CN117751140A - 包含靶向尿激酶型纤溶酶原激活物受体相关蛋白(uPARAP)的人源化抗体的抗体-药物缀合物 - Google Patents
包含靶向尿激酶型纤溶酶原激活物受体相关蛋白(uPARAP)的人源化抗体的抗体-药物缀合物 Download PDFInfo
- Publication number
- CN117751140A CN117751140A CN202280046878.1A CN202280046878A CN117751140A CN 117751140 A CN117751140 A CN 117751140A CN 202280046878 A CN202280046878 A CN 202280046878A CN 117751140 A CN117751140 A CN 117751140A
- Authority
- CN
- China
- Prior art keywords
- antibody
- drug conjugate
- ser
- val
- active agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims abstract description 261
- 239000000611 antibody drug conjugate Substances 0.000 title claims abstract description 260
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 18
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 18
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 title abstract description 4
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 title abstract description 4
- 230000008685 targeting Effects 0.000 title description 7
- 239000013543 active substance Substances 0.000 claims abstract description 82
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 76
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 210000004027 cell Anatomy 0.000 claims description 109
- 238000000034 method Methods 0.000 claims description 97
- 125000005647 linker group Chemical group 0.000 claims description 65
- 239000003814 drug Substances 0.000 claims description 48
- 201000011510 cancer Diseases 0.000 claims description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims description 39
- 239000013598 vector Substances 0.000 claims description 36
- 206010039491 Sarcoma Diseases 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 32
- 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 31
- 108091033319 polynucleotide Proteins 0.000 claims description 28
- 239000002157 polynucleotide Substances 0.000 claims description 28
- 102000040430 polynucleotide Human genes 0.000 claims description 28
- 108010093470 monomethyl auristatin E Proteins 0.000 claims description 26
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 26
- -1 anthracyclines Substances 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 22
- 229940127121 immunoconjugate Drugs 0.000 claims description 20
- 229940124597 therapeutic agent Drugs 0.000 claims description 20
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 18
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 18
- 239000002246 antineoplastic agent Substances 0.000 claims description 18
- 230000000340 anti-metabolite Effects 0.000 claims description 17
- 229940100197 antimetabolite Drugs 0.000 claims description 17
- 239000002256 antimetabolite Substances 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 17
- 239000003112 inhibitor Substances 0.000 claims description 15
- 206010003246 arthritis Diseases 0.000 claims description 14
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 14
- 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 claims description 12
- 239000000872 buffer Substances 0.000 claims description 12
- 229920001184 polypeptide Polymers 0.000 claims description 12
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims description 11
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims description 11
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 claims description 11
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 claims description 11
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 11
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 11
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 11
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 11
- 229940043355 kinase inhibitor Drugs 0.000 claims description 11
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 11
- 229910052697 platinum Inorganic materials 0.000 claims description 11
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 11
- BQQGAGGSEMLWRS-UHFFFAOYSA-N (4-aminophenyl)methyl carbamate Chemical compound NC(=O)OCC1=CC=C(N)C=C1 BQQGAGGSEMLWRS-UHFFFAOYSA-N 0.000 claims description 10
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 10
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 10
- 230000003007 single stranded DNA break Effects 0.000 claims description 10
- 239000012624 DNA alkylating agent Substances 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 210000000988 bone and bone Anatomy 0.000 claims description 9
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 125000006850 spacer group Chemical group 0.000 claims description 9
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 8
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 claims description 8
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 claims description 8
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 claims description 8
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 claims description 8
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 claims description 8
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 claims description 8
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 8
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 claims description 8
- 102100022949 Immunoglobulin kappa variable 2-29 Human genes 0.000 claims description 8
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 8
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 8
- 229960004050 aminobenzoic acid Drugs 0.000 claims description 8
- 239000003080 antimitotic agent Substances 0.000 claims description 8
- 229940127089 cytotoxic agent Drugs 0.000 claims description 8
- 208000005017 glioblastoma Diseases 0.000 claims description 8
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 201000008968 osteosarcoma Diseases 0.000 claims description 8
- CJHKJXZMFZKGHI-UHFFFAOYSA-N 1h-pyrido[2,3-i][1,2]benzodiazepine Chemical compound N1N=CC=CC2=CC=C(N=CC=C3)C3=C12 CJHKJXZMFZKGHI-UHFFFAOYSA-N 0.000 claims description 7
- 230000000970 DNA cross-linking effect Effects 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 7
- 229940034982 antineoplastic agent Drugs 0.000 claims description 7
- 229960002173 citrulline Drugs 0.000 claims description 7
- 239000003431 cross linking reagent Substances 0.000 claims description 7
- 239000002254 cytotoxic agent Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000002503 metabolic effect Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 claims description 7
- 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 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- 229940126161 DNA alkylating agent Drugs 0.000 claims description 6
- 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 claims description 6
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 6
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 6
- 208000016604 Lyme disease Diseases 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 6
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 6
- 206010061309 Neoplasm progression Diseases 0.000 claims description 6
- 208000031839 Peripheral nerve sheath tumour malignant Diseases 0.000 claims description 6
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 6
- 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 claims description 6
- 150000001720 carbohydrates Chemical group 0.000 claims description 6
- 235000014633 carbohydrates Nutrition 0.000 claims description 6
- 229960004562 carboplatin Drugs 0.000 claims description 6
- 230000030833 cell death Effects 0.000 claims description 6
- 229960004316 cisplatin Drugs 0.000 claims description 6
- 230000004761 fibrosis Effects 0.000 claims description 6
- 229960004768 irinotecan Drugs 0.000 claims description 6
- 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 claims description 6
- 229940083980 lavender extract Drugs 0.000 claims description 6
- 235000020723 lavender extract Nutrition 0.000 claims description 6
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 claims description 6
- 229960004857 mitomycin Drugs 0.000 claims description 6
- 108010059074 monomethylauristatin F Proteins 0.000 claims description 6
- 208000029974 neurofibrosarcoma Diseases 0.000 claims description 6
- 229960001756 oxaliplatin Drugs 0.000 claims description 6
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 6
- 230000035755 proliferation Effects 0.000 claims description 6
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 6
- 230000005751 tumor progression Effects 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 108020004414 DNA Proteins 0.000 claims description 5
- 108010016626 Dipeptides Proteins 0.000 claims description 5
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 claims description 5
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 claims description 5
- 230000001946 anti-microtubular Effects 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 208000037976 chronic inflammation Diseases 0.000 claims description 5
- 230000006020 chronic inflammation Effects 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 210000002540 macrophage Anatomy 0.000 claims description 5
- 239000002773 nucleotide Substances 0.000 claims description 5
- 125000003729 nucleotide group Chemical group 0.000 claims description 5
- 230000002018 overexpression Effects 0.000 claims description 5
- 239000003910 polypeptide antibiotic agent Substances 0.000 claims description 5
- 210000004881 tumor cell Anatomy 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 claims description 4
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 4
- 229940123014 DNA polymerase inhibitor Drugs 0.000 claims description 4
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 claims description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 4
- 206010027406 Mesothelioma Diseases 0.000 claims description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 claims description 4
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 claims description 4
- 239000012270 PD-1 inhibitor Substances 0.000 claims description 4
- 239000012668 PD-1-inhibitor Substances 0.000 claims description 4
- 239000012271 PD-L1 inhibitor Substances 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- 229940122277 RNA polymerase inhibitor Drugs 0.000 claims description 4
- 229940123237 Taxane Drugs 0.000 claims description 4
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 claims description 4
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims description 4
- 150000001345 alkine derivatives Chemical class 0.000 claims description 4
- 208000008524 alveolar soft part sarcoma Diseases 0.000 claims description 4
- 239000003972 antineoplastic antibiotic Substances 0.000 claims description 4
- 108010044540 auristatin Proteins 0.000 claims description 4
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 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 claims description 4
- 229960005395 cetuximab Drugs 0.000 claims description 4
- 229960001338 colchicine Drugs 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000000539 dimer Substances 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 claims description 4
- 229930188854 dolastatin Natural products 0.000 claims description 4
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 claims description 4
- 229950005837 entinostat Drugs 0.000 claims description 4
- 238000006911 enzymatic reaction Methods 0.000 claims description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 4
- 229960005304 fludarabine phosphate Drugs 0.000 claims description 4
- 229960002584 gefitinib Drugs 0.000 claims description 4
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940045109 genistein Drugs 0.000 claims description 4
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims description 4
- 235000006539 genistein Nutrition 0.000 claims description 4
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims description 4
- 201000010536 head and neck cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 claims description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 4
- 229960002411 imatinib Drugs 0.000 claims description 4
- 238000001802 infusion Methods 0.000 claims description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
- 230000001394 metastastic effect Effects 0.000 claims description 4
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 4
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 claims description 4
- 229950007221 nedaplatin Drugs 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 229960003301 nivolumab Drugs 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 229940121655 pd-1 inhibitor Drugs 0.000 claims description 4
- 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 4
- 229960002621 pembrolizumab Drugs 0.000 claims description 4
- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 claims description 4
- 229950005566 picoplatin Drugs 0.000 claims description 4
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 claims description 4
- 229930192524 radicicol Natural products 0.000 claims description 4
- 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 claims description 4
- 229960000303 topotecan Drugs 0.000 claims description 4
- 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 claims description 4
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 claims description 4
- 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 claims description 4
- 229960004528 vincristine Drugs 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- 229960002066 vinorelbine Drugs 0.000 claims description 4
- 229960000237 vorinostat Drugs 0.000 claims description 4
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 claims description 4
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 claims description 3
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 3
- PRXXYMVLYKJITB-IZZDOVSWSA-N (e)-n-(2-aminophenyl)-3-[1-[4-(1-methylpyrazol-4-yl)phenyl]sulfonylpyrrol-3-yl]prop-2-enamide Chemical compound C1=NN(C)C=C1C1=CC=C(S(=O)(=O)N2C=C(\C=C\C(=O)NC=3C(=CC=CC=3)N)C=C2)C=C1 PRXXYMVLYKJITB-IZZDOVSWSA-N 0.000 claims description 3
- WUPXZZWTHIZICK-UHFFFAOYSA-N 1-[2-[4-[4-amino-5-(3-methoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]phenyl]ethyl]piperidin-4-ol Chemical compound COC1=CC=CC(C=2C3=C(N)N=CN=C3N(C=3C=CC(CCN4CCC(O)CC4)=CC=3)C=2)=C1 WUPXZZWTHIZICK-UHFFFAOYSA-N 0.000 claims description 3
- FDAYLTPAFBGXAB-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)ethanamine Chemical compound ClCCN(CCCl)CCCl FDAYLTPAFBGXAB-UHFFFAOYSA-N 0.000 claims description 3
- MAIJHAHHYNROMG-UHFFFAOYSA-N 3,4,12-triazatetracyclo[9.7.0.02,8.013,18]octadeca-1,3,5,7,9,11,13,15,17-nonaene Chemical compound C1=CN=NC2=C3C4=CC=CC=C4N=C3C=CC2=C1 MAIJHAHHYNROMG-UHFFFAOYSA-N 0.000 claims description 3
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 3
- GFZFAQOKWZGMQL-UHFFFAOYSA-N 3-[3,5-bis(trifluoromethyl)phenyl]-3-oxopropanenitrile Chemical compound FC(F)(F)C1=CC(C(=O)CC#N)=CC(C(F)(F)F)=C1 GFZFAQOKWZGMQL-UHFFFAOYSA-N 0.000 claims description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 3
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims description 3
- IFPPYSWJNWHOLQ-UHFFFAOYSA-N 6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-methylpyrido[2,3-d]pyrimidin-7-one Chemical compound C1=CC(OCCN(CC)CC)=CC=C1NC1=NC=C(C=C(C=2C(=CC=CC=2Cl)Cl)C(=O)N2C)C2=N1 IFPPYSWJNWHOLQ-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 3
- 239000005660 Abamectin Substances 0.000 claims description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 201000003076 Angiosarcoma Diseases 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 3
- PLXLYXLUCNZSAA-QLXKLKPCSA-N CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=C1N=C1C=C(F)C(C)=C4CC[C@H](NC(=O)CO)C3=C14)C2=O Chemical compound CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=C1N=C1C=C(F)C(C)=C4CC[C@H](NC(=O)CO)C3=C14)C2=O PLXLYXLUCNZSAA-QLXKLKPCSA-N 0.000 claims description 3
- HFOBENSCBRZVSP-LKXGYXEUSA-N C[C@@H](O)[C@H](NC(=O)N[C@@H](CC(N)=O)c1nc(no1)[C@@H](N)CO)C(O)=O Chemical compound C[C@@H](O)[C@H](NC(=O)N[C@@H](CC(N)=O)c1nc(no1)[C@@H](N)CO)C(O)=O HFOBENSCBRZVSP-LKXGYXEUSA-N 0.000 claims description 3
- 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 claims description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 239000004971 Cross linker Substances 0.000 claims description 3
- 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 claims description 3
- 101710112752 Cytotoxin Proteins 0.000 claims description 3
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 claims description 3
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 claims description 3
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims description 3
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims description 3
- 108010092160 Dactinomycin Proteins 0.000 claims description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
- 201000005231 Epithelioid sarcoma Diseases 0.000 claims description 3
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 3
- KPBNHDGDUADAGP-VAWYXSNFSA-N FK-866 Chemical compound C=1C=CN=CC=1/C=C/C(=O)NCCCCC(CC1)CCN1C(=O)C1=CC=CC=C1 KPBNHDGDUADAGP-VAWYXSNFSA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 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 claims description 3
- 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 claims description 3
- 201000003803 Inflammatory myofibroblastic tumor Diseases 0.000 claims description 3
- 206010067917 Inflammatory myofibroblastic tumour Diseases 0.000 claims description 3
- 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 claims description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 206010066948 Myxofibrosarcoma Diseases 0.000 claims description 3
- PBBRWFOVCUAONR-UHFFFAOYSA-N PP2 Chemical compound C12=C(N)N=CN=C2N(C(C)(C)C)N=C1C1=CC=C(Cl)C=C1 PBBRWFOVCUAONR-UHFFFAOYSA-N 0.000 claims description 3
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- LOGJQOUIVKBFGH-UHFFFAOYSA-N SU6656 Chemical compound C1CCCC(N2)=C1C=C2C=C1C(=O)NC2=CC=C(S(=O)(=O)N(C)C)C=C21 LOGJQOUIVKBFGH-UHFFFAOYSA-N 0.000 claims description 3
- 206010046799 Uterine leiomyosarcoma Diseases 0.000 claims description 3
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 3
- NLMBVBUNULOTNS-HOKPPMCLSA-N [4-[[(2s)-5-(carbamoylamino)-2-[[(2s)-2-[6-(2,5-dioxopyrrol-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-o Chemical compound C1([C@H](O)[C@@H](C)NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=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)OCC=2C=CC(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN3C(C=CC3=O)=O)C(C)C)=CC=2)C(C)C)OC)=CC=CC=C1 NLMBVBUNULOTNS-HOKPPMCLSA-N 0.000 claims description 3
- DAHMXVAETAAQOZ-UHFFFAOYSA-N [4-[[n'-[6-(4-chlorophenoxy)hexyl]-n-cyanocarbamimidoyl]amino]pyridin-1-ium-1-yl]methyl 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl carbonate;chloride Chemical compound [Cl-].C1=C[N+](COC(=O)OCCOCCOCCOCCOC)=CC=C1N\C(NC#N)=N\CCCCCCOC1=CC=C(Cl)C=C1 DAHMXVAETAAQOZ-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 229960000548 alemtuzumab Drugs 0.000 claims description 3
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 claims description 3
- 208000002849 chondrocalcinosis Diseases 0.000 claims description 3
- 229960002436 cladribine Drugs 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- 239000002619 cytotoxin Substances 0.000 claims description 3
- 229960000640 dactinomycin Drugs 0.000 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- 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 claims description 3
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- 230000003511 endothelial effect Effects 0.000 claims description 3
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 3
- 229960001904 epirubicin Drugs 0.000 claims description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 3
- 229960001433 erlotinib Drugs 0.000 claims description 3
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 3
- 229960000961 floxuridine Drugs 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- 239000004052 folic acid antagonist Substances 0.000 claims description 3
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 3
- 229960005277 gemcitabine Drugs 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 229960000908 idarubicin Drugs 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 206010024627 liposarcoma Diseases 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- 208000037819 metastatic cancer Diseases 0.000 claims description 3
- 208000011575 metastatic malignant neoplasm Diseases 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- MIUCZFWBCFZKEU-UHFFFAOYSA-N n-[2-[[2-phenyl-6-[4-(3-phenylpropyl)piperazine-1-carbonyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]amino]ethyl]acetamide Chemical compound C=1C=2C(NCCNC(=O)C)=NC(C=3C=CC=CC=3)=NC=2NC=1C(=O)N(CC1)CCN1CCCC1=CC=CC=C1 MIUCZFWBCFZKEU-UHFFFAOYSA-N 0.000 claims description 3
- QRGHOAATPOLDPF-VQFNDLOPSA-N nanatinostat Chemical compound N1=CC(C(=O)NO)=CN=C1N1C[C@@H]([C@@H]2NCC=3N=C4C=CC(F)=CC4=CC=3)[C@@H]2C1 QRGHOAATPOLDPF-VQFNDLOPSA-N 0.000 claims description 3
- 230000017066 negative regulation of growth Effects 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 229960005184 panobinostat Drugs 0.000 claims description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 3
- 229960002340 pentostatin Drugs 0.000 claims description 3
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 claims description 3
- 229960001237 podophyllotoxin Drugs 0.000 claims description 3
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 claims description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 206010042863 synovial sarcoma Diseases 0.000 claims description 3
- VAZAPHZUAVEOMC-UHFFFAOYSA-N tacedinaline Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N VAZAPHZUAVEOMC-UHFFFAOYSA-N 0.000 claims description 3
- 229960003087 tioguanine Drugs 0.000 claims description 3
- 229950002860 triplatin tetranitrate Drugs 0.000 claims description 3
- 190014017283 triplatin tetranitrate Chemical compound 0.000 claims description 3
- 208000022810 undifferentiated (embryonal) sarcoma Diseases 0.000 claims description 3
- 229960000604 valproic acid Drugs 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 3
- 229960004355 vindesine Drugs 0.000 claims description 3
- RVNSQVIUFZVNAU-UHFFFAOYSA-N 5-[(2-hydroxynaphthalen-1-yl)methyl]-6-phenyl-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound OC1=CC=C2C=CC=CC2=C1CC(C(NC(=S)N1)=O)=C1C1=CC=CC=C1 RVNSQVIUFZVNAU-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- 201000009500 myxoid chondrosarcoma Diseases 0.000 claims description 2
- 229960004641 rituximab Drugs 0.000 claims description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 claims description 2
- 229960003452 romidepsin Drugs 0.000 claims description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 claims description 2
- 108010091666 romidepsin Proteins 0.000 claims description 2
- 229960005399 satraplatin Drugs 0.000 claims description 2
- 190014017285 satraplatin Chemical compound 0.000 claims description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 2
- 229960003048 vinblastine Drugs 0.000 claims description 2
- 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 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 10
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims 2
- 190000008236 carboplatin Chemical compound 0.000 claims 2
- 238000007914 intraventricular administration Methods 0.000 claims 2
- 210000004276 hyalin Anatomy 0.000 claims 1
- 238000001361 intraarterial administration Methods 0.000 claims 1
- 238000007917 intracranial administration Methods 0.000 claims 1
- 238000007912 intraperitoneal administration Methods 0.000 claims 1
- 238000007913 intrathecal administration Methods 0.000 claims 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 claims 1
- 229960004586 rosiglitazone Drugs 0.000 claims 1
- 239000000562 conjugate Substances 0.000 abstract description 5
- 150000001413 amino acids Chemical group 0.000 description 53
- 241001529936 Murinae Species 0.000 description 21
- 230000014509 gene expression Effects 0.000 description 14
- 241000880493 Leptailurus serval Species 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108010087924 alanylproline Proteins 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 8
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 8
- 102000005600 Cathepsins Human genes 0.000 description 7
- 108010084457 Cathepsins Proteins 0.000 description 7
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 7
- 108010076504 Protein Sorting Signals Proteins 0.000 description 7
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 7
- 108010092854 aspartyllysine Proteins 0.000 description 7
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 7
- 108010010147 glycylglutamine Proteins 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 7
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 6
- HPNDKUOLNRVRAY-BIIVOSGPSA-N Asn-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N)C(=O)O HPNDKUOLNRVRAY-BIIVOSGPSA-N 0.000 description 6
- BJVBMSTUUWGZKX-JYJNAYRXSA-N Gln-Tyr-His Chemical compound N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O BJVBMSTUUWGZKX-JYJNAYRXSA-N 0.000 description 6
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 6
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 6
- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 description 6
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 6
- VBTFUDNTMCHPII-UHFFFAOYSA-N Val-Trp-Tyr Natural products C=1NC2=CC=CC=C2C=1CC(NC(=O)C(N)C(C)C)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 VBTFUDNTMCHPII-UHFFFAOYSA-N 0.000 description 6
- 108010068265 aspartyltyrosine Proteins 0.000 description 6
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 6
- 108010089804 glycyl-threonine Proteins 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000013600 plasmid vector Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- UCIYCBSJBQGDGM-LPEHRKFASA-N Ala-Arg-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N UCIYCBSJBQGDGM-LPEHRKFASA-N 0.000 description 5
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 5
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 5
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 5
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 5
- RVGMVLVBDRQVKB-UWVGGRQHSA-N Gly-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN RVGMVLVBDRQVKB-UWVGGRQHSA-N 0.000 description 5
- VNNRLUNBJSWZPF-ZKWXMUAHSA-N Gly-Ser-Ile Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNNRLUNBJSWZPF-ZKWXMUAHSA-N 0.000 description 5
- FKYQEVBRZSFAMJ-QWRGUYRKSA-N Gly-Ser-Tyr Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FKYQEVBRZSFAMJ-QWRGUYRKSA-N 0.000 description 5
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 5
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 5
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 5
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 5
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 5
- QDDJNKWPTJHROJ-UFYCRDLUSA-N Pro-Tyr-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 QDDJNKWPTJHROJ-UFYCRDLUSA-N 0.000 description 5
- VDVYTKZBMFADQH-AVGNSLFASA-N Ser-Gln-Tyr Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 VDVYTKZBMFADQH-AVGNSLFASA-N 0.000 description 5
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 5
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 5
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 5
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 5
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 5
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 5
- 125000002091 cationic group Chemical group 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 108010049041 glutamylalanine Proteins 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 5
- 108010051242 phenylalanylserine Proteins 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 108010031719 prolyl-serine Proteins 0.000 description 5
- 108010070643 prolylglutamic acid Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000013603 viral vector Substances 0.000 description 5
- YLTKNGYYPIWKHZ-ACZMJKKPSA-N Ala-Ala-Glu Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O YLTKNGYYPIWKHZ-ACZMJKKPSA-N 0.000 description 4
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 4
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 4
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 4
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 4
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 4
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 4
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 4
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 4
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- GYEPCBNTTRORKW-PCBIJLKTSA-N Phe-Ile-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O GYEPCBNTTRORKW-PCBIJLKTSA-N 0.000 description 4
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 4
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 4
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 4
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 4
- CDVFZMOFNJPUDD-ACZMJKKPSA-N Ser-Gln-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CDVFZMOFNJPUDD-ACZMJKKPSA-N 0.000 description 4
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 4
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 4
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 4
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 4
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 4
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 4
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 4
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 4
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 4
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 4
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 4
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 4
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 4
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 4
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 4
- WHNSHJJNWNSTSU-BZSNNMDCSA-N Val-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 WHNSHJJNWNSTSU-BZSNNMDCSA-N 0.000 description 4
- 150000001408 amides Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 4
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 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 4
- 229920001436 collagen Polymers 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 108010078144 glutaminyl-glycine Proteins 0.000 description 4
- 108010037850 glycylvaline Proteins 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 4
- 230000002132 lysosomal effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 108010077112 prolyl-proline Proteins 0.000 description 4
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 4
- 108010073969 valyllysine Proteins 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 3
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 3
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 3
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 3
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 3
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 3
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 3
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 3
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 3
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 3
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 3
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 3
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 3
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 3
- 206010073140 Clear cell sarcoma of soft tissue Diseases 0.000 description 3
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 3
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 3
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 3
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 3
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 3
- XQDGOJPVMSWZSO-SRVKXCTJSA-N Gln-Pro-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)N)N XQDGOJPVMSWZSO-SRVKXCTJSA-N 0.000 description 3
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 3
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 3
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 3
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 3
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 3
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 3
- DTRUBYPMMVPQPD-YUMQZZPRSA-N Gly-Gln-Arg Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DTRUBYPMMVPQPD-YUMQZZPRSA-N 0.000 description 3
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 3
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 3
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 3
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 3
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 3
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 3
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 3
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-N 0.000 description 3
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 3
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 3
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 3
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 3
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 3
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 3
- QQPSCXKFDSORFT-IHRRRGAJSA-N Lys-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN QQPSCXKFDSORFT-IHRRRGAJSA-N 0.000 description 3
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 3
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 3
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 3
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 3
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 3
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 3
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 3
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 3
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 3
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 3
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 3
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 3
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 3
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 3
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 3
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 3
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 3
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 3
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 3
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 3
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 3
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 3
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 3
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 3
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 3
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 3
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 3
- RPECVQBNONKZAT-WZLNRYEVSA-N Thr-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H]([C@@H](C)O)N RPECVQBNONKZAT-WZLNRYEVSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 3
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 3
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 3
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 3
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 3
- GQVZBMROTPEPIF-SRVKXCTJSA-N Tyr-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GQVZBMROTPEPIF-SRVKXCTJSA-N 0.000 description 3
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 3
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 3
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 3
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 3
- 108010008355 arginyl-glutamine Proteins 0.000 description 3
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 3
- 108010038633 aspartylglutamate Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 229960000397 bevacizumab Drugs 0.000 description 3
- 201000000292 clear cell sarcoma Diseases 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 3
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 108010027338 isoleucylcysteine Proteins 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 108010073101 phenylalanylleucine Proteins 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 3
- 108010026333 seryl-proline Proteins 0.000 description 3
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 108010051110 tyrosyl-lysine Proteins 0.000 description 3
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- KDAHPBGYDUMHRL-QPEQYQDCSA-N (2z)-2-[(3,4-dihydroxyphenyl)methylidene]-4,5,6-trimethoxy-1-benzofuran-3-one Chemical compound O=C1C=2C(OC)=C(OC)C(OC)=CC=2O\C1=C/C1=CC=C(O)C(O)=C1 KDAHPBGYDUMHRL-QPEQYQDCSA-N 0.000 description 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 2
- 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 2
- ULTTYPMRMMDONC-UHFFFAOYSA-N 5-[(2,5-dihydroxyphenyl)methyl-[(2-hydroxyphenyl)methyl]amino]-2-hydroxybenzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(N(CC=2C(=CC=CC=2)O)CC=2C(=CC=C(O)C=2)O)=C1 ULTTYPMRMMDONC-UHFFFAOYSA-N 0.000 description 2
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 2
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 2
- ROLXPVQSRCPVGK-XDTLVQLUSA-N Ala-Glu-Tyr Chemical compound N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O ROLXPVQSRCPVGK-XDTLVQLUSA-N 0.000 description 2
- QQACQIHVWCVBBR-GVARAGBVSA-N Ala-Ile-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QQACQIHVWCVBBR-GVARAGBVSA-N 0.000 description 2
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 2
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 2
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 2
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 2
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 2
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 2
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 2
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 2
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 2
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 2
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 2
- YQNBILXAUIAUCF-CIUDSAMLSA-N Asn-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N YQNBILXAUIAUCF-CIUDSAMLSA-N 0.000 description 2
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 2
- QUAWOKPCAKCHQL-SRVKXCTJSA-N Asn-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N QUAWOKPCAKCHQL-SRVKXCTJSA-N 0.000 description 2
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 2
- LTDGPJKGJDIBQD-LAEOZQHASA-N Asn-Val-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LTDGPJKGJDIBQD-LAEOZQHASA-N 0.000 description 2
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 2
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 2
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 2
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 2
- QSFHZPQUAAQHAQ-CIUDSAMLSA-N Asp-Ser-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O QSFHZPQUAAQHAQ-CIUDSAMLSA-N 0.000 description 2
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 2
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 2
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 2
- 102100025351 C-type mannose receptor 2 Human genes 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 2
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 2
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 2
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 2
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 2
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 2
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 2
- QZQYITIKPAUDGN-GVXVVHGQSA-N Gln-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N QZQYITIKPAUDGN-GVXVVHGQSA-N 0.000 description 2
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 2
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 2
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 2
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 2
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 2
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 2
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 2
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 2
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-N 0.000 description 2
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 2
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 2
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 2
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 2
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 2
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- YXTFLTJYLIAZQG-FJXKBIBVSA-N Gly-Thr-Arg Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YXTFLTJYLIAZQG-FJXKBIBVSA-N 0.000 description 2
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- MCAHMSDENAOJFZ-UHFFFAOYSA-N Herbimycin A Natural products N1C(=O)C(C)=CC=CC(OC)C(OC(N)=O)C(C)=CC(C)C(OC)C(OC)CC(C)C(OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-UHFFFAOYSA-N 0.000 description 2
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000576898 Homo sapiens C-type mannose receptor 2 Proteins 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 2
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 2
- ZGKVPOSSTGHJAF-HJPIBITLSA-N Ile-Tyr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CO)C(=O)O)N ZGKVPOSSTGHJAF-HJPIBITLSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- RSFGIMMPWAXNML-MNXVOIDGSA-N Leu-Gln-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RSFGIMMPWAXNML-MNXVOIDGSA-N 0.000 description 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 2
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 2
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 2
- FIICHHJDINDXKG-IHPCNDPISA-N Leu-Lys-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O FIICHHJDINDXKG-IHPCNDPISA-N 0.000 description 2
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 2
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 2
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 2
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 2
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 2
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 2
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 2
- QYOXSYXPHUHOJR-GUBZILKMSA-N Lys-Asn-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYOXSYXPHUHOJR-GUBZILKMSA-N 0.000 description 2
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 2
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 2
- HYSVGEAWTGPMOA-IHRRRGAJSA-N Lys-Pro-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O HYSVGEAWTGPMOA-IHRRRGAJSA-N 0.000 description 2
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 2
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 2
- 108010031099 Mannose Receptor Proteins 0.000 description 2
- 206010027452 Metastases to bone Diseases 0.000 description 2
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- LBSARGIQACMGDF-WBAXXEDZSA-N Phe-Ala-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 LBSARGIQACMGDF-WBAXXEDZSA-N 0.000 description 2
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 2
- FSPGBMWPNMRWDB-AVGNSLFASA-N Phe-Cys-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N FSPGBMWPNMRWDB-AVGNSLFASA-N 0.000 description 2
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 2
- FQUUYTNBMIBOHS-IHRRRGAJSA-N Phe-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FQUUYTNBMIBOHS-IHRRRGAJSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 2
- KWMUAKQOVYCQJQ-ZPFDUUQYSA-N Pro-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 KWMUAKQOVYCQJQ-ZPFDUUQYSA-N 0.000 description 2
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 2
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 2
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 2
- VMVNCJDKFOQOHM-GUBZILKMSA-N Ser-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N VMVNCJDKFOQOHM-GUBZILKMSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 2
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 2
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 2
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 2
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 2
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 2
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 2
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 2
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 2
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 2
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 2
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 2
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 2
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 2
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 2
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 2
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-N 0.000 description 2
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 2
- PWONLXBUSVIZPH-RHYQMDGZSA-N Thr-Val-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O PWONLXBUSVIZPH-RHYQMDGZSA-N 0.000 description 2
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 2
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 2
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 2
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 2
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 2
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 2
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 2
- DJIJBQYBDKGDIS-JYJNAYRXSA-N Tyr-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C)C(O)=O DJIJBQYBDKGDIS-JYJNAYRXSA-N 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 2
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 2
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 2
- QPPZEDOTPZOSEC-RCWTZXSCSA-N Val-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](C(C)C)N)O QPPZEDOTPZOSEC-RCWTZXSCSA-N 0.000 description 2
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 2
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 2
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 2
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 2
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 2
- 229950011276 belotecan Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229960000455 brentuximab vedotin Drugs 0.000 description 2
- 230000000981 bystander Effects 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
- 239000000969 carrier Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000003570 cell viability assay Methods 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229920003086 cellulose ether Polymers 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000008344 egg yolk phospholipid Substances 0.000 description 2
- 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 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 2
- KDAHPBGYDUMHRL-UHFFFAOYSA-N hamiltrone Natural products O=C1C=2C(OC)=C(OC)C(OC)=CC=2OC1=CC1=CC=C(O)C(O)=C1 KDAHPBGYDUMHRL-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 108010025306 histidylleucine Proteins 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000012482 interaction analysis Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 108010034529 leucyl-lysine Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108010038320 lysylphenylalanine Proteins 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 244000309459 oncolytic virus Species 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000010845 search algorithm Methods 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 108010061238 threonyl-glycine Proteins 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 230000010474 transient expression Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 2
- FJQZXCPWAGYPSD-UHFFFAOYSA-N 1,3,4,6-tetrachloro-3a,6a-diphenylimidazo[4,5-d]imidazole-2,5-dione Chemical compound ClN1C(=O)N(Cl)C2(C=3C=CC=CC=3)N(Cl)C(=O)N(Cl)C12C1=CC=CC=C1 FJQZXCPWAGYPSD-UHFFFAOYSA-N 0.000 description 1
- XSHQBIXMLULFEV-UHFFFAOYSA-N 1-NA-PP1 Chemical compound C12=C(N)N=CN=C2N(C(C)(C)C)N=C1C1=CC=CC2=CC=CC=C12 XSHQBIXMLULFEV-UHFFFAOYSA-N 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical compound SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 1
- MAUCONCHVWBMHK-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide Chemical compound O1C2=CC=CC=C2C(CN(C)C)=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 MAUCONCHVWBMHK-UHFFFAOYSA-N 0.000 description 1
- LULATDWLDJOKCX-UHFFFAOYSA-N 5-[(2,5-dihydroxyphenyl)methylamino]-2-hydroxybenzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(NCC=2C(=CC=C(O)C=2)O)=C1 LULATDWLDJOKCX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000005748 Aggressive Fibromatosis Diseases 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- FBHOPGDGELNWRH-DRZSPHRISA-N Ala-Glu-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FBHOPGDGELNWRH-DRZSPHRISA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- VNFSAYFQLXPHPY-CIQUZCHMSA-N Ala-Thr-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNFSAYFQLXPHPY-CIQUZCHMSA-N 0.000 description 1
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010027164 Amanitins Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229940124293 CD30 monoclonal antibody Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 1
- WXKWQSDHEXKKNC-ZKWXMUAHSA-N Cys-Asp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N WXKWQSDHEXKKNC-ZKWXMUAHSA-N 0.000 description 1
- CFQVGYWKSLKWFX-KBIXCLLPSA-N Cys-Glu-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CFQVGYWKSLKWFX-KBIXCLLPSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 1
- 206010059352 Desmoid tumour Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical group SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 229920000896 Ethulose Polymers 0.000 description 1
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 201000003364 Extraskeletal myxoid chondrosarcoma Diseases 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 1
- ZSIDREAPEPAPKL-XIRDDKMYSA-N Glu-Trp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N ZSIDREAPEPAPKL-XIRDDKMYSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
- SDTPKSOWFXBACN-GUBZILKMSA-N His-Glu-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O SDTPKSOWFXBACN-GUBZILKMSA-N 0.000 description 1
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- AQTWDZDISVGCAC-CFMVVWHZSA-N Ile-Asp-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N AQTWDZDISVGCAC-CFMVVWHZSA-N 0.000 description 1
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 1
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 1
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- 108010064171 Lysosome-Associated Membrane Glycoproteins Proteins 0.000 description 1
- 102000014944 Lysosome-Associated Membrane Glycoproteins Human genes 0.000 description 1
- 102100025354 Macrophage mannose receptor 1 Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- MHQXIBRPDKXDGZ-ZFWWWQNUSA-N Met-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)[C@@H](N)CCSC)C(O)=O)=CNC2=C1 MHQXIBRPDKXDGZ-ZFWWWQNUSA-N 0.000 description 1
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 1
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- YALNUENQHAQXEA-UHFFFAOYSA-N N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester Chemical compound C1=CC2=CC(CN(CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 YALNUENQHAQXEA-UHFFFAOYSA-N 0.000 description 1
- PAWIYAYFNXQGAP-UHFFFAOYSA-N N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide Chemical compound C12=CC=CC=C2N(C)C=C1CNCC(CC1)CCN1C1=NC=C(C(=O)NO)C=N1 PAWIYAYFNXQGAP-UHFFFAOYSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 1
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 108010010056 Terlipressin Proteins 0.000 description 1
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 0.000 description 1
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 1
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- LTFLDDDGWOVIHY-NAKRPEOUSA-N Val-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N LTFLDDDGWOVIHY-NAKRPEOUSA-N 0.000 description 1
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 1
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 1
- HQYVQDRYODWONX-DCAQKATOSA-N Val-His-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CO)C(=O)O)N HQYVQDRYODWONX-DCAQKATOSA-N 0.000 description 1
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 1
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 1
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 1
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 1
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229950008805 abexinostat Drugs 0.000 description 1
- 108010081404 acein-2 Proteins 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- CIORWBWIBBPXCG-JZTFPUPKSA-N amanitin Chemical compound O=C1N[C@@H](CC(N)=O)C(=O)N2CC(O)C[C@H]2C(=O)N[C@@H](C(C)[C@@H](O)CO)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H](C(C)CC)C(=O)NCC(=O)N[C@H]1CS(=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-JZTFPUPKSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940044684 anti-microtubule agent Drugs 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- NOFOAYPPHIUXJR-APNQCZIXSA-N aphidicolin Chemical compound C1[C@@]23[C@@]4(C)CC[C@@H](O)[C@@](C)(CO)[C@@H]4CC[C@H]3C[C@H]1[C@](CO)(O)CC2 NOFOAYPPHIUXJR-APNQCZIXSA-N 0.000 description 1
- SEKZNWAQALMJNH-YZUCACDQSA-N aphidicolin Natural products C[C@]1(CO)CC[C@]23C[C@H]1C[C@@H]2CC[C@H]4[C@](C)(CO)[C@H](O)CC[C@]34C SEKZNWAQALMJNH-YZUCACDQSA-N 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 229950007712 camrelizumab Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940121420 cemiplimab Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 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 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229940121432 dostarlimab Drugs 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 230000002121 endocytic effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical class CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 1
- 229950009429 exatecan Drugs 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229950010415 givinostat Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 201000000284 histiocytoma Diseases 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000010039 intracellular degradation Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 108010078274 isoleucylvaline Proteins 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000503 lectinlike effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical class CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 229950007812 mocetinostat Drugs 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940045795 other cytotoxic antibiotic in ATC Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920002006 poly(N-vinylimidazole) polymer Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 229950010654 quisinostat Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229950007213 spartalizumab Drugs 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BENFXAYNYRLAIU-QSVFAHTRSA-N terlipressin Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CN)CSSC1 BENFXAYNYRLAIU-QSVFAHTRSA-N 0.000 description 1
- 229960003813 terlipressin Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229950007123 tislelizumab Drugs 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
-
- 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
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- 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
Abstract
本公开涉及靶向尿激酶型纤溶酶原激活物受体相关蛋白(uPARAP)的人源化抗体和分子缀合物,特别是包含针对uPARAP的人源化抗体的抗体‑药物缀合物(ADC),及其在将活性剂递送至表达uPARAP的细胞和组织中的用途。本公开进一步涉及所述ADC在治疗涉及uPARAP表达细胞的疾病,例如某些癌症中的用途。
Description
技术领域
本发明涉及靶向受体uPARAP的抗体和分子缀合物,特别是包含针对uPARAP的人源化抗体的抗体-药物缀合物(ADC)及其在将活性剂递送至表达uPARAP的细胞和组织中的用途。本发明进一步涉及所述ADC在治疗涉及表达uPARAP的细胞的疾病,例如某些癌症中的用途。
发明背景
尿激酶型纤溶酶原激活物受体相关蛋白(Urokinase-type PlasminogenActivator Receptor Associated Protein,uPARAP),也称为CD280、Endo180和2型甘露糖受体C,是内吞跨膜糖蛋白的巨噬细胞甘露糖受体家族的成员。uPARAP是参与组织重塑过程中的基质周转,特别是胶原蛋白的摄取和细胞内降解的一种膜蛋白。uPARAP受体由N端富含半胱氨酸的结构域(CysR)、II型纤连蛋白(FN-II)结构域和八个C型凝集素样结构域(CTLD1-8)组成。
受体uPARAP在包括肉瘤和晚期胶质母细胞瘤的特定癌症的肿瘤细胞中上调。另外,该受体还最常在实体瘤周围的基质细胞中上调,并且一些文献表明uPARAP在前列腺癌的骨转移中高表达(Caley et al.,2012,J.Pathol 5:775-783)。在健康成人个体中,该受体表现出受限的表达模式(Melander etal.,2015,Int J Oncol 47:1177-1188)。
抗体-药物缀合物(ADC)是一类被设计为用于靶向治疗,特别是用于癌症治疗的高效生物药物。ADC是由抗体(完整mAb或抗体片段)通过可能具有不稳定键的稳定化学接头与活性剂(例如生物活性药物或细胞毒性化合物)连接而组成的复杂分子。通过将抗体的独特靶向能力与细胞毒性药物的细胞杀伤能力相结合,抗体-药物缀合物可以根据抗体抗原的表达来灵敏地区分健康组织和患病组织。这意味着,与传统的化疗药物相比,抗体-药物缀合物主动靶向并攻击癌细胞,从而使得具有很少或没有抗原表达的健康细胞受影响较小。迄今为止,已有超过10种ADC获得市场批准,并且有多种ADC目前正在进行临床试验。
WO 2010/111198公开了包含抗uPARAP抗体的缀合物,并建议使用此类缀合物将治疗剂递送至表达uPARAP的细胞。
WO 2017/133745公开了针对uPARAP的ADC。
目前大多数癌症类型都有治疗方法。然而,在许多情况下,效果并不令人满意或者由于治疗剂的高剂量而产生副作用。因此,需要效力增加的更有效的治疗。
发明概述
本文提供了鼠9b7抗体的人源化版本及其在靶向uPARAP受体的抗体-药物缀合物(ADC)中的应用。鼠9b7抗体最初描述于WO 2017/133745中。本文所述的抗体和ADC能够特异性靶向表达uPARAP的细胞和组织,并且与包含鼠9b7抗体的ADC相比显示出增强的功效,并且与鼠9b7抗体的其他人源化版本相比显示出增强的功效。
具体地,本公开涉及结合uPARAP的抗体,其包含:
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成;和/或
b.免疫球蛋白重链可变区,其包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成。
此外,本公开还涉及抗体-药物缀合物(ADC),其包含:
a.如上文所定义的抗体,
b.活性剂,和
c.任选地,连接a)和b)的接头。
此外,本公开还涉及一种用于治疗以表达uPARAP的细胞为特征的疾病的方法,所述方法包括向受试者施用如上文定义的抗体、如上文定义的ADC或包含如上文所定义的抗体或ADC的药物组合物。
本公开的另一方面是包含SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列或由SEQID NO:2和/或SEQ ID NO:5的氨基酸序列组成的多肽;编码本文定义的氨基酸序列的分离的多核苷酸;包含如上所定义的多核苷酸的载体;以及包含如上文所定义的多核苷酸和/或如上文所定义的载体的宿主细胞。
本公开的又一个方面是试剂盒,所述试剂盒包含如上文所定义的抗体、如上文所定义的ADC或包含如上文所定义的抗体或ADC的药物组合物,任选地,所述试剂盒进一步包含用于向受试者施用抗体或抗体-药物缀合物的装置(means)和/或使用说明。
附图说明
图1:对暴露于包含LC0HC0抗体(包含与人IgG恒定区融合的原始鼠9b7抗体的可变结构域)或人源化LC4HC3抗体的基于MMAE的ADC的U937癌细胞系进行体外细胞活力测定。但对于抗体来说,这两种ADC是相同的,并且是通过相同的方法生产的。将细胞孵育96小时,然后通过比色活力测定进行分析。对U937细胞系的测定表明,与LC0HC0 ADC相比,基于LC4HC3的ADC对总体细胞活力的降低显著更大。
图2:人源化抗体LC4HC3和LC3HC3在SAOS-2骨肉瘤细胞中的内化。详细方案在实施例2中给出。该数据显示,与LC3HC3相比,LC4HC3在SAOS-2骨肉瘤细胞中的内化不仅更快,而且程度更高。
图3:基于LC4HC3(LC4HC3-vc-MMAE,图3a)和LC3HC3(LC3HC3-vc-MMAE,图3b)的Vedotin型ADC的体内功效。将CB17小鼠接种U937细胞以诱导肿瘤生长。密切监测肿瘤大小,一旦达到约80-150mm3的大小就开始治疗。但对于抗体来说,这两种ADC是相同的,并且通过相同的方法生产。图3a和3b的每一行代表了每天两次施用4mg/kg剂量的参考ADC共7天的小鼠的肿瘤大小。该数据显示,与基于不同的人源化9b7抗体LC3HC3的ADC相比,基于人源化9b7抗体LC4HC3的ADC是更优异的抗肿瘤剂。
发明详述
本公开的抗体在与细胞表面的uPARAP受体结合后被内化,从而允许抗体-药物缀合物复合物的活性剂在细胞内发挥作用。
本文提供了结合uPARAP受体的人源化版本的鼠9b7抗体。
抗uPARAP人源化抗体
产生抗体的方法是本领域众所周知的。例如,可以通过采用诱导抗体分子的体内产生、筛选免疫球蛋白文库或通过培养细胞系产生单克隆抗体分子的几种方法中的任何一种来产生抗体。这些方法包括但不限于杂交瘤技术、人B细胞杂交瘤技术和Epstein-Barr病毒(EBV)杂交瘤技术。
人源化抗体在用于人类的药物中通常是优选的,并且对抗体进行人源化的方法是本领域众所周知的。尽管人源化技术是已知的,但获得保留初始抗体的结合特性的人源化抗体仍可能是一个挑战,并且更有挑战的是获得具有改善的特性(例如与初始抗体相比具有改善的配体亲和力和功效)的人源化抗体。
本发明人在此提供了改进的抗uPARAP抗体,其是9b7鼠抗体的人源化版本,并且与9b7鼠抗体相比表现出改善的配体亲和力和功效,以及与9b7抗体的其他人源化版本相比表现出改善的内化和体内功效。
本公开的抗uPARAP抗体可以是任何免疫球蛋白类别,包括IgG、IgM、IgD、IgE、IgA及其任何亚类。IgG亚类也是本领域技术人员众所周知的,并且包括但不限于人IgG1、IgG2、IgG3和IgG4。在一个实施方案中,抗体是IgG单克隆抗体。在一个实施方案中,抗体是IgG1κ。
本公开的抗uPARAP抗体是结合uPARAP受体的人源化9b7抗体,更具体地,本文公开的人源化9b7抗体至少结合uPARAP受体的纤连蛋白II型(FN-II)结构域。
人源化9b7抗体,在本文中也称为980.2LC4HC3,包含含有SEQ ID NO:3的氨基酸的轻链可变区(其是LC4的可变区)和含有SEQ ID NO:6的氨基酸的重链可变区(其是HC3的可变区)。
人源化9b7抗体,在本文中也称为980.2LC4HC3,可以包含含有SEQ ID NO:1或由SEQ ID NO:1组成的氨基酸的轻链(其为LC4),和包含含有SEQ ID NO:4或由SEQ ID NO:4组成的氨基酸的重链(其为HC3)。
在本公开的一个实施方案中,本文定义的抗uPARAP抗体包含:
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成;和/或
b.免疫球蛋白重链可变区,其包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成。
在本公开的一个实施方案中,本文定义的结合uPARAP的抗体包含:
a.包含SEQ ID NO:1的氨基酸序列的免疫球蛋白轻链(LC4);和/或
b.包含SEQ ID NO:4的氨基酸序列的免疫球蛋白重链(HC3)。
在本公开的一个实施方案中,本文定义的结合uPARAP的抗体包含:
a.由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链(LC4);和
b.由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链(HC3)。
多肽、多核苷酸、载体和宿主细胞
本公开的一个实施方案是包含SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列或由SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列组成的多肽。SEQ ID NO:2和SEQ ID NO:5分别对应于SEQ ID NO:1和SEQ ID NO:4,但进一步具有用于表达目的的N端信号肽。
本公开的一个实施方案是编码本文公开的任何多肽的分离的多核苷酸,即编码SEQ ID NO:1、2、3、4、5和/或6中任一个的氨基酸序列的分离的多核苷酸。
在一个实施方案中,所述多核苷酸包含分别编码SEQ ID NO:2和SEQ ID NO:5的SEQ ID NO:11和/或SEQ ID NO:12。
在一个实施方案中,所述多肽包含SEQ ID NO:2的氨基酸序列或由SEQ ID NO:2的氨基酸序列组成,任选地,其中所述多肽还包含SEQ ID NO:5的氨基酸序列。
在一个实施方案中,本公开提供了分离的多核苷酸,其编码SEQ ID NO:1、2或3中任一个的氨基酸序列,任选地,其中所述多核苷酸还编码SEQ ID NO:4、5或6中任一个的氨基酸序列。
在一个实施方案中,本公开提供了包含SEQ ID NO:11的分离的多核苷酸,任选地,其中所述多核苷酸进一步包含SEQ ID NO:12。
在一个实施方案中,所述多肽是分离的多肽。
本公开的一个实施方案是包含本文定义的多核苷酸的载体,例如表达载体。
在本公开的一个实施方案中,所述载体是哺乳动物表达载体。
在本公开的一个实施方案中,所述载体为质粒载体,例如选自pD2610-v13(ATUM)、pSV和pCMV系列质粒载体的质粒载体。
在本公开的一个实施方案中,所述载体为病毒载体,例如选自腺病毒载体、慢病毒载体、腺相关病毒载体、疱疹病毒载体、牛痘病毒载体(vaccinia viral vector)、痘病毒载体(poxviral vector)、杆状病毒载体和溶瘤病毒载体的病毒载体。
本公开的另一个实施方案是包含本文定义的多核苷酸和/或载体的宿主细胞。
在本公开的一个实施方案中,包含本文所述的多核苷酸和/或载体的宿主细胞选自CHO(中国仓鼠卵巢)细胞、COS(起源于CV-1(猿)并携带SV40遗传物质)细胞、HEK(人胚胎肾)细胞和HeLa(Henrietta Lacks)细胞。
在一个实施方案中,宿主细胞是CHO。
在一个实施方案中,宿主细胞是重组宿主细胞。
包含抗uPARAP人源化抗体的抗体-药物缀合物(ADC)
发明人的数据令人惊讶地显示,与基于LC0HC0(具有与人IgG恒定区融合的9b7鼠抗体的可变结构域)的ADC相比,基于LC4HC3(人源化9b7抗体)的ADC导致总体细胞活力的降低显著更大。与基于LC3HC3(另一种人源化9b7抗体)的ADC相比,基于LC4HC3的ADC还表现出改善的内化和体内功效。
本公开的一个特别优选的实施方案是抗体-药物缀合物(ADC),其包含:
a.如本文所定义的抗体,
b.活性剂,和
c.任选地,连接a)和b)的接头。
在本公开的一个实施方案中,本文定义的抗体-药物缀合物(ADC)包含:
a.如本文所定义的抗体,其包含:
i)含有SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成的免疫球蛋白轻链可变区;和/或
ii)含有SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成的免疫球蛋白重链可变区;
b.活性剂,以及
c.任选地,连接a)和b)的接头。
在本公开的一个实施方案中,本文定义的抗体-药物缀合物(ADC)包含:
a.如本文所定义的抗体,其包含:
i)含有SEQ ID NO:1的氨基酸序列或由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链;和/或
ii)含有SEQ ID NO:4的氨基酸序列或由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链;
b.活性剂,以及
c.任选地,连接a)和b)的接头。
在本公开的一个实施方案中,本文定义的抗体-药物缀合物(ADC)包含:
a.如本文所定义的抗体,其包含:
i)由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链;和
ii)由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链
b.活性剂,以及
c.任选地,连接a)和b)的接头。
活性剂
本公开的ADC包含可以在细胞内递送至表达uPARAP的细胞的活性剂,例如药物。活性剂可以是例如治疗剂、放射性同位素或可检测标记。在优选的实施方案中,活性剂是治疗剂。
在一个实施方案中,活性剂可以是放射性同位素或包含放射性同位素。放射性同位素可以用作辐射发射物(radiation emitter),用于治疗受影响的组织或用于诊断目的。在一个实施方案中,放射性同位素可以由60Co、89Sr、90Y、99mTc、131I、137Cs、153Sm或223Rd组成或包含60Co、89Sr、90Y、99mTc、131I、137Cs、153Sm或223Rd。在本公开的一个实施方案中,放射性同位素可以与螯合剂例如DOTA或EDTA或本领域公知的其他螯合剂组合。
在一个实施方案中,活性剂是治疗剂。治疗剂的类别包括DNA交联剂、DNA烷化剂、DNA链断裂剂(DNA strand scission agent)、蒽环类、抗代谢物、抗微管/抗有丝分裂剂、组蛋白脱乙酰酶抑制剂、激酶抑制剂、代谢抑制剂、肽抗生素、免疫检查点抑制剂、基于铂的抗肿瘤剂、拓扑异构酶抑制剂、DNA或RNA聚合酶抑制剂、基于核苷酸的剂和细胞毒性抗生素。
在一个优选的实施方案中,活性剂是允许有效杀伤表达uPARAP的细胞的细胞毒性剂。
在一个实施方案中,活性剂是化疗剂。
在一个实施方案中,活性剂是DNA交联剂,例如选自顺铂或顺铂衍生物例如卡铂或奥沙利铂、丝裂霉素C(MMC)、吡咯并苯二氮(pyrrolobenzodiazepine)和二聚吡咯并苯二氮/>衍生物例如SGD-1882或任一这些的衍生物的DNA交联剂。
在本公开的一个实施方案中,活性剂是DNA烷化剂,例如选自氮芥类如三(2-氯乙基)胺、吡啶并苯二氮(pyridinobenzodiazepine)或吡啶并苯二氮/>衍生物、吲哚并苯二氮/>二聚体(indolinobenzodiazepine dimer)和Duocarmycin SA或任一这些的衍生物的DNA烷化剂。
在一个实施方案中,活性剂是DNA链断裂剂,例如选自卡利奇霉素(calicheamicin)和哈密酮(hamiltrone)或任一这些的衍生物的DNA链断裂剂。
在一个实施方案中,活性剂是蒽环,例如选自柔红霉素、多柔比星、表柔比星、伊达比星和PNU-159682或任一这些的衍生物的蒽环。
在一个实施方案中,活性剂是抗代谢物,例如选自叶酸拮抗剂例如氨甲喋呤(methotrexate)、嘌呤抗代谢物例如6-巯基嘌呤或6-硫鸟嘌呤或磷酸氟达拉滨(fludarabine phosphate)或喷司他丁(pentostatin)或克拉屈滨(cladribine),以及嘧啶抗代谢物例如5-氟尿嘧啶或5-氟脱氧尿苷或阿糖胞苷(cytarabine)或吉西他滨(gemcitabine)或任一这些的衍生物的抗代谢物。
在一个实施方案中,活性剂是抗有丝分裂剂,例如选自奥瑞他汀(auristatin)或多拉司他汀(dolastatin)的衍生物,例如单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)等,紫杉烷例如紫杉醇(Paclitaxel)或多西他赛(Docetaxel)等,长春花生物碱(vinca alkaloid)例如长春花碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)或长春瑞滨(Vinorelbine)等,mayatansinoid、秋水仙碱(Colchicine)和鬼臼毒素(Podophyllotoxin)或任一这些的衍生物。在一个实施方案中,活性剂是单甲基奥瑞他汀E(MMAE)或其衍生物。
MMAE通过阻断微管蛋白聚合来抑制细胞分裂,由于其毒性较大,不能作为单药化疗药物使用。然而,MMAE与抗CD30单克隆抗体(维布妥昔单抗(Brentuximab Vedotin),商品名AdcetrisTM)连接的组合已被证明在细胞外液体中稳定,可被组织蛋白酶裂解并且对于治疗是安全的。
在一个实施方案中,活性剂是组蛋白脱乙酰酶抑制剂,例如选自曲古抑菌素A(trichostatin A)、伏立诺他(vorinostat)、贝林司他(belinostat)、帕比司他(panabiostat)、吉维司他(givinostat)、瑞米司他(resminostat)、艾贝司他(abexinostat)、奎司他(quisinostat)、罗西林司他(rocilinostat)、普拉诺司他(practinostat)、CHR-3996、丙戊酸、丁酸、苯丁酸、恩替诺特(entinostat)、乙酰地那林(tacedinaline)、4SC202、莫西司他(mocetinostat)、罗米地辛(romidepsin)、烟酰胺、西替诺(sirtinol)、cambinol和EX-527或任一这些的衍生物的组蛋白脱乙酰酶抑制剂。在一个实施方案中,活性剂是激酶抑制剂,例如选自金雀异黄素(genistein)、薰草菌素C(lavendustin C)、PP1-AG1872、PP2-AG1879、SU6656、CGP77675、PD166285、伊马替尼(imatinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、薰草菌素A(lavendustin A)、西妥昔单抗(cetuximab)、UCS15A、除莠霉素A(herbimycin A)和根赤壳菌素(radicicol)或任一这些的衍生物的激酶抑制剂。
在一个实施方案中,活性剂是代谢抑制剂,例如NAMPT抑制剂。NAMPT抑制剂的实例包括APO866、GMX-1777、GMX-1778ATG-019和OT-82或任一这些的衍生物。
在一个实施方案中,活性剂是免疫检查点抑制剂,例如PD-1抑制剂或PD-L1抑制剂。PD-1抑制剂的实例包括派姆单抗(Pembrolizumab)、纳武单抗(Nivolumab)、西米普利单抗(Cemiplimab)、JTX-4014、司他利珠单抗(Spartalizumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、替雷利珠单抗(Tislelizumab)、特瑞普利单抗(Toripalimab)、多塔利单抗(Dostarlimab)、AMP-224和AMP-514。PD-L1抑制剂的实例包括阿特珠单抗(Atezolizumab)、阿维鲁单抗(Avelumab)、度伐利尤单抗(Durvalumab)、KN035、CK-301、AUNP12、CA-170和BMS-986189或任一这些的衍生物。
在一个实施方案中,活性剂是基于铂的抗肿瘤剂,例如选自脂铂(lipoplatin)、顺铂、卡铂、奥沙利铂、奈达铂(nedaplatin)、吡铂(picoplatin)、菲铂(phenanthriplatin)、沙铂(satraplatin)和四硝酸三铂或任一这些的衍生物的基于铂的抗肿瘤剂。在一个实施方案中,活性剂是拓扑异构酶抑制剂,例如选自喜树碱(camptothecin)或其衍生物如托泊替康(topotecan)、贝洛替康(belotecan)、勒托替康(lurtotecan)、伊立替康(irinotecan)、SN-38、依喜替康(exatecan)和Dxd或任一这些的衍生物的拓扑异构酶抑制剂。在一个实施方案中,活性剂是DNA或RNA聚合酶抑制剂,例如选自鹅膏蕈碱(amanitin)或α-鹅膏蕈碱或其衍生物、放线菌素D和阿菲迪霉素(aphidicolin)或任一这些的衍生物的聚合酶抑制剂。
在一个实施方案中,活性剂是基于核苷酸的剂,例如RNA-寡核苷酸或DNA-寡核苷酸,例如siRNA或miRNA。
每个抗体分子可以有一个或多个药物单位。每个抗体相对的药物分子数之比表示为药物与抗体比率(DAR)。在一个实施方案中,DAR在1与10之间,例如在2与8之间,例如在2与6之间,例如2或4。
接头
抗体和活性剂之间的稳定连接是ADC技术的一个重要方面。接头可以例如基于化学基序,包括二硫化物、腙或肽(可裂解的)或硫醚(不可裂解的),并且控制细胞毒性剂向靶细胞的分布和递送。可裂解和不可裂解类型的接头已在临床前和临床试验中被证明是安全的。例如,维布妥昔单抗包含酶敏感的可裂解接头,其可将强效且高毒性的抗微管剂单甲基奥瑞他汀E(MMAE,一种合成抗肿瘤剂)递送至细胞。
恩美曲妥珠单抗(Trastuzumab Emtansine)是另一种获批的ADC,它是微管形成抑制剂mertansine(DM-1)(美登素的衍生物)和抗体曲妥珠单抗(HerceptinTM,Genentech/Roche)的组合,通过稳定的、不可裂解的接头连接。
接头的类型(可裂解或不可裂解)赋予所递送的药物特定的性质。例如,可裂解接头可以例如被靶细胞中的酶裂解,导致活性剂例如细胞毒性剂的有效细胞内释放。相比之下,含有不可裂解接头的ADC没有药物释放机制,必须依赖于靶向抗体降解等机制来释放药物。此外,如本领域技术人员所理解的,接头组成可以影响关键因素,例如ADC作为整体的溶解度和药代动力学性质。
对于两种类型的接头,药物释放是获得细胞效应的关键。能够自由扩散穿过细胞膜的药物可从靶细胞逃逸,并在称为“旁观者杀伤(bystander killing)”的过程中攻击邻近细胞,例如表达uPARAP的靶细胞附近的癌细胞。
在本公开的一个优选实施方案中,本文公开的靶向uPARAP的ADC包含连接抗体与活性剂的接头。
在本公开的一个实施方案中,接头可以是可裂解的或不可裂解的。
可裂解基团包括二硫键、酰胺键、肽键形式的取代酰胺键、硫代酰胺键、酯键、硫酯键、邻二醇键或半缩醛。这些基团或其他可裂解的键可以包括可酶促裂解的键,例如肽键(被肽酶裂解)、磷酸键(被磷酸酶裂解)、核酸键(被内切核酸酶裂解)和糖键(被糖苷酶裂解)。
在本公开的另一个实施方案中,接头是可裂解的接头,允许活性剂在靶细胞内的细胞内释放。
在进一步的实施方案中,接头是肽接头。肽序列的选择对于缀合物的成功至关重要。在一些实施方案中,接头对于血清蛋白酶是稳定的,但被靶细胞中的溶酶体酶裂解。
在进一步的实施方案中,接头是含有可酶促裂解的肽的接头,例如含有可被组织蛋白酶裂解的肽的接头。组织蛋白酶可以是几种组织蛋白酶类型中的一种,是一组溶酶体蛋白酶中的一种。
在本公开的另一个实施方案中,接头包含二肽或由二肽组成,例如缬氨酸-瓜氨酸(VC)或缬氨酸-丙氨酸(VA)。
在一个实施方案中,接头包含二肽或由二肽组成,例如缬氨酸-瓜氨酸(VC)或缬氨酸-丙氨酸(VA),其可以进一步通过酰胺键连接至其他结构元件。其中的瓜氨酸羧基功能被修饰为取代的酰胺的基于缬氨酸-瓜氨酸的接头可以被溶酶体组织蛋白酶裂解,而其中的丙氨酸羧基功能被修饰为取代的酰胺的基于缬氨酸-丙氨酸的接头可以被包括其他组织蛋白酶在内的其他溶酶体蛋白酶裂解。
在本公开的又一个实施方案中,本文定义的抗体-药物缀合物还包含间隔子,例如包含对氨基苯甲酸(PAB)、对氨基苄基氨基甲酸酯(PABC)、对氨基苯甲酰氧基羰基或聚乙二醇(PEG)的间隔子。
在本公开的一个实施方案中,本文定义的抗体-药物缀合物包含对氨基苄基氨基甲酸酯(PABC)。
在本公开的另一个实施方案中,本文定义的抗体-药物缀合物还包含连接基团(attachment group),例如包含以下或由以下组成的连接基团:马来酰亚胺和己酸(MC),N-羟基琥珀酰亚胺,针对修饰的或未修饰的蛋白结合碳水化合物的反应性连接基团,酶促反应所需的肽序列,叠氮化物或炔烃,或通过与抗体或其化学或酶促产生的衍生物反应而衍生自以上这些。
在本公开的一个实施方案中,本公开的ADC还包括连接实体(attachmententity)。所述连接实体可以例如连接抗体和可裂解接头,其中连接实体是抗体氨基酸侧链和接头前体中的反应性连接基团之间的反应产物。在一个实施方案中,这种反应性连接基团包含马来酰亚胺和己酸(MC)或由马来酰亚胺和己酸(MC)组成,其中马来酰亚胺优选在偶联过程中与半胱氨酸硫醇反应。在其他实施方案中,连接基团包含以下或由以下组成:N-羟基琥珀酰亚胺,针对修饰或未修饰的蛋白结合碳水化合物的反应性连接基团,酶促反应所需的肽序列,叠氮化物或炔烃,或通过与抗体或其化学或酶促产生的衍生物反应而衍生自以上这些。
在本公开的一个实施方案中,ADC包含如本文定义的靶向uPARAP的抗体和接头-药物复合物Vedotin。Vedotin是一种接头-药物复合物,其包含细胞毒性剂MMAE、间隔子(对氨基苯甲酸)、可被组织蛋白酶裂解的接头(缬氨酸-瓜氨酸二肽)和由己酸和马来酰亚胺组成的连接基团。Vedotin是MC-VC-PAB-MMAE。
在一个实施方案中,本公开的靶向uPARAP的ADC包含如本文所定义的抗体,以及接头-间隔子-毒素单元VC-PAB-MMAF。
在一个实施方案中,本公开的靶向uPARAP的ADC包含如本文所定义的抗体以及接头-间隔子-毒素单元VC-PABC-MMAF。
在一个实施方案中,本公开的靶向uPARAP的ADC包含以下或由以下组成:
a.如本文所定义的抗体,其包含:
i)由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链,和
ii)由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链;
b.VC接头;
c.MC连接基团;
d.PAB或PABC间隔子;以及
e.活性剂MMAE。
在一个实施方案中,本公开的靶向uPARAP的ADC包含以下或由以下组成:
a.如本文所定义的抗体,其包含:
i)包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成的免疫球蛋白轻链可变区,和/或
ii)包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成的免疫球蛋白重链可变区;
b.VC接头;
c.MC连接基团;
d.PAB或PABC间隔子;以及
e.活性剂MMAE。
治疗用途
本文所述的针对uPARAP的ADC可用于将活性剂(例如治疗剂或细胞毒性剂)递送至表达uPARAP和类似蛋白的细胞,并因此用于治疗以所述蛋白的表达或过表达为特征的一系列疾病和病症。
因此,本公开的一个实施方案是本文所定义的抗体或抗体-药物缀合物用作药物。
本公开的一个实施方案是药物组合物,其包含有效量的本文所定义的抗体或抗体-药物缀合物,以及药学上可接受的缓冲剂、稀释剂、载体、佐剂或赋形剂。
如本文所用,“治疗有效量”或“有效量”或“治疗有效”是指为给定病症和施用方案提供治疗效果的量。这是预定量的活性物质,其经计算可与所需的添加剂和稀释剂(即载体或施用媒介物)结合产生所需的治疗效果。此外,它旨在表示足以减少并且最优选预防宿主的活性、功能和反应的临床显著亏损的量。或者,治疗有效量足以引起宿主的有临床意义的病症的改善。如本领域技术人员所理解的,化合物的量可以根据其特定活性而变化。合适的剂量可含有预定量的活性组合物,其经计算可与所需的稀释剂结合产生所需的治疗效果。
本公开的ADC可配制为本领域已知的适合于其递送的任何类型的药物组合物。
药物组合物可以以本领域已知的方式制备,具有足够的储存稳定性并且适合施用于人和/或动物。例如,药物组合物可以冻干,例如通过冷冻干燥、喷雾干燥、喷雾冷却或通过使用来自超临界颗粒形成的颗粒形成。
“药学上可接受的”是指不会降低ADC有效性的无毒物质。此类药学上可接受的缓冲剂、载体或赋形剂是本领域众所周知的(参见Remington'sPharmaceutical Sciences,18版,A.R Gennaro,Ed.,Mack Publishing Company(1990)和handbook of PharmaceuticalExcipients,3版,A.Kibbe,Ed.,Pharmaceutical Press(2000),其公开内容通过引用并入本文)。
术语“缓冲液”旨在意指含有酸碱混合物的水性溶液,其目的是稳定pH。药学上可接受的缓冲剂是本领域众所周知的。
术语“稀释剂”旨在意指用于稀释药物制备物中的药剂的水性或非水性溶液。
术语“佐剂”旨在意指添加到制剂中以增加本发明药剂的生物效应的任何化合物。佐剂可以是具有不同阴离子的锌盐、铜盐或银盐中的一种或多种,例如但不限于氟化物、氯化物、溴化物、碘化物、硫氰酸盐、亚硫酸盐、氢氧化物、磷酸盐、碳酸盐、乳酸盐、乙醇酸盐、柠檬酸盐、硼酸盐、酒石酸盐和乙酸盐,其具有不同酰基组成。佐剂还可以是阳离子聚合物如阳离子纤维素醚、阳离子纤维素酯、脱乙酰透明质酸、壳聚糖、阳离子树状聚合物、阳离子合成聚合物如聚(乙烯基咪唑)以及阳离子多肽如聚组氨酸、聚赖氨酸、聚精氨酸和含有这些氨基酸的肽。
赋形剂可以是碳水化合物、聚合物、脂质和矿物质中的一种或多种。碳水化合物的实例包括乳糖、葡萄糖、蔗糖、甘露糖醇和环糊精,它们被添加到组合物中例如用于促进冻干。聚合物的实例是淀粉、纤维素醚、纤维素羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、乙基羟乙基纤维素、藻酸盐、角叉菜胶、透明质酸及其衍生物、聚丙烯酸、聚磺酸盐、聚乙二醇/聚环氧乙烷、聚环氧乙烷/聚环氧丙烷共聚物、不同水解度的聚乙烯醇/聚乙酸乙烯酯和聚乙烯吡咯烷酮,所有均具有不同分子量,被添加到组合物中,例如用于粘度控制、用于实现生物粘附或用于保护脂质免受化学和蛋白水解降解。脂质的实例是脂肪酸、磷脂、甘油单酯、甘油二酯和甘油三酯、神经酰胺、鞘脂和糖脂,所有不同的酰基链长度和饱和度、蛋卵磷脂、大豆卵磷脂、氢化蛋和大豆卵磷脂,它们被添加到组合物的原因与聚合物类似。矿物质的例子是滑石、氧化镁、氧化锌和氧化钛,它们被添加到组合物中以获得诸如减少液体积聚或有利的颜料特性等益处。
本公开的另一个实施方案是一种用于治疗以受试者中的细胞表达uPARAP为特征的疾病的方法,所述方法包括向受试者施用本文所定义的抗体或抗体-药物缀合物。
多个研究小组已对uPARAP在癌症中的表达和作用进行了研究;参见Melander等人的综述(Melander et al.,2015,Int J Oncol 47:1177-1188)和Engelholm等人的文章(Engelholm et al.,2016,J.Pathol.238,120-133)。
在本公开的一个实施方案中,所述方法是如本文所定义的方法,其中以表达uPARAP的细胞为特征的疾病选自癌症、骨退化疾病如骨质疏松症、纤维化和巨噬细胞相关疾病或病症如动脉粥样硬化、关节炎或慢性炎症。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中关节炎选自骨关节炎、炎症性关节炎、类风湿性关节炎、银屑病性关节炎、狼疮、莱姆病诱发的关节炎例如莱姆关节炎、痛风或假痛风和强直性脊柱炎。
在本公开的一个实施方案中,所述方法是如本文所定义的方法,其中所述疾病是癌症。
以uPARAP过表达为特征的癌症的实例包括但不限于肉瘤,包括骨肉瘤(Engelholmet al.,2016,J Pathol 238(1):120-33)以及其他肉瘤、胶质母细胞瘤(Huijbers et al.,2010,PLoS One 5(3):e9808)、前列腺癌和来自前列腺癌的骨转移(Kogianni et al.,2009,Eur J Cancer 45(4):685-93)、乳腺癌,特别是“基底样”乳腺癌(Wienke et al.,2007,Cancer Res 1;67(21):10230-40)、头颈癌(Sulek et al.,2007,J HistochemCytochem 55(4):347-53)和间皮瘤(etal.,2021,Int J Mol Sci 22(21):11452)。
在本公开的一个实施方案中,所述方法是如本文所定义的方法,其中所述癌症选自肉瘤、胶质母细胞瘤、间皮瘤、结肠癌、前列腺癌、来自前列腺癌的骨转移、乳腺癌、头颈癌和白血病。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中所述癌症是白血病,例如急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓系白血病(CML),或这些的亚型。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中所述癌症是肉瘤,例如骨肉瘤或软组织肉瘤(STS),或这些的亚型。
在本公开的一个实施方案中,所述方法是本文所定义的方法,所述软组织肉瘤(STS)选自上皮样肉瘤、透明细胞肉瘤(clear cell sarcoma)、腺泡软组织肉瘤(alveolarsoft part sarcoma)、骨外粘液样软骨肉瘤(extraskeletal myxoid chondrosarcoma)、上皮样血管内皮瘤、炎性肌纤维母细胞瘤、未分化胚胎性肉瘤、腺泡软组织肉瘤(ASPS)、血管肉瘤、软骨肉瘤、隆起皮肤纤维肉瘤(dermatofibrosarcoma protuberens,DFSP)、韧带样肉瘤(desmoid sarcoma)、尤文氏肉瘤(Ewing’s sarcoma)、纤维肉瘤、粘液纤维肉瘤、胃肠间质瘤(GIST)、非子宫平滑肌肉瘤、子宫平滑肌肉瘤、脂肪肉瘤、恶性纤维性组织细胞瘤(malignant fibro histiocytoma,MFH)、恶性外周神经鞘瘤(MPNST)、横纹肌肉瘤、滑膜肉瘤和/或平滑肌肉瘤(LMS)。
在本公开的一个实施方案中,所述方法是如本文所定义的方法,其中癌症是转移性癌症。
在本公开的一个实施方案中,所述方法是如本文所定义的方法,其中癌症是实体瘤。
在本公开的一个实施方案中,所述方法是如本文所定义的方法,其中癌症是胶质母细胞瘤。
在本公开的一个实施方案中,癌症不是实体瘤。例如,本公开的ADC可以例如用于治疗表达uPARAP的白血病,例如来自巨噬细胞-单核细胞谱系的白血病。
在本公开的其他实施方案中,以表达uPARAP的细胞为特征的疾病或病症不是癌症。
uPARAP参与骨生长和体内平衡(Madsen et al.,2013,PLoS One 5;8(8):e71261)。因此,在一个实施方案中,本公开的ADC可用于治疗以骨退化为特征的疾病,其中骨退化是由非恶性细胞介导的,例如骨质疏松症。
由于在胶原蛋白积累中的作用,uPARAP在纤维化中也显示出作用(Madsen etal.,2012,J Pathol 227(1):94-105)。因此,在一个实施方案中,本公开的ADC可以用于治疗纤维化,例如肾、肺和肝的纤维化。
在本公开的一个实施方案中,本公开的ADC可用于治疗与巨噬细胞相关的疾病和病症,包括动脉粥样硬化、关节炎和慢性炎症。
本公开的ADC或包含所述ADC的药物组合物可以通过本领域技术人员已知的任何合适的途径施用。因此,可能的施用途径包括肠胃外(静脉内、皮下和肌内)、局部、经眼、经鼻、经肺、经颊、口服、经阴道和经直肠。此外,还可以通过植入物进行施用。
在一个优选的实施方案中,药物组合物经肠胃外施用,例如静脉内、脑室内、关节内、动脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下施用,或者它们可以通过输注技术施用。它们方便地以无菌水性溶液的形式使用,该无菌水性溶液可以含有其他物质,例如足够的盐或葡萄糖以使溶液与血液等渗。如有必要,水性溶液应适当缓冲。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中抗体-药物缀合物经肠胃外施用,例如静脉内、脑室内、关节内、动脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下施用,或通过输注技术。
适合肠胃外施用的制剂包括水性和非水性无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂(bacteriostat)和使制剂与目标接受者的血液等渗的溶质;以及水性和非水性无菌悬浮液,其可包含悬浮剂和增稠剂。制剂可以存在于单位剂量(unit-dose)或多剂量(multi-dose)容器中,例如密封的安瓿瓶和小瓶,并且可以储存在冷冻-干燥(冻干)条件下,仅需要在使用紧前添加无菌液体载体,例如注射用水。临时注射溶液和悬浮液可以由前述类型的无菌粉末、颗粒和片剂制备。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中抗体-药物缀合物或抗体静脉内施用。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中抗体-药物缀合物或抗体皮下施用。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中抗体-药物缀合物或抗体与一种或多种另外的药剂例如一种或多种另外的治疗剂组合施用。
在本公开的一个实施方案中,本公开的ADC或抗体与可以增加ADC的功能性效应的另外的试剂和/或治疗剂联合施用,例如增加溶酶体膜渗透性从而促进从溶酶体内部向细胞质的分子进入的成熟药物或新药物,或增加血脑屏障渗透性的药物。
在本公开的一个实施方案中,本文所述的ADC或抗体可以与一系列抗癌药剂组合施用,例如抗代谢物、烷化剂、蒽环类和其他细胞毒性抗生素、长春花碱类、抗微管/抗有丝分裂剂、组蛋白脱乙酰酶抑制剂、激酶抑制剂、肽抗生素、免疫检查点抑制剂、基于铂的抗肿瘤药、依托泊苷(etoposide)、紫杉烷类、拓扑异构酶抑制剂、抗增殖免疫抑制剂、皮质类固醇、性激素和激素拮抗剂、细胞毒性抗生素和其他治疗剂。
因此,在本公开的一个实施方案中,所述方法是本文所定义的方法,其中表达uPARAP的细胞表现出uPARAP过表达。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中表达uPARAP的细胞是肿瘤细胞。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中表达uPARAP的细胞是肿瘤相关细胞。
肿瘤相关细胞包括但不限于活化的成纤维细胞、肌成纤维细胞、巨噬细胞-单核细胞谱系或其他白细胞类型的新生血管系统细胞和浸润细胞以及肿瘤周围基质组织的细胞。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中抗体或抗体-药物缀合物诱导表达uPARAP的细胞的细胞死亡和/或抑制表达uPARAP的细胞的生长和/或增殖。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中抗体或抗体-药物缀合物诱导游离细胞毒素从表达uPARAP的细胞中释放,导致邻近癌细胞的细胞死亡和/或邻近癌细胞的生长和/或增殖受到抑制。
在本公开的一个实施方案中,所述方法是本文所定义的方法,其中治疗是改善性的或治愈性的。
本公开的另一个实施方案是用于抑制受试者中的肿瘤进展的方法,所述方法包括向所述受试者施用本文所定义的抗体或抗体-药物缀合物或药物组合物。
本公开的另一个实施方案是抑制、降低或消除受试者中肿瘤的转移能力的方法,所述方法包括向所述受试者施用本文所定义的抗体或抗体-药物缀合物或药物组合物。
本公开的又一个实施方案是试剂盒,其包含本文定义的抗体或抗体-药物缀合物或药物组合物,任选地还包含用于向受试者施用所述抗体-药物缀合物或药物组合物的装置和/或使用说明。
在一个实施方案中,本公开涉及本文所述的抗体-药物缀合物或本文所述的药物组合物,用于制造治疗以表达uPARAP的细胞为特征的疾病如癌症的药物。
在一个实施方案中,本公开涉及抗体、抗体-药物缀合物或包含所述抗体或抗体-药物缀合物的药物组合物,用于制造用于治疗特征在于表达uPARAP的细胞的疾病例如癌症的药物,其中所述抗体或抗体-药物缀合物是抗体或包含抗体,所述抗体包含:
a.包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成的免疫球蛋白轻链可变区;和
b.包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成的免疫球蛋白重链可变区。
在一个实施方案中,本公开涉及抗体、抗体-药物缀合物或包含所述抗体或抗体-药物缀合物的药物组合物,用于制造用于治疗特征在于表达uPARAP的细胞的疾病例如癌症的药物,其中所述抗体或抗体-药物缀合物是抗体或包含抗体,所述抗体包含:
a.包含SEQ ID NO:1的氨基酸序列或由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链;和
b.包含SEQ ID NO:4的氨基酸序列或由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链。
在一个实施方案中,本公开涉及抗体、抗体-药物缀合物或包含所述抗体或抗体-药物缀合物的药物组合物,用于制造用于治疗特征在于表达uPARAP的细胞的疾病例如癌症的药物,其中所述抗体或抗体-药物缀合物是抗体或包含抗体,所述抗体包含:
a.由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链;和
b.由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链。
实施例
实施例1:鼠9b7抗体的人源化和基于其的ADC的效力
材料和方法
针对uPARAP的鼠抗体9b7人源化
鼠抗体9b7的氨基酸序列及其CDR区的数据可见于已公开的专利申请WO2017/133745。
9b7抗体的人源化变体由第三方(Fusion Antibodies,Belfast,UK)构建。简而言之,对鼠亲本抗体(克隆9b7)进行测序,并在计算机中将共有CDR序列移植到人供体序列中。
为此目的,使用许多人框架序列(参见下面的搜索程序)作为CDR序列的受体框架。这些受体序列均来自人来源的成熟人IgG,而不是来自噬菌体展示或其他技术。由抗体9b7序列生成的人源化变体是轻链和重链的组合,称为Ab 980.2LCXHCX(轻链X,重链X),不同之处在于LC0HC0是指其中原始鼠抗体的可变结构域与人源化抗体中使用的相同的人IgG恒定区融合的嵌合抗体。成熟的人源化抗体是IgG1 Kappa型的完整IgG分子。
对于重链,使用BLAST搜索算法搜索人IgG序列的在线数据库以与鼠VH结构域进行比较,并从前200个BLAST结果中选择候选的人可变结构域。基于框架同源性、维持关键框架残基和规范环结构的组合,将它们减少到四个候选者。
对于轻链,使用BLAST搜索算法搜索人IgK序列的在线数据库以与鼠VL结构域进行比较,并从前200个BLAST结果中选择候选的人可变结构域。基于框架同源性、维持关键框架残基和规范环结构的组合,将它们减少到四个候选者。
因此总共选择了编码4种人源化轻链和4种人源化重链的DNA序列。所有所得的16种轻链和重链组合均用于CHO细胞中的蛋白表达。为了实现蛋白表达,每个可变轻链结构域的位置都与人IgK同种型恒定结构域序列符合读框,而每个可变重链结构域都与人IgG1同种型恒定结构域序列符合读框。表达嵌合抗体LC0HC0以进行比较,在该抗体中鼠蛋白的可变结构域与相同的人IgG恒定区融合。
对于蛋白表达(由第三方(Fusion Antibodies,Belfast,UK)进行),将编码每个变体的哺乳动物表达载体转染到CHO细胞中,并且使每个变体的分批培养物生长长达7天。随后通过亲和层析从细胞培养物上清液中纯化表达的抗体。测定所纯化的抗体产物的浓度和纯度。
将获得的序列克隆到哺乳动物瞬时表达质粒pD2610-v13(ATUM)中。使用基于CHO的瞬时表达系统表达人源化抗体变体,并通过离心和过滤澄清所得的含有抗体的细胞培养物上清液。然后通过亲和层析从细胞培养物上清液中纯化(使用最先进的AKTA层析设备)人源化变体。将纯化的抗体透析/缓冲液交换至磷酸盐缓冲盐水溶液中。通过十二烷基硫酸钠聚丙烯酰胺凝胶判断,确定抗体纯度>95%。
在所得的16种人源化抗体中,基于有利的蛋白表达产量和抗原结合特性,选择了名为LC4HC3的组合进行进一步研究。选择另一种名为LC3HC3的人源化抗体与LC4HC3的关键参数(例如可制造性、内化和体内功效)进行比较。
用于测定抗体-配体亲和力的SPR分析
在获得合适的抗体后,可以测试它们的抗原特异性,例如通过表面等离子共振(SPR)或ELISA。当将由uPARAP的三个N端结构域(CysR、FN-II和CTLD-1)组成的可溶性重组蛋白固定在BIAcore设置中时,mAb 9b7与该构建体结合。
进行SPR分析以确定所获得的抗体对uPARAP的亲和力。这些分析是使用Biacore2000仪器(Biaffin GmbH,Kassel,德国),使用带有用于抗体结合的抗人Fc捕获表面的CM5传感器芯片来进行的。分析温度设定为25℃。抗体与该表面结合,然后使可溶性全长uPARAP穿过芯片,并从所得的结合曲线得出所得的结合和解离速率。对于动力学相互作用分析,使用30μL/min的流速,分析缓冲液由10mM HEPES pH 7.4、150mM NaCl、3mM EDTA、0.05%Tween 20组成。
抗体-药物缀合物(ADC)的制备和评估
这些研究中使用的ADC是使用成熟的缀合方法生成的。简而言之,通过轻度还原链间二硫键,然后通过马来酰亚胺基团与剩余的有效负载(payload)缀合至约为4的中等平均药物-抗体比(DAR),将靶向抗体与“vedotin”类型的有效负载(MC-VC-PABC-MMAE)缀合。然后使用PD-10脱盐柱(GE Healthcare)纯化ADC。
细胞系
U937细胞系获自ATCC,并维持在RPMI、10%胎牛血清、1%青霉素/链霉素中于37℃、5%CO2气氛的培养箱中。
ADC的体外细胞毒性-细胞活力测定
将U937细胞以低密度(20%汇合,每孔2x103个细胞)接种在平底96孔板的90μL培养基中,并孵育过夜。第二天,将使用上述方法类似地合成的LC4HC3和LC0HC0抗体的基于MMAE的ADC在PBS中制备成系列稀释液(1:4),并以10μL的体积添加到每个孔中,最终最大ADC浓度为0.1μg/mL ADC(mAb组分)。将细胞孵育96小时,然后添加12μLCellTiter96AQueous One Solution Cell Proliferation Assay(MTS,Promega),并孵育适当的时间以形成颜色(约60分钟)。然后使用读板器在490nm处读取平板,并减去在630nm处的背景,以得出所得的活力估计值。仅用PBS处理的细胞用作未经处理的对照,将ADC处理的孔相对于该对照的活力进行归一化。
结果
LC4HC3和LC3HC3的可制造性和表达:
命名为LC4HC3和LC3HC3的人源化抗体在CHO细胞中表达并如上所述进行纯化。对两种抗体执行相同的程序。结果总结在下面的表1中,其清楚地表明LC4HC3可以以足够的纯度以显著更高的量生产:
表1-人源化抗体LC3HC3和LC4HC3的可制造性数据
抗体ID | 浓度(mg/ml) | 体积(ml) | 总(mg) | 估算纯度(%) |
LC4HC3 | 3.69 | 3.02 | 11.14 | >95% |
LC3HC3 | 2.42 | 3.06 | 7.41 | >95% |
SPR分析:
如上文材料和方法中所述,通过SPR分析LC4HC3和LC0HC0。具体地,将LC4HC3的结合动力学与LC0HC0的结合动力学进行了比较(表2)。从这些分析中可以明显看出,抗体LC4HC3的较低KD表明其配体亲和力比亲本抗体LC0HC0高约1.7倍。
表2-基于SPR测量的动力学相互作用分析的结果概述
ADC体外效能分析:
如上所述制备包含抗体LC4HC3和LC0HC0之一的含有MMAE的ADC。使用ADC浓度系列测试这些ADC针对uPARAP阳性U937细胞的体外细胞毒性(图1)。显然,对于细胞根除所需的ADC量,基于LC4HC3的ADC低于基于LC0HC0的ADC,因为与用LC0HC0-vc-MMAE处理的曲线相比,用LC4HC3-vc-MMAE处理的活力曲线向较低浓度移动了数倍。
结论
人源化抗体980.2LC4HC3是从鼠单克隆抗体mAb 9b7开发而来。通过与嵌合抗体980.2LC0HC0(其中将整个鼠可变序列保留在人IgG设置中)进行比较,可以将这种新型抗体的特性直接与亲代可变序列产生的特性进行比较。该比较表明,1)人源化980.2LC4HC3比980.2LC0HC0具有更高的配体亲和力,和2)基于980.2LC4HC3的ADC在细胞毒性方面与除了基于980.2LC0HC0之外在其他方面等同的ADC相比更高效。
实施例2:鼠9b7抗体的人源化变体LC3HC3和LC4HC3的内化
材料和方法
抗体标记
将Iodogen(Thermo Fischer)以120μg/ml溶解在氯仿中,并通过蒸发包被在玻璃管底部。在包被的管中,使200μg/ml人源化抗体(LC3HC3或LC4HC3)与588ng/ml I-125(Perkin Elmer)在0.1M TRIS缓冲液中于pH 7.6下反应10分钟。通过添加九倍过量的含有0.01% Tween-80的0.1M Tris pH8.1缓冲液,来终止反应。通过PD-10柱将未结合的碘与胶原蛋白分离,标记的抗体在pH 8.1 0.1M Tris/HCl缓冲液、0.01% Tween-80中洗脱。假设所有抗体均在该缓冲液中洗脱,则浓度为8μg/ml。经标记的胶原蛋白的完整性和放射性通过将其在SDS-PAGE上运行、然后进行考马斯染色和磷光成像来进行常规确认。
细胞培养和抗体内化程序
将SAOS-2骨肉瘤细胞(Finsenlab;活力98.7%,密度1.07x10^6/ml)稀释至1x10^5/ml,每24-孔接种1ml进行实验。让细胞粘附过夜。在添加被放射性标记的抗体之前至少30分钟,将培养基替换为由DMEM/F12、1.5%FBS和20mM HEPES组成的内化培养基。将不含细胞的内化培养基接种到单独的孔中作为对照。假定这些样品的放射性代表了粘附在塑料上并经胰蛋白酶处理后回收的被放射性标记的蛋白的量。这些测量值可以被认为是“基线水平”,并且可以从确实含有细胞的样品的测量值中减去。将5μlLC4HC3或LC3HC3(基于上述假定,认为略少于40ng)添加到每个孔中。1小时或4小时后,抽吸除去培养基,并用500μl冰冷的PBS洗涤细胞3次。将含50μg/ml蛋白酶K的500μl胰蛋白酶-EDTA添加到每个孔中,持续2分钟。收获细胞,转移至Eppendorf管中并在4℃下以1000g离心1分钟。分别收集上清液(含有结合细胞的抗体)和沉淀,并在伽马计数器上进行分析。同时分析2μl标记抗体储备液,以评估标记效率。
结果
图2所示的结果清楚地表明,与人源化抗体LC3HC3相比,人源化抗体LC4HC3的内化不仅显著更快,而且程度更高。
结论
人源化抗体LC4HC3以时间依赖性方式最大程度地被SAOS-2骨肉瘤细胞内化。LC3HC3也被内化,但程度要低得多,并且不如LC4HC3那么快。两种参考抗体包含相同的重链,内化的差异可仅归因于轻链氨基酸序列的差异。
实施例3:基于人源化鼠9b7抗体LC3HC3和LC4HC3的ADC的体内功效
材料和方法
细胞培养和制备
U937(如上所述)细胞根据标准程序传代,直到获得足够用于该实验的细胞。将细胞以150g离心5分钟,并在冷PBS(Gibco)中洗涤3次。将细胞浓度调节至3.6x106个细胞/ml。这意味着每100μl大约有300万个活细胞,这是预期的接种量。
异种移植肿瘤接种
将受体CB17小鼠用Zoletil(AEM)麻醉,施用Viscotears滴眼液,并做耳标记。将右侧胁腹剃毛并用70%乙醇消毒。使用25G针将100μl重悬的U937细胞注射到皮下空间(无需切口或缝合)。让小鼠在其笼子里从麻醉中恢复。监测恢复情况直至小鼠能够活动。第二天再次监测小鼠,并密切监测肿瘤大小直至治疗开始。
一旦肿瘤达到适当的尺寸(约80-150mm3)就开始治疗。
ADC治疗和监测
如上所述制备包含LC3HC3或LC4HC3人源化抗体的Vedotin型(MMAE)ADC。将小鼠分组,每组3-5只动物(N=3-5),各组的区别在于所采用的ADC或所述ADC的施用剂量。在接受2、4或6mg/kg浓度的组中,使用LC3HC3 ADC测试一个小鼠队列,并在接受相同浓度范围的组中,使用LC4HC3 ADC测试另一个队列。
对于每个组,小鼠每周一次静脉内(尾静脉)注射受控量的ADC,总共注射两次(qd7x2),并且在治疗后也密切监测肿瘤进展。示例性地,图3a和3b显示了分别用4mg/kg剂量的LC4HC3和LC3HC3 ADC治疗的组中的肿瘤进展。
监测包括检查整体健康状况,并用数字卡尺测量肿瘤的宽度和长度维度。所有观察结果和测量结果均由手工记录并在检查后转移到数字数据表中。如果肿瘤尺寸在一个维度上超过12mm,如果肿瘤体积(计算为(长度x宽度2)/2)超过1000mm3,或者如果观察到对总体健康的严重影响,则对动物实施安乐死。通过颈椎脱位对动物实施安乐死。
结果
使用基于LC4HC3和LC3HC3的ADC治疗后的U937肿瘤体积分别如图3a和3b所示。图3a显示了一组四只小鼠(N=4)的肿瘤体积,每只小鼠以4mg/kg的剂量每周一次注射LC4HC3ADC,总共注射两次(qd7x2),图3b显示了不同组的四只小鼠(N=4)的肿瘤体积,每只小鼠以4mg/kg剂量每周一次注射LC3HC3 ADC,总共注射两次(qd7x2)。
结论
比较图3a和3b可以明显看出,基于LC4HC3 ADC的治疗完全治愈了所有小鼠,在治疗后期间没有肿瘤再生长,特别是在所有测试剂量下均如此。相比之下,基于LC3HC3的相同治疗不能杀伤所有肿瘤细胞,并且在一些情况下在治疗后监测期间观察到侵袭性肿瘤生长。
数据显示,人源化抗体LC4HC3以及包含所述人源化抗体的ADC是强力的抗肿瘤剂,与另一种人源化抗体LC3HC3相比具有改善的体内功效。两种参考抗体包含相同的重链,功效差异仅归因于轻链氨基酸序列的变化。
序列概述
/>
/>
/>
/>
/>
第1组的项
1.结合uPARAP的抗体,其包含:
a.包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成的免疫球蛋白轻链可变区;和/或
b.包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成的免疫球蛋白重链可变区。
2.根据项1的抗体,其中所述抗体包含:
a.包含SEQ ID NO:1的氨基酸序列的免疫球蛋白轻链;和/或
b.包含SEQ ID NO:4的氨基酸序列的免疫球蛋白重链。
3.根据前述项中任一项所述的抗体,其中所述抗体包含:
a.由SEQ ID NO:1的氨基酸序列组成的免疫球蛋白轻链;和
b.由SEQ ID NO:4的氨基酸序列组成的免疫球蛋白重链。
4.抗体-药物缀合物(ADC),其包含:
a.根据前述项中任一项所述的抗体,
b.活性剂,和
c.可选地,连接a)和b)的接头。
5.根据项4的抗体-药物缀合物,其中所述活性剂选自治疗剂、放射性同位素和可检测标记。
6.根据项4至5中任一项的抗体-药物缀合物,其中所述活性剂是细胞毒性剂。
7.根据项4至6中任一项所述的抗体-药物缀合物,其中所述活性剂是治疗剂,例如选自抗微管/抗有丝分裂剂、DNA交联剂、DNA烷化剂、DNA链断裂剂、蒽环类、抗代谢物、组蛋白脱乙酰酶抑制剂、激酶抑制剂、代谢抑制剂、肽抗生素、免疫检查点抑制剂、基于铂的抗肿瘤剂、拓扑异构酶抑制剂、DNA或RNA聚合酶抑制剂、基于核苷酸的剂和细胞毒性抗生素的治疗剂。
8.根据项4至7中任一项的抗体-药物缀合物,其中所述活性剂是抗有丝分裂剂,例如选自奥瑞他汀或多拉司他汀的衍生物,例如单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)等,紫杉烷例如紫杉醇或多西他赛等,长春花生物碱如长春花碱、长春新碱、长春地辛或长春瑞滨等,mayatansinoid、秋水仙碱和鬼臼毒素。
9.根据项4至8中任一项的抗体-药物缀合物,其中所述活性剂是单甲基奥瑞他汀E(MMAE)。
10.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是DNA交联剂,例如选自顺铂或顺铂衍生物例如卡铂或奥沙利铂、丝裂霉素C(MMC)、吡咯并苯二氮和二聚吡咯并苯二氮/>衍生物例如SGD-1882的DNA交联剂。
11.根据项4至7中任一项的抗体-药物缀合物,其中所述活性剂是DNA烷化剂,例如选自氮芥类例如三(2-氯乙基)胺、吡啶并苯二氮或吡啶并苯二氮/>衍生物、吲哚并苯二氮/>二聚体和Duocarmycin SA的DNA烷化剂。
12.根据项4至7中任一项的抗体-药物缀合物,其中所述活性剂是DNA链断裂剂,例如选自卡利奇霉素和哈密酮的DNA链断裂剂。
13.根据项4至7中任一项的抗体-药物缀合物,其中所述活性剂是蒽环,例如选自柔红霉素、多柔比星、表柔比星、伊达比星和PNU-159682的蒽环。
14.根据项4至7中任一项的抗体-药物缀合物,其中所述活性剂是抗代谢物,例如选自叶酸拮抗剂例如氨甲喋呤、嘌呤抗代谢物例如6-巯基嘌呤或6-硫鸟嘌呤或磷酸氟达拉滨或喷司他丁或克拉屈滨以及嘧啶抗代谢物如5-氟尿嘧啶或5-氟脱氧尿苷或阿糖胞苷或吉西他滨的抗代谢物。
15.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是组蛋白脱乙酰酶抑制剂,例如选自曲古抑菌素A、伏立诺他、贝林司他、帕比司他、吉维司他、瑞米司他、艾贝司他、奎司他、罗西林司他、普拉诺司他、CHR-3996、丙戊酸、丁酸、苯丁酸、恩替诺特、乙酰地那林、4SC202、莫西司他、罗米地辛、烟酰胺、西替诺、cambinol和EX-527的组蛋白脱乙酰酶抑制剂。
16.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是激酶抑制剂,例如选自金雀异黄素、薰草菌素C、PP1-AG1872、PP2-AG1879、SU6656、CGP77675、PD166285、伊马替尼、厄洛替尼、吉非替尼、薰草菌素A、西妥昔单抗、UCS15A、除莠霉素A和根赤壳菌素的激酶抑制剂。
17.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是代谢抑制剂,例如选自APO866、GMX-1777、GMX-1778ATG-019和OT-82的NAMPT抑制剂。
18.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是免疫检查点抑制剂,例如选自派姆单抗、纳武单抗、西米普利单抗、JTX-4014、司他利珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗、多塔利单抗、AMP-224和AMP-514的PD-1抑制剂;或选自阿特珠单抗、阿维鲁单抗、度伐利尤单抗、KN035、CK-301、AUNP12、CA-170和BMS-986189的PD-L1抑制剂。
19.根据项4至7中任一项的抗体-药物缀合物,其中所述活性剂是基于铂的抗肿瘤剂,例如选自脂铂、顺铂、卡铂、奥沙利铂、奈达铂、吡铂、菲铂、沙铂和四硝酸三铂的基于铂的抗肿瘤剂。
20.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是拓扑异构酶抑制剂,例如选自喜树碱或其衍生物如托泊替康、贝洛替康、勒托替康、伊立替康、SN-38、依喜替康和Dxd的拓扑异构酶抑制剂。
21.根据项4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是DNA聚合酶抑制剂或RNA聚合酶抑制剂,例如选自鹅膏蕈碱或α-鹅膏蕈碱或其衍生物、放线菌素D和阿菲迪霉素的聚合酶抑制剂。
22.根据项4至21中任一项的抗体-药物缀合物,其中所述活性剂包含选自60Co、89Sr、90Y、99mTc、131I、137Cs、153Sm和223Rd的放射性同位素。
23.根据项4至22中任一项所述的抗体-药物缀合物,其中药物与抗体比率(DAR)是1至10,例如2至8,例如2至6,例如2或4。
24.根据项4至23中任一项的抗体-药物缀合物,其中所述抗体-药物缀合物包含选自可裂解和不可裂解接头的接头。
25.根据项4至24中任一项的抗体-药物缀合物,其中所述接头是肽接头。
26.根据项4至25中任一项的抗体-药物缀合物,其中所述接头包含二肽或由二肽组成,所述二肽例如是缬氨酸-瓜氨酸(VC)或缬氨酸-丙氨酸(VA)。
27.根据项4至26中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物进一步包含间隔子,例如包含对氨基苯甲酸(PAB)、对氨基苄基氨基甲酸酯(PABC)、对氨基苯甲酰氧基羰基或聚乙二醇(PEG)的间隔子。
28.根据项4至27中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物还包含连接基团,例如包含以下或由以下组成的连接基团:马来酰亚胺和己酸(MC)、N-羟基琥珀酰亚胺、针对修饰的或未修饰的蛋白结合碳水化合物的反应性连接基团、酶促反应所需的肽序列、叠氮化物或炔烃、或通过与抗体或其化学或酶促产生的衍生物反应而衍生自以上这些。
29.根据项4至28中任一项的抗体-药物缀合物,其中所述抗体-药物缀合物包含以下或由以下组成:
a.项3中定义的抗体,
b.VC接头,
c.MC连接基团,
d.PAB或PABC间隔子,以及
e.活性剂MMAE。
30.根据项4至9和23至29中任一项的抗体-药物缀合物,其中所述抗体-药物缀合物由如项3中定义的抗体和MC-VC-PAB-MMAE组成。
31.根据项4至9和23至29中任一项的抗体-药物缀合物,其中所述抗体-药物缀合物由项3中定义的抗体和MC-VC-PABC-MMAE组成。
32.多肽,其包含SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列或由SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列组成。
33.分离的多核苷酸,其编码SEQ ID NO:1、2、3、4、5和/或6中任一个的氨基酸序列。
34.根据项33的分离的多核苷酸,其中所述多核苷酸包含SEQ ID NO:11和/或SEQID NO:12。
35.载体,其包含项33至34中任一项定义的多核苷酸。
36.根据项35的载体,其中所述载体是哺乳动物表达载体。
37.根据项35至36中任一项所述的载体,其中所述载体是质粒载体,例如选自pD2610-v13(ATUM)、pSV和pCMV系列质粒载体的质粒载体。
38.根据项35至37中任一项所述的载体,其中所述载体是病毒载体,例如选自腺病毒载体、慢病毒载体、腺相关病毒载体、疱疹病毒载体、牛痘病毒载体、痘病毒载体、杆状病毒载体和溶瘤病毒载体的病毒载体。
39.宿主细胞,其包含项32至33的多核苷酸和/或项35至38中任一项的载体。
40.根据项39的宿主细胞,其中所述宿主细胞选自CHO(中国仓鼠卵巢)细胞、COS(起源于CV-1(猿)并携带SV40遗传物质)细胞、HEK(人胚胎肾)细胞和HeLa(HenriettaLacks)细胞。
41.根据项1至3中任一项的抗体或根据项4至31中任一项的抗体-药物缀合物,用作药物。
42.药物组合物,其包含项1至3中任一项的抗体或项4至31中任一项的抗体-药物缀合物和药学上可接受的缓冲剂、稀释剂、载体、佐剂或赋形剂。
43.一种治疗以表达uPARAP的细胞为特征的疾病的方法,所述方法包括向受试者施用项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42的药物组合物。
44.根据项43的方法,其中所述以表达uPARAP的细胞为特征的疾病选自癌症、骨退化疾病例如骨质疏松症、纤维化和巨噬细胞相关疾病或病症例如动脉粥样硬化、关节炎或慢性炎症。
45.根据项44的方法,其中所述关节炎选自骨关节炎、炎症性关节炎、类风湿性关节炎、银屑病性关节炎、狼疮、莱姆病诱发的关节炎例如莱姆关节炎、痛风或假痛风以及强直性脊柱炎。
46.根据项43至44中任一项的方法,其中所述疾病是癌症。
47.根据项46的方法,其中所述癌症选自肉瘤、胶质母细胞瘤、间皮瘤、结肠癌、前列腺癌、来自前列腺癌的骨转移、乳腺癌、头颈癌和白血病。
48.根据项46至47中任一项的方法,其中所述癌症是实体瘤。
49.根据项46至47中任一项的方法,其中癌症是白血病,例如急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓系白血病(CML)。
50.根据项46至48中任一项的方法,其中所述癌症是胶质母细胞瘤。
51.根据项46至48中任一项的方法,其中所述癌症是肉瘤,例如骨肉瘤或软组织肉瘤(STS)。
52.根据项51的方法,其中所述软组织肉瘤(STS)选自上皮样肉瘤、透明细胞肉瘤、腺泡软组织肉瘤、骨外粘液样软骨肉瘤、上皮样血管内皮瘤、炎性肌纤维母细胞瘤、未分化胚胎性肉瘤、腺泡软组织肉瘤(ASPS)、血管肉瘤、软骨肉瘤、隆起皮肤纤维肉瘤(DFSP)、韧带样肉瘤、尤文氏肉瘤、纤维肉瘤、粘液纤维肉瘤、胃肠间质瘤(GIST)、非子宫平滑肌肉瘤、子宫平滑肌肉瘤、脂肪肉瘤、恶性纤维性组织细胞瘤(MFH)、恶性外周神经鞘瘤(MPNST)、横纹肌肉瘤、滑膜肉瘤和/或平滑肌肉瘤(LMS)。
53.根据项46至52中任一项的方法,其中所述癌症是转移性癌症。
54.根据项43至53中任一项所述的方法,其中项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物是肠胃外施用,例如静脉内、脑室内、关节内、动脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下,或通过输注技术施用。
55.根据项43至54中任一项所述的方法,其中项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物是静脉内施用。
56.根据项43至55中任一项所述的方法,其中项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物是与一种或多种另外的药剂例如一种或多种另外的治疗剂组合施用。
57.根据项43至56中任一项的方法,其中表达uPARAP的细胞表现出uPARAP过表达。
58.根据项43至57中任一项的方法,其中表达uPARAP的细胞是肿瘤细胞和/或肿瘤相关细胞。
59.根据项43至58中任一项所述的方法,其中项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物诱导表达uPARAP的细胞的细胞死亡和/或抑制表达uPARAP的细胞的生长和/或增殖。
60.根据项43至59中任一项所述的方法,其中项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物诱导从表达uPARAP的细胞中释放游离细胞毒素,导致邻近癌细胞的细胞死亡和/或邻近癌细胞的生长和/或增殖受到抑制。
61.根据项43至60中任一项的方法,其中所述治疗是改善性的或治愈性的。
62.一种抑制受试者中的肿瘤进展的方法,其包括向受试者施用项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物。
63.一种抑制、降低或消除受试者中表达uPARAP的肿瘤的转移能力的方法,其包括向受试者施用项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物。
64.试剂盒,其包含项1至3中任一项所述的抗体、项4至31中任一项所述的抗体-药物缀合物或项42所述的药物组合物,任选地进一步包含用于向受试者施用所述抗体或抗体-药物缀合物的工具和/或使用说明。
65.项1至3中任一项的抗体、项4至31中任一项的抗体-药物缀合物或项42的药物组合物,用于制造用于治疗以表达uPARAP的细胞为特征的疾病例如癌症的药物。
第2组的项
1.结合uPARAP的抗体,其包含:
a.包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成的免疫球蛋白轻链可变区;和/或
b.包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成的免疫球蛋白重链可变区。
2.抗体-药物缀合物(ADC),其包含:
a.项1的抗体,
b.活性剂,以及
c.可选地,连接a)和b)的接头。
3.根据项2所述的抗体-药物缀合物,其中所述活性剂是治疗剂,例如选自抗微管/抗有丝分裂剂、DNA交联剂、DNA烷化剂、DNA链断裂剂、蒽环类、抗代谢物、组蛋白脱乙酰酶抑制剂、激酶抑制剂、代谢抑制剂、肽抗生素、免疫检查点抑制剂、基于铂的抗肿瘤剂、拓扑异构酶抑制剂、DNA或RNA聚合酶抑制剂、基于核苷酸的剂和细胞毒性抗生素的治疗剂。
4.根据项2至3中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物包含选自可裂解接头和不可裂解接头的接头。
5.根据项2至4中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物还包含间隔子,例如包含对氨基苯甲酸(PAB)、对氨基苄基氨基甲酸酯(PABC)、对氨基苯甲酰氧基羰基或聚乙二醇(PEG)的间隔子。
6.根据项2至5中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物包含以下或由以下组成:
a.项1中定义的抗体,
b.VC接头,
c.MC连接基团,
d.PAB或PABC间隔子,以及
e.活性剂MMAE。
7.多肽,其包含SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列或由SEQ ID NO:2和/或SEQ ID NO:5的氨基酸序列组成。
8.分离的多核苷酸,其编码SEQ ID NO:1、2、3、4、5和/或6中任一个的氨基酸序列。
9.项1的抗体或项2至6中任一项的抗体-药物缀合物,用作药物。
10.药物组合物,其包含项1所述的抗体或项2至6中任一项所述的抗体-药物缀合物以及药学上可接受的缓冲剂、稀释剂、载体、佐剂或赋形剂。
11.项1的抗体、项2至6中任一项的抗体-药物缀合物或项10的药物组合物,用于治疗以表达uPARAP的细胞为特征的疾病的方法中。
12.项1的抗体、项2至6中任一项的抗体-药物缀合物或项10的药物组合物用于项11的用途,其中以表达uPARAP的细胞为特征的疾病选自癌症、骨退化疾病例如骨质疏松症、纤维化和巨噬细胞相关疾病或病症例如动脉粥样硬化、关节炎或慢性炎症。
13.项1的抗体、项2至6中任一项的抗体-药物缀合物或项10的药物组合物,用于抑制受试者中的肿瘤进展的方法中。
14.项1的抗体、项2至6中任一项的抗体-药物缀合物或项10的药物组合物,用于抑制、降低或消除表达uPARAP的肿瘤的转移能力的方法中。
15.试剂盒,其包含项1所述的抗体、项2至6中任一项所述的抗体-药物缀合物或项10所述的药物组合物,任选地进一步包含用于向受试者施用所述抗体或抗体-药物缀合物的工具和/或使用说明。
序列表
<110> 丹麦国家医院(Rigshospitalet)
哥本哈根大学(University of Copenhagen)
<120> 包含靶向uPARAP的人源化抗体的抗体-药物缀合物
<130> P5888PC00
<160> 13
<170> PatentIn version 3.5
<210> 1
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC4HC3的完整轻链序列(LC4)
<220>
<221> MISC_FEATURE
<222> (1)..(214)
<400> 1
Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asn Val Asp Thr Tyr
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Gln Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln Tyr His Asn Ser Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 2
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC4HC3的完整轻链序列(LC4)与在CHO细胞表达系统中使用的信号肽的组合;下划线为信号肽
<220>
<221> MISC_FEATURE
<222> (1)..(234)
<400> 2
Met Val Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asn
35 40 45
Val Asp Thr Tyr Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
50 55 60
Gln Pro Leu Ile Tyr Ser Ala Ser Ser Arg Phe Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln Tyr His
100 105 110
Asn Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 3
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC4HC3的轻链(LC4)可变区
<220>
<221> MISC_FEATURE
<222> (1)..(107)
<400> 3
Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asn Val Asp Thr Tyr
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Gln Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Ile Tyr Tyr Cys Gln Gln Tyr His Asn Ser Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 4
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC4HC3 的完整重链序列(HC3)
<220>
<221> MISC_FEATURE
<222> (1)..(449)
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ile Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Ser Ile Asn Thr Lys Ser Gly Val Ser Thr Tyr Ala Ala Glu Phe
50 55 60
Lys Gly Arg Val Thr Ile Tyr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Pro Pro Tyr Tyr Ser Gln Tyr Gly Ser Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 5
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC4HC3的完整重链序列(HC3)与在CHO细胞表达系统中使用的信号肽的组合;下划线为信号肽
<220>
<221> MISC_FEATURE
<222> (1)..(468)
<400> 5
Met Gly Trp Thr Leu Val Phe Leu Phe Leu Leu Ser Val Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe
35 40 45
Ile Asp Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu
50 55 60
Glu Trp Met Gly Ser Ile Asn Thr Lys Ser Gly Val Ser Thr Tyr Ala
65 70 75 80
Ala Glu Phe Lys Gly Arg Val Thr Ile Tyr Ser Asp Thr Ser Ala Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Phe Cys Ala Arg Pro Pro Tyr Tyr Ser Gln Tyr Gly Ser Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
225 230 235 240
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
245 250 255
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 6
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC4HC3的重链(HC3)可变区
<220>
<221> MISC_FEATURE
<222> (1)..(119)
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ile Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Ser Ile Asn Thr Lys Ser Gly Val Ser Thr Tyr Ala Ala Glu Phe
50 55 60
Lys Gly Arg Val Thr Ile Tyr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Pro Pro Tyr Tyr Ser Gln Tyr Gly Ser Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 7
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 嵌合LC0HC0的完整轻链序列(LC0)
<220>
<221> MISC_FEATURE
<222> (1)..(214)
<400> 7
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Tyr
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Thr Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr His Asn Ser Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 8
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 嵌合LC0HC0的轻链(LC0)可变区
<220>
<221> MISC_FEATURE
<222> (1)..(107)
<400> 8
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Tyr
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Thr Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr His Asn Ser Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 9
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 嵌合LC0HC0的完整重链序列(HC0)
<220>
<221> MISC_FEATURE
<222> (1)..(449)
<400> 9
Gln Val His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ile Asp Tyr
20 25 30
Gly Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Ser Ile Asn Thr Lys Ser Gly Val Ser Thr Tyr Ala Ala Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Pro Pro Tyr Tyr Ser Gln Tyr Gly Ser Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 10
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 嵌合LC0HC0的重链(HC0)可变区
<220>
<221> MISC_FEATURE
<222> (1)..(119)
<400> 10
Gln Val His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ile Asp Tyr
20 25 30
Gly Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Ser Ile Asn Thr Lys Ser Gly Val Ser Thr Tyr Ala Ala Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Pro Pro Tyr Tyr Ser Gln Tyr Gly Ser Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 11
<211> 705
<212> DNA
<213> 人工序列
<220>
<223> 编码包括信号肽的LC4的多核苷酸
<220>
<221> misc_feature
<222> (1)..(705)
<400> 11
atggtcagct ctgctcaatt tctcggactc cttcttctgt gctttcaagg aacacgctgc 60
gagatcgtga tgactcagtc cccggactca ctggcagtgt ccttgggcga aagagccacc 120
atcaactgta aagccagcca gaacgtggac acctacgtgg tctggtacca gcagaagcct 180
ggacagccac cgcagccgtt gatctactcg gcctcatcaa ggttctccgg ggtgccggac 240
cgcttctccg gatccggctc cggcaccgat ttcaccctga ccatctcctc actgcaagcc 300
gaggacgtgg ctatctacta ttgccagcag taccacaact ccccactgac cttcggtggc 360
ggaactaagg tcgagattaa gcggaccgtg gcggccccct ctgtgttcat tttccctccc 420
tcggacgaac agctgaagtc gggaacagcc tccgtcgtgt gcctgctcaa caacttctac 480
ccccgggaag cgaaggtcca gtggaaagtg gataacgcac tccaatcggg gaactcccag 540
gaatccgtga ctgagcagga ctcgaaggat tccacttact ccctgtcgtc caccctgact 600
ctgagcaagg ccgactacga gaagcataag gtctacgcct gcgaagtgac ccaccagggt 660
ctgagctccc ctgtgaccaa gagctttaat cggggcgaat gttga 705
<210> 12
<211> 1407
<212> DNA
<213> 人工序列
<220>
<223> 编码包括信号肽的HC3的多核苷酸
<220>
<221> misc_feature
<222> (1)..(1407)
<400> 12
atgggttgga ccctcgtctt tctgttcctt ctttccgtca ccgctggagt gcatagccag 60
gtccaattgg tgcagtcagg cgccgaagtg aaaaagcctg gggcgtcggt gaaagtgtcc 120
tgcaaagcct cgggctacat ctttattgac tacggaatgc actgggtccg ccaggccccg 180
ggccagaggc tggagtggat gggatccatt aacaccaaga gcggagtgtc aacttacgca 240
gccgagttca agggacgggt gaccatctat agcgatacct ctgcgtcgac cgcctacatg 300
gaattgtcat cactccggtc cgaggacact gccgtgtact tctgcgcaag gccaccctac 360
tactcgcaat acggcagcta ctggggccag ggaacacttg tgaccgtgtc gagcgcgtcc 420
accaagggtc cctccgtgtt ccctctcgcg ccgtcctcaa agtctacctc cggtggaact 480
gccgcgctcg gttgtctcgt gaaggactac ttcccggagc ctgtgactgt ctcctggaac 540
tccggggccc tcaccagcgg agtgcacact ttccccgccg tgctgcaatc ctccggcctg 600
tacagcctgt cctccgtcgt gactgtgcct agctcctccc tgggaaccca gacctacatc 660
tgcaacgtga accacaagcc ctccaacacc aaggtcgaca agaaggtcga accgaagtcg 720
tgcgacaaga ctcatacgtg ccctccttgc ccggccccgg aactgctggg aggcccatcc 780
gtgttcctgt tcccacccaa gcctaaggat accctgatga tcagcagaac accggaagtg 840
acctgtgtgg tggtggacgt cagccacgaa gatcccgagg tcaagttcaa ttggtacgtg 900
gacggggtgg aggtgcacaa cgcaaagacc aagccccggg aggaacagta caactccacc 960
tatcgcgtgg tgtcggtgct gacggtgctg caccaggact ggttgaacgg aaaggagtat 1020
aagtgcaaag tgtcgaacaa ggccctgccc gctcctatcg aaaagaccat ctccaaggcc 1080
aagggccagc cgcgggaacc ccaggtctac actctcccac cgagccgcga cgaactgact 1140
aagaatcaag tgtcgctgac ttgcctcgtc aagggcttct acccgtccga catcgccgtg 1200
gaatgggaga gcaacggcca gccggaaaac aactacaaga ccacccctcc cgtgctggat 1260
tccgacgggt ccttcttcct gtactcaaaa ctgaccgtgg ataagtccag atggcagcag 1320
ggcaatgtct tttcatgctc cgtgatgcac gaggctctgc ataaccacta cacccagaag 1380
tcgctgtccc tgtccccggg gaagtga 1407
<210> 13
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 人源化LC3HC3的完整轻链序列(LC3)
<220>
<221> MISC_FEATURE
<222> (1)..(234)
<400> 13
Met Val Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Val Val Met Thr Gln Ser Pro Asp Ser Leu Ala
20 25 30
Val Ser Leu Gly Glu Arg Val Thr Ile Asn Cys Lys Ala Ser Gln Asn
35 40 45
Val Asp Thr Tyr Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro
50 55 60
Lys Leu Leu Ile Tyr Ser Ala Ser Ser Arg Phe Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr His
100 105 110
Asn Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
Claims (58)
1.结合uPARAP的抗体,其包含:
a.免疫球蛋白轻链可变区,所述免疫球蛋白轻链可变区包含SEQ ID NO:3的氨基酸序列或由SEQ ID NO:3的氨基酸序列组成;和
b.免疫球蛋白重链可变区,所述免疫球蛋白重链可变区包含SEQ ID NO:6的氨基酸序列或由SEQ ID NO:6的氨基酸序列组成。
2.根据权利要求1所述的抗体,其中所述抗体包含:
a.免疫球蛋白轻链,所述免疫球蛋白轻链包含SEQ ID NO:1的氨基酸序列;和
b.免疫球蛋白重链,所述免疫球蛋白重链包含SEQ ID NO:4的氨基酸序列。
3.根据前述权利要求中任一项所述的抗体,其中所述抗体包含:
a.免疫球蛋白轻链,所述免疫球蛋白轻链由SEQ ID NO:1的氨基酸序列组成;和
b.免疫球蛋白重链,所述免疫球蛋白重链由SEQ ID NO:4的氨基酸序列组成。
4.抗体-药物缀合物(ADC),其包含:
a.前述权利要求中任一项所定义的抗体,
b.活性剂,以及
c.可选地,连接a)和b)的接头。
5.根据权利要求4所述的抗体-药物缀合物,其中所述活性剂选自治疗剂、放射性同位素和可检测标记。
6.根据权利要求4至5中任一项所述的抗体-药物缀合物,其中所述活性剂是细胞毒性剂。
7.根据权利要求4至6中任一项所述的抗体-药物缀合物,其中所述活性剂是治疗剂,例如选自抗微管/抗有丝分裂剂、DNA交联剂、DNA烷化剂、DNA链断裂剂、蒽环类、抗代谢物、组蛋白脱乙酰酶抑制剂、激酶抑制剂、代谢抑制剂、肽抗生素、免疫检查点抑制剂、基于铂的抗肿瘤剂、拓扑异构酶抑制剂、DNA或RNA聚合酶抑制剂、基于核苷酸的剂和细胞毒性抗生素的治疗剂。
8.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是抗有丝分裂剂,例如选自奥瑞他汀或多拉司他汀的衍生物,例如单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)等,紫杉烷例如紫杉醇或多西他赛等,长春花生物碱例如长春花碱、长春新碱、长春地辛或长春瑞滨等,mayatansinoid、秋水仙碱和鬼臼毒素。
9.根据权利要求4至8中任一项所述的抗体-药物缀合物,其中所述活性剂是单甲基奥瑞他汀E(MMAE)。
10.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是DNA交联剂,例如选自顺铂或顺铂衍生物例如卡铂或奥沙利铂、丝裂霉素C(MMC)、吡咯并苯二氮和二聚吡咯并苯二氮/>衍生物例如SGD-1882的DNA交联剂。
11.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是DNA烷化剂,例如选自氮芥类例如三(2-氯乙基)胺、吡啶并苯二氮或吡啶并苯二氮/>衍生物、吲哚并苯二氮/>二聚体和Duocarmycin SA的DNA烷化剂。
12.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是DNA链断裂剂,例如选自卡利奇霉素和哈密酮的DNA链断裂剂。
13.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是蒽环,例如选自柔红霉素、多柔比星、表柔比星、伊达比星和PNU-159682的蒽环。
14.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是抗代谢物,例如选自叶酸拮抗剂例如氨甲喋呤、嘌呤抗代谢物例如6-巯基嘌呤或6-硫鸟嘌呤或磷酸氟达拉滨或喷司他丁或克拉屈滨以及嘧啶抗代谢物例如5-氟尿嘧啶或5-氟脱氧尿苷或阿糖胞苷或吉西他滨的抗代谢物。
15.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是组蛋白脱乙酰酶抑制剂,例如选自曲古抑菌素A、伏立诺他、贝林司他、帕比司他、吉维司他、瑞米司他、艾贝司他、奎司他、罗西林司他、普拉诺司他、CHR-3996、丙戊酸、丁酸、苯丁酸、恩替诺特、乙酰地那林、4SC202、莫西司他、罗米地辛、烟酰胺、西替诺、cambinol和EX-527的组蛋白脱乙酰酶抑制剂。
16.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是激酶抑制剂,例如选自金雀异黄素、薰草菌素C、PP1-AG1872、PP2-AG1879、SU6656、CGP77675、PD166285、伊马替尼、厄洛替尼、吉非替尼、薰草菌素A、西妥昔单抗、UCS15A、除莠霉素A和根赤壳菌素的激酶抑制剂。
17.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是代谢抑制剂,例如选自APO866、GMX-1777、GMX-1778ATG-019和OT-82的NAMPT抑制剂。
18.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是免疫检查点抑制剂,例如选自派姆单抗、纳武单抗、西米普利单抗、JTX-4014、司他利珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗、多塔利单抗、AMP-224和AMP-514的PD-1抑制剂;或选自阿特珠单抗、阿维鲁单抗、度伐利尤单抗、KN035、CK-301、AUNP12、CA-170和BMS-986189的PD-L1抑制剂。
19.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是基于铂的抗肿瘤剂,例如选自脂铂、顺铂、卡铂、奥沙利铂、奈达铂、吡铂、菲铂、沙铂和四硝酸三铂的基于铂的抗肿瘤剂。
20.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是拓扑异构酶抑制剂,例如选自喜树碱或其衍生物如托泊替康、贝洛替康、勒托替康、伊立替康、SN-38、依喜替康和Dxd的拓扑异构酶抑制剂。
21.根据权利要求4至7中任一项所述的抗体-药物缀合物,其中所述活性剂是DNA聚合酶抑制剂或RNA聚合酶抑制剂,例如选自鹅膏蕈碱或α-鹅膏蕈碱或其衍生物、放线菌素D和阿菲迪霉素的聚合酶抑制剂。
22.根据权利要求4至21中任一项所述的抗体-药物缀合物,其中所述活性剂包含选自60Co、89Sr、90Y、99mTc、131I、137Cs、153Sm和223Rd的放射性同位素。
23.根据权利要求4至22中任一项所述的抗体-药物缀合物,其中所述药物与抗体比率(DAR)是1至10,例如2至8,例如2至6,例如2或4。
24.根据权利要求4至23中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物包含选自可裂解接头和不可裂解接头的接头,任选地其中所述接头是肽接头。
25.根据权利要求4至24中任一项所述的抗体-药物缀合物,其中所述接头包含二肽或由二肽组成,所述二肽例如是缬氨酸-瓜氨酸(VC)或缬氨酸-丙氨酸(VA)。
26.根据权利要求4至25中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物还包含间隔子,例如包含对氨基苯甲酸(PAB)、对氨基苄基氨基甲酸酯(PABC)、对氨基苯甲酰氧基羰基或聚乙二醇(PEG)的间隔子。
27.根据权利要求4至26中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物还包含连接基团,例如包含以下或由以下组成的连接基团:马来酰亚胺和己酸(MC)、N-羟基琥珀酰亚胺、针对修饰的或未修饰的蛋白结合碳水化合物的反应性连接基团、酶促反应所需的肽序列、叠氮化物或炔烃、或以上基团通过与抗体或其化学或酶促产生的衍生物反应而衍生的基团。
28.根据权利要求4至9和23至27中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物包含以下或由以下组成:
a.权利要求3中定义的抗体,
b.VC接头,
c.MC连接基团,
d.PAB或PABC间隔子,以及
e.活性剂MMAE。
29.根据权利要求4至9和23至28中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物由权利要求3中所定义的抗体和MC-VC-PAB-MMAE组成。
30.根据权利要求4至9和23至29中任一项所述的抗体-药物缀合物,其中所述抗体-药物缀合物由权利要求3中所定义的抗体和MC-VC-PABC-MMAE组成。
31.多肽,其包含SEQ ID NO:2的氨基酸序列或由SEQ ID NO:2的氨基酸序列组成,任选地还包含SEQ ID NO:5的氨基酸序列。
32.分离的多核苷酸,其编码SEQ ID NO:1、2或3中任一个的氨基酸序列,任选地其中所述多核苷酸还编码SEQ ID NO:4、5或6中任一个的氨基酸序列。
33.根据权利要求33所述的分离的多核苷酸,其中所述多核苷酸包含SEQ ID NO:11,任选地还包含SEQ ID NO:12。
34.载体,其包含权利要求32至33中任一项所定义的多核苷酸。
35.宿主细胞,其包含权利要求32或33中任一项所定义的多核苷酸和/或权利要求34中所定义的载体。
36.根据权利要求1至3中任一项所述的抗体或根据权利要求4至30中任一项所述的抗体-药物缀合物,用作药物。
37.药物组合物,其包含权利要求1至3中任一项所述的抗体或权利要求4至30中任一项所述的抗体-药物缀合物和药学上可接受的缓冲剂、稀释剂、载体、佐剂或赋形剂。
38.权利要求1至3中任一项所述的抗体、权利要求4至30中任一项所述的抗体-药物缀合物或权利要求37所述的药物组合物,用于治疗以表达uPARAP的细胞为特征的疾病。
39.根据权利要求38所述使用的抗体、抗体-药物缀合物或组合物,其中所述以表达uPARAP的细胞为特征的疾病选自癌症、骨退化疾病例如骨质疏松症、纤维化和巨噬细胞相关疾病或病症例如动脉粥样硬化、关节炎或慢性炎症。
40.根据权利要求39所述使用的抗体、抗体-药物缀合物或组合物,其中所述关节炎选自骨关节炎、炎症性关节炎、类风湿性关节炎、银屑病性关节炎、狼疮、莱姆病诱发的关节炎例如莱姆关节炎、痛风或假痛风以及强直性脊柱炎。
41.根据权利要求38至39中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述疾病是癌症,例如其中所述癌症选自肉瘤、胶质母细胞瘤、间皮瘤、结肠癌、前列腺癌、来自前列腺癌的骨转移、乳腺癌、头颈癌和白血病。
42.根据权利要求41所述使用的抗体、抗体-药物缀合物或组合物,其中所述癌症是实体瘤。
43.根据权利要求41所述使用的抗体、抗体-药物缀合物或组合物,其中癌症是白血病,例如急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓系白血病(CML)。
44.根据权利要求41至42中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述癌症是胶质母细胞瘤。
45.根据权利要求41至42中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述癌症是肉瘤,例如骨肉瘤或软组织肉瘤(STS)。
46.根据权利要求45所述使用的抗体、抗体-药物缀合物或组合物,其中所述软组织肉瘤(STS)选自上皮样肉瘤、透明细胞肉瘤、腺泡软组织肉瘤、骨外粘液样软骨肉瘤、上皮样血管内皮瘤、炎性肌纤维母细胞瘤、未分化胚胎性肉瘤、腺泡软组织肉瘤(ASPS)、血管肉瘤、软骨肉瘤、隆起皮肤纤维肉瘤(DFSP)、韧带样肉瘤、尤文氏肉瘤、纤维肉瘤、粘液纤维肉瘤、胃肠间质瘤(GIST)、非子宫平滑肌肉瘤、子宫平滑肌肉瘤、脂肪肉瘤、恶性纤维性组织细胞瘤(MFH)、恶性外周神经鞘瘤(MPNST)、横纹肌肉瘤、滑膜肉瘤和/或平滑肌肉瘤(LMS)。
47.根据权利要求41至46中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述癌症是转移性癌症。
48.根据权利要求38至47中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中施用是肠胃外例如静脉内、脑室内、关节内、动脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下、或通过输注技术的施用。
49.根据权利要求38至48中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中施用是静脉内施用。
50.根据权利要求38至49中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述抗体、抗体-药物缀合物或组合物与一种或多种另外的药剂例如一种或多种另外的治疗剂组合施用。
51.根据权利要求38至50中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述表达uPARAP的细胞表现出uPARAP过表达,任选地,其中所述表达uPARAP的细胞是肿瘤细胞和/或肿瘤相关细胞。
52.根据权利要求38至51中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述抗体、抗体-药物缀合物或组合物诱导所述表达uPARAP的细胞的细胞死亡和/或抑制所述表达uPARAP的细胞的生长和/或增殖。
53.根据权利要求38至52中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述抗体、抗体-药物缀合物或组合物诱导从所述表达uPARAP的细胞中释放游离细胞毒素,导致邻近癌细胞的细胞死亡和/或邻近癌细胞的生长和/或增殖受到抑制。
54.根据权利要求38至53中任一项所述使用的抗体、抗体-药物缀合物或组合物,其中所述治疗是改善性的或治愈性的。
55.权利要求1至3中任一项所述的抗体、权利要求4至30中任一项所述的抗体-药物缀合物或权利要求37所述的药物组合物,用于抑制受试者中的肿瘤进展的方法中。
56.权利要求1至3中任一项所述的抗体、权利要求4至30中任一项所述的抗体-药物缀合物或权利要求37所述的药物组合物,用于抑制、降低或消除受试者中表达uPARAP的肿瘤的转移能力的方法中。
57.试剂盒,其包含权利要求1至3中任一项所述的抗体、权利要求4至30中任一项所述的抗体-药物缀合物或权利要求37所述的药物组合物,任选地还包含用于向受试者施用所述抗体或抗体-药物缀合物的工具和/或使用说明。
58.权利要求1至3中任一项所述的抗体、权利要求4至30中任一项所述的抗体-药物缀合物或权利要求37所述的药物组合物,用于制造用于治疗以表达uPARAP的细胞为特征的疾病例如癌症的药物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21182271 | 2021-06-29 | ||
EP21182271.3 | 2021-06-29 | ||
PCT/EP2022/067832 WO2023275112A1 (en) | 2021-06-29 | 2022-06-29 | Antibody-drug conjugates comprising humanized antibodies targeting urokinase type plasminogen activator receptor associated protein (uparap) |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117751140A true CN117751140A (zh) | 2024-03-22 |
Family
ID=76999593
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280046878.1A Pending CN117751140A (zh) | 2021-06-29 | 2022-06-29 | 包含靶向尿激酶型纤溶酶原激活物受体相关蛋白(uPARAP)的人源化抗体的抗体-药物缀合物 |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP4363447A1 (zh) |
KR (1) | KR20240024816A (zh) |
CN (1) | CN117751140A (zh) |
AU (1) | AU2022302907A1 (zh) |
BR (1) | BR112023024500A2 (zh) |
CA (1) | CA3219011A1 (zh) |
IL (1) | IL309336A (zh) |
WO (1) | WO2023275112A1 (zh) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2753388C (en) | 2009-03-23 | 2016-11-29 | Quark Pharmaceuticals, Inc. | Endo180 antibody to treat cancer and fibrotic disease |
LT3895736T (lt) * | 2016-02-05 | 2023-06-12 | Rigshospitalet | Antikūno-vaisto konjugatai, kurių taikinys uparap |
-
2022
- 2022-06-29 WO PCT/EP2022/067832 patent/WO2023275112A1/en active Application Filing
- 2022-06-29 EP EP22740821.8A patent/EP4363447A1/en active Pending
- 2022-06-29 CA CA3219011A patent/CA3219011A1/en active Pending
- 2022-06-29 KR KR1020237042954A patent/KR20240024816A/ko unknown
- 2022-06-29 CN CN202280046878.1A patent/CN117751140A/zh active Pending
- 2022-06-29 BR BR112023024500A patent/BR112023024500A2/pt unknown
- 2022-06-29 AU AU2022302907A patent/AU2022302907A1/en active Pending
- 2022-06-29 IL IL309336A patent/IL309336A/en unknown
Also Published As
Publication number | Publication date |
---|---|
BR112023024500A2 (pt) | 2024-02-15 |
EP4363447A1 (en) | 2024-05-08 |
AU2022302907A1 (en) | 2023-11-30 |
AU2022302907A9 (en) | 2023-12-07 |
WO2023275112A1 (en) | 2023-01-05 |
CA3219011A1 (en) | 2023-01-05 |
IL309336A (en) | 2024-02-01 |
KR20240024816A (ko) | 2024-02-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA3067829A1 (en) | Ror1 antibody immunoconjugates | |
ES2534726T3 (es) | Antígeno ED-A del fibrinógeno que está asociado con linfomas | |
TW200539855A (en) | Calicheamicin conjugates | |
AU2015339012A1 (en) | Anti-CS1 antibodies and antibody drug conjugates | |
ES2936527T3 (es) | Conjugados de anticuerpo-fármaco y sus usos para el tratamiento del cáncer | |
WO2017196764A1 (en) | Antibody-drug conjugate of an anti-glypican-3 antibody and a tubulysin analog, preparation and uses | |
CN111989138B (zh) | 人源化抗前列腺特异性膜抗原(psma)抗体药物缀合物 | |
CA2858133A1 (en) | Uses of immunoconjugates targeting cd138 | |
Khandare et al. | Antibodies and peptides in cancer therapy | |
EP3813863A1 (en) | Targeting of multiple antigens with multiplex car t cells in solid and liquid malignancies | |
CN115666642A (zh) | 含有α-烯醇酶抗体的药物缀合物和其用途 | |
CN117751140A (zh) | 包含靶向尿激酶型纤溶酶原激活物受体相关蛋白(uPARAP)的人源化抗体的抗体-药物缀合物 | |
RU2740311C2 (ru) | НАЦЕЛЕННЫЕ НА uPARAP КОНЪЮГАТЫ АНТИТЕЛО-ЛЕКАРСТВЕННОЕ СРЕДСТВО | |
EP4201431A1 (en) | Intermediate for preparing antibody-drug conjugate (adc), preparation method therefor, and use thereof | |
KR20230018454A (ko) | 항-c-Met 항체-약물 접합체 및 이의 용도 | |
WO2022237874A1 (en) | Antibody conjugate comprising anti-p-cadherin antibody and uses thereof | |
CA3184403A1 (en) | Anti-claudin 18.2 antibody and antibody-drug conjugate thereof | |
JP2024519585A (ja) | 抗p-カドヘリン抗体を含む抗体コンジュゲートおよびその使用 | |
JP2023539522A (ja) | 療法抗体およびその使用 | |
JP2014091687A (ja) | 軟骨又は骨の破壊の診断薬 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |