDR3)區(Kabat et al.,Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。根據Chotia 的定義包含例如,從大約胺基酸位置在輕鏈可變區(VL)之26-32(CDR1)、50-52(CDR2)和91-96(CDR3)區以及重鏈可變區(VH)之26-32(CDR1)、53-55(CDR2)和96-101(CDR3)(Chothia and Lesk;J Mol Biol 196:901-917(1987))。在某些情形中,CDR可包含根據Kabat和Chotia定義之CDR區的胺基酸。
視重鏈之固定區位的胺基酸序列而定,抗體可分成不同的類別。有五個主要的完整抗體類別:IgA、IgD、IgE、IgG和IgM,且其中數個可被進一步分成次類別。(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。該重鏈的固定區位對等於不同類別者,稱作[alpha/α],[delta/δ],[epsilon/ε],[gamma/γ]和[my/μ]。抗體是三維結構和次單元體結構是已知的。
抗體/免疫球蛋白之「功能性片段」或「與抗原結合的抗體片段」一詞係定義為一個抗體/免疫球蛋白片段(例如IgG的可變區位),其仍包含抗體/免疫球蛋白的抗原結合區位。一抗體之「抗原結合區位」典型上包含一個以上抗體的高度可變區,例如:CDR、CDR2和/或CDR3區。然而,一抗體的「架構」或「骨幹」區亦可在抗體結合至抗原期間扮演著角色。該架構區形成CDRs的骨幹。較佳是該抗原結合區位包含至少胺基酸4到103之可變輕鏈和胺基酸5到109之可變重鏈,更好是胺基酸4到107之可變輕鏈和胺基酸4到111之可變重鏈,尤佳是該完整的可變輕鏈和重鏈,亦即VL
的胺基酸1-109和VH的1-113(根據WO97/08320編號)。
本發明的「功能性片段」或「與抗原結合的抗體片段」非決定性地涵蓋Fab、Fab’、F(ab’)2和Fv片段、雙重專一性抗體、單一區位抗體(DAbs)、線性抗體、個別抗體鏈(單一鏈的Fv,縮寫為scFv);和多重專一性抗體,如二重和三重專一性抗體,例如從抗體片段C形成。A.K Borrebaeck,editor(1995)Antibody Engineering(Breakthroughs in Molecular Biology),Oxford University Press;R.Kontermann & S.Duebel,editors(2001)Antibody Engineering(Springer Laboratory Manual),Springer Verlag。「多重專一性」或「多重功能性」抗體以外之抗體是那些具有完全相同之結合位置的抗體。多重專一性抗體可對同一抗原之不同抗原決定基具專一性或可對一種以上抗原具專一性(請參考例如WO 93/17715;WO 92/08802;WO 91/00360;WO 92/05793;Tutt,et al.,1991,J.Immunol.14760 69;U.S.Pat.Nos.4,474,893;4,714,68 1;4,925,648;5,573,920;5,601,8 19;或Kostelny et al.,1992,J.Immunol.148 1547 1553)。F(ab')2或Fab分子可被建構而使其在Ch1和CL區位之間發生的分子內雙硫鍵交互作用數目可降低或完全被防止。
「抗原決定基」係指能特定結合至免疫球蛋白或T細胞受體的蛋白質決定因子。抗原決定基的決定因子包含分子之具化學活性的表面基團,如胺基酸或糖的側鏈或其組合,且通常具有特定的三維結構性質以及特定的電荷性質。
「功能性片段」或「與抗原結合的抗體片段」可與另一並非源自於抗體的多肽或蛋白質經由其胺基端或羧基端利用共價鍵(例如肽連接體)融合。此外,抗體和與抗原結合的片段可在經定義的位置導入具反應活性的半胱胺酸做為修飾,以求輔助其結合至一毒簇(請參考Junutula et al.Nat Biotechnol.2008 Aug;26(8):925-32)。
多株抗體可藉普通熟習本技藝者已知的方法製備。單株抗體可利用普通
熟習本技藝者已知的方法製備(Köhler and Milstein,Nature,256,495-497,1975)。人類的和人類化的單株抗體可利用普通熟習本技藝者已知的方法製備(Olsson et al.,Meth Enzymol.92,3-16 or Cabilly et al US 4,816,567 or Boss et al US 4,816,397)。
普通熟習本技藝者知道製備人類抗體及其片段的多樣方法,例如,利用基因轉殖的小鼠(N Lonberg and D Huszar,Int Rev Immunol.1995;13(1):65-93)或噬菌體呈現技術(Clackson et al.,Nature.1991 Aug 15;352(6336):624-8)。本發明的抗體可得自重組抗體庫,其包含例如從大量健康自願者收集的多樣胺基酸序列。抗體亦可利用已知的重組DNA技術生產。抗體的核酸序列可藉由例行的定序獲得或可得自公開之可登入資料庫。
一種「經分離的」抗體或結合劑已被純化以除去其他細胞的組成份。細胞的污染成分會干擾診斷或治療用途者為例如:酵素、激素,或細胞之其他胜肽的或非胜肽的成分。一較佳抗體或結合劑是經純化相對於抗體或結合劑達到大於95%重量比的程度(此係以例如勞瑞(Lowry)法、UV-可見光光譜法或以SDS毛細作用膠體電泳法測定)。甚且一抗體已被純化至能測定至少15個位在N-端的或內部胺基酸序列之殘基的程度,或已被純化至均質,該均質性係以SDS-PAGE在還原或非還原條件下(其偵測可利用考馬斯藍染劑(Coomassie blue)染色或較佳是銀著色)來進行。然而,一種抗體通常是以一個以上的純化步驟製備。
「特定的結合」或「特定地結合」係指抗體或結合至預先決定之抗原/標靶分子的結合劑。抗體或結合劑之特定的結合典型上是說明具有至少10-7M(以Kd值表示,亦即較好是具有小於10-7M的Kd值)之親和力的抗體或結合劑,具有對預決定之抗原/標靶分子比非特定抗原/標靶分子(例如牛血清蛋白或酪蛋白)至少高過兩倍親和力的抗體或結合劑,該非特定抗原/標靶分子不是預先決定之抗原/標靶分子或密切相關的抗原/標靶分子。抗體或結合
劑之特定的結合不排除結合至複數個抗原/標靶分子(例如不同物種之直系同源體)的抗體或結合劑。該抗體較好是具有至少10-7M的親和力(以Kd值表示,換言之較好是具有小於10-7M之Kd值),較好是至少10-8M,更好是從10-9M到10-11M的範圍。該Kd值可利用例如表面電漿子共振光譜來測定。
本發明之抗體-藥劑結合物同樣地在這這些範圍裡展現親和力。該親和力較好基本上不會被與藥物共軛所影響(一般而言,該親和力被降低少於一個級數大小,換句話說例如最多從10-8M到10-7M)。
依照本發明所使用的抗體亦較好是因高度選擇性而值得注意。高度選擇性之存在是當本發明的抗體展現較佳是比獨立的其他抗原,例如人類血清蛋白至少兩倍更佳,較好是五倍以上或更好是十倍更佳之對於標靶蛋白質的親和力(親和力可利用例如表面電漿子共振光譜來測定)。
此外,所使用的本發明抗體較好是具交叉反應活性的。為了能輔助和較佳詮釋臨床前研究例如毒理學或活性研究(例如在異種皮移植小鼠體內),若依照本發明所使用的抗體不僅能與人類標靶蛋白質且還能與用於研究之物種的標靶蛋白質結合,對此目的會是有利的。在一實施例中,除人類標靶蛋白質以外,依照本發明所使用的抗體對於至少另一物種的標靶蛋白質有交叉的反應活性。對於毒理學和活性研究,較好是使用囓齒科、犬和非人類的靈長類物種。較佳的齧齒科物種是小鼠和大鼠。較佳的非人類的靈長類物種是恆河猴、黑猩猩和長尾獼猴。
除人類標靶蛋白質以外,依照本發明所使用的抗體對於至少另一物種的標靶蛋白質有交叉的反應活性,該物種選自包含小鼠、大鼠和長尾獼猴(Macaca fascicularis)的物主群。特別較佳者是依照本發明所使用的抗體,其除了人類標靶蛋白質外至少對於小鼠的標靶蛋白質具有交叉反應活性。較佳者當屬具交叉和活性的抗體,其對於更多非人類物種的標靶蛋白質之親
和力與對人類標靶蛋白質的親和力相比有不超過50倍的差異,更尤其不超過十倍的差異。
導向(抗)癌症標靶分子的抗體
結合劑例如抗體或其與抗原結合的片段所導向之標靶分子較好是癌症標靶分子。「癌症標靶分子」說明一標靶分子,其在同型組織的一種以上癌細胞中要比在同型組織的非癌細胞更大量。較好是與同型組織的非癌細胞相比,該癌症標靶分子選擇性的存在於一種以上的癌細胞類別,其中選擇性地說明與同型組織的非癌細胞相比在癌細胞上有至少兩倍的增強(「選擇性的癌症標靶分子」)。癌症標靶分子的使用使吾人得以利用根據本發明的結合物選擇性的治療癌症細胞。
特定對抗一種抗原,例如:癌細胞抗原的抗體可由對本技藝普通熟習者藉其熟習的方法(例如重組表現)或可購得(例如購自德國Merck KGaA公司)。已知用於癌症治療之市售抗體Erbitux®(爾必得舒[cetuximab單抗],Merck KGaA公司出品)、Avastin®(癌思停[bevacizumab單抗],Roche公司出品)和Herceptin®(賀癌平[trastuzumab單抗],Genentech公司出品)。賀癌平是一IgG1kappa型式的重組人類化單株抗體,其在以細胞為依據的檢驗(Kd=5nM)中以高親和力與人類上皮生長受體細胞外區位結合。該抗體在CHO細胞中以重組方式產生。所有這些抗體亦可生產為這些抗體之去糖基化變異體-經PNGaseF去糖基化或藉著把重鏈的N297(Kabat編碼)突變成其他胺基酸所產生。
在一項較佳實施例中,該標靶分子是一選擇性的癌症標靶分子。
在一尤佳實施例中,該標靶分子是一蛋白質。
在一實施例中,該標靶分子是一細胞外的標靶分子。在一項較佳實施例中,該細胞外的標靶分子是一蛋白質。
癌症標靶分子對熟習本技藝者而言是已知的。這些分子的實例列示於以下。
癌症標靶分子的實例為:
(1)EGFR(EGF受體,NCBI參考序列NP_005219.2,NCBI基因ID:1956)
(2)間皮素(SwissProt資料庫的參考序列Q13421-3),間皮素被胺基酸296-598編碼。胺基酸37-286編碼巨核細胞刺激因子。間皮素藉著GPI支撐物被固定在細胞膜中且位在細胞外部。
(3)碳酸酐酶[Carboanhydrase]IX(CA9,SwissProt資料庫的參考序列Q16790),NCBI基因ID:768)
(4)C4.4a(NCBI參考序列NP_055215.2;同義字LYPD3,NCBI基因ID:27076)
(5)CD52(NCBI參考序列NP_001794.2)
(6)Her2(ERBB2;NCBI參考序列NP_004439.2;NCBI基因ID:2064)
(7)CD20(NCBI參考序列NP_068769.2)
(8)淋巴細胞活化抗原CD30(SwissProt ID P28908)
(9)淋巴細胞黏著分子CD22(SwissProt ID P20273;NCBI基因ID:933)
(10)骨髓細胞表面抗原CD33(SwissProt ID P20138;NCBI基因ID:945)
(11)穿越細胞膜之醣蛋白NMB(GPNMB,SwissProt ID Q14956,NCBI基因ID:10457)
(12)黏著分子CD56(SwissProt ID P13591)
(13)表面分子CD70(SwissProt ID P32970,NCBI基因ID:970)
(14)表面分子CD74(SwissProt ID P04233,NCBI基因ID:972)
(15)B-淋巴細胞抗原CD19(SwissProt ID P15391,NCBI基因ID:930)
(16)表面蛋白黏蛋白-1(MUC1,SwissProt ID P15941,NCBI基因ID:4582)
(17)表面蛋白CD138(SwissProt ID P18827)
(18)整合素阿法V(NCBI參考序列:NP_002201.1,NCBI基因ID:3685)
(19)生殖細胞瘤-衍生的生長因子1蛋白質TDGF1(NCBI參考序列:NP_003203.1,NCBI基因ID:6997)
(20)前列腺專一性蛋白質抗原PSMA(Swiss Prot ID:Q04609;NCBI基因ID:2346)
(21)酪胺酸蛋白激酶EPHA2(Swiss Prot ID:P29317,NCBI基因ID:1969)
(22)表面蛋白SLC44A4(NCBI參考序列:NP_001171515.1,NCBI基因ID:80736)
(23)表面蛋白BMPR1B(SwissProt:O00238)
(24)運輸蛋白SLC7A5(SwissProt:Q01650)
(25)上皮前列腺抗原STEAP1(SwissProt:Q9UHE8,基因ID:26872)
(26)卵巢癌抗原MUC16(SwissProt:Q8WXI7,基因ID:94025)
(27)運輸蛋白SLC34A2(SwissProt:O95436,基因ID:10568)
(28)表面蛋白SEMA5b(SwissProt:Q9P283)
(29)表面蛋白LYPD1(SwissProt:Q8N2G4)
(30)B型內皮素受體EDNRB(SwissProt:P24530,NCBI基因ID:1910)
(31)環指蛋白RNF43(SwissProt:Q68DV7)
(32)前列腺癌-關聯的蛋白質STEAP2(SwissProt:Q8NFT2)
(33)陽離子通道TRPM4(SwissProt:Q8TD43)
(34)互補受體CD21(SwissProt:P20023)
(35)B細胞抗原受體複合物關聯的蛋白質CD79b(SwissProt:P40259,NCBI基因ID:974)
(36)細胞黏著抗原CEACAM6(SwissProt:P40199)
(37)二肽酶DPEP1(SwissProt:P16444)
(38)介白素受體IL20Rα(SwissProt:Q9UHF4,NCBI基因ID:3559)
(39)蛋白聚醣BCAN(SwissProt:Q96GW7)
(40)Eph受體EPHB2(SwissProt:P29323)
(41)前列腺幹細胞關聯的蛋白質PSCA(NCBI參考序列:NP_005663.2)
(42)表面蛋白LHFPL3(SwissProt:Q86UP9)
(43)受體蛋白TNFRSF13C(SwissProt:Q96RJ3)
(44)B細胞抗原受體複合物關聯的蛋白質CD79a(SwissProt:P11912)
(45)受體蛋白CXCR5(CD185;SwissProt:P32302;NCBI基因ID 643,NCBI參考序列:NP_001707.1)
(46)離子通道P2X5(SwissProt:Q93086)
(47)淋巴細胞抗原CD180(SwissProt:Q99467)
(48)受體蛋白FCRL1(SwissProt:Q96LA6)
(49)受體蛋白FCRL5(SwissProt:Q96RD9)
(50)MHC第二類分子Ia抗原HLA-DOB(NCBI參考序列:NP_002111.1)
(51)T細胞蛋白VTCN1(SwissProt:Q7Z7D3)
(52)TWEAKR(FN14,TNFRSF12A,NCBI參考序列:NP_057723.1,NCBI基因ID:51330)
(53)淋巴細胞抗原CD37(Swiss Prot:P11049,NCBI基因ID:951)
(54)FGF受體2;FGFR2(NCBI基因ID:2263;Official Symbol:FGFR2)。FGFR2受體發生在相異接合變異體中(α、β、IIIb、IIIc)。所有接合變異體均可作用為標靶分子。
(55)穿越細胞膜之醣蛋白B7H3(CD276;NCBI基因ID:80381 NCBI參考序列:NP_001019907.1,Swiss Prot:Q5ZPR3-1)
(56)B細胞受體BAFFR(CD268;NCBI基因ID:115650)
(57)受體蛋白ROR 1(NCBI基因ID:4919)
(58)表面受體CD123(IL3RA;NCBI基因ID:3563;NCBI參考序列:
NP_002174.1;Swiss-Prot:P26951)
(59)受體蛋白胎盤融合性蛋白(NCBI基因ID 30816)
(60)天冬胺酸β-羥基化酶(ASPH;NCBI基因ID 444)
(61)細胞表面醣蛋白CD44(NCBI基因ID:960)
(62)CDH15(鈣粘蛋白[Cadherin]15,NCBI基因ID:1013)
(63)細胞表面醣蛋白CEACAM5(NCBI基因ID:1048)
(64)細胞黏著分子L1-like(CHL1,NCBI基因ID:10752)
(65)受體酪胺酸激酶c-Met(NCBI基因ID:4233)
(66)納曲[notch]配體DLL3(NCBI基因ID:10683)
(67)Eph A4(EFNA4,NCBI基因ID:1945)
(68)核苷酸內焦磷酸酶/磷酸二酯酶3(ENPP3,NCBI基因ID:5169)
(69)凝血因子III(F3,NCBI基因ID:2152)
(70)FGF受體3(FGFR3,NCBI基因ID:2261)
(71)葉酸水解酶FOLH1(NCBI基因ID:2346)
(72)葉酸受體1(FOLR1;NCBI基因ID:2348)
(73)鳥糞嘌呤核苷酸環化酶2C(GUCY2C,NCBI基因ID:2984)
(74)KIT前致癌基因受體酪胺酸激酶(NCBI基因ID:3815)
(75)溶酶體關聯的膜蛋白1(LAMP1,NCBI基因ID:3916)
(76)淋巴細胞抗原6複合物,E位置(LY6E,NCBI基因ID:4061)
(77)蛋白質NOTCH3(NCBI基因ID:4854)
(78)蛋白質酪胺酸激酶7(PTK7,NCBI基因ID:5754)
(79)連結素[nectin]細胞黏著分子4(PVRL4,NECTIN4,NCBI基因ID:81607)
(80)穿越細胞膜之蛋白質syndecan 1(SDC1,NCBI基因ID:6382)
(81)SLAM家族成員7(SLAMF7,NCBI基因ID:57823)
(82)運輸蛋白SLC39A6(NCBI基因ID:25800)
(83)似SLIT-和NTRK-的家族成員6(SLITRK6,NCBI基因ID:84189)
(84)細胞表面受體TACSTD2(NCBI基因ID:4070)
(85)受體蛋白TNFRSF8(NCBI基因ID:943)
(86)受體蛋白TNFSF13B(NCBI基因ID:10673)
(87)醣蛋白TPBG(NCBI基因ID:7162)
(88)細胞表面受體TROP2(TACSTD2,NCBI基因ID:4070)
(89)似加拉寧神經肽[galanin]之G蛋白結合受體KISS1R(GPR54,NCBI基因ID:84634)
(90)運輸蛋白SLAMF6(NCBI基因ID:114836)
在本發明之較佳試驗品中,癌症標靶分子係選自癌症標靶分子EGFR、CD123、Her2、B7H3、TWEAKR和CXCR5,尤其是CD123、CXCR5和B7H3的群組。
在本發明之更佳的實驗品中,該結合劑結合至選自癌症標靶分子EGFR、CD123、Her2、B7H3、TWEAKR和CXCR5群組,尤其是CD123、CXCR5和B7H3的細胞外癌症標靶分子。
在本發明之更佳的實驗品中,該結合劑特定結合至選自癌症標靶分子EGFR、CD123、Her2、B7H3、TWEAKR和CXCR5群組,尤其是CD123、CXCR5和B7H3的細胞外癌症標靶分子。在一項較佳實施例中,該結合劑在與其標靶細胞上的細胞外標靶分子結合之後,透過結合被該標靶細胞內化。這造成可能為免疫結合物或ADC之結合劑-藥劑結合物被標靶細胞吸收。然後該結合劑較好是以細胞內溶酶體為優先的方式加工。
在一實施例中,該結合劑是一結合蛋白質。在一較佳實施例中,該結合劑是一抗體、一與抗原結合的抗體片段、多重專一性抗體或一抗體模仿物。
較佳的抗體模仿物是親合體、阿奈亭(adnectins,一類新型類抗體藥物)、抗嘉林[anticalins]、DARPins、高親和性多聚體[avimers]或奈米抗體。較佳之多重專一性抗體是雙重專一性和三重專一性的抗體。
在一較佳實施例中,該結合劑是一抗體或一與抗原結合的抗體片段,更好是一經分離的抗體或一經分離之與抗原結合的抗體片段。
較佳之與抗原結合的抗體片段是Fab、Fab'、F(ab')2和Fv片段、雙重專一性抗體、DAbs、線性抗體和scFv。尤佳者為Fab、雙重專一性抗體和scFv。
在一尤佳實施例中,該結合劑是一抗體。尤佳者為單株抗體或其與抗原結合的抗體片段。更尤佳者為人類的、人類化的或嵌合型抗體或其與抗原結合的抗體片段。
能和癌症標靶分子結合的抗體或與抗原結合的抗體片段可由熟習本技藝者用已知的方法,例如化學合成或重組表現來製備。用於癌症標靶分子的結合劑可購得或可由可由熟習本技藝者用已知的方法,例如化學合成或重組表現來製備。更多用於製備抗體或與抗原結合的抗體片段的方法說明在WO 2007/070538(請參考[原文]第22頁「抗體」)。熟習本技藝者知道怎樣收集方法如噬菌體呈現技術基因庫(例如Morphosys HuCAL Gold)和用於發現抗體或與抗原結合的抗體片段(請參考WO 2007/070538,p.24 ff和p.70的AK實例1、p.72的AK實例2)。此外利用得自B細胞之DNA資料庫製備抗體的方法說明在例如p.26(WO 2007/070538)。人類化抗體的方法說明在WO2007070538的p.30-32且詳細說明在Queen,et al.,Pros.Natl.Acad.Sci.USA 8610029-10033,1989或在WO 90/0786。此外,用於一般蛋白質和尤其抗體的重組表現法是熟習本技藝用者已知的(請參考例如Berger and Kimrnel(Guide to Molecular Cloning Techniques,Methods in Enzymology,Vol.152,Academic Press,Inc.);Sambrook,et al.,(Molecular Cloning A Laboratory
Manual,(Second Edition,Cold Spring Harbor Laboratory Press;Cold Spring Harbor,N.Y.;1989)Vol.1-3);Current Protocols in Molecular Biology,(F.M.Ausabel et al.[Eds.],Current Protocols,Green Publishing Associates,Inc./John Wiley & Sons,Inc.);Harlow et al.,(Monoclonal Antibodies A Laboratory Manual,Cold Spring Harbor Laboratory Press(19881,Paul[Ed.]);Fundamental Immunology,(Lippincott Williams & Wilkins(1998));和Harlow,et al.,(Using Antibodies A Laboratory Manual,Cold Spring Harbor Laboratory Press(1998))。熟習本技藝者知道用於表現蛋白質/抗體所需之對應載體、啟動子和信號肽。普通的方法亦說明於WO 2007/070538,p.41-45。製備IgG1抗體的方法說明在例如WO 2007/070538於p.74ff的實例6。容許抗體在與其抗原結合後內化的測定方法是熟習本技藝者已知的且說明在例如WO 2007/070538,p.80。熟習本技藝者能使用WO 2007/070538說明的方法,該方法以相似於製備具有相異標靶分子專一性之抗體的方式被用於製備碳酸酐酶IX(Mn)抗體。
細菌的表現
熟習本技藝者知道其中抗體與其抗原結合片段或其變異體可借助細菌表現而生產的方法。
用於使細菌表現所需蛋白質的適當表現載體是藉由插入功能性讀取框位中編碼所需蛋白質的DNA片段,併同適當的轉譯起始和轉譯終止信號與一功能性啟動子得到的。該載體包含一種以上可以表現型篩選的記號和一複製原點以使載體滯留,且若需要使其在宿主細胞中的量放大。用於轉型之原核宿主包括但不限於大腸桿菌(E.coli)、枯草桿菌(Bacillus subtilis)、腸道沙門氏菌(Salmonella typhimurium)和各種出自假單孢菌屬(Pseudomonas)、鏈黴菌屬(Streptomyces)、和葡萄球菌屬(Staphylococcus)的菌種。細菌載體可
根據:例如,噬菌體、質體、或噬粒。這些載體可包含可挑選的標記和得自市售質體之細菌複製原點。許多市售質體典型上包含以詳知的轉殖載體pBR322(ATCC 37017)。在細菌的系統中,有好處之表現載體數目可根據吾人意圖待表現蛋白質的用途來挑選。
將適當宿主細胞株轉型並將該宿主細胞株培養到適當的細胞密度之後,以適當方法使該經挑選的啟動子去除再被啟動/誘發(例如:改變溫度或化學誘導),且該細胞被培養另外一段時間。該細胞典型上以離心法收穫且若需要以物理方式或化學方法將其消化分解,並將所得到的粗萃取物保留以供進一步純化。
因此,本發明進一步的實施例是一包含編碼本發明之新穎抗體的核酸之表現用載體。
本發明的抗體或其與抗原結合的片段包括天然純化的產品,源自化學合成的產品,以及由各種原核宿主中進行的重組技術產生之產物,例如:大腸桿菌、枯草桿菌、腸道沙門氏菌和各種出自假單孢菌屬、鏈黴菌屬、和葡萄球菌屬的菌種,較好是大腸桿菌。
哺乳類細胞之表現
熟習本技藝者知道其中抗體、其與抗原結合片段或其變異體可借助哺乳動物細胞表現的方法。
哺乳動物細胞宿主身上之表現的較佳調控序列包括能導致哺乳動物細胞中高度表現之病毒元素,如衍生自巨細胞病毒(CMV)(如CMV啟動子/促進子)、猿猴病毒40(SV40)(如SV40啟動子/促進子),衍生自腺病毒(例如腺病毒的主要慢發啟動子(AdMLP))和得自多形瘤的啟動子/或表現放大器。抗體的表現可為本質上的或受調控的(例如藉由添加或其除掉小分子誘導物如四環素與Tet系統組合)。
為了進一步說明病毒調控元素及其序列,因此提出參考文獻,例如:Stinski提申的U.S.5,168,062、Bell等人提申的U.S.4,510,245和Schaffner等人提申的U.S.4,968,615。該重組表現載體同樣的可包括一重組原點和可挑選的標記(請參考例如U.S.4,399,216,4,634,665和U.S.5,179,017)。適當之可挑選標記包括當載體被導入細胞時能賦予其對於如G418、普洛黴素、潮黴素、保米黴素、博來黴素/撲類惡注射劑或甲氨蝶呤物質抗性的基因,或導致宿主細胞營養缺陷的可挑選的標記,如麩胺醯胺合成酶(Bebbington et al.,Biotechnology(NY)。1992 Feb;10(2):169-75)。
舉例而言,二氫葉酸還原酶(DHFR)基因賦予對甲氨蝶呤的抗性,該新型基因賦予對G418的抗性,得自土麴菌(Aspergillus terreus)的bsd基因賦予對保米黴素的抗性,普洛黴素N-轉乙醯酶賦予對普洛黴素的抗性,Sh ble基因產物賦予對博來黴素的抗性,對於潮黴素的抗性是由大腸桿菌的抗潮黴素基因(hyg或hph)賦予的。可挑選的標記如DHFR或麩胺醯胺合成酶連同MTX和MSX也對於放大技術有幫助。
將表現載體轉移感染到細胞中可借助標準技術來執行,包括藉由電穿洞法、核轉染法、磷酸鈣沉澱法、脂質體轉染法、多陽離子為基礎的轉染法如聚乙烯亞胺(PEI)為基礎的感染和DEAE-葡聚醣轉染法。
用於抗體、其與抗原結合的片段或其變異體表現之適當哺乳動物細胞包括倉鼠的卵巢(CHO)細胞如CHO-K1、CHO-S、CHO-K1SV[包括DHFR-CHO細胞,說明於Urlaub and Chasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220和Urlaub et al.,Cell.1983 Jun;33(2):405-12;與DHFR-選擇性標記一起使用,如R.J.Kaufman and P.A.Sharp(1982)Mol.Biol.159:601-621中所說明;以及其他剔除細胞,詳如Fan et al.,Biotechnol Bioeng.2012 Apr;109(4):1007-15)、NS0骨髓癌細胞、COS細胞、HEK293細胞、HKB11細胞、BHK21細胞、CAP細胞、EB66細胞和SP2細胞。
抗體、其與抗原結合的片段或其變異體的表現亦可用短暫的或半穩定的方式在表現系統如HEK293、HEK293T、HEK293-EBNA、HEK293E、HEK293-6E、HEK293 Freestyle、HKB11、Expi293F、293EBNALT75、CHO自由式、CHO-S、CHO-K1、CHO-K1SV、CHOEBNALT85、CHOS-XE、CHO-3E7或CAP-T細胞(如同Durocher et al.,Nucleic Acids Res.2002 Jan 15;30(2):E9)中實行。
在某些實施例中,表現載體係以下述方式建構:使待表現的蛋白質分泌到宿主細胞生長的細胞培養基中。抗體、其與抗原結合的片段或其變異體可借助熟習本技藝者已知的蛋白質純化法從細胞培養基中獲得。
純化
抗體、其與抗原結合的片段,或其變異體可從重組細胞培養物中借助已知的方法獲得和純化,其實例包括硫酸銨或乙醇沉澱、酸萃取、蛋白質A層析法、蛋白質G層析法、陰離子或陽離子交換層析法、磷酸化纖維素層析法、疏水性交互作用層析法(HIC)、親和性層析法、羥基磷灰石層析法和凝集素層析法。高壓液相層析法(「HPLC」)同樣可被採用於純化。請參考例如Colligan,Current Protocols in Immunology,或Current Protocols in Protein Science,John Wiley & Sons,NY,N.Y.,(1997-2001),例如第1、4、6、8、9、10章。
本發明的抗體或其與抗原結合的片段或其變異體包括天然純化的產物,得自化學合成法的產物和借助重組技術在原核或真核細胞中生產的產物。真核宿主包括例如:酵母菌細胞、較高等的植物細胞、昆蟲細胞和哺乳動物細胞。視被挑選用於重組表現的宿主細胞而定,表現出來的蛋白質可能呈糖基化或非糖基化的形式。
在一項較佳實施例中,抗體經純化(1)達到大於95%重量比的程度,此係
以例如勞瑞(Lowry)法、UV-可見光光譜法或以SDS毛細作用膠體電泳法(例如使用Caliper LabChip GXII,GX 90或Biorad Bioanalyzer儀器)測定,且在更佳的實施例中大於99%重量比,(2)達到適於測定至少15個N-端或內部胺基酸序列殘基的程度,或(3)達到以SDS-PAGE在還原或非還原條件下借助考馬斯藍染劑(Coomassie blue)染色或較佳是銀染測定均質的程度。
通常,經單離的抗體係借助至少一種蛋白質純化步驟獲得。
抗-CD123抗體
根據本發明,吾人可使用抗-CD123抗體。
「抗-CD123抗體」或「特定結合至CD123的抗體」的表現係關於一與癌症標靶分子CD123(IL3RA;NCBI-Gene ID:3563;NCBI參考序列:NP_002174.1;Swiss-Prot:P26951;SEQ ID NO:111)結合的抗體,較好是具有足以供給診斷和/或治療應用的親和力。在特別的實施例中,該抗體結合至CD123,其解離常數(KD)1μM、100nM、10nM、1nM、0.1nM、0.01nM,或0.001nm。
Sun等人(Sun et al.,1996,Blood 87(1)83-92)說明單株抗體7G3的生產及其性質,該抗體與IL-3Rα、CD123的N端區位結合。美國專利案第6,177,078號(Lopez)係關於抗-CD123抗體7G3。此抗體之嵌合的變異體(CSL360)說明於WO 2009/070844,以及人類化的版本(CSL362)說明於WO 2012/021934。7G3抗體的序列揭示於EP2426148。此序列構成以CDR移植得到的人類化抗體之起始點。
在與細胞表面抗原結合之後內化尤佳之抗體是Kuo等人揭示之抗-CD123抗體12F1(Kuo et al.,2009,Bioconjug Chem.20(10):1975-82)。抗體12F1要比抗體7G3以較高的親和力結合至CD123,並且在細胞表面抗原結合後比7G3之內化顯著較快。根據12F1之雙重專一性scFv免疫融合蛋
白揭示於WO 2013/173820。抗體TPP-6013是一12F1的嵌合變異體。
本發明尤其關於具有抗體或與抗原結合的抗體片段或其變異體的結合物,該抗體係得自源於小鼠之抗體7G3(Sun et al.,1996,Blood 87(1):83-92)和12F1(Kuo et al.,2009,Bioconjug Chem.20(10):1975-82),或者關於具有得自抗體12F1之抗體或與抗原結合的抗體片段或其變異體之結合物(Kuo et al.,2009,Bioconjug Chem.20(10):1975-82)。
鼠科7G3抗體和鼠科12F1抗體的人類化變異體係藉由CDR移植到人類架構並緊接著最佳化,並且是本發明內容中之較佳實例。
在本發明之內容中尤佳者當屬抗-CD123抗體TPP-9476、TPP-8988、TPP-8987和TPP-6013。
抗-CXCR5抗體
根據本發明,吾人可使用抗-CXCR5抗體。
「抗-CXCR5抗體」或「特定結合至CXCR5的抗體」的表現係關於一與癌症標靶分子CXCR5(NCBI參考序列:NP_001707.1;SEQ ID NO:112)結合的抗體,較好是具有足以供給診斷和/或治療應用的親和力。在特別的實施例中,該抗體結合至CXCR5,其解離常數(KD)1μM、100nM、10nM、1nM、0.1nM、0.01nM,或0.001nm。
結合至CXCR5的抗體和與抗原結合片段的實例是熟習本技藝者已知的,且說明於例如EP2195023。
用於大鼠抗體RF8B2(ACC2153)的融合瘤細胞係購自DSMZ公司並且抗體的序列係以標準法鑑認。此序列構成以CDR移植所得人類化抗體之起始點。
此抗體的人類化變異體是由CDR移植進入胚系序列所產生的。
這些抗體和與抗原結合的片段可被用在本發明的情形中。
在本發明之內容中尤佳者當屬抗-CXCR5抗體TPP-9574和TPP-9580。
抗-B7H3抗體
根據本發明,吾人可使用抗-B7H3抗體。
「抗-B7H3抗體」或「特定結合至B7H3的抗體」的表現係關於一與癌症標靶分子B7H3(NCBI參考序列:NP_001019907.1SEQ ID NO:113)結合的抗體,較好是具有足以供給診斷和/或治療應用的親和力。在特別的實施例中,該抗體結合至B7H3,其解離常數(KD)1μM、100nM、10nM、1nM、0.1nM、0.01nM,或0.001nm。
結合至B7H3之抗體和與抗原結合的片段的實例是熟習本技藝者已知的並且說明在例如WO201109400、EP1773884和WO2014061277。EP2121008說明抗-B7H3抗體8H9及其CDR序列。
者些抗體和與抗原結合的片段可被用在本發明的情形中。
抗-B7H3抗體的較佳實例係藉由篩選能展現重組小鼠B7H3(小鼠CD276;基因ID:102657)和人類B7H3(人類CD276;基因ID:80381)細胞之抗體噬菌體呈現技術基因庫。所得到的抗體經轉型成人類IgG1形式。抗-B7H3抗體TPP-8382是一較佳實例。
在本發明之內容中尤佳者當屬抗-B7H3抗體TPP-8382。
抗-TWEAKR抗體
根據本發明,吾人可使用抗-TWEAKR抗體。
「抗-TWEAKR抗體」或「特定結合至TWEAKR的抗體」的表現係關於一與癌症標靶分子TWEAKR(NCBI參考序列:NP_057723.1SEQ ID NO:114)結合的抗體,較好是具有足以供給診斷和/或治療應用的親和力。在特別的實施例中,該抗體結合至TWEAKR,其解離常數(KD)1μM、100nM、
10nM、1nM、0.1nM、0.01nM,或0.001nm。
結合至TWEAKR的抗體實例被揭示於,例如:WO2009/020933(A2)、WO2009/140177(A2)、WO 2014/198817(A1)和WO 2015/189143(A1)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
ITEM-4是一抗TWEAKR抗體,其由Nakayama等人說明(Nakayama,et al.,2003,Biochem Biophy Res Comm,306:819-825)。以CDR移植為基礎之此抗體的人類化變異體由Zhou等人(Zhou et al.,2013,J Invest Dermatol.133(4):1052-62)和在WO 2009/020933中說明。這些抗體和與抗原結合的片段可被用在本發明的情形中。
在本發明之內容中尤佳者當屬抗-TWEAKR抗體TPP-7006和TPP-7007。這些是抗體ITEM-4之人類化變異體。這些抗體和與抗原結合的片段可優先被用於本發明的情形中。
抗-HER2抗體:
根據本發明,吾人可使用抗-HER2抗體。
「抗-HER2抗體」或「特定結合至HER2的抗體」的表現係關於一與癌症標靶分子HER2(NCBI參考序列:NP_004439.2SEQ ID NO:115)結合的抗體,較好是具有足以供給診斷和/或治療應用的親和力。在特別的實施例中,該抗體結合至HER2,其解離常數(KD)1μM、100nM、10nM、1nM、0.1nM、0.01nM,或0.001nm。
一種結合至癌症標靶分子Her2的抗體是賀癌平(Genentech公司出品)。賀癌平是一尤其用於治療乳癌的人類化抗體。在一尤佳的實施例中,抗-HER2抗體是TPP-1015(賀癌平類似物)。
更多結合至HER2的抗體實例除賀癌平(INN 7637,CAS No.:RN:180288-69-1)和培爾珠單抗[pertuzumab](CAS No.:380610-27-5)以外,該抗體
揭示於WO 2009/123894-A2、WO 200/8140603-A2或WO 2011/044368-A2。抗-HER2結合物的實例是賀癌平-賀癌寧(INN-No.9295)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
在本發明內容中,較佳者當屬抗HER2抗體TPP-1015(相似於賀癌平)。
抗-EGFR抗體
根據本發明,吾人可使用抗-EGFR抗體。
「抗-EGFR抗體」或「特定結合至EGFR的抗體」的表現係關於一與癌症標靶分子EGFR(NCBI參考序列:NP_005219.2 SEQ ID NO:116)結合的抗體,較好是具有足以供給診斷和/或治療應用的親和力。在特別的實施例中,該抗體結合至EGFR,其解離常數(KD)1μM、100nM、10nM、1nM、0.1nM、0.01nM,或0.001nm。
在一項較佳實施例中,抗-EGFR抗體係選自TPP-981、爾必得舒、維必施[panitumumab單抗]、尼妥珠單抗[nimotuzumab]的群組。在一尤佳實施例中,該抗-EGFR抗體是TPP-981。
另外的EGFR抗體實施例如下:
˙札魯圖單抗[zalutumumab]/2F8/HuMax-EGFr,得自Genmab單抗A/S(WO 02/100348、WO 2004/056847、INN編號8605)
˙耐昔妥珠單抗[necitumumab]/11F8,ImClone/IMC-11F8,得自ImClone Systems Inc.公司[Eli Lilly & Co](WO 2005/090407(EP 01735348-A1、US 2007/0264253-A1、US 7,598,350、WO 2005/090407-A1)、INN編號9083)
˙馬妥珠單抗[matuzumab]/抗-EGFR MAb,Merck KGaA/抗-EGFR MAb,Takeda/EMD 72000/EMD-6200/EMD-72000和EMD-55900/MAb 425/單株抗體425,得自Merck KGaA/Takeda(WO 92/15683、
INN編號8103(馬妥珠單抗[matuzumab]))
˙RG-7160/GA-201/GA201/R-7160/R7160/RG7160/RO-4858696/RO-5083945/RO4858696/RO5083945,得自Glycart Biotechnology AG公司(Roche Holding AG)(WO 2010/112413-A1、WO 2010/115554)
˙GT-MAB 5.2-GEX/CetuGEX,得自Glycotope GmbH(WO 2008/028686-A2(EP 01900750-A1、EP 01911766-A1、EP 02073842-A2、US 2010/0028947-A1)
˙ISU-101,得自Isu Abxis Inc公司(ISU Chemical Co Ltd)/Scancell公司(WO 2008/004834-A1)
˙ABT-806/mAb-806/ch-806/抗-EGFR單株抗體806,得自Ludwig Institute for Cancer Research公司/Abbott公司/Life Science Pharmaceuticals公司(WO 02/092771、WO 2005/081854和WO 2009/023265)
˙SYM-004(包含兩個嵌合的IgG1抗體(992 and 1024)),得自Symphogen A/S(WO 2010/022736-A2)
˙MR1-1/MR1-1KDEL,得自IVAX Corp公司(Teva Pharmaceutical Industries Ltd)(杜克大學),(專利:WO2001/062931-A2)
˙對抗缺損突變株EGFRvIII的抗體,得自Amgen/Abgenix(WO 2005/010151,US 7,628,986)
˙SC-100,得自Scancell Ltd公司(WO 01/088138-A1)
˙MDX-447/EMD 82633/BAB-447/H 447/MAb、EGFR、Medarex/Merck KgaA,得自Bristol-Myers Squibb(US)/Merck KGaA(DE)/Takeda(JP)、(WO 91/05871、WO 92/15683)
˙抗-EGFR-Mab,得自Xencor公司(WO 2005/056606)
˙DXL-1218/抗-EGFR單株抗體(癌症),InNexus,得自InNexus
Biotechnology Inc公司,Pharmaprojects PH048638
抗-碳酸酐酶IX抗體
癌症標靶分子碳酸酐酶IX結合之抗體實例說明於WO 2007/070538-A2(例如請求項s 1-16)。
抗-C4.4a抗體:
C4.4a抗體和與抗原結合的片段的抗體說明於WO 2012/143499 A2。抗體的序列給在WO 2012/143499 A2的表1中,其中每一列顯示第一縱列所列出抗體之可變輕鏈或可變重鏈的相對CDR胺基酸序列。
抗-CD20抗體:
一結合至癌症標靶分子CD20的抗體是立圖喜單抗[rituximab]單抗(Genentech公司)。立圖喜單抗[rituximab](CAS編號:174722-31-7)是一用於治療非何杰金氏淋巴瘤(Non-Hodgkin Lymphoma)嵌合抗體。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD52抗體:
一個抗體結合至癌症標靶分子CD52的實例是阿侖單抗[alemtuzumab](Genzyme公司)。阿侖單抗[alemtuzumab](CAS編號:216503-57-0)是一用於治療慢性淋巴球白血症的人類化抗體。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-間皮素抗體:
抗-間皮素抗體的實例說明在例如:WO2009/068204。所有
WO2009/068204說明的抗體和其與抗原結合的片段可被用於本說明書中揭示的本發明內容。更好是WO2009/068204中揭示的抗體是MF-T。
抗-CD30抗體
結合至癌症標靶分子CD30且可被用於治療癌症,例如:何杰金氏淋巴瘤的抗體實例是布侖圖希單抗[brentuximab]、依拉圖姆單抗[iratumumab]和WO 2008/092117、WO 2008/036688或WO 2006/089232中揭示的抗體。一抗-CD30結合物的實例是布侖圖希單抗-威多亭[brentuximab vedotin](INN No.9144)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD22抗體
結合至癌症標靶分子CD22且可被用於治療癌症,例如:何杰金氏淋巴瘤的抗體實例是因諾圖祖單抗[inotuzumab]和依普拉圖單抗[epratuzumab]。抗-CD22結合物的實例為因諾圖祖單抗[inotuzumab]-歐札嘉黴素[ozagamycin](INN No.8574)或抗-CD22-MMAE和抗-CD22-MC-MMAE(個別為CAS RN:139504-50-0和474645-27-7)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD33抗體
結合至癌症標靶分子CD33且可被用於治療癌症,例如:血癌的抗體實例是吉妥珠單抗[gemtuzumab]和林圖珠單抗[lintuzumab](INN 7580)。一抗-CD33結合物的實例是吉妥珠單抗[gemtuzumab]-歐札嘉黴素[ozagamycin]。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-NMB抗體
結合至癌症標靶分子NMB且可被用於治療癌症,例如:黑色素瘤或乳癌的抗體實例是格利巴圖單抗[glembatumumab](INN 9199)。一抗-NMB結合物的實例是格利巴圖單抗-威多亭[glembatumumab vedotin](CAS RN:474645-27-7)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD56抗體
結合至癌症標靶分子CD56且可被用於治療癌症,例如:多發性骨髓瘤、小細胞肺癌、MCC或卵巢癌的抗體實例是洛佛圖珠單抗[lorvotuzumab]。抗-CD57結合物是洛佛圖珠單抗[lorvotuzumab]梅爾他新[mertansine](CAS RN:139504-50-0)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD70抗體
結合至癌症標靶分子CD70且可被用於治療癌症,例如:非何杰金氏淋巴瘤或腎細胞癌的抗體實例揭示於WO 2007/038637-A2和WO 2008/070593-A2。抗-CD70結合物的實例是SGN-75(CD70 MMAF)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD74抗體
結合至癌症標靶分子CD74且可被用於治療癌症,例如:多發性骨髓癌的抗體實例是米拉圖祖單抗[milatuzumab]。抗-CD74結合物的實例是米拉圖祖單抗[milatuzumab]-阿黴素[doxorubicin](CAS RN:23214-92-8)。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD19抗體
結合至癌症標靶分子CD19且可被用於治療癌症,例如:非何杰金氏淋巴瘤的抗體實例揭示於WO 2008/031056-A2。更多抗體和抗-CD19結合物(SAR3419)的實例揭示於WO2008/047242-A2。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-黏蛋白抗體
與癌症標靶分子黏蛋白-1結合和可被用於治療癌症,例如:非何杰金氏淋巴瘤的抗體實例為樂利伐珠單抗[clivatuzumab]和揭示於WO 2003/106495-A2、WO 2008/028686-A2的抗體。抗-黏蛋白結合物的實例揭示於WO 2005/009369-A2。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-CD138抗體
結合至癌症標靶分子CD138及其結合物可被用於治療癌症,例如:多發性骨髓癌的抗體實例揭示於WO 2009/080829-A1、WO 2009/080830-A1。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-integrin-alphaV抗體
與癌症標靶分子整合素αV結合且可被用於治療癌症,例如:黑色素瘤、肉瘤或癌的抗體實例是因特圖木單抗[intetumumab](CAS RN:725735-28-4)、阿布西吉單抗[abciximab](CAS RN:143653-53-6)、艾塔西珠[etaracizumab]單抗(CAS RN:892553-42-3)和US 7,465,449、EP 719859-A1、WO 2002/012501-A1和WO2006/062779-A2中所揭示的抗體。抗-整合素αV結合物的實例是因特圖木單抗[intetumumab]-DM4其他揭示於WO 2007/024536-A2的ADCs。
這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-TDGF1抗體
與癌症標靶分子TDGF1結合且可被用於治療癌症的抗體實例是揭示於WO 02/077033-A1、US 7,318,924、WO 2003/083041-A2和WO 2002/088170-A2的抗體。抗-TDGF1結合物的實例揭示於WO 2002/088170-A2。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-PSMA抗體
與癌症標靶分子PSMA結合且可被用於治療癌症例如:前列腺癌的抗體實例是揭示於WO 97/35616-A1、WO 99/47554-A1、WO 01/009192-A1和WO2003/034903的抗體。抗-PSMA結合物的實例揭示於WO 2009/026274-A1和WO 2007/002222。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-EPHA2抗體
與癌症標靶分子EPHA2結合且可被用於製備結合物和治療癌症的抗體實例揭示於WO 2004/091375-A2。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-SLC44A4抗體
與癌症標靶分子SLC44A4結合且可用於製備結合物和治療癌症,例如胰臟癌或前列腺癌的抗體實例揭示於WO2009/033094-A2和US2009/0175796-A1。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-HLA-DOB抗體
與癌症標靶分子HLA-DOB結合的抗體實例是抗體Lym-1(CAS RN:301344-99-0),其可被用於治療癌症,例如:非何杰金氏淋巴瘤。抗-HLA-DOB結合物的實例揭示於例如WO 2005/081711-A2。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-VTCN1抗體
與癌症標靶分子VTCN1結合且可用於製備結合物和治療癌症,例如卵巢癌、胰臟癌、肺癌或乳癌的抗體實例揭示於WO 2006/074418-A2。這些抗體和其與抗原結合的片段可被用在本發明的情形中。
抗-FGFR2抗體
抗-FGFR2抗體和與抗原結合的片段的實例說明於WO2013076186。抗體序列顯示在WO2013076186之表9和表10中。較佳者當屬得自稱為M048-D01和M047-D08之抗體、與抗原結合的片段及抗體之變異體。
根據本發明用作結合劑-藥劑結合物之較佳抗體和與抗原結合的抗體片段
在本申請案關於結合劑-藥劑結合物的內容中,參考以下較佳抗體,如下表所示:TPP-981、TPP-1015、TPP-6013、TPP-7006、TPP-7007、TPP-8382、TPP-8987、TPP-8988、TPP-9476、TPP-9574和TPP-9580。
TPP-981、TPP-1015、TPP-6013、TPP-7006、TPP-7007、TPP-8382、TPP-8987、TPP-8988、TPP-9476、TPP-9574和TPP-9580是包含一個以上於上表中指明之位在重鏈可變區(VH)或輕鏈可變區(VL)的CDR序列(H-CDR1、H-CDR2、H-CDR3、L-CDR1、L-CDR2、L-CDR3)之抗體。較好是該抗體包含該指明的重鏈可變區(VH)和/或輕鏈可變區(VL)。較好是該抗體包含重鏈的指明區域(IgG重鏈)和/或輕鏈的指明區域(IgG輕鏈)。
TPP-981是一抗-EGFR抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:2所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:3所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:4所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:6所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:7所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:8所示的輕鏈可變區(VL)。
TPP-1015是一抗-HER2抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:12所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:13所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:14所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:16所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:17所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:18所示的輕鏈可變區(VL)。
TPP-6013是一抗-CD123抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:22所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:23所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:24所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:26所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:27所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:28所示的輕鏈可變區(VL)。
TPP-7006是一抗-TWEAKR抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:32所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:33所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:34所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-
CDR1),如SEQ ID NO:36所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:37所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:38所示的輕鏈可變區(VL)。
TPP-7007是一抗-TWEAKR抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:42所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:43所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:44所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:46所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:47所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:48所示的輕鏈可變區(VL)。
TPP-8382是一抗-B7H3抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:52所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:53所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:54所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:56所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:57所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:58所示的輕鏈可變區(VL),
TPP-8987是一抗-CD123抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:62所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:63所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:64所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:66所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:67所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:68所示的輕鏈可變區(VL)。
TPP-8988是一抗-CD123抗體代表一抗-CD123抗體,其包含一含該重
鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:72所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:73所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:74所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:76所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:77所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:78所示的輕鏈可變區(VL)。
TPP-9476是一抗-CD123抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:82所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:83所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:84所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:86所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:87所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:88所示的輕鏈可變區(VL)。
TPP-9574是一抗-CXCR5抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:92所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:93所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:94所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:96所示、該輕鏈之可變CDR2序列(L-CDR2),如SEQ ID NO:97所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:98所示的輕鏈可變區(VL)。
TPP-9580是一抗-CXCR5抗體,其包含一含該重鏈之可變CDR1序列(H-CDR1),如SEQ ID NO:102所示、該重鏈之可變CDR2序列(H-CDR2),如SEQ ID NO:103所示和該重鏈之可變CDR3序列(H-CDR3),如SEQ ID NO:104所示之重鏈可變區(VH),以及一含該輕鏈之可變CDR1序列(L-CDR1),如SEQ ID NO:106所示、該輕鏈之可變CDR2序列(L-CDR2),如
SEQ ID NO:107所示和該輕鏈之可變CDR3序列(L-CDR3),如SEQ ID NO:108所示的輕鏈可變區(VL)。
TPP-981是一抗EGFR抗體,其較佳包含如SEQ ID NO:1所示之重鏈可變區(VH),和如SEQ ID NO:5所示之輕鏈可變區(VL)。
TPP-1015是一抗HER2抗體,其較佳包含如SEQ ID NO:11所示之重鏈可變區(VH),和如SEQ ID NO:15所示之輕鏈可變區(VL)。
TPP-6013是一抗CD123抗體,其較佳包含如SEQ ID NO:21所示之重鏈可變區(VH),和如SEQ ID NO:25所示之輕鏈可變區(VL)。
TPP-7006是一抗TWEAKR抗體,其較佳包含如SEQ ID NO:31所示之重鏈可變區(VH),和如SEQ ID NO:35所示之輕鏈可變區(VL)。
TPP-7007是一抗TWEAKR抗體,其較佳包含如SEQ ID NO:41所示之重鏈可變區(VH),和如SEQ ID NO:45所示之輕鏈可變區(VL)。
TPP-8382是一抗B7H3抗體,其較佳包含如SEQ ID NO:51所示之重鏈可變區(VH),和如SEQ ID NO:55所示之輕鏈可變區(VL)。
TPP-8987是一抗CD123抗體,其較佳包含如SEQ ID NO:61所示之重鏈可變區(VH),和如SEQ ID NO:65所示之輕鏈可變區(VL)。
TPP-8988是一抗CD123抗體,其較佳包含如SEQ ID NO:71所示之重鏈可變區(VH),和如SEQ ID NO:75所示之輕鏈可變區(VL)。
TPP-9476是一抗CD123抗體,其較佳包含如SEQ ID NO:81所示之重鏈可變區(VH),和如SEQ ID NO:85所示之輕鏈可變區(VL)。
TPP-9574是一抗CXCR5抗體,其較佳包含如SEQ ID NO:91所示之重鏈可變區(VH),和如SEQ ID NO:95所示之輕鏈可變區(VL)。
TPP-9580是一抗CXCR5抗體,,其較佳包含如SEQ ID NO:1所示之重鏈可變區(VH),和如SEQ ID NO:5所示之輕鏈可變區(VL)。
TPP-981是一抗EGFR抗體,其較佳包含如SEQ ID NO:9所示之重鏈
區,和如SEQ ID NO:10所示之輕鏈區。
TPP-1015是一抗HER2抗體,其較佳包含如SEQ ID NO:19所示之重鏈區,和如SEQ ID NO:20所示之輕鏈區。
TPP-6013是一抗CD123抗體,其較佳包含如SEQ ID NO:29所示之重鏈區,和如SEQ ID NO:30所示之輕鏈區。
TPP-7006是一抗TWEAKR抗體,其較佳包含如SEQ ID NO:39所示之重鏈區,和如SEQ ID NO:40所示之輕鏈區。
TPP-7007是一抗TWEAKR抗體,其較佳包含如SEQ ID NO:49所示之重鏈區,和如SEQ ID NO:50所示之輕鏈區。
TPP-8382是一抗B7H3抗體,其較佳包含如SEQ ID NO:59所示之重鏈區,和如SEQ ID NO:60所示之輕鏈區。
TPP-8987是一抗CD123抗體,其較佳包含如SEQ ID NO:69所示之重鏈區,和如SEQ ID NO:70所示之輕鏈區。
TPP-8988是一抗CD123抗體,其較佳包含如SEQ ID NO:79所示之重鏈區,和如SEQ ID NO:80所示之輕鏈區。
TPP-9476是一抗CD123抗體,其較佳包含如SEQ ID NO:89所示之重鏈區,和如SEQ ID NO:90所示之輕鏈區。
TPP-9574是一抗CXCR5抗體,其較佳包含如SEQ ID NO:99所示之重鏈區,和如SEQ ID NO:100所示之輕鏈區。
TPP-9580是一抗CXCR5抗體,其較佳包含如SEQ ID NO:109所示之重鏈區,和如SEQ ID NO:110所示之輕鏈區。
同位素、鹽、溶劑化物、同位素的變異體
本發明亦涵蓋所有本發明化合物之適當的同位素變異體。本發明化合物之同位素變異體在本說明書中被瞭解為意指本發明化合物中至少有一原子
經置換成另一原子之化合物,另一原子與被置換原子的原子序相同但具有異於自然界中通常或主要發生的原子質量。可併入本發明化合物的同位素實例是那些氫、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。根據本發明之化合物的特殊同位素變異體,特別是那些其中一個以上放射性同位素已併入者會有好處,例如對於檢驗作用機制和活性成分在體內的分布;因為該比較簡單的可製備性和偵測性,尤其是以3H或14C同位素標記的化合物適用於此目的。此外,同位素例如:氘的併入可導致特殊的治療好處,結果是化合物有較大的代謝穩定性,例如:延長在體內的半生期或減少需求的活性劑量;根據本發明之化合物的此種修改因此在某些情形亦可構成本發明之一項較佳實施例。根據本發明之化合物的同位素變異體可藉由熟習本技藝者已知的方法製備,例如藉由更下方說明的方法和在可行實例中說明的方法,利用對應的同位素修改個別試劑和/或起始化合物。
在本發明的內容中較佳鹽是生理上可接受之本發明化合物的鹽。同樣涵蓋者為本身並不適合醫藥施用但可被用在例如分離或純化本發明化合物的鹽類。
根據本發明的化合物之生理上可接受的鹽包括礦物酸、羧酸和磺酸的酸加成鹽,例如:鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苯磺酸、甲基本磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、蘋果酸、檸檬酸、反丁烯二酸、順丁烯二酸和苯甲酸的鹽。
根據本發明的化合物之生理上可接受的鹽亦包括傳統鹼類的鹽,舉例而言且較佳者為鹼金屬鹽(例如鈉鹽和鉀鹽)、鹼土金屬鹽(例如鈣鹽和鎂鹽)以及從氨或具有1到16個碳原子的有機胺得到的銨鹽,舉例而言且較佳者為乙胺、二乙胺、三乙胺、乙基二異丙胺、單乙醇胺、二乙醇胺、三乙醇胺、
二環己胺、二甲基胺基乙醇、普魯卡因[procaine]、二苄基胺、N-甲基哌啶、N-甲基嗎啉、精胺酸、離胺酸和1,2-乙二胺。
本發明內容中溶劑化物被說明為本發明化合物的形式,其藉著在與溶劑分子配位在固態或液態形成複合物。水合物是溶劑化物的特定形式,其中與水發生配位。在本發明內容中較佳的溶劑化物是水合物。
治療用途
根據本發明的化合物可採用於治療之高度增生性疾病,包括尤其是癌和腫瘤疾病的群組。在本發明內容中,這些被瞭解為意指尤其是以下疾病,但不限於此:乳腺癌和乳腺腫瘤(乳腺癌包括導管的和小葉的形式,也發生在原位)、呼吸道腫瘤(小細胞和非小細胞癌、支氣管癌)、腦瘤(例如在腦幹和海馬迴的、星形細胞瘤、室管細胞瘤、膠質母細胞瘤、膠質瘤、髓母細胞瘤、腦膜瘤和神經外胚層與松果體腫瘤)、消化器官的腫瘤(食道、胃、膽囊、小腸、大腸、直腸的癌症和肛門癌)、肝腫瘤(尤其肝細胞癌、膽管癌與混合的肝細胞膽管癌)、頭頸區域的腫瘤(喉、下咽部、鼻咽部、口咽部、唇和口腔癌、口腔黑色素瘤)、皮膚腫瘤(基底細胞癌、脊髓細胞癌、鱗狀細胞癌、卡氏(Kaposi's)肉瘤、惡性黑色素瘤、非黑色素瘤皮膚癌、馬凱爾(Merkel)細胞皮膚癌、肥大細胞腫瘤)、結締組織腫瘤(尤其軟組織肉瘤、骨肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、纖維肉瘤、血管肉瘤、平滑肌肉瘤、脂肪肉瘤、淋巴肉瘤和橫紋肌肉瘤)、眼部腫瘤(尤其眼球內黑色素瘤和視網膜母細胞瘤)、內分泌腺和外分泌腺腫瘤(例如甲狀腺或副甲狀腺、胰臟和唾液腺癌、腺癌)、泌尿道腫瘤(膀胱、陰莖、腎、腫瘤、腎、腎盂和輸尿管的腫瘤)和生殖器官腫瘤(女性的子宮內膜、子宮頸、卵巢、陰道、陰戶和子宮的癌與男性的前列腺癌和睪丸癌)。這些也包括血液、淋巴系統和脊索增生的疾病,以固體形式且呈循環細胞的,如白血症、淋巴瘤和骨髓增生性疾病,例如:
急性骨髓性的、急性淋巴母細胞的、慢性淋巴細胞的、慢性骨髓性的和毛細胞白血症,以及與AIDS相關的淋巴瘤、霍金氏(Hodgkin's)淋巴瘤、非何杰金氏淋巴瘤、皮膚T細胞淋巴瘤、博基氏(Burkitt's)淋巴瘤和位在中樞神經系統的淋巴瘤。
這些發生在人類之詳細鑑認特徵的疾病亦以可互比之病因發生在其他哺乳類動物身上且同樣可用本發明的化合物治療該處。
本說明書中說明且導向抗CD123的結合劑-或抗體-藥劑結合物(ADCs)較好可用於治療CD123-表現之病症,如CD123-表現之癌症。典型上,此種癌細胞展現在蛋白質(例如使用免疫檢驗)或RNA層次上可測得的CD123含量。這些癌組織中有某些顯示與同型式之非癌細胞組織相比具提高的CD123量,較好是在同一病患身上測量到。視需要在使用根據本發明的抗體-藥物結合物(ADC)進行癌症治療開始前測量CD123含量(病患分組評估)。導向抗CD123的結合劑-藥劑結合物(ADCs)較好可用於治療CD123-表現之病症,如CD123-表現之癌症-如造血和淋巴組織的腫瘤或造血的和淋巴的惡性腫瘤。與CD123表現關聯的癌症實力包括骨髓疾病,如急性骨髓性白血病(AML)和骨髓發育不良症候群(MDS)。其他癌症疾病包括B-細胞急性淋巴母細胞白血症(B-ALL)、毛細胞白血症、母細胞性漿細胞樣樹突細胞腫瘤(BPDCN)、霍金氏(Hodgkin's)淋巴瘤、發育不良的T-細胞急性淋巴母細胞白血症(發育不良的T-ALL)、博基氏(Burkitt's)淋巴瘤、濾泡性淋巴瘤、慢性淋巴細胞白血病(CLL)、被套細胞淋巴癌(MCL)。本發明說明之方法包括治療罹患CD123-表現癌症的病患,該方法包含施用根據本發明之抗體-藥物結合物(ADC)。
用根據本發明的化合物治療以上所提到的癌症包括治療固體腫瘤和治療其轉移或循環形式。
在本發明內容中,「治療」或「處理」一詞以傳統意義被使用且意指致
力於照顧和對病患護理,目標在於對抗、減少、調節獲緩合疾病或健康異常,並且改良因此疾(例如在癌症的情形中)受損的生活條件。
本發明因而尚提供本發明化合物用於治療和/或預防病症,尤其是先前提到之病症的用途。
本發明尚提供本發明化合物用於生產治療和/或預防病症,尤其是先前提到病症的醫藥品之用途。
本發明尚提供本發明化合物用於治療和/或預防病症,尤其是先前提到病症的方法。
本發明尚提供治療和/或預防病症尤其是先前提到病症的方法,其使用有效量之至少一項本發明化合物。
本發明的化合物可單獨使用或者若需要與一種以上其他藥理學活性物質組合在一起,若此組合不會導致不想要和不可接受的副作用。因此本發明尚提供醫藥品,其包含至少一項本發明化合物和一項以上此外的藥物,尤其是被使用於治療和/或預防先前提到之病症者。
例如,本發明化合物可與已知對抗過度增生的、抑制細胞生長的、細胞毒性的或免疫治療物質合併用於治療癌症。
適當之藥物組合的實例包括:131I-chTNT、阿巴利克(abarelix)、阿比特龍(abiraterone)、阿柔比星(aclarubicin)、阿達利姆單抗(adalimumab)、賀癌平/賀癌寧混合物、妥復克(afatinib)、阿扶利伯賽(aflibercept)、普留淨(aldesleukin)、阿侖單抗[alemtuzumab]、阿侖磷酸、阿利維A酸、六甲蜜胺、氨磷汀、氨魯米特、己基-5-胺基乙醯丙酸、氨柔比星、安吖啶、阿那曲唑、安塞司亭、茴香腦二硫雜環戊二烯硫酮、阿涅圖單抗-拉芙坦辛[anetumab ravtansine]、血管收縮素第二型、抗凝血酵素第三型、止敏吐[aprepitant]、阿西莫單抗[arcitumomab]、阿格拉賓[arglabin]、三氧化二砷、天冬醯胺酸酶、阿提佐珠單抗
[atezolizumab]、阿維魯單抗[avelumab]、阿齊提尼[axitinib]、氮雜胞苷[azacytidine]、貝洛替康[belotecan]、苯達莫司汀[bendamustine]、貝希利索單抗[besilesomab]、必利諾斯達[belinostat]、癌思停、倍克洛丁[bexarotene]、畢卡魯醯胺[bicalutamide]、必生群[bisantrene]、撲類惡注射劑、卜立納圖單抗[blinatumomab]、硼替佐米[bortezomib]、布希瑞林[buserelin]、博舒替尼[bosutinib]、布侖圖希單抗[brentuximab]維多亭[vedotin]、補束剋[busulfan]、去癌達[cabazitaxel]、卡博替尼[cabozantinib]、降血鈣素、甲醯四氫葉酸鈣、左亞葉酸鈣、截瘤達[capecitabine]、卡羅單抗[capromab]、卡馬西平[carbomazepine]、佳鉑帝[carboplatin]、佳博孔[carboquon]、卡非佐米[carfilzomib]、卡莫氟[carmofur]、卡莫司丁[carmustine]、卡妥索單抗[catumaxomab]、希樂葆[celecoxib]、克利默金[celmoleukin]、色瑞替尼[ceritinib]、爾必得舒[cetuximab]、瘤克寧[chlorambucil]、氯地孕酮[chlormadinone]、氮芥[chlormethine]、核苷酸類似物[cidofovir]、銳克鈣[cinacalcet]、順鉑[cisplatin]、克拉爵賓[cladribine]、氯膦酸、克洛法賓[clofarabine]、可泰利[cobimetinib]、可潘立西[copanlisib]、歐文氏菌源性天冬醯胺酶[crisantaspase]、克立佐替尼[crizotinib]、環磷醯胺[cyclophosphamide]、環丙氯地孕酮[cyproterone]、賽德薩[cytarabine]、達卡巴仁[dacarbazine]、更生黴素[dactinomycin]、達拉土姆單抗[daratumumab]、達拉非尼[dabrafenib]、達洛醯胺[darolutamide]、達司替尼[dasatinib]、唐黴素[daunorubicin]、迭西他賓[decitabine]、迪嘉瑞立[degarelix]、地尼白介素[denileukin-diftitox]、保骼麗[denosumab]、地普奧肽[depreotide]、地洛瑞林[deslorelin]、右雷佐生[dexrazoxane]、二溴螺氯銨[dibrospidium chloride]、脫水半乳糖醇、二氯芬納[diclofenac]、剋癌易[docetaxel]、多拉斯瓊[dolasetron]、多西扶利丁[doxifluridine]、阿黴素[doxorubicin]]、阿黴素[doxorubicin]+雌素酮、屈大麻酚[dronabinol]、度伐魯單抗[durvalumab]、依決洛單抗
[Edrecolomab]、依利醋銨[Elliptinium acetate]、內皮抑素[Endostatin]、伊諾他濱[Enocitabine]、安札魯醯胺[Enzalutamide]、依巴佳司達[Epacadostat]、泛艾黴素[Epirubicin]、環硫雄醇[Epitiostanol]、依泊汀-α、依泊汀-β、依泊汀-ζ、依鉑[Eptaplatin]、賀樂維[Eribulin]、得舒緩[Erlotinib]、耐適恩[Esomeprazole]、雌莫司汀[Estramustine]、醫百幸[Etoposide]、乙炔基雌二醇、埃佛洛穆斯[Everolimus]、諾曼癌素[Exemestane]、酮康唑[fadrozole]、吩坦尼[fentanyl]、氟每特隆[fluoxymesterone]、5-氟脫氧尿苷[floxuridine]、福達樂[fludarabine]、服樂癌[fluorouracil]、氟他胺[flutamide]、葉酸、諾曼癌素[formestane]、福沙坦[fosaprepitant]、福莫司汀[fotemustine]、法洛德[fulvestrant]、蓋多維斯[gadobutrol]、釓特醇[gadoteridol]、釓特酸葡胺鹽[gadoteric acid meglumine salt]、釓弗塞胺[gadoversetamide]、卜邁維斯[gd-EOB-DTPA-二鈉鹽]、硝酸鎵、加尼利克[ganirelix]、傑菲替尼[gefitinib]、健擇[gemcitabine]、吉妥珠單抗[gemtuzumab]、谷卡匹酶[glucarpidase]、氧化型谷胱甘肽[glutoxim]、戈舍瑞林[goserelin]、格蘭司瓊[granisetron]、顆粒性白血球聚落刺激因子(G-CSF)、顆粒性白血球巨噬細胞聚落刺激因子(GM-CSF)、組織胺二鹽酸鹽]、組氨瑞林[Histrelin]、羥基脲[Hydroxycarbamide]、I-125種子、骨維壯[ibandronic acid]、替伊莫單抗[ibritumomab-tiuxetan]、依魯替尼[ibrutinib]、艾達黴素[idarubicin]、好克癌[ifosfamide]、伊瑪替尼[imatinib]、咪喹莫特[imiquimod]、英丙舒凡[improsulfan]、因地西瓊[indisetron]、英卡膦酸[incadronic acid]、畢卡妥凝膠[ingenol mebutate]、干擾素-α、干擾素-β、干擾素-γ、去甲基乙醯碘六醇[iobitridol]、碘苄胍[iobenguane(123I)]、碘美普爾[iomeprol]、益伏單抗[ipilimumab]、抗癌妥[irinotecan]、伊曲康唑[itraconazole]、易莎平[ixabepilone]、伊莎佐尼[ixazomib]、舒得寧[lanreotide]、藍索拉唑[lansoprazole]、拉帕替尼[lapatinib]、拉索扣林[lasocholine]、來納度胺[lenalidomide]、樂伐替尼[lenvatinib]、顆球諾得[lenograstim]、香菇多醣[lentinan]、復乳納[letrozole]、
柳菩林[leuprorelin]、左美索[levamisole]、愉婷錠[levonorgestrel]、左旋甲狀腺素[levothyroxin-sodium]、立佩非格斯汀[lipegfilgrastim]、麥角乙脲[lisuride]、樂鉑[lobaplatin]、洛莫斯汀[lomustine]、氯尼達明[lonidamine]、馬索羅酚[masoprocol]、黃體素[medroxyprogesteron]、麥格斯[megestrol]、馬拉索普[melarsoprol]、威克瘤[melphalan]、美匹替歐坦[mepitiostan]、巰基嘌呤、麥斯納[mesna]、美沙酮[methadone]、甲氨蝶呤、甲氧沙林[methoxsalen]、甲基胺基乙醯丙酸、甲基普立朗錠[methylprednisolone]、甲基睪固酮、甲酪氨酸、米伐木肽[mifamurtide]、米替福新[miltefosine]、米鉑[miriplatin]、二溴甘露醇、米托胍腙[mitoguazone]、二溴衛矛醇、排多癌[mitomycin]、米托坦[mitotan]、雙羥蒽醌[mitoxantrone]、莫加利祖單抗[mogamulizumab]、莫拉司亭[molgramostim]、莫哌達醇[mopidamol]、嗎啡鹽酸鹽、嗎啡硫酸鹽、那比隆[nabilone]、四氫大麻酚[nabiximols]、萘法瑞林[nafarelin]、納絡酮+潘他唑新[pentazocine]、那曲酮[naltrexone]、那托司亭[nartograstim]、耐昔妥珠單抗、奈達鉑[nedaplatin]、奈拉濱[nelarabine]、奈立膦酸、[聶圖匹坦/帕洛諾司瓊[palonosetrone]、尼佛魯單抗[nivolumab]、尼佛魯單抗、胜肽銦腫瘤注射劑[pentetreotide]、尼洛替尼[nilotinib]、尼魯醯胺[nilutamide]、尼莫唑[nimorazole]、尼妥珠單抗、尼莫司汀[nimustine]、寧帖達尼[nintedanib]、尼查克林[nitracrine]、尼佛魯單抗[nivolumab]、奧比妥珠單抗[obinutuzumab]、奧曲肽[octreotide]、歐伐圖木單抗[ofatumumab]、奧拉帕尼[olaparib]、奧拉圖單抗[olaratumab]、新力博[(商品名Synribo)omacetaxin mepesuccinate]、護胃康[omeprazole]、歐丹司瓊[ondansetron]、超氧化物歧化酶[orgotein]、歐利羅摩[orilotimod]、歐斯莫替尼[osimertinib]、益樂鉑[oxaliplatin]、氧可酮[oxycodone]、羥甲烯龍[oxymetholone]、歐左加米素[ozogamicin]、p53基因療法、汰癌勝[paclitaxel]、愛乳適[palbociclib]、帕立佛明[palifermine]、鈀-103種晶、巴隆司瓊[palonosetron]、帕米膦酸[pamidronic acid]、維必施、帕
諾賓斯達[panobinostat]、潘普拉唑[pantoprazole]、帕左帕尼[pazopanib]、培門冬酶、培博利單抗[pembrolizumab]、培格干擾素α-2b、潘泊利祖單抗[pembrolizumab]、愛寧達注射劑[pemetrexed]、噴司達汀[pentostatin]、培洛黴素[peplomycin]、全氟丁烷[perflubutane]、全磷醯胺[perfosfamide]、培圖祖單抗[pertuzumab]、皮希斑尼[picibanil]、毛果芸香鹼[pilocarpine]、吡柔比星[pirarubicin]、匹杉瓊[pixantron]、賽諾菲[plerixafor]、普利佳黴素[plicamycin]、聚氨葡糖[poliglusam]、多雌二醇磷酸鹽、聚乙烯吡咯酮+玻尿酸鈉、多醣-K、波馬利竇邁[pomalidomide]、波納替尼[ponatinib]、福得靈[porfimer-sodium]、服瘤停[pralatrexate]、普列尼莫斯汀[prednimustine]、強體松[prednisone]、普卡巴嗪[procarbazine]、普可達唑[procodazole]、普萘洛爾[propranolol]、喹高萊[quinagolide]、百抑潰[rabeprazole]、拉可圖莫單抗[racotumomab]、鐳-223氯化物、拉朵替尼[radotinib]、拉羅希芬[raloxifene]、雷替曲塞[raltitrexed]、拉摩司瓊[ramosetron]、拉木希魯單抗[ramucirumab]、拉尼莫斯汀[ranimustine]、拉斯布利卡[rasburicase]、拉左杉[razoxan]、瑞發米替尼[refametinib]、癌瑞格[regorafenib]、萊司雙膦酸[risedronic acid]、錸-186依替膦酸、立圖喜單抗[rituximab]、若佳拉替尼[rogaratinib]、若拉皮坦[rolapitant]、若米戴新[romidepsin]、若莫提得[romurtid]、羅尼西利[roniciclib]、來昔決南釤[samarium(153Sm)lexidronam]、撒土莫單抗[satumomab]、腸促胰泌素[secretin]、西圖吉單抗[siltuximab]、癌療疫苗[sipuleucel-T]、西左菲藍[sizofiran]、索布佐生[sobuzoxane]、甘氨雙唑鈉[sodium glycididazole]、索尼德吉[sonidegib]、蕾莎瓦膜衣錠[sorafenib]、羥甲雄烷吡唑[stanozolol]、鏈脲佐菌素[streptozocin]、紓癌特[sunitinib]、塔拉泊芬[Talaporfin]、塔利摩(癌轉移新藥)[Talimogen laherparepvec]、塔米巴洛亭[Tamibarotene]、塔莫西芬[Tamoxifen]、塔潘他多[Tapentadol]、塔索納明[Tasonermin]、泰西白素[Teceleukin]、佛魯瑪(商品名Verluma;Technetium(99mTc)nofetumomab
merpentan]、99mTc-HYNIC-[Tyr3]-奧曲肽、太佳氟[Tegafur]、愛斯萬膠囊[Tegafur+gimeracil+oteracil]、替莫泊芬[Temoporfin]、帝盟多[Temozolomide]、特癌適[Temsirolimus]、太尼泊苷[Teniposide]、睪固酮、太曲伏明[Tetrofosmin]、沙利竇邁[Thalidomide]、沙奧特帕[Thiotepa]、胸腺法新[Thymalfasin]、促甲狀腺激素α、硫鳥嘌呤[Tioguanine]、[Tocilizumab單抗]、癌康定[Topotecan]、托瑞米芬[Toremifene]、脫司圖摩單抗[Tositumomab]、查貝帖汀[Trabectedin]、曲美替尼[Trametinib]、妥美度[Tramadol]、賀癌平、曲奧舒凡[Treosulfan]、全反式視黃酸[Tretinoin]、曲氟尿苷複方片[Trifluridine+tipiracil、查美替尼[Trametinib]、曲洛斯坦[Trilostane]、曲托瑞林[Triptorelin]、曲磷胺[Trofosfamide]、血小板生成素[Thrombopoietin]、烏苯美司[ubenimex]、戊柔比星[valrubicin]、凡德他尼[vandetanib]、維普利肽[vapreotide]、伐他拉尼[vatalanib]、威羅菲尼[vemurafenib]、敏畢瘤[vinblastine]、敏克瘤[vincristine]、溫得辛[vindesine]、長春氟寧[vinflunine]、溫諾平[vinorelbine]、維莫德吉[vismodegib]、維洛司達[vorinostat]、釔-90玻璃微珠、淨司他丁[zinostatin]、淨司他丁斯酯[zinostatin stimalamer]、骨力強[zoledronic acid]、佐柔比星[zorubicin]此外本發明的化合物可與例如結合劑(例如抗體)組合,例如其可結合至以下標靶:OX-40、CD137/4-1BB、DR3、IDO1/IDO2、LAG-3、CD40。
因為結合劑-藥劑結合物(ADC)的分\非細胞可滲透毒簇之代謝物應對於適應之免疫系統的細胞無損害影響,因此本發明上提供根據本發明之結合劑-藥劑結合物(ADC)的與一癌症免疫療法的組合用於治療癌症或腫瘤。細胞毒性之結合劑-藥劑結合物之內部作用機制包含直接引發腫瘤細胞死亡,並因而釋出腫瘤抗原,可刺激免疫反應。此外,有徵兆指示KSP抑制劑毒簇類會在體外誘發免疫性細胞死亡(ICD)的標記物。因此本發明之結合劑-藥劑結合物(ADCs)與一種以上免疫療法或與一種以上化合物(較佳是抗體),導
向對抗癌症免疫療法之標靶的治療方法代表一較佳之癌症或腫瘤治療方法。i)癌症免疫療法的治療方法實例包括導向對抗癌症免疫療法之標靶的免疫調節單株抗體和低分子量物質、疫苗、CART-細胞、雙重專一性T-細胞的吸收抗體、溶腫瘤的病毒、根據細胞的疫苗接種方法。ii)適用於免疫調節性單株抗體之癌症免疫療法的挑選標靶實例包括:CTLA-4、PD-1/PDL-1、OX-40、CD137、DR3、IDO1、IDO2、TDO2、LAG-3、TIM-3CD40.、ICOS/ICOSL、TIGIT;GITR/GITRL、VISTA、CD70、CD27、HVEM/BTLA、CEACAM1、CEACAM6、ILDR2、CD73、CD47、B7H3、TLRs。因此將根據本發明之結合劑-藥劑結合物(ADC)與癌症免疫療法合併另一方面可以使具弱免疫性的腫瘤更具免疫性,並且促進癌症免疫療法的有效性,進而展開持久的治療作用。
此外,根據本發明的化合物亦可與本發明的放射療法和/或手術介入組合使用。
一般而言,吾人可利用本發明的化合物與其他細胞鎮定的、細胞毒性或免疫治療活性的藥劑組合以追求下述目標:˙與使用個別活性成分治療相比,降低腫瘤生長、降低其大小或甚至完全消滅它的經改良效力;˙與單一療法的情形相比,以較低劑量使用化學治療劑的可能性;˙與個別施用相比,具較少副作用之更耐受療法的可能性;˙治療更範圍更廣之腫瘤病症的可能性;˙達成對治療更高的反應速率;˙與目前標準療法相比使病患有較長的存活期。
此外,根據本發明的化合物亦可與放射療法和/或手術介入合併使用。本發明尚提供包含至少一種本發明化合物的醫藥品,其典型上與一種以上惰性、無毒、醫藥上適合的賦形劑一起,且其用於先前所提到之目的用途。
本發明的化合物可全身和/或局部作用。為此目的,其可以適當的方式施用,例如:非經腸的,可能為吸入的方式或作為植入物或支架。
本發明的化合物可以適用於施用途徑的施用形式被施用。
非經腸的施用可借道於吸收步驟(例如:靜脈內、動脈內、心臟內、脊柱內或腰椎內)或包括一項吸收作用(例如肌內的、皮下的、皮內的、經皮的或腹膜內的)。適用於非經腸的施用形式包括用於注射和灌注之呈溶液、懸浮物、乳化物或冷凍乾燥物形式之製備物。較佳者當屬非經腸施用,尤其是靜脈注射。
一般而言,吾人已發現在非經腸施用的情形中有利的是施用大約0.1到20mg/kg,較佳是大約0.3 to 7mg/kg體重的劑量以達到有效的結果。
不過在某些情形中可能需要偏離所述劑量,並且特定呈重量、施用途徑、對活性成分之個別反應、製備物本質和施用發生的時間或間隔之函數。因而在某些情形中,或許可充分使用少於以上提到的最小量來操作,但是在其他情形中則必須超過所提到的上限。在施用較大量藥劑的情形中,或許可建議的是在在一天裡將其分成數個個別分劑。
以下實例說明本發明。本發明並不受限於這些實例。
除非另有申明,否則以下試驗和實例中的百分率是重量百分率;份數是重量份數。液體/液體溶液的溶劑比率、稀釋比率和濃度數據是以每一案例中之體積作為依據。
合成途徑:
以上反應流程圖中,X1、X2、X3、n和AK2具有式(I)所給的意義。
a):HATU、DMF、N,N-二異丙基乙胺,RT;b)H2、10% Pd-C、甲醇1.5h,RT;c)1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮、N,N-二異丙基乙胺、DMF,在室溫下攪拌至隔夜;d)AK2在PBS中,在氬氣下添加3-5當量溶於DMSO的活性酯,在室溫於氬氣下攪拌60min,添加另外3-5當量溶於DMSO的活性酯,在室溫於氬氣下攪拌60min,然後利用以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)進行純化並緊接著用超離心濃縮並且用PBS緩衝液(pH
7.2)]設置所想要的濃度。在體內批次的情形中,這步驟視需要接著做殺菌過濾。
以上反應流程圖中,X1、X2、X3、n和AK1具有式(I)所給的意義。
a):HATU、DMF、N,N-二異丙基乙胺,RT;b)氯化鋅、三氟乙醇、50℃、
EDTA c):HATU、DMF、N,N-二異丙基乙胺,RT;d)H2、10% Pd-C、甲醇1.5h,RT;e)1-{6-[(2,5-二酮基吡咯啶-1-基)氧基]-6-酮基己基}-1H-吡咯-2,5-二酮、N,N-二異丙基乙胺、DMF,在RT下攪拌;f)AK1溶解在PBS中,在氬氣下添加3-4當量的TCEP溶於PBS緩衝液並在RT下攪拌約30min,然後添加5-10當量化合物E溶於DMSO,在RT下攪拌約90min,然後利用以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)進行純化並緊接著用超離心濃縮並且用PBS緩衝液(pH 7.2)]設置所想要的濃度。在體內批次的情形中,這步驟視需要接著做殺菌過濾。
在以上反應流程圖中,X1、X2、X3、n和AK1具有式(I)所給的意義。
a):HATU、DMF、N,N-二異丙基乙胺,RT;b)氯化鋅、三氟乙醇、
50℃、EDTA c):HATU、DMF、N,N-二異丙基乙胺,RT;d)H2、10% Pd-C、甲醇1.5h,RT;e)1-{2-[(2,5-二酮基吡咯啶-1-基)氧基]-2-酮基乙基}-1H-吡咯-2,5-二酮、N,N-二異丙基乙胺、DMF、在RT下攪拌f)AK1溶解於PBS,在氬氣下添加3-4當量TCEP溶於PBS緩衝液,並在RT下攪拌大約30min,然後添加5-10當量溶於DMSO中的化合物E,在RT下攪拌約90min,利用以PBS緩衝液(pH 8)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)再緩衝至pH 8,然後在RT下攪拌至隔夜,然後視需要利用以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)進行純化並緊接著用超離心濃縮並且用PBS緩衝液(pH 7.2)]設置所想要的濃度。在體內批次的情形中,這步驟視需要接著做殺菌過濾。
A.實例
HPLC和LC-MS方法:
方法1(LC-MS):
儀器:Waters ACQUITY SQD UPLC系統:管柱Waters Acquity UPLC HSS T3 1.8μ 50 x 1mm;移動相A:1公升水+0.25ml的99%濃度的甲酸;移動相B:1公升乙腈+0.25ml的99%濃度的甲酸;梯度:0.0min 90% A→1.2min 5% A→2.0min 5% A;烤箱:50℃;流速:0.40ml/min;UV偵測:208-400nm。
方法2(LC-MS):
MS儀器型式:Waters Synapt G2S;UPLC儀器型式:Waters Acquity I-CLASS;管柱:Waters,BEH300,2.1 x 150mm,C18 1.7μm;移動相A:1公升水+0.01%甲酸;移動相B:1公升乙腈+0.01%甲酸;梯度:0.0min 2% B→1.5min 2% B→8.5min 95% B→10.0min 95% B;烤箱:50℃;流速:0.50ml/min;UV偵測:220nm
方法3(LC-MS):
MS儀器:Waters(Micromass)QM;HPLC儀器:Agilent 1100系列;管柱:Agilent ZORBAX Extend-C18 3.0 x 50mm 3.5μm;移動相A:1公升水+0.01mol碳酸銨,移動相B:1公升乙腈;梯度:0.0min 98% A→0.2min 98% A
→3.0min 5% A→4.5min 5% A;烤箱:40℃;流速:1.75ml/min;UV偵測:210nm
方法4(LC-MS):
MS儀器型式:Waters Synapt G2S;UPLC儀器型式:Waters Acquity I-CLASS;管柱:Waters,HSST3,2.1 x 50mm,C18 1.8μm;移動相A:1公升水+0.01%甲酸;移動相B:1公升乙腈+0.01%甲酸;梯度:0.0min 10% B→0.3min 10% B→1.7min 95% B→2.5min 95% B;烤箱:50℃;流速:1.20ml/min;UV偵測:210nm
方法5(LC-MS):
儀器:Waters ACQUITY SQD UPLC系統:管柱Waters Acquity UPLC HSS T3 1.8μ 50 x 1mm;移動相A:1公升水+0.25ml的99%濃度的甲酸;移動相B:1公升乙腈+0.25ml的99%濃度的甲酸;梯度:0.0min 95% A→6.0min 5% A→7.5min 5% A;烤箱:50℃;流速:0.35ml/min;UV偵測:210-400nm。
方法6(LC-MS):
儀器:Micromass Quattro Premier配備Waters UPLC Acquity;管柱:Thermo Hypersil GOLD 1.9μ,50 x 1mm;移動相A:1公升水+0.5ml of 50%濃度的甲酸;移動相B:1公升乙腈+0.5ml的50%濃度的甲酸;梯度:0.0min 97% A→0.5min 97% A→3.2min 5% A→4.0min 5% A;烤箱:50℃;流速:0.3ml/min;UV偵測:210nm。
方法7(LC-MS):
儀器:Agilent MS Quad 6150;HPLC:Agilent 1290;管柱:Waters Acquity UPLC HSS T3 1.8μ 50 x 2.1mm;移動相A:1公升水+0.25ml的99%濃度的甲酸;移動相B:1公升乙腈+0.25ml的99%濃度的甲酸;梯度:0.0min 90% A→0.3min 90% A→1.7min 5% A→3.0min 5% A;烤箱:50℃;流速:1.20ml/min;UV偵測:205-305nm。
方法8(LC-MS):
MS儀器型式:Waters Synapt G2S;UPLC儀器型式:Waters Acquity I-CLASS;管柱:Waters,HSST3,2.1 x 50mm,C18 1.8μm;移動相A:1公升水+0.01%甲酸;移動相B:1公升乙腈+0.01%甲酸;梯度:0.0min 2% B→2.0min 2% B→13.0min 90% B→15.0min 90% B;烤箱:50℃;流速:1.20ml/min;UV偵測:210nm。
方法9:(LC-MS製備用純畫法)
MS儀器:Waters,HPLC儀器:Waters(管柱Waters X-Bridge C18,19mm x 50mm,5μm,溶離劑A:水+0.05%氨水,移動相B:乙腈(ULC)以梯度進行;流速:40ml/min;UV偵測:DAD;210-400nm)。
或
MS儀器:Waters,HPLC儀器:Waters(管柱Phenomenex Luna 5μ C18(2)100A,AXIA Tech.50 x 21.2mm,溶離劑A:水+0.05%甲酸,溶離劑B:乙腈(ULC)以梯度進行;流速:40ml/min;UV偵測:DAD;210-400nm)。
方法10:(LC-MS分析方法)
MS儀器:Waters SQD;HPLC儀器:Waters UPLC;管柱:Zorbax SB-Aq
(Agilent),50mm x 2.1mm,1.8μm;移動相A:水+0,025%甲酸,溶離劑B:乙腈(ULC)+0.025%甲酸;梯度:0.0min 98%A-0.9min 25%A-1.0min 5%A-1.4min 5%A-1.41min 98%A-1.5min 98%A;烤箱:40℃;流速:0.600ml/min;UV偵測:DAD;210nm。
方法11(HPLC):
儀器:HP1100系列
管柱:Merck Chromolith SpeedROD RP-18e,50-4.6mm,型錄號1.51450.0001;前置管柱Chromolith Guard管匣套組,RP-18e,5-4.6mm,型錄號1.51470.0001
梯度:流速5ml/min注射體積5μl溶劑A:HClO4(70%)in water(4ml/l)溶劑B:乙腈起始20% B 0.50min 20% B 3.00min 90% B 3.50min 90% B 3.51min 20% B 4.00min 20% B管柱溫度:40℃
波長:210nm
方法12(LC-MS):
MS儀器型式:Thermo Scientific FT-MS;儀器型式UHPLC+:Thermo
Scientific UltiMate 3000;管柱:Waters,HSST3,2.1 x 75mm,C18 1.8μm;移動相A:1公升水+0.01%甲酸;移動相B:1公升乙腈+0.01%甲酸;梯度:0.0min 10% B→2.5min 95% B→3.5min 95% B;烤箱:50℃;流速:0.90ml/min;UV偵測:210nm/最佳整合途徑210-300nm。
方法13:(LC-MS):
MS儀器:Waters(Micromass)Quattro Micro;儀器:Waters UPLC Acquity;管柱:Waters BEH C18 1.7μ 50 x 2.1mm;移動相A:1公升水+0.01mol甲酸銨,移動相B:1公升乙腈;梯度:0.0min 95% A→0.1min 95% A→2.0min 15% A→2.5min 15% A→2.51min 10% A→3.0min 10% A;烤箱:40℃;流速:0.5ml/min;UV偵測:210nm。
方法14:(LC-MS)(MCW-LTQ-POROSHELL-TFA98-10min)
MS儀器型式:ThermoFisherScientific LTQ-Orbitrap-XL;HPLC儀器型式:Agilent 1200SL;管柱:Agilent,POROSHELL 120,3 x 150mm,SB-C18 2.7μm;移動相A:1公升水+0.1%三氟乙酸;移動相B:1公升乙腈+0.1%三氟乙酸;梯度:0.0min 2% B→0.3min 2% B→5.0min 95% B→10.0min 95% B;烤箱:40℃;流速:0.75ml/min;UV偵測:210nm
本說明書之後的所有反應物或試劑製備未詳盡說明者係購自一般可獲得的來源。所有其他以相似方式製備且無法購得或從非一般可獲得來源得到的反應物或試劑則未在本說明書之後作說明,請參考其中有該物質製備方法的出版文獻。
起始化合物與中間體:
中間體C52
(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙烷-1-胺
最初將4-溴-1H-吡咯-2-羧酸甲酯10.00g(49.01mmol)加到100.0ml的DMF中,並添加20.76g(63.72mmol)碳酸銫和9.22g(53.91mmol)苄基溴。反應混合物在室溫下攪拌至隔夜。使反應混合物在水和乙酸乙酯間分布並將水溶液相用乙酸乙酯萃取。把合併的有機相用硫酸鎂乾燥並將溶劑減壓蒸發。用4-溴-1H-吡咯-2-羧酸甲酯90.0g重複進行該實驗。
將兩個合併的實驗以製備用的RP-HPLC(管柱:Daiso 300x100;10μ,流速:250ml/min,MeCN/water)純化。將溶劑減壓蒸發掉並將殘留物在高真空下乾燥。這樣產生化合物1-苄基-4-溴-1H-吡咯-2-羧酸甲酯125.15g(87%理論值產率).
LC-MS(方法1):Rt=1.18min;MS(ESIpos):m/z=295[M+H]+.
在氬氣下,一開始將1-苄基-4-溴-1H-吡咯-2-羧酸甲酯4.80g(16.32mmol)加到DMF,並添加(2,5-二氟苯基)硼酸3.61g(22.85mmol)、飽和碳酸鈉溶液19.20ml和[1,1'-雙(二苯膦基)二茂鐵]-二氯鈀(II)1.33g(1.63mmol):二氯甲烷。將反應混合物在85℃攪拌至隔夜。反應混合物經矽藻土過濾並用乙酸乙酯沖洗濾餅。用水對有機相進行萃取,然後用飽和NaCl溶液沖洗。用硫酸鎂使有機相乾燥並將溶劑減壓蒸發。殘留物在矽膠上純化(移動相:環己烷/乙酸乙酯100:3)。將溶劑減壓蒸發掉並將殘留物在高真空下乾燥。
如此產生1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-羧酸甲酯3.60g(67%理論值產率)。
LC-MS(方法7):Rt=1.59min;MS(ESIpos):m/z=328[M+H]+.
一開始將1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-羧酸甲酯3.60g(11.00mmol)加入THF 90.0ml中並在0℃添加1.04g(27.50mmol)氫化鋁鋰(2.4M在THF)。在0℃攪拌反應混合物30分鐘。在0℃添加飽和的酒石酸鈉鉀溶液並將反應混合物與乙酸乙酯混合。用飽和的酒石酸鈉鉀溶液對有機相進行萃取三次。用飽和NaCl溶液沖洗有機相一次並以硫酸鎂乾燥。將溶劑減壓蒸發並將殘留物溶解於二氯甲烷30.0ml中。添加氧化錳(IV)3.38g(32.99mmol),並將混合物在RT攪拌48h。添加另外的2.20g(21.47mmol),並將混合物在RT攪拌至隔夜。用矽藻土過濾反應混合物並將濾餅以二氯甲烷沖洗。將溶劑減壓蒸發並且不做進一步純化即使用殘留物(1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲醛)2.80g在下一合成步驟。
LC-MS(方法7):Rt=1.48min;MS(ESIpos):m/z=298[M+H]+.
最初將1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲醛28.21g(94.88mmol)和(R)-2-甲基丙烷-2-亞磺醯胺23.00g(189.77mmol)一起充入無水THF403.0ml中,並添加異丙氧基鈦(IV)並將混合物在RT攪拌至隔夜。添加飽和NaCl溶液500ml和乙酸乙酯1000.0ml,將混合物在RT攪拌1h。用矽藻土過濾混合物並將濾液用飽和NaCl溶液沖洗兩次。有機相用硫酸鎂乾燥,將溶劑減壓蒸發並用Biotage Isolera(矽膠,管柱1500+340g SNAP,流速200ml/min,乙酸乙酯/環己烷1:10)純化殘留物。
LC-MS(方法7):Rt=1.63min;MS(ESIpos):m/z=401[M+H]+.
最初在氬氣下將(R)-N-{(E/Z)-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]甲基ene}-2-甲基丙烷-2-亞磺醯胺25.00g(62.42mmol)充入無水THF中並將其冷卻至-78℃。然後在-78℃添加第三丁基鋰12.00g(187.27mmol)(1.7M
溶液在戊烷中)並將混合物在此溫度攪拌3h。然後在-78℃,連續添加甲醇71.4ml和飽和氯化銨溶液214.3ml並容許反應混合物回溫至RT,且在RT攪拌1h。將混合物用乙酸乙酯稀釋並且用水沖洗。以硫酸鎂使有機相乾燥並將溶劑減壓蒸發。未進一步純化即在下一合成步驟中使用殘留物(R)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-甲基丙烷-2-亞磺醯胺。
LC-MS(方法6):Rt=2.97min;MS(ESIpos):m/z=459[M+H]+.
最初將(R)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-甲基丙烷-2-亞磺醯胺28.00g(61.05mmol)充入1,4-環氧己烷186.7ml中然後添加HCl在1,4-環氧己烷的溶液45.8ml(4.0M)。將反應混合物在RT攪拌2h並將溶劑減壓蒸發。以製備用的HPLC(管柱:Kinetix 100x30;流速:60ml/min,MeCN/water)純化殘留物。將乙腈減壓蒸發並添加二氯甲烷到水溶液殘留物。用碳酸氫鈉溶液沖洗有機相並且用硫酸鎂乾燥。將溶劑減壓蒸發並使殘留物在高真空下乾燥。如此產生標題化合物16.2g(75%理論值產率)。
LC-MS(方法6):Rt=2.10min;MS(ESIpos):m/z=338[M-NH2]+,709[2M+H]+.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.87(s,9H),1.53(s,2H),3.59(s,1H),5.24(d,2H),6.56(s,1H),6.94(m,1H),7.10(d,2H),7.20(m,1H),7.26(m,2H),7.34(m,2H),7.46(m,1H)。
中間體C58
(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-2-({[2-(三甲基矽基)乙氧基]羰基}胺基)丁酸
將4.3g中間體C52(12.2mmol)溶解在DCM525ml中,並且添加三乙醯氧基硼氫化鈉3.63g(17.12mmol)和乙酸8.4ml。在RT下攪拌約5min後,添加8.99g中間體L57(24.5mmol)溶解在DCM 175ml的溶液並將反應在RT再攪拌45min。然後用DCM 300ml將反應稀釋並且用100ml碳酸氫鈉溶液沖洗兩次並且用飽和NaCl溶液沖洗一次。用硫酸鎂使有機相乾燥,將溶劑減壓蒸發並使殘留物在高真空下乾燥。然後用製備用的RP-HPLC(管柱:Chromatorex C18)純化殘留物。將適當的部分收集物合併之後,將溶劑減壓蒸發並使殘留物在高真空下乾燥。如此產生(2S)-4-({(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}胺基)-2-({[2-(三甲基矽基)乙氧基]羰基}胺基)丁酸甲酯4.6g(61%理論值產率)。
LC-MS(方法12):Rt=1.97min;MS(ESIpos):m/z=614(M+H)+.
最初將此中間體2.06g(3.36mmol)充入DCM 76ml中並且用2-氯-2-酮基乙酸乙酯0.81ml(7.17mmol)於三乙胺2.1ml存在下乙醯化。在RT攪拌20h之後,添加2-氯-2-酮基乙酸乙酯0.36ml和三乙胺0.94ml並將反應在RT再攪拌15min。然後用乙酸乙酯500ml稀釋混合物並且連續用5%檸檬酸300ml萃取兩次、用飽和碳酸氫鈉300ml萃取兩次和用飽和氯化鈉溶液100ml萃取一次、然後用硫酸鎂乾燥並予濃縮。在高真空下乾燥產生
經保護的中間體2.17g(79%理論值產率)。
LC-MS(方法1):Rt=1.48min;MS(ESIpos):m/z=714(M+H)+.
將此中間體2.17mg(2.64mmol)溶解在THF 54ml和水27ml中,並添加2M氫氧化鋰溶液26ml。將混合物在RT下攪拌30min然後用1.4ml TFA將pH調整到3和4之間。將混合物減壓濃縮。一旦大部分THF已被蒸餾掉,用DCM對水溶液萃取兩次,然後減壓濃縮至乾。將殘留物用製備用的HPLC(管柱:Chromatorex C18)純化。將適當的部分收集物合併,將溶劑減壓蒸發掉並將殘留物從乙腈/水中冷凍乾燥。如此產生標題化合物1.1g(63%理論值產率)。
LC-MS(方法1):Rt=1.34min;MS(ESIpos):m/z=656(M-H)-.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.03(s,9H),0.58(m,1H),0.74-0.92(m,11H),1.40(m,1H),3.3(m,2H),3.7(m,1H),3.8-4.0(m,2H),4.15(q,2H),4.9 and 5.2(2d,2H),5.61(s,1H),6.94(m,2H),7.13-7.38(m,7H),7.48(s,1H),7.60(m,1H),12.35(s,1H)。
中間體C61
N-[(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-2-({[2-(三甲基矽基)乙氧基]羰基}胺基)丁醯基]-β-丙胺酸
標題化合物係藉著將中間體60mg C58(0.091mmol)與ß-丙胺酸甲酯結合,接著用2M氫氧化鋰水溶液切斷酯。如此經兩步驟產生標題化合物67mg(61%理論值產率)。
LC-MS(方法1):Rt=1.29min;MS(ESIpos):m/z=729(M+H)+.
中間體C102
(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-2-{[(苄氧基)羰基]胺基}丁酸
首先,以相似於中間體C2的方式將中間體C52用(2S)-2-{[(苄氧基)羰基]胺基}-4-酮基丁酸苄酯還原性的烷基化。然後用2-氯-2-酮基乙酸乙酯將二級胺基醯化,然後用2M氫氧化鋰水溶液溶於甲醇將兩個酯基水解。
LC-MS(方法1):Rt=1.31min;MS(ESIpos):m/z=646(M-H)-.
中間體C110(D)
N-{(2S)-2-胺基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]丁醯基}-β-丙胺醯基-D-麩胺酸二苄酯
標題化合物是藉著將D-麩胺酸二苄酯與中間體C61在HATU和N,N-二異丙基乙胺存在下結合,並且緊接著利用氯化鋅在三氟乙醇中使其與Teoc保護基分離;D-麩胺酸二苄酯事先就已在乙酸乙酯和5%碳酸氫鈉水溶液之間分佈從其對-甲基苯磺酸鹽釋出。
LC-MS(方法1):Rt=1.08min;MS(ESIpos):m/z=894[M+H]+.
中間體C111
N-{(2S)-2-胺基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]丁醯基}-β-丙胺醯基-D-麩胺酸二-第三丁酯
首先,用傳統胜肽化學的方法藉著在HATU存在下結合市售的N-[(苄氧基)羰基]-β-丙胺酸和D-麩胺酸二-第三丁酯鹽酸鹽(1:1),並緊接著以氫解方式使Z保護基分開,製備出二肽衍生物β-丙胺醯基-D-麩胺酸二-第三丁酯。然後將此中間體與中間體C102在HATU和N,N-二異丙基乙胺結合,緊接著用10%活性碳鈀在DCM-甲醇1:1中,於標準氫氣壓力和在室溫下氫化一小時將Z保護基移除掉製備標題化合物。
LC-MS(方法1):Rt=1.06min;MS(ESIpos):m/z=826[M+H]+.
中間體C117
N-{(2S)-2-(L-天冬醯胺基胺基)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]丁醯基}-β-丙胺醯基-D-麩胺酸三氟乙酸二苄酯
將中間體C110D和2,5-二酮基吡咯啶-1-基-N2-(第三丁氧基羰基)-L-天冬醯胺酸(251mg,764μmol)溶解在DMF 21ml中並添加N,N-二異丙基乙胺(363μl,2.01mmol)。將反應在RT下攪拌然後直接以製備用RP-HPLC(管柱:Chromatorex C18-10)純化。將溶劑減壓蒸發並將殘留物冷凍乾燥。
然後將所得到的中間體(578mg,52μmol)溶解在三氟乙醇20.0ml中。將反應混合物與氯化鋅(426mg,3.13mmol)混合並在50℃攪拌40min。將該混合物與乙二胺-N,N,N',N'-四乙酸(914mg,3.13mmol)混合並且用水20ml稀釋,添加TFA(200μl)並將混合物短暫地攪拌。然後過濾混合物並且以製備用TP-HPLC(管柱:Chromatorex C18-5;125x40,流速:100ml/min,MeCN/水,0.1% TFA梯度)純化。以冷凍乾燥法產生標題化合物。
中間體L57
(2S)-4-酮基-2-({[2-(三甲基矽基)乙氧基]羰基}胺基)丁酸甲酯
最初將L-天冬醯胺酸甲酯鹽酸鹽500.0mg(2.72mmol)與2,5-二酮基吡咯啶-1-羧酸2-(三甲基矽基)乙酯充入1,4-環氧己烷5.0ml中,並添加三乙胺826.8mg(8.17mmol)。將反應混合物在RT攪拌至隔夜。直接以製備用RP-HPLC(管柱:Reprosil 250x40;10μ,流速50ml/min,MeCN/water,0.1% TFA)純化反應混合物。然後將溶劑減壓蒸發並將殘留物以高真空乾燥。如此產生化合物(3S)-4-甲氧基-4-酮基-3-({[2-(三甲基矽基)乙氧基]羰基}胺基)丁酸583.9mg(74%理論值產率)。
LC-MS(方法1):Rt=0.89min;MS(ESIneg):m/z=290(M-H)-.
最初(3S)-4-甲氧基-4-酮基-3-({[2-(三甲基矽基)乙氧基]羰基}胺基)丁酸592.9mg充入1,2-二甲氧基乙烷10.0ml,將混合物冷卻至-15℃並添加4-甲基嗎啉205.8mg(2.04mmol)和氯甲酸異丁酯277.9mg(2.04mmol)。15min後將沉澱物用抽吸法濾出,並且在每一情形中以1,2-二甲氧基乙烷10.0ml處理二次。將濾液冷卻至-10℃,並添加溶解於水10ml的硼氫化鈉115.5mg(3.05mmol)並劇烈攪拌。把兩相分開並將有機相用飽和碳酸氫鈉溶液和飽和NaCl溶液各沖洗一次。用硫酸鎂使有機相乾燥,將溶劑減壓蒸發並使殘留物在高真空下乾燥。如此產生化合物N-{[2-(三甲基矽基)乙氧基]羰基}-L-同絲胺酸甲酯515.9mg(91%理論值產率)。
LC-MS(方法1):Rt=0.87min;MS(ESIpos):m/z=278(M+H)+.
最初將N-{[2-(三甲基矽基)乙氧基]羰基}-L-同絲胺酸甲酯554.9mg(2.00mmol)充入二氯甲烷30.0ml中,並添加戴斯-馬丁過碘化物(Dess-Martin periodinane)1.27g(3.0mmol)和吡啶474.7mg(6.00mmol)。將混合物在RT攪拌至隔夜。4小時之後,將反應用二氯甲烷稀釋並在每一案例中將有機相用10%濃度的Na2S2O3溶液、10%濃度的檸檬酸溶液和飽和的碳酸氫鈉溶液沖洗三次。用硫酸鎂使有機相乾燥並將溶劑減壓蒸發。如此產生標題化合物565.7mg(97%理論值產率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.03(s,9H),0.91(m,2H),2.70-2.79(m,1H),2.88(dd,1H),3.63(s,3H),4.04(m,2H),4.55(m,1H),7.54(d,1H),9.60(t,1H)。
中間體L95
N-[(苄氧基)羰基]-L-纈胺醯基-L-丙胺酸
藉由胜肽化學之傳統方法從N-[(苄氧基)羰基]-L-纈胺酸和L-丙胺酸第三丁酯鹽酸鹽開始製備此中間體。
LC-MS(方法12):Rt=1.34min;MS(ESIpos):m/z=323.16(M+H)+.
中間體L103
N-(吡啶-4-基乙醯基)-L-丙胺醯基-L-丙胺醯基-L-天冬醯胺三氟乙酸酯
用胜肽化學的傳統方法將4-吡啶乙酸與市售的L-丙胺醯基-L-丙胺酸第三丁酯於HATU和N,N-二異丙基乙胺存在下結合,接著用三氟乙酸脫除保護基,與天冬醯胺酸第三丁酯結合並緊接著用三氟乙酸脫除羧酸基團以製
備標題化合物。
LC-MS(方法1):Rt=0.15min;MS(ESIpos):m/z=394(M+H)+.
中間體L116
N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺酸
用胜肽化學的傳統方法將市售的N-[(苄氧基)羰基]-L-丙胺酸於HATU存在下與N-甲基-L-丙胺酸第三丁酯的鹽酸鹽結合,且最終用TFA移除第三丁酯保護基以製備標題化合物。
LC-MS(方法1):Rt=0.68min;MS(ESIpos):m/z=309[M+H]+
中間體L117
N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺醯基-L-天冬醯胺三氟乙酸鹽
用胜肽化學的傳統方法將市售的4-天冬醯胺酸第三丁酯於HATU存在下與N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺酸(中間體L116)結合,且最終用TFA移除第三丁酯保護基以製備標題化合物。
LC-MS(方法1):Rt=0.57min;MS(ESIneg):m/z=421[M-H]-
中間體L118
N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺醯基-L-丙胺酸
用胜肽化學的傳統方法將市售的L-丙胺酸第三丁酯鹽酸鹽於HATU存在下與N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺酸(中間體L116)偶合,且最終用TFA移除第三丁酯保護基以製備標題化合物。
LC-MS(方法12):Rt=1.25min;MS(ESIneg):m/z=378[M-H]-
中間體L121
N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺醯基-L-白胺酸
用胜肽化學的傳統方法將市售的L-白胺酸第三丁酯鹽酸鹽於HATU存在下與N-[(苄氧基)羰基]-L-丙胺醯基-N-甲基-L-丙胺酸(中間體L116)結合,且最終用TFA移除第三丁酯保護基以製備標題化合物。
LC-MS(方法12):Rt=0.83min;MS(ESIneg):m/z=420[M-H]-
中間體L122
(5S,8S,11S)-11-(2-胺基-2-酮基乙基)-8-[2-(苄氧基)-2-酮基乙基]-5-甲基-3,6,9-三酮基-1-苯基-2-氧雜-4,7,10-三氮雜十二烷-12-酸
用胜肽化學的傳統方法將市售的4-苄基-1-第三丁基-L-天冬胺酸鹽酸鹽(1:1)最初與2,5-二酮基吡咯啶-1-基-N-[(苄氧基)羰基]-L-丙胺酸結合,然後用TFA移除第三丁酯保護基,然後緊接著與4-天冬醯胺酸第三丁酯在HATU存在下結合且最終用TFA再次移除第三丁酯保護基以製備標題化合物。
LC-MS(方法1):Rt=0.76min;MS(ESIpos):m/z=543[M+H]+
中間體L138
1-溴-2-酮基-6,9,12,15-四氧雜-3-氮雜十八烷-18-酸
在N,N-二異丙基乙胺存在下將1-胺基-3,6,9,12-四氧雜十五烷-15-酸與溴乙酸酐結合製備出標題化合物。
LC-MS(方法5):Rt=1.05min;MS(ESIpos):m/z=386 and 388(M+H)+.
中間體Q1
N-[(2,5-二酮基-2,5-二氫-1H-吡咯-1-基)乙醯基]-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-天冬胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L117。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1-{2-[(2,5-二酮基吡咯啶-1-基)氧基]-2-酮基乙基}-1H-吡咯-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法12):Rt=1.66min;MS(ESIneg):m/z=1119[M-H]-.
中間體Q2
N-{5-[(2,5-二酮基吡咯啶-1-基)氧基]-5-酮基戊醯基}-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-天冬胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L117。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=0.93min;MS(ESIpos):m/z=1195[M+H]+.
中間體Q3
N-{5-[(2,5-二酮基吡咯啶-1-基)氧基]-5-酮基戊醯基}-L-丙胺醯基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺
基]-1-酮基丁-2-基}-L-天冬胺醯胺
首先藉著在HATU和N,N-二異丙基乙胺存在下結合至N-(第三丁氧基羰基)-L-丙胺醯基-L-丙胺酸從化合物C117製備標題化合物。然後把中間體溶於三氟乙醇並且藉著在50℃氯化鋅存在下攪拌使受到第三丁氧基羰基保護的胺釋出。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有苄基保護基移除掉,然後藉著與1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮在N,N-二異丙基乙胺存在下反應轉變成標題化合物。
LC-MS(方法1):Rt=0.90min;MS(ESIneg):m/z=1181[M-H]-.
中間體Q4
N-[(2,5-二酮基-2,5-二氫-1H-吡咯-1-基)己醯基]-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-天冬胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L117。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1-{6-[(2,5-二酮基吡咯啶-1-基)氧基]-6-酮基己基}-1H-吡咯-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=3.2min;MS(ESIpos):m/z=1177[M+H]+.
中間體Q5
N-{5-[(2,5-二酮基吡咯啶-1-基)氧基]-5-酮基戊醯基}-L-丙胺醯基-N-甲基-L-丙胺醯基-N-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-丙胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L118。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=0.96min;MS(ESIpos):m/z=1152[M+H]+.
中間體Q6
N-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-2-[(N-{5-[(2,5-二酮基吡咯啶-1-基)氧基]-5-酮基戊醯基}-L-纈胺醯基-L-丙胺醯基)胺基]丁醯基}-β-丙胺醯基-D-麩胺酸
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L95。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
中間體Q7
N-[(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-2-({N-[(2,5-二酮基-2,5-二氫-1H-吡咯-1-基)乙醯基]-L-纈胺醯基-L-丙胺醯基}胺基)丁醯基]-β-丙胺醯基-D-麩胺酸
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L95。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1-{2-[(2,5-二酮基吡咯啶-1-基)氧基]-2-酮基乙基}-1H-吡咯-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=0.98min;MS(ESIpos):m/z=1021[M+H]+.
中間體Q8
N-{5-[(2,5-二酮基吡咯啶-1-基)氧基]-5-酮基戊醯基}-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-白胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L121。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=1.02min;MS(ESIpos):m/z=1194[M+H]+.
中間體Q9
N-{5-[(2,5-二酮基吡咯啶-1-基)氧基]-5-酮基戊醯基}-L-丙胺醯基-N-甲基-L-α-天冬胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-天冬胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L122。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與3當量1,1'-[(1,5-二酮基戊烷-1,5-二基)雙(氧基)]二吡咯啶-2,5-二酮在N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=0.89min;MS(ESIpos):m/z=1225[M+H]+.
中間體Q10
N-(溴乙醯基)-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-天冬胺醯胺
從化合物C110D開始製備標題化合物,首先在HATU和N,N-二異丙基乙胺存在下結合至中間體L117。在下一步驟中,用10%活性碳鈀在DCM-甲醇1:1中於標準氫氣壓力在室溫下氫化一小時將所有保護基移除掉,然後藉著與溴乙酸酐在3當量N,N-二異丙基乙胺存在下反應將脫除保護的中間體轉換成標題化合物。
LC-MS(方法1):Rt=0.95min;MS(ESIpos):m/z=1104 and 1106[M+H]+.
中間體Q11
N-(18-溴-17-酮基-4,7,10,13-四氧雜-16-氮雜十八烷-1-oyl)-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-{(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-[(3-{[(1R)-1,3-二羧基丙基]胺基}-3-酮基丙基)胺基]-1-酮基丁-2-基}-L-天冬胺醯胺
標題化合物的合成是藉著最初將中間體C111與中間體L117在DMF中於1.5當量的HATU和3當量的N,N-二異丙基乙胺存在下結合來實行的。緊接著用10%活性碳鈀在乙醇中於標準氫氣壓力在室溫下氫化2小時將Z保護基移除掉。然後將該脫除保護的中間體與中間體L138在DMF中於1.5當量的HATU和3當量的N,N-二異丙基乙胺存在下反應。在最後一步驟中,藉著在50℃下與8當量氯化鋅於三氟乙醇中切下第三丁基酯基以產生標題化合物。
LC-MS(方法8):Rt=4.06min;MS(ESI-pos):m/z=1353[M+H]+.
B:抗體-藥劑結合物(ADC)之製備
B1.產生抗體之一般方法
藉由熟習本技藝者已知的方法將所使用抗體的蛋白質序列(胺基酸序列),例如:TPP-981、TPP-1015、TPP-6013、TPP-7006、TPP-7007、TPP-8382、TPP-8987、TPP-8988、TPP-9476、TPP-9574和TPP-9580轉型成編碼對應蛋白質的DNA序列,並將其插入表現適用於短暫哺乳動物細胞表培養的載體中(說明如Tom et al.,Chapter 12 in Methods Express:Expression Systems,edited by Michael R.Dyson and Yves Durocher,Scion Publishing Ltd,2007)。
B-2.在哺乳動物細胞內表現抗體的一般方法
於短暫哺乳動物細胞表培養中生產出例如:TPP-981、TPP-1015、TPP-6013、TPP-7006、TPP-7007、TPP-8382、TPP-8987、TPP-8988、TPP-9476、TPP-9574和TPP-9580之抗體,如Tom et al.,Chapter 12 in Methods Express:Expression Systems,edited by Michael R.Dyson and Yves Durocher,Scion Publishing Ltd,2007說明之方法。
B-3.從細胞懸浮物中純化抗體的一般方法
從細胞培養懸浮物中獲得例如:TPP-981、TPP-1015、TPP-6013、TPP-7006、TPP-7007、TPP-8382、TPP-8987、TPP-8988、TPP-9476、TPP-9574和TPP-9580之抗體。用細胞離心法使細胞懸浮物澄清。然後在一MabSelect Sure(GE Healthcare公司出品)層析管柱上用親和力層析法純化細胞懸浮物。為此目的,將管柱在DPBS pH 7.4(Sigma/Aldrich公司出品)中平衡,施加細胞懸浮物並將管柱用大約10根管柱體積的DPBS pH 7.4+500mM氯化鈉沖洗。該抗體係以50mM乙酸鈉pH 3.5+500mM氯化鈉溶離,然後進一步用膠體過濾層析法在Superdex 200管柱(GE Healthcare公司出品)上以DPBS pH 7.4進行純化。
市售抗體係以標準層析法(蛋白質A層析法、製備用膠體過濾層析法(SEC-大小排除層析法)從市售產品中純化出來。
B-4.用於結合至半胱胺酸測鏈的一般方法
以下抗體被用於結合反應:
實例a:TPP-981爾必得舒(抗-EGFR AK)
實例c:TPP-6013(抗-CD123 AK)TPP-8987(抗-CD123 AK)TPP-8988(抗-CD123 AK)TPP-9476(抗-CD123 AK)
實例h:TPP-8382(抗-B7H3 AK)
實例e:TPP-1015(抗-Her2 AK)
實例k:TPP-7006(抗-TWEAKR AK)TPP-7007(抗-TWEAKR AK)
實例x:TPP-9574(抗-CXCR5 AK)TPP-9580(抗-CXCR5 AK)
該偶結合反應通常是在氬氣下實行。
將介於2和5當量之間溶解於PBS緩衝液的參(2-羧乙基)膦鹽酸鹽(TCEP)添加到適當抗體溶於PBS緩衝液的溶液中,濃度範圍介在1mg/ml和20mg/ml之間,較好是在大約10mg/ml到15mg/ml的範圍,且在室溫下將混合物攪拌1h。為此目的,以可行實例中陳述的濃度採用被使用之個別抗體溶液,或其亦可視需要以PBS緩衝液稀釋到所述起始濃度的大約一半以求得到較佳的濃度範圍。緊接著,視所意圖的裝載量而定,將2到12當量、較好大約5-10當量待結合的順丁烯二醯亞胺前驅化合物或鹵化物前驅化合物以DMSO溶液添加。在本說明書中,DMSO的量不應超過總體積的10%。在順丁烯二醯亞胺前驅體的情形中,將混合物在RT下攪拌60-240min,且在鹵化物前驅體的情形中在RT下攪拌8和24h之間的時數,然後將其裝載到PBS-平衡過的PD 10管柱(Sephadex® G-25,GE Healthcare)上並且以PBS緩衝液溶離。一般而言,除非另有指明,某則將該論及抗體5mg of溶於PBS緩衝液的溶液用於還原並緊接著進行結合。在每一案例中於PD10管柱上純化因而產生個別ADCs溶於3.5ml PBS緩衝液的溶液。然後將樣品以超離心法濃縮並視需要用PBS緩衝液再稀釋。若需要,為使較佳地移除低分子量的成分,用超過濾法重複濃縮。若需要為了進行生物試驗,最終ADC樣品的濃度會視需要以再稀釋調整到0.5-15mg/ml的範圍。測定說明在可行實例中ADC溶液的個別蛋白質濃度。此外,用B-6下方說明的
方法測定抗體裝載量(藥物/mAb的比率)。
視連接體而定,實例中顯示的ADCs亦可以稍低或稍高程度經水解的開鏈琥珀醯胺連接至抗體之形式存在。
尤其以下連接體結構連接至抗體的硫醇基之KSP-I-ADCs
亦可視需要選擇性地藉著在pH 8結合與攪拌大約20-24h來製備,根據流程圖28經開鏈的琥珀醯胺與ADCs連接。
#1代表該硫橋接至抗體,且#2代表連接至經修改的KSP抑制劑之接點。
此種連接體經由水解的開鏈琥珀醯胺連接至抗體的ADCs亦可視需要選擇性地以小規模和大規模的結合反應來製備,本說明書中以實例顯示:將2和7當量的三(2-羧乙基)膦鹽酸鹽(TCEP)間,溶解於PBS緩衝液的溶液添加到適當抗體2-5mg溶於PBS緩衝液濃度介在1mg/ml和20mg/ml之間、較好是介在大約5mg/ml到15mg/ml範圍的溶液中,並將該混合物在RT攪拌30min至1h。緊接著,視所意圖的裝載量而定,以溶於DMSO之溶液形式添加2到20當量,較好是大約5-10當量待結合的順丁烯二醯亞胺前驅體化合物。為達到較高的DARs,亦可使用15-20當量。在本說明書中,DMSO的量應不超出總體積的10%。將該混合物在RT攪拌60-240分鐘。用PBS緩衝液pH 8將析出液稀釋到1-5mg/ml的濃度,然後使其通過一支以PBS緩衝液pH 8平衡過的PD 10管柱(Sephadex® G-25,GE Healthcare),並且用PBS緩衝液pH 8進行溶離。析出液在RT在氬氣下攪拌至隔夜。緊接著將溶液用超離心法濃縮並以PBS緩衝液(pH 7.2)再稀釋。
中型規模的結合作用:
在氬氣下,將2-7當量,較好是3當量TCEP溶於PBS緩衝液的溶液
(c~0.2-0.8mg/ml,較好是0.5mg/ml)添加到所提到抗體20-200mg溶於PBS緩衝液的溶液中(c~5-15mg/ml)。將混合物在RT下攪拌30min,然後添加2-20當量、較好是5-10當量的順丁烯二醯亞胺前驅體化合物溶於DMSO的溶液。未達到較高的DARs,亦可使用15-20當量。在RT下再攪拌1.5h-2h,將混合物用已事先被調整為pH 8的PBS緩衝液稀釋。然後將此溶液施加到以PBS緩衝液(pH8)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 8)進行溶離。將析出液用PBS緩衝液pH 8稀釋到2-7mg/ml的濃度。將此溶液在RT氬氣下攪拌至隔夜。若需要將溶液再緩衝至pH 7.2。用超離心法濃縮該ADC溶液,用PBS緩衝液(pH 7.2)再稀釋,然後視需要再度濃縮成大約10mg/ml。
在所示結構式中,AK1可具以下意義:
實例a:TPP-981爾必得舒(部分還原的)-S§1
實例c:TPP-6013(抗-CD123 AK)(部分還原的)-S§1 TPP-8987(抗-CD123 AK)(部分還原的)-S§1 TPP-8988(抗-CD123 AK)(部分還原的)-S§1 TPP-9476(抗-CD123 AK)(部分還原的)-S§1
實例e:TPP-1015(抗-Her2 AK)(部分還原的)-S§1
實例h:TPP-8382(抗-B7H3 AK)(部分還原的)-S§1
實例k:TPP-7006(抗-TWEAKR)(部分還原的)-S§1 TPP-7007(抗-TWEAKR)(部分還原的)-S§1
實例x:TPP-9574(抗-CXCR5 AK)(部分還原的)-S§1 TPP-9580(抗-CXCR5 AK)(部分還原的)-S§1
其中§1 代表與琥珀醯亞胺基團或與任何異構之經水解開鏈之琥珀醯胺或從其產生之伸烷基的連接
以及S 代表部分還原之抗體的半胱胺酸之硫原子。
B-5.結合至離胺酸側鏈的一般方法
以下抗體被用於結合反應:
實例a:TPP-981爾必得舒(抗-EGFR AK)
實例c:TPP-6013(抗-CD123 AK)TPP-8987(抗-CD123 AK)TPP-8988(抗-CD123 AK)TPP-9476(抗-CD123 AK)
實例e:TPP-1015(抗-Her2 AK)
實例k:TPP-7006(抗-TWEAKR AK)TPP-7007(抗-TWEAKR AK)
實例x:TPP-9574(抗-CXCR5 AK)TPP-9580(抗-CXCR5 AK)
該結合反應通常在氬氣下進行。
將2到8當量待結合前驅體化合物溶於DMSO的溶液添加到濃度介在1mg/ml和20mg/ml之間,較好是大約10mg/ml(視所意圖之裝載量而定)之該論及抗體溶於PBS緩衝液的溶液中。在RT下攪拌30min到6h之後,再次添加同量之前驅體化合物溶於DMSO的溶液。在本說明書中,DMSO的量不應超過總體基之10%。在RT下另外攪拌30min到6h後,將混合物施加到以PBS平衡過的PD 10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液溶離。PD10管柱上純化而在每一案例中產生對應之ADCs溶於PBS緩衝液的溶液。然後將樣品用超離心法濃縮並視需要用PBS緩衝液再稀釋。若需要,為了較佳地移除掉低分子量的成分故在以PBS
緩衝液再稀釋後用超離心予以濃縮。若需要為了進行生物試驗,視需要將最終的ADC樣品濃度以再稀釋調整到0.5-15mg/ml的範圍。
測定可行實例中所敘述的個別蛋白質之ADC溶液濃度此外,用B-6說明的方法測定抗體裝載量(藥物/mAb的比率)。
在所示的結構式中,AK2具有以下意義:
實例a:TPP-981爾必得舒(抗-EGFR AK)-NH§2
實例c:TPP-6013(抗-CD123 AK)-NH§2 TPP-8987(抗-CD123 AK)-NH§2 TPP-8988(抗-CD123 AK)-NH§2 TPP-9476(抗-CD123 AK)-NH§2
實例e:TPP-1015(抗-Her2 AK)-NH§2
實例k:TPP-7006(抗-TWEAKR AK)-NH§2 TPP-7007(抗-TWEAKR AK)-NH§2
實例x:TPP-9574(抗-CXCR5 AK)-NH§2TPP-9580(抗-CXCR5 AK)-NH§2
其中§2 代表與羰基的連接且NH代表抗體之離胺酸殘基的胺基側鏈。
進一步純化和鑑認根據本發明的結合物特徵
反應之後,在某些實例中反應混合物被濃縮,例如:藉由超過濾,然後去鹽和以層析法純化,例如:利用Sephadex® G-25管柱。進行溶離,例如用磷酸鹽緩衝的鹽液(PBS)。然後將溶液殺菌過濾並冷凍。或者,結合物可經冷凍乾燥。
B-6.抗體的測定,毒簇裝載量與開放的半胱胺酸加合物之比率
為了鑑認蛋白質,除了在糖基化和/或變性後測定分子量之外,進行胰蛋白酶的消化作用,在變性、還原和衍生反應後經由胰蛋白酶處理發現的胜肽確認蛋白質的身份。
說明在可行實例中之結合物所得溶於PBS緩衝液的毒簇裝載(在表中稱之為DAR,藥物對抗體的比率)之測定如下:測定離胺酸-連接的ADCs之毒簇裝載是用質譜法測定個別結合物種的分子量。在本說明書中,首先用PNGaseF將抗體結合物去糖基化,並將樣品酸化且在HPLC之後分離/去鹽,利用ESI-MicroTofQ(Bruker Daltonik公司出品)以質譜法進行分析。將TIC(全離子層析圖譜)中所有圖譜信號加起來,並根據MaxEnt去迴旋法計算不同結合物種的分子量。然後再將不同物種的信號積分之後計算出DAR(=藥物/抗體比率)。為此目的,將所有物種以毒簇記數加權積分之結果總和除以所有物種簡單加權積分之結果總和。
藉著對還原和變性的ADCs進行逆相層析法以測定半胱胺酸連接的的結合物之毒簇裝載。添加鹽酸胍(GuHCl)(28.6mg)和DL-二硫蘇糖醇(DTT)(500mM,3μl)溶液到ADC溶液(1mg/ml,50μl)。將混合物在55℃下培育1小時並以HPLC分析。
HPLC分析是在一Agilent 1260 HPLC系統以進行的,在220nm波長下進行偵測。使用一支Polymer Laboratories公司出品的PLRP-S聚合物逆相管柱(目錄編號為PL1912-3802)(2.1 x150mm,8μm顆粒大小,1000Å),流速為1ml/min而以下述梯度:0min,25%B;3min,25%B;28min,50%B進行層析。溶離劑A包含0.05%三氟乙酸(TFA)水溶液。溶離劑B為0.05%三氟乙酸容溶於乙腈。
藉著與非軛合的抗體之輕鏈(L0)和重鏈(H0)比較以滯留時間派定所偵測到的尖峰。專門只在軛合樣品中偵測到的尖峰被派定為具有一個毒簇(L1)的
輕鏈且其重鏈具有一、二和三個毒簇(H1,H2,H3)者。
具毒簇之抗體的平均裝載量(稱為DAR,藥物對抗體的比率)是從積分測定之尖峰面積計算出來的,其為HC裝載量和LC裝載量總和的雙倍,其中LC裝載量是從所有LC毒簇尖峰之數目平均加權積分結果的總和,除以所有LC毒簇尖峰單獨加權積分結果的總和計算出來,且HC裝載量是從所有HC毒簇尖峰之數目平均加權積分結果的總和,除以所有HC毒簇尖峰單獨加權積分結果的總和計算出來。在個別情形中,有可能因為某些尖峰是被共同溶離出來的,所以不可能準確地測出毒簇裝載量。
在輕鏈和重鏈無法用HPLC充分分離的情形中,與半胱胺酸連接的結合物之毒簇裝載測定是以質譜法測定輕鏈和重鏈之個別結合物種的分子量來測定的。
為此目的,將鹽酸胍(GuHCl)(28.6mg)和DL-二硫蘇糖醇(DTT)(500mM,3μl)溶液添加到ADC溶液。將混合物在55℃培育一小時並使用ESI-MicroTofQ(Bruker Daltonik公司出品)於線上脫鹽後以質譜法進行分析。
為了測定DAR(藥物對抗體比率),將TIC(全離子層析圖譜)中所有圖譜信號相加起來,並根據MaxEnt去迴旋法計算輕鏈和重鏈之不同結合物種的分子量。具毒簇之抗體的平均裝載量(稱為DAR,藥物對抗體的比率)是從積分測定之尖峰面積計算出來的,其為HC裝載量和LC裝載量總和的雙倍。在本發明內容中,LC裝載量是從所有以毒簇記數加權之LC尖峰積分結果的總和,除以所有LC尖峰簡單加權積分結果的總和計算出來,且HC裝載量是從所有以毒簇記數加權之HC尖峰積分結果的總和,除以所有HC尖峰簡單加權積分結果的總和計算出來。
在開放的建構體之情形中,為了測定開放之半胱胺酸加合物的比例,測定所有單獨軛合的輕鏈和重鏈變異體之閉鎖相對於開放之半胱胺酸加合物(分子量δ=18道爾吞)的分子量面積。所有變異體的平均值能產生開放半胱
胺酸加合物的比例。
B-7.證實抗原與ADCs之結合
結合劑結合至標靶分子的能力是在結合已發生之後檢查。熟習本技藝者孰悉各種可用於此目的方法;例如結合物的親和力可利用’ELISA技術或表面電漿子共振分析(BIAcoreTM measurement)檢查。結合物的濃度可藉熟習本技藝者利用傳統方法,例如對於抗體結合物使用蛋白質測定法(亦請參考Doronina et al.;Nature Biotechnol.2003;21:778-784 and Polson et al.,Blood 2007;1102:616-623)來測定。
代謝物之可行實例
實例M1
N-{(2S)-2-胺基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]丁醯基}-β-丙胺醯基-D-麩胺酸
在RT於標準壓力下於乙醇中以10%活性碳鈀進行一小時氫化而將中間體C110D轉變為標題化合物。
LC-MS(方法1):Rt=1.78min;MS(ESIpos):m/z=714[M+H]+.
以下顯示作為範例之ADCs能釋放出較佳的代謝物M1,其具有較佳的藥理學性質。
可行實例之ADCs
可行實例中以結構式顯示之ADCs,藉順丁烯二醯亞胺基被偶結合至抗體的半胱胺酸側鏈者視連接體和結合方法而定,在每一案例中主要以開環或閉環的形式存在。然而,該製備物可能包含少部分對應之其他形式。該結合反應是在氬氣下進行的。所有較大批次的體內試驗均在製備結束後殺菌過濾。
實例1
範例方法A:
在氬氣下,將TCEP 0.029mg溶於PBS緩衝液0.05ml的溶液添加到5mg該論及抗體溶於0.5ml PBS(c=10mg/ml)的溶液中。將混合物在RT下攪拌30min,然後添加溶解於50μl DMSO的中間體Q10.26mg(0.00023mmol)。RT下再攪拌90min之後,將混合物用事先被調整到pH8的PBS緩衝液稀釋成2.5ml體積,然後使其通過用PBS緩衝液pH 8平衡過的PD 10管柱(Sephadex® G-25,GE Healthcare),並且用PBS緩衝液pH 8進行溶離。在RT氬氣下攪拌該析出液至隔夜。接著以超離心濃縮並且用PBS緩衝液(pH 7.2)再稀釋。
範例方法B:
在氬氣下,將TCEP 0.172mg溶於PBS緩衝液0.3ml的溶液添加到30mg該論及抗體溶於3ml PBS(c=10mg/ml)的溶液中。將混合物在RT下攪拌30min,然後添加中間體Q1 1.57mg(0.0014mmol)溶解於DMSO的溶液。RT下再攪拌90min之後,將混合物用事先被調整到pH8的PBS緩衝液稀釋成5ml體積,然後使其通過用PBS緩衝液pH 8平衡過的PD 10管柱(Sephadex® G-25,GE Healthcare),並且用PBS緩衝液pH 8進行溶離。用PBS緩衝液pH 8將析出液稀釋到稀釋至7.5ml體積並在RT氬氣下攪拌至隔夜。然後將此溶液施加到以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 7.2)進行溶離。然後將析出液用超離心濃縮,用PBS緩衝液(pH 7.2)再稀釋並且再濃縮和再殺菌過濾。
實例2
範例方法A:
在氬氣下,將溶解於50μl DMSO之5當量(0.2mg)中間體Q2添加到5mg該論及抗體溶於0.5ml PBS(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。緊接著將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋。
範例方法B:
在氬氣下,將溶解於50μl DMSO之4當量中間體Q2(1mg)添加到30mg該論及抗體溶於3ml PBS緩衝液(pH7.2)(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。然後將反應混合物用PBS緩衝液(pH 7.2)稀釋至5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋,和再濃縮並再次殺菌過濾。
範例方法C:
在氬氣下,將溶解於250μl DMSO之2.5當量中間體Q2(1mg)添加到
50mg該論及抗體溶於5ml PBS緩衝液(pH7.2)(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。然後將反應混合物用PBS緩衝液(pH 7.2)稀釋至7.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋,和再濃縮並再次殺菌過濾。
範例方法D:
在氬氣下,將溶解於7.5ml DMSO之4.5當量中間體Q2(36mg)添加到1000mg該論及抗體溶於150ml PBS緩衝液(pH7.2)(c=6.7mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。然後將此批樣品用交叉流動過濾法純化、濃縮並殺菌過濾。
實例3
範例方法A:
在氬氣下,將溶解於50μl DMSO之5當量中間體Q3(0.2mg)添加到5mg該論及抗體溶於0.5ml PBS(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。緊接著將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋。
範例方法B:
在氬氣下,將溶解於50μl DMSO之4當量中間體Q3(1mg)添加到30mg該論及抗體溶於3ml PBS(c=10mg/ml)緩衝液(pH 7.2)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。然後將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋,和再濃縮並再次殺菌過濾。
實例4
範例方法A:
在氬氣下,將TCEP 0.029mg溶於PBS緩衝液0.05ml的溶液添加到5mg該論及抗體溶於0.4ml PBS緩衝液(pH 7.2)(c=12.5mg/ml)的溶液中。將混合物在RT下攪拌30min,然後添加0.275mg(0.00023mmol)中間體Q4溶於DMSO 50μl的溶液。在RT下攪拌約90min後,用PBS緩衝液將反應稀釋到總體積為2.5ml。然後將此溶液施加到以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 7.2)進行溶離。然後將此溶液施加到以PBS緩衝液(pH 7.2)平衡過
的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 7.2)進行溶離。接著以超離心濃縮並且用PBS緩衝液(pH 7.2)再稀釋。
實例5
範例方法A:
在氬氣下,將溶解於50μl DMSO之5當量中間體Q5(0.2mg)添加到5mg該論及抗體溶於0.5ml PBS(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。緊接著將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋。
實例6
範例方法A:
在氬氣下,將溶解於50μl DMSO之5當量中間體Q6(0.18mg)添加到5mg該論及抗體溶於0.4ml PBS(c=12.5mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。緊接著將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋。
實例7
範例方法A:
在氬氣下,將TCEP 0.029mg溶於PBS緩衝液0.05ml的溶液添加到5mg該論及抗體溶於0.4ml PBS(c=12.5mg/ml)的溶液中。將混合物在RT下攪拌30min,然後添加0.24mg(0.00023mmol)中間體Q7溶解在50μl DMSO的溶液。在RT另外攪拌90min後,將混合物用事先調整為pH 8的PBS緩衝液稀釋至2.5ml體積,然後使其通過以PBS緩衝液pH 8平衡過的PD10管柱(Sephadex® G-25,GE Healthcare)。在RT氬氣下攪拌該析出液至隔夜。接著以超離心濃縮並且用PBS緩衝液(pH 7.2)再稀釋。
實例8
範例方法A:
在氬氣下,將溶解於50μl DMSO之5當量中間體Q8(0.2mg)添加到5mg該論及抗體溶於0.5ml PBS(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。緊接著將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋。
實例9
範例方法A:
在氬氣下,將溶解於50μl DMSO之5當量中間體Q9(0.2mg)添加到5mg該論及抗體溶於0.5ml PBS(c=10mg/ml)的溶液中。在RT攪拌1h之後,再添加同量並將混合物在RT另外攪拌1h。緊接著將反應混合物用PBS緩衝液(pH 7.2)稀釋至2.5ml,以Sephadex管柱純化,然後用超離心法濃縮並且用PBS(pH 7.2)再稀釋。
實例10
範例方法A:
在氬氣下,將TCEP 0.029mg溶於PBS緩衝液0.05ml的溶液添加到5mg該論及抗體溶於0.5ml PBS緩衝液(pH 7.2)(c=10mg/ml)的溶液。將混合物在RT下攪拌30min,然後添加0.295mg(0.00023mmol)中間體Q10溶解於50μl DMSO的溶液。在RT下另外攪拌20h後,用PBS緩衝液將反應稀釋至總體積2.5ml。然後將此溶液施加到以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 7.2)進行溶離。這接著以超離心濃縮並且用PBS緩衝液(pH 7.2)再稀釋。
用於獲得較高DAR之範例方法C:
在氬氣下,將TCEP 0.057mg溶於PBS緩衝液0.05ml的溶液添加到5mg該論及抗體溶於0.5ml PBS(pH 7.2)(c=10mg/ml)的溶液中。將混合物在RT下攪拌30min,然後添加0.59mg(0.00053mmol)中間體Q10溶解在50μl DMSO的溶液。在RT下另外攪拌20h後,用PBS緩衝液將反應稀釋至總體積2.5ml。然後將此溶液施加到以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 7.2)進行溶離。這接著以超離心濃縮並且用PBS緩衝液(pH 7.2)再稀釋。
實例11
範例方法A:
在氬氣下,將TCEP 0.029mg溶於PBS緩衝液0.05ml的溶液添加到5mg該論及抗體溶於0.4ml PBS緩衝液(pH 7.2)(c=12.5mg/ml)的溶液。將混合物在RT下攪拌30min,然後添加0.32mg(0.00023mmol)中間體Q11溶於50μl DMSO的溶液。在RT下另外攪拌20h後,用PBS緩衝液將反應稀釋至總體積2.5ml。然後將此溶液施加到以PBS緩衝液(pH 7.2)平衡過的PD10管柱(Sephadex® G-25,GE Healthcare公司出品)並且用PBS緩衝液(pH 7.2)進行溶離。接著以超離心濃縮並且用PBS緩衝液(pH 7.2)再稀釋。
為了比較的目的,製備以下ADCs:
參考實例R1:
此種ADCs被揭示在WO2015/096982和在WO2016/096610,以各種抗體包括例如:爾必得舒和賀癌平進行。為了比較的目的,此外其中揭示的前驅物中間體F194亦與TPP-6013(抗-CD123 AK)反應。以下ADCs係用於比較的目的:
參考實例R2:
此種揭示於WO2016/096610的ADCs具去糖基化的抗-TWEAKR抗體。為了比較的目的,揭示於其中的前驅物中間體F291另外亦與TPP-9574(抗-CXCR5 AK)、TPP-981(抗-EGFR)和TPP-1015(抗-HER2 AK)反應。以下ADCs係用於比較的目的:
對於參考實例R1,WO2015/096982說明從其衍生的代謝物實例98。對於參考實例R2,WO2016/096610說明完全相同的代謝物實例M9,其在本說明書中以參考實例R3M被列出。
參考實例R3M:
N-(3-胺基丙基)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-羥基乙醯胺
該製備物以實例98說明於WO2015/096982中。
這些揭示在該申請案的參考化合物或被取得以供新穎參考化合物之生物數據說明在章節C中。
C:生物效力的評估
根據本發明化合物的生物活性可顯示在以下說明的檢驗中:
a. C-1a ADCs之細胞毒性效果測定
ADCs之細胞毒性效果分析是以各種細胞株進行的。
NCI-H29:人類的粘液表皮樣肺癌細胞,ATCC-CRL-1848,標準培養基:RPMI 1640(Biochrom;#FG1215,穩定的麩胺醯胺)+10% FCS(Sigma;#F2442),TWEAKR-陽性;EGFR-陽性。
BXPC3:人類的胰臟癌細胞,ATCC-CRL-1687,標準培養基:RPMI 1640(Biochrom;#FG1215,穩定的麩胺醯胺)+10% FCS(Sigma;#F2442),TWEAKR-陽性。
LoVo:人類的結腸直腸癌細胞,ATCC No.CCL-229,培養用於MTT檢驗;標準培養基:凱恩氏(Kaighn's)+L-麩胺醯胺(Invitrogen 21127)+10%熱失活的FCS(購自Gibco,No.10500-064)。培養用於CTG檢驗:RPMI 1640(Biochrom;#FG1215,穩定的麩胺醯胺)+10% FCS(Sigma #F2442)。TWEAKR-陽性。
KPL4:人類的乳癌細胞株,Bayer Pharma AG(於2012年7月19日,在DSMZ進行身分確認及檢查),標準培養基:RPMI 1640購自Gibco;#21875-059,穩定的L-麩胺醯胺)+10%熱失活的FCS(Gibco,No.10500-064);HER2-陽性。
SK-HEP-1:人類的肝癌細胞株,ATCC No.HTB-52,標準培養基:含有爾氏(Earle's)鹽的MEM+Glutamax I(Invitrogen 41090)+10%熱失活的FCS(購自Gibco,No.10500-064);EGFR-陽性,TWEAKR-陽性
MOLM-13:人類的急性單核球白血病細胞(AML-M5a),DSMZ,No.ACC 554,標準培養基:RPMI 1640購自Gibco;#21875-059,穩定的L-麩胺醯胺)+20%熱失活的FCS(Gibco,No.10500-064);CD123-陽性。
MV-4-11:人類雙表現型B骨髓單核球性白血病細胞得自周圍血液者,ATCC-CRL-9591,標準培養基:IMDM(ATCC:30-2005)+10%熱失活的FCS(Gibco,No.10500-064);CD123-陽性。
NB4:人類的急性前骨髓細胞性白血病細胞,得自骨髓,DSMZ,No.ACC 207,標準培養基:RPMI 1640+GlutaMAXI(Invitrogen 61870)+10%熱失活的FCS(Gibco,No.10500-064)+2.5g葡萄糖(20%葡萄糖溶液,Gibco,No.19002)+10mM Hepes(Invitrogen 15630)+1mM丙酮酸鈉(Invitrogen 11360);CD123-陰性
Rec-1:人類的被套細胞淋巴癌細胞(B細胞非何杰金氏淋巴瘤)ATCC CRL-3004,標準培養基:RPMI 1640+GlutaMAXI(Invitrogen 61870)+10%熱失活的FCS(Gibco,No.10500-064)+10mM)CXCR5-陽性
U251:人類的膠質母細胞瘤細胞,標準培養基:RPMI 1640(Biochrom;#FG1215,穩定的麩胺醯胺)+10% FCS(Biochrom;#S0415),B7H3-陽性。
HBL-1:人類的B細胞淋巴癌細胞(擴散大B-細胞淋巴癌)ATT CRL-RRID(創始來源鑑認):CVCL_4213,首先說明在Abe et al.Cancer 61:483-
490(1988),得自Prof.Lenz,Universität Münster;標準培養基:RPMI 1640(Biochrom;#FG1215,穩定的麩胺醯胺)+10% FCS(Biochrom;#S0415),培養相似於Rec-1細胞;CXCR5-陽性
該細胞係以如美國組織培養保存中心(ATCC)或德國微生物與細胞蒐集中心(DSMZ)陳述的標準方法對論及之細胞株進行培養。
CTG檢驗
以標準法培養細胞,使用C-1指明之培養基。該試驗的進行是用胰蛋白酶溶液(0.05%)和EDTA(0.02%)溶於PBS(Biochrom AG #L2143)的溶液使細胞分勘、離心成小塊、再懸浮於培養基、計算和播種到96孔白底培養盤(Costar #3610)(以75μl/每孔,以下每孔的細胞數目為:NCI-H292:2500細胞/每孔、BxPC32500細胞/每孔、LoVo 3000細胞/每孔)並且培育在37℃培養箱和5%二氧化碳中。計算懸浮液細胞並且將其播種於96孔白底培養盤(Costar #3610)(at 75μl/每孔,以下每孔細胞數為Rec-1:3000細胞/每孔、HBL-1:6000細胞/每孔)。24h以後,將在25μl培養基中的抗體藥物結合物(濃縮四倍)添加到細胞以產生最終的抗體藥物結合物,濃度為3 x 10-7M到3 x 10-11M在細胞上(三個複本)。然後將細胞培育在37℃培養箱和5%二氧化碳中。在一平行實驗的盤中,細胞活性在開始藥物處理時(第零日)被測定,係使用細胞滴定生長[Cell Titer Glow,CTG)冷光細胞存活檢驗(Promega #G7573和#G7571)進行。為達此目的,對每批細胞添加100μl基質,然後用鋁箔紙只把盤蓋上,在盤皿震盪器上以180rpm震動2分鐘,將其在實驗室桌上留置8分鐘然後用冷光測量儀(Victor X2,Perkin Elmer公司出品)測量。該基質偵測在產生冷光信號的活細胞中的ATP含量,該信號強度直接正比於細胞的存活力。與抗體藥物結合物培育72h之後,如以上說明使用細胞滴定發光之冷光細胞存活檢驗來測定細胞的存活力。從測量的
數據計算出生長抑制的IC50,利用DRC(Dose Response Curve)分析試算表和四參數擬合法與第零日比較。DRC分析試算表是由拜耳藥品公司和拜耳服務公司在IDBS E-WorkBook套件平台(IDBS:ID Business Solutions Ltd.公司,位在英國Guildford市)研發出的生物書試算表。
MTT檢驗
以標準法培養細胞,使用C-1指明之培養基。該試驗是用溶於PBS的溶液(購自Biochrom AG #L2143)使細胞分開、離心成小塊、再懸浮於培養基、計算和播種到96孔白底培養盤(Costar #3610)(以75μl/每孔,以下每孔的細胞數目為:NCI-H292:2500細胞/每孔、SK-HEP-1:1000細胞/每孔;KPL-4:1200細胞/每孔;總體積為100μl)來實行的。然後將細胞培育在37℃和5%二氧化碳的培育箱中。每48h置換培養基。然後將溶於10μl培養基之濃度從10-5M到10-13M抗體藥物結合物用滴管加到細胞(三個複本),然後將該檢驗培育在37℃和5%二氧化碳的培育箱中。計算懸浮液細胞並將其播種到96孔白底培養盤(得自Costar #3610)(#3610)(MOLM-13:2000細胞/每孔;NB4:7000細胞/每孔;MV-4-11:5000細胞/每孔,總體積為100μl)。在37℃和5%二氧化碳中培育六小時之後,改變培養基並用滴管添加濃度為10-5M to 10-13M之抗體-藥劑結合物或代謝物到90μl細胞(三個複本)中。將該批細胞培育在37℃和5%二氧化碳的培育箱中。96h之後,利用MTT檢驗(ATCC,美國維吉尼亞州Manassas市,型錄編號30-1010K)偵測細胞的增殖。為此目的,將該MTT試劑與細胞培育4h,接著添加清潔劑使細胞溶解至隔夜。在波長570nm偵測所形成的染劑(Infinite M1000 pro,Tecan公司出品)。利用DRC(劑量反應曲線)將所測量的數據用於使用計算生長抑制作用的IC50。未以試驗物質處理但另外以完全相同方式處理的細胞被定義為100%。
以下表1c中列出得自這些檢驗之參考實例的IC50值。
所報告之活性數據係關說明於本發明之實驗部分具所指明的藥物/mAB比率的可行實例。對於不同的藥物/mAB比率,該數值會因不同的藥物/mAB比率而偏離。該IC50值是數個獨立實驗或個別述職的平均值。抗體藥物結合物的作用對包含個別連接體和毒簇的個別同型對照組是具選擇性的。對
於導向對抗CD123的ADCs而言,該標靶專一性另外藉由試驗CD123-陰性細胞來證明。
一般而言,根據本發明的ADCs與對應的參考實例相較顯著展現改良的細胞毒性效力。
C-1b挑選實例對於紡錘體驅動蛋白KSP/Eg5之抑制作用的測定
將人類紡錘體驅動蛋白KSP/Eg5(tebu-bio/Cytoskeleton Inc,No.027EG01-XL)的動力區位培育以10nM濃度與微管(牛或豬的,tebu-bio/Cytoskeleton Inc)一起培育,該微管以50μg/ml紫杉醇(Sigma No.T7191-5MG)在RT於15mM PIPES,pH 6.8(5mM MgCl2和10mM DTT,Sigma)穩定化五分鐘。將新鮮製備的混合物等量分成384 MTP(購自Corning公司)。然後添加濃度為1.0 x 10-6M到1.0 x 10-13M之待檢驗抑制劑和ATP(最終濃度為500μM,Sigma公司)。在RT培育2h。利用孔雀綠(Biomol公司出品)測定無機磷酸鹽形成來測定ATPase的活性。添加試劑之後,將檢驗在RT下培育50min,然後偵測在波長620nm下的吸光值。所使用的陽性對照組是莫納醇[monastrol](Sigma,M8515-1mg)和伊斯賓尼[ispinesib](AdooQ Bioscience A10486)。對劑量活性曲線的個別數據進行八倍測定。IC50值是兩個獨立實驗的平均值。100%對照組是未經抑制劑處理的樣品。
所報告的活性數據係關本發明之實驗部分中說明的可行實例。
C-1c酵素檢驗
a:半胱胺酸蛋白酶[Cathepsin]B的檢驗
對每一待檢驗之可被半胱胺酸蛋白酶[Cathepsin]B切斷的前藥,在一微反應容器中製備其混合物(0.5ml,得自Eppendorf公司)。本說明書中所使用的酵素係得自人類的肝組織。起初添加2μg半胱胺酸蛋白酶[Cathepsin]B(Sigma C8571 25μg)並以50mM磷酸鈉緩衝液,pH6.0,2mM DTT將總體積加到200μl。然後用滴管添加50μl待檢驗的基質溶液。將混合物培育在一加熱模塊(購自Thermo Fisher Scientific公司)於40℃,300rpm下固定攪拌。以動力學方式控制酵素反應。為此目的,在不同時間取出10μl試樣。將取出的試樣與20μl用冰冷確的甲醇迅速混合以中止酵素反應,然後冷卻至-20℃。所挑選的取樣時間為10分鐘、2h、4h和24h之後。試樣用RP-HPLC分析(逆相HPLC,Agilent Technologies 1200系列)做檢驗。測定毒簇的釋出能測出酵素反應的半生期t1/2。
b:列格曼酵素檢驗
列格曼酵素是以檢驗重組人類酵素實行的。將重組人類列格曼酵素溶液(型錄編號2199-CY,R&D Systems公司出品)西是在50mM乙酸鈉緩衝液/100mM NaCl,pH 4.0至所需濃度並預培育在37℃經2h。然後將重組人類列格曼酵素調整為最終濃度1ng/μl於50mM MES緩衝液,250mM NaCl,pH 5.0。對於每一待檢驗之可被列格曼酵素切斷的前藥,在一微反應容器中製備其混合物(0.5ml,得自Eppendorf公司)。為此目的,將基質溶液以0mM MES緩衝液,250mM NaCl,pH 5.0調整到所需濃度(雙倍濃度)。為了
進行酵素反應之動力學測量,最初添加250μl列格曼酵素溶液並藉著添加250μl基質溶液使反應開始(最終濃度:單一濃度;3μM)。在不同的時間點取出50μl試樣。迅速地添加100μl用冰冷卻的甲醇到試樣以中止酵素反應,然後冷卻至-20℃。所挑選的取樣時間為0.5h、1h、3h和24h之後。試樣用RP-HPLC分析法和LC-MS分析法進行分析。測定毒簇的釋出能測出酵素反應的半生期t1/2。
作為顯示列格曼酵素調節的切斷反應之代表性實例,在該列格曼酵素檢驗中產ㄥ的基質是模式化合物A和B。
參考實例之模式化合物A
N-(吡啶-4-基乙醯基)-L-丙胺醯基-L-丙胺醯基-N1-[(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-(甲基胺基)-1-酮基丁-2-基]-L-天冬胺醯胺
首先,三氟乙酸(2S)-2-胺基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-N-甲基丁醯胺係如WO 2015096982 A1中說明的方式製備。緊接著,此中間體藉著在DMF中於結合至中間體L103在DMF中於HATU和N,N-二異丙基乙胺存在下用於製
備標題化合物。
LC-MS(方法1):Rt=0.86min;MS(ESIpos):m/z=902[M+H]+.
參考實例之模式化合物B
N-(吡啶-4-基乙醯基)-L-丙胺醯基-N-甲基-L-丙胺醯基-N1-[(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-1-(甲基胺基)-1-酮基丁-2-基]-L-天冬胺醯胺
首先,三氟乙酸(2S)-2-胺基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(甘醇醯基)胺基]-N-甲基丁醯胺係如WO 2015096982 A1中說明的方法製備。緊接著,此中間體藉著在DMF中於結合至中間體L118在DMF中於HATU和N,N-二異丙基乙胺存在下用於製備標題化合物。
LC-MS(方法1):Rt=0.83min;MS(ESIpos):m/z=916[M+H]+.
模式化合物A在以上對於列格曼酵素說明的條件下被切割成為半衰期0.4h的標靶化合物。
模式化合物B在以上對於列格曼酵素說明的條件下被切割成為半衰期0.5h的標靶化合物。
C-2內化的檢驗
內化是一能在抗原表現之癌細胞中藉抗體-藥物結合物(ADC)特定且有效提供細胞毒性酬載的主要方法。此種方法係藉由螢光標記特定抗體和同型之對照組抗體來監測。首先,該螢光染料被軛合至該抗體的離胺酸。軛合作用是利用一兩倍到十倍莫耳濃度過量的CypHer 5E單NHS酯(Batch 357392,GE Healthcare公司出品)在pH 8.3實行的。結合作用之後,該反應
混合物藉膠體層析術純化(Zeba旋轉脫鹽管柱,40K,Thermo Scientific公司出品,型錄號87768;溶離緩衝液:DULBECCO'S PBS,Sigma-Aldrich公司出品,型錄號D8537)以縮減過量的染劑並調整pH。用VIVASPIN 500管柱(Sartorius stedim biotec公司出品)將蛋白質溶液濃縮。用光譜分析(得自NanoDrop)的方法測定抗體之染劑負載並緊接著進行計算(D/P=Adye εprotein:(A280-0.16Adye)εdye)。
本說明書中檢驗的抗體之染劑負載和同型之對照組具有可相比的大小級數。在細胞結合檢驗中,吾人確認結合不會導致抗體親和力的變化。
用經標記的抗體進行內化檢驗。在處理開始之前,將細胞(2 x 104/每孔)播種於96孔MTP(胖寬、黑色、底部透明,型錄號4308776,Applied Biosystems出品)之100μl培養基中。在37℃/5%CO2培育18小時之後,置換培養基並以不同濃度添加標記過的抗體(10、5、2.5、1、0.1μg/ml)。將同樣的處理方法應用到經標記的同型對照組(陰性對照組)。經選擇之培育時間為0h、0.25h、0.5h、1h、1.5h、2h、3h、6h和24h。該螢光測量是利用InCellAnalyzer 1000(GE Healthcare公司出品)來進行的。接著以動力學評估藉由測量顆粒數/每細胞和總顆粒密度/每細胞之參數。
結合至受體之後,檢驗抗體之內化容量。為此目的,選擇具有不同受體表現程度的細胞。以抗體觀察標靶調節的專一性內化作用,反之同型對照組顯示沒有內化作用。
用懸浮的細胞進行C-2b的內化檢驗
螢光染劑的結合如同C2說明的方式實行。待檢測的抗原是藉以造血懸浮細胞實行檢測;緊接著內化作用是在以FACS為基礎的內化檢驗實行檢測。
檢驗具有不同標靶表現程度的細胞。將細胞(5x104/每孔)播種在一96-MTP(Greiner bio-one,細胞TAR,650 180,U型底部)中,總體積為100μl。
以10μg/ml最終濃度添加特定於標靶的抗體之後,將該批次培育在37℃經不同期間(1h、2h、6h,每一期間有三個複製)。對同型之對照組在完全相同的條件下進行處理。平行的批次經處理並且穩定培育在4℃(陰性對照組)。FACS分析是利用Guava流式細胞儀(Millipore公司出品)進行的。動力學評估式藉由測量螢光強度進行,且評估是利用guavaSoft 2.6軟體(Millipore公司出品)實行。對於本說明書中說明的標靶和特定於標靶的抗體而言,許多細胞被測得顯著且特定的內化作用;同型對照組則顯示沒有內化作用。
C-2c抗-CD123抗體的共區域化檢驗
由於連接體的緣故,該抗體-藥物結合物的活性代謝物是藉溶酶體分解作用產生的。因此內化後發生細胞內的交通流動非常重要。使用特定於溶酶體胞器之標記物(例如表面分子或小GTPases)進行之抗體共區域化研究容許吾人挑選具有所需數據的抗體。為此目的,將總體積為100μl的標靶陽性細胞(5x104/每孔)播種到96-MTP(Greiner bio-one,CELLTAR,650 180,U型底部)。接著添加CypHer5E標記的抗標靶抗體(最終濃度為20μg/ml),將該批試樣(每一時間點有兩個複本)培育在37℃經30分鐘、2h和6h在培育箱(5% CO2)之中。在所選的培育時間結束前30分鐘,添加特定於溶酶體之標記物到待檢驗的批次。將溶酶體用CytoPainter LysoGreen指示劑染色(最終濃度1:2000;abcam,ab176826)。在培育之後,添加200μl用冰冷卻的FACS緩衝液(DULBECCO'S PBS,Sigma-Aldrich公司,No.D8537+3% FBS熱失活的FBS,Gibco公司,No.10500-064)並將細胞懸浮物在400 x g和4℃離心5分鐘。將細胞小塊物重新懸浮在300μl用冰冷卻的FACS緩衝液並再次離心(4min,400 x g at 4℃)。離心之後,將上澄液丟棄並將細胞小塊溶到30μl of用冰冷卻的FACS緩衝液中。然後立即將試樣用FACS/影像分析(FlowSight amnis,Millipore)處理。用特殊的軟體(共區域化軟體IDEAS
Application v6.1)評估共區域化。表3以範例的方式摘錄抗-CD123抗體之此項檢驗的結果。
人類化抗體TPP-9476和TPP-8987與老鼠抗體母株相較展現顯著改良的數據。
C-3測定細胞滲透性的體外試驗
物質的細胞滲透性可利用體外試驗在一流動檢驗中使用Caco-2細胞進行研究[M.D.Troutman and D.R.Thakker,Pharm.Res.20(8),1210-1224(2003)]。為此目的,將細胞在24孔過濾盤上培養15-16天。為了測定滲透性,將個別的試驗物質在HEPES緩衝液中以頂部(A)或底部(B)的方式施加到細胞並且培育2小時。在0小時和2小時之後,從順和反的隔間取樣。將試樣用逆相管柱以HPLC(Agilent 1200,德國Böblingen市)予以分開。該HPLC系統以渦輪離子噴灑介面結合至一台三重的四極矩質譜儀API 4000(AB SCIEX Deutschland GmbH,德國Darmstadt市)。以Papp值為基礎評估滲透性,利用Schwab等人發表的公式計算Papp值[D.Schwab et al.,J.Med.Chem.46,1716-1725(2003)]。當Papp(B-A)對Papp(A-B)的比率(流出比率)>2或<0.5時,一物質被歸類為主動運輸的。
對於細胞內釋出的毒簇非常重要的是從B到A的滲透性[Papp(B-A)]和Papp(B-A)對Papp(A-B)的比率(流出比率):滲透性愈低,則物質通過Caco-2細胞單層的主動與被動運輸過程就愈緩慢,因而該物質在細胞內釋出之後劉在細胞中較久。因為該代謝物留在細胞中較久,與生化標靶(在本說明書中為紡錘體驅動蛋白KSP/Eg5)的交互作用的可能性增加,造成增進的細胞毒性作用。
可從根據本發明之結合劑-藥劑結合物形成的代謝物M1與參考用代謝物R3M相較,展現從細胞減少運輸和減少的流出比率,R3M可從參考實例2的結合劑-藥劑結合物形成。
C-4用於測定P-醣蛋白(P-gp)基質性質的體外試驗
許多腫瘤細胞表現運送藥物的運輸蛋白,且這經常伴隨對細胞生長抑制劑產生抗性。因此不是此種運輸蛋白例如P-醣蛋白(P-gp)或BCRP之基質的物質無法展現改良的活性數據。
對於P-gp之物質(ABCB1)的基質性質是以流動檢驗使用會過度表現P-gp的LLC-PK1細胞(L-MDR1細胞)來測定的[A.H.Schinkel et al.,J.Clin.Invest.96,1698-1705(1995)]。為此目的,將LLC-PK1細胞或L-MDR1細胞培養在96孔過濾盤經3-4天。為了測定滲透性,將代表的試驗物質,單獨
或於一種抑制劑(例如埃佛麥亭[ivermectin]或佛拉帕密[verapamil])存在下溶於HEPES緩衝液中以頂部(A)或底部(B)方式施用到細胞並且培育兩小時。在0小時和2小時之後,從順和反的隔間取樣。將試樣用逆相管柱以HPLC予以分開。該HPLC系統以渦輪離子噴灑介面結合至一台三重的四極矩質譜儀API 4000(AB SCIEX Deutschland GmbH,德國Darmstadt市)。以Papp值為基礎評估滲透性,利用Schwab等人發表的公式計算Papp值[D.Schwab et al.,J.Med.Chem.46,1716-1725(2003)]。當Papp(B-A)對Papp(A-B)的流出比率>2時,一物質就被歸類為P-gp的基質。
吾人可對L-MDR1和LLC-PK1細胞中的流出比率,或抑制劑存在與不存在下的流出比率作比較,以作為評估P-gp基質性質的進一步論據。若這些數值的差異倍數大於2,則提到的物質是一種P-gp基質。
C-5藥物動力學
在雄性Wistar大鼠身上以靜脈注射實例2c-9476(DAR 6.3)和實例2c-9476(DAR 3.4)5mg/kg之後,用ELISA測定ADCs在血漿中的濃度,並且計算藥物動力學參數如廓清率(CL)、曲線下的面積(AUC)和半生期(t1/2)。
表5 摘錄實例2c-9476使用DAR 6.3和DAR 3.4之藥物動力學參數。
在此項對大鼠之探索性PK研究中,在靜脈注射之後兩個實例都觀察到典型的IgG數據。在使用DAR 6.3的實例2c-9476和在使用DAR 3.4的實例2c-9476之間未觀察到顯著的差異。
對於所使用之ADC的定量分析
ADCs的抗體部分是利用配體結合檢驗(ELISA)測定為在血漿試樣和腫瘤溶解物中的IgG總濃度。在本說明書中,使用三明治ELISA的形式。這項ELISA已合格並且被證實適用於測定血漿和腫瘤的試樣。將ELISA盤用抗-人類的山羊IgG Fc抗體包覆。與試樣培育在一起後,將該盤沖洗並用偵測用的結合物-猴子的抗-人類IgG(H+L)抗體與辣根過氧化酶(HRP)一起培育。,在更多沖洗步驟之後,將HRP基質添加到OPD並且經由490nm波長的吸光值監測顏色生成。利用一項四個參數的公式將具有已知IgG濃度的標準試樣代入。在較低(LLOQ)和較高(ULOQ)的定量限度內,用插入法測定未知的濃度。
C5a:體外內化之後對ADC代謝物的鑑認
方法之說明
進行免疫結合物之內化研究以分析細胞內形成的代謝物。為此目的,將人類肺腫瘤細胞NCI H292(3x105/每孔)播種在六孔盤中並培育至隔夜(37℃,
5% CO2)。以10μg/ml(66nM)待檢驗的ADC處理細胞。內化作用在37℃和5%CO2下進行。取出細胞試樣以供進一步在不同時間(0、4、24、48、72h)作分析。首先,收穫懸浮物(大約5ml)並且在離心(2分鐘,RT,1000rpm Heraeus Variofuge 3.0R)之後貯存在-80℃。用PBS沖洗細胞並用細胞剝離試劑[Accutase]使細胞分離,測定細胞的數目。在另一次沖洗後,將定義之細胞數目(2 x 105)用100ml溶解用的緩衝液(哺乳類細胞溶解套組(Sigma MCL1)處理並且用連續震盪法(加熱攪拌器,15分鐘,4℃,650rpm)培育在Protein LoBind試管(Eppendorf公司型錄號0030 108.116)中。培育之後,將溶解物離心(10min,4℃,12000g,eppendorf 5415R)。收穫上澄液。將所得到的上澄液貯存在-80℃。然後所有試樣均以如下方式分析。
為了收成50μl培養物上澄液/細胞溶解物,添加150μl沉澱試劑(甲醇)並將混合物震盪10秒。該沉澱試劑包含濃度適當的內部標準物(ISTD)(一般而言在20-100μg/l的範圍)。在1881g離心10分鐘之後,將上澄液倒入一個自動取樣機的小管中,用300μl與溶離劑相配的緩衝液調整並再震盪和在1881g離心10分鐘。
最後用購自AB SCIEX Deutschland GmbH之HPLC結合的API6500三重的四極矩矩質譜儀分析細胞溶解物和上澄液試樣。
為了校正,將空白的溶解物或空白的上澄液以適當的濃度混合(0.1-1000μg/l)。測定限度(LLOQ)約為0.2μg/l。
用於試驗確實性的品質對照組含有4和40μg/l。
C5b:體內鑑認ADC代謝物
在靜脈注射3-30mg/kg不同的ADCs之後,可測量ADCs的血漿和腫瘤濃度以及任何產生的代謝物,並且可計算藥物動力學參數如廓清率(CL)、曲線下的面積(AUC)和半生期(t1/2)。
可能代謝物的定量分析
將蛋白質一般用甲醇沉澱之後,接著用高壓液相層析法(HPLC)結合至三重的四極矩質譜儀(MS)分析血漿、腫瘤、肝和腎中的化合物。
為了收成50μl血漿,添加150μl沉澱試劑(通常是甲醇)並將混合物震盪10秒。該沉澱試劑包含濃度適當的內部標準物(ISTD)(一般而言在20-100μg/l的範圍)。在1881g離心10分鐘之後,將上澄液倒入一個自動取樣機的小管中,用300μl與溶離劑相配的緩衝液調整並再震盪。
在收成腫瘤或器官物質時,將該特殊物質與3-20倍量的萃取緩衝液混合。該萃取緩衝液包含50ml組織蛋白萃取試劑(Pierce公司出品,伊利諾州Rockford市)、兩小塊完整蛋白酶抑制劑雞尾酒(Roche Diagnostics GmbH公司出品,德國Mannheim市)和最終濃度為1mM之苯基甲基硫醯氟(Sigma公司出品,密蘇里州聖路易市)。根據組織的型式(硬的:腫瘤;軟的:肝、腎),挑選Prescellys 24溶解與均質化系統(Bertin Technologies公司出品)的溶解與均質化程序(www.prescellys.com)。將均質化的試樣在4℃留置到隔夜。將50μl均質物倒入自動取樣機的小管中並且用150μl包含ISTD的甲醇補足、攪動10秒然後留置5分鐘。添加300μl乙酸銨緩衝液(pH 6.8)並短暫攪動之後,將試樣在1881g離心10分鐘。
為了校正,將用於血漿試樣的血漿和用於組織試樣的對應空白基質以0.6-1000μg/l的濃度混合。根據試樣型式或組織型式,偵測限度(LOQ)介在1和20μg/l之間。
最後用購自AB SCIEX Deutschland GmbH之HPLC結合的API6500三重的四極矩矩質譜儀分析血漿和培養基試樣。
用於試驗確實性的品質對照組含有4、40和400μg/l。
表6顯示在MOLM-13異種移植的小鼠模式中施用5mg/kg得自實例
2c-9476(n=3)的ADC之後,於腫瘤、肝、腎和血漿測量到的代謝物濃度。所測量到的代謝物為:M1。n.c.=未計算;LOQ:定量的限度。
施用具有可被列格曼酵素切斷之連接體的根據本發明實例2c-9476之ADC能導致與其他健康的器官/組織相比,顯著選擇性地在標靶組織(腫瘤)處有豐富的活性化合物。
C-6體內活性試驗
在體內測試根據本發明的結合物的活性,例如使用異種移值模式。熟習本技藝者會熟習先前技藝中的方法,該方法容許根據本發明的化合物被測試(請參考例如WO 2005/081711;Polson et al.,Cancer Res.2009 Mar 15;69(6):2358-64)。為此目的,將表現該結合劑之標靶分子的腫瘤細胞株接種到囓齒科(例如小鼠)。然後將根據本發明的結合物、同型抗體對照結合物、對照抗體或、對照抗體或等張的鹽水施加到經接種的動物身上。該施用進行一次或一次以上。接著是數天的培育,藉著與結合物處理過的動物或對照組比較測量腫瘤的大小。結合物處理過的動物展現較小的腫瘤大小。
C-6a.小鼠體內實驗腫瘤的生長抑制/復原
將能表現對抗抗體藥物結合物之抗原的人類腫瘤細胞皮下接種到免疫受到抑制的小鼠例如NMRi裸鼠或SCID小鼠的脅腹,將1-10百萬個細胞從細胞培養物中分離出來、離心並在懸浮於培養基或培養基/基質膠體中。將細胞懸浮物注射到小鼠的皮下。
在幾天之內腫瘤長出。在腫瘤被建立之後於腫瘤大小約40mm2開始處理。為了檢驗較大腫瘤的影響,處理可在僅50-100mm2的腫瘤大小就開始。
使用APDCs和ADCs的處理係以靜脈注射的途徑注射到小鼠尾巴靜脈來實行。以5ml/kg的量施用ADC。
該處理方法視抗體的藥物動力學而定。使用根據本發明的結合物,每週一次實行處理經二或三週為標準。對於快速評估而言,單一處理的方法也可能適用。然而,該處理疫可持續,或三次處理的第二輪可接續在較晚的時間進行。
以每個處理組使用八隻動物作為標準。除了施用活性物質的組以外,一組僅使用緩衝液根據同樣的方法處理以作為對照組。
在實驗期間,經常地用測徑器對兩個維度(長/寬)測量腫瘤面積。腫瘤面積測量為長度x寬度。被處理組的平均腫瘤面積相對於對照組的比率稱為T/C面積。
在處理結束後,當所有實驗組別同時終止時可將腫瘤移除並秤重。被處理組的平均腫瘤重量相對於對照組的比率稱為T/C重量。
C-6b.根據本發明之ADCs在各種腫瘤模式中的效力
將腫瘤細胞(例如NCI-H292、REC-1、MOLM-13和MV-4-11皮下接種到are inoculated皮下雌性NMRI裸鼠(Janvier品種)的脅腹。在腫瘤大小為~40mm2時,用抗體-藥物結合物進行靜脈注射。處理完後,若適當則持續
監測腫瘤的生長。
相較於對照組和軛合之同型對照組抗體,使用根據本發明之處理會產生卓越的且在某些情形中持久地抑制腫瘤生長。表7顯示在本實驗的個別結束日對腫瘤面積所測得的T/C值,係從處理開始計算出的結果。
<110> 德商拜耳廠股份有限公司 Bayer Pharma Aktiengesellschaft
<120> 具有酶裂解基團之結合劑-藥劑偶聯物(ADCs) Binder-drug conjugates(ADCs)having enzymatically cleavable groups
<130> BHC 16 1 067
<160> 116
<170> PatentIn version 3.5
<210> 1
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 2
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 3
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 4
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 5
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 6
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 7
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 9
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 10
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 11
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 12
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 13
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 14
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 15
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 16
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 19
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 20
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 21
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 22
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 23
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 24
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 25
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 26
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 29
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 30
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 31
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 32
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 33
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 34
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 35
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 36
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 37
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 38
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 39
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 40
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 41
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 42
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 43
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 44
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 45
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 46
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 48
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 49
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 50
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 51
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 52
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 53
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 54
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 55
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 56
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 57
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 58
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 59
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 60
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 61
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 62
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 63
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 64
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 65
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 66
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 67
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 68
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 69
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 70
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 71
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 72
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 73
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 74
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 75
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 76
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 77
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 78
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 79
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 80
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 81
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 82
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 83
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 84
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 85
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 86
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 87
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 88
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 89
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 90
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 91
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 92
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 93
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 94
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 95
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 96
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 97
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 98
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 99
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 100
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 101
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 102
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 103
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 104
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 105
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 106
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 107
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 108
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 109
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 110
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 抗體序列
<210> 111
<211> 378
<212> PRT
<213> 智人
<210> 112
<211> 372
<212> PRT
<213> 智人
<210> 113
<211> 534
<212> PRT
<213> 智人
<210> 114
<211> 129
<212> PRT
<213> 智人
<210> 115
<211> 1255
<212> PRT
<213> 智人
<210> 116
<211> 1210
<212> PRT
<213> 智人
Claims (31)
- 一種式(I)之抗體-藥劑結合物或其醫藥上可接受之鹽,
- 根據請求項1的式(I)抗體-藥劑結合物或其醫藥上可接受之鹽,其中R1 代表氫或甲基,R2 代表甲基或異丙基,R3 代表甲基或-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表1到50的數,AK 代表抗體或與抗原結合的抗體片段, # 代表結合至化合物的鍵,及### 代表結合至該抗體之離胺酸側鏈氮原子的鍵。
- 根據請求項1的式(I)抗體-藥劑結合物或其醫藥上可接受之鹽,其中R1 代表甲基,R2 代表甲基,R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表1到50的數,AK 代表抗體或與抗原結合的抗體片段,# 代表結合至化合物的鍵,及### 代表結合至該抗體之離胺酸側鏈氮原子的鍵。
- 根據請求項1的式(I)抗體-藥劑結合物或其醫藥上可接受之鹽,其中R1 代表甲基,R2 代表甲基,R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表1到20的數,AK 代表抗體或與抗原結合的抗體片段,# 代表結合至化合物的鍵,及### 代表結合至該抗體之離胺酸側鏈氮原子的鍵。
- 根據請求項1的式(I)抗體-藥劑結合物或其醫藥上可接受之鹽,其中R1 代表甲基,R2 代表甲基, R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表1到20的數以及AK 代表抗-CD123抗體、抗-CXCR5抗體、抗-B7H3抗體、抗-TWEAKR抗體、抗-Her2抗體或抗-EGFR抗體或代表該等抗體之結合至抗原的抗體片段,# 代表結合至該化合物的鍵,及### 代表與抗體(AK)或其結合抗原之抗體片段中離胺酸側鏈之氮原子相連的鍵。
- 根據請求項1的式(I)抗體-藥劑結合物或其醫藥上可接受之鹽,其中R1 代表甲基,R2 代表甲基,R3 代表-CH2-C(=O)-NH2,M 代表基團#-C(=O)-CH(CH3)-NH-C(=O)-(CH2)3-C(=O)-###,n 代表1到20的數,以及AK 代表選自TPP-9476、TPP-8988、TPP-8987和TPP-6013組成群組之抗-CD123抗體,代表選自TPP-9574和TPP-9580組成群組之抗-CXCR5抗體,代表抗-B7H3抗體TPP-8382,代表選自TPP-7006和TPP-7007組成群組之抗-TWEAKR抗體,代表抗-Her2抗體TPP-1015或代表抗-EGFR抗體TPP-981或代表該等抗體與抗原結合的抗體片段,# 代表結合該化合物的鍵,及### 代表與抗體(AK)或其結合抗原之抗體片段中離胺酸側鏈之氮原子 相連的鍵。
- 根據請求項7的抗體-藥劑結合物或其醫藥上可接受之鹽,其中n代表1到20的數。
- 根據請求項7的抗體-藥劑結合物或其醫藥上可接受之鹽,其中n代表1到8的數。
- 根據請求項7的抗體-藥劑結合物或其醫藥上可接受之鹽,其中n代表4到8的數。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表選自TPP-8382(抗B7H3)、TPP-6013(抗-CD123)、TPP-8987(抗-CD123)、TPP-8988(抗-CD123)、TPP 9476(抗-CD123)、TPP-9580(抗-CXCR5)和TPP 9574(抗-CXCR5)組成群組之抗體,或該等抗體與抗原結合的片段。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表TPP 9476(抗-CD123)。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表TPP 9574(抗-CXCR5)。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CD123抗體TPP-6013,代表抗-CD123抗體TPP-8987,代表抗-CD123抗體TPP-8988,或代表抗-CD123抗體TPP-9476,或該等抗體與抗原結合的片段。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)(i)代表抗-B7H3抗體,其包含含有如SEQ ID NO:52所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:53所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:54所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:56所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:57所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:58所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),(ii)代表抗-CD123抗體,其包含含有如SEQ ID NO:22所示重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:23所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:24所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:26所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:27所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:28所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),(iii)代表抗-CD123抗體,其包含含有如SEQ ID NO:62所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:63所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:64所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:66所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:67所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:68所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),(iv)代表抗-CD123抗體,其包含含有如SEQ ID NO:72所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:73所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:74所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:76所示之輕鏈可變CDR1序列(L- CDR1)、如SEQ ID NO:77所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:78所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),(v)代表抗-CD123抗體,其包含含有如SEQ ID NO:82所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:83所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:84所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:86所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:87所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:88所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),(vi)代表抗-CXCR5抗體,其包含含有如SEQ ID NO:92所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:93所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:94所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:96所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:97所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:98所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),或(vii)代表抗-CXCR5抗體,其包含含有如SEQ ID NO:102所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:103所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:104所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:106所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:107所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:108所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL),或代表該等抗體之與抗原結合的片段。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CD123抗體,其包含含有如SEQ ID NO:82所示 之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:83所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:84所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:86所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:87所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:88所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL)。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CXCR5抗體,其包含含有如SEQ ID NO:92所示之重鏈可變CDR1序列(H-CDR1)、如SEQ ID NO:93所示之重鏈可變CDR2序列(H-CDR2)和如SEQ ID NO:94所示之重鏈可變CDR3序列(H-CDR3)的重鏈可變區(VH),以及含有如SEQ ID NO:96所示之輕鏈可變CDR1序列(L-CDR1)、如SEQ ID NO:97所示之輕鏈可變CDR2序列(L-CDR2)和如SEQ ID NO:98所示之輕鏈可變CDR3序列(L-CDR3)的輕鏈可變區(VL)。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)(i)代表抗-B7H3抗體,其包含如SEQ ID NO:51所示的重鏈可變區(VH)和如SEQ ID NO:55所示的輕鏈可變區(VL),(ii)代表抗-CD123抗體,其包含如SEQ ID NO:21所示的重鏈可變區(VH)和如SEQ ID NO:25所示的輕鏈可變區(VL),(iii)代表抗-CD123抗體,其包含如SEQ ID NO:61所示的重鏈可變區(VH)和如SEQ ID NO:65所示的輕鏈可變區(VL),(iv)代表抗-CD123抗體,其包含如SEQ ID NO:71所示的重鏈可變區(VH)和如SEQ ID NO:75所示的輕鏈可變區(VL),(v)代表抗-CD123抗體,其包含如SEQ ID NO:81所示的重鏈可變區(VH) 和如SEQ ID NO:85所示的輕鏈可變區(VL),(vi)代表抗-CXCR5抗體,其包含如SEQ ID NO:91所示的重鏈可變區(VH)和如SEQ ID NO:95所示的輕鏈可變區(VL),(vii)代表抗-CXCR5抗體,其包含如SEQ ID NO:101所示的重鏈可變區(VH)和如SEQ ID NO:105所示的輕鏈可變區(VL),或代表該等抗體之與抗原結合的片段。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CD123抗體,其包含如SEQ ID NO:81所示的重鏈可變區(VH)和如SEQ ID NO:85所示的輕鏈可變區(VL)。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CXCR5抗體,其包含如SEQ ID NO:91所示的重鏈可變區(VH)和如SEQ ID NO:95所示的輕鏈可變區(VL)。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)(i)代表抗-B7H3抗體,其包含如SEQ ID NO:59所示的重鏈區和如SEQ ID NO:60所示的輕鏈區,(ii)代表抗-CD123抗體,其包含如SEQ ID NO:29所示的重鏈區和如SEQ ID NO:30所示的輕鏈區,(iii)代表一抗-CD123抗體,其包含如SEQ ID NO:69所示的重鏈區和如SEQ ID NO:70所示的輕鏈區,(iv)代表一抗-CD123抗體,其包含如SEQ ID NO:79所示的重鏈區和如SEQ ID NO:80所示的輕鏈區,(v)代表抗-CD123抗體,其包含如SEQ ID NO:89所示的重鏈區和如SEQ ID NO:90所示的輕鏈區,(vi)代表一抗-CXCR5抗體,其包含如SEQ ID NO:99所示的重鏈區和 如SEQ ID NO:100所示的輕鏈區,或(vii)代表抗-CXCR5抗體,其包含如SEQ ID NO:109所示的重鏈區和如SEQ ID NO:110所示的輕鏈區,或代表該等抗體之與抗原結合的片段。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CD123抗體,其包含如SEQ ID NO:89所示的重鏈區和如SEQ ID NO:90所示的輕鏈區。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中AK(AK1、AK2)代表抗-CXCR5抗體,其包含如SEQ ID NO:99所示的重鏈區和如SEQ ID NO:100所示的輕鏈區。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中該抗體或該與抗原結合的抗體片段結合至細胞外的標靶分子。
- 根據請求項1的抗體-藥劑結合物或其醫藥上可接受之鹽,其中該抗體或該與抗原結合的抗體片段結合至細胞外的癌症標靶分子。
- 根據請求項1的抗體-藥劑結合物,其中該抗體或該與抗原結合的抗體片段在結合至其細胞外目標細胞上的標靶分子後,透過該結合被目標細胞內化。
- 一種醫藥組成物,其包含至少一種根據請求項1至26中任一項之抗體-藥劑結合物或其醫藥上可接受之鹽,以及惰性、非毒性醫藥上適當之輔劑。
- 一種根據請求項1至26中任一項之抗體-藥劑結合物或其醫藥上可接受之鹽或根據請求項27之醫藥組成物之用途,其係用於製備治療和/或預防疾病之醫藥品。
- 一種根據請求項1至26中任一項之抗體-藥劑結合物或其醫藥上可接受之鹽或根據請求項27之醫藥組成物之用途,其係用於製備治療 過度增生和/或血管生成的病症之醫藥品。
- 一種根據請求項1至26中任一項之抗體-藥劑結合物或其醫藥上可接受之鹽或根據請求項27之醫藥組成物之用途,其係用於製備治療癌症和腫瘤之醫藥品。
- 一種根據請求項1至26中任一項之抗體-藥劑結合物或其醫藥上可接受之鹽或根據請求項27之醫藥組成物之用途,其係用於製備與一或多種用在癌症免疫療法的治療方式或與一或多種針對癌症免疫療法之分子標靶的活性化合物併用以治療癌症或腫瘤之醫藥品。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
??16205868.9 | 2016-12-21 | ||
EP16205868.9 | 2016-12-21 | ||
EP16205868 | 2016-12-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201827086A TW201827086A (zh) | 2018-08-01 |
TWI781125B true TWI781125B (zh) | 2022-10-21 |
Family
ID=57614197
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW111134796A TWI823564B (zh) | 2016-12-21 | 2017-12-19 | 具有酶裂解基團之抗體-藥劑結合物 |
TW106144529A TWI781125B (zh) | 2016-12-21 | 2017-12-19 | 具有酶裂解基團之抗體-藥劑結合物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW111134796A TWI823564B (zh) | 2016-12-21 | 2017-12-19 | 具有酶裂解基團之抗體-藥劑結合物 |
Country Status (15)
Country | Link |
---|---|
US (3) | US11660351B2 (zh) |
EP (1) | EP3558388A1 (zh) |
JP (2) | JP7066714B2 (zh) |
KR (3) | KR102556826B1 (zh) |
CN (2) | CN110312534B (zh) |
AR (1) | AR110418A1 (zh) |
AU (1) | AU2017380871A1 (zh) |
BR (1) | BR112019012883A2 (zh) |
CA (1) | CA3047489A1 (zh) |
IL (3) | IL291308B1 (zh) |
MX (1) | MX2019007641A (zh) |
PE (1) | PE20191235A1 (zh) |
RU (1) | RU2761390C2 (zh) |
TW (2) | TWI823564B (zh) |
WO (1) | WO2018114578A1 (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG10201908685QA (en) | 2015-06-22 | 2019-10-30 | Bayer Pharma AG | Antibody drug conjugates (adcs) and antibody prodrug conjugates (apdcs) with enzymatically cleavable groups |
CN107921146A (zh) | 2015-06-23 | 2018-04-17 | 拜耳医药股份有限公司 | 纺锤体驱动蛋白(ksp)抑制剂与抗‑cd123的抗体的抗体药物缀合物(adc) |
BR112017027811A2 (pt) | 2015-06-23 | 2018-08-28 | Bayer Pharma AG | conjugados específicos de inibidores de ksp |
PE20181852A1 (es) | 2016-03-24 | 2018-12-03 | Bayer Pharma AG | Profarmacos de farmacos citotoxicos que tienen grupos enzimaticamente escindibles |
US11001636B2 (en) | 2016-06-15 | 2021-05-11 | Bayer Pharma Aktiengesellschaft | Specific antibody-drug-conjugates (ADCs) with KSP inhibitors and anti-CD123-antibodies |
CA3047522A1 (en) | 2016-12-21 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Specific antibody drug conjugates (adcs) having ksp inhibitors |
CA3047489A1 (en) | 2016-12-21 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Antibody drug conjugates (adcs) having enzymatically cleavable groups |
CN111094349A (zh) * | 2017-08-23 | 2020-05-01 | 马克思-德布鲁克-分子医学中心亥姆霍兹联合会 | 嵌合抗原受体和结合cxcr5的car-t细胞 |
CN112601553A (zh) * | 2018-06-18 | 2021-04-02 | 拜耳股份有限公司 | 具有可酶切的接头和改善的活性谱的针对cxcr5的结合剂-药物缀合物 |
EP4294453A1 (en) * | 2021-02-16 | 2023-12-27 | Glykos Finland Oy | Linker-payloads and conjugates thereof |
TW202320857A (zh) | 2021-07-06 | 2023-06-01 | 美商普方生物製藥美國公司 | 連接子、藥物連接子及其結合物及其使用方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007064759A2 (en) * | 2005-11-29 | 2007-06-07 | The Scripps Research Institute | Inhibiting tumour cell invasion, metastasis and angiogenesis through targetting legumain |
WO2016096610A1 (de) * | 2014-12-15 | 2016-06-23 | Bayer Pharma Aktiengesellschaft | Antikörper-wirkstoff-konjugate (adcs) von ksp-inhibitoren mit aglycosylierten anti-tweakrantikörpern |
Family Cites Families (150)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CU22545A1 (es) | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico |
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4714681A (en) | 1981-07-01 | 1987-12-22 | The Board Of Reagents, The University Of Texas System Cancer Center | Quadroma cells and trioma cells and methods for the production of same |
US4474893A (en) | 1981-07-01 | 1984-10-02 | The University of Texas System Cancer Center | Recombinant monoclonal antibodies |
US4510245A (en) | 1982-11-18 | 1985-04-09 | Chiron Corporation | Adenovirus promoter system |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US4968615A (en) | 1985-12-18 | 1990-11-06 | Ciba-Geigy Corporation | Deoxyribonucleic acid segment from a virus |
DE8808645U1 (zh) | 1988-07-06 | 1988-08-25 | Hofer, Daniel, 7730 Villingen-Schwenningen, De | |
US4925648A (en) | 1988-07-29 | 1990-05-15 | Immunomedics, Inc. | Detection and treatment of infectious and inflammatory lesions |
US5601819A (en) | 1988-08-11 | 1997-02-11 | The General Hospital Corporation | Bispecific antibodies for selective immune regulation and for selective immune cell binding |
DK0479909T3 (da) | 1989-06-29 | 1997-04-07 | Medarex Inc | Bispecifikke reagenser til AIDS-behandling |
ES2133139T3 (es) | 1989-10-20 | 1999-09-01 | Medarex Inc | Hetero anticuerpos biespecificos con funciones efectoras dobles. |
US5270163A (en) | 1990-06-11 | 1993-12-14 | University Research Corporation | Methods for identifying nucleic acid ligands |
ATE175118T1 (de) | 1990-10-05 | 1999-01-15 | Medarex Inc | Gezielte immunostimulierung mit bispezifischen stoffen |
EP0557300B1 (en) | 1990-10-29 | 1997-11-19 | Chiron Corporation | Bispecific antibodies, method of production, and uses thereof |
CA2082160C (en) | 1991-03-06 | 2003-05-06 | Mary M. Bendig | Humanised and chimeric monoclonal antibodies |
IE921342A1 (en) | 1991-04-26 | 1992-11-04 | Surface Active Ltd | Novel antibodies, and methods for their use |
US6004554A (en) | 1992-03-05 | 1999-12-21 | Board Of Regents, The University Of Texas System | Methods for targeting the vasculature of solid tumors |
ATE188874T1 (de) | 1992-08-18 | 2000-02-15 | Centro Inmunologia Molecular | Monoklonale antikörper gegen den epidermalen wachstumsfaktorrezeptor, zellen und verfahren zur ihrer herstellung und sie erhaltende zusammensetzungen |
DK0719859T3 (da) | 1994-12-20 | 2003-10-20 | Merck Patent Gmbh | Anti-alfa V-integrin monoklonalt antistof |
ATE219517T1 (de) | 1995-08-18 | 2002-07-15 | Morphosys Ag | Protein-/(poly)peptidbibliotheken |
WO1997024373A1 (en) | 1995-12-29 | 1997-07-10 | Medvet Science Pty. Limited | Monoclonal antibody antagonists to haemopoietic growth factors |
US6150508A (en) | 1996-03-25 | 2000-11-21 | Northwest Biotherapeutics, Inc. | Monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen |
ES2260788T3 (es) | 1996-03-25 | 2006-11-01 | Medarex, Inc. | Anticuerpos monoclonales especificos para el dominio estracelular de antigeno de membrana especifico de la prostata. |
ES2277846T3 (es) | 1999-07-29 | 2007-08-01 | Medarex, Inc. | Anticuerpos monoclonales humanos para antigeno prostatico especifico. |
AU3985701A (en) | 2000-02-25 | 2001-09-03 | Us Health | Anti-EGFRviii SCFVS with improved cytotoxicity and yield, immunotoxins based thereon, and methods of use thereof |
KR100480985B1 (ko) | 2000-05-19 | 2005-04-07 | 이수화학 주식회사 | 표피 성장 인자 수용체에 대한 사람화된 항체 |
US6884446B1 (en) | 2000-07-27 | 2005-04-26 | Red Arrow Products Co., Llc | Article for browning and flavoring foodstuffs |
US7288390B2 (en) | 2000-08-07 | 2007-10-30 | Centocor, Inc. | Anti-dual integrin antibodies, compositions, methods and uses |
AUPR395801A0 (en) | 2001-03-26 | 2001-04-26 | Austin Research Institute, The | Antibodies against cancer |
EA007469B1 (ru) | 2001-04-26 | 2006-10-27 | Байоджен Айдек Эмэй Инк. | Антитела, блокирующие cripto, и их применения |
US7589180B2 (en) | 2001-05-11 | 2009-09-15 | Abbott Laboratories Inc. | Specific binding proteins and uses thereof |
US7595378B2 (en) | 2001-06-13 | 2009-09-29 | Genmab A/S | Human monoclonal antibodies to epidermal growth factor receptor (EGFR) |
RU2335507C2 (ru) | 2001-06-13 | 2008-10-10 | Генмаб А/С | Человеческие моноклональные антитела к рецептору эпидермального фактора роста (egfr), способ их получения и их использование, гибридома, трансфектома, трансгенное животное, экспрессионный вектор |
AU2002365195A1 (en) | 2001-07-12 | 2003-07-30 | Incyte Genomics, Inc. | Intracellular signaling molecules |
SG114505A1 (en) | 2001-10-17 | 2005-09-28 | First Cube Pte Ltd | System and method for facilitating delivery and return service |
WO2003034903A2 (en) | 2001-10-23 | 2003-05-01 | Psma Development Company, L.L.C. | Psma antibodies and protein multimers |
AU2002363960B2 (en) | 2001-12-06 | 2008-07-10 | Merck Sharp & Dohme Corp. | Mitotic kinesin inhibitors |
US20080193445A1 (en) | 2002-01-18 | 2008-08-14 | Liliane Goetsch | Novel anti-IGF-IR antibodies and uses thereof |
JP4473117B2 (ja) | 2002-03-13 | 2010-06-02 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | 抗αvβ6抗体 |
EP1494693B1 (en) | 2002-03-22 | 2010-12-08 | Biogen Idec MA Inc. | Cripto-specific antibodies |
CA2489467C (en) | 2002-06-14 | 2015-02-24 | Immunomedics, Inc. | Humanized monoclonal antibody hpam4 |
PL375889A1 (en) | 2002-10-11 | 2005-12-12 | Cytokinetics, Inc. | Compounds for treating cellular proliferative diseases, compositions containing them and their application |
US8512701B2 (en) * | 2002-11-15 | 2013-08-20 | Morehouse School Of Medicine | Anti-CXCL13 and anti-CXCR5 antibodies for the prevention and treatment of cancer and cancer cell migration |
US8658377B2 (en) * | 2002-11-15 | 2014-02-25 | Morehouse School Of Medicine | Detecting cancer with anti-CCL25 and anti-CCR9 antibodies |
US20050059592A1 (en) | 2003-04-11 | 2005-03-17 | Kiener Peter A. | EphA2 and hyperproliferative cell disorders |
WO2004100873A2 (en) | 2003-05-07 | 2004-11-25 | Cytokinetics, Inc. | Compounds, compositions, and methods |
AU2004260936B2 (en) | 2003-06-27 | 2010-06-10 | Amgen Fremont Inc. | Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof |
FR2857811A1 (fr) | 2003-07-16 | 2005-01-21 | St Microelectronics Sa | Methode de chiffrage d'un flux audio ou video compresse a tolerance d'erreurs |
MXPA06000830A (es) | 2003-07-21 | 2006-04-18 | Immunogen Inc | Un conjugado citotoxico ca6 antigeno-especifico y metodos para utilizar el mismo. |
BR122018071808B8 (pt) | 2003-11-06 | 2020-06-30 | Seattle Genetics Inc | conjugado |
SI1689724T1 (sl) | 2003-11-25 | 2012-04-30 | Novartis Ag | Spojine kinazolinona kot sredstva proti raku |
US20050142133A1 (en) | 2003-12-03 | 2005-06-30 | Xencor, Inc. | Optimized proteins that target the epidermal growth factor receptor |
US7662581B1 (en) | 2003-12-18 | 2010-02-16 | Novartis Vaccines And Diagnostics, Inc. | Eg5 co-crystals |
US7767792B2 (en) | 2004-02-20 | 2010-08-03 | Ludwig Institute For Cancer Research Ltd. | Antibodies to EGF receptor epitope peptides |
US7598350B2 (en) | 2004-03-19 | 2009-10-06 | Imclone Llc | Human anti-epidermal growth factor receptor antibody |
US7576221B2 (en) | 2004-06-18 | 2009-08-18 | Novartis Vaccines And Diagnostics, Inc. | Substituted imidazole derivatives |
ES2381557T3 (es) | 2004-08-03 | 2012-05-29 | Innate Pharma | Métodos terapéuticos y de diagnóstico y composiciones para determinar 4IG-B7-H3 y su receptor homólogo en las células NK |
US7449486B2 (en) | 2004-10-19 | 2008-11-11 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
WO2006060737A2 (en) | 2004-12-03 | 2006-06-08 | Takeda San Diego, Inc. | Mitotic kinesin inhibitors |
BRPI0515745A (pt) | 2004-12-09 | 2008-08-05 | Centocor Inc | imunoconjugados de antiintegrina, métodos e usos |
GB0428250D0 (en) | 2004-12-23 | 2005-01-26 | Novartis Ag | Organic compounds |
DE602006013275D1 (de) | 2005-01-07 | 2010-05-12 | Diadexus Inc | Ovr110-antikörperzusammensetzungen und verwendungsverfahren dafür |
ES2498794T3 (es) | 2005-02-18 | 2014-09-25 | Medarex, L.L.C. | Anticuerpos monoclonales contra CD30 que carecen de restos fucosilo |
GB0505969D0 (en) | 2005-03-23 | 2005-04-27 | Novartis Ag | Organic compounds |
DK1912677T3 (da) | 2005-06-20 | 2014-01-13 | Psma Dev Company L L C | PSMA-antistof-lægemiddel-konjugater |
TW200800951A (en) | 2005-08-09 | 2008-01-01 | Novartis Ag | Substituted imidazole compounds as KSP inhibitors |
AU2006283726C1 (en) | 2005-08-24 | 2015-05-07 | Immunogen, Inc. | Process for preparing maytansinoid antibody conjugates |
US8124738B2 (en) | 2005-09-26 | 2012-02-28 | Medarex, Inc. | Human monoclonal antibodies to CD70 |
EP1790664A1 (en) | 2005-11-24 | 2007-05-30 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against claudin-18 for treatment of cancer |
DOP2006000277A (es) | 2005-12-12 | 2007-08-31 | Bayer Pharmaceuticals Corp | Anticuerpos anti mn y métodos para su utilización |
WO2008004834A1 (en) | 2006-07-06 | 2008-01-10 | Isu Abxis Co., Ltd | Humanized monoclonal antibody highly binding to epidermal growth factor receptor, egf receptor |
US8323653B2 (en) | 2006-09-08 | 2012-12-04 | Medimmune, Llc | Humanized anti-CD19 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
EP1911766A1 (en) | 2006-10-13 | 2008-04-16 | Glycotope Gmbh | Use of human cells of myeloid leukaemia origin for expression of antibodies |
EP1900750A1 (en) | 2006-09-18 | 2008-03-19 | Glycotope Gmbh | Fully human high yield production system for improved antibodies |
PL2073842T3 (pl) | 2006-09-10 | 2015-06-30 | Glycotope Gmbh | Zastosowanie ludzkich komórek pochodzących z białaczki szpikowej do ekspresji przeciwciał |
AU2007299843B2 (en) | 2006-09-18 | 2012-03-08 | Xencor, Inc | Optimized antibodies that target HM1.24 |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
PL2099823T5 (pl) | 2006-12-01 | 2023-02-20 | Seagen Inc. | Wariant środków wiążących cel i jego zastosowania |
US8652466B2 (en) | 2006-12-08 | 2014-02-18 | Macrogenics, Inc. | Methods for the treatment of disease using immunoglobulins having Fc regions with altered affinities for FcγRactivating and FcγRinhibiting |
US7820646B2 (en) | 2007-01-05 | 2010-10-26 | Novartis Vaccines And Diagnostics, Inc. | Cyclized derivatives as Eg-5 inhibitors |
WO2008092117A2 (en) | 2007-01-25 | 2008-07-31 | Xencor, Inc. | Immunoglobulins with modifications in the fcr binding region |
CA2680111C (en) | 2007-03-22 | 2018-05-08 | Sloan-Kettering Institute For Cancer Research | Use of the anti-b7h3 (cd276) antibody, 8h9, for the treatment of neuroblastoma tumors |
BRPI0810082A2 (pt) | 2007-03-29 | 2014-10-21 | Novartis Ag | 3-imidazolil-indóis para o tratamento de doenças proliferativas |
WO2008127735A1 (en) | 2007-04-13 | 2008-10-23 | Stemline Therapeutics, Inc. | Il3ralpha antibody conjugates and uses thereof |
NZ556142A (en) | 2007-06-25 | 2009-11-27 | Novartis Ag | Animal remedy dispensing means |
CA2691008A1 (en) | 2007-06-28 | 2008-12-31 | Thomson Licensing | Dual use video mixer crosspoint matrix |
CA2694751C (en) | 2007-08-03 | 2015-07-14 | Facet Biotech Corporation | Therapeutic use of anti-tweak receptor antibodies |
CA2696360C (en) | 2007-08-14 | 2018-11-20 | Ludwig Institute For Cancer Research | Monoclonal antibody targeting the egfr receptor and uses thereof |
WO2009026274A1 (en) | 2007-08-22 | 2009-02-26 | Medarex, Inc. | Site-specific attachment of drugs or other agents to engineered antibodies with c-terminal extensions |
NZ583605A (en) * | 2007-08-29 | 2012-10-26 | Sanofi Aventis | Humanized anti-cxcr5 antibodies, derivatives thereof and their uses |
CA2698287A1 (en) | 2007-09-07 | 2009-03-12 | Agensys, Inc. | Antibodies and related molecules that bind to 24p4c12 proteins |
US8039597B2 (en) | 2007-09-07 | 2011-10-18 | Agensys, Inc. | Antibodies and related molecules that bind to 24P4C12 proteins |
ES2569513T3 (es) | 2007-11-26 | 2016-05-11 | Bayer Intellectual Property Gmbh | Anticuerpos antimesotelina y usos de los mismos |
AU2008331436A1 (en) | 2007-12-06 | 2009-06-11 | Csl Limited | Method of inhibition of leukemic stem cells |
US8252832B2 (en) | 2007-12-14 | 2012-08-28 | Novartis Ag | Kinesin inhibitors as cancer therapeutics |
HUE024291T2 (en) | 2007-12-26 | 2016-01-28 | Biotest Ag | Immunoconjugates and Applications for CD138 |
ES2475201T3 (es) | 2007-12-26 | 2014-07-10 | Biotest Ag | Agentes dirigidos contra CD138 y usos de los mismos |
CN102046195A (zh) | 2008-04-02 | 2011-05-04 | 宏观基因有限公司 | HER2/neu-特异性抗体和其使用方法 |
AU2009246640A1 (en) | 2008-05-15 | 2009-11-19 | Biogen Idec Ma Inc. | Anti-Fn14 antibodies and uses thereof |
CN102137874B (zh) | 2008-08-29 | 2015-02-18 | 西福根有限公司 | 抗表皮生长因子受体的重组抗体组合物 |
US20110275685A1 (en) | 2009-01-26 | 2011-11-10 | Michael Mutz | Salt and polymorphs of a kinesin inhibitor compound |
WO2010112413A1 (en) | 2009-03-31 | 2010-10-07 | Roche Glycart Ag | Treatment of cancer with a humanized anti-egfr igg1 antibody and irinotecan |
AR075982A1 (es) | 2009-03-31 | 2011-05-11 | Roche Glycart Ag | Terapia de combinacion de un anticuerpo afucosilado y una o mas de las citoquinas seleccionadas de gm- csf humano, m -csf humano y/o il-3 humano y composicion |
CN104558179A (zh) | 2009-04-27 | 2015-04-29 | 协和发酵麒麟株式会社 | 用于治疗血液肿瘤的抗IL-3Rα抗体 |
CN101959216B (zh) | 2009-07-20 | 2014-06-18 | 电信科学技术研究院 | 一种分载波配置增强cell_fach的方法、系统和设备 |
US9096877B2 (en) | 2009-10-07 | 2015-08-04 | Macrogenics, Inc. | Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use |
WO2012010582A1 (en) * | 2010-07-21 | 2012-01-26 | Roche Glycart Ag | Anti-cxcr5 antibodies and methods of use |
NZ604510A (en) | 2010-08-17 | 2013-10-25 | Csl Ltd | Dilutable biocidal compositions and methods of use |
CA2833477A1 (en) | 2011-04-21 | 2012-10-26 | Seattle Genetics, Inc. | Novel binder-drug conjugates (adcs) and their use |
CN103747804B (zh) | 2011-06-10 | 2016-08-17 | 梅尔莎纳医疗公司 | 蛋白质-聚合物-药物共轭物 |
US9726666B2 (en) * | 2011-06-13 | 2017-08-08 | Tla Targeted Immunotherapies Ab | Diagnosing and treating inflammatory diseases |
AR088941A1 (es) | 2011-11-23 | 2014-07-16 | Bayer Ip Gmbh | Anticuerpos anti-fgfr2 y sus usos |
UA112096C2 (uk) | 2011-12-12 | 2016-07-25 | Байєр Інтеллектуал Проперті Гмбх | Заміщені триазолопіридини та їх застосування як інгібіторів ttk |
CA2864872C (en) * | 2012-02-24 | 2022-07-05 | Alteogen Inc. | Modified antibody in which motif comprising cysteine residue is bound |
EP2850106B1 (en) | 2012-05-18 | 2022-03-23 | Aptevo Research and Development LLC | Bispecific scfv immunofusion (bif) binding to cd123 and cd3 |
US9872924B2 (en) | 2012-10-19 | 2018-01-23 | Daiichi Sankyo Company, Limited | Antibody-drug conjugate produced by binding through linker having hydrophilic structure |
US9872918B2 (en) | 2012-12-12 | 2018-01-23 | Mersana Therapeutics, Inc. | Hydroxyl-polymer-drug-protein conjugates |
TW201437211A (zh) | 2013-03-01 | 2014-10-01 | Bayer Pharma AG | 經取代咪唑并嗒□ |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
EP2968591A1 (en) * | 2013-03-15 | 2016-01-20 | Novartis AG | Cell proliferation inhibitors and conjugates thereof |
US9498540B2 (en) * | 2013-03-15 | 2016-11-22 | Novartis Ag | Cell proliferation inhibitors and conjugates thereof |
CN105392802B (zh) * | 2013-05-02 | 2019-09-03 | 阿雷斯贸易股份有限公司 | 针对cxcr5的单克隆抗体 |
EP3008090A1 (en) | 2013-06-14 | 2016-04-20 | Bayer Pharma Aktiengesellschaft | Anti-tweakr antibodies and uses thereof |
EP3054991B1 (en) | 2013-10-11 | 2019-04-03 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
KR20160097336A (ko) | 2013-12-12 | 2016-08-17 | 스템센트알엑스 인코포레이티드 | 신규 항-dpep3 항체 및 이의 사용 방법 |
BR112016014830A2 (pt) * | 2013-12-23 | 2017-09-19 | Bayer Pharma AG | Conjugados de fármaco de anticorpo (adcs) com inibidores de ksp |
EA201691827A1 (ru) | 2014-03-12 | 2017-01-30 | Новартис Аг | Конкретные участки для модификации антител с целью получения иммуноконъюгатов |
WO2015189143A1 (en) | 2014-06-12 | 2015-12-17 | Bayer Pharma Aktiengesellschaft | Aglycosyl anti-tweakr antibodies and uses thereof |
WO2016020791A1 (en) | 2014-08-05 | 2016-02-11 | Novartis Ag | Ckit antibody drug conjugates |
US9765146B2 (en) * | 2014-08-22 | 2017-09-19 | Sorrento Therapeutics, Inc. | Fully human anti-CXC chemokine receptor 5 (CXCR5) antibodies |
SG11201701128YA (en) * | 2014-09-12 | 2017-03-30 | Genentech Inc | Cysteine engineered antibodies and conjugates |
TW201709932A (zh) | 2015-06-12 | 2017-03-16 | 西雅圖遺傳學公司 | Cd123抗體及其共軛物 |
SG10201908685QA (en) * | 2015-06-22 | 2019-10-30 | Bayer Pharma AG | Antibody drug conjugates (adcs) and antibody prodrug conjugates (apdcs) with enzymatically cleavable groups |
JP2018524313A (ja) | 2015-06-23 | 2018-08-30 | バイエル ファーマ アクチエンゲゼルシャフト | キネシンスピンドルタンパク質(ksp)阻害剤の抗b7h3抗体との抗体薬物複合体 |
CN107921146A (zh) | 2015-06-23 | 2018-04-17 | 拜耳医药股份有限公司 | 纺锤体驱动蛋白(ksp)抑制剂与抗‑cd123的抗体的抗体药物缀合物(adc) |
JP6905941B2 (ja) | 2015-06-23 | 2021-07-21 | バイエル ファーマ アクチエンゲゼルシャフト | キネシンスピンドルタンパク質(ksp)阻害剤の抗b7h3抗体との抗体薬物複合体 |
BR112017027811A2 (pt) * | 2015-06-23 | 2018-08-28 | Bayer Pharma AG | conjugados específicos de inibidores de ksp |
US20180318438A1 (en) | 2015-06-23 | 2018-11-08 | Bayer Pharma Aktiengesellschaft | Antibody drug conjugates of kinesin spindel protein (ksp) inhibitors with anti-tweakr-antibodies |
PE20181852A1 (es) * | 2016-03-24 | 2018-12-03 | Bayer Pharma AG | Profarmacos de farmacos citotoxicos que tienen grupos enzimaticamente escindibles |
US11001636B2 (en) | 2016-06-15 | 2021-05-11 | Bayer Pharma Aktiengesellschaft | Specific antibody-drug-conjugates (ADCs) with KSP inhibitors and anti-CD123-antibodies |
US20190351066A1 (en) | 2016-12-21 | 2019-11-21 | Bayer Aktiengesellschaft | Prodrugs of cytotoxic active agents having enzymatically cleavable groups |
CA3047489A1 (en) | 2016-12-21 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Antibody drug conjugates (adcs) having enzymatically cleavable groups |
CA3047522A1 (en) | 2016-12-21 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Specific antibody drug conjugates (adcs) having ksp inhibitors |
CN112601553A (zh) | 2018-06-18 | 2021-04-02 | 拜耳股份有限公司 | 具有可酶切的接头和改善的活性谱的针对cxcr5的结合剂-药物缀合物 |
AU2019376293A1 (en) | 2018-11-05 | 2021-06-03 | Bayer Pharma Aktiengesellschaft | Cytostatic conjugates with integrin ligands |
-
2017
- 2017-12-14 CA CA3047489A patent/CA3047489A1/en active Pending
- 2017-12-14 RU RU2019122802A patent/RU2761390C2/ru active
- 2017-12-14 EP EP17837949.1A patent/EP3558388A1/de active Pending
- 2017-12-14 KR KR1020197020706A patent/KR102556826B1/ko active IP Right Grant
- 2017-12-14 CN CN201780087040.6A patent/CN110312534B/zh active Active
- 2017-12-14 PE PE2019001293A patent/PE20191235A1/es unknown
- 2017-12-14 BR BR112019012883A patent/BR112019012883A2/pt unknown
- 2017-12-14 JP JP2019533395A patent/JP7066714B2/ja active Active
- 2017-12-14 WO PCT/EP2017/082789 patent/WO2018114578A1/de unknown
- 2017-12-14 IL IL291308A patent/IL291308B1/en unknown
- 2017-12-14 US US16/472,749 patent/US11660351B2/en active Active
- 2017-12-14 MX MX2019007641A patent/MX2019007641A/es unknown
- 2017-12-14 AU AU2017380871A patent/AU2017380871A1/en active Pending
- 2017-12-14 IL IL310558A patent/IL310558A/en unknown
- 2017-12-14 KR KR1020237018663A patent/KR102628678B1/ko active IP Right Grant
- 2017-12-14 CN CN202310307417.1A patent/CN116327974A/zh active Pending
- 2017-12-14 KR KR1020237018668A patent/KR102583006B1/ko active IP Right Grant
- 2017-12-19 TW TW111134796A patent/TWI823564B/zh active
- 2017-12-19 TW TW106144529A patent/TWI781125B/zh active
- 2017-12-21 AR ARP170103619A patent/AR110418A1/es unknown
-
2019
- 2019-06-18 IL IL267473A patent/IL267473B/en unknown
-
2021
- 2021-09-01 US US17/464,565 patent/US11478554B2/en active Active
-
2022
- 2022-04-26 JP JP2022072343A patent/JP7307231B2/ja active Active
-
2023
- 2023-03-10 US US18/182,093 patent/US20230338559A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007064759A2 (en) * | 2005-11-29 | 2007-06-07 | The Scripps Research Institute | Inhibiting tumour cell invasion, metastasis and angiogenesis through targetting legumain |
WO2016096610A1 (de) * | 2014-12-15 | 2016-06-23 | Bayer Pharma Aktiengesellschaft | Antikörper-wirkstoff-konjugate (adcs) von ksp-inhibitoren mit aglycosylierten anti-tweakrantikörpern |
Non-Patent Citations (1)
Title |
---|
網路文獻 Wang, Y. et.al., Protease-Activatable Hybrid Nanoprobe for Tumor Imaging. Advanced Functional Materials, 24(34) (2014) page: 5443–5453. * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI781125B (zh) | 具有酶裂解基團之抗體-藥劑結合物 | |
JP7174704B2 (ja) | 酵素開裂基を有する細胞毒性活性剤のプロドラッグ | |
US11806404B2 (en) | Site specific homogeneous with KSP inhibitors | |
JP7251981B2 (ja) | 酵素開裂基を有する細胞毒性活性剤のプロドラッグ | |
US20220362392A1 (en) | Specific antibody drug conjugates (adcs) having ksp inhibitors | |
KR20210033470A (ko) | 효소에 의해 절단 가능한 링커 및 개선된 활성 프로파일을 갖는, cxcr5에 대해 유도된 결합제-약물 접합체 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
GD4A | Issue of patent certificate for granted invention patent |