TWI471334B - 抗體-藥物共軛體 - Google Patents
抗體-藥物共軛體 Download PDFInfo
- Publication number
- TWI471334B TWI471334B TW101110867A TW101110867A TWI471334B TW I471334 B TWI471334 B TW I471334B TW 101110867 A TW101110867 A TW 101110867A TW 101110867 A TW101110867 A TW 101110867A TW I471334 B TWI471334 B TW I471334B
- Authority
- TW
- Taiwan
- Prior art keywords
- antibody
- seq
- cancer
- drug conjugate
- drug
- Prior art date
Links
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims description 72
- 239000000611 antibody drug conjugate Substances 0.000 title claims description 67
- 206010028980 Neoplasm Diseases 0.000 claims description 63
- 239000003814 drug Substances 0.000 claims description 54
- 230000027455 binding Effects 0.000 claims description 52
- 229940079593 drug Drugs 0.000 claims description 50
- 239000000427 antigen Substances 0.000 claims description 46
- 108091007433 antigens Proteins 0.000 claims description 46
- 102000036639 antigens Human genes 0.000 claims description 46
- 201000011510 cancer Diseases 0.000 claims description 41
- 125000005647 linker group Chemical group 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 31
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 13
- -1 maleimide-mercapto-proline Chemical compound 0.000 claims description 12
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 11
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 11
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 claims description 10
- 125000000539 amino acid group Chemical group 0.000 claims description 10
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid 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=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 claims description 9
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 8
- 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 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 102000006388 human trophoblastic glycoprotein 5T4 Human genes 0.000 claims description 6
- 108010083654 human trophoblastic glycoprotein 5T4 Proteins 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 229960002173 citrulline Drugs 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 66
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 16
- 210000004881 tumor cell Anatomy 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 12
- 108060003951 Immunoglobulin Proteins 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 11
- 239000000562 conjugate Substances 0.000 description 11
- 102000018358 immunoglobulin Human genes 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 241000282693 Cercopithecidae Species 0.000 description 10
- 230000012010 growth Effects 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 229940127089 cytotoxic agent Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 108091033319 polynucleotide Proteins 0.000 description 9
- 102000040430 polynucleotide Human genes 0.000 description 9
- 239000002157 polynucleotide Substances 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 description 8
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 description 8
- 125000003396 thiol group Chemical class [H]S* 0.000 description 8
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 108091026890 Coding region Proteins 0.000 description 5
- 101100425828 Mus musculus Tpbg gene Proteins 0.000 description 5
- 239000002254 cytotoxic agent Substances 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 231100000599 cytotoxic agent Toxicity 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- 206010014733 Endometrial cancer Diseases 0.000 description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 description 3
- 206010057644 Testis cancer Diseases 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 201000003120 testicular cancer Diseases 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- WOWDZACBATWTAU-FEFUEGSOSA-N (2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-n-[(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]-n,3-dimethylbutanamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 WOWDZACBATWTAU-FEFUEGSOSA-N 0.000 description 2
- 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 2
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 description 2
- OKARNAREDZHGLR-UHFFFAOYSA-N 1,3-diiodopropan-2-one Chemical compound ICC(=O)CI OKARNAREDZHGLR-UHFFFAOYSA-N 0.000 description 2
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 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 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 101100288142 Mus musculus Klkb1 gene Proteins 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 102000004243 Tubulin Human genes 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
- NMPVEAUIHMEAQP-UHFFFAOYSA-N alpha-bromo-acetaldehyde Natural products BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 108010044540 auristatin Proteins 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
- IAQRGUVFOMOMEM-ARJAWSKDSA-N cis-but-2-ene Chemical compound C\C=C/C IAQRGUVFOMOMEM-ARJAWSKDSA-N 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 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 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 2
- XJTQJERLRPWUGL-UHFFFAOYSA-N iodomethylbenzene Chemical compound ICC1=CC=CC=C1 XJTQJERLRPWUGL-UHFFFAOYSA-N 0.000 description 2
- 210000004901 leucine-rich repeat Anatomy 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- 239000004094 surface-active agent Substances 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
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 231100000588 tumorigenic Toxicity 0.000 description 2
- 230000000381 tumorigenic effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- 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 compound 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
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-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
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- AQYNZOSCOWGGTP-UHFFFAOYSA-N 2-pyridin-2-ylsulfanylpyridine Chemical compound C=1C=CC=NC=1SC1=CC=CC=N1 AQYNZOSCOWGGTP-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-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
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- YAUQCRXGRYJZBA-NRFANRHFSA-N C(CCCCC)[C@@]1(N(CCC1)CCCCCCCCCC)C(=O)O Chemical compound C(CCCCC)[C@@]1(N(CCC1)CCCCCCCCCC)C(=O)O YAUQCRXGRYJZBA-NRFANRHFSA-N 0.000 description 1
- 241000288952 Callithrix argentata Species 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 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
- 102000053602 DNA Human genes 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010011906 Death Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101001050473 Homo sapiens Intelectin-1 Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 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
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 102100023353 Intelectin-1 Human genes 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 108010006444 Leucine-Rich Repeat Proteins Proteins 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 241000187722 Micromonospora echinospora Species 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- GHAZCVNUKKZTLG-UHFFFAOYSA-N N-ethyl-succinimide Natural products CCN1C(=O)CCC1=O GHAZCVNUKKZTLG-UHFFFAOYSA-N 0.000 description 1
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 1
- ODQUDRGGWYOGBJ-UHFFFAOYSA-N NN.C=C Chemical compound NN.C=C ODQUDRGGWYOGBJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 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
- 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
- 239000013543 active substance Substances 0.000 description 1
- 239000000488 activin Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012131 assay buffer Substances 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
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin 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
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical class CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 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 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 150000002337 glycosamines Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 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
- 229960000908 idarubicin Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 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
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001972 liquid chromatography-electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 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
- 230000009401 metastasis Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229960004857 mitomycin 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
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008884 pinocytosis Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- WYDUSKDSKCASEF-UHFFFAOYSA-N procyclidine Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCC1 WYDUSKDSKCASEF-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 239000001990 protein-drug conjugate Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006578 reductive coupling reaction Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 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 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 229960001612 trastuzumab emtansine 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
- 229960004528 vincristine Drugs 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
- 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
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- 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
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pulmonology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本發明大抵關於用於治療癌之抗5T4抗體-藥物共軛體。
抗體-藥物共軛體(ADC)兼具單株抗體之結合特異性及化學治療劑之效力。與發展抗腫瘤相關性標靶分子之單株抗體有關之技術、更有效之細胞毒性劑之用途及共價結合這些成份之化學連接子的設計,在近年來已快速進展(Ducry L.,et al.Bioconjugate Chemistry,21:5-13,2010)。
極具潛力之ADC諸如SGN-75(US2009/148942)和曲妥珠單抗(trastuzumab)-DM1(US2009/0226465)目前正進行臨床試驗。然而,因考慮以其他腫瘤相關性抗原作為標靶,仍存在許多挑戰。各種單株抗體必須被分別特徵化並設計適當之連接子,並且識別在遞送至腫瘤細胞時仍保留彼之效力之適當細胞毒性劑。必須考慮癌標靶上之抗原密度,及正常組織是否表現該標靶抗原。其他考量包括當與標靶結合時該整個ADC是否被內化、考慮可能的正常組織暴露及/或欲治療之癌類型及分期時以選用細胞靜止劑或細胞毒性劑為較佳、及連接該抗體與該載荷藥物之連接子係可被切割或不可切割之鍵結。另外,該抗體對藥物基團之共軛比必須足夠,且不損害該抗體之結合活性及/或該藥物之效力。很明顯地,ADC係複雜之生物製劑,且發展有
效ADC之挑戰仍然很高。
人5T4腫瘤相關性抗原係本發明之標靶抗原。最近已有資料顯示,該5T4抗原係以高量表現於某些高成瘤性細胞上,這些高成瘤性細胞亦稱為引發腫瘤細胞(WO2010/111659)。引發腫瘤細胞顯示對標準療法之抗藥性,其被認為是造成腫瘤復發及轉移的原因,因此代表另一種ADC發展之障礙。
本發明之新穎的抗5T4 ADC克服該些與ADC技術相關之挑戰,提供能與表現5T4抗原之腫瘤細胞結合且遞送足夠細胞毒性藥物至該等細胞之高特異性及強效之ADC,因此提供創新且有效之癌治療。
在一實施態樣中,本發明之抗體-藥物共軛體具有下式:Ab-(LU-D)p
或彼之醫藥上可接受之鹽,其中Ab係抗5T4抗體或彼之抗原結合部位,該抗5T4抗體或彼之抗原結合部位包含具有如SEQ ID NO:5所示之VH CDR1區、如SEQ ID NO:6所示之VH CDR2區及如SEQ ID NO:7所示之VH CDR3區之重鏈可變區,LU係選自順丁烯二醯亞胺基己醯基或順丁烯二醯亞胺基己醯基-纈胺酸(Val)-瓜胺酸(Cit)-PABA之連接子單位,p
係自約1至約8之整數,且D係選自MMAE、MMAF或MMAD之藥物單位。
本發明另提供抗5T4抗體-藥物共軛體,其中該抗
5T4抗體或彼之抗原結合部位包含具有(a)如SEQ ID NO:5所示之VH CDR1區、(b)如SEQ ID NO:6所示之VH CDR2區、及(c)如SEQ ID NO:7所示之VH CDR3區之重鏈可變區。
本發明另提供抗5T4抗體-藥物共軛體,其中該抗ST4抗體或彼之抗原結合部位包含具有(a)如SEQ ID NO:8所示之VL CDR1區、(b)如SEQ ID NO:9所示之VL CDR2區、及(c)如SEQ ID NO:10所示之VL CDR3區之輕鏈可變區。
本發明另提供抗5T4抗體-藥物共軛體,其中該抗5T4抗體或彼之抗原結合部位另包含重鏈可變區及輕鏈可變區,該重鏈可變區具有(a)如SEQ ID NO:5所示之VH CDR1區、(b)如SEQ ID NO:6所示之VH CDR2區、及(c)如SEQ ID NO:7所示之VH CDR3區,且該輕鏈可變區具有(a)如SEQ ID NO:8所示之VL CDR1區、(b)如SEQ ID NO:9所示之VL CDR2區、及(c)如SEQ ID NO:10所示之VL CDR3區。
本發明另提供一種抗5T4抗體-藥物共軛體,其中該抗5T4抗體或彼之抗原結合部位包含SEQ ID NO:3之VH區及SEQ ID NO:4之VL區。
本發明另提供一種抗5T4抗體-藥物共軛體,其中該抗5T4抗體係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成。
本發明另提供一種抗5T4抗體-藥物共軛體,其中:
(a)該抗5T4抗體係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成、(b)該LU係順丁烯二醯亞胺基己醯基、(c)該藥物係MMAF、及(d)p
係大約4之整數。
本發明另提供一種抗5T4抗體-藥物共軛體,其中:(a)該抗ST4抗體係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成、(b)該LU係順丁烯二醯亞胺基己醯基-Val-Cit-PABA、(c)該藥物係MMAE、及(d)p
係大約4之整數。
本發明另提供一種抗5T4抗體-藥物共軛體,其中(a)該抗5T4抗體係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成、(b)該LU係順丁烯二醯亞胺基己醯基-Val-Cit-PABA、(c)該藥物係MMAD、及(d)p
係自約1至約8之整數。
本發明另提供一種抗5T4抗體-藥物共軛體,其中:(a)該抗5T4抗體係由具有SEQ ID NO:15之重鏈及具有SEQ ID NO:2之輕鏈組成、(b)該LU係順丁烯二醯亞胺基己醯基-Val-Cit-PABA、(c)該藥物係MMAE、及(d)p
係自約1至約8之整數。
本發明提供一種抗5T4抗體-藥物共軛體,其中該抗體辨識人5T4抗原上之表位,其中該表位包含SEQ ID NO:11之胺基酸序列的胺基酸殘基173至258及282至361。
本發明提供一種醫藥組成物,其包含上述之抗體-藥物共軛體及醫藥上可接受之載劑。
本發明另提供一種治療有需要治療之病患的5T4陽性癌之方法,該方法包含對該病患投予上述之抗體-藥物共軛體。
本發明另提供一種治療5T4陽性癌之方法,其中該癌係選自膀胱癌、乳癌、子宮頸癌、結腸癌、子宮內膜癌、腎癌、肺癌、食道癌、卵巢癌、***癌、胰癌、肝癌、皮膚癌、胃癌或睪丸癌。
更佳地,本發明提供一種治療5T4陽性癌之方法,其中該癌係選自結直腸癌、乳癌、胰癌或非小細胞肺癌。
本發明另提供一種用於治療之上述之抗體-藥物共軛體。
本發明另提供一種上述之抗體-藥物共軛體於製造藥物之用途。
本發明另提供上述之用途,其中該用途係治療5T4陽性癌且其中該癌係選自膀胱癌、乳癌、子宮頸癌、子宮內膜癌、腎癌、肺癌、食道癌、卵巢癌、***癌、胰癌、皮膚癌、胃癌或睪丸癌。
更佳地,本發明另提供上述之用途,其中該用途係治療5T4陽性癌且其中該癌係選自結直腸癌、乳癌、胰癌或非小細胞肺癌。
本發明另提供編碼抗5T4抗體之核酸、包含該核酸之載體及包含該載體之宿主細胞。
本發明另提供一種產製抗5T4抗體之方法,該方法包含培養包含該上述之載體之宿主細胞及自該細胞培養回收
該抗體。
本發明另提供一種產製抗5T4抗體-藥物共軛體之方法,該方法包含:(a)取得自該細胞培養回收之抗體,(b)使該抗體經由選自順丁烯二醯亞胺基己醯基或順丁烯二醯亞胺基己醯基-Val-Cit之連接子單位與選自MMAE、MMAD或MMAF之藥物單位化學連接,及(c)純化該抗體-藥物共軛體。
本發明提供用於治療癌之抗5T4抗體-藥物共軛體。為了更清楚地瞭解本發明,首先定義一些用語。
本揭示內容中使用之所有胺基酸縮寫係該些於37 C.F.R.§ 1.822(B)(I)闡述之美國專利商標局接受之縮寫。
5T4係指5T4腫瘤胎兒抗原,其為72 kDa之高度糖基化的跨膜糖蛋白,該跨膜糖蛋白包含42 kDa之非糖基化核心(見US 5,869,053)。人5T4係表現於多種癌類型,包括膀胱癌、乳癌、子宮頸癌、結腸癌、子宮內膜癌、腎癌、肺癌、食道癌、卵巢癌、***癌、胰癌、肝癌、皮膚癌、胃癌及睪丸癌。高成瘤性細胞又稱為癌幹細胞或引發腫瘤細胞已經顯示具有高量之5T4表現(WO2010/111659)。本發明之抗5T4抗體包括與該人5T4抗原特異性結合之抗體(見US 2007/0231333)。
「抗體」係免疫球蛋白分子,其可透過位於該免疫球蛋白分子之可變區的至少一個抗原辨認區特異性地與目標
結合,諸如碳水化合物、多核苷酸、脂肪、多肽等。此處所使用之「抗體」不僅包含完整之多株或單株抗體,亦包含彼等之任何抗原結合片段(即「抗原結合部位」)或單鏈、包含抗體之融合蛋白及包含抗原辨認區之免疫球蛋白分子的任何其他經修飾之構型,包括例如但不限於Fab、Fab’、F(ab’)2
、由VH和CH1結構域組成之Fd片段、由抗體之單臂的VL和VH結構域組成之Fv片段、經分離之互補決定區(CDR)、scFv、單結構域抗體(例如鯊魚及駱駝抗體)、大型抗體(maxibodies)、迷你抗體(minibodies)、細胞內抗體(intrabodies)、雙價抗體、三價抗體、四價抗體、v-NAR及bis-scFv。
抗體包括任何類型之抗體,諸如IgG、IgA或IgM(或彼等之亞型),且該抗體不需要是任何特定類型。根據彼之重鏈的恆定區之抗體胺基酸序列,免疫球蛋白可被分成不同類型。有五種主要的免疫球蛋白類型:IgA、IgD、IgE、IgG及IgM,其中某些類型可進一步分成亞型(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。對應不同類型之免疫球蛋白的重鏈恆定區分別被稱為α、δ、ε、γ和μ。不同類型之免疫球蛋白的次單位結構及三維構型係廣為週知。
抗體之「可變區」係指抗體輕鏈之可變區或抗體重鏈之可變區(不論單獨或組合)。如該領域所知,重鏈及輕鏈之可變區各由四個架構區(FR)及連接該四個架構區之三個互補決定區(CDR)(亦稱為超變異區)組成,以形成該抗體
之抗原結合部位。若主體可變區之變異體係為所欲,特別是具有CDR區以外(即架構區)之胺基酸殘基取代,適當之胺基酸取代(較佳地保守性胺基酸取代)可藉由比較該主體可變區與其他包含和該主體可變區相同之典範類型(canonical class)的CDR1及CDR2序列之抗體的可變區加以識別(Chothia and Lesk,J Mol Biol 196(4):901-917,1987)。當選擇FR以於旁側連接主體CDR時,例如當人化或最佳化抗體時,源自包含該相同典範類型之CDR1及CDR2序列的抗體之FR係較佳。
可變結構域之「CDR」係位於可變區內之胺基酸殘基,其係根據卡巴(Kabat)定義、柯西亞(Chothia)定義、卡巴及柯西亞二者之累積定義、AbM定義、接觸定義、及/或構形定義、或該領域廣為周知之任何CDR測定方法加以識別。抗體CDR可能被識別為原本由卡巴等人所定義之超變異區。見例如Kabat et al.,1992,Sequences of Proteins of Immunological Interest,5th ed.,Public Health Service,NIH,Washington,D.C.。該等CDR之位置亦可能被識別為最初由柯西亞等人所描述之結構環狀結構。見例如Chothia et al.,1989,Nature 342:877-883。其他其他識別CDR之方法包括「AbM定義」(其係卡巴法及柯西亞法之折衷,源自利用牛津分子(Oxford Molecular)之AbM抗體模式軟體(現為Accelrys®
)),或如MacCallum et al.,1996,J.Mol.Biol.,262:732-745所述以觀察到之抗原接觸為基礎之CDR的「接觸定義」。在此處稱為CDR之「構形定義」之
另一方法中,CDR之位置可能被鑑別為對抗原結合造成焓貢獻之殘基。見例如Makabe et al.,2008,Journal of Biological Chemistry,283:1156-1166。其他CDR邊界定義可能不嚴格遵守上述方法中之一者,但將與至少部分之卡巴CDR重疊,雖然它們可能根據特定殘基或殘基群或甚至整個CDR不顯著影響抗原結合之預測或實驗結果被縮短或延長。此處所使用之CDR可能指由該領域已知之任何方法(包括多種方法之組合)所定義之CDR。此處所使用之方法可利用根據這些方法中任一者所定義之CDR。以包含超過一種CDR之任何給定實施態樣而言,該CDR可根據卡巴、柯西亞、延長、AbM、接觸及/或構形定義中任一者加以定義。
用語「單株抗體」(Mab)係指源自單一細胞或細胞株之抗體,包括例如任何真核、原核或噬菌體株,並不是指彼之產製方法。較佳地,本發明之單株抗體存在於均質或實質上均質之族群。
「人化」抗體係指非人(例如鼠)抗體之形式,其為包含源自非人免疫球蛋白之最少序列之嵌合性免疫球蛋白、免疫球蛋白鏈或彼等之片段(諸如Fv、Fab、Fab’、F(ab’)2
)或抗體之其他抗原結合子序列)。較佳地,人化抗體係其中源自接受者之互補決定區(CDR)的殘基被源自諸如具有該所欲特異性、親和性及能力之小鼠、大鼠或兔等非人物種(捐贈者抗體)之CDR的殘基所取代之人免疫球蛋白(接受者抗體)。
用語「嵌合抗體」係用來指其中該可變區序列係源自一物種且該恆定區序列係源自另一物種之抗體,諸如其中該可變區序列係源自小鼠抗體且該恆定區序列係源自人抗體之抗體。
本發明之抗體可利用該領域廣為周知之技術製備,例如重組技術、噬菌體展示技術、合成技術或該等技術之組合、或該領域已知之其他技術(見例如Jayasena,S.D.,Clin.Chem.,45:1628-50(1999)及Fellouse,F.A.,et al,J.Mol.Biol.,373(4):924-40(2007))。
下表1及2說明用於本發明之抗體之較佳CDR。
本發明包括一種抗體或彼之抗原結合部位,該抗體或
彼之抗原結合部位包含:a)輕鏈可變區,該輕鏈可變區包含:i)具有選自SEQ ID NO:8或17之胺基酸序列的LCDR1,ii)具有選自SEQ ID NO:9或18之胺基酸序列的LCDR2,及iii)具有選自SEQ ID NO:10或19之胺基酸序列的LCDR3,和b)重鏈可變區,該重鏈可變區包含:i)具有選自SEQ ID NO:5或22之胺基酸序列的HCDR1,ii)具有選自SEQ ID NO:6或23之胺基酸序列的HCDR2,及iii)具有選自SEQ ID NO:7或24之胺基酸序列的HCDR3。
本發明之較佳抗體或彼之抗原結合部位包含:a)LCVR,其包含SEQ ID NO:8之LCDR1、SEQ ID NO:9之LCDR2及SEQ ID NO:10之LCDR3,及b)HCVR,其包含SEQ ID NO:5之HCDR1、SEQ ID NO:6之HCDR2及SEQ ID NO:7之HCDR3。
本發明之較佳單株抗體在此處被稱為A1(人化抗5T4 IgG1抗體)、A1-IgG4(人化抗5T4 IgG4抗體)、A3(小鼠/人嵌合抗體)、及A3hu(人化抗5T4 IgG1抗體)。編碼單株抗體A1、A1-IgG4及A3之胺基酸序列的SEQ ID NO係提供於
下表3:
用語「辨識抗原之抗體」及「對抗原具特異性之抗體」在此處可與用語「與抗原特異性結合之抗體」互相交換使用。
抗5T4抗體-藥物共軛體係指抗5T4抗體或彼之抗原結合部位如此處所述之經由連接子單位分子(LU)與細胞毒性藥物基團(D)連接。
連接子單位(LU):LU描述該抗體與該藥物間之直接或間接鍵結。將連接子連接至mAb可經由許多方式完成,諸如經由表面離胺酸、還原偶合至經氧化之碳水化合物、及經由還原鏈間雙硫鍵所釋放之半胱胺酸殘基。多種ADC鍵接系統係該領域所知,包括以腙、雙硫及肽為基底之鍵接。
藥物(D):藥物係具有生物性或可偵測之活性之任何物質(例如治療劑、可偵測之標記、結合劑等)及在活體內被代謝成活性劑之前藥。用語「藥物」及「載荷藥物」可互相交換使用。在一些實施態樣中,該藥物係耳抑素(auristatin),諸如耳抑素E(該領域亦稱之為海兔毒素(dolastatin)-10之衍生物)或彼之衍生物。該耳抑素可為例如由耳抑素E和
酮酸形成之酯。舉例來說,耳抑素E可與對乙醯基苯甲酸或苯甲醯基戊酸反應以分別產生AEB及AEVB。其他典型耳抑素包括AFP、MMAF及MMAE。示範性耳抑素之合成及結構係描述於美國專利第6,884,869、7,098,308、7,256,257、7,423,116、7,498,298及7,745,394號,各以參照方式整體納入此處以符合所有目的。
耳抑素已經顯示可干擾微管動力學及核***和細胞***,且具有抗癌活性。本發明之耳抑素與微管蛋白結合,並展示對5T4表現細胞或細胞系之細胞毒性或細胞靜止效應。有一些該領域已知之不同的檢測方法可被用於測定耳抑素或其形成之抗體-藥物共軛體是否對所欲之細胞或細胞系展現細胞靜止或細胞毒性效應。測定化合物是否與微管蛋白結合之方法係該領域所知。見例如Muller et al.,Anal.Chem 2006,78,4390-4397、Hamel et al.,Molecular Pharmacology,1995 47:965-976、及Hamel et al.,The Journal of Biological Chemistry,1990 265:28,17141-17149。
藥物或載荷藥物之實例係選自DM1(美坦素(maytansine)、N2'-去乙醯基-N2'-(3-氫硫基-1-側氧基丙基)-或N2'-去乙醯基-N2'-(3-氫硫基-1-側氧基丙基)-美坦素)、mc-MMAD(6-順丁烯二醯亞胺基己醯基-一甲基耳抑素-D或N-甲基-L-異纈胺醯基-N-[(1S,2R)-2-甲氧基-4-[(2S)-2-[(1R,2R)-1-甲氧基-2-甲基-3-側氧基-3-[[(1S)-2-苯基-1-(2-噻唑基)乙基]胺基]丙基]-1-吡咯啶基]-1-[(1S)-1-甲基丙基]-4-側氧基丁
基]-N-甲基-(9Cl)-L-纈胺醯胺)、mc-MMAF(順丁烯二醯亞胺基己醯基-一甲基耳抑素F或N-[6-(2,5-二氫-2,5-二側氧基-1H-吡咯-1-基)-1-側氧基己基]-N-甲基-L-異纈胺醯基-L-異纈胺醯基-(3R,4S,5S)-3-甲氧基-5-甲基-4-(甲基胺基)庚醯基-(αR,βR,2S)-β-甲氧基-α-甲基-2-吡咯啶基丙醯基-L-***酸)、或mc-Val-Cit-PABA-MMAE(6-順丁烯二醯亞胺基己醯基-ValcCit-(p-胺基苯甲氧基羰基)-一甲基耳抑素E或N-[[[4-[[N-[6-(2,5-二氫-2,5-二側氧基-1H-吡咯-1-基)-1-側氧基己基]-L-異纈胺醯基-N5-(胺基羰基)-L-鳥胺醯基]胺基]苯基]甲氧基]羰基]-N-甲基-L-異纈胺醯基-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-羥基-1-甲基-2-苯基乙基]胺基]-1-甲氧基-2-甲基-3-側氧基丙基]-1-吡咯啶基]-2-甲氧基-1-[(1S)-1-甲基丙基]-4-側氧基丁基]-N-甲基-L-纈胺醯胺)。DM1係微管蛋白抑制劑美坦素之衍生物,而MMAD、MMAE及MMAF係耳抑素衍生物。本發明之較佳的載荷藥物係選自mc-MMAF或mc-Val-Cit-PABA-MMAE。
用語「表位」係指能被抗體之一或多個抗原結合區所辨認及結合之分子的部位。表位通常係由分子之化學活性表面基團組成,諸如胺基酸或糖側鏈,且具有特定三維結構特徵以及特定電荷特徵。此處使用之用語「抗原性表位」係定義為多肽之一部分,該部分藉由該領域廣為周知之任何方法(例如習用之免疫測定法)測定可被抗體專一性結合。「非線性表位」或「構型表位」包含在抗原性蛋白質內之不連續多肽(或胺基酸),該不連續多肽(或胺基酸)被對該表位
具專一性之抗體所結合。
此處所使用之用語「結合親和性(KD
)」係意圖指稱特定抗原-抗體交互作用之解離常數。KD
係解離速率(亦稱"off-rate (koff
)")對結合速率(或稱"on-rate(kon
)")之比。因此,KD
等於koff
/kon
,並以莫耳濃度(M)表示。由此可知當KD
越小時,該結合之親和性越強。因此,KD
等於1 μM表示相較於KD
等於1 nM具有微弱之結合親和性。抗體之KD
值可利用該領域完整建立之方法測定。一種用於測定抗體之KD
之方法係利用表面電漿共振(SPR),通常使用諸如Biacore®
系統之生物感測器系統。
此處所使用之用語「特異性結合」關於抗體與5T4抗原之間的結合且在25℃以SPR測定時該抗體以小於約30 nM之KD
與該5T4抗原結合。
此處所使用之醫藥上可接受之鹽係指分子或巨分子之醫藥上可接受之有機或無機鹽。
用語「效力」係生物活性之測量值,可以IC50
表示,或如實施例3所描述之抑制50%之5T4陽性細胞系生長所需之抗體的有效濃度。或者,效力可能指如實施例4所示之活體內腫瘤異種移植模式中測定之抗腫瘤活性。
此處所使用之用語「多核苷酸」或「核酸分子」係意圖包括DNA分子及RNA分子。核酸分子可為單股或雙股,但較佳係雙股DNA。
編碼本發明之抗體之多核苷酸可能包括下列:僅該變異體之編碼序列、該變異體之編碼序列及額外之編碼序列
諸如功能性多肽或信號或分泌性序列或原蛋白質序列、該抗體之編碼序列及非編碼序列諸如該抗體之編碼序列的內含子或5’及/或3’非編碼序列。用語「編碼抗體之多核苷酸」包含包括額外之變異體的編碼序列之多核苷酸,但亦包含包括額外之編碼及/或非編碼序列之多核苷酸。該領域已知的是,對於特定宿主細胞/表現系統而言最佳化之多核苷酸序列可輕易地得自該所欲蛋白質之胺基酸序列(見GENEART®
AG,德國雷根斯堡(Regensburg,Germany))。
編碼本發明之抗體之多核苷酸通常將包括與該抗體編碼序列可操作性連接之表現控制多核苷酸序列,包括該領域已知之天然相關性或異源性啟動子區域。較佳地,該表現控制序列將為能轉形或轉染真核宿主細胞之載體中的真核啟動子系統,但用於原核宿主之控制序列亦可被使用。一旦該載體被納入適當宿主細胞系之後,該宿主細胞在適合表現該核苷酸序列之條件下增殖,及如所欲,收集及純化該抗體。較佳之真核細胞系包括CHO細胞系、各種COS細胞系、海拉(HeLa)細胞、骨髓瘤細胞系、經轉形之B細胞、或人胚胎腎細胞系。最佳之宿主細胞係CHO細胞系。
本發明包含與5T4抗原上之特定表位結合之抗體或彼等之抗原結合部位。該經識別之表位係非線性或構型表位,其包含在人5T4抗原(SEQ ID NO:11)之胺基酸殘基173與252之間的第一接觸及包含在胺基酸殘基276與355之間的第二接觸(見實施例7)。因此,此處所描述之
CDR及重鏈和輕鏈之可變區被用來製備全長抗體以及功能性片段及類似物,以維持該採用對5T4抗原之上述表位具特異性之CDR的蛋白質之結合親和性。
本發明之抗體的結合親和性係利用SPR測定(實施例6)。在這些試驗中,該5T4抗原係以低密度固定於BIAcore®
晶片上,抗體則流經該晶片。在晶片表面上累積之物質係經測量。此分析方法允許即時測定結合速率及解離速率二者以獲得結合之親和性(KD
)。本發明之人化抗體具有介於約0.30至約30 nM、約0.30至約20 nM、約0.30至約10 nM、約0.5至約7 nM、約1.0至約5 nM、及約1.0至約3 nM之KD
。
該藥物已經或係經修飾以包括與該抗體上之共軛點具反應性之基團。舉例來說,藥物可藉由烷化(例如該抗體之ε-胺基離胺酸或N端)、還原胺化經氧化之碳水化合物、羥基與羧基之間轉酯化、醯胺化胺基或羧基及與硫醇共軛加以連接。在一些實施態樣中,與每個抗體分子共軛之藥物基團的數目p介於1至8、1至7、1至6、1至5、1至4、1至3、或1至2之平均值。在一些實施態樣中,p介於2至8、2至7、2至6、2至5、2至4、或2至3之平均值。在其他實施態樣中,p係1、2、3、4、5、6、7或8之平均值。在一些實施態樣中,p介於約1至約8、約1至約7、約1至約6、約1至約5、約1至約4、約1
至約3、或約1至約2之平均值。在一些實施態樣中,p介於約2至約8、約2至約7、約2至約6、約2至約5、約2至約4、或約2至約3。以可被用於共軛之化學為例,見例如Current Protocols in Protein Science(John Wiley & Sons,Inc.),第15章(蛋白質之化學修飾)(該文獻之揭示內容以參照方式整體納入此處)。
舉例來說,當以化學活化蛋白質導致形成游離硫醇基團時,該蛋白質可能利用氫硫基反應劑共軛。在一態樣中,該劑係實質上對游離硫醇基具特異性之劑。該等劑包括例如順丁烯二醯亞胺、鹵代乙醯胺(例如碘代乙醯胺、溴代乙醯胺或氯代乙醯胺)、鹵代酯(例如碘代酯、溴代酯或氯代酯)、鹵代甲基酮(例如碘代甲基酮、溴代甲基酮或氯代甲基酮)、鹵化苄(例如碘化苄、溴化苄或氯化苄)、乙烯碸及吡啶基硫。
該藥物可藉由連接子與抗體連接。適當之連接子包括例如可切割及不可切割之連接子。可切割之連接子在細胞內之條件下通常易受切割。適當之可切割性連接子包括例如可被細胞內蛋白酶(諸如溶酶體蛋白酶或核內體蛋白酶)切割之肽連接子。在示範性實施態樣中,該連接子可為雙肽連接子,諸如纈胺酸-瓜胺酸(val-cit)、***酸-離胺酸(phe-lys)連接子或順丁烯二醯亞胺基己醯基-纈胺酸-瓜胺酸-p-胺基苯甲氧基羰基(mc-Val-Cit-PABA)連接子。另
一連接子係磺基琥珀醯亞胺基-4-[N-順丁烯二醯亞胺基甲基]環己烷-1-羧酸酯(smcc)。磺基-smcc共軛經由順丁烯二醯亞胺基發生,該順丁烯二醯亞胺基與氫硫基(硫醇基,-SH)反應,同時彼之磺基-NHS酯係對一級胺有反應性(如在離胺酸及該蛋白質或肽N端中可見)。還有另一種連接子係順丁烯二醯亞胺基己醯基(mc)。其他適當之連接子包括可在特定pH或pH範圍內被水解之連接子,諸如腙連接子。其他適當之可切割性連接子包括二硫化物連接子。該連接子可與該抗體共價連接,該共價連接之程度使得該抗體必須在細胞內被降解才能讓該藥物被釋放,例如mc連接子及該類似物。
連接子可包括用於與該抗體鍵接之基團。舉例來說,連接子可包括胺基、羥基、羧基或氫硫基反應基團(例如順丁烯二醯亞胺、鹵代乙醯胺(例如碘代乙醯胺、溴代乙醯胺或氯代乙醯胺)、鹵代酯(例如碘代酯、溴代酯或氯代酯)、鹵代甲基酮(例如碘代甲基酮、溴代甲基酮或氯代甲基酮)、鹵化苄(例如碘化苄、溴化苄或氯化苄)、乙烯碸及吡啶基硫)。一般可見Wong,Chemistry of Protein Conjugation and Cross-linking;CRC Press,Inc.,Boca Raton,1991。
就免疫療法而言,抗體可與適當之藥物共軛,諸如細胞毒性劑、細胞靜止劑、免疫抑制劑、放射性同位素、毒素或該類似物。該共軛體可被用於抑制腫瘤細胞或癌細胞
之增生、造成腫瘤細胞或癌細胞之細胞凋亡、或用於治療病患之癌。該共軛體可據此被用於不同條件以治療動物癌症。該共軛體可被用於遞送藥物至腫瘤細胞或癌細胞。在不受理論束縛之前提下,在一些實施態樣中,該共軛體與癌細胞或腫瘤相關抗原結合或相連,且該共軛體及/或藥物可經由受體媒介性胞飲作用進入腫瘤細胞或癌細胞內。該抗原可附著於腫瘤細胞或癌細胞,或可為與該腫瘤細胞或癌細胞相連之細胞外基質蛋白質。一旦進入細胞內,該共軛體內(例如在連接子中)之一或多種特定肽序列被一或多種腫瘤細胞或癌細胞相關性蛋白酶水解切割,導致釋放該藥物。該經釋放之藥物接著可自由在細胞內移動以誘導細胞毒性或細胞靜止或其他活性。在一些實施態樣中,該藥物係在腫瘤細胞或癌細胞之外與該抗體切割,該藥物接著進入該細胞內或作用在該細胞表面。
如上所述,癌(包括但不限於腫瘤、轉移或其他以不受控制之細胞生長為特徵之疾病或病狀)可藉由投予蛋白質-藥物共軛體加以治療或預防。
在其他實施態樣中,本發明提供治療或預防癌之方法,包括對有需要治療或預防癌之病患投予有效量之共軛體及化學治療劑。在一些實施態樣中,該化學治療劑係指以其治療癌尚未發現有不反應性之劑。在一些實施態樣中,該化學治療劑係指以其治療癌已發現有不反應性之劑。該
共軛體可被投予至亦接受治療(諸如用於治療癌之手術)之病患。在另一實施態樣中,該額外之治療方法係放射療法。
治療癌之方法包括對有需要治療之病患投予有效量之抗體-藥物共軛體及另一種係抗癌劑之治療劑。適當之抗癌劑包括但不限於甲胺喋呤(methotrexate)、紫杉醇(taxol)、L-天冬醯胺酶、巰基嘌呤(mercaptopurine)、硫鳥嘌呤、羥基脲、阿糖胞苷(cytarabine)、環磷醯胺(cyclophosphamide)、異環磷酸胺(ifosfamide)、亞硝基尿素、順鉑(cisplatin)、卡鉑(carboplatin)、絲裂黴素、氮烯唑胺(dacarbazine)、甲基苄肼(procarbizine)、拓撲替康(topotecan)、氮芥子氣、環磷醯胺(cytoxan)、依扥泊苷(etoposide)、5-氟尿嘧啶(5-fluorouracil)、BCNU、伊立替康(irinotecan)、喜樹鹼(camptothecin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、伊達比星(idarubicin)、正定黴素(daunorubicin)、達克黴素(dactinomycin)、普卡黴素(plicamycin)、雙羥葱醌(mitoxantrone)、天冬醯胺酶、長春鹼(vinblastine)、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、太平洋紫杉醇(paclitaxel)、卡利奇黴素(calicheamicin)及多西紫杉醇(docetaxel)。
本發明之ADC可為供投予之醫藥組成物之形式,其係經調製成適用於經選擇之投予模式,及醫藥上可接受之稀釋劑或賦形劑,諸如緩衝劑、界面活性劑、保存劑、助
溶劑、等滲劑、穩定劑、載劑及該類似物。以參照方式納入此處之Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton Pa.,18th
ed.,1995提供該領域通常熟知之調製技術的概要。
這些醫藥組成物可藉由該領域已知之可達成治療癌之一般性目的之任何方法投予。較佳之投予途徑係非口服,在此處定義為包括但不限於靜脈內、肌肉內、腹腔內、皮下及關節內注射及灌注之投予模式。經投予之劑量將視接受者之年齡、健康及體重、併用治療之種類(若有的話)、治療頻率、及所欲效應之性質而定。
在本發明之範圍內的組成物包括其中ADC係以能有效達成治療癌之所欲醫學效應的量存在之所有組成物。雖然個體需求可能因每位病患而異,決定該等所有成份之有效量的理想範圍係具有一般技藝之臨床醫師之能力範圍之內。
5T4-A1抗體藥物共軛體(ADC)之製備係藉由三(2-羧基乙基)膦(TCEP)部分還原該mAb,接著由經還原之Cys殘基與該所欲之順丁烯二醯亞胺端連接子-載荷藥物反應。特別是,5T4-A1 mAb係藉由添加於100 mM HEPES(4-(2-羥基乙基)-1-哌嗪乙磺酸緩衝液)pH 7.0中之2.8莫耳
過量之三(2-羧基乙基)膦(TCEP)及1 mM二伸乙基三胺五乙酸(DTPA)於37℃部分還原2小時。該所欲之連接子-載荷藥物接著被添加至該反應混合物,該連接子-載荷藥物/mAb-硫醇之莫耳比係5.5(順丁烯二醯亞胺基己醯基-一甲基耳抑素F[mc-MMAF])或8(順丁烯二醯亞胺基己醯基-纈胺酸-瓜胺酸-p-胺基苯甲氧基羰基-一甲基耳抑素E[mc-Val-Cit-PABA-MMAE]),在15%體積比之二甲基乙醯胺(DMA)存在時於25℃再反應1小時。經1小時之培養期後,添加N-乙基順丁烯二醯亞胺(為mc-MMAF之4.5倍過量及mc-Val-Cit-PABA-MMAE之2倍過量)以加蓋未反應之硫醇基,允許反應15分鐘,接著添加6倍過量之L-Cys以淬熄任何未反應之連接子-載荷藥物。該反應混合物係於磷酸緩衝鹽水(PBS)pH 7.4、4℃中隔夜透析,並經由SEC(AKTA explorer蛋白質純化儀,Superdex 200 10/30 GL管柱)純化。該ADC接著利用大小排除層析(SEC)分析純度,以疏水交互作用層析(HIC)及液體層析電噴灑離子化串聯質譜儀(LC-ESI MS)計算載荷量,並經由UV分光光度計測定濃度。
表現5T4抗原之細胞及陰性對照拉許(Raji)細胞係以密度500,000細胞/孔被接種至非組織培養處理之96孔盤並保存於冰上。A1及A1-IgG4抗體或A1-mcMMAF ADC
之稀釋液係以3%牛血清白蛋白BSA於達爾柏克(Dulbecco)氏磷酸緩衝鹽水(DPBS)中製備,並添加至該盤上使終濃度成為10μg/mL。該等孔盤接著於冰上培養1小時,然後清洗2次。二級抗體(與PE(藻紅素)共軛之山羊抗人IgG Fc)係經添加至孔槽。在4℃培養30分鐘後,利用流式細胞分析儀測量平均螢光強度。
表4中之資料顯示該A1抗體與多種5T4陽性細胞系結合。表5之資料顯示A1與A1-IgG4抗體以及A1-mcMMAFADC對多種不同細胞表現類似之結合性。
表現5T4之細胞系及陰性對照Raji細胞系係與漸增濃度之ADC一起培養。經過四天後,檢測各培養之存活性。IC50
值係藉由邏輯非線性回歸計算並以ng Ab/mL表示。A1-mcMMAF、A1-vcMMAE、A3-mcMMAF及A3-mcMMAE顯示可抑制5T4表現細胞系之生長(MDAMB435/5T4、MDAMB468及MDAMB361DYT2),但對5T4陰性細胞(Raji)無反應性(表6)。
此外,5T4+原發性肺腫瘤37622a細胞係經分離及生長於培養中。細胞與漸增濃度之ADC一起培養。十天之後,各培養之存活性係利用MTS方法檢測。IC50
值係藉由邏輯非線性回歸計算並以ng Ab/ml表示。A1-mcMMAF、A1-vcMMAE、A3-mcMMAF及A3-vcMMAE抑制原發性肺腫瘤細胞之生長(表7)。
無胸腺(裸)母鼠(或另一種免疫抑制小鼠品系)係經皮下注射MDAMB435/5T4、MDAMB361DYT2或H1975腫瘤細胞。具有分期腫瘤大約0.1至0.3克之小鼠(n=6至10隻小鼠/治療組)經靜脈投予Q4Dx4之生理鹽水(載具)、A1-mcMMAF、A1-vcMMAE、A1-mcMMAD、A1-smccDM1、A3-mcMMAF、A3-vcMMAE或與mcMMAF或vcMMAE共軛之非結合性對照抗體,劑量為3 mg Ab/kg。所有ADC皆根據Ab含量投予。每周至少測量一次腫瘤,彼等之大
小(mm2
±SEM)係由下式計算:mm2
=0.5x(腫瘤寬度2
)x(腫瘤長度)。
表8中之資料顯示A1-mcMMAF、A1-vcMMAE、A1-vcMMAD、A3-mcMMAF及A3-vcMMAE抑制MDAMB435/5T4異種移植之生長,然而A1-mcMMAD及A1-smccDM1在此模式中不具活性。
表9中之資料顯示A1-mcMMAF、A1-vcMMAE、A1-vcMMAD、A1-smccDM1、A3-mcMMAF及A3-vcMMAE抑制MDAMB361DYT2異種移植之生長,然而A1-mcMMAD在此模式中不具活性。
表10中之資料顯示A1-mcMMAF、A1-vcMMAE、A1-vcMMAD、A3-mcMMAF及A3-vcMMAE抑制H1975異種移植之生長,然而A1-mcMMAD及A1-smccDM1在此模式中不具活性。
或者,具有皮下建立之37622a原發性腫瘤細胞異種移植之裸鼠係以劑量3 mg Ab/kg之A1-mcMMAF、A1-mcMMAD、A1-vcMMAD或A3-mcMMAF經靜脈注射Q4Dx4治療,腫瘤生長係於96天期間監測。表11顯示相較於載具對照治療之動物,A1-mcMMAF、A1-vcMMAD及A3-mcMMAF抑制37622a原發性腫瘤異種移植之生長,然而A1-mcMMAD在此模式中不具活性。
不預期地,表8至11中之資料顯示具有相同抗體及載荷藥物但連接子不同之ADC具有不同之療效特性,即所有四個異種移植模式中之A1-mcMMAD與A1-vcMMAD。此外,該資料顯示具有相同抗體及連接子但具有不同載荷藥物之ADC亦具有不同之療效特性,即所有四個異種移植模式中之A1-mcMMAF與A1-mcMMAD。因此,藥物MMAD藉由vc連接子與A1抗體連接時在所有四個異種移植模式中皆有效,但當藉由mc連接子連接時在任一測試之異種移植模式中皆不具活性。相反地,藥物MMAF藉由mc連接子與A1抗體連接時在所有四個異種移植模式中皆高度有效,然而該化學相關之藥物MMAD藉由該相同連接子與該相同之抗體連接時,在所有四個異種移植模式中
皆不具活性。
還有另一項未預期之觀察出現在ADC A1-smccDM1(表8至10)。此ADC對MDAMB361DYT2異種移植非常有效,但對MDAMB435/5T4及H1975異種移植不具實質療效,即使所有異種移植皆高度表現該5T4標靶抗原。此資料顯示該連接子-載荷藥物之療效無法預測,即使利用該相同之高親和性抗體或甚至使用該相同之ADC。
收集健康志願者之血液至含有肝素鈉之BD Vacutainer CPT細胞製備管。取人週邊血液單核球(PBMC),將之重懸於檢測緩衝液(RPMI 1640添加10 mM HEPES)成為2.5×107
細胞/ml。標靶細胞(MDAMB435/5T4或MDAMB435/neo)係以密度1×104
細胞/孔接種於96孔測試盤。添加A1抗體或A1-mcMMAF,接著添加人PBMC效應細胞(5×105
)至孔槽中以使效應:標靶細胞比(E:T)為50:1。該檢測盤係於37℃培養4小時以檢測ADCC活性。藉由添加等體積之CytoTox-One試劑(普羅麥加(Promega)公司)以採收該盤。添加停止溶液(Promega;50 ul)至各孔,測量螢光強度以定量乳酸去氫酶之釋放。以陽性對照而言,每孔添加2 μl之溶解緩衝液以於對照孔槽產生最大LDH釋放(100%細胞毒性)。利用下式計算細胞毒性百分比:
當「實驗性」對應在該等實驗條件中之一者測量之信號,「效應自發性」對應僅PBMC存在時測量之信號,「標靶自發性」對應僅標靶細胞存在時測量之信號,及「標靶最大值」對應僅清潔劑溶解之標靶細胞存在時測量之信號。
A1-IgG1 Ab及A1-mcMMAF相較於A1-IgG4 Ab之ADCC活性係顯示於表12。該A1抗體及A1-mcMMAF兩者顯示相當之ADCC活性,表示A1-mcMMAF之ADCC活性可能促進彼之抗腫瘤活性。
表面電漿共振(SPR)分析係利用BIAcore®
實施,以測定A1-IgG1及A1-IgG4與人或馬來猴(cynomolgus)5T4於pH 6.0及pH 7.4結合之親和常數。BIAcore®
技術利用表面層之折射率在該huA1抗體變異體與固定在該表面層之人5T4蛋白質結合時的變化。結合係藉由SPR偵測,即偵
測自表面折射之雷射光。分析信號動力學如結合速率及解離速率能區別非特異性及特異***互作用。用於此分析之5T4蛋白質係由與人IgG1-Fc結構域融合之人或馬來猴(cynomolgus)5T4胞外域組成,並以低密度(人及馬來猴分別為45.1及45.4 RU)固定於CM5晶片上以正確測量親和常數。
與該5T4胞外域之特異性結合的測量係藉由減去與參考表面之結合獲得,該參考表面係只有人IgG1-Fc蛋白質以和該5T4-Fc表面上固定之相同密度固定於CM5晶片上。接著,於HBS-EP pH 7.4或MES-EP pH 6.0緩衝液中之不同濃度的A1、A1-IgG4或A3抗體被注射至該表面。該表面在注射週期之間係利用甘胺酸pH 1.7+0.05%界面活性劑P20(GE醫療集團,BR-1000-54)再生二次。
結果顯示使用低密度5T4表面於pH 6.0及pH 7.4時,A1相較於A1-IgG4具有稍微較高之對人5T4之親和性(分別為1.5倍及1.2倍,表13)。此外,A1於pH 6.0及pH 7.4時皆比A1-IgG4展現稍微較佳之對馬來猴5T4之結合(分別為1.7倍及1.2倍),且A1及A1-IgG4二者與人5T4之結合皆高於馬來猴5T4之結合3至4倍(表12)。
比較A1及A3抗體,很明顯地該A1抗體與人及馬來猴5T4之結合在pH 7.4時優於pH 6.0時,然而該A3抗體在pH 6.0時展現相較於pH 7.4時增進之結合(表14)。
為了識別A1及A3抗體結合之表位,利用暫時表現於COS-1細胞中之(1)5T4胞外域Fc建構體及(2)人/小鼠
5T4嵌合物建構體實施酶連接免疫吸附測定(ELISA)。該胞外域包括胺基端區域、二個富含白胺酸之重複及介於其間之親水區。小鼠及大鼠5T4胞外域包含在彼等之親水性區域內之6個胺基酸直接重複。
包含5T4胞外域及源自人IgG1之Fc恆定區的融合蛋白質係利用人5T4(胺基酸1-355)、小鼠5T4(胺基酸1-361)、大鼠5T4(胺基酸1-361)、馬來猴5T4(胺基酸1-355)、黑猩猩5T4(胺基酸1-355)及黑尾狨猴5T4(胺基酸1-355)製備。與人/小鼠5T4嵌合性建構體之結合結果係摘列於表15,其顯示A1及A3抗體之特異性結合、部分結合或缺乏結合。
表15係指抗體與不同之人/小鼠嵌合體之結合能力,該名稱係由小鼠5T4內容命名。當未觀察到結合時,這表示此為該抗體與人5T4結合之處,因為這些抗體不與小鼠5T4結合。舉例來說,A3抗體具有最多之N端結合表位(介於83-163之間),結果顯示其與殘基83-163經小鼠5T4取代之5T4嵌合體缺乏結合,因此A3無法與之結合。根據這些結果,可以得知人化A1抗體與人5T4在胺基酸殘基173及252之間具有第一接觸,與人5T4在胺基酸殘基276及355之間具有第二接觸。該A3抗體與人5T4之介於胺基酸殘基83至163之間的第一富含白胺酸重複區結合。該胺基酸殘基之數目對應SEQ ID NO:I1之人5T4抗原胺基酸序列。
比較A1-mcMMAF與A1-IgG4-AcBut卡利奇黴素(calicheamicin)(A1-IGG4-CM)之安全性及療效。A1-4-CM係由A1-IgG4抗體與連接子AcBut[-(4’乙醯基苯氧基)丁酸]共軛至卡利奇黴素載荷藥物組成。卡利奇黴素係一種有效之抗腫瘤劑,其係源自細菌棘孢小單孢菌(Micromonospora echinospora)之烯二炔抗生素類。
A1 Ab、A1-IgG4 Ab、A1-mcMMAF ADC及A1-IgG4-CM ADC之細胞結合活性係利用數種5T4陽性細胞系比較(見實施例2,表5)。資料顯示在A1抗體、A1-IgG4抗體及A1-mcMMAF ADC觀察到類似之結合性,彼等皆對所有測試之5T4陽性細胞系具有相較於A1-IgG4-CM更高之平均螢光強度。
A1-mcMMAF及A1-IgG4-CM係於MDAMB435/5T4皮下異種移植模式中並行測試。二種ADC皆於腫瘤體積到達大約200 mm2
時經靜脈給予(Q4dx2)。劑量3 mg/kg之A1-IgG4-CM的抗腫瘤活性與以10 mg/kg之劑量投予之
A1-mcMMAF的抗腫瘤活性類似(表16)。根據這些結果,A1-IgG4-CM之抗腫瘤活性大約高出A1-mcMMAF 3.3倍。
可預期的是,A1-IgG4-CM相較於A1-mcMMAF高3.3倍之效力可被解讀為A1-mcMMAF在動物毒性試驗中之安全範圍係A1-IgG4-CM之安全範圍的3.3倍。然而,當回顧A1-IgG4-CM於馬來猴(cynomolgus macque)中之安全性時,可得知A1-IgG4-CM在馬來猴中之毒性至少高出A1-mcMMAF 100倍。當A1-IgG4-CM係以0.032、0.095及0.32 mg Ab/kg/週期(2、6、20 μg之卡利奇黴素/kg/週期)投予至公馬來猴(n=3)及母馬來猴(n=3)時,各種劑量皆觀察到毒性。在投予2個週期(2劑)後,0.095治療組之6隻動物中之4隻被安樂死或發現死亡。相反地,在高達10 mg/kg劑量之A1-mcMMAF組(247 μg mcMMAF/kg/週期),在2次週期(2劑)後之相同的4周期間並未觀察到任何死
亡。總結來說,當二者皆投予兩次至馬來猴於4周觀察期間,10 mg/kg劑量組之A1-mcMMAF係安全的,然而0.096 mg/kg劑量組之A1-IgG4-CM被認為具有毒性。
不預期地,這些結果顯示A1-mcMMAF之安全範圍係A1-IgG4-CM之安全範圍的105倍(10/0.095=105),而不是根據各ADC之相對抗腫瘤效力所預期之3.3倍安全範圍。此資料顯示利用針對相同抗原標靶之抗體但與不同之載荷藥物共軛之抗體-藥物共軛體具有無法預測之特性。
PK/PD模式已被用於小鼠異種移植試驗以量化A1-mcMMAF之腫瘤反應,以測定對不同細胞系之有效濃度。此處使用之通過區室(transit compartment)腫瘤殺滅PK/PD模式先前係由Simeoni等人描述(Simeoni et al,Cancer Res,64:1094,(2004))。該模式已被改良以應用於腫瘤之線性、指數及S型曲線生長及藥物之飽和殺滅。PK/PD模式參數包括:
kg ex
指數生長
kg
S型曲線生長
w0
最初腫瘤體積
tau 轉導速率
kmax
最大殺滅速率
kC50
一半最大殺滅速率之濃度
該PK/PD模式結果係用於計算腫瘤靜止濃度(TSC,算式1)。此為當腫瘤生長速率等於腫瘤死亡速率且腫瘤體積維持不變時之藥物濃度。TSC可被定義為療效所需之最小濃度。TSC係用於給予臨床劑量選擇之參考,濃度需大於(>)TSC以求臨床上之療效。
以A1-mcMMAF而言,小鼠PK係於分開之試驗測定(3mg/kg IV,無胸腺nu/nu母鼠)。小鼠異種移植試驗係利用3種不同之5T4細胞系完成,每四天投予劑量介於1至30 mg/kg之A1-mcMMAF:細胞系MDAMB435/5T4(劑量1、3、10及30 mg/kg)、細胞系H1975(劑量1、3及10 mg/kg)及細胞系37622A(劑量1及10 mg/kg)。PK/PD模式係如下述實施,TSC如表17所示。
各異種移植細胞系之小鼠PK/PD參數係與A1-mcMMAF之預期人PK結合以模擬達成臨床療效所需之劑量。利用此方法,A1-mcMMAF具有約0.22至約2.3 mg/kg Q3周[每三周]之預期最小有效臨床劑量(表17)。
在本發明之一實施態樣中,劑量範圍可為每三周投予自約0.18 mg/kg至約2.7 mg/kg、自約0.22 mg/kg至約2.6 mg/kg、自約0.27 mg/kg至約2.5 mg/kg、自約0.32 mg/kg至約2.3 mg/kg、自約0.37 mg/kg至約2.15 mg/kg、自約0.42 mg/kg至約2.10 mg/kg、自約0.47 mg/kg至約2.05 mg/kg、自約0.52 mg/kg至約2.00 mg/kg、自約0.57 mg/kg至約1.95 mg/kg、自約0.62 mg/kg至約1.90 mg/kg、自約0.67 mg/kg至約1.85 mg/kg、自約0.72
mg/kg至約1.80mg/kg、自約0.82mg/kg至約1.70mg/kg、自約0.92mg/kg至約1.60mg/kg、自約1.02mg/kg至約1.50mg/kg、自約1.12mg/kg至約1.40mg/kg、或自約1.20mg/kg至約1.30mg/kg。較佳地,劑量範圍可為自約0.22mg/kg至約2.3mg/kg。
<110> 惠氏有限責任公司(Wyeth LLC)
<120> 抗體-藥物共軛體
<140> TW 101110867
<141> 2012-03-28
<150> US 61/470,576
<151> 2011-04-01
<150> US 61/593,549
<151> 2012-02-01
<150> US 61/602,349
<151> 2012-02-23
<160> 34
<170> PatentIn版本3.5
<210> 1
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A1人IgG1重鏈
<400> 1
<210> 2
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A1人Kappa輕鏈
<400> 2
<210> 3
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-VH
<400> 3
<210> 4
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-VL
<400> 4
<210> 5
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-HC CDR1
<400> 5
<210> 6
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-HC CDR2
<400> 6
<210> 7
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列A1-HC CDR3
<400> 7
<210> 8
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-LC-CDR1
<400> 8
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-LC-CDR2
<400> 9
<210> 10
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-LC-CDR3
<400> 10
<210> 11
<211> 420
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人5T4抗原
<400> 11
<210> 12
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A1人IgG4m重鏈
<400> 12
<210> 13
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人IgG4m VH(A1-IGG4-VH)
<400> 13
<210> 14
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列A1-IgG4-VH-CDR1
<400> 14
<210> 15
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3重鏈(muA3-huIgG1)
<400> 15
<210> 16
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VH
<400> 16
<210> 17
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VH-CDR1
<400> 17
<210> 18
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VH-CDR2
<400> 18
<210> 19
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VH-CDR3
<400> 19
<210> 20
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3輕鏈(muA3-huKappa)
<400> 20
<210> 21
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VL
<400> 21
<210> 22
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VL-CDR1
<400> 22
<210> 23
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VL-CDR2
<400> 23
<210> 24
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列嵌合性A3 VL-CDR3
<400> 24
<210> 25
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3人IgG1重鏈
<400> 25
<210> 26
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VH
<400> 26
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VH-CDR1
<400> 27
<210> 28
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VH-CDR2
<400> 28
<210> 29
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VH-CDR3
<400> 29
<210> 30
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3人Kappa輕鏈
<400> 30
<210> 31
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VL
<400> 31
<210> 32
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VL-CDR1
<400> 32
<210> 33
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VL-CDR2
<400> 33
<210> 34
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列人化A3 VL-CDR3
<400> 34
Claims (14)
- 一種下式之抗體-藥物共軛體:Ab-(LU-D)p或彼之醫藥上可接受之鹽,其中(a)Ab係抗5T4抗體或彼之抗原結合部位,其包含:(i)如SEQ ID NO:5所示之VH CDR1區,(ii)如SEQ ID NO:6所示之VH CDR2區,(iii)如SEQ ID NO:7所示之VH CDR3區,(iv)如SEQ ID NO:8所示之VL CDR1區,(v)如SEQ ID NO:9所示之VL CDR2區,及(vi)如SEQ ID NO:10所示之VL CDR3區,(b)LU係選自順丁烯二醯亞胺基己醯基(maleimidocaproyl)或順丁烯二醯亞胺基己醯基-纈胺酸(Val)-瓜胺酸(Cit)-PABA之連接子單位,(c)p係自1至8之整數,且(d)D係選自MMAE、MMAD或MMAF之藥物單位,唯當LU係順丁烯二醯亞胺基己醯基時,D不為MMAD。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中該抗5T4抗體或彼之抗原結合部位包含SEQ ID NO:3之VH區及SEQ ID NO:4之VL區。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中該抗5T4抗體或彼之抗原結合部位係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中該 抗體或彼之抗原結合部位辨識人5T4抗原上之表位,其中該表位包含SEQ ID NO:11之胺基酸序列的胺基酸殘基173至258及282至361。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中該LU係順丁烯二醯亞胺基己醯基。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中該藥物係MMAF。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中p係自1至4之整數。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中:(a)該抗5T4抗體係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成,(b)該LU係順丁烯二醯亞胺基己醯基,(c)該藥物係MMAF,且(d)p係自1至8之整數。
- 如申請專利範圍第1項之抗體-藥物共軛體,其中:(a)該抗5T4抗體係由具有SEQ ID NO:1之重鏈及具有SEQ ID NO:2之輕鏈組成,(b)該LU係順丁烯二醯亞胺基己醯基,(c)該藥物係MMAF,且(d)p係自1至4之整數。
- 如申請專利範圍第1至9項中任一項之抗體-藥物共軛體,其係用於治療5T4陽性癌。
- 一種醫藥組成物,其包含如申請專利範圍第1至9 項中任一項之抗體-藥物共軛體及醫藥上可接受之載劑。
- 一種如申請專利範圍第1至9項中任一項之抗體-藥物共軛體於製造供治療病患之5T4陽性癌的藥物之用途。
- 如申請專利範圍第12項之用途,其中該癌係選自結直腸癌、乳癌、胰癌或非小細胞肺癌。
- 一種用於產製抗5T4抗體-藥物共軛體之方法,該方法包含:(a)化學連接選自順丁烯二醯亞胺基己醯基或順丁烯二醯亞胺基己醯基-Val-Cit-PABA之連接子單位與選自MMAE、MMAD或MMAF之藥物單位,(b)使該連接子-藥物與如申請專利範圍第1至9項中任一項所述之抗5T4抗體或彼之抗原結合部位共軛,及(c)純化該抗體-藥物共軛體。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161470576P | 2011-04-01 | 2011-04-01 | |
US201261593549P | 2012-02-01 | 2012-02-01 | |
US201261602349P | 2012-02-23 | 2012-02-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201302795A TW201302795A (zh) | 2013-01-16 |
TWI471334B true TWI471334B (zh) | 2015-02-01 |
Family
ID=45895455
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW101110867A TWI471334B (zh) | 2011-04-01 | 2012-03-28 | 抗體-藥物共軛體 |
TW103141450A TWI549968B (zh) | 2011-04-01 | 2012-03-28 | 抗體-藥物共軛體 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW103141450A TWI549968B (zh) | 2011-04-01 | 2012-03-28 | 抗體-藥物共軛體 |
Country Status (26)
Country | Link |
---|---|
US (4) | US8309094B2 (zh) |
EP (2) | EP3130356A1 (zh) |
JP (3) | JP5925875B2 (zh) |
KR (2) | KR101529810B1 (zh) |
CN (2) | CN103517719B (zh) |
AR (1) | AR085747A1 (zh) |
AU (3) | AU2012235817B2 (zh) |
BR (1) | BR112013025186A2 (zh) |
CA (1) | CA2830338C (zh) |
CO (1) | CO6771458A2 (zh) |
DK (1) | DK2694111T3 (zh) |
ES (1) | ES2596194T3 (zh) |
HK (2) | HK1193052A1 (zh) |
HU (1) | HUE031017T2 (zh) |
IL (1) | IL228404A0 (zh) |
MX (1) | MX342860B (zh) |
MY (1) | MY170719A (zh) |
PE (1) | PE20140573A1 (zh) |
PL (1) | PL2694111T3 (zh) |
PT (1) | PT2694111T (zh) |
RU (1) | RU2624141C2 (zh) |
SA (1) | SA112330402B1 (zh) |
SG (2) | SG193324A1 (zh) |
SI (1) | SI2694111T1 (zh) |
TW (2) | TWI471334B (zh) |
WO (1) | WO2012131527A1 (zh) |
Families Citing this family (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8435529B2 (en) | 2002-06-14 | 2013-05-07 | Immunomedics, Inc. | Combining radioimmunotherapy and antibody-drug conjugates for improved cancer therapy |
US9770517B2 (en) | 2002-03-01 | 2017-09-26 | Immunomedics, Inc. | Anti-Trop-2 antibody-drug conjugates and uses thereof |
US9745380B2 (en) | 2002-03-01 | 2017-08-29 | Immunomedics, Inc. | RS7 antibodies |
ES2871905T3 (es) | 2002-03-01 | 2021-11-02 | Immunomedics Inc | Inmunoconjugado que comprende anticuerpos de RS7 humanizados |
EP1572242B1 (en) | 2002-12-13 | 2014-04-16 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US9707302B2 (en) | 2013-07-23 | 2017-07-18 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
US10058621B2 (en) | 2015-06-25 | 2018-08-28 | Immunomedics, Inc. | Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers |
DK2368914T3 (en) * | 2006-03-10 | 2019-03-04 | Wyeth Llc | Anti-5T4 antibodies and uses thereof |
DK2575870T3 (en) * | 2010-06-04 | 2017-02-13 | Wyeth Llc | vaccine Formulations |
CN103517719B (zh) * | 2011-04-01 | 2016-10-12 | 惠氏有限责任公司 | 抗体-药物缀合物 |
WO2013068874A1 (en) * | 2011-11-11 | 2013-05-16 | Pfizer Inc. | Antibody-drug conjugates |
MX361058B (es) | 2012-01-24 | 2018-11-23 | Pfizer | Método para detectar células tumorales circulantes 5t4-positivas y métodos de diagnóstico de cáncer 5t4-positivo en un sujeto mamífero. |
CA2869704A1 (en) * | 2012-04-04 | 2013-10-10 | Perseus Proteomics Inc. | Drug conjugate comprising anti-cdh3 (pcadherin) antibody |
PL3912642T3 (pl) * | 2012-10-23 | 2023-08-14 | Synaffix B.V. | Zmodyfikowane przeciwciało, koniugat przeciwciała i sposób ich otrzymywania |
TW201726746A (zh) * | 2012-11-07 | 2017-08-01 | 輝瑞股份有限公司 | 抗切口3(anti-notch3)抗體及抗體-藥物共軛體 |
EP2928503B1 (en) | 2012-12-10 | 2019-02-20 | Mersana Therapeutics, Inc. | Conjugates of auristatin compounds |
US10137196B2 (en) | 2012-12-13 | 2018-11-27 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
US10206918B2 (en) | 2012-12-13 | 2019-02-19 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
US9492566B2 (en) | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
KR102536723B1 (ko) | 2012-12-13 | 2023-05-30 | 이뮤노메딕스, 인코오포레이티드 | 개선된 효능 및 감소된 독성을 위한 항체 및 sn-38의 면역컨쥬게이트의 투약 |
WO2014137931A1 (en) * | 2013-03-06 | 2014-09-12 | Imaginab, Inc. | Antigen binding constructs to 5t4 |
WO2014160305A1 (en) | 2013-03-14 | 2014-10-02 | Albany Molecular Research, Inc. | Ligand-therapeutic agent conjugates and silicon-based linkers |
SI2991683T1 (sl) | 2013-05-02 | 2020-01-31 | Glykos Finland Oy | Konjugati glikoproteina ali glikana s toksično obremenitvijo |
CN116063479A (zh) | 2013-06-04 | 2023-05-05 | 西托姆克斯治疗公司 | 用于缀合可活化抗体的组合物和方法 |
US11253606B2 (en) | 2013-07-23 | 2022-02-22 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
WO2015017552A1 (en) * | 2013-08-01 | 2015-02-05 | Agensys, Inc. | Antibody drug conjugates (adc) that bind to cd37 proteins |
WO2015051159A1 (en) * | 2013-10-02 | 2015-04-09 | The Rockefeller University | Amyloid protofibril antibodies and methods of use thereof |
CA2926586C (en) | 2013-10-11 | 2020-04-07 | Mersana Therapeutics, Inc. | Polymeric scaffold based on phf for targeted drug delivery |
WO2015054669A1 (en) | 2013-10-11 | 2015-04-16 | Asana Biosciences, Llc | Protein-polymer-drug conjugates |
BR112016010051A2 (pt) | 2013-11-04 | 2017-12-05 | Pfizer | ?conjugados de anticorpo-fármaco anti-efna4? |
EP3107577B1 (en) | 2014-02-21 | 2024-03-20 | IBC Pharmaceuticals, Inc. | Disease therapy by inducing immune response to trop-2 expressing cells |
WO2015155345A1 (en) * | 2014-04-11 | 2015-10-15 | Medimmune Limited | Antibodies and antibody-drug conjugates |
WO2015173133A1 (en) | 2014-05-12 | 2015-11-19 | Chiesi Farmaceutici S.P.A. | Formulations and methods of treating alzheimer's disease and other proteinopathies by combination therapy |
SG11201609372UA (en) * | 2014-05-22 | 2016-12-29 | Synthon Biopharmaceuticals Bv | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
MA40069A (fr) | 2014-05-29 | 2021-04-14 | Macrogenics Inc | Molécules de liaison trispécifiques et leurs procédés d'utilisation |
WO2016022939A1 (en) * | 2014-08-08 | 2016-02-11 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Human monoclonal antibodies specific for 5t4 and methods of their use |
CN107106685A (zh) | 2014-10-10 | 2017-08-29 | 辉瑞公司 | 协同澳瑞他汀组合 |
US20180028658A1 (en) * | 2015-02-16 | 2018-02-01 | New York Blood Center, Inc. | Antibody-drug conjugates for reducing the latent hiv reservoir |
CA2981543A1 (en) | 2015-04-22 | 2016-10-27 | Immunomedics, Inc. | Isolation, detection, diagnosis and/or characterization of circulating trop-2-positive cancer cells |
CN106279352B (zh) | 2015-05-29 | 2020-05-22 | 上海新理念生物医药科技有限公司 | 海兔毒素10的衍生物及其应用 |
US10195175B2 (en) | 2015-06-25 | 2019-02-05 | Immunomedics, Inc. | Synergistic effect of anti-Trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or PARP inhibitors |
DK3380122T3 (da) | 2015-11-24 | 2021-07-05 | Byondis Bv | Anti-5t4 antistoffer og antistoflægemiddel konjugater |
US20210198377A1 (en) * | 2015-12-24 | 2021-07-01 | Xdcexplorer (Shanghai) Co., Ltd. | Tpbg antibody and preparation method therefor, conjugate and use thereof |
EP3413914A4 (en) | 2016-02-10 | 2019-10-16 | Immunomedics, Inc. | COMBINATION INHIBITORS ABCG2-SACITUZUMAB GOVITECAN (IMMU-132) OVERCOMES RESISTANCE TO SN-38 IN CANCERS EXPRESSING TOO 2 |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
US20200338210A1 (en) * | 2016-12-22 | 2020-10-29 | Ardeagen Corporation | Anti-ror1 antibody and conjugates thereof |
CN108285487B (zh) * | 2017-01-08 | 2021-02-19 | 浙江昭华生物医药有限公司 | 抗5t4抗体-药物偶联物及其应用 |
KR102609624B1 (ko) | 2017-03-15 | 2023-12-05 | 옥스포드 바이오메디카(유케이) 리미티드 | 방법 |
US10918734B2 (en) | 2017-03-27 | 2021-02-16 | Immunomedics, Inc. | Treatment of high Trop-2 expressing triple negative breast cancer (TNBC) with sacituzumab govitecan (IMMU-132) overcomes homologous recombination repair (HRR) rescue mediated by Rad51 |
CN108690136B (zh) * | 2017-04-05 | 2022-09-20 | 凯惠科技发展(上海)有限公司 | 一种人源化抗tpbg抗体及其制备方法、其偶联物和应用 |
EP3624854A1 (en) * | 2017-05-16 | 2020-03-25 | Université de Strasbourg | Protein-drug conjugates and their use in the treatment of cancers |
US11638760B2 (en) | 2017-11-27 | 2023-05-02 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
US20220305127A1 (en) | 2017-12-21 | 2022-09-29 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
CN110507824A (zh) * | 2018-05-21 | 2019-11-29 | 荣昌生物制药(烟台)有限公司 | 一种抗间皮素抗体及其抗体药物缀合物 |
AU2019369340A1 (en) | 2018-10-29 | 2021-05-20 | Mersana Therapeutics, Inc. | Cysteine engineered antibody-drug conjugates with peptide-containing linkers |
WO2021048423A1 (en) * | 2019-09-12 | 2021-03-18 | Genmab A/S | Bispecific antibodies binding to 5t4 and cd3 for use in treatment of cancer |
US20210316003A1 (en) | 2020-03-20 | 2021-10-14 | Immunomedics, Inc. | Biomarkers for sacituzumab govitecan therapy |
WO2023045141A1 (zh) * | 2021-09-26 | 2023-03-30 | 上海迈泰君奥生物技术有限公司 | 一种双功能融合蛋白 |
WO2023107954A1 (en) * | 2021-12-08 | 2023-06-15 | Dragonfly Therapeutics, Inc. | Antibodies targeting 5t4 and uses thereof |
WO2023155925A1 (en) * | 2022-02-21 | 2023-08-24 | Concept To Medicine Biotech Co., Ltd. | Anti-5t4 antibodies and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200804424A (en) * | 2006-03-10 | 2008-01-16 | Wyeth Corp | Anti-5T4 antibodies and uses thereof |
US7750116B1 (en) * | 2006-02-18 | 2010-07-06 | Seattle Genetics, Inc. | Antibody drug conjugate metabolites |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5869053A (en) | 1988-03-04 | 1999-02-09 | Cancer Research Campaign Technology, Ltd. | 5T4 antigen from human trophoblasts |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US7256257B2 (en) | 2001-04-30 | 2007-08-14 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US20090068178A1 (en) * | 2002-05-08 | 2009-03-12 | Genentech, Inc. | Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin |
WO2006113909A2 (en) | 2005-04-19 | 2006-10-26 | Seattle Genetics, Inc. | Humanized anti-cd70 binding agents and uses thereof |
NZ547633A (en) * | 2003-11-06 | 2010-08-27 | Seattle Genetics Inc | Monomethylvaline compounds capable of conjugation to ligands |
BRPI0515113A (pt) * | 2004-09-10 | 2008-07-01 | Wyeth Corp | anticorpos anti-5t4 humanizados e conjugados de anticorpo anti-5t4/caliqueamicina |
EP1942944A2 (en) | 2005-10-31 | 2008-07-16 | Genentech, Inc. | Macrocyclic depsipeptide antibody-drug conjugates and methods |
BRPI0619476A2 (pt) * | 2005-12-05 | 2011-10-04 | Wyeth Corp | composições de interleucina-11 e métodos de uso |
AR059900A1 (es) * | 2006-03-17 | 2008-05-07 | Genentech Inc | Anticuerpos anti-tat226 e inmunoconjugados |
US8044778B2 (en) * | 2007-07-12 | 2011-10-25 | Henry Schein, Inc. | Injection device and case with reporting ability |
JP5394246B2 (ja) * | 2007-03-30 | 2014-01-22 | ジェネンテック, インコーポレイテッド | 抗体及びイムノコンジュゲートとこれらの使用方法 |
PT2211904T (pt) * | 2007-10-19 | 2016-11-02 | Seattle Genetics Inc | Agentes de ligação a cd19 e seus usos |
US8521761B2 (en) * | 2008-07-18 | 2013-08-27 | Google Inc. | Transliteration for query expansion |
JP5788863B2 (ja) | 2009-03-27 | 2015-10-07 | ワイス・エルエルシー | 腫瘍開始細胞およびその使用方法 |
CN103517719B (zh) * | 2011-04-01 | 2016-10-12 | 惠氏有限责任公司 | 抗体-药物缀合物 |
-
2012
- 2012-03-19 CN CN201280015379.2A patent/CN103517719B/zh not_active Expired - Fee Related
- 2012-03-19 BR BR112013025186A patent/BR112013025186A2/pt not_active IP Right Cessation
- 2012-03-19 RU RU2013142004A patent/RU2624141C2/ru not_active IP Right Cessation
- 2012-03-19 PT PT127112795T patent/PT2694111T/pt unknown
- 2012-03-19 CA CA2830338A patent/CA2830338C/en not_active Expired - Fee Related
- 2012-03-19 MY MYPI2013701616A patent/MY170719A/en unknown
- 2012-03-19 CN CN201510626833.3A patent/CN105288644A/zh active Pending
- 2012-03-19 ES ES12711279.5T patent/ES2596194T3/es active Active
- 2012-03-19 MX MX2013011353A patent/MX342860B/es active IP Right Grant
- 2012-03-19 JP JP2014501747A patent/JP5925875B2/ja not_active Expired - Fee Related
- 2012-03-19 HU HUE12711279A patent/HUE031017T2/en unknown
- 2012-03-19 SI SI201230704A patent/SI2694111T1/sl unknown
- 2012-03-19 SG SG2013066915A patent/SG193324A1/en unknown
- 2012-03-19 WO PCT/IB2012/051304 patent/WO2012131527A1/en active Application Filing
- 2012-03-19 PL PL12711279T patent/PL2694111T3/pl unknown
- 2012-03-19 EP EP16181944.6A patent/EP3130356A1/en not_active Withdrawn
- 2012-03-19 EP EP12711279.5A patent/EP2694111B1/en not_active Not-in-force
- 2012-03-19 PE PE2013002166A patent/PE20140573A1/es not_active Application Discontinuation
- 2012-03-19 KR KR1020137025712A patent/KR101529810B1/ko active IP Right Grant
- 2012-03-19 AU AU2012235817A patent/AU2012235817B2/en not_active Ceased
- 2012-03-19 KR KR1020157002692A patent/KR101783529B1/ko active IP Right Grant
- 2012-03-19 SG SG10201605401WA patent/SG10201605401WA/en unknown
- 2012-03-19 DK DK12711279.5T patent/DK2694111T3/en active
- 2012-03-28 TW TW101110867A patent/TWI471334B/zh not_active IP Right Cessation
- 2012-03-28 TW TW103141450A patent/TWI549968B/zh not_active IP Right Cessation
- 2012-03-28 SA SA112330402A patent/SA112330402B1/ar unknown
- 2012-03-29 AR ARP120101072A patent/AR085747A1/es unknown
- 2012-03-30 US US13/435,731 patent/US8309094B2/en not_active Expired - Fee Related
- 2012-09-14 US US13/616,030 patent/US8586049B2/en not_active Expired - Fee Related
-
2013
- 2013-09-12 IL IL228404A patent/IL228404A0/en unknown
- 2013-09-27 CO CO13230718A patent/CO6771458A2/es unknown
- 2013-10-14 US US14/052,942 patent/US20140081005A1/en not_active Abandoned
-
2014
- 2014-07-03 HK HK14106730.6A patent/HK1193052A1/zh not_active IP Right Cessation
-
2016
- 2016-04-20 JP JP2016084139A patent/JP6333882B2/ja not_active Expired - Fee Related
- 2016-05-23 US US15/161,972 patent/US20170319711A1/en not_active Abandoned
- 2016-06-09 AU AU2016203839A patent/AU2016203839A1/en not_active Abandoned
- 2016-08-03 HK HK16109256.2A patent/HK1221153A1/zh unknown
-
2017
- 2017-12-08 AU AU2017272321A patent/AU2017272321A1/en not_active Abandoned
-
2018
- 2018-04-25 JP JP2018084261A patent/JP2018140997A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7750116B1 (en) * | 2006-02-18 | 2010-07-06 | Seattle Genetics, Inc. | Antibody drug conjugate metabolites |
TW200804424A (en) * | 2006-03-10 | 2008-01-16 | Wyeth Corp | Anti-5T4 antibodies and uses thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI471334B (zh) | 抗體-藥物共軛體 | |
US20240084032A1 (en) | Anti-cub domain-containing protein 1 (cdcp1) antibodies, antibody drug conjugates, and methods of use thereof | |
ES2719548T3 (es) | Anticuerpos humanizados para liv-1 y uso de los mismos para tratar el cáncer | |
CA3066918A1 (en) | Anti-il1rap antibodies and antibody drug conjugates | |
CN110121507B (zh) | 抗sez6l2抗体和抗体药物缀合物 | |
US11827709B2 (en) | Anti-AVB6 antibodies and antibody-drug conjugates | |
CN116251196A (zh) | 抗-edb抗体和抗体-药物缀合物 | |
TW202330599A (zh) | 抗ccr8單株抗體及其用途 | |
CN118271442A (zh) | 抗sez6l2抗体和抗体药物缀合物 | |
NZ615308B2 (en) | Antibody-drug conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |