WO2015177360A1 - Site-specific conjugation of linker drugs to antibodies and resulting adcs - Google Patents
Site-specific conjugation of linker drugs to antibodies and resulting adcs Download PDFInfo
- Publication number
- WO2015177360A1 WO2015177360A1 PCT/EP2015/061456 EP2015061456W WO2015177360A1 WO 2015177360 A1 WO2015177360 A1 WO 2015177360A1 EP 2015061456 W EP2015061456 W EP 2015061456W WO 2015177360 A1 WO2015177360 A1 WO 2015177360A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- cancer
- adc
- drug
- heavy chain
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 124
- 229940079593 drug Drugs 0.000 title claims abstract description 117
- 230000021615 conjugation Effects 0.000 title description 44
- 229940049595 antibody-drug conjugate Drugs 0.000 claims abstract description 169
- 239000000611 antibody drug conjugate Substances 0.000 claims abstract description 163
- 235000018417 cysteine Nutrition 0.000 claims abstract description 75
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 65
- 241000282414 Homo sapiens Species 0.000 claims abstract description 39
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 206010066476 Haematological malignancy Diseases 0.000 claims abstract description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 8
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 206010027406 Mesothelioma Diseases 0.000 claims abstract description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 6
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 6
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 6
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims abstract description 5
- 201000007270 liver cancer Diseases 0.000 claims abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 5
- 206010044412 transitional cell carcinoma Diseases 0.000 claims abstract description 5
- 206010046766 uterine cancer Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 65
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 56
- 210000004027 cell Anatomy 0.000 claims description 38
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 31
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims description 22
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 20
- 239000000427 antigen Substances 0.000 claims description 16
- 108091007433 antigens Proteins 0.000 claims description 16
- 102000036639 antigens Human genes 0.000 claims description 16
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 10
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 10
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical class COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- 239000012634 fragment Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000008176 lyophilized powder Substances 0.000 claims description 3
- 210000000170 cell membrane Anatomy 0.000 claims description 2
- 102000000412 Annexin Human genes 0.000 claims 1
- 108050008874 Annexin Proteins 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 abstract description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 57
- 238000000034 method Methods 0.000 description 22
- 239000002299 complementary DNA Substances 0.000 description 17
- RFQYSAASDBNNDZ-UCGHAGIGSA-N [(1s)-1-(chloromethyl)-3-[6-[(4-hydroxybenzoyl)amino]imidazo[1,2-a]pyridine-2-carbonyl]-9-methyl-1,2-dihydrobenzo[e]indol-5-yl] n-[2-[[4-[[(2s)-5-(carbamoylamino)-2-[[(2s)-2-[2-[2-(2,5-dioxopyrrol-1-yl)ethoxy]ethoxycarbonylamino]-3-methylbutanoyl]amino]pe Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=O)C(=O)NC=1C=CC(COC(=O)N(C)CCN(CCOCCO)C(=O)OC=2C3=CC=CC(C)=C3C=3[C@H](CCl)CN(C=3C=2)C(=O)C=2N=C3C=CC(NC(=O)C=4C=CC(O)=CC=4)=CN3C=2)=CC=1)C(=O)OCCOCCN1C(=O)C=CC1=O RFQYSAASDBNNDZ-UCGHAGIGSA-N 0.000 description 16
- 238000001727 in vivo Methods 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 12
- 102000004225 Cathepsin B Human genes 0.000 description 11
- 108090000712 Cathepsin B Proteins 0.000 description 11
- 238000003776 cleavage reaction Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 230000007017 scission Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 150000001945 cysteines Chemical class 0.000 description 10
- 229940127089 cytotoxic agent Drugs 0.000 description 10
- 229960005027 natalizumab Drugs 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 8
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 8
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 229960002885 histidine Drugs 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 239000000562 conjugate Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000002209 hydrophobic effect Effects 0.000 description 7
- 108010093470 monomethyl auristatin E Proteins 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 150000003573 thiols Chemical class 0.000 description 7
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 6
- 235000004279 alanine Nutrition 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- -1 cysteine side chain thiols Chemical class 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 229960005501 duocarmycin Drugs 0.000 description 6
- 229930184221 duocarmycin Natural products 0.000 description 6
- 239000008241 heterogeneous mixture Substances 0.000 description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 230000036515 potency Effects 0.000 description 6
- 102220563037 BLOC-1-related complex subunit 5_S41C_mutation Human genes 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 229940121849 Mitotic inhibitor Drugs 0.000 description 5
- 229960000455 brentuximab vedotin Drugs 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 150000002019 disulfides Chemical class 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000003032 molecular docking Methods 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 229960001612 trastuzumab emtansine Drugs 0.000 description 5
- 239000013598 vector Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 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 description 4
- 206010041067 Small cell lung cancer Diseases 0.000 description 4
- 229940123237 Taxane Drugs 0.000 description 4
- 229940122803 Vinca alkaloid Drugs 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 230000000340 anti-metabolite Effects 0.000 description 4
- 229940100197 antimetabolite Drugs 0.000 description 4
- 239000002256 antimetabolite Substances 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960002173 citrulline Drugs 0.000 description 4
- 230000001268 conjugating effect Effects 0.000 description 4
- 239000002254 cytotoxic agent Substances 0.000 description 4
- 229960003668 docetaxel Drugs 0.000 description 4
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 4
- 229960005277 gemcitabine Drugs 0.000 description 4
- 235000018977 lysine Nutrition 0.000 description 4
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 208000000587 small cell lung carcinoma Diseases 0.000 description 4
- 231100001274 therapeutic index Toxicity 0.000 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 description 4
- 229960002066 vinorelbine Drugs 0.000 description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 108020004635 Complementary DNA Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 3
- 229930126263 Maytansine Natural products 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 102100033579 Trophoblast glycoprotein Human genes 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 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 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- 239000013628 high molecular weight specie Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 125000003588 lysine group Chemical class [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 229960005079 pemetrexed Drugs 0.000 description 3
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 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 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 2
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 2
- SBJKKFFYIZUCET-UHFFFAOYSA-N Dehydroascorbic acid Natural products OCC(O)C1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-UHFFFAOYSA-N 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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 2
- 108060008539 Transglutaminase Proteins 0.000 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 description 2
- 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 group 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 description 2
- 229960004103 abiraterone acetate Drugs 0.000 description 2
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 229950001537 amatuximab Drugs 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
- 108010080146 androgen receptors Proteins 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 108010044540 auristatin Proteins 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 2
- 229960001573 cabazitaxel Drugs 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229960001602 ceritinib Drugs 0.000 description 2
- WRXDGGCKOUEOPW-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)NS(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 WRXDGGCKOUEOPW-UHFFFAOYSA-N 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 235000020960 dehydroascorbic acid Nutrition 0.000 description 2
- 239000011615 dehydroascorbic acid Substances 0.000 description 2
- 229960001251 denosumab Drugs 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229960004671 enzalutamide Drugs 0.000 description 2
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000003054 hormonal effect Effects 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 239000013600 plasmid vector Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 229960002633 ramucirumab Drugs 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 102000003601 transglutaminase Human genes 0.000 description 2
- 230000010474 transient expression Effects 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 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 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 1
- GAJBPZXIKZXTCG-VIFPVBQESA-N (2s)-2-amino-3-[4-(azidomethyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(CN=[N+]=[N-])C=C1 GAJBPZXIKZXTCG-VIFPVBQESA-N 0.000 description 1
- ZXSBHXZKWRIEIA-JTQLQIEISA-N (2s)-3-(4-acetylphenyl)-2-azaniumylpropanoate Chemical compound CC(=O)C1=CC=C(C[C@H](N)C(O)=O)C=C1 ZXSBHXZKWRIEIA-JTQLQIEISA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- 125000000981 3-amino-3-oxopropyl group Chemical group [H]C([*])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101100330723 Arabidopsis thaliana DAR2 gene Proteins 0.000 description 1
- 101100330725 Arabidopsis thaliana DAR4 gene Proteins 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229960005532 CC-1065 Drugs 0.000 description 1
- WZHVLILJVZZLNS-UHFFFAOYSA-N CCC(N1CCN(C)CC1)=O Chemical compound CCC(N1CCN(C)CC1)=O WZHVLILJVZZLNS-UHFFFAOYSA-N 0.000 description 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N CCCCC(N)=O Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- 0 CCCCCC(C(O)=O)NC(O*(C)CC*C)=O Chemical compound CCCCCC(C(O)=O)NC(O*(C)CC*C)=O 0.000 description 1
- RDFMDVXONNIGBC-LURJTMIESA-N CCCCC[C@@H](C(O)=O)N Chemical compound CCCCC[C@@H](C(O)=O)N RDFMDVXONNIGBC-LURJTMIESA-N 0.000 description 1
- 229940124293 CD30 monoclonal antibody Drugs 0.000 description 1
- ZQMLCXCWBUNFAZ-UHFFFAOYSA-N CNC(c(cc1)ccc1OCCCO)=O Chemical compound CNC(c(cc1)ccc1OCCCO)=O ZQMLCXCWBUNFAZ-UHFFFAOYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 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
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 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
- 230000000970 DNA cross-linking effect Effects 0.000 description 1
- 231100001074 DNA strand break Toxicity 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 230000010777 Disulfide Reduction Effects 0.000 description 1
- AZVARJHZBXHUSO-UHFFFAOYSA-N Duocarmycin A Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3CC4CC44C5=C(C(C=C43)=O)NC(C5=O)(C)C(=O)OC)=CC2=C1 AZVARJHZBXHUSO-UHFFFAOYSA-N 0.000 description 1
- VQNATVDKACXKTF-UHFFFAOYSA-N Duocarmycin SA Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C(C64CC6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-UHFFFAOYSA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001646716 Escherichia coli K-12 Species 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 229940125646 FDA-approved antibody drug Drugs 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 238000011993 High Performance Size Exclusion Chromatography Methods 0.000 description 1
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- QXSAKPUBHTZHKW-UHFFFAOYSA-N NC(c(cc1)ccc1O)=O Chemical compound NC(c(cc1)ccc1O)=O QXSAKPUBHTZHKW-UHFFFAOYSA-N 0.000 description 1
- 229920002274 Nalgene Polymers 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 102100031013 Transgelin Human genes 0.000 description 1
- 101710190034 Trophoblast glycoprotein Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229950009084 adecatumumab Drugs 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 239000001166 ammonium sulphate Substances 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000008228 bacteriostatic water for injection Substances 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 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 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940127276 delta-like ligand 3 Drugs 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960005519 duocarmycin A Drugs 0.000 description 1
- 229960005510 duocarmycin SA Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229950009569 etaracizumab Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 229950009929 farletuzumab Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 125000005179 haloacetyl group Chemical group 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 102000054751 human RUNX1T1 Human genes 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229950000518 labetuzumab Drugs 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000006674 lysosomal degradation Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229950001869 mapatumumab Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- AZVARJHZBXHUSO-DZQVEHCYSA-N methyl (1R,4R,12S)-4-methyl-3,7-dioxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),8-diene-4-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 AZVARJHZBXHUSO-DZQVEHCYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 229950002142 minretumomab Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 229940127284 new molecular entity Drugs 0.000 description 1
- 229950010203 nimotuzumab Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229950007283 oregovomab Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229960005570 pemtumomab Drugs 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 239000012562 protein A resin Substances 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 102200003959 rs11556986 Human genes 0.000 description 1
- 102200005861 rs137852379 Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229950008684 sibrotuzumab Drugs 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- BNJNAEJASPUJTO-DUOHOMBCSA-N vadastuximab talirine Chemical compound COc1ccc(cc1)C2=CN3[C@@H](C2)C=Nc4cc(OCCCOc5cc6N=C[C@@H]7CC(=CN7C(=O)c6cc5OC)c8ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN9C(=O)C[C@@H](SC[C@H](N)C(=O)O)C9=O)C(C)C)cc8)c(OC)cc4C3=O BNJNAEJASPUJTO-DUOHOMBCSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229950001212 volociximab Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/17—Metallocarboxypeptidases (3.4.17)
- C12Y304/17021—Glutamate carboxypeptidase II (3.4.17.21)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- 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
- C07K2317/77—Internalization into the cell
Definitions
- the present invention relates to antibody-drug conjugates (ADCs) wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine, and their use in the treatment of human solid tumours and haematological malignancies, in particular breast cancer, gastric cancer, colorectal cancer, urothelial cancer, ovarian cancer, uterine cancer, lung cancer, mesothelioma, liver cancer, pancreatic cancer, prostate cancer, and leukaemia.
- ADCs antibody-drug conjugates
- ADCs Antibody-drug conjugates
- Drugs and linkers have been the focus of ADC development, in addition to (monoclonal) antibody (mAb) and target selection. Recently, however, the importance of conjugate homogeneity was realized.
- the conventional methods for drug attachment to an antibody lead to a heterogeneous mixture, and some individual constituents of that mixture can have poor in vivo performance.
- Newer methods for site-specific drug attachment lead to more homogeneous conjugates and allow control of the site of drug attachment. These subtle improvements can have profound effects on in vivo efficacy and/or in vivo safety and thereby on the therapeutic index.
- Methods for site-specific drug conjugation to antibodies are comprehensively reviewed by C.R. Behrens and B. Liu in rriAbs, Vol. 6, Issue 1, 2014, pages 1-8.
- ADCs are typically produced by conjugating the linker drug to the antibody through the side chains of either surface-exposed lysines or free cysteines generated through reduction of interchain disulfide bonds. Because antibodies contain many lysine residues and cysteine disulfide bonds, conventional conjugation typically produces heterogeneous mixtures that present challenges with respect to analytical characterization and manufacturing. Furthermore, the individual constituents of these mixtures exhibit different physicochemical properties and pharmacology with respect to their pharmacokinetic, efficacy, and safety profiles, hindering a rational approach to optimizing this modality.
- Brentuximab vedotin (AdcetrisTM, Seattle Genetics) consists of an anti-CD30 monoclonal antibody conjugated to the highly cytotoxic drug monomethyl auristatin E (MMAE) via modification of native cysteine side chain thiols.
- MMAE monomethyl auristatin E
- the manufacture involves partial reduction of the solvent-exposed interchain disulfides followed by modification of the resulting thiols with maleimide- containing linker drugs.
- the thiols were modified with mc-vc-PAB- MMAE, which incorporates a cathepsin B protease cleavage site (vc, valine-citrulline) and a self-immolative linker (PAB, para-aminobenzyloxycarbonyl) between the maleimide group (mc, maleimidocaproyl) and the cytotoxic drug (MMAE).
- the cysteine attachment strategy results in maximally two drugs per reduced disulfide.
- Most human IgG molecules have four solvent-exposed disulfide bonds, and so a range of from zero to eight drugs per antibody is possible.
- the exact number of drugs per antibody is determined by the extent of disulfide reduction and the number of molar equivalents of linker drug used in the ensuing conjugation reaction. Full reduction of all four disulfide bonds gives a homogeneous construct with eight drugs per antibody, while a partial reduction typically results in a heterogeneous mixture with zero, two, four, six, or eight drugs per antibody.
- Brentuximab vedotin has an average of about 4 drugs per antibody.
- T-DM1 ado-trastuzumab emtansine
- KadcylaTM ado-trastuzumab emtansine
- DM1 maytansine
- a bifunctional linker (SMCC, succinimidyl 4- (N-maleimidomethyl)cyclohexane-l-carboxylate) with a maleimide at one end and an N-hydroxysuccinimidyl (NHS) ester at the other end was reacted with lysine primary amine side chains to form a stable amide bond.
- the modified maytansine (DM1) was then attached to the antibody through conjugation to the maleimide end of the bifunctional linker.
- this linker In contrast to the linker utilized in brentuximab vedotin, this linker has no (protease) cleavage site and thus requires lysosomal degradation of the antibody part of the ADC to liberate the active DM1 -linker- lysine metabolite.
- the attachment method resulted in a heterogeneous mixture of conjugates with an average of 3.5 drugs per antibody. Compared with the cysteine method described above, this strategy gave a more heterogeneous mixture because 20 to 40 lysine residues were found to be modified, whereas only maximally 8 different cysteine residues are modified using the native cysteine modification method.
- ADCs may be improved by applying site-specific conjugation technologies that make use of surface-exposed cysteine residues engineered into antibodies that are then conjugated to a linker drug, resulting in site- specifically conjugated ADCs with defined drug-to-antibody ratios (DARs).
- DARs drug-to-antibody ratios
- the first site-specific conjugation approach was developed at Genentech by introducing a cysteine residue using site-directed mutagenesis at positions showing high thiol reactivity as elaborated in WO2006/034488.
- This common practice in protein modification was more complicated in an antibody because of the various native cysteine residues already present. Introducing the extra cysteine residue in an unsuitable position could result in improper formation of interchain disulfide bonds and therefore improper folding of the antibody.
- Engineered cysteine residues in suitable positions in the mutated antibody are often capped by other thiols, such as cysteine or glutathione, to form disulfides.
- Drug attachment to the mutant residues was achieved by reducing both the native interchain and mutant disulfides, then re-oxidizing the native interchain cysteines using a mild oxidant such as CuS0 4 or dehydroascorbic acid, followed by standard conjugation of the liberated mutant cysteine with a linker drug. Under optimal conditions, two drugs per antibody will be attached (if one cysteine is engineered into the heavy chain or light chain of the niAb).
- the engineered cysteine method proved to be suitable for developing the site- specific ADC SGN-CD33A (Seattle Genetics), which recently entered a Phase I dose- escalation clinical study as a treatment for acute myeloid leukaemia (AML), as well as a Phase lb clinical trial in combination with standard of care chemotherapy, including cytarabine and daunorubicin.
- ADC SGN-CD33A Steattle Genetics
- This ADC comprises a cleavable dipeptide linker (i.e., valine- alanine) and a DNA-cross-linking, pyrrolobenzodiazepine (PBD) dimer as the drug linked to heavy chain position S239C in the Fc part of IgGl mAb h2H12 (DAR 1.9; Sutherland et al. Blood 2013; 122(8): 1455-1463).
- PBD pyrrolobenzodiazepine
- WO2014/124316 from Novartis specifically focuses on the identification of surface accessible sites in the constant regions of the antibody heavy and light chains, at which sites substitution for a cysteine residue enables efficient conjugation of payloads and provides conjugates with high stability.
- Transglutaminase is an enzyme that catalyzes amide bond formation between the acyl group of a glutamine side chain and the primary amine of a lysine side chain.
- orthogonal chemistry conjugation has also been used to site- specifically modify a wide variety of proteins using non-natural amino acids (notably technologies from Ambrx and Sutro Biopharma).
- non-natural amino acids notably technologies from Ambrx and Sutro Biopharma.
- p-acetylphenyl- alanine and p-azidomethyl-L-phenylalanine were chosen as the non-natural amino acids, because they, respectively, contain a ketone and an azide functional group that is not found in any of the 20 natural amino acid side chains. This allows for specific modification of the ketone cq. azide groups without interference from other amino acids.
- This method provided an additional route for constructing ADCs with a maximum of two drugs per antibody (per one such non-natural amino acid).
- the present invention relates to antibody-drug conjugates (ADCs) wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine at one or more specific positions of said antibody, and their use in the treatment of human solid tumours and haematological malignancies, in particular breast cancer, gastric cancer, colorectal cancer, urothelial cancer, ovarian cancer, uterine cancer, lung cancer, mesothelioma, liver cancer, pancreatic cancer, prostate cancer, and leukaemia.
- ADCs antibody-drug conjugates
- FIG. 1A Identification of suitable linker drug conjugation positions in the Fab part of an antibody
- Figure IB Docking of duocarmycin linker drug vc-seco-DUBA in the Fab cavity of an antibody (overlay of multiple vc-seco-DUBA dockings)
- FIG. 1C Identification of suitable linker drug conjugation positions in the Fc part of an antibody
- Figure ID Docking of duocarmycin linker drug vc-seco-DUBA in the Fc cavity of an antibody (overlay of multiple vc-seco-DUBA dockings)
- Figure 2A In vivo efficacy of engineered cysteine anti-PSMA (VH S41C) ADC (SYD1091) versus vehicle control, comparator engineered cysteine anti-PSMA (CH T120C) ADC (SYD1035), and non-engineered anti-PSMA (wild-type) wt ADC (SYD998) at 2 mg/kg each Figure 2B. In vivo efficacy of engineered cysteine anti-PSMA (VH S41C) ADC (SYD1091) versus vehicle control, comparator engineered cysteine anti-PSMA (CH T120C) ADC (SYD1035), and non-engineered anti-PSMA wt ADC (SYD998) at 10 mg/kg each
- FIG. 4A In vivo efficacy of engineered cysteine anti-5T4 (VH P41C) H8 ADC (H8-41C-vc-5 , eco-DUBA) versus vehicle control, and non-engineered anti-5T4 wt H8 ADC (HS-vc-seco-DUBA) at 3 mg/kg each
- FIG. 4B In vivo efficacy of engineered cysteine anti-5T4 (VH P41C) H8 ADC (H8-41C-vc-5 , eco-DUBA) versus vehicle control, and non-engineered anti-5T4 wt H8 ADC (HS-vc-seco-DUBA) at 10 mg/kg each
- ADCs Antibody-drug conjugates
- Antibodies have been conjugated to a variety of cytotoxic drugs, including small molecules that bind DNA (e.g. anthracyclines), alkylate or crosslink DNA (e.g. duocarmycins or pyrrolobenzodiazepine dimers, respectively), cause DNA strand breaks (e.g.
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein a linker drug is site- specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41, 89 (Kabat numbering), 152, 153, 155, 171, 247, 297, 339, 375 and 376 (Eu numbering), and light chain 40, 41 (Kabat numbering), 165 and 168 (Eu numbering).
- ADC antibody-drug conjugate
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41, 89, 152, 153, 155, 171, 247, 297, 339 and 375, and light chain 40, 41, and 165.
- ADC antibody-drug conjugate
- the present invention relates to an antibody- drug conjugate compound wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41 and 89 (according to Kabat numbering) and light chain 40 and 41 (according to Kabat numbering).
- duocarmycin type linker drugs e.g. vc-seco-DUBA (i.e., SYD980; an ADC compound thereof is depicted in formula II), were shown to have a strong preference for binding in cavities which are present in all antibody structures (see Figures IB and ID for the Fab and the Fc part of an antibody, respectively). Multiple suitable conjugation positions for linker drug attachment were identified in and in close proximity to these cavities, i.e., with good accessibility of engineered cysteines at these locations (see Figures 1A and 1C for the Fab and the Fc part of an antibody, respectively).
- Kabat numbering is used for indicating the amino acid positions of engineered cysteines in the heavy chain (HC) and light chain (LC) variable regions and Eu numbering is used for indicating the positions in the heavy chain and light chain constant regions of the antibody.
- the exact amino acid to be substituted by cysteine can be different for different antibodies.
- IgG antibodies in the heavy chain of the variable region (VH), there usually is an A or S at position 40, a P at position 41 and a V at position 89 and in the light chain of the variable region (VL), there usually is a P at position 40 and a G at position 41.
- Kabat numbering refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a framework region (FR) or complementary determining region (CDR) of the variable domain.
- the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard” Kabat numbered sequence.
- Eu numbering refers to the Eu index as in Kabat, E.A. et al.,
- Heavy chain positions 40, 41 and 89 are located in the variable region and positions 152, 153, 155, 171, 247, 297, 339, 375 and 376 are located in the constant region of the antibody.
- Light chain positions 40 and 41 are located in the variable region and positions 165 and 168 are located in the constant region of the antibody.
- Heavy chain positions 40, 41, 89, 152, 153, 155 and 171 and light chain positions 40, 41, 165 and 168 are located in the Fab part and heavy chain positions 247, 297, 339, 375 and 376 are located in the Fc part of the antibody.
- engineered cysteine means replacing a non-cysteine amino acid in the heavy chain or light chain of an antibody by a cysteine. As is known by the person skilled in the art, this can be done either at the amino acid level or at the DNA level, e.g. by using site-directed mutagenesis.
- the present inventors surprisingly have found that the site- specifically conjugated ADC compounds of the present invention show improved physicochemical, pharmacological and/or pharmacokinetic properties, as compared to ADCs wherein the linker drug is conjugated through native interchain disulfide bonds of the antibody and, moreover, as compared to engineered cysteine ADCs wherein the linker drug is conjugated at positions disclosed in the prior art from the ones specifically claimed in this patent application.
- the ADC compounds in accordance with the present invention have binding properties similar to the naked antibodies, good in vivo efficacy, an increased therapeutic index and/or improved stability. Notably, it was found that the ADC compounds are generally less hydrophobic and less susceptible to cathepsin B cleavage and therefore likely also to other intra- or extracellular
- tumour mass tumor microenvironment
- ADCs enzymes/proteases in the tumour mass (tumour microenvironment) than ADCs that are site- specifically conjugated at different positions, but still show similar in vitro cytotoxicity.
- ADCs in accordance with the present invention show improved in vivo efficacy in a tumour xenograft animal model as compared to ADCs that are site- specifically conjugated at other positions.
- linker drugs when linker drugs are conjugated at the specific positions of the antibody as claimed herein, said linker drug fits into either the Fab cavity that is formed by the CHI, VH, VL and CL domains of the antibody or the Fc cavity that is formed by the two CH2 and two CH3 domains of the antibody.
- the top of the Fc cavity is formed by the
- the linker drug (which typically is more hydrophobic than the antibody) is shielded from the hydrophilic aqueous environment surrounding the antibody and the ADC as such is less hydrophobic as compared to ADCs wherein the linker drug is conjugated through native disulfide bonds of the antibody and is much less hydrophobic as compared to ADCs wherein the linker drug is site- specifically conjugated at different positions that are not presently claimed and where the linker drug is forced to the outside of the antibody, i.e., is pointed in a direction away from the antibody.
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41, 152, 153, 247, 339 and 375, and light chain 40, 41, and 165.
- ADC antibody-drug conjugate
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein a linker drug is site- specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41, 89, 247, 297 and 376, and light chain 40 and 41.
- ADC antibody-drug conjugate
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41, 89, 152, 153, 155 and 171, and light chain 40, 41, 165 and 168 in the Fab part of said antibody.
- ADC antibody-drug conjugate
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein a linker drug is site- specifically conjugated to an antibody through an engineered cysteine at one or more positions of said antibody selected from heavy chain 40, 41, 152 and 153, and light chain 40, 41 and 165 in the Fab part of said antibody.
- ADC antibody-drug conjugate
- the present invention relates to an antibody-drug conjugate (ADC) compound wherein said engineered cysteine is at one or more positions of said antibody selected from heavy chain 40, 41 and 89 and light chain 40 and 41 in the Fab part of said antibody.
- ADC antibody-drug conjugate
- said engineered cysteine is at heavy chain position 40 or 41 and/or light chain position 40 or 41, more preferably at heavy chain position 41 and/or light chain position 40 or 41, most preferably at heavy chain position 41.
- tumour-associated proteases in the tumour microenvironment can partially cleave the Fc constant domains, under the hinge region, conjugation in the Fab part is preferred over conjugation in the Fc part. Cleavage of the Fc constant domains would result in loss of Fc- conjugated linker drugs, which in turn could lead to a decreased activity of the ADC in vivo.
- the antibody-drug conjugate (ADC) compound of the above preferred embodiment may further comprise an additional engineered cysteine at one or more positions of the antibody selected from heavy chain 152, 153, 155, 171, 339 and 375, and light chain 165 and 168.
- said further engineered cysteine is at heavy chain position 375 in the Fc part of said antibody.
- the one or more cysteine residues can be engineered into the antibody by using conventional molecular cloning techniques or the heavy chain or light chain domain(s) of the antibody carrying the cysteine mutation(s) can be synthesized as such using known (peptide or DNA) synthesis equipment and procedures.
- any linker drug known in the art of ADCs can be used for site-specific conjugation to an antibody, provided it has a chemical group which can react with the thiol group of an engineered cysteine, typically a maleimide or haloacetyl group.
- Suitable linker drugs may comprise a duocarmycin, calicheamicin,
- pyrrolobenzodiazepine (PBD) dimer maytansinoid or auristatin derivative as a cytotoxic drug. Either a cleavable or a non-cleavable linker may be used in accordance with the present invention.
- Suitable examples of maytansinoid drugs include DM1 and DM4.
- Suitable examples of auristatin drugs include MMAE and MMAF.
- linker drugs known to the person skilled in the art include mc-vc-PAB-MMAE (also abbreviated as mc-vc-MMAE and vc-MMAE), mc-MMAF, and mc-vc-MMAF.
- the linker used is a cleavable linker, such as valine-citrulline (vc) or valine- alanine (va).
- the present invention relates to an ADC compound wherein said linker drug comprises a duocarmycin derivative.
- Duocarmycins first isolated from a culture broth of Streptomyces species, are members of a family of antitumour antibiotics that include duocarmycin A, duocarmycin SA, and CC- 1065. These extremely potent agents allegedly derive their biological activity from an ability to sequence- selectively alkylate DNA at the N3 position of adenine in the minor groove, which initiates a cascade of events that terminates in an apoptotic cell death mechanism.
- WO2011/133039 discloses a series of linker drugs comprising a duocarmycin derivative of CC-1065. Suitable linker-duocarmycin derivatives to be used in accordance with the present invention are disclosed on pages 182-197. The chemical synthesis of a number of these linker drugs is described in Examples 1-12 of WO2011/133039.
- the present invention relates to a compound of formula (I)
- n is 0-3, preferably 0-1,
- m represents an average DAR of from 1 to 6, preferably of from 1 to 4,
- R 1 is selected from
- n represents an integer from 0 to 3
- m represents an average drug-to-antibody ratio (DAR) of from 1 to 6.
- DAR drug-to-antibody ratio
- the DAR and drug load distribution can be determined, for example, by using hydrophobic interaction chromatography (HIC) or reversed phase high-performance liquid chromatography (RP-HPLC). HIC is particularly suitable for determining the average DAR.
- Suitable methods for site-specifically conjugating linker drugs can for example be found in Examples 7 and 8 of WO2005/084390, which describe complete reduction strategies for (partial) loading of antibodies with the linker drug vc-MMAE, in Examples 11 and 12 of WO2006/034488, which describe site-specific conjugation of a maytansine (DM1)- comprising linker drug, and in Doronina et al. Bioconjugate Chem. 17 (2006): 114-124, which describes the conjugation with mc-MMAF.
- DM1 maytansine
- Conjugation to two or more of the engineered cysteine sites of the present invention allows for the preparation of ADCs comprising hydrophobic drug classes with a higher DAR, notably DAR 4, without getting too much aggregate.
- one or two engineered cysteines can be incorporated into the heavy chain and/or light chain of the antibody, under optimal reaction conditions resulting in an ADC compound having a DAR of 2 or 4, respectively.
- one engineered cysteine When one engineered cysteine is introduced, it can be located either in the Fab or in the Fc part of the antibody. It is preferred to introduce said cysteine in the Fab part of the antibody at position HC 40, 41, 89, 152 or 153 or LC 40, 41 or 165, preferably HC 40, 41 or 89 or LC 40, 41 or 165, more preferably HC 40 or 41 or LC 40 or 41, even more preferably HC 41 or LC 40 or 41, most preferably HC 41.
- these two cysteines can both be located in the Fab or in the Fc part of the antibody or, preferably, one can be in the Fab part, preferably HC 40, 41, 152 or 153 or LC 40, 41 or 165, more preferably HC 40 or 41 or LC 40 or 41, even more preferably HC 41 or LC 40 or 41, most preferably HC 41, and the other can be in the Fc part of the antibody, preferably HC 247, 297, 339 or 375, more preferably HC 339 or 375, most preferably HC 375.
- one cysteine residue may be introduced in the heavy chain and the other cysteine is introduced in the light chain of the antibody, e.g. HC 40 or 41 and LC 40 or 41.
- one cysteine residue may be introduced at one of the specific positions as identified in the present invention, e.g. HC 40 or 41 or LC 40 or 41, and the other may be located at a surface-exposed (i.e., not herein claimed) engineered cysteine position leading to a higher DAR and still acceptable hydrophobicity.
- the present invention relates to a compound of the formula (I) as disclosed hereinabove, wherein n is 0-1, m represents an average DAR of from 1 to 6, preferably of from 1 to 4, more preferably of from 1 to 2, most preferably of from 1.5 to 2,
- R 1 is selected from
- y is 1-16, preferably 1-4, and
- R is selected from
- the present invention relates to a compound of the structural formula (I) as disclosed hereinabove, wherein n is 0-1, m represents an average DAR of from 1.5 to 2, R 1 is
- y is 1-4, and R is selected from
- the present invention relates to a compound of formula (II)
- any antibody - particularly any antibody known to have therapeutic activity or any antibody known in the art of ADCs - or any antigen binding fragment thereof can be used for site- specific conjugation of a linker drug at the specific antibody positions claimed herein.
- Said antibody can be an IgA, IgD, IgE, IgG or IgM antibody.
- Said antibody can have ⁇ (kappa) light chains or ⁇ (lambda) light chains.
- Said IgG antibody can be an IgGl, IgG2, IgG3 or IgG4 antibody.
- the antibody binds to a(n) antigen target that is expressed in or on the cell membrane (e.g., on the cell surface) of a tumour cell, more preferably, the antibody is internalised by the cell after binding to the (antigen) target, after which the toxin is released intracellularly.
- the antibody is an IgG antibody, more preferably an IgGl antibody, most preferably an IgGl antibody having ⁇ light chains.
- the IgG antibody carries a native glycoside/carbohydrate moiety attached at N297 of the heavy chain of the antibody.
- Suitable antibodies include an anti-annexin Al antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-CD30 antibody, an anti-CD33 antibody, an anti-CD37 antibody, an anti-CD38 antibody, an anti-CD44 antibody, an anti-CD47 antibody, an anti-CD56 antibody, an anti-CD70 antibody, an anti-CD74 antibody, an anti-CD79 antibody, an anti- CD115 antibody, an anti-CD123 antibody, an anti-CD138 antibody, an anti-CD203c antibody, an anti-CD303 antibody, an anti-CEACAM antibody, an anti-CLL-1 antibody, an anti-c-MET (or anti-HGFR) antibody, an anti-Cripto antibody, an anti-DLL3 antibody, an anti-EGFR antibody, an anti-EPCAM antibody, an anti-EphA2 antibody, an anti-EphB3 antibody, an anti-ETBR antibody, an anti-FcRL5 antibody, an anti-FOLRl antibody, an anti- GCC antibody, an anti-GPNMB antibody, an
- the antibody is an anti-annexin Al antibody, an anti-CD115 antibody, an anti-CD 123 antibody, an anti-CLL-1 antibody, an anti-c-MET antibody, an anti-MUCl antibody, an anti-PSMA antibody, an anti-5T4 antibody or an anti-TF antibody. More preferably, the antibody is an anti-PSMA antibody or an anti-5T4 antibody.
- the antibody to be used in accordance with the present invention preferably is a monoclonal antibody (rriAb) and can be a chimeric, humanized or human mAb. More preferably, in accordance with the present invention a humanized or human mAb is used, even more preferably a humanized or human IgG antibody, most preferably a humanized or human IgGl mAb. Preferably, said antibody has ⁇ (kappa) light chains, i.e., a humanized or human IgGl- ⁇ antibody. In humanized antibodies, the antigen-binding CDRs in the variable regions are derived from antibodies from a non-human species, commonly mouse, rat or rabbit.
- non-human CDRs are placed within a human framework (FRl, FR2, FR3 and FR4) of the variable region, and are combined with human constant regions.
- these humanized antibodies can be numbered according to the Kabat numbering system.
- the present invention particularly relates to an ADC compound wherein said engineered cysteine is at a position selected from VH 40, VH 41, VH 89, VL 40 or VL 41 in the human framework (i.e., VH 40, VH 41, VL 40 and VL 41 are in the middle of FR2, VH 89 is in FR3) of a humanized antibody, more particularly at VH 40, VH 41, VL 40 or VL 41, even more particularly at VH 41, VL 40 or VL 41, especially at VH 41.
- these specific residues in the framework regions are both suitable for conjugation of a linker drug and do not lead to significant reduction of antigen binding properties of the antibody after conjugation of the linker drug. Furthermore, these sites are not only suitable in antibodies, but also in any antigen binding fragments thereof.
- the present invention relates to an ADC compound as described hereinabove wherein said antibody is an anti-annexin Al antibody, an anti-CD115 antibody, an anti-CD 123 antibody, an anti-CLL-1 antibody, an anti-c-MET antibody, an anti- MUC1 antibody, an anti-PSMA antibody, an anti-5T4 antibody or an anti-TF antibody and said linker drug comprises a duocarmycin derivative, preferably an ADC compound in accordance with formula (I) or (II).
- the present invention relates to an ADC compound as described hereinabove wherein said antibody is an anti-PSMA (monoclonal) antibody or an anti-5T4 (monoclonal) antibody and said linker drug comprises a duocarmycin derivative, preferably an ADC compound in accordance with formula (I) or (II).
- the present invention relates to an ADC compound as described hereinabove, wherein said linker drug comprises a duocarmycin derivative and is conjugated at position 41 of the heavy chain variable region of an anti-PSMA (monoclonal) antibody or an anti-5T4 (monoclonal) antibody, most preferably an ADC compound according to formula (II).
- Suitable anti-PSMA antibodies are described in WO98/03873 (e.g., Example 12), WO02/098897 (e.g., Figs. 1-2), WO2007/002222 (e.g., Table 1) and
- Suitable anti-5T4 antibodies include H8, which is described in WO2006/031653, and the Al and A3 antibodies which are described in WO2007/ 106744, as well as any antibodies binding to the same epitope as these known antibodies.
- the heavy chain of the anti-PSMA antibody comprises the amino acid sequence of SEQ ID NO:2 and the light chain of the anti-PSMA antibody comprises the amino acid sequence of SEQ ID NO:5. More preferably, the heavy chain of the anti-PSMA antibody comprises the amino acid sequences of SEQ ID NO:2 and SEQ ID NO:3, and the light chain of the anti-PSMA antibody comprises the amino acid sequences of SEQ ID NO:5 and SEQ ID NO:6.
- the present invention relates to an ADC compound of formula (II), wherein the antibody is an anti-PSMA antibody, the heavy chain of said anti-PSMA antibody comprising the amino acid sequence of SEQ ID NO:2 and the light chain of said anti-PSMA antibody comprising the amino acid sequence of SEQ ID NO:5. More preferably, the heavy chain of said anti-PSMA antibody comprises the amino acid sequences of SEQ ID NO:2 and SEQ ID NO:3, and the light chain of said anti-PSMA antibody comprises the amino acid sequences of SEQ ID NO:5 and SEQ ID NO:6.
- the heavy chain of the anti-5T4 antibody comprises the amino acid sequence of SEQ ID NO: 8 and the light chain of the anti-5T4 antibody comprises the amino acid sequence of SEQ ID NO: 11. More preferably, the heavy chain of the anti-5T4 antibody comprises the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO:9, and the light chain of the anti-5T4 antibody comprises the amino acid sequences of SEQ ID NO: 11 and SEQ ID NO:6.
- the present invention relates to an ADC compound of formula (II), wherein the antibody is an anti-5T4 antibody, the heavy chain of said anti-5T4 antibody comprising the amino acid sequence of SEQ ID NO: 8 and the light chain of said anti-5T4 antibody comprising the amino acid sequence of SEQ ID NO: 11. More preferably, the heavy chain of said anti-5T4 antibody comprises the amino acid sequences of SEQ ID NO:8 and SEQ ID NO:9, and the light chain of said anti-5T4 antibody comprises the amino acid sequences of SEQ ID NO: 11 and SEQ ID NO:6.
- the present invention further relates to an ADC compound as described hereinabove for use as a medicament.
- the present invention relates to an ADC compound as described hereinabove for use in the treatment of human solid tumours and haematological
- the present invention relates to an ADC compound as described hereinabove for use in the treatment of human solid tumours selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, urothelial cancer (e.g. bladder cancer), ovarian cancer, uterine cancer, lung cancer (especially no n- small cell lung cancer and small-cell lung cancer), mesothelioma (especially malignant pleural
- liver cancer mesothelioma
- pancreatic cancer pancreatic cancer
- prostate cancer prostate cancer
- the present invention relates to an ADC compound as described hereinabove, particularly a compound comprising an anti-PSMA (monoclonal) antibody and a duocarmycin derivative linker drug, for use in the treatment of prostate cancer.
- the present invention relates to an ADC compound as described hereinabove, particularly a compound comprising an anti-5T4 (monoclonal) antibody and a duocarmycin derivative linker drug, for use in the treatment of human solid tumours selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, ovarian cancer, lung cancer (especially non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC)), and malignant pleural mesothelioma.
- NSCLC non-small cell lung cancer
- SCLC small-cell lung cancer
- the present invention relates to an ADC compound as described hereinabove for use in the treatment of human haematological malignancies, particularly leukaemia, selected from the group consisting of acute lymphoblastic and myeloid leukaemia (ALL and AML, respectively).
- human haematological malignancies particularly leukaemia, selected from the group consisting of acute lymphoblastic and myeloid leukaemia (ALL and AML, respectively).
- ALL and AML acute lymphoblastic and myeloid leukaemia
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising an ADC compound as described hereinabove and one or more pharmaceutically acceptable excipients.
- Typical pharmaceutical formulations of therapeutic proteins such as monoclonal antibodies and (monoclonal) antibody-drug conjugates take the form of lyophilized cakes (lyophilized powders), which require (aqueous) dissolution (i.e., reconstitution) before intravenous infusion, or frozen (aqueous) solutions, which require thawing before use.
- the pharmaceutical composition is provided in the form of a lyophilized cake.
- suitable pharmaceutically acceptable excipients for inclusion into the pharmaceutical composition (before freeze-drying) in accordance with the present invention include buffer solutions (e.g. citrate, histidine or succinate containing salts in water), lyoprotectants (e.g. sucrose, trehalose), tonicity modifiers (e.g. sodium chloride), surfactants (e.g. polysorbate), and bulking agents (e.g. mannitol, glycine).
- buffer solutions e.g. citrate, histidine or succinate containing salts in water
- lyoprotectants e.g. sucrose, trehalose
- tonicity modifiers e.g. sodium chloride
- surfactants e.g. polysorbate
- bulking agents e.g. mannitol, glycine
- the sterile, lyophilized powder single-use formulation of KadcylaTM contains - upon reconstitution with Bacteriostatic or Sterile Water for Injection (BWFI or SWFI) - 20 mg/mL ado -trastuzumab emtansine, 0.02% w/v polysorbate 20, 10 mM sodium succinate, and 6% w/v sucrose with a pH of 5.0.
- BWFI or SWFI Bacteriostatic or Sterile Water for Injection
- the present invention also relates to the use of a compound or a pharmaceutical composition as described hereinabove for the treatment of human solid tumours and haematological malignancies as described hereinabove.
- the present invention further relates to the use of a sequentially or simultaneously administered combination of a compound or a pharmaceutical composition as described hereinabove with a therapeutic antibody and/or a chemotherapeutic agent, for the treatment of human solid tumours and haematological malignancies as described hereinabove.
- the therapeutic antibody is adecatumumab, alemtuzumab, amatuximab, bevacizumab, cetuximab, denosumab, etaracizumab,
- the chemotherapeutic agent is i) an alkylating agent, particularly nitrogen mustards, such as mechlorethamine, chlorambucil,
- cyclophosphamide ifosfamide and melphalan, nitrosoureas, such as streptozocin, carmustine and lomustine, alkyl sulfonates, such as busulfan, triazines, such as dacarbazine and temozolomide, ethylenimines, such as thiotepa and altretamine, or platinum drugs, such as cisplatin, carboplatin and oxaliplatin, ii) an anti-metabolite, particularly 5-fluorouracil, 6- mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate or pemetrexed, iii) an anti-tumour antibiotic, particularly daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin D, bleomycin, mitomycin-C or
- mitoxantrone iv) a topoisomerase inhibitor, particulary topoisomerase I inhibitors, such as topotecan and irinotecan, or topoisomerase II inhibitors, such as etoposide, teniposide and mitoxantrone, v) a mitotic inhibitor, particularly taxanes, such as paclitaxel, cabazitaxel and docetaxel, epothilones, such as ixabepilone, vinca alkaloids, such as vinblastine, vincristine and vinorelbine, or estramustine, vi) a signalling cascade inhibitor, particularly mTOR (mammalian target of rapamycin) inhibitors, such as temsirolimus and everolimus, or tyrosine kinase inhibitors, such as gefitinib, erlotinib, imatinib, pazopanib, ceritinib, crizotini
- the therapeutic antibody is bevacizumab, denosumab, pertuzumab or trastuzumab and the chemo therapeutic agent is a topoisomerase II inhibitor, particularly mitoxantrone, a mitotic inhibitor, particularly a taxane, more particularly cabazitaxel or docetaxel, a corticosteroid, particularly prednisone, or a hormonal therapeutic agent, particularly an androgen receptor modulating agent, more particularly enzalutamide or abiraterone acetate.
- the therapeutic antibody is bevacizumab, cetuximab, nivolumab, or ramucirumab and the chemotherapeutic agent is an alkylating agent, particularly a platinum drug, more particularly cisplatin or carboplatin, an anti-metabolite, particularly gemcitabine or pemetrexed, a topoisomerease II inhibitor, particularly etoposide, a mitotic inhibitor, particularly a taxane or a vinca alkaloid, more particularly paclitaxel or docetaxel, or vinblastine or vinorelbine, or a signalling cascade inhibitor, particularly a tyrosine kinase inhibitor, more particularly erlotinib, ceritinib, crizotinib or afatinib.
- the chemotherapeutic agent is an alkylating agent, particularly a platinum drug, more particularly cisplatin or carboplatin, an anti-metabolite, particularly gemcitabine or pemetrexe
- the therapeutic antibody is bevacizumab and the chemotherapeutic agent is an alkylating agent, particularly a nitrogen mustard, a platinum drug or a triazine, more particularly cyclophosphamide, ifosfamide, cisplatin, or temozolomide, an anti-tumour antibiotic, particularly doxorubicin, an antimetabolite, particularly gemcitabine, a topoisomerease I or II inhibitor, particularly topotecan, irinotecan or etoposide, or a mitotic inhibitor, particularly a taxane or a vinca alkaloid, more particularly paclitaxel or docetaxel, or vincristine or vinorelbine.
- the chemotherapeutic agent is an alkylating agent, particularly a nitrogen mustard, a platinum drug or a triazine, more particularly cyclophosphamide, ifosfamide, cisplatin, or temozolomide, an anti-tumour
- the therapeutic antibody is amatuximab and the chemotherapeutic agent is an alkylating agent, particularly a platinum drug, more particularly cisplatin or carboplatin, an anti-metabolite, particularly gemcitabine or pemetrexed, or a mitotic inhibitor, particularly a vinca alkaloid, more particularly vinorelbine.
- the chemotherapeutic agent is an alkylating agent, particularly a platinum drug, more particularly cisplatin or carboplatin, an anti-metabolite, particularly gemcitabine or pemetrexed, or a mitotic inhibitor, particularly a vinca alkaloid, more particularly vinorelbine.
- a therapeutically effective amount of the compounds in accordance with the present invention lies in the range of about 0.01 to about 15 mg/kg body weight, particularly in the range of about 0.1 to about 10 mg/kg body weight, more particularly in the range of about 0.3 to about 10 mg/kg body weight. This latter range corresponds roughly to a flat dose in the range of 20 to 800 mg of the ADC compound.
- the compound of the present invention may be administered weekly, bi-weekly, three-weekly or monthly, for example weekly for the first 12 weeks and then every three weeks until disease progression. Alternative treatment regimens may be used depending upon the severity of the disease, the age of the patient, the compound being administered, and such other factors as would be considered by the treating physician.
- the cDNA sequence for the heavy chain was obtained from the amino acid sequences of a leader sequence (SEQ ID NO: l), the heavy chain variable region of an anti-PSMA antibody (SEQ ID NO:2, Kabat numbering, having a cysteine residue at position 41) and the human IgGl heavy chain constant region (SEQ ID NO:3, sequential numbering, Eu numbering starting at alanine 118) by back- translating the combined amino acid sequences into a cDNA sequence optimized for expression in human cells ⁇ Homo sapiens) (SEQ ID NO:4).
- the cDNA sequence for the light chain was obtained from the amino acid sequences of a secretion signal (SEQ ID NO: l), the light chain variable region of an anti- PSMA antibody (SEQ ID NO:5, Kabat numbering), and the human ⁇ Ig light chain constant region (SEQ ID NO:6, sequential numbering) by back-translating the combined amino acid sequences into a cDNA sequence optimized for expression in human cells ⁇ Homo sapiens) (SEQ ID NO:7).
- SEQ ID NO: 10 was obtained from the amino acid sequences of a leader sequence (SEQ ID NO: l), the heavy chain variable region of the H8 antibody (SEQ ID NO:8, sequential numbering, having a cysteine residue at position 41) and the human IgGl heavy chain constant region (SEQ ID NO:9, sequential numbering, Eu numbering starting at alanine 118).
- the cDNA sequence for the H8 antibody light chain (SEQ ID NO: 12) was obtained from the amino acid sequences of a leader sequence (SEQ ID NO: l), the light chain variable region of the H8 antibody (SEQ ID NO: 11, Kabat numbering), and the human ⁇ Ig light chain constant region (SEQ ID NO:6, sequential numbering).
- the cDNA sequence for the heavy chain of natalizumab was obtained from the amino acid sequences of a leader sequence (SEQ ID NO: 13), the heavy chain variable region of natalizumab (SEQ ID NO: 14, Kabat numbering) and the human IgG4 heavy chain constant region (SEQ ID NO: 15, sequential numbering, Eu numbering starting at alanine 118; having a proline residue at position 225 and a cysteine residue at position 375).
- the cDNA sequence for the natalizumab light chain was obtained from the amino acid sequences of a leader sequence (SEQ ID NO: 17), the light chain variable region of natalizumab (SEQ ID NO: 18, Kabat numbering), and the human ⁇ Ig light chain constant region (SEQ ID NO:6, sequential numbering).
- the heavy chain and light chain cDNA constructs were chemically synthesized by and obtained from a commercial source (Life Technologies). Cleavage of the leader sequence corresponded to the predicted cleavage site using the SignalP program
- the mammalian expression vector 0098 was constructed as follows.
- the CMV:BGHpA expression cassette was excised from the pcDNA3.1(-) (Life Technologies) plasmid and re-inserted back into the same original vector (still containing an intact CMV:BGHpA expression cassette), thereby duplicating the CMV:BGHpA expression cassette, to allow expression of both HC and LC cDNAs from a single plasmid vector.
- an IRES-DHFR fragment was isolated from the vector pOptiVEC-TOPO (Life Technologies) and inserted between the CMV promoter and the BGHpA polyadenylation sequence in one of the CMV:BGHpA expression cassettes.
- the cDNAs for the heavy chain (HC) and the light chain (LC) were ligated into pMA- RQ and pMA-T plasmid vectors (Life Technologies), respectively, using Sfil restriction sites.
- the LC cDNA was transferred to the mammalian expression vector 0098 using Ascl and Hpal restriction sites.
- the resulting vector was digested with BamHI and Nhel restriction enzymes, and ligated with the HC cDNA fragment, digested with the same restriction enzymes.
- the final vector, containing both the HC and LC expression cassettes (CMV:HC:BGHpA and CMV:LC-BGHpA, respectively) was transferred to and expanded in E. coli NEB 5-alpha cells (New England Bio labs).
- Expi293F cells were transfected with the antibody mutant expression vector prepared under 1) above using the ExpiFectamine transfection agent (Life Technologies) according to the manufacturer's instructions as follows: 75 x 10' cells were seeded in 300 mL Expi293 Expression medium; 300 ⁇ g of the antibody mutant expression vector was combined with 800 ⁇ of ExpiFectamine transfection agent and added to the cells. One day after transfection, 1.5 mL Enhancer 1 and 15 mL Enhancer 2 were added to the culture. Six days post transfection, the cell culture supernatant was harvested by centrifugation at 4,000 g for 15 minutes and filtering the clarified harvest over MF 75 filters (Nalgene).
- the antibodies were purified using commercially available protein A resin (MabSelect SuRe, GE Healthcare), using Akta chromatographic equipment (GE Healthcare). A 20 cm bed height column was used with a maximum load of 25 mg/mL packed resin. The process was performed at RT.
- the purification step After equilibration (PBS pH7.4) and loading the purification step employed two wash steps (PBS pH7.4 and NaAc pH5, respectively) and an elution step (25 mM NaAc, pH3) followed by a regeneration, rinse and cleaning step, respectively, before a new cycle was started. During the elution step the target protein was collected in a peak starting and stopping at an absorbance of 0.05-0.1 AU (0.2 cm cell length). After purification the protein was stored at -20°C to -80°C.
- Protein A eluates were, if needed, concentrated to 20-25 mg/mL using Vivaspin centrifugal devices (5 or 30 kDa cut-off, Vivaproducts). After obtaining the desired concentrations the concentrated solutions (typically 25 mg/mL) were dialyzed twice using PD10 columns (GE Healthcare) and 4.2 mM L-Histidine + 50 mM Trehalose pH6.0 buffer. Alternatively, when protein A eluate concentrations were approximately 10 mg/mL, no concentration step was employed and the eluate was immediately dialyzed three times using snakeskin dialysis tube (10 kDa cut-off, Thermo Scientific) against 4.2 mM L-Histidine + 50 mM Trehalose pH6.0 buffer.
- cysteine engineered antibody (5-10 mg/ml in 4.2 mM histidine, 50 mM trehalose, pH 6) EDTA (25 mM in water, 4% v/v) was added.
- the pH was adjusted to -7.4 using TRIS (1 M in water, pH 8) after which TCEP (10 mM in water, 20 equivalents) was added and the resulting mixture was incubated at room temperature for 1-3 hrs.
- the excess TCEP was removed by either a PD-10 desalting column or a Vivaspin centrifugal concentrator (30 kDa cut-off, PES) using 4.2 mM histidine, 50 mM trehalose, pH 6.
- the pH of the resulting antibody solution was raised to -7.4 using TRIS (1 M in water, pH 8) after which dehydroascorbic acid (10 mM in water, 20 equivalents) was added and the resulting mixture was incubated at room temperature for 1-2 hrs. DMA was added followed by a solution of linker drug (10 mM in DMA). The final concentration of DMA was 5-10%. The resulting mixture was incubated at room temperature in the absence of light for 1-16 hrs. In order to remove the excess of linker drug, activated charcoal was added and the mixture was incubated at room temperature for 1 hr.
- the coal was removed using a 0.2 ⁇ PES filter and the resulting ADC was formulated in 4.2 mM histidine, 50 mM trehalose, pH 6 using a Vivaspin centrifugal concentrator (30 kDa cut-off, PES). Finally, the ADC solution was sterile filtered using a 0.22 ⁇ PES filter.
- the relative hydrophobicity is a measure that allows a facile comparison between the hydrophobicity of the engineered ADCs versus the wt-conjugated counterparts based on HIC data.
- the data are summarized in Tables 1, 2 and 3.
- HMW are high molecular weight species, reflecting the amount of aggregates formed Defined as (RT D AR2 - RTDARO) / (RT D AR2, -ADC - RTDARO, -ADC), R is retention time Based on MS-data
- HMW are high molecular weight species, reflecting the amount of aggregates formed Defined as (RT D AR2 - RTDARO) / (RT D AR2, -ADC - RTDARO, -ADC), R is retention time ND is not determined; wild-type H8-vc-MMAE was not prepared
- HMW are high molecular weight species, reflecting the amount of aggregates formed 2 Defined as (RT D AR2 - RTDARO) / (RT D AR2, -ADC - RTDARO, -ADC), R is retention time
- Two anti-5T4 ADCs H8-wt and H8-HC40 had equal binding affinities on 5T4- expressing MDA-MB-468 cells (EC 50 in the range of 0.1-1.2 ⁇ g/ml) similar to the wild-type H8 antibody, and both ADCs were unable to bind to 5T4-negative SK-MEL-30 cells (EC 50 >10 Mg/ml).
- the antigen binding properties of the ADCs were thus unaffected by the attached duocarmycin derivative linker drug.
- the potencies of the site- specifically conjugated anti-PSMA ADCs were similar to the conventionally linked wild-type ADC (SYD998) on PSMA-expressing LNCaP-C4.2 cells (IC 50 in the range of 0.1-0.5 nM, based on drug equivalents, see Table 4 below). All ADCs were inactive on PSMA-negative DU-145 cells (IC 50 >70 nM) indicating selective killing of tumour cells through PSMA.
- the two non-binding control ADCs were at least 50-times less potent than the anti- PSMA ADCs on each of the cell lines evaluated.
- ADC vc- Cys mutations PSMA-positive cell line LNCaP-C4.2 seco-OUBA
- Percentage efficacy was given at the highest concentration tested (-100 nM) and calculated by dividing the measured luminescence for each drug or ADC with the average mean of untreated cells (only growth medium) multiplied by 100.
- Percentage efficacy was given at the highest concentration tested (-100 nM) and calculated by dividing the measured luminescence for each drug or ADC with the average mean of untreated cells (only growth medium) multiplied by 100.
- the potencies of the engineered anti-5T4 ADCs were equal to the conventionally linked ADC H8-wt on 5T4-expressing MDA-MB-468 cells (IC 50 between 0.07 and 0.09 nM, Table 6).
- the anti-5T4 ADCs were inactive on 5T4-negative SK-MEL-30 cells (IC 50 >90nM).
- Percentage efficacy was given at the highest concentration tested (-100 nM) and calculated by dividing the measured luminescence for each drug or ADC with the average mean of untreated cells (only growth medium) multiplied by 100.
- valine-citrulline moiety present in the linker of the ADCs with vc-seco-DUBA (SYD980) and vc-MMAE can be cleaved by cysteine proteases, such as cathepsin B, which results in subsequent intracellular release of the (seco-)DXJBA or MMAE drug inside the tumour lysosomes or extracellular in the tumour microenvironment.
- cysteine proteases such as cathepsin B
- cathepsin B cysteine proteases
- the ADCs were treated for 2 minutes and 4 hours with activated cathepsin B (Calbiochem).
- the cytotoxic activity of the released drug from the anti-PSMA ADCs was measured on PSMA- negative DU-145 cells.
- the cytotoxic activity of the released drug from the anti-5T4 ADCs was measured on 5T4-negative SK-MEL-30 cells.
- 1 mg/ml of each ADC was mixed with 5 ⁇ g/ml cathepsin B (0.04 units/well) in 0.1M Na-acetate pH 5 containing 4 mM DTT.
- 1 mg/ml of each ADC was directly diluted in culture medium (RPMI 1640, 10% qualified FBS). Serial dilutions were made from these ADC solutions in culture medium.
- PSMA- negative DU-145 cells 1,000 cells/well
- 5T4-negative SK-MEL-30 cells 2,000 cells/well
- CCG CellTiter-GloTM
- the in vivo efficacy of three anti-PSMA ADCs was evaluated in the LNCaP C4-2 prostate cancer xenograft model.
- the LnCaP-C4.2 cell line is a human prostate carcinoma epithelial cell line derived from a xenograft that was serially propagated in mice after castration-induced regression and relapse of the parental, androgen-dependent LnCaP-FGC xenograft cell line.
- Tumours were induced subcutaneously by injecting 1x10 of LnCap C4.2 cells in 200 ⁇ . of RPMI 1640 containing matrigel (50:50, v: v) into the right flank of male CB 17- SCID mice.
- LnCaP-C4.2 tumour cell implantation was performed 24 to 72 hours after a whole body irradiation with a ⁇ -source (1.44 Gy, 60 Co, BioMep, Bretenieres, France). Treatments were started when the tumours reached a mean volume of 100-200 mm . Mice were randomized according to their individual tumour volume into groups and received a single i.v. injection of anti-PSMA ADC (2 or 10 mg/kg) or vehicle in the tail vein.
- SYD1091 is even more pronounced at 10 mg/kg as shown in Figure 2B. Mice bearing LnCap C4.2 tumours develop cachexia as illustrated in Figure 3. This loss of body weight is often restored after administration of efficacious treatments and is considered a sensitive efficacy bio marker. Treatment with SYD1091 resulted in much faster restoration of the body weights than was seen with the comparator SYD1035 or native, non-engineered SYD998 ( Figure 3).
- the in vivo efficacy of two anti-5T4 ADCs i.e. the native H8-vc-secoDUBA (average DAR 2.0) and the engineered cysteine (VH P41C) ADC H8-41C-vc-sec6>-DUBA (average DAR 1.7), was evaluated in the PA-1 ovarian cancer xenograft model.
- the PA-1 cell line was established from cells taken from ascitic fluid collected from a woman with ovarian carcinoma (Zeuthen J. et al. Int. J. Cancer 1980; 25(1): 19-32).
- PA-1 tumours were induced subcutaneously by injecting 1x10 cells in 100 ⁇ ⁇
- PA-1 tumour cell injection was performed 24 to 72 hours after a whole body irradiation with a ⁇ -source (2 Gy, 60 Co, BioMep, Bretenieres, France). Treatments were started when the tumours reached a mean volume of 200-300 mm . Mice were randomized according to their individual tumour volume into groups and received a single i.v. injection of anti-5T4 ADC (3 or 10 mg/kg) or vehicle in the tail vein and changes in tumour volumes ( Figures 4A and 4B) were monitored.
- SEQ ID NO:3 human IgGl antibody HC constant region
- SEQ ID NO:6 human IgG antibody LC ⁇ constant region
- SEQ ID NO:9 human IgGl antibody HC constant region
- DIVMTQSPDS LAVSLGERAT INCKASQSVS NDVAWYQQKP GQSPKLLISY TSSRYAGVPD RFSGSGSGTD FTLTISSLQA EDVAVYFCQQ DYNSPPTFGG GTKLEIK
- SEQ ID NO: 14 (natalizumab HC)
- SEQ ID NO: 15 (natalizumab HC S225P, S375C)
- SEQ ID NO: 16 (natalizumab HC S225P, S375C cDNA)
- SEQ ID NO: 18 (natalizumab LC)
- SEQ ID NO: 19 (natalizumab LC cDNA)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Reproductive Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (25)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HRP20211710TT HRP20211710T1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
EP15724638.0A EP3151865B1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
RU2016150377A RU2670157C2 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
ES15724638T ES2895623T3 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of drug binders with resulting antibodies and ADCs |
CA2947238A CA2947238A1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
JP2016568847A JP6517240B2 (en) | 2014-05-22 | 2015-05-22 | Site-Specific Conjugation of Linker Drug to Antibody and ADC Obtained |
SG11201609372UA SG11201609372UA (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
DK15724638.0T DK3151865T3 (en) | 2014-05-22 | 2015-05-22 | SITE SPECIFIC CONJUGATION OF LINKS MEDICINE FOR ANTIBODY AND RESULTS ADCS |
MYPI2016001883A MY183480A (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
KR1020167036019A KR102419766B1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
CN201580026468.0A CN106456794B (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and the resulting ADCs |
EP19160619.3A EP3539544A1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
MX2016015176A MX2016015176A (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs. |
US15/312,436 US10407743B2 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting ADCs |
EP21161774.1A EP3868379A1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
BR112016026744-3A BR112016026744B1 (en) | 2014-05-22 | 2015-05-22 | COMPOUND OF ANTIBODY-DRUG CONJUGATE, AND PHARMACEUTICAL COMPOSITION. |
PL15724638T PL3151865T3 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
LTEPPCT/EP2015/061456T LT3151865T (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
AU2015261768A AU2015261768B2 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting ADCs |
ZA2016/07109A ZA201607109B (en) | 2014-05-22 | 2016-10-14 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
US16/457,244 US11104968B2 (en) | 2014-05-22 | 2019-06-28 | Site-specific conjugation of linker drugs to antibodies and resulting ADCS |
US16/457,186 US11136633B2 (en) | 2014-05-22 | 2019-06-28 | Site-specific conjugation of linker drugs to antibodies and resulting ADCS |
AU2020200175A AU2020200175B2 (en) | 2014-05-22 | 2020-01-09 | Site-specific conjugation of linker drugs to antibodies and resulting ADCS |
US17/409,462 US20210388115A1 (en) | 2014-05-22 | 2021-08-23 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
CY20211101044T CY1125232T1 (en) | 2014-05-22 | 2021-11-29 | SITE-SPECIFIC COUPLING OF DRUG-BINDING ANTIBODIES AND CONSEQUENTIAL ANTIBODY-DRUG CONJUGATIONS (ADCs) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14169493.5 | 2014-05-22 | ||
EP14169493 | 2014-05-22 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/312,436 A-371-Of-International US10407743B2 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting ADCs |
US16/457,186 Division US11136633B2 (en) | 2014-05-22 | 2019-06-28 | Site-specific conjugation of linker drugs to antibodies and resulting ADCS |
US16/457,244 Continuation US11104968B2 (en) | 2014-05-22 | 2019-06-28 | Site-specific conjugation of linker drugs to antibodies and resulting ADCS |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015177360A1 true WO2015177360A1 (en) | 2015-11-26 |
Family
ID=50771151
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2015/061456 WO2015177360A1 (en) | 2014-05-22 | 2015-05-22 | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
Country Status (22)
Country | Link |
---|---|
US (4) | US10407743B2 (en) |
EP (3) | EP3868379A1 (en) |
JP (2) | JP6517240B2 (en) |
KR (1) | KR102419766B1 (en) |
CN (1) | CN106456794B (en) |
AU (2) | AU2015261768B2 (en) |
CA (1) | CA2947238A1 (en) |
CL (1) | CL2016002941A1 (en) |
CY (1) | CY1125232T1 (en) |
DK (1) | DK3151865T3 (en) |
ES (1) | ES2895623T3 (en) |
HR (1) | HRP20211710T1 (en) |
HU (1) | HUE056023T2 (en) |
LT (1) | LT3151865T (en) |
MX (1) | MX2016015176A (en) |
MY (1) | MY183480A (en) |
PL (1) | PL3151865T3 (en) |
PT (1) | PT3151865T (en) |
RU (1) | RU2670157C2 (en) |
SG (2) | SG11201609372UA (en) |
WO (1) | WO2015177360A1 (en) |
ZA (1) | ZA201607109B (en) |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017137628A1 (en) * | 2016-02-12 | 2017-08-17 | Synthon Biopharmaceuticals B.V. | Selective reduction of cysteine-engineered antibodies |
WO2018006785A1 (en) * | 2016-07-05 | 2018-01-11 | 江苏恒瑞医药股份有限公司 | Egfr antibody-drug conjugate and pharmaceutical use thereof |
US9890159B2 (en) | 2014-06-05 | 2018-02-13 | Synthon Biopharmaceuticals B.V. | Process for making duocarmycin prodrugs |
WO2018033749A1 (en) * | 2016-08-18 | 2018-02-22 | Polytherics Limited | Anti-psma antibodies, uses thereof and conjugates thereof |
WO2018069375A1 (en) | 2016-10-11 | 2018-04-19 | Synthon Biopharmaceuticals B.V. | Non-linear self-immolative linkers and conjugates thereof |
WO2018086993A1 (en) | 2016-11-14 | 2018-05-17 | Synthon Biopharmaceuticals B.V. | PROCESS FOR THE PREPARATION OF MONO-PROTECTED alpha,omega-DIAMINO ALKANES |
WO2018113136A1 (en) * | 2015-12-24 | 2018-06-28 | 凯惠科技发展(上海)有限公司 | Tpbg antibody and preparation method therefor and conjugate and application thereof |
WO2018134691A2 (en) | 2017-01-20 | 2018-07-26 | Juno Therapeutics Gmbh | Cell surface conjugates and related cell compositions and methods |
WO2018187791A1 (en) | 2017-04-07 | 2018-10-11 | Juno Therapeutics, Inc | Engineered cells expressing prostate-specific membrane antigen (psma) or a modified form thereof and related methods |
WO2018215427A1 (en) | 2017-05-23 | 2018-11-29 | Synthon Biopharmaceuticals B.V. | Dual conjugation process for preparing antibody-drug conjugates |
WO2018232088A1 (en) * | 2017-06-16 | 2018-12-20 | Eli Lilly And Company | Engineered antibody compounds and conjugates thereof |
WO2019101850A1 (en) | 2017-11-24 | 2019-05-31 | Synthon Biopharmaceuticals B.V. | Improved process for the synthesis of linker-drug vc-seco-duba |
JP2020500540A (en) * | 2016-12-09 | 2020-01-16 | アレクトル エルエルシー | Anti-SIRP-α antibody and method of using the same |
WO2020094561A1 (en) | 2018-11-09 | 2020-05-14 | Synthon Biopharmaceuticals B.V. | Filterable duocarmycin-containing antibody-drug conjugate compositions and related methods |
JP2020514302A (en) * | 2017-01-08 | 2020-05-21 | 浙江昭華生物医薬有限公司 | Anti-5T4 antibody-drug conjugate and use thereof |
US11008400B2 (en) | 2015-11-24 | 2021-05-18 | Byondis B.V. | Anti-5T4 antibodies and antibody-drug conjugates |
WO2021156289A1 (en) | 2020-02-06 | 2021-08-12 | Byondis B.V. | Combination containing a duocarmycin derivative-comprising antibody-drug conjugate and thiosulfate |
WO2022008419A1 (en) | 2020-07-06 | 2022-01-13 | Byondis B.V. | Antifolate linker-drugs and antibody-drug conjugates |
US11319373B2 (en) | 2018-05-25 | 2022-05-03 | Alector Llc | Anti-SIRPA antibodies and methods of use thereof |
WO2022214517A1 (en) | 2021-04-08 | 2022-10-13 | Byondis B.V. | Anti-c-met antibodies and antibody-drug conjugates |
US11485792B2 (en) | 2016-06-06 | 2022-11-01 | Polytherics Limited | Antibodies, uses thereof and conjugates thereof |
WO2023275025A1 (en) | 2021-06-28 | 2023-01-05 | Byondis B.V. | Conjugates comprising phosphoantigens and their use in therapy |
US11634497B2 (en) * | 2017-02-03 | 2023-04-25 | Novartis Ag | Anti-CCR7 antibody drug conjugates |
WO2023126297A1 (en) | 2021-12-30 | 2023-07-06 | Byondis B.V. | Antifolate linker-drugs and antibody-drug conjugates |
CN116761824A (en) * | 2021-01-18 | 2023-09-15 | 上海药明合联生物技术有限公司 | Engineered anti-TROP 2 antibodies and antibody-drug conjugates thereof |
WO2023222580A1 (en) | 2022-05-16 | 2023-11-23 | Byondis B.V. | Novel masked antibodies |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
KR101901555B1 (en) | 2010-04-21 | 2018-09-21 | 신타가 비.브이. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
EP3069735B1 (en) | 2014-01-10 | 2018-03-14 | Synthon Biopharmaceuticals B.V. | Duocarmycin adcs for use in the treatment of bladder cancer |
MY189713A (en) | 2014-01-10 | 2022-02-28 | Univ Yale | Duocarmycin adcs for use in treatment of endometrial cancer |
DK3151865T3 (en) * | 2014-05-22 | 2021-10-25 | Byondis Bv | SITE SPECIFIC CONJUGATION OF LINKS MEDICINE FOR ANTIBODY AND RESULTS ADCS |
EP3411075A1 (en) * | 2016-02-05 | 2018-12-12 | Millennium Pharmaceuticals, Inc. | Gcc-targeted antibody-drug conjugates |
WO2018223958A1 (en) * | 2017-06-06 | 2018-12-13 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition comprising c-met antibody-drug conjugate and use thereof |
WO2018227018A1 (en) * | 2017-06-07 | 2018-12-13 | Silverback Therapeutics, Inc. | Antibody conjugates of immune-modulatory compounds and uses thereof |
SG11202001762RA (en) * | 2017-09-02 | 2020-03-30 | Abbvie Inc | Anti-egfr antibody drug conjugates (adc) and uses thereof |
EP3679066A4 (en) | 2017-09-06 | 2021-06-09 | Airway Therapeutics, Inc. | Methods and compositions for preparing surfactant protein d (sp-d) |
AU2018328113B2 (en) * | 2017-09-06 | 2023-09-07 | Airway Therapeutics, Inc. | Methods, compositions and cells for preparing surfactant protein D (SP-D) |
MX2020005473A (en) * | 2017-11-27 | 2020-08-27 | Purdue Pharma Lp | Humanized antibodies targeting human tissue factor. |
CN108187065B (en) * | 2017-12-29 | 2023-04-28 | 广东众生药业股份有限公司 | anti-5T 4 antibody and maytansine derivative DM4 coupling complex, and preparation method and application thereof |
FI3765525T3 (en) | 2018-03-13 | 2023-10-16 | Zymeworks Bc Inc | Anti-her2 biparatopic antibody-drug conjugates and methods of use |
EP3768714A1 (en) * | 2018-03-23 | 2021-01-27 | Seagen Inc. | Use of antibody drug conjugates comprising tubulin disrupting agents to treat solid tumor |
EP3836950A4 (en) * | 2018-08-16 | 2022-04-06 | Genmab A/S | Anti-tissue factor antibody-drug conjugates and their use in the treatment of cancer |
KR20230051318A (en) * | 2018-08-29 | 2023-04-17 | 레메젠 코, 리미티드 | Use of anti-her2 antibody-drug conjugate in treating urothelial carcinoma |
US20210393791A1 (en) * | 2018-10-31 | 2021-12-23 | Health Research, Inc. | Combination treatment with anti-cd123 antibody drug conjugate and parp inhibitor |
CN117843795A (en) * | 2019-03-11 | 2024-04-09 | 凯惠科技发展(上海)有限公司 | Cysteine-containing antibody, drug conjugate and application thereof |
IL291902A (en) | 2019-10-04 | 2022-06-01 | TAE Life Sciences | Antibody compositions comprising fc mutations and site-specific conjugation properties |
CN114106180B (en) * | 2021-12-13 | 2023-07-28 | 中国药科大学 | Monoclonal antibody and application thereof |
WO2024027795A1 (en) * | 2022-08-04 | 2024-02-08 | 苏州开拓药业股份有限公司 | Antibody-drug conjugate containing myc protein degradation agent bioactive compound, preparation method therefor, and use thereof |
CN116212045A (en) * | 2023-03-31 | 2023-06-06 | 温州医科大学 | Novel antibody drug conjugate targeting MUC1 on cancer cell surface as well as preparation method and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040120958A1 (en) * | 2001-06-01 | 2004-06-24 | Bander Neil H. | Modified antibodies to prostate-specific membrane antigen and uses thereof |
WO2006034488A2 (en) * | 2004-09-23 | 2006-03-30 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
WO2007038658A2 (en) * | 2005-09-26 | 2007-04-05 | Medarex, Inc. | Antibody-drug conjugates and methods of use |
WO2011133039A2 (en) * | 2010-04-21 | 2011-10-27 | Syntarga B.V. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
WO2013093809A1 (en) * | 2011-12-23 | 2013-06-27 | Pfizer Inc. | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6107090A (en) | 1996-05-06 | 2000-08-22 | Cornell Research Foundation, Inc. | Treatment and diagnosis of prostate cancer with antibodies to extracellur PSMA domains |
WO2002098897A2 (en) | 2001-06-01 | 2002-12-12 | Cornell Research Foundation, Inc. | Modified antibodies to prostate-specific membrane antigen and uses thereof |
WO2005084390A2 (en) | 2004-03-02 | 2005-09-15 | Seattle Genetics, Inc. | Partially loaded antibodies and methods of their conjugation |
WO2006031653A2 (en) * | 2004-09-10 | 2006-03-23 | Wyeth | Humanized anti-5t4 antibodies and anti-5t4 antibody / calicheamicin conjugates |
CN103127523A (en) | 2005-06-20 | 2013-06-05 | Psma开发有限公司 | Psma antibody-drug conjugates |
AU2007226696C1 (en) | 2006-03-10 | 2016-02-04 | Wyeth Llc | Anti-5T4 antibodies and uses thereof |
US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
WO2009017394A1 (en) | 2007-08-01 | 2009-02-05 | Syntarga B.V. | Substituted cc-1065 analogs and their conjugates |
CN102317283A (en) | 2008-11-03 | 2012-01-11 | 辛塔佳股份有限公司 | Novel cc-1065 analogs and their conjugates |
CA2782333C (en) * | 2009-12-02 | 2019-06-04 | Imaginab, Inc. | J591 minibodies and cys-diabodies for targeting human prostate specific membrane antigen (psma) and methods for their use |
MX342860B (en) * | 2011-04-01 | 2016-10-14 | Wyeth Llc | Antibody-drug conjugates. |
EP2906250B1 (en) * | 2012-10-12 | 2018-05-30 | ADC Therapeutics SA | Pyrrolobenzodiazepine-anti-psma antibody conjugates |
DK2953976T3 (en) | 2013-02-08 | 2021-06-21 | Novartis Ag | SPECIFIC MODIFICATION PLACES IN ANTIBODIES FOR THE PRODUCTION OF IMMUNE CONJUGATES |
MY189713A (en) | 2014-01-10 | 2022-02-28 | Univ Yale | Duocarmycin adcs for use in treatment of endometrial cancer |
EP3069735B1 (en) | 2014-01-10 | 2018-03-14 | Synthon Biopharmaceuticals B.V. | Duocarmycin adcs for use in the treatment of bladder cancer |
MY177390A (en) | 2014-01-10 | 2020-09-14 | Byondis Bv | Method for purifying cys-linked antibody-drug conjugates |
DK3151865T3 (en) * | 2014-05-22 | 2021-10-25 | Byondis Bv | SITE SPECIFIC CONJUGATION OF LINKS MEDICINE FOR ANTIBODY AND RESULTS ADCS |
EP3152191B1 (en) | 2014-06-05 | 2019-05-15 | Synthon Biopharmaceuticals B.V. | Improved process for making duocarmycin prodrugs |
WO2016046173A1 (en) | 2014-09-22 | 2016-03-31 | Synthon Biopharmaceuticals B.V. | Pan-reactive antibodies to duocarmycins |
-
2015
- 2015-05-22 DK DK15724638.0T patent/DK3151865T3/en active
- 2015-05-22 SG SG11201609372UA patent/SG11201609372UA/en unknown
- 2015-05-22 HU HUE15724638A patent/HUE056023T2/en unknown
- 2015-05-22 CN CN201580026468.0A patent/CN106456794B/en active Active
- 2015-05-22 EP EP21161774.1A patent/EP3868379A1/en active Pending
- 2015-05-22 LT LTEPPCT/EP2015/061456T patent/LT3151865T/en unknown
- 2015-05-22 JP JP2016568847A patent/JP6517240B2/en active Active
- 2015-05-22 HR HRP20211710TT patent/HRP20211710T1/en unknown
- 2015-05-22 EP EP15724638.0A patent/EP3151865B1/en active Active
- 2015-05-22 KR KR1020167036019A patent/KR102419766B1/en active IP Right Grant
- 2015-05-22 MX MX2016015176A patent/MX2016015176A/en active IP Right Grant
- 2015-05-22 RU RU2016150377A patent/RU2670157C2/en active
- 2015-05-22 PT PT157246380T patent/PT3151865T/en unknown
- 2015-05-22 US US15/312,436 patent/US10407743B2/en active Active
- 2015-05-22 ES ES15724638T patent/ES2895623T3/en active Active
- 2015-05-22 CA CA2947238A patent/CA2947238A1/en active Pending
- 2015-05-22 PL PL15724638T patent/PL3151865T3/en unknown
- 2015-05-22 WO PCT/EP2015/061456 patent/WO2015177360A1/en active Application Filing
- 2015-05-22 MY MYPI2016001883A patent/MY183480A/en unknown
- 2015-05-22 SG SG10201913977TA patent/SG10201913977TA/en unknown
- 2015-05-22 AU AU2015261768A patent/AU2015261768B2/en active Active
- 2015-05-22 EP EP19160619.3A patent/EP3539544A1/en active Pending
-
2016
- 2016-10-14 ZA ZA2016/07109A patent/ZA201607109B/en unknown
- 2016-11-18 CL CL2016002941A patent/CL2016002941A1/en unknown
-
2019
- 2019-01-11 JP JP2019003501A patent/JP6900408B2/en active Active
- 2019-06-28 US US16/457,244 patent/US11104968B2/en active Active
- 2019-06-28 US US16/457,186 patent/US11136633B2/en active Active
-
2020
- 2020-01-09 AU AU2020200175A patent/AU2020200175B2/en active Active
-
2021
- 2021-08-23 US US17/409,462 patent/US20210388115A1/en active Pending
- 2021-11-29 CY CY20211101044T patent/CY1125232T1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040120958A1 (en) * | 2001-06-01 | 2004-06-24 | Bander Neil H. | Modified antibodies to prostate-specific membrane antigen and uses thereof |
WO2006034488A2 (en) * | 2004-09-23 | 2006-03-30 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
WO2007038658A2 (en) * | 2005-09-26 | 2007-04-05 | Medarex, Inc. | Antibody-drug conjugates and methods of use |
WO2011133039A2 (en) * | 2010-04-21 | 2011-10-27 | Syntarga B.V. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
WO2013093809A1 (en) * | 2011-12-23 | 2013-06-27 | Pfizer Inc. | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
Non-Patent Citations (1)
Title |
---|
JAGATH R JUNUTULA ET AL: "Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index", NATURE BIOTECHNOLOGY, NATURE PUBLISHING GROUP, UNITED STATES, vol. 26, no. 8, 1 August 2008 (2008-08-01), pages 925 - 932, XP002727747, ISSN: 1546-1696, [retrieved on 20080720], DOI: 10.1038/NBT.1480 * |
Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9890159B2 (en) | 2014-06-05 | 2018-02-13 | Synthon Biopharmaceuticals B.V. | Process for making duocarmycin prodrugs |
US11584801B2 (en) | 2015-11-24 | 2023-02-21 | Byondis B.V. | Anti-5T4 antibodies and antibody-drug conjugates |
US11008400B2 (en) | 2015-11-24 | 2021-05-18 | Byondis B.V. | Anti-5T4 antibodies and antibody-drug conjugates |
WO2018113136A1 (en) * | 2015-12-24 | 2018-06-28 | 凯惠科技发展(上海)有限公司 | Tpbg antibody and preparation method therefor and conjugate and application thereof |
WO2017137628A1 (en) * | 2016-02-12 | 2017-08-17 | Synthon Biopharmaceuticals B.V. | Selective reduction of cysteine-engineered antibodies |
AU2017218615B2 (en) * | 2016-02-12 | 2022-02-10 | Byondis B.V. | Selective reduction of cysteine-engineered antibodies |
US10814009B2 (en) | 2016-02-12 | 2020-10-27 | Byondis B.V. | Selective reduction of cysteine-engineered antibodies |
US11485792B2 (en) | 2016-06-06 | 2022-11-01 | Polytherics Limited | Antibodies, uses thereof and conjugates thereof |
WO2018006785A1 (en) * | 2016-07-05 | 2018-01-11 | 江苏恒瑞医药股份有限公司 | Egfr antibody-drug conjugate and pharmaceutical use thereof |
CN110049999B (en) * | 2016-08-18 | 2023-12-19 | 阿布泽纳(英国)有限公司 | anti-PSMA antibodies, uses thereof, and conjugates thereof |
JP2022084715A (en) * | 2016-08-18 | 2022-06-07 | ポリセリックス・リミテッド | Anti-psma antibodies, uses thereof and conjugates thereof |
JP7039554B2 (en) | 2016-08-18 | 2022-03-22 | ポリセリックス・リミテッド | Anti-PSMA antibody, its use and its conjugate |
JP7486538B2 (en) | 2016-08-18 | 2024-05-17 | ポリセリックス・リミテッド | Anti-PSMA antibodies, uses thereof and conjugates thereof |
WO2018033749A1 (en) * | 2016-08-18 | 2018-02-22 | Polytherics Limited | Anti-psma antibodies, uses thereof and conjugates thereof |
CN110049999A (en) * | 2016-08-18 | 2019-07-23 | 宝力泰锐克斯有限公司 | Anti- PSMA antibody, its purposes and its conjugate |
JP2019535232A (en) * | 2016-08-18 | 2019-12-12 | ポリセリックス・リミテッド | Anti-PSMA antibodies, uses thereof and conjugates thereof |
US11059903B2 (en) | 2016-08-18 | 2021-07-13 | Polytherics Limited | Anti-PSMA antibodies, uses thereof and conjugates thereof |
RU2755899C2 (en) * | 2016-10-11 | 2021-09-22 | Байондис Б.В. | Non-linear self-splitting linkers and their conjugates |
KR20190068589A (en) * | 2016-10-11 | 2019-06-18 | 신톤 바이오파머슈티칼즈 비.브이. | Non-linear self sacrificing linker and conjugate thereof |
KR102574659B1 (en) | 2016-10-11 | 2023-09-04 | 비온디스 비.브이. | Non-linear self-immolative linkers and conjugates thereof |
US11419944B2 (en) | 2016-10-11 | 2022-08-23 | Byondis B.V. | Non-linear self-immolative linkers and conjugates thereof |
WO2018069375A1 (en) | 2016-10-11 | 2018-04-19 | Synthon Biopharmaceuticals B.V. | Non-linear self-immolative linkers and conjugates thereof |
WO2018086993A1 (en) | 2016-11-14 | 2018-05-17 | Synthon Biopharmaceuticals B.V. | PROCESS FOR THE PREPARATION OF MONO-PROTECTED alpha,omega-DIAMINO ALKANES |
US10815194B2 (en) | 2016-11-14 | 2020-10-27 | Byondis B.V. | Process for the preparation of mono-protected α,ω-diamino alkanes |
JP2020500540A (en) * | 2016-12-09 | 2020-01-16 | アレクトル エルエルシー | Anti-SIRP-α antibody and method of using the same |
JP7173971B2 (en) | 2016-12-09 | 2022-11-16 | アレクトル エルエルシー | ANTI-SIRP-α ANTIBODY AND METHOD OF USE THEREOF |
US11779642B2 (en) | 2016-12-09 | 2023-10-10 | Alector Llc | Anti-SIRP-alpha antibodies and methods of use thereof |
JP2020514302A (en) * | 2017-01-08 | 2020-05-21 | 浙江昭華生物医薬有限公司 | Anti-5T4 antibody-drug conjugate and use thereof |
WO2018134691A2 (en) | 2017-01-20 | 2018-07-26 | Juno Therapeutics Gmbh | Cell surface conjugates and related cell compositions and methods |
US11517627B2 (en) | 2017-01-20 | 2022-12-06 | Juno Therapeutics Gmbh | Cell surface conjugates and related cell compositions and methods |
US11634497B2 (en) * | 2017-02-03 | 2023-04-25 | Novartis Ag | Anti-CCR7 antibody drug conjugates |
WO2018187791A1 (en) | 2017-04-07 | 2018-10-11 | Juno Therapeutics, Inc | Engineered cells expressing prostate-specific membrane antigen (psma) or a modified form thereof and related methods |
WO2018215427A1 (en) | 2017-05-23 | 2018-11-29 | Synthon Biopharmaceuticals B.V. | Dual conjugation process for preparing antibody-drug conjugates |
RU2771310C2 (en) * | 2017-05-23 | 2022-04-29 | Байондис Б. В. | Method for double conjugation for obtaining antibody-drug conjugates |
CN110831976A (en) * | 2017-05-23 | 2020-02-21 | 斯索恩生物制药有限公司 | Dual conjugation process for preparing antibody-drug conjugates |
US11696958B2 (en) | 2017-05-23 | 2023-07-11 | Byondis B.V. | Dual conjugation process for preparing antibody-drug conjugates |
WO2018232088A1 (en) * | 2017-06-16 | 2018-12-20 | Eli Lilly And Company | Engineered antibody compounds and conjugates thereof |
WO2019101850A1 (en) | 2017-11-24 | 2019-05-31 | Synthon Biopharmaceuticals B.V. | Improved process for the synthesis of linker-drug vc-seco-duba |
US11633492B2 (en) | 2017-11-24 | 2023-04-25 | Byondis B.V. | Process for the synthesis of linker-drug vc-seco-DUBA |
US11319373B2 (en) | 2018-05-25 | 2022-05-03 | Alector Llc | Anti-SIRPA antibodies and methods of use thereof |
US11976119B2 (en) | 2018-05-25 | 2024-05-07 | Alector Llc | Anti-SIRPa antibodies and methods of use thereof |
WO2020094561A1 (en) | 2018-11-09 | 2020-05-14 | Synthon Biopharmaceuticals B.V. | Filterable duocarmycin-containing antibody-drug conjugate compositions and related methods |
WO2021156289A1 (en) | 2020-02-06 | 2021-08-12 | Byondis B.V. | Combination containing a duocarmycin derivative-comprising antibody-drug conjugate and thiosulfate |
WO2022008419A1 (en) | 2020-07-06 | 2022-01-13 | Byondis B.V. | Antifolate linker-drugs and antibody-drug conjugates |
CN116761824A (en) * | 2021-01-18 | 2023-09-15 | 上海药明合联生物技术有限公司 | Engineered anti-TROP 2 antibodies and antibody-drug conjugates thereof |
WO2022214517A1 (en) | 2021-04-08 | 2022-10-13 | Byondis B.V. | Anti-c-met antibodies and antibody-drug conjugates |
WO2023275025A1 (en) | 2021-06-28 | 2023-01-05 | Byondis B.V. | Conjugates comprising phosphoantigens and their use in therapy |
WO2023126297A1 (en) | 2021-12-30 | 2023-07-06 | Byondis B.V. | Antifolate linker-drugs and antibody-drug conjugates |
WO2023222580A1 (en) | 2022-05-16 | 2023-11-23 | Byondis B.V. | Novel masked antibodies |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11104968B2 (en) | Site-specific conjugation of linker drugs to antibodies and resulting ADCS | |
US11584801B2 (en) | Anti-5T4 antibodies and antibody-drug conjugates | |
US11396543B2 (en) | Biparatopic FR-α antibodies and immunoconjugates | |
KR20240004708A (en) | Antibody-drug conjugate targeting nectin-4 and method and use thereof | |
RU2773536C2 (en) | Site-specific conjugation of linker drugs with antibodies and resulting adc | |
BR112016026744B1 (en) | COMPOUND OF ANTIBODY-DRUG CONJUGATE, AND PHARMACEUTICAL COMPOSITION. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15724638 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2947238 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2015261768 Country of ref document: AU Date of ref document: 20150522 Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2015724638 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015724638 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15312436 Country of ref document: US Ref document number: MX/A/2016/015176 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2016568847 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016026744 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 20167036019 Country of ref document: KR Kind code of ref document: A Ref document number: 2016150377 Country of ref document: RU Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112016026744 Country of ref document: BR Kind code of ref document: A2 Effective date: 20161116 |