CN110352201A - 用于癌症疗法的抗体药物缀合物的皮下施用 - Google Patents
用于癌症疗法的抗体药物缀合物的皮下施用 Download PDFInfo
- Publication number
- CN110352201A CN110352201A CN201880010028.XA CN201880010028A CN110352201A CN 110352201 A CN110352201 A CN 110352201A CN 201880010028 A CN201880010028 A CN 201880010028A CN 110352201 A CN110352201 A CN 110352201A
- Authority
- CN
- China
- Prior art keywords
- antibody
- cancer
- adc
- weeks
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000007920 subcutaneous administration Methods 0.000 title claims abstract description 50
- 229940049595 antibody-drug conjugate Drugs 0.000 title abstract description 191
- 239000000611 antibody drug conjugate Substances 0.000 title abstract description 189
- 238000011275 oncology therapy Methods 0.000 title description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 261
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims abstract description 177
- 201000011510 cancer Diseases 0.000 claims abstract description 123
- 238000000034 method Methods 0.000 claims abstract description 116
- 239000003814 drug Substances 0.000 claims abstract description 115
- 238000011282 treatment Methods 0.000 claims abstract description 86
- 229940079593 drug Drugs 0.000 claims abstract description 83
- 238000002347 injection Methods 0.000 claims abstract description 39
- 239000007924 injection Substances 0.000 claims abstract description 39
- 102100025473 Carcinoembryonic antigen-related cell adhesion molecule 6 Human genes 0.000 claims abstract description 20
- 101000914326 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 6 Proteins 0.000 claims abstract description 20
- 238000002512 chemotherapy Methods 0.000 claims abstract description 13
- 238000001990 intravenous administration Methods 0.000 claims abstract description 12
- 206010059866 Drug resistance Diseases 0.000 claims abstract description 8
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 8
- 108020003175 receptors Proteins 0.000 claims abstract description 8
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims abstract description 7
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 claims abstract description 7
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims abstract description 7
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 claims abstract description 7
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims abstract description 6
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims abstract description 6
- 229940064302 folacin Drugs 0.000 claims abstract description 6
- 235000019152 folic acid Nutrition 0.000 claims abstract description 6
- 239000011724 folic acid Substances 0.000 claims abstract description 6
- 238000001959 radiotherapy Methods 0.000 claims abstract description 6
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims abstract description 5
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims abstract description 5
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims abstract description 4
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims abstract description 4
- 101000961414 Homo sapiens Membrane cofactor protein Proteins 0.000 claims abstract description 3
- 102100039373 Membrane cofactor protein Human genes 0.000 claims abstract description 3
- 102000006354 HLA-DR Antigens Human genes 0.000 claims abstract 3
- 108010058597 HLA-DR Antigens Proteins 0.000 claims abstract 3
- 239000000427 antigen Substances 0.000 claims description 76
- 108091007433 antigens Proteins 0.000 claims description 76
- 102000036639 antigens Human genes 0.000 claims description 76
- -1 CSAp Proteins 0.000 claims description 51
- 229960004768 irinotecan Drugs 0.000 claims description 40
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 37
- 206010009944 Colon cancer Diseases 0.000 claims description 36
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 36
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 230000001225 therapeutic effect Effects 0.000 claims description 34
- 239000003795 chemical substances by application Substances 0.000 claims description 28
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 28
- 238000002560 therapeutic procedure Methods 0.000 claims description 24
- 206010006187 Breast cancer Diseases 0.000 claims description 23
- 208000026310 Breast neoplasm Diseases 0.000 claims description 23
- 208000020816 lung neoplasm Diseases 0.000 claims description 23
- 201000009030 Carcinoma Diseases 0.000 claims description 22
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 21
- 229960000575 trastuzumab Drugs 0.000 claims description 19
- 229940127121 immunoconjugate Drugs 0.000 claims description 18
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 17
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 17
- 229930012538 Paclitaxel Natural products 0.000 claims description 16
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- 229960001592 paclitaxel Drugs 0.000 claims description 16
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 15
- 201000005202 lung cancer Diseases 0.000 claims description 15
- 230000001394 metastastic effect Effects 0.000 claims description 15
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 14
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 13
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 13
- 206010005003 Bladder cancer Diseases 0.000 claims description 12
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 12
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 12
- 206010017758 gastric cancer Diseases 0.000 claims description 12
- 210000004072 lung Anatomy 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 12
- 210000002784 stomach Anatomy 0.000 claims description 12
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 11
- 229910052697 platinum Inorganic materials 0.000 claims description 11
- 201000011549 stomach cancer Diseases 0.000 claims description 11
- 239000003053 toxin Substances 0.000 claims description 11
- 231100000765 toxin Toxicity 0.000 claims description 11
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 11
- 230000003442 weekly effect Effects 0.000 claims description 11
- 206010055114 Colon cancer metastatic Diseases 0.000 claims description 10
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 10
- 229940009456 adriamycin Drugs 0.000 claims description 10
- 208000029742 colonic neoplasm Diseases 0.000 claims description 10
- 229960000485 methotrexate Drugs 0.000 claims description 10
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 10
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 9
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 238000004458 analytical method Methods 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 102000004190 Enzymes Human genes 0.000 claims description 8
- 108090000790 Enzymes Proteins 0.000 claims description 8
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 8
- 229940088598 enzyme Drugs 0.000 claims description 8
- 238000012546 transfer Methods 0.000 claims description 8
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 7
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 7
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 7
- 229960004562 carboplatin Drugs 0.000 claims description 7
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 7
- 229940088013 hycamtin Drugs 0.000 claims description 7
- 102000005962 receptors Human genes 0.000 claims description 7
- 206010052358 Colorectal cancer metastatic Diseases 0.000 claims description 6
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 6
- 150000001454 anthracenes Chemical class 0.000 claims description 6
- 230000000295 complement effect Effects 0.000 claims description 6
- 229940111134 coxibs Drugs 0.000 claims description 6
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 6
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 6
- 229960002949 fluorouracil Drugs 0.000 claims description 6
- JYEFSHLLTQIXIO-SMNQTINBSA-N folfiri regimen Chemical compound FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1.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 JYEFSHLLTQIXIO-SMNQTINBSA-N 0.000 claims description 6
- 229960002584 gefitinib Drugs 0.000 claims description 6
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 6
- 210000003734 kidney Anatomy 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 6
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 6
- 229960003171 plicamycin Drugs 0.000 claims description 6
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 108010033040 Histones Proteins 0.000 claims description 5
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 5
- 102000014429 Insulin-like growth factor Human genes 0.000 claims description 5
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 claims description 5
- UVSVTDVJQAJIFG-VURMDHGXSA-N LFM-A13 Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC(Br)=CC=C1Br UVSVTDVJQAJIFG-VURMDHGXSA-N 0.000 claims description 5
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 5
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 5
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 claims description 5
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 claims description 5
- 150000003851 azoles Chemical class 0.000 claims description 5
- 201000003914 endometrial carcinoma Diseases 0.000 claims description 5
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 5
- 229960001433 erlotinib Drugs 0.000 claims description 5
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 5
- 229960005277 gemcitabine Drugs 0.000 claims description 5
- 230000001939 inductive effect Effects 0.000 claims description 5
- 210000002751 lymph Anatomy 0.000 claims description 5
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 5
- 229940087004 mustargen Drugs 0.000 claims description 5
- CDOOFZZILLRUQH-GDLZYMKVSA-N n-[3-[6-[4-[(2r)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide Chemical compound CN1CCN(C)C(=O)[C@H]1C(C=C1)=CC=C1NC1=NC(C=2C(=C(NC(=O)C=3SC=4CCCCC=4C=3)C=CC=2)C)=CN(C)C1=O CDOOFZZILLRUQH-GDLZYMKVSA-N 0.000 claims description 5
- 229960000572 olaparib Drugs 0.000 claims description 5
- 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 claims description 5
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 claims description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 4
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 claims description 4
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 4
- 102100023635 Alpha-fetoprotein Human genes 0.000 claims description 4
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 4
- 102100037086 Bone marrow stromal antigen 2 Human genes 0.000 claims description 4
- 102100032937 CD40 ligand Human genes 0.000 claims description 4
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 102000013691 Interleukin-17 Human genes 0.000 claims description 4
- 108050003558 Interleukin-17 Proteins 0.000 claims description 4
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 4
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims description 4
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- 108010082093 Placenta Growth Factor Proteins 0.000 claims description 4
- 102000007066 Prostate-Specific Antigen Human genes 0.000 claims description 4
- 108010072866 Prostate-Specific Antigen Proteins 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 208000019065 cervical carcinoma Diseases 0.000 claims description 4
- 208000010932 epithelial neoplasm Diseases 0.000 claims description 4
- 229950009760 epratuzumab Drugs 0.000 claims description 4
- 229960005420 etoposide Drugs 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 201000010536 head and neck cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 229960001507 ibrutinib Drugs 0.000 claims description 4
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 claims description 4
- 229960004891 lapatinib Drugs 0.000 claims description 4
- 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 claims description 4
- 230000002045 lasting effect Effects 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 208000020717 oral cavity carcinoma Diseases 0.000 claims description 4
- 210000001550 testis Anatomy 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 229960004528 vincristine Drugs 0.000 claims description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 4
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 4
- 229960002066 vinorelbine Drugs 0.000 claims description 4
- APOKYMYZOKIMLM-LUMVZWMBSA-N (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-[4-[[(2s,3s,4s,6r)-3-hydroxy-2-methyl-6-[[(1s,3s)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]oxan-4-yl]carbamoyloxymethyl]-2-nitrophenoxy]oxane-2-carboxylic acid Chemical compound N([C@H]1C[C@@H](O[C@@H](C)[C@H]1O)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(=O)OCC(C=C1[N+]([O-])=O)=CC=C1O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O APOKYMYZOKIMLM-LUMVZWMBSA-N 0.000 claims description 3
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 3
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 claims description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 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 claims description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 3
- 108010006654 Bleomycin Proteins 0.000 claims description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
- 102100032912 CD44 antigen Human genes 0.000 claims description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 3
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 3
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims description 3
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 claims description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 3
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 claims description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 3
- 102000002322 Egg Proteins Human genes 0.000 claims description 3
- 108010000912 Egg Proteins Proteins 0.000 claims description 3
- 108010079505 Endostatins Proteins 0.000 claims description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
- 102100038595 Estrogen receptor Human genes 0.000 claims description 3
- 102100037362 Fibronectin Human genes 0.000 claims description 3
- 108010067306 Fibronectins Proteins 0.000 claims description 3
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 claims description 3
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 3
- 208000017604 Hodgkin disease Diseases 0.000 claims description 3
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 claims description 3
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 3
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 3
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 3
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 3
- 108090000467 Interferon-beta Proteins 0.000 claims description 3
- 108010074328 Interferon-gamma Proteins 0.000 claims description 3
- 102000003810 Interleukin-18 Human genes 0.000 claims description 3
- 108010002350 Interleukin-2 Proteins 0.000 claims description 3
- 102000000588 Interleukin-2 Human genes 0.000 claims description 3
- 108090001005 Interleukin-6 Proteins 0.000 claims description 3
- 102000004889 Interleukin-6 Human genes 0.000 claims description 3
- 108090001007 Interleukin-8 Proteins 0.000 claims description 3
- 102000004890 Interleukin-8 Human genes 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 3
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 3
- 239000002145 L01XE14 - Bosutinib Substances 0.000 claims description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 3
- 229930192392 Mitomycin Natural products 0.000 claims description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 3
- 108091034117 Oligonucleotide Proteins 0.000 claims description 3
- 239000012661 PARP inhibitor Substances 0.000 claims description 3
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 3
- 102100040120 Prominin-1 Human genes 0.000 claims description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 3
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 claims description 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 3
- 108010026331 alpha-Fetoproteins Proteins 0.000 claims description 3
- 229950010817 alvocidib Drugs 0.000 claims description 3
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 claims description 3
- 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 claims description 3
- 229960002932 anastrozole Drugs 0.000 claims description 3
- 229940125644 antibody drug Drugs 0.000 claims description 3
- 229960003005 axitinib Drugs 0.000 claims description 3
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims description 3
- 230000003796 beauty Effects 0.000 claims description 3
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 3
- 229960002707 bendamustine Drugs 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 claims description 3
- 201000001528 bladder urothelial carcinoma Diseases 0.000 claims description 3
- 229960001561 bleomycin Drugs 0.000 claims description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 3
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 claims description 3
- 229960003736 bosutinib Drugs 0.000 claims description 3
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 claims description 3
- 229960005539 bryostatin 1 Drugs 0.000 claims description 3
- 229960002092 busulfan Drugs 0.000 claims description 3
- 229960005243 carmustine Drugs 0.000 claims description 3
- 229960004630 chlorambucil Drugs 0.000 claims description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002436 cladribine Drugs 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- 229960003901 dacarbazine Drugs 0.000 claims description 3
- 229960000640 dactinomycin Drugs 0.000 claims description 3
- 229960002448 dasatinib Drugs 0.000 claims description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 claims description 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 3
- 229960003668 docetaxel Drugs 0.000 claims description 3
- 229960001904 epirubicin Drugs 0.000 claims description 3
- 229960001842 estramustine Drugs 0.000 claims description 3
- 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 claims description 3
- 108010038795 estrogen receptors Proteins 0.000 claims description 3
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 claims description 3
- 229960000752 etoposide phosphate Drugs 0.000 claims description 3
- 229960000255 exemestane Drugs 0.000 claims description 3
- 229960000961 floxuridine Drugs 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229960002074 flutamide Drugs 0.000 claims description 3
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 3
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims description 3
- 235000008191 folinic acid Nutrition 0.000 claims description 3
- 239000011672 folinic acid Substances 0.000 claims description 3
- 201000010175 gallbladder cancer Diseases 0.000 claims description 3
- 150000002338 glycosides Chemical class 0.000 claims description 3
- 229960001330 hydroxycarbamide Drugs 0.000 claims description 3
- 229960000908 idarubicin Drugs 0.000 claims description 3
- 229960003445 idelalisib Drugs 0.000 claims description 3
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 claims description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 3
- 229960001101 ifosfamide Drugs 0.000 claims description 3
- 229960002411 imatinib Drugs 0.000 claims description 3
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 3
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 claims description 3
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 3
- 229960004942 lenalidomide Drugs 0.000 claims description 3
- 229960001691 leucovorin Drugs 0.000 claims description 3
- 229960002247 lomustine Drugs 0.000 claims description 3
- 238000012423 maintenance Methods 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 229960004857 mitomycin Drugs 0.000 claims description 3
- 229960000350 mitotane Drugs 0.000 claims 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 claims description 3
- 229960001156 mitoxantrone Drugs 0.000 claims description 3
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 claims description 3
- 229960001346 nilotinib Drugs 0.000 claims description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002340 pentostatin Drugs 0.000 claims description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000624 procarbazine Drugs 0.000 claims description 3
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 claims description 3
- 229940117820 purinethol Drugs 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 3
- 229960004622 raloxifene Drugs 0.000 claims description 3
- 229960003787 sorafenib Drugs 0.000 claims description 3
- 229960001052 streptozocin Drugs 0.000 claims description 3
- 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 claims description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 3
- 229940034785 sutent Drugs 0.000 claims description 3
- 229960004964 temozolomide Drugs 0.000 claims description 3
- 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 claims description 3
- 229960001278 teniposide Drugs 0.000 claims description 3
- 229960003433 thalidomide Drugs 0.000 claims description 3
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960003087 tioguanine Drugs 0.000 claims description 3
- 229960001055 uracil mustard Drugs 0.000 claims description 3
- DENYZIUJOTUUNY-MRXNPFEDSA-N (2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one Chemical compound FC=1C=C2C=3C=4C(CN5[C@@](C4NC3C1)(CCC5)C)=NNC2=O DENYZIUJOTUUNY-MRXNPFEDSA-N 0.000 claims description 2
- SVNJBEMPMKWDCO-KCHLEUMXSA-N (2s)-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate Chemical compound C=1C(=O)C2=CC=CC(C=3C=CC=CC=3)=C2OC=1[N+]1(COC(=O)CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C([O-])=O)CCOCC1 SVNJBEMPMKWDCO-KCHLEUMXSA-N 0.000 claims description 2
- QDITZBLZQQZVEE-YBEGLDIGSA-N (5z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)\C1=C\C1=CC=C(N=CC=C2C=3C=CN=CC=3)C2=C1 QDITZBLZQQZVEE-YBEGLDIGSA-N 0.000 claims description 2
- CTLOSZHDGZLOQE-UHFFFAOYSA-N 14-methoxy-9-[(4-methylpiperazin-1-yl)methyl]-9,19-diazapentacyclo[10.7.0.02,6.07,11.013,18]nonadeca-1(12),2(6),7(11),13(18),14,16-hexaene-8,10-dione Chemical compound O=C1C2=C3C=4C(OC)=CC=CC=4NC3=C3CCCC3=C2C(=O)N1CN1CCN(C)CC1 CTLOSZHDGZLOQE-UHFFFAOYSA-N 0.000 claims description 2
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 claims description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 2
- HDXDQPRPFRKGKZ-INIZCTEOSA-N 3-(3-fluorophenyl)-2-[(1s)-1-(7h-purin-6-ylamino)propyl]chromen-4-one Chemical compound C=1([C@@H](NC=2C=3NC=NC=3N=CN=2)CC)OC2=CC=CC=C2C(=O)C=1C1=CC=CC(F)=C1 HDXDQPRPFRKGKZ-INIZCTEOSA-N 0.000 claims description 2
- UJIAQDJKSXQLIT-UHFFFAOYSA-N 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol Chemical compound C=1C=CC(O)=CC=1C1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC(O)=C1 UJIAQDJKSXQLIT-UHFFFAOYSA-N 0.000 claims description 2
- GSCPDZHWVNUUFI-UHFFFAOYSA-N 3-aminobenzamide Chemical compound NC(=O)C1=CC=CC(N)=C1 GSCPDZHWVNUUFI-UHFFFAOYSA-N 0.000 claims description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 2
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 claims description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 claims description 2
- SEJLPXCPMNSRAM-GOSISDBHSA-N 6-amino-9-[(3r)-1-but-2-ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one Chemical compound C1N(C(=O)C#CC)CC[C@H]1N1C(=O)N(C=2C=CC(OC=3C=CC=CC=3)=CC=2)C2=C(N)N=CN=C21 SEJLPXCPMNSRAM-GOSISDBHSA-N 0.000 claims description 2
- ZTUJNJAKTLHBEX-UHFFFAOYSA-N 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=CC(C=2C(=C(C=CC=2)N2C(C3=C(F)C=C(C=C3C=C2)C2CC2)=O)CO)=CN(C)C1=O ZTUJNJAKTLHBEX-UHFFFAOYSA-N 0.000 claims description 2
- YEAHTLOYHVWAKW-UHFFFAOYSA-N 8-(1-hydroxyethyl)-2-methoxy-3-[(4-methoxyphenyl)methoxy]benzo[c]chromen-6-one Chemical compound C1=CC(OC)=CC=C1COC(C(=C1)OC)=CC2=C1C1=CC=C(C(C)O)C=C1C(=O)O2 YEAHTLOYHVWAKW-UHFFFAOYSA-N 0.000 claims description 2
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 claims description 2
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 claims description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 2
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 claims description 2
- 102100032412 Basigin Human genes 0.000 claims description 2
- 102100036842 C-C motif chemokine 19 Human genes 0.000 claims description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 claims description 2
- 102100036846 C-C motif chemokine 21 Human genes 0.000 claims description 2
- 102100032367 C-C motif chemokine 5 Human genes 0.000 claims description 2
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 claims description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 claims description 2
- 108010029697 CD40 Ligand Proteins 0.000 claims description 2
- 101150013553 CD40 gene Proteins 0.000 claims description 2
- 108010065524 CD52 Antigen Proteins 0.000 claims description 2
- 102100022002 CD59 glycoprotein Human genes 0.000 claims description 2
- 102100025221 CD70 antigen Human genes 0.000 claims description 2
- 102100035793 CD83 antigen Human genes 0.000 claims description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 claims description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 claims description 2
- 102000016550 Complement Factor H Human genes 0.000 claims description 2
- 108010053085 Complement Factor H Proteins 0.000 claims description 2
- 102100025680 Complement decay-accelerating factor Human genes 0.000 claims description 2
- 102100032768 Complement receptor type 2 Human genes 0.000 claims description 2
- 102000001301 EGF receptor Human genes 0.000 claims description 2
- 108060006698 EGF receptor Proteins 0.000 claims description 2
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 2
- 102100038651 Four and a half LIM domains protein 1 Human genes 0.000 claims description 2
- 101710127220 Four and a half LIM domains protein 1 Proteins 0.000 claims description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 claims description 2
- 101710103773 Histone H2B Proteins 0.000 claims description 2
- 102100021639 Histone H2B type 1-K Human genes 0.000 claims description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 2
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 claims description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 2
- 101000713106 Homo sapiens C-C motif chemokine 19 Proteins 0.000 claims description 2
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 claims description 2
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 claims description 2
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 claims description 2
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 claims description 2
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 claims description 2
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 claims description 2
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 claims description 2
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 claims description 2
- 101001046683 Homo sapiens Integrin alpha-L Proteins 0.000 claims description 2
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 claims description 2
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 claims description 2
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 claims description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 2
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 claims description 2
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 2
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 claims description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 2
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims description 2
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 claims description 2
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 2
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 claims description 2
- 101000972284 Homo sapiens Mucin-3A Proteins 0.000 claims description 2
- 101000972286 Homo sapiens Mucin-4 Proteins 0.000 claims description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 2
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 claims description 2
- 206010021143 Hypoxia Diseases 0.000 claims description 2
- GNWHRHGTIBRNSM-UHFFFAOYSA-N IC-87114 Chemical compound CC1=CC=CC=C1N1C(=O)C2=C(C)C=CC=C2N=C1CN1C2=NC=NC(N)=C2N=C1 GNWHRHGTIBRNSM-UHFFFAOYSA-N 0.000 claims description 2
- 102100022339 Integrin alpha-L Human genes 0.000 claims description 2
- 102100025304 Integrin beta-1 Human genes 0.000 claims description 2
- 102100025390 Integrin beta-2 Human genes 0.000 claims description 2
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 claims description 2
- 102100026720 Interferon beta Human genes 0.000 claims description 2
- 102100037850 Interferon gamma Human genes 0.000 claims description 2
- 102000006992 Interferon-alpha Human genes 0.000 claims description 2
- 108010047761 Interferon-alpha Proteins 0.000 claims description 2
- 102100020793 Interleukin-13 receptor subunit alpha-2 Human genes 0.000 claims description 2
- 102000003812 Interleukin-15 Human genes 0.000 claims description 2
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 claims description 2
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 2
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 claims description 2
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 claims description 2
- 108010048043 Macrophage Migration-Inhibitory Factors Proteins 0.000 claims description 2
- 102100037791 Macrophage migration inhibitory factor Human genes 0.000 claims description 2
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 claims description 2
- 102100034256 Mucin-1 Human genes 0.000 claims description 2
- 102100034263 Mucin-2 Human genes 0.000 claims description 2
- 102100022497 Mucin-3A Human genes 0.000 claims description 2
- 102100022693 Mucin-4 Human genes 0.000 claims description 2
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 2
- KUIFHYPNNRVEKZ-VIJRYAKMSA-N O-(N-acetyl-alpha-D-galactosaminyl)-L-threonine Chemical compound OC(=O)[C@@H](N)[C@@H](C)O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O KUIFHYPNNRVEKZ-VIJRYAKMSA-N 0.000 claims description 2
- 108700020796 Oncogene Proteins 0.000 claims description 2
- QIUASFSNWYMDFS-NILGECQDSA-N PX-866 Chemical compound CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2C2=C1[C@@]1(C)[C@@H](COC)OC(=O)\C(=C\N(CC=C)CC=C)C1=C(O)C2=O QIUASFSNWYMDFS-NILGECQDSA-N 0.000 claims description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 102100035721 Syndecan-1 Human genes 0.000 claims description 2
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 2
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 claims description 2
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 claims description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 2
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 claims description 2
- 206010054094 Tumour necrosis Diseases 0.000 claims description 2
- 108091008605 VEGF receptors Proteins 0.000 claims description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 2
- HGVNLRPZOWWDKD-UHFFFAOYSA-N ZSTK-474 Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CCOCC2)=NC=1N1CCOCC1 HGVNLRPZOWWDKD-UHFFFAOYSA-N 0.000 claims description 2
- LJFFDOBFKICLHN-IXWHRVGISA-N [(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[methyl(4-sulfanylpentanoyl)amino]propanoate Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)S)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 LJFFDOBFKICLHN-IXWHRVGISA-N 0.000 claims description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 2
- 229960001686 afatinib Drugs 0.000 claims 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 claims description 2
- 101150061829 bre-3 gene Proteins 0.000 claims description 2
- 229950003628 buparlisib Drugs 0.000 claims description 2
- BWVHYDYUKQEFHG-UHFFFAOYSA-N cep-8983 Chemical compound COC1=CC=CC2=C1C1=C3C(=O)NC(=O)C3=C3CCCC3=C1N2 BWVHYDYUKQEFHG-UHFFFAOYSA-N 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 229950006418 dactolisib Drugs 0.000 claims description 2
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000014103 egg white Nutrition 0.000 claims description 2
- 210000000969 egg white Anatomy 0.000 claims description 2
- 229960000390 fludarabine Drugs 0.000 claims description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 230000007954 hypoxia Effects 0.000 claims description 2
- 238000011221 initial treatment Methods 0.000 claims description 2
- 108040003607 interleukin-13 receptor activity proteins Proteins 0.000 claims description 2
- 102000008616 interleukin-15 receptor activity proteins Human genes 0.000 claims description 2
- 108040002039 interleukin-15 receptor activity proteins Proteins 0.000 claims description 2
- 102000053460 interleukin-17 receptor activity proteins Human genes 0.000 claims description 2
- 108040001304 interleukin-17 receptor activity proteins Proteins 0.000 claims description 2
- 108040006849 interleukin-2 receptor activity proteins Proteins 0.000 claims description 2
- 108040006852 interleukin-4 receptor activity proteins Proteins 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 201000000564 macroglobulinemia Diseases 0.000 claims description 2
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 claims description 2
- 229960005558 mertansine Drugs 0.000 claims description 2
- 238000012737 microarray-based gene expression Methods 0.000 claims description 2
- 238000012243 multiplex automated genomic engineering Methods 0.000 claims description 2
- KXBDTLQSDKGAEB-UHFFFAOYSA-N n-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound C1=CC(OCCOC)=CC=C1NC1=NC=C(F)C(NC=2C=C(NC(=O)C=C)C=CC=2)=N1 KXBDTLQSDKGAEB-UHFFFAOYSA-N 0.000 claims description 2
- GDCJHDUWWAKBIW-UHFFFAOYSA-N n-[4-[4-[2-(difluoromethyl)-4-methoxybenzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]phenyl]-2-(dimethylamino)ethanesulfonamide Chemical compound FC(F)C1=NC=2C(OC)=CC=CC=2N1C(N=1)=NC(N2CCOCC2)=NC=1C1=CC=C(NS(=O)(=O)CCN(C)C)C=C1 GDCJHDUWWAKBIW-UHFFFAOYSA-N 0.000 claims description 2
- JOWXJLIFIIOYMS-UHFFFAOYSA-N n-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide Chemical compound C1=NC(OC)=CC=C1C1=NC(N2CCOCC2)=C(SC(CN(C)C=2N=CC(=CN=2)C(=O)NO)=C2)C2=N1 JOWXJLIFIIOYMS-UHFFFAOYSA-N 0.000 claims description 2
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 claims description 2
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 claims description 2
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 claims description 2
- 229950010632 perifosine Drugs 0.000 claims description 2
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 claims description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 2
- 229960003440 semustine Drugs 0.000 claims description 2
- BLGWHBSBBJNKJO-UHFFFAOYSA-N serabelisib Chemical compound C=1C=C2OC(N)=NC2=CC=1C(=CN12)C=CC1=NC=C2C(=O)N1CCOCC1 BLGWHBSBBJNKJO-UHFFFAOYSA-N 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 229960001196 thiotepa Drugs 0.000 claims description 2
- 210000001635 urinary tract Anatomy 0.000 claims description 2
- 229950011257 veliparib Drugs 0.000 claims description 2
- 108010086097 viridin Proteins 0.000 claims description 2
- YEIGUXGHHKAURB-UHFFFAOYSA-N viridine Natural products O=C1C2=C3CCC(=O)C3=CC=C2C2(C)C(O)C(OC)C(=O)C3=COC1=C23 YEIGUXGHHKAURB-UHFFFAOYSA-N 0.000 claims description 2
- JFCFGYGEYRIEBE-YVLHJLIDSA-N wob38vs2ni Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 JFCFGYGEYRIEBE-YVLHJLIDSA-N 0.000 claims description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 claims description 2
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 claims description 2
- 190000008236 carboplatin Chemical compound 0.000 claims 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 102100036466 Delta-like protein 3 Human genes 0.000 claims 2
- 102100033553 Delta-like protein 4 Human genes 0.000 claims 2
- 101000928513 Homo sapiens Delta-like protein 3 Proteins 0.000 claims 2
- 101000872077 Homo sapiens Delta-like protein 4 Proteins 0.000 claims 2
- 239000012828 PI3K inhibitor Substances 0.000 claims 2
- 102000003666 Placenta Growth Factor Human genes 0.000 claims 2
- 101100499376 Xenopus laevis dll2 gene Proteins 0.000 claims 2
- QQOBRRFOVWGIMD-OJAKKHQRSA-N azaribine Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=N1 QQOBRRFOVWGIMD-OJAKKHQRSA-N 0.000 claims 2
- 229950010054 azaribine Drugs 0.000 claims 2
- 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 claims 2
- 229960001467 bortezomib Drugs 0.000 claims 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims 2
- 229940127276 delta-like ligand 3 Drugs 0.000 claims 2
- 229940043355 kinase inhibitor Drugs 0.000 claims 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims 2
- PXOMSWXCVZBBIV-PQKSKRJKSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4S,6R)-4-amino-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound C[C@H]1[C@@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C2C(=C4C(=C3O)C(=O)C5=C(C4=O)C(=CC=C5)OC)O)(C(=O)CO)O)N)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)C(=O)O)O)O)O PXOMSWXCVZBBIV-PQKSKRJKSA-N 0.000 claims 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 1
- 208000011691 Burkitt lymphomas Diseases 0.000 claims 1
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 claims 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 1
- 102000004127 Cytokines Human genes 0.000 claims 1
- 108090000695 Cytokines Proteins 0.000 claims 1
- 101150029707 ERBB2 gene Proteins 0.000 claims 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims 1
- 101100369992 Homo sapiens TNFSF10 gene Proteins 0.000 claims 1
- 101710123134 Ice-binding protein Proteins 0.000 claims 1
- 101710082837 Ice-structuring protein Proteins 0.000 claims 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 claims 1
- 108090000015 Mesothelin Proteins 0.000 claims 1
- 102000003735 Mesothelin Human genes 0.000 claims 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 1
- 108700012411 TNFSF10 Proteins 0.000 claims 1
- 241000218636 Thuja Species 0.000 claims 1
- 102100024598 Tumor necrosis factor ligand superfamily member 10 Human genes 0.000 claims 1
- 101710107540 Type-2 ice-structuring protein Proteins 0.000 claims 1
- IUEWAGVJRJORLA-HZPDHXFCSA-N bmn-673 Chemical compound CN1N=CN=C1[C@H]1C(NNC(=O)C2=CC(F)=C3)=C2C3=N[C@@H]1C1=CC=C(F)C=C1 IUEWAGVJRJORLA-HZPDHXFCSA-N 0.000 claims 1
- 229960004424 carbon dioxide Drugs 0.000 claims 1
- 235000011089 carbon dioxide Nutrition 0.000 claims 1
- 229940047495 celebrex Drugs 0.000 claims 1
- 229960000590 celecoxib Drugs 0.000 claims 1
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 claims 1
- 201000003444 follicular lymphoma Diseases 0.000 claims 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims 1
- 208000019420 lymphoid neoplasm Diseases 0.000 claims 1
- 229960001924 melphalan Drugs 0.000 claims 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 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 210000005036 nerve Anatomy 0.000 claims 1
- WDXARTMCIRVMAE-UHFFFAOYSA-N quinoline-2-carbonitrile Chemical compound C1=CC=CC2=NC(C#N)=CC=C21 WDXARTMCIRVMAE-UHFFFAOYSA-N 0.000 claims 1
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 claims 1
- 210000002435 tendon Anatomy 0.000 claims 1
- 210000002700 urine Anatomy 0.000 claims 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 claims 1
- YEIGUXGHHKAURB-VAMGGRTRSA-N viridin Chemical compound O=C1C2=C3CCC(=O)C3=CC=C2[C@@]2(C)[C@H](O)[C@H](OC)C(=O)C3=COC1=C23 YEIGUXGHHKAURB-VAMGGRTRSA-N 0.000 claims 1
- 230000001988 toxicity Effects 0.000 abstract description 27
- 231100000419 toxicity Toxicity 0.000 abstract description 27
- 230000008901 benefit Effects 0.000 abstract description 10
- 238000011272 standard treatment Methods 0.000 abstract description 3
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 abstract description 2
- 238000009169 immunotherapy Methods 0.000 abstract description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 108
- 210000004027 cell Anatomy 0.000 description 93
- 239000000562 conjugate Substances 0.000 description 72
- 229950000143 sacituzumab govitecan Drugs 0.000 description 68
- ULRUOUDIQPERIJ-PQURJYPBSA-N sacituzumab govitecan Chemical compound N([C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O ULRUOUDIQPERIJ-PQURJYPBSA-N 0.000 description 68
- 230000000694 effects Effects 0.000 description 54
- 229940027941 immunoglobulin g Drugs 0.000 description 38
- 229940090044 injection Drugs 0.000 description 36
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 36
- 230000021615 conjugation Effects 0.000 description 35
- 241001465754 Metazoa Species 0.000 description 32
- 108090000623 proteins and genes Proteins 0.000 description 31
- 239000000203 mixture Substances 0.000 description 30
- 230000004044 response Effects 0.000 description 29
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 27
- 230000014509 gene expression Effects 0.000 description 26
- 238000005516 engineering process Methods 0.000 description 25
- 210000001519 tissue Anatomy 0.000 description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- 238000012545 processing Methods 0.000 description 24
- 210000002966 serum Anatomy 0.000 description 24
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 22
- 238000011160 research Methods 0.000 description 22
- 210000004408 hybridoma Anatomy 0.000 description 21
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 19
- 239000002202 Polyethylene glycol Substances 0.000 description 18
- 229920001223 polyethylene glycol Polymers 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 17
- CBNAAKBWBABMBY-LQCKLLCCSA-N labetuzumab-sn38 Chemical compound N([C@@H](CCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O CBNAAKBWBABMBY-LQCKLLCCSA-N 0.000 description 17
- 230000008685 targeting Effects 0.000 description 17
- 229940124597 therapeutic agent Drugs 0.000 description 17
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 16
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 229940127089 cytotoxic agent Drugs 0.000 description 16
- 238000000338 in vitro Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- 230000003902 lesion Effects 0.000 description 15
- 210000004185 liver Anatomy 0.000 description 15
- 208000008443 pancreatic carcinoma Diseases 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 241000282693 Cercopithecidae Species 0.000 description 14
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 14
- 150000001540 azides Chemical class 0.000 description 14
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 14
- 230000000259 anti-tumor effect Effects 0.000 description 13
- 239000010949 copper Substances 0.000 description 13
- 230000036541 health Effects 0.000 description 13
- 238000001727 in vivo Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 12
- 230000003013 cytotoxicity Effects 0.000 description 12
- 231100000135 cytotoxicity Toxicity 0.000 description 12
- 230000005847 immunogenicity Effects 0.000 description 12
- 238000001802 infusion Methods 0.000 description 12
- 235000015170 shellfish Nutrition 0.000 description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 11
- 229940127093 camptothecin Drugs 0.000 description 11
- 229910052802 copper Inorganic materials 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 230000004048 modification Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 11
- 210000000496 pancreas Anatomy 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 238000005336 cracking Methods 0.000 description 10
- 208000037821 progressive disease Diseases 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 9
- 239000004472 Lysine Substances 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 9
- CMVRBCDBISKHME-URBSQPMJSA-N N([C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)C=CC1=O Chemical compound N([C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)C=CC1=O CMVRBCDBISKHME-URBSQPMJSA-N 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 230000006907 apoptotic process Effects 0.000 description 9
- 230000000903 blocking effect Effects 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 238000006352 cycloaddition reaction Methods 0.000 description 9
- ZPWOOKQUDFIEIX-UHFFFAOYSA-N cyclooctyne Chemical compound C1CCCC#CCC1 ZPWOOKQUDFIEIX-UHFFFAOYSA-N 0.000 description 9
- 239000002254 cytotoxic agent Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 229960003646 lysine Drugs 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 208000004235 neutropenia Diseases 0.000 description 9
- 229960004641 rituximab Drugs 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 102000003886 Glycoproteins Human genes 0.000 description 8
- 108090000288 Glycoproteins Proteins 0.000 description 8
- 206010027457 Metastases to liver Diseases 0.000 description 8
- 206010041067 Small cell lung cancer Diseases 0.000 description 8
- 150000001345 alkine derivatives Chemical class 0.000 description 8
- 210000001072 colon Anatomy 0.000 description 8
- 125000005647 linker group Chemical group 0.000 description 8
- 201000002528 pancreatic cancer Diseases 0.000 description 8
- 238000002823 phage display Methods 0.000 description 8
- 208000000587 small cell lung carcinoma Diseases 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 7
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 7
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 7
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 7
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- 241001416177 Vicugna pacos Species 0.000 description 7
- SSDFVXUQLUAHIC-DPMVZHECSA-N [4-[[(2S)-6-amino-2-[[(2S)-2-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[[[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethoxy]acetyl]amino]-3-phenylpropanoyl]amino]hexanoyl]amino]phenyl]methyl [(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl] carbonate Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN1N=NC(CNC(=O)C2CCC(CN3C(C=CC3=O)=O)CC2)=C1)C1=CC=CC=C1 SSDFVXUQLUAHIC-DPMVZHECSA-N 0.000 description 7
- 229960003767 alanine Drugs 0.000 description 7
- 235000004279 alanine Nutrition 0.000 description 7
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 7
- 150000001720 carbohydrates Chemical group 0.000 description 7
- 229960005395 cetuximab Drugs 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 230000000875 corresponding effect Effects 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 229960002989 glutamic acid Drugs 0.000 description 7
- 235000013922 glutamic acid Nutrition 0.000 description 7
- 239000004220 glutamic acid Substances 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 229960003136 leucine Drugs 0.000 description 7
- 235000018977 lysine Nutrition 0.000 description 7
- 229930182817 methionine Natural products 0.000 description 7
- 229960004452 methionine Drugs 0.000 description 7
- 238000011580 nude mouse model Methods 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 150000003839 salts Chemical group 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 230000004614 tumor growth Effects 0.000 description 7
- 239000004475 Arginine Substances 0.000 description 6
- 206010012735 Diarrhoea Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
- 206010027458 Metastases to lung Diseases 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
- 229960003121 arginine Drugs 0.000 description 6
- 235000009697 arginine Nutrition 0.000 description 6
- 230000001588 bifunctional effect Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 231100000599 cytotoxic agent Toxicity 0.000 description 6
- 230000001472 cytotoxic effect Effects 0.000 description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000004744 fabric Substances 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 239000002955 immunomodulating agent Substances 0.000 description 6
- 210000000936 intestine Anatomy 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000009115 maintenance therapy Methods 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 210000001685 thyroid gland Anatomy 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- 108090000712 Cathepsin B Proteins 0.000 description 5
- 102000004225 Cathepsin B Human genes 0.000 description 5
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 5
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 5
- 206010066901 Treatment failure Diseases 0.000 description 5
- 244000126014 Valeriana officinalis Species 0.000 description 5
- 235000013832 Valeriana officinalis Nutrition 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 229960005261 aspartic acid Drugs 0.000 description 5
- 235000003704 aspartic acid Nutrition 0.000 description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 5
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 238000001212 derivatisation Methods 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 210000004907 gland Anatomy 0.000 description 5
- 239000010931 gold Substances 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 229940121354 immunomodulator Drugs 0.000 description 5
- 230000002584 immunomodulator Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 229940039472 irinotecan injection Drugs 0.000 description 5
- 208000037841 lung tumor Diseases 0.000 description 5
- 208000037819 metastatic cancer Diseases 0.000 description 5
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 5
- 210000001672 ovary Anatomy 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000002271 resection Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 150000003573 thiols Chemical group 0.000 description 5
- 238000011830 transgenic mouse model Methods 0.000 description 5
- 235000016788 valerian Nutrition 0.000 description 5
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- NRGONRDRXCPMIC-GDKBPFBDSA-N N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 NRGONRDRXCPMIC-GDKBPFBDSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 229960002433 cysteine Drugs 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 229960002449 glycine Drugs 0.000 description 4
- 230000009036 growth inhibition Effects 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 210000005075 mammary gland Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000002534 radiation-sensitizing agent Substances 0.000 description 4
- 208000020615 rectal carcinoma Diseases 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 239000007929 subcutaneous injection Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- URYYVOIYTNXXBN-OWOJBTEDSA-N trans-cyclooctene Chemical compound C1CCC\C=C\CC1 URYYVOIYTNXXBN-OWOJBTEDSA-N 0.000 description 4
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 4
- 210000003932 urinary bladder Anatomy 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 201000004384 Alopecia Diseases 0.000 description 3
- 241000282832 Camelidae Species 0.000 description 3
- 241000282836 Camelus dromedarius Species 0.000 description 3
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 206010015548 Euthanasia Diseases 0.000 description 3
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 3
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 3
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 3
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010028813 Nausea Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000057297 Pepsin A Human genes 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- FADYJNXDPBKVCA-STQMWFEESA-N Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 FADYJNXDPBKVCA-STQMWFEESA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 240000002825 Solanum vestissimum Species 0.000 description 3
- 235000018259 Solanum vestissimum Nutrition 0.000 description 3
- 229940123237 Taxane Drugs 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000002494 anti-cea effect Effects 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 238000011717 athymic nude mouse 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
- 238000004820 blood count Methods 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000012650 click reaction Methods 0.000 description 3
- 238000011284 combination treatment Methods 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000003431 cross linking reagent Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 201000004101 esophageal cancer Diseases 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 229940028334 follicle stimulating hormone Drugs 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 235000004554 glutamine Nutrition 0.000 description 3
- 229960002743 glutamine Drugs 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229960002885 histidine Drugs 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 3
- 229940124302 mTOR inhibitor Drugs 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 3
- 230000008693 nausea Effects 0.000 description 3
- 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 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- 229940111202 pepsin Drugs 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 231100000614 poison Toxicity 0.000 description 3
- 239000002574 poison Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 239000003207 proteasome inhibitor Substances 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 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
- 230000004797 therapeutic response Effects 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 210000001541 thymus gland Anatomy 0.000 description 3
- 231100000167 toxic agent Toxicity 0.000 description 3
- 239000003440 toxic substance Substances 0.000 description 3
- 231100000440 toxicity profile Toxicity 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 241001515965 unidentified phage Species 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- 210000004291 uterus Anatomy 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 102000039968 CEA family Human genes 0.000 description 2
- 108091069214 CEA family Proteins 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 2
- 101710169849 Catalase isozyme A Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 206010058314 Dysplasia Diseases 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
- 206010063045 Effusion Diseases 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- 206010061968 Gastric neoplasm Diseases 0.000 description 2
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 2
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 235000019766 L-Lysine Nutrition 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 241000233855 Orchidaceae Species 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 244000131316 Panax pseudoginseng Species 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 102100035194 Placenta growth factor Human genes 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 108091030071 RNAI Proteins 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 2
- 102000006612 Transducin Human genes 0.000 description 2
- 108010087042 Transducin Proteins 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 101150117115 V gene Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229960000548 alemtuzumab Drugs 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 231100000360 alopecia Toxicity 0.000 description 2
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 2
- LBDSXVIYZYSRII-IGMARMGPSA-N alpha-particle Chemical compound [4He+2] LBDSXVIYZYSRII-IGMARMGPSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940124650 anti-cancer therapies Drugs 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 239000003080 antimitotic agent Substances 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 239000000688 bacterial toxin Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000006287 biotinylation Effects 0.000 description 2
- 238000007413 biotinylation Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- 230000002759 chromosomal effect Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000012321 colectomy Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 210000001671 embryonic stem cell Anatomy 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- 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 2
- 229940031098 ethanolamine Drugs 0.000 description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- PJZDLZXMGBOJRF-CXOZILEQSA-L folfirinox Chemical compound [Pt+4].[O-]C(=O)C([O-])=O.[NH-][C@H]1CCCC[C@@H]1[NH-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1.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 PJZDLZXMGBOJRF-CXOZILEQSA-L 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 239000003667 hormone antagonist Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000002637 immunotoxin Effects 0.000 description 2
- 229940051026 immunotoxin Drugs 0.000 description 2
- 239000002596 immunotoxin Substances 0.000 description 2
- 231100000608 immunotoxin Toxicity 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000000893 inhibin Substances 0.000 description 2
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 description 2
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 2
- 229950002654 lurtotecan Drugs 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 2
- 231100000782 microtubule inhibitor Toxicity 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 229950003734 milatuzumab Drugs 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 2
- 229940055729 papain Drugs 0.000 description 2
- 235000019834 papain Nutrition 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 238000009520 phase I clinical trial Methods 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 229930000184 phytotoxin Natural products 0.000 description 2
- 239000003123 plant toxin Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000007674 radiofrequency ablation Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000003151 transfection method Methods 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 150000004654 triazenes Chemical class 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- 210000002229 urogenital system Anatomy 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- 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 1
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- KQODQNJLJQHFQV-UHFFFAOYSA-N (-)-hemiasterlin Natural products C1=CC=C2C(C(C)(C)C(C(=O)NC(C(=O)N(C)C(C=C(C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-UHFFFAOYSA-N 0.000 description 1
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 1
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- AZMIIVUEOLBHBL-LKTVYLICSA-N (3s,3as,8bs)-7-bromo-3,3a,6,8b-tetramethyl-2,3-dihydro-1h-cyclopenta[b][1]benzofuran Chemical compound BrC1=C(C)C=C2O[C@@]3(C)[C@@H](C)CC[C@@]3(C)C2=C1 AZMIIVUEOLBHBL-LKTVYLICSA-N 0.000 description 1
- GWMHBVLPNWHWGW-CNYBTUBUSA-N (3s,6z)-3-benzyl-6-[[5-(2-methylbut-3-en-2-yl)-1h-imidazol-4-yl]methylidene]piperazine-2,5-dione Chemical compound N1C=NC(\C=C/2C(N[C@@H](CC=3C=CC=CC=3)C(=O)N\2)=O)=C1C(C)(C=C)C GWMHBVLPNWHWGW-CNYBTUBUSA-N 0.000 description 1
- INAUWOVKEZHHDM-PYBHCKQVSA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-(5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl)oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.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(OC(C)C1O)CC1N1CCOCC1 INAUWOVKEZHHDM-PYBHCKQVSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 1
- KQODQNJLJQHFQV-MKWZWQCGSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-(1-methylindol-3-yl)butanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound C1=CC=C2C(C(C)(C)[C@@H](C(=O)N[C@H](C(=O)N(C)[C@H](\C=C(/C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-MKWZWQCGSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- NOGGBVNCVONHHC-RVDMUPIBSA-N (z)-2-(3,4-dimethoxyphenyl)-3-[5-(4-hydroxypiperidin-1-yl)thiophen-2-yl]prop-2-enenitrile Chemical compound C1=C(OC)C(OC)=CC=C1C(\C#N)=C\C1=CC=C(N2CCC(O)CC2)S1 NOGGBVNCVONHHC-RVDMUPIBSA-N 0.000 description 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- ZUQUTHURQVDNKF-WZPXOXCRSA-N 1-[(3S,4R,5S,6R)-3-amino-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]ethanone Chemical compound C(C)(=O)C1(O)[C@@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO ZUQUTHURQVDNKF-WZPXOXCRSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 1
- ONUNVPBLXDDEFR-UHFFFAOYSA-N 2-(4-ethoxypiperazin-1-yl)ethanesulfonic acid Chemical compound CCON1CCN(CCS(O)(=O)=O)CC1 ONUNVPBLXDDEFR-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- PIMQWRZWLQKKBJ-SFHVURJKSA-N 2-[(2S)-1-[3-ethyl-7-[(1-oxido-3-pyridin-1-iumyl)methylamino]-5-pyrazolo[1,5-a]pyrimidinyl]-2-piperidinyl]ethanol Chemical compound C=1C(N2[C@@H](CCCC2)CCO)=NC2=C(CC)C=NN2C=1NCC1=CC=C[N+]([O-])=C1 PIMQWRZWLQKKBJ-SFHVURJKSA-N 0.000 description 1
- DSBSVDCHFMEYBX-FFXKMJQXSA-N 2-[(2r)-2-methylpyrrolidin-2-yl]-1h-benzimidazole-4-carboxamide;dihydrochloride Chemical compound Cl.Cl.N=1C2=C(C(N)=O)C=CC=C2NC=1[C@@]1(C)CCCN1 DSBSVDCHFMEYBX-FFXKMJQXSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QYKHWEFPFAGNEV-UHFFFAOYSA-N 2-[4-[6-chloro-2-[4-(dimethylamino)phenyl]-1h-imidazo[4,5-b]pyridin-7-yl]piperazin-1-yl]-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=CC(N(C)C)=CC=C1C(NC1=NC=C2Cl)=NC1=C2N1CCN(CC(=O)NC=2SC=CN=2)CC1 QYKHWEFPFAGNEV-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- MWYDSXOGIBMAET-UHFFFAOYSA-N 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide Chemical compound NC1=NC=C(C=N1)C(=O)N=C1N=C2C(=C(C=CC2=C2N1CCN2)OCCCN1CCOCC1)OC MWYDSXOGIBMAET-UHFFFAOYSA-N 0.000 description 1
- STNZNCWQNMGRIM-UHFFFAOYSA-N 2-benzyl-1,4,7,10-tetrakis-(4-methylphenyl)sulfonyl-1,4,7,10-tetrazacyclododecane Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CCN(S(=O)(=O)C=2C=CC(C)=CC=2)CC(CC=2C=CC=CC=2)N(S(=O)(=O)C=2C=CC(C)=CC=2)CCN(S(=O)(=O)C=2C=CC(C)=CC=2)CC1 STNZNCWQNMGRIM-UHFFFAOYSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 1
- NUFBIAUZAMHTSP-UHFFFAOYSA-N 3-(n-morpholino)-2-hydroxypropanesulfonic acid Chemical compound OS(=O)(=O)CC(O)CN1CCOCC1 NUFBIAUZAMHTSP-UHFFFAOYSA-N 0.000 description 1
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 1
- LRPGMVPQQLBMNE-UHFFFAOYSA-N 3-furanyl-[4-[5-(2-furanyl)-2-phenyl-7-pyrazolo[1,5-a]pyrimidinyl]-1-piperazinyl]methanone Chemical compound C1=COC=C1C(=O)N(CC1)CCN1C(N1N=2)=CC(C=3OC=CC=3)=NC1=CC=2C1=CC=CC=C1 LRPGMVPQQLBMNE-UHFFFAOYSA-N 0.000 description 1
- QEDXSHCYPROEOK-UHFFFAOYSA-N 3-phosphanylpropanoic acid Chemical class OC(=O)CCP QEDXSHCYPROEOK-UHFFFAOYSA-N 0.000 description 1
- INZOTETZQBPBCE-NYLDSJSYSA-N 3-sialyl lewis Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@H](O)CO)[C@@H]([C@@H](NC(C)=O)C=O)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 INZOTETZQBPBCE-NYLDSJSYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 206010001167 Adenocarcinoma of colon Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- AZMIIVUEOLBHBL-UHFFFAOYSA-N Aplysin Natural products BrC1=C(C)C=C2OC3(C)C(C)CCC3(C)C2=C1 AZMIIVUEOLBHBL-UHFFFAOYSA-N 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- PCGDPFBKONPAFQ-UHFFFAOYSA-N C1#CCCCCCC1.N1C=CC=CC=C1 Chemical compound C1#CCCCCCC1.N1C=CC=CC=C1 PCGDPFBKONPAFQ-UHFFFAOYSA-N 0.000 description 1
- 108700012439 CA9 Proteins 0.000 description 1
- 108010062802 CD66 antigens Proteins 0.000 description 1
- 101150045267 CEA gene Proteins 0.000 description 1
- 101150030298 CEACAM5 gene Proteins 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102100025597 Caspase-4 Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- PGJBQBDNXAZHBP-UHFFFAOYSA-N Dimefox Chemical compound CN(C)P(F)(=O)N(C)C PGJBQBDNXAZHBP-UHFFFAOYSA-N 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 1
- 241000508725 Elymus repens Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 208000002633 Febrile Neutropenia Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 241000989913 Gunnera petaloidea Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010061188 Haematotoxicity Diseases 0.000 description 1
- 206010018873 Haemoconcentration Diseases 0.000 description 1
- 229930195695 Halichondrin Natural products 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101000933112 Homo sapiens Caspase-4 Proteins 0.000 description 1
- 101000685848 Homo sapiens Zinc transporter ZIP6 Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 1
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 102000049772 Interleukin-16 Human genes 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 102000000646 Interleukin-3 Human genes 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102100039897 Interleukin-5 Human genes 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102100021592 Interleukin-7 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 102000000585 Interleukin-9 Human genes 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 102100020880 Kit ligand Human genes 0.000 description 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 102000013013 Member 2 Subfamily G ATP Binding Cassette Transporter Human genes 0.000 description 1
- 108010090306 Member 2 Subfamily G ATP Binding Cassette Transporter Proteins 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000935589 Mus musculus Flavin reductase (NADPH) Proteins 0.000 description 1
- 102100031789 Myeloid-derived growth factor Human genes 0.000 description 1
- DBXNUXBLKRLWFA-UHFFFAOYSA-N N-(2-acetamido)-2-aminoethanesulfonic acid Chemical compound NC(=O)CNCCS(O)(=O)=O DBXNUXBLKRLWFA-UHFFFAOYSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 241000192656 Nostoc Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- 229920000305 Nylon 6,10 Polymers 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000282373 Panthera pardus Species 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 244000221860 Podophyllum emodi Species 0.000 description 1
- 235000010169 Podophyllum emodi Nutrition 0.000 description 1
- 229920001054 Poly(ethylene‐co‐vinyl acetate) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000014128 RANK Ligand Human genes 0.000 description 1
- 108010025832 RANK Ligand Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- SSJQVDUAKDRWTA-CAYKMONMSA-N SN38 glucuronide Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O SSJQVDUAKDRWTA-CAYKMONMSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- XJTXBUKLGQCZHC-UHFFFAOYSA-N Steganacin Natural products C1=C2C=3C(OC)=C(OC)C(OC)=CC=3CC3C(=O)OCC3C(OC(C)=O)C2=CC2=C1OCO2 XJTXBUKLGQCZHC-UHFFFAOYSA-N 0.000 description 1
- 108010039445 Stem Cell Factor Proteins 0.000 description 1
- 101100313471 Streptomyces sp getA gene Proteins 0.000 description 1
- 241000544632 Suberites Species 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 102100038126 Tenascin Human genes 0.000 description 1
- 108010008125 Tenascin Proteins 0.000 description 1
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- 241001052560 Thallis Species 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 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 1
- 102100029152 UDP-glucuronosyltransferase 1A1 Human genes 0.000 description 1
- 101710205316 UDP-glucuronosyltransferase 1A1 Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102100023144 Zinc transporter ZIP6 Human genes 0.000 description 1
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- PPZYBFUYKJPWBY-UHFFFAOYSA-N acetylene azide Chemical compound C#C.[N-]=[N+]=[N-] PPZYBFUYKJPWBY-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940125666 actinium-225 Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 108010035879 albumin-bilirubin complex Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 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 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 1
- 229960004991 artesunate Drugs 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
- NJAPCAIWQRPQPY-UHFFFAOYSA-N benzyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1 NJAPCAIWQRPQPY-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 239000006177 biological buffer Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 229960000419 catumaxomab Drugs 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000023402 cell communication Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- HWGQMRYQVZSGDQ-HZPDHXFCSA-N chembl3137320 Chemical compound CN1N=CN=C1[C@H]([C@H](N1)C=2C=CC(F)=CC=2)C2=NNC(=O)C3=C2C1=CC(F)=C3 HWGQMRYQVZSGDQ-HZPDHXFCSA-N 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 201000010918 connective tissue cancer Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000037029 cross reaction Effects 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229950009859 dinaciclib Drugs 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229960001776 edrecolomab Drugs 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 229960003649 eribulin Drugs 0.000 description 1
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JEFPWOBULVSOTM-PPHPATTJSA-N ethyl n-[(2s)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamate;2-hydroxyethanesulfonic acid Chemical compound OCCS(O)(=O)=O.C=1([C@H](C)NC=2C=C(N=C(N)C=2N=1)NC(=O)OCC)C1=CC=CC=C1 JEFPWOBULVSOTM-PPHPATTJSA-N 0.000 description 1
- 125000003916 ethylene diamine group Chemical group 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000001400 expression cloning Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229930183060 fumitremorgin Natural products 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000011990 functional testing Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 238000013110 gastrectomy Methods 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 238000012637 gene transfection Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 230000023611 glucuronidation Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 108010057806 hemiasterlin Proteins 0.000 description 1
- 229930187626 hemiasterlin Natural products 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000005161 hepatic lobe Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 210000001624 hip Anatomy 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011337 individualized treatment Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 108040002014 interleukin-18 receptor activity proteins Proteins 0.000 description 1
- 102000008625 interleukin-18 receptor activity proteins Human genes 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 108010090785 inulinase Proteins 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000002684 laminectomy Methods 0.000 description 1
- 210000001821 langerhans cell Anatomy 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 108010045758 lysosomal proteins Proteins 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 210000001006 meconium Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 231100001224 moderate toxicity Toxicity 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- BOQOXLAQTDFJKU-UHFFFAOYSA-N morpholine-4-carbonitrile Chemical compound N#CN1CCOCC1 BOQOXLAQTDFJKU-UHFFFAOYSA-N 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- WKEBQZAUNGERGA-UHFFFAOYSA-N n-[2-[[4-[2-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]phenyl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=CC=CC=C1C(=O)NC(C=C1)=CC=C1CCN1CC2=CC(OC)=C(OC)C=C2CC1 WKEBQZAUNGERGA-UHFFFAOYSA-N 0.000 description 1
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical compound CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000012753 partial hepatectomy Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 235000021110 pickles Nutrition 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 108700028325 pokeweed antiviral Proteins 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 208000014081 polyp of colon Diseases 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 235000020004 porter Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229940051022 radioimmunoconjugate Drugs 0.000 description 1
- 229960005562 radium-223 Drugs 0.000 description 1
- 108010061338 ranpirnase Proteins 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 208000015608 reproductive system cancer Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- FCCGJTKEKXUBFZ-UHFFFAOYSA-N rucaparib phosphate Chemical compound OP(O)(O)=O.C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 FCCGJTKEKXUBFZ-UHFFFAOYSA-N 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000004999 sex organ Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 229960003466 sibutramine hydrochloride Drugs 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- XJTXBUKLGQCZHC-GCKMJXCFSA-N steganacin Chemical compound C1=C2C=3C(OC)=C(OC)C(OC)=CC=3C[C@@H]3C(=O)OC[C@H]3[C@H](OC(C)=O)C2=CC2=C1OCO2 XJTXBUKLGQCZHC-GCKMJXCFSA-N 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 230000004206 stomach function Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000001646 thyrotropic effect Effects 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 230000009258 tissue cross reactivity Effects 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000003741 urothelium Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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
- A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6853—Carcino-embryonic antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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
- A61K47/6857—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 lung cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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
- A61K47/6859—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 liver or pancreas cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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
- A61K47/6863—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 stomach or intestines cancer cell
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- C07K16/18—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
- C07K16/3007—Carcino-embryonic Antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及使用皮下施用抗体‑药物缀合物(ADC)的癌症治疗方法。优选地,所述ADC包含结合至Trop‑2、CEACAM5、CEACAM6、CD20、CD22、CD30、CD46、CD74、Her‑2、叶酸受体或HLA‑DR的抗体。更优选地,所述药物是SN‑38。皮下施用至少与静脉内施用相同ADC一样有效。出人意料地,能够使用皮下施用而不会在注射部位引起难以控制的不良局部毒性。皮下施用的优点是需要较低频率的施用、显著减少静脉内施用所需的时间,并降低在静脉内施用的情况下观察到的全身毒性水平。当以指定的剂量和时间表施用时,所述ADC可减小实体肿瘤的大小、减少或消除转移并且有效治疗对标准疗法,如放射疗法、化学疗法或免疫疗法具有耐药性的癌症。
Description
相关申请
本申请根据美国法典第35篇第119条(e)款要求2017年4月3日提交的美国临时专利申请62/480,789的权益,所述临时申请的文本以引用的方式整体并入本文。
序列表
本申请含有已通过EFS网以ASCII格式提交,并且据此以引用的方式整体并入本文的序列表。所述ASCII副本创建于2018年3月7日,名称为IMM371WO1_SL.txt并且大小为13,316字节。
技术领域
本发明涉及皮下施用抗体-药物缀合物(ADC),所述抗体-药物缀合物包含与抗体或抗原结合抗体片段缀合的一个或多个细胞毒性药物部分。优选地,所述抗体是优选地与SN-38缀合的抗Trop-2、抗CEACAM5、抗CD20、抗CD74、抗CD22、抗CD30、抗CD46或抗HLA-DR抗体。更优选地,可使用诸如CL2A的接头将药物附接至所述抗体或抗体片段。然而,可使用其他接头、某些其他已知的细胞毒性药物以及将药物缀合至抗体的其他已知的方法。最优选地,所述抗体或其抗原结合片段结合至人抗原。所述抗体或片段可与每个抗体或片段,药物部分或药物-接头部分的1-12、1-6、1-5、6-8或7-8个拷贝附接。所述ADC用于治疗实体癌,如乳腺癌、卵巢癌、子宫颈癌、子宫内膜癌、肺癌、前列腺癌、结肠癌、胃癌、食道癌、膀胱癌、肾癌、胰腺癌、甲状腺癌、上皮癌、尿路上皮癌和头颈癌;或液体瘤,如淋巴瘤(霍奇金和非霍奇金)、白血病(淋巴性和骨髓性)和多发性骨髓瘤。ADC可特别用于治疗对一种或多种标准抗癌疗法具有耐药性的癌症,如三阴性乳腺癌、转移性胰腺癌、转移性胃肠癌、转移性尿路上皮癌、转移性结肠直肠癌、急性骨髓性白血病、急性淋巴性白血病或多发性骨髓瘤。ADC可单独使用或与一种或多种选自由以下组成的组的治疗方式一起作为组合疗法使用:外科手术、放射疗法、化学疗法、免疫调节剂、细胞因子、化学治疗剂、促凋亡剂、抗血管生成剂、细胞毒性剂、药物、毒素、放射性核素、RNAi、siRNA、第二抗体或抗体片段以及免疫缀合物。在优选的实施方案中,ADC与其他治疗方式的组合表现出协同作用,并且比单独ADC或其他治疗方式或单独施用的ADC和其他治疗方式的作用果的总和更有效地诱导癌细胞死亡。出人意料地,ADC的皮下施用不会在施用部位产生不可接受的局部毒性,这是选择在ADC中连接的适当药物的基础,因为许多在一定浓度以上具有引起局部组织坏死的毒性概况。如连接在剂中,使用SN-38作为ADC中的选择的药物,沙西妥珠单抗戈维替康、拉贝珠单抗(抗CEACAM5)戈维替康、抗CEACAM6/SN-38、依帕珠单抗(抗CD22)戈维替康、抗CD74/SN-38和抗CD20/SN-38由于缺乏在注射部位引起的局部毒性而是优选的。
相关技术
多年来,特定靶向药物治疗领域的科学家一直致力于使用单克隆抗体(MAb)将毒性剂特异性递送至人癌症。肿瘤相关MAb和合适毒性剂的缀合物已被开发出,但已经在人癌症的治疗中获得各种成功。毒性剂最常见的是化学治疗药物,但是发射粒子的放射性核素或细菌或植物毒素也与MAb缀合,特别是用于治疗癌症(Sharkey和Goldenberg,CA CancerJ Clin.2006年7月-8月;56(4):226-243),并且最近,放射免疫缀合物用于某些感染性疾病的临床前治疗(Dadachova和Casadevall,Q J Nucl Med Mol Imaging 2006;50(3):193-204)。
使用MAb-化学治疗药物缀合物的优点是(a)化学治疗药物本身在结构上明确地定义;(b)使用非常明确定义的缀合化学将化学治疗药物连接至MAb蛋白,通常在远离MAb的抗原结合区的特定位点;(c)MAb-化学治疗药物缀合物可比涉及MAb和细菌或植物毒素的化学缀合物更可重复地制备并且通常具有更低的免疫原性,并且因此更易于商业开发和监管批准;(d)MAb-化学治疗药物缀合物在系统上比放射性核素MAb缀合物的毒性低几个数量级,特别是对辐射敏感的骨髓而言。
目前,极少数细胞毒性药物皮下施用以用于癌症治疗(例如Leveque等人,2014,Anticancer Res 34:1579-86)。这是因为大多数已知的抗癌细胞毒性剂是刺激剂和/或起疱剂,已知其在外渗后在皮下或真皮下组织中引起局部损伤(Leveque等人,2014)。虽然与抗体缀合可能降低局部毒性,但单克隆抗体曲妥珠单抗和阿仑单抗的低吸收率也可能表明难以皮下施用抗体-药物缀合物(ADC)(Leveque等人,2014)。另一个困难是需要维持皮下施用的低注射体积,这进而需要高浓度的ADC用于皮下使用(Leveque等人,2014)。
对于更有效的制备和施用抗体-药物缀合物,如抗体-SN-38缀合物的方法存在需要。优选地,所述方法包括优化的给药和皮下施用方案,所述给药和皮下施用方案使用于人患者的治疗用途的抗体-药物缀合物的功效最大化并使毒性最小化。
发明内容
在各种实施方案中,本发明涉及用抗体-药物缀合物(ADC)治疗癌症,优选地通过皮下施用。所述ADC可单独使用或作为与一种或多种其他治疗方式的组合疗法使用,所述其他治疗方式如外科手术、放射疗法、化学疗法、免疫调节剂、细胞因子、化学治疗剂、促凋亡剂、抗血管生成剂、细胞毒性剂、药物、毒素、放射性核素、RNAi、siRNA、第二抗体或抗体片段或免疫缀合物。在优选的实施方案中,所述ADC可用于治疗标准疗法无效的癌症,如转移性胰腺癌、转移性结肠直肠癌或三阴性乳腺癌。更优选地,ADC与其他治疗方式的组合比单独使用或个别治疗的作用的总和更有效。
在具体优选实施方案中,抗Trop-2抗体可以是人源化RS7抗体(参见例如,美国专利号7,238,785,其附图和实施例部分以引用的方式并入本文),其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1);CDR2(SASYRYT,SEQ ID NO:2);和CDR3(QQHYITPLT,SEQ IDNO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。然而,如下文所讨论,其他抗Trop-2抗体是已知的并且可用于主题ADC中。许多用于癌症治疗的细胞毒性药物是本领域熟知的,并且任何这种已知的药物均可缀合至目标抗体,只要它不会引起局部部位的严重毒性、刺激或坏死。在更优选的实施方案中,与抗体缀合的药物是喜树碱或蒽环霉素,最优选SN-38或具有纳摩尔毒性的另一种药物(参见,例如,美国专利号9,028,833,其附图和实施例部分以引用的方式并入本文)。药物缀合的抗Trop-2抗体可用于治疗任何Trop-2阳性癌症,包括但不限于口腔癌、食道癌、胃肠道癌、肺道癌、肺癌、胃癌、结肠癌、直肠癌、乳腺癌、卵巢癌、前列腺癌、子宫癌、子宫内膜癌、宫颈癌、膀胱癌、胰腺癌、骨癌、脑癌、结缔组织癌、甲状腺癌、肝癌、胆囊癌、膀胱(尿路上皮)癌、肾癌、皮肤癌、中枢神经系统癌、尿路上皮癌以及睾丸癌。
在另一个优选的实施方案中,包含抗CEACAM5抗体(例如,hMN-14、拉贝珠单抗(labretuzumab))和/或抗CEACAM6抗体(例如,hMN-3或hMN-15)的治疗性缀合物可用于治疗表达CEACAM5和/或CEACAM6的各种癌症中的任一种,如美国专利号7,541,440;7,951,369;5,874,540;6,676,924和8,267,865中所公开;所述专利各自的实施例部分以引用的方式并入本文)。可使用抗CEACAM5、抗CEACAM6或两者的组合治疗的实体瘤包括但不限于乳腺癌、肺癌、胰腺癌、食道癌、甲状腺髓样癌、卵巢癌、结肠癌、直肠癌、膀胱癌、口腔癌和胃癌。大多数癌,包括胃肠癌、呼吸道癌、泌尿生殖系统癌和乳腺癌表达CEACAM5并且可用主题ADC治疗。hMN-14抗体是包含轻链可变区CDR序列CDR1(KASQDVGTSVA;SEQ ID NO:9)、CDR2(WTSTRHT;SEQ ID NO:10)和CDR3(QQYSLYRS;SEQ ID NO:11)以及重链可变区CDR序列CDR1(TYWMS;SEQ ID NO:12)、CDR2(EIHPDSSTINYAPSLKD;SEQ ID NO:13)和CDR3(LYFGFPWFAY;SEQ ID NO:14)的人源化抗体。hMN-3抗体是包含轻链可变区CDR序列CDR1(RSSQSIVHSNGNTYLE,SEQ ID NO:15)、CDR2(KVSNRFS,SEQ ID NO:16)和CDR3(FQGSHVPPT,SEQ ID NO:17)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:18)、CDR2(WINTYTGEPTYADDFKG,SEQ ID NO:19)和CDR3(KGWMDFNSSLDY,SEQ ID NO:20)的人源化抗体。hMN-15抗体是包含轻链可变区CDR序列SASSRVSYIH(SEQ ID NO:21)、GTSTLAS(SEQ ID NO:22)和QQWSYNPPT(SEQID NO:23)以及重链可变区CDR序列DYYMS(SEQ ID NO:24)、FIANKANGHTTDYSPSVKG(SEQ IDNO:25)和DMGIRWNFDV(SEQ ID NO:26)的人源化抗体。
在另一个优选的实施方案中,包含抗HLA-DR MAb(如hL243)的治疗性缀合物可用于治疗淋巴瘤、白血病、皮肤癌、食道癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、卵巢癌、膀胱癌、子宫内膜癌、宫颈癌、睾丸癌、肾癌、肝癌、黑素瘤或其他产生HLA-DR的肿瘤,如美国专利号7,612,180中所公开,其实施例部分以引用的方式并入本文。hL243抗体是包含重链CDR序列CDR1(NYGMN,SEQ ID NO:27)、CDR2(WINTYTREPTYADDFKG,SEQ ID NO:28)和CDR3(DITAVVPTGFDY,SEQ ID NO:29)以及轻链CDR序列CDR1(RASENIYSNLA,SEQ ID NO:30)、CDR2(AASNLAD,SEQ ID NO:31)和CDR3(QHFWTTPWA,SEQ ID NO:32)的人源化抗体。
所述抗体部分可以是单克隆抗体、抗原结合抗体片段、双特异性或其他多价抗体或其他基于抗体的分子。所述抗体可具有各种同种型,优选地人IgG1、IgG2、IgG3或IgG4,更优选地包含人IgG1铰链和恒定区序列。所述抗体或其片段可以是嵌合、人源化或人抗体,以及其变型,如半IgG4抗体(被称为“单一抗体”),如由van der Neut Kolfschoten等人(Science 2007;317:1554-1557)所描述。更优选地,所述抗体或其片段可被设计或选择为包含属于特定同种异型的人恒定区序列,其可在所述ADC施用至人受试者时导致减小的免疫原性。用于施用的优选同种异型包括非G1m1同种异型(nG1m1),如G1m3、G1m3,1、G1m3,2或G1m3,1,2。更优选地,所述同种异型选自由以下组成的组:nG1m1、G1m3、nG1m1,2和Km3同种异型(Jefferies和Lefranc,2009,mAbs 1(4):1-7)。
待缀合至所述抗体或抗体片段的药物可选自由以下组成的组:蒽环类药物、喜树碱、微管蛋白抑制剂、美登木素生物碱(maytansinoid)、刺孢霉素、奥瑞斯他汀、氮芥、乙烯亚胺衍生物、烷基磺酸酯、亚硝基脲、三氮烯、叶酸类似物、紫杉烷、COX-2抑制剂、嘧啶类似物、嘌呤类似物、抗生素、酶抑制剂、表鬼臼毒素、铂配位络合物、长春花生物碱、取代的脲、甲基肼衍生物、肾上腺皮质抑制剂、激素拮抗剂、抗代谢物、烷基化剂、抗有丝分裂剂、抗血管生成剂、酪氨酸激酶抑制剂、mTOR抑制剂、热休克蛋白(HSP90)抑制剂、蛋白酶体抑制剂、HDAC抑制剂、促凋亡剂,只要所述药物具有纳摩尔范围的细胞毒性。
有用的具体药物可选自由以下组成的组:5-氟尿嘧啶、阿法替尼、阿普利啶、阿扎立平、阿那曲唑、蒽环类药物、阿西替尼、AVL-101、AVL-291、苯达莫司汀、博来霉素、硼替佐米、博舒替尼、苔藓虫素-1、白消安、刺孢霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、塞来昔布、苯丁酸氮芥、顺铂、COX-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、喜树碱、克唑替尼、环磷酰胺、阿糖胞苷、达卡巴嗪、达沙替尼、地尼西宝(dinaciclib)、多西他赛、更生霉素、柔红霉素、DM1、DM3、DM4、阿霉素、2-吡咯啉子基阿霉素(2-PDox)、2-PDox的前药形式(pro-2-PDox)、氰基-吗啉代阿霉素、阿霉素葡糖苷酸、内皮抑素、表柔比星葡糖苷酸、埃罗替尼、雌莫司汀、表鬼臼毒素、埃罗替尼、恩替诺特、雌激素受体结合剂、依托泊苷(VP16)、依托泊苷葡糖苷酸、磷酸依托泊苷、依西美坦、芬戈莫德、氟尿苷(FUdR)、3’,5’-O-二油酰基-FudR(FUdR-dO)、氟达拉滨、氟他胺、法尼基-蛋白转移酶抑制剂、夫拉平度、福他替尼、吉尼替彼、GDC-0834、GS-1101、吉非替尼、吉西他滨、羟基脲、依鲁替尼、伊达比星、伊德利塞、异环磷酰胺、伊马替尼、拉帕替尼、来那度胺、亚叶酸、LFM-A13、洛莫司汀、氮芥、美法仑、巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、光辉霉素、丝裂霉素、米托坦、单甲基奥瑞斯他汀F(MMAF)、单甲基奥瑞斯他汀D(MMAD)、单甲基奥瑞斯他汀E(MMAE)、诺维本、来那替尼、尼洛替尼、亚硝基脲、奥拉帕尼、普卡霉素、丙卡巴肼、紫杉醇、PCI-32765、喷司他丁、PSI-341、雷洛昔芬、司莫司汀、SN-38、索拉非尼、链脲霉素、SU11248、舒尼替尼、他莫昔芬、替莫唑胺、反铂、沙利度胺、硫鸟嘌呤、塞替哌、替尼泊苷、托泊替康、乌拉莫司汀、瓦他拉尼、长春瑞滨、长春碱、长春新碱、长春花生物碱以及ZD1839。优选地,所述药物是SN-38。
在优选的实施方案中,所述治疗剂是ABCG2抑制剂,如烟曲酶毒素(fumitremorgin)C、Kol43、GF120918、YHO-13351、姜黄素、CID44640177、CID1434724、CID46245505、CCT129202、青蒿琥酯、ST1481、二氢吡啶、富马酸多非喹达(dofequjidarfumarate)、吉非替尼、甲磺酸伊马替尼、拉帕替尼、WK-X-34或YHO-13177。
在替代优选的实施方案中,与DNA断裂ADC(如SN-38抗体缀合物)组合使用的治疗剂是PARP抑制剂,如奥拉帕尼、他拉唑帕尼(BMN-673)、鲁卡帕尼、维利帕尼、CEP 9722、MK4827、BGB-290、ABT-888、AG014699、BSI-201、CEP-8983或3-氨基苯甲酰胺。
在另一个替代方案中,所述药物可以是酪氨酸激酶抑制剂,如依鲁替尼(PCI-32765)、PCI-45292、CC-292(AVL-292)、ONO-4059、GDC-0834、LFM-A13或RN486;或PI3K抑制剂,如伊德利塞、渥曼青霉素、去甲氧基绿胶霉素、哌立福辛、PX-866、IPI-145(度维利塞)、BAY 80-6946、BEZ235、RP6530、TGR1202、SF1126、INK1117、GDC-0941、BKM120、XL147、XL765、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、PI-103、GNE477、CUDC-907、AEZS-136或LY294002。
或者,药物可以是本领域中已知的微管抑制剂,如长春花生物碱(例如长春新碱、长春碱)、紫杉烷(例如紫杉醇)、美登木素生物碱(例如美登素)和奥瑞斯他汀。其他已知的微管抑制剂包括秋水仙胺、诺考达唑、埃博霉素、多西他赛、圆皮海绵内酯(discodermolide)、秋水仙碱、康普瑞汀、鬼臼毒素、CI-980、苯基阿夕斯丁、五加前胡素、卡拉新、2-甲氧基雌二醇、E7010、甲氧基苯磺酰胺、长春瑞滨、长春氟宁、长春地辛、尾海兔素、海绵抑制素、根霉素、泰斯多汀、软海绵素、哈米特林(hemiasterlin)、念珠藻素52、MMAE以及甲磺酸艾日布林(参见例如,Dumontet&Jordan,2010,Nat Rev Drug Discov 9:790-803)。
主题ADC的优选最佳剂量可包括介于4mg/kg与18mg/kg之间的剂量,优选每周一次、每周两次或每隔一周给与。最佳给药方案可包括以下治疗周期:治疗连续两周、随后停药一周、两周、三周或四周,或交替的治疗周和停药周,或治疗一周、随后停药两周、三周或四周,或治疗三周、随后停药一周、两周、三周或四周,或治疗四周、随后停药一周、两周、三周或四周,或治疗五周、随后停药一周、两周、三周、四周或五周,或每两周一次、每三周一次或每月一次施用。治疗可延长任何数量的周期,优选至少2、至少4、至少6、至少8、至少10、至少12、至少14或至少16个周期。使用的示例性剂量可包括1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、11mg/kg、12mg/kg、13mg/kg、14mg/kg、15mg/kg、16mg/kg、17mg/kg、18mg/kg、19mg/kg、20mg/kg、22mg/kg和24mg/kg。优选的剂量是4、6、8、9、10、12、14、16或18mg/kg。更优选的剂量是6-12、6-8、7-8、8-10、10-12或8-12mg/ml。普通技术人员将认识到,在选择ADC的最佳剂量时,可考虑多种因素,如年龄、一般健康状况、特定器官功能或重量以及先前疗法对特定器官系统(例如,骨髓)的影响,并且可在治疗过程期间增加或减少施用的剂量和/或频率。可根据需要重复剂量,在少至4至8个剂量后观察到肿瘤缩小的迹象。本文公开的优化的施用剂量和时间表在人受试者中显示出出人意料的优异功效和降低的毒性,这可能是从动物模型研究无法预测的。出人意外地,优异的功效允许治疗先前被发现对一种或多种标准抗癌疗法具有耐药性的肿瘤。更出人意料地,已经发现所述治疗在先前对喜树碱具有耐药性的肿瘤中是有效的,如伊立替康(SN-38的母体化合物)。
所述ADC用于治疗癌症,如乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、肺癌、前列腺癌、结肠癌、胃癌、食道癌、膀胱癌、肾癌、胰腺癌、甲状腺癌、上皮癌或头颈癌。所述ADC可特别用于治疗对一种或多种标准抗癌疗法具有耐药性的癌症,如转移性结肠癌、三阴性乳腺癌、HER+、ER+、黄体酮+乳腺癌、转移性非小细胞肺癌(NSCLC)、转移性胰腺癌、转移性肾细胞癌、转移性胃癌、转移性前列腺癌或转移性小细胞肺癌。
最出人意料地,有效剂量的ADC可通过皮下施用来递送,而不会诱导不可接受的局部不良反应。基于先前证明的皮下施用抗体和/或抗体-药物缀合物的困难,可能不能预测此结果(参见例如,Leveque等人,2014,Anticancer Res 34:1579-86)。
附图说明
图1.使用hRS7(抗Trop-2)、hPAM4(抗MUC5ac)、hMN-14(抗CEACAM5)或非特异性对照hA20(抗CD20)的SN-38缀合物,携带Capan 1人胰腺癌的无胸腺裸鼠的临床前体内治疗。
图2.与对照相比,使用抗TROP2-CL2A-SN-38缀合物,携带BxPC3人胰腺癌的无胸腺裸鼠的临床前体内治疗。
图3A.CL2-SN-38和CL2A-SN-38的结构。
图3B.使用COLO 205结肠腺癌,连接至CL2对CL2A接头的抗Trop-2 ADC对比hA20ADC和盐水对照的比较功效。如箭头所示,每周两次处理动物,持续4周。将COLO 205小鼠(N=6)用0.4mg/kg ADC处理并且每周两次测量肿瘤。
图3C.使用Capan-1胰腺癌,连接至CL2对CL2A接头的抗Trop-2 ADC对比hA20 ADC和盐水对照的比较功效。如箭头所示,每周两次处理动物,持续4周。将Capan-1小鼠(N=10)用0.2mg/kg ADC处理并且每周测量肿瘤。
图4A.hRS7-SN-38 ADC在若干实体瘤-异种移植物疾病模型中的治疗功效。在携带人非小细胞肺肿瘤、结肠直肠肿瘤、胰腺肿瘤或鳞状细胞肺肿瘤异种移植物的小鼠中研究hRS7-CL2-SN-38和hRS7-CL2A-SN-38 ADC处理的功效。所有ADC和对照以指定的量施用(表示为每剂量SN-38的量;长箭头=缀合物注射液,短箭头=伊立替康注射液)。将携带Calu-3肿瘤的小鼠(N=5–7)每4天注射hRS7-CL2-SN-38,共注射4次(q4dx4)。
图4B.hRS7-SN-38 ADC在若干实体瘤-异种移植物疾病模型中的治疗功效。在携带人非小细胞肺肿瘤、结肠直肠肿瘤、胰腺肿瘤或鳞状细胞肺肿瘤异种移植物的小鼠中研究hRS7-CL2-SN-38和hRS7-CL2A-SN-38ADC处理的功效。所有ADC和对照以指定的量施用(表示为每剂量SN-38的量;长箭头=缀合物注射液,短箭头=伊立替康注射液)。将携带COLO 205肿瘤的小鼠(N=5)用ADC注射8次(q4dx8)或每2天用伊立替康的MTD注射总共5次(q2dx5)。
图4C.hRS7-SN-38 ADC在若干实体瘤-异种移植物疾病模型中的治疗功效。在携带人非小细胞肺肿瘤、结肠直肠肿瘤、胰腺肿瘤或鳞状细胞肺肿瘤异种移植物的小鼠中研究hRS7-CL2-SN-38和hRS7-CL2A-SN-38 ADC处理的功效。所有ADC和对照以指定的量施用(表示为每剂量SN-38的量;长箭头=缀合物注射液,短箭头=伊立替康注射液)。将Capan-1(N=10)用指示的剂每周两次处理,持续4周。
图4D.hRS7-SN-38 ADC在若干实体瘤-异种移植物疾病模型中的治疗功效。在携带人非小细胞肺肿瘤、结肠直肠肿瘤、胰腺肿瘤或鳞状细胞肺肿瘤异种移植物的小鼠中研究hRS7-CL2-SN-38和hRS7-CL2A-SN-38 ADC处理的功效。所有ADC和对照以指定的量施用(表示为每剂量SN-38的量;长箭头=缀合物注射液,短箭头=伊立替康注射液)。将携带BxPC-3肿瘤的小鼠(N=10)用指示的剂每周两次处理,持续4周。
图4E.hRS7-SN-38 ADC在若干实体瘤-异种移植物疾病模型中的治疗功效。在携带人非小细胞肺肿瘤、结肠直肠肿瘤、胰腺肿瘤或鳞状细胞肺肿瘤异种移植物的小鼠中研究hRS7-CL2-SN-38和hRS7-CL2A-SN-38 ADC处理的功效。所有ADC和对照以指定的量施用(表示为每剂量SN-38的量;长箭头=缀合物注射液,短箭头=伊立替康注射液)。除了每周给予两次ADC持续4周外,携带SK-MES-1肿瘤(N=8)的小鼠接受CPT-11的MTD(q2dx5)。
图5A.hRS7-CL2A-SN-38在Swiss-Webster小鼠中的耐受性。向五十六只Swiss-Webster小鼠相隔3天给予缓冲液或hRS7-CL2A-SN-38的2个腹膜内剂量(每个剂量4、8或12mg/kg的SN-38;每个剂量250、500或750mg缀合蛋白/kg)。在最后一次注射后7天和15天,将来自每组的7只小鼠实施安乐死,进行血细胞计数和血清化学分析。图表示出每组中具有升高的AST水平的动物的百分比。
图5B.hRS7-CL2A-SN-38在Swiss-Webster小鼠中的耐受性。向五十六只Swiss-Webster小鼠相隔3天给予缓冲液或hRS7-CL2A-SN-38的2个腹膜内剂量(每个剂量4、8或12mg/kg的SN-38;每个剂量250、500或750mg缀合蛋白/kg)。在最后一次注射后7天和15天,将来自每组的7只小鼠实施安乐死,进行血细胞计数和血清化学分析。图表显示每组中具有升高的ALT水平的动物的百分比。
图5C.hRS7-CL2A-SN-38在食蟹猴中的耐受性。将每组6只猴用缓冲液(对照)或0.96mg/kg的hRS7-CL2A-SN-38或1.92mg/kg的SN-38当量/剂量(60和120mg/kg缀合物蛋白)间隔3天注射两次。所有动物在第-1天、第3天和第6天取血。在第11天在0.96mg/kg组中和在第3天在1.92mg/kg组中将4只猴子放血。食蟹猴中的嗜中性粒细胞计数的变化。
图5D.hRS7-CL2A-SN-38在食蟹猴中的耐受性。将每组6只猴用缓冲液(对照)或0.96mg/kg的hRS7-CL2A-SN-38或1.92mg/kg的SN-38当量/剂量(60和120mg/kg缀合物蛋白)间隔3天注射两次。所有动物在第-1天、第3天和第6天取血。在第11天在0.96mg/kg组中和在第3天在1.92mg/kg组中将4只猴子放血。食蟹猴中血小板计数的变化。
图6.抗Trop-2-紫杉醇ADC针对MDA-MB-468人乳腺癌的体外功效。
图7.抗Trop-2-紫杉醇ADC针对BxPC-3人胰腺癌的体外功效。
图8A.抗Trop-2 ADC(hRS7-SN-38对MAB650-SN-38)在Capan-1人胰腺癌中的体外功效的比较。
图8B.抗Trop-2 ADC(hRS7-SN-38对MAB650-SN-38)在BxPC-3人胰腺癌中的体外功效的比较。
图8C.抗Trop-2 ADC(hRS7-SN-38对MAB650-SN-38)在NCI-N87人胃腺癌中的体外功效的比较。
图9A.裸或SN-38缀合的hRS7对162-46.2抗体在BxPC-3人胰腺癌中的细胞毒性的比较。
图9B.裸或SN-38缀合的hRS7对162-46.2抗体在MDA-MB-468人乳腺癌中的细胞毒性的比较。
图10.根据RECIST标准最佳应答的IMMU-132 I/II期数据。
图11.用于进展时间和最佳应答(RECIST)的IMMU-132 I/II期数据。
图12.将雌性NCr无胸腺nu/nu小鼠以指示剂量的IMMU-132每周两次皮下注射,持续四周。圆圈指示注射部位。在向小鼠施用最终注射后24小时拍摄照片。
图13.将雌性NCr无胸腺nu/nu小鼠以指示剂量的IMMU-132每周两次皮下注射,持续四周。圆圈指示注射部位。在向小鼠施用最终注射后7天拍摄照片。
图14.用IMMU-132的静脉内注射液处理的小鼠在第82天的平均肿瘤体积为0.066±0.076cm3,其显著小于在第15天开始实验时(0.263±0.058cm3;P=0.0017,双尾t-检验)。同样,IMMU-132的皮下施用导致肿瘤显著小于实验开始时(0.111±0.057cm3对比0.247±0.055cm3;P=0.0179,双尾t-检验)。当将静脉内施用与皮下比较时,最终肿瘤体积没有显著差异,因为两者都产生等效抗肿瘤作用。
具体实施方式
定义
除非另外指明,否则一个/种(a/an)意指一个(种)或多个(种)。
如本文所用,“约”意指加或减10%。例如,“约100”将包括介于90与110之间的任何数字。
如本文所描述,抗体是指全长(即,天然存在的或通过正常免疫球蛋白基因片段重组方法形成的)免疫球蛋白分子(如,IgG抗体)或免疫球蛋白分子的免疫活性(即,特异性结合)部分,如抗体片段。
抗体片段是抗体的一部分,诸如F(ab’)2、Fab’、Fab、Fv、sFv等等。抗体片段也可包括单结构域抗体和IgG4半分子,如下文所讨论。无论结构如何,抗体片段与全长抗体识别的相同抗原结合。术语“抗体片段”也包括由抗体的可变区组成的分离片段,如由重链和轻链的可变区组成的“Fv”片段,以及其中轻链可变区和重链可变区通过肽接头(“scFv蛋白”)连接的重组单链多肽分子。
嵌合抗体是重组蛋白,其含有包括来源于一种物种的抗体、优选啮齿动物抗体的互补决定区(CDR)可变结构域,而抗体分子的恒定结构域来源于人抗体的恒定结构域。对于兽医学应用,嵌合抗体的恒定结构域可来源于其他物种,如猫或狗的恒定结构域。
人源化抗体是重组蛋白,其中将来自一种物种的抗体(例如啮齿动物抗体)的CDR从啮齿动物抗体的可变重链和可变轻链转移到人重链和轻链可变结构域(例如,框架区序列)中。抗体分子的恒定区来源于人抗体的那些恒定区。在某些实施方案中,可将来自亲本(啮齿动物)抗体的有限数量的框架区氨基酸残基取代到人抗体框架区序列中。
人抗体是例如从转基因小鼠获得的抗体,所述转基因小鼠已被“工程化”以响应于抗原激发产生特异性人抗体。在这种技术中,将人重链和轻链基因座的元件引入到来源于胚胎干细胞系的小鼠品系中,所述胚胎干细胞系含有内源性鼠类重链和轻链基因座的靶向破坏。转基因小鼠可合成对特定抗原具有特异性的人抗体,并且小鼠可用于产生分泌人抗体的杂交瘤。用于从转基因小鼠获得人抗体的方法由Green等人,Nature Genet.7:13(1994);Lonberg等人,Nature 368:856(1994)和Taylor等人,Int.Immun.6:579(1994)描述。完全人抗体也可通过基因或染色体转染方法以及噬菌体展示技术构建,所有技术都是本领域已知的。参见例如McCafferty等人,Nature 348:552-553(1990)从来自未免疫供体的免疫球蛋白可变结构域基因组库(repertoire)体外产生人抗体及其片段)。在这种技术中,将抗体可变结构域基因同框克隆到丝状噬菌体的主要或次要外壳蛋白基因中,并在噬菌体颗粒的表面上展示为功能性抗体片段。因为丝状颗粒包含噬菌体基因组的单链DNA拷贝,所以基于抗体的功能性质的选择也导致选择编码表现出这些性质的抗体的基因。以此方式,噬菌体模拟B细胞的一些性质。噬菌体展示可以多种形式进行,关于综述,参见例如Johnson和Chiswell,Current Opinion in Structural Biology 3:5564-571(1993)。人抗体也可通过体外活化的B细胞来生成。参见美国专利号5,567,610和5,229,275,其实施例部分以引用的方式并入本文。
治疗剂是与抗体部分分开、同时或依序施用或者与抗体部分(即,抗体或抗体片段或子片段)缀合并且适用于治疗疾病的化合物、分子或原子。治疗剂的实例包括抗体、抗体片段、药物、毒素、核酸酶、激素、免疫调节剂、促凋亡剂、抗血管生成剂、硼化合物、光敏剂或染料以及放射性同位素。所使用的治疗剂在下文更详细地描述。
免疫缀合物是与至少一种治疗剂和/或诊断剂缀合的抗体、抗体片段或融合蛋白。
多特异性抗体是可同时结合至至少两个具有不同结构的靶标(例如,两种不同的抗原、在同一抗原上的两个不同表位或半抗原和/或抗原或表位)的抗体。多特异性、多价抗体是具有多于一个结合位点的构建体,并且所述结合位点具有不同的特异性。
双特异性抗体是可同时结合至两个不同靶标的抗体。双特异性抗体(bsAb)和双特异性抗体片段(bsFab)可具有至少一个特异性地结合至例如肿瘤相关抗原的臂和至少一个特异性地结合至带有治疗剂或诊断剂的可靶向缀合物的其他臂。许多双特异性融合蛋白可使用分子工程化产生。
抗Trop-2抗体
主题ADC可包括结合至Trop-2的抗体或其片段。在具体的优选实施方案中,抗Trop-2抗体可以是人源化RS7抗体(参见例如,美国专利号7,238,785,所述专利以引用的方式整体并入本文),其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SA SYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQ ID NO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。
RS7抗体是针对人原发性鳞状细胞肺癌的粗膜制备而产生的鼠IgG1。(Stein等人,Cancer Res.50:1330,1990)。RS7抗体识别表征为簇13的46-48kDa糖蛋白。(Stein等人,Int.J.Cancer Supp.8:98-102,1994)。所述抗原被命名为EGP-1(上皮糖蛋白-1),但也称为Trop-2。
Trop-2是I型跨膜蛋白,并且已从人(Fornaro等人,Int J Cancer 1995;62:610-8)和小鼠细胞(Sewedy等人,Int J Cancer 1998;75:324-30)二者克隆。除了作为肿瘤相关钙信号转导蛋白(Ripani等人,Int J Cancer 1998;76:671-6)的作用之外,人Trop-2的表达还显示出对于肿瘤发生和结肠癌细胞的侵袭性是必要的,这可有效地减少针对Trop-2的细胞外结构域的多克隆抗体(Wang等人,Mol Cancer Ther 2008;7:280-5)。
Trop-2作为实体癌的治疗靶标的日益增长的兴趣(Cubas等人,Biochim BiophysActa 2009;1796:309-14)由另外的报告证明,所述报告记录了过表达的Trop-2在乳腺癌(Huang等人,Clin Cancer Res 2005;11:4357-64)、结肠直肠癌(Ohmachi等人,ClinCancer Res 2006;12:3057-63;Fang等人,Int J Colorectal Dis 2009;24:875-84)和口腔鳞状细胞癌(Fong等人,Modern Pathol 2008;21:186-91)中的临床意义。表达高水平的Trop-2的前列腺基底细胞被富集以获得体外和体内干细胞活性的最新证据尤其值得注意(Goldstein等人,Proc Natl Acad Sci USA 2008;105:20882-7)。
流式细胞术和免疫组织化学染色研究已经显示,RS7 MAb检测许多肿瘤类型上的抗原,与正常人组织的结合有限(Stein等人,1990)。Trop-2主要由癌,如肺癌、胃癌、膀胱癌、乳腺癌、卵巢癌、子宫癌和前列腺癌表达。在动物模型中使用放射性标记的鼠RS7 MAb进行的定位和治疗研究已证明肿瘤靶向和治疗功效(Stein等人,1990;Stein等人,1991)。
在来自肺、乳腺、膀胱、卵巢、子宫、胃和前列腺的肿瘤中显示出强RS7染色。(Stein等人,Int.J.Cancer 55:938,1993)肺癌病例包括鳞状细胞癌和腺癌二者。(Stein等人,Int.J.Cancer 55:938,1993)两种细胞类型均被强染色,从而表明RS7抗体不能鉴别非小细胞肺癌的组织学分类。
RS7 MAb快速内化到靶细胞中(Stein等人,1993)。RS7 MAb的内化速率常数介于两种其他快速内化MAb的内化速率常数之间,其已被证明可用于免疫毒素产生。(同上)已充分证明免疫毒素缀合物的内化是抗肿瘤活性的要求。(Pastan等人,Cell 47:641,1986)药物ADC的内化已被描述为抗肿瘤功效的主要因素。(Yang等人,Proc.Nat'l Acad.Sci.USA 85:1189,1988)因此,RS7抗体表现出治疗应用的若干重要性质。
虽然hRS7抗体是优选的,但其他抗Trop-2抗体是已知的和/或可公开获得的,并且在替代实施方案中可用于主题ADC中。虽然人源化或人抗体对于降低的免疫原性是优选的,但在替代实施方案中可使用嵌合抗体。如下文所讨论,抗体人源化的方法是本领域熟知的,并且可用于将可用的鼠或嵌合抗体转化为人源化形式。
抗Trop-2抗体可从许多来源商购获得,并且包括LS-C126418、LS-C178765、LS-C126416、LS-C126417(LifeSpan BioSciences,Inc.,Seattle,WA);10428-MM01、10428-MM02、10428-R001、10428-R030(Sino Biological Inc.,Beijing,China);MR54(eBioscience,San Diego,CA);sc-376181、sc-376746,Santa Cruz Biotechnology(SantaCruz,CA);MM0588-49D6(Novus Biologicals,Littleton,CO);ab79976和ab89928(Cambridge,MA)。
其他抗Trop-2抗体已经公开于专利文献中。例如,美国公开号2013/0089872公开了保藏在日本筑波的国际专利生物保藏中心(International Patent OrganismDepositary,Tsukuba,Japan)的抗Trop-2抗体K5-70(登录号FERM BP-11251)、K5-107(登录号FERM BP-11252)、K5-116-2-1(登录号FERM BP-11253)、T6-16(登录号FERM BP-11346)和T5-86(登录号FERM BP-11254)。美国专利号5,840,854公开了抗Trop-2单克隆抗体BR110(ATCC号HB11698)。美国专利号7,420,040公开了以登录号141205-05保藏在IDAC(加拿大国际保藏机构,温尼伯,加拿大)的杂交瘤细胞系AR47A6.4.2产生的抗Trop-2抗体。美国专利号7,420,041公开了以登录号141205-03保藏在IDAC的杂交瘤细胞系AR52A301.5产生的抗Trop-2抗体。美国公布号2013/0122020公开了抗Trop-2抗体3E9、6G11、7E6、15E2、18B1。编码代表性抗体的杂交瘤保藏在美国典型培养物保藏中心(ATCC),登录号PTA-12871和PTA-12872。美国专利号8,715,662公开了以保藏号PD 08019、PD 08020和PD 08021保藏在AID-ICLC(Genoa,Italy)的杂交瘤产生的抗Trop-2抗体。美国专利申请公布号20120237518公开了抗Trop-2抗体77220、KM4097和KM4590。美国专利号8,309,094(Wyeth)公开了通过序列表鉴定的抗体A1和A3。本段落上述引用的每个专利或专利申请的实施例部分以引用的方式并入本文。非专利公布Lipinski等人(1981,Proc Natl.Acad Sci USA,78:5147-50)公开了抗Trop-2抗体162-25.3和162-46.2。King等人的出版物(Invest New Drugs,2018年1月15日付印前的电子版)公开了PF-06664178抗Trop-2抗体-药物缀合物。Strop等人的出版物(2016,Mol Cancer Ther 15:2698-708)公开了RN927C抗Trop-2 ADC。
许多抗Trop-2抗体是本领域已知的和/或可公开获得的。如下文所论述,用于制备针对已知抗原的抗体的方法是本领域常规的。人Trop-2蛋白的序列也是本领域已知的(参见例如,GenBank登录号CAA54801.1)。用于产生人源化、人或嵌合抗体的方法也是已知的。普通技术人员在根据本领域的一般知识阅读本公开时将能够将能够在主题ADC中制造和使用抗Trop-2抗体的种属。
已经公开了除ADC以外的免疫治疗剂的抗Trop-2抗体的用途。鼠IgG2a抗体依决洛单抗已被用于治疗结肠直肠癌,尽管鼠抗体不适合人类临床使用(Baeuerle&Gires,2007,Br.J Cancer 96:417-423)。据报告,低剂量皮下施用依决洛单抗可诱导针对疫苗抗原的体液免疫应答(Baeuerle和Gires,2007)。阿德木单抗(MT201)(一种完全人抗Trop-2抗体)已被用于转移性乳腺癌和早期前列腺癌,并且据报告通过ADCC和CDC活性发挥作用(Baeuerle和Gires,2007)。已报告MT110(一种单链抗Trop-2/抗CD3双特异性抗体构建体)针对卵巢癌的功效(Baeuerle和Gires,2007)。卡妥索单抗(一种对Trop-2、CD3和Fc受体具有结合亲和力的杂合小鼠/大鼠抗体)据报告具有针对卵巢癌的活性(Baeuerle和Gires,2007)。普罗昔铵(一种包含与假单胞菌外毒素融合的抗Trop-2单链抗体的免疫毒素)已经在头颈癌和膀胱癌中进行了测试(Baeuerle和Gires,2007)。这些研究均未包括关于使用抗Trop-2抗体-药物缀合物的任何公开内容。
抗CEA抗体
某些实施方案可涉及使用针对CEACAM5或CEACAM6的缀合的抗体。CEA(CEACAM5)是一种通常在许多上皮癌中表达的癌胚抗原,最通常在结肠中出现的那些,但也在乳腺、肺、胰腺、甲状腺(髓质型)和卵巢中出现(Goldenberg等人,J.Natl.Cancer Inst.57:11-22,1976;Shively等人,Crit.Rev.Oncol.Hematol.2:355-399,1985)。人CEA基因家族由属于CEACAM亚组的7种已知基因组成。这些亚组成员主要与细胞膜相关,并且在正常组织和癌组织中显示复杂的表达模式。CEACAM5基因(也称为CD66e)编码CEA蛋白(Beauchemin等人,ExpCell Res 252:243,1999)。CEACAM5在1965年首次描述为胃肠癌胚抗原(Gold等人,J ExpMed 122:467-481,1965),但现在已知在大多数癌中过表达,包括胃肠道、呼吸系统和泌尿生殖系统以及乳腺癌症的那些(Goldenberg等人,J Natl Cancer Inst.57:11-22,1976;Shively和Beatty,Crit Rev Oncol Hematol 2:355-99,1985)。
CEACAM6(也称为CD66c或NCA-90)是非特异性交叉反应糖蛋白抗原,其与CEACAM5共有一些但非全部抗原决定簇(Kuroki等人,BiochemBiophys Res Comm 182:501-06,1992)。CEACAM6在来自各种器官的粒细胞和上皮细胞上表达,并且与正常粘膜以及许多人癌症相比,在增生性结肠息肉和腺瘤的增殖细胞中具有更宽的表达区(Scholzel等人,Am JPathol 157:1051-52,2000;Kuroki等人,AnticancerRes 19:5599-5606,1999)。在患有肺癌、胰腺癌、乳腺癌、结肠直肠癌和肝细胞癌的患者中发现相对高的CEACAM6血清水平。CEACAM6的量与表达的CEACAM5的量不相关(Kuroki等人,AnticancerRes 19:5599-5606,1999)。
CEACAM6在结肠直肠癌中的表达与细胞分化呈负相关(Ilantzis等人,Neoplasia4:151-63,2002),并且是与较高复发风险相关的独立预后因素(Jantscheff等人,J ClinOncol 21:3638-46,2003)。CEACAM5和CEACAM6两者均在细胞粘附、侵袭和转移中起作用。CEACAM5已显示参与同嗜性(CEA至CEA)和异嗜性(CEA与非CEA分子的结合)相互作用(Bechimol等人,Cell 57:327-34,1989;Oikawa等人,BiochemBiophys Res Comm 164:39-45,1989),从而向一些人表明它是参与癌症侵袭和转移的细胞间粘附分子(Thomas等人,Cancer Lett 92:59-66,1995)。这些反应通过抗CEACAM5抗体的Fab'片段完全抑制(Oikawa等人,Biochem Biophys Res Comm 164:39-45,1989)。CEACAM6还表现出与CEA家族的其他成员的同型结合以及与整联蛋白受体的异型相互作用(Stanners和Fuks,于:Cell Adhesion and Communication by the CEA Family,(Stanners编辑)第5卷,第57-72页,Harwood Academic Publ.,Amsterdam,1998)。靶向CEACAM6的N-结构域的抗体干扰细胞-细胞相互作用(Yamanka等人Biochem Biophys Res Comm 219:842-47,1996)。许多乳腺癌、胰腺癌、结肠癌和非小细胞肺癌(NSCLC)细胞系表达CEACAM6,并且抗CEACAM6抗体抑制抗原阳性细胞的体外迁移、侵袭和粘附(Blumenthal等人,Cancer Res 65:8809-17,2005)。
抗CEA抗体取决于它们与除CEA以外的抗原的交叉反应性分为不同类别。抗CEA抗体分类由Primus和Goldenberg,美国专利号4,818,709描述(所述专利以引用的方式从第3栏、第5行至第26栏、第49行并入本文)。抗CEA抗体的分类通过它们与CEA、胎粪抗原(MA)和非特异性交叉反应抗原(NCA)的结合来确定。I类抗CEA抗体结合至所有三种抗原。II类抗体结合至MA和CEA,但不结合至NCA。III类抗体仅结合至CEA(U.S.4,818,709)。已知各类抗CEA抗体的实例,如MN-3、MN-15和NP-1(I类);MN-2、NP-2和NP-3(II类);以及MN-14和NP-4(III类)(U.S.4,818,709;Blumenthal等人BMC Cancer 7:2(2007))。
还鉴定了各种抗CEA抗体的表位结合位点。MN-15抗体结合至CEA的A1B1结构域,MN-3抗体结合至CEA的N-末端结构域,并且MN-14抗体结合至CEA的A3B3(CD66e)结构域(Blumenthal等人BMC Cancer 7:2(2007))。表位结合位点与抗CEA抗体的类别之间没有直接相关性。例如,MN-3和MN-15都是I类抗CEA抗体,与NCA、MA和CEA反应,但分别结合至CEA的N-末端和A1B1结构域。Primus和Goldenberg(US 4,818,709)报告了不同抗CEA抗体之间的交叉阻断活性的复杂模式,其中NP-1(I类)和NP-2(II类)交叉阻断与彼此的CEA的结合,但不阻断NP-3(II类)的结合。然而,根据定义,I类抗CEA抗体结合至CEACAM5和CEACAM6两者,而III类抗CEA抗体仅结合至CEACAM5。
已经提出抗CEA抗体用于治疗性治疗多种癌症。例如,局限于甲状腺的甲状腺髓样癌(MTC)通常通过全甲状腺切除术和中央淋巴结清扫术治疗。然而,疾病在大约50%的这些患者中复发。此外,患有不可切除的疾病或远处转移的患者的预后较差,少于30%存活10年(Rossi等人,Amer.J.Surgery,139:554(1980);Samaan等人,J.Clin.Endocrinol.Metab.,67:801(1988);Schroder等人,Cancer,61:806(1988))。这些患者几乎没有治疗选择(Principles and Practice of Oncology,DeVita,Hellman和Rosenberg(编辑),NewYork:JB Lippincott Co.,第1333-1435页(1989);Cancer等人,CurrentProblemsSurgery,22:1(1985))。III类抗CEA抗体MN-14据报告当与促凋亡剂如DTIC、CPT-11和5-氟尿嘧啶结合使用时,在动物异种移植物模型系统中对人甲状腺髓样癌的治疗有效(美国专利申请序列号10/680,734,其实施例部分以引用的方式并入本文)。III类抗CEA抗体据报告使癌细胞对使用化学治疗剂的治疗敏感,并且据报告与单独抗体或化学治疗剂相比,抗体与化学治疗剂的组合对肿瘤具有协同作用(USSN 10/680,734)。已经提出不同类别的抗CEA抗体(如MN-3、MN-14和MN-15)用于治疗多种肿瘤。
在一个优选的实施方案中,包含抗CEACAM5抗体(例如,hMN-14、拉贝珠单抗)和/或抗CEACAM6抗体(例如,hMN-3或hMN-15)的治疗性缀合物可用于治疗表达CEACAM5和/或CEACAM6的各种癌症中的任一种,如美国专利号7,541,440;7,951,369;5,874,540;6,676,924和8,267,865中所公开;所述专利各自的实施例部分以引用的方式并入本文)。可使用抗CEACAM5、抗CEACAM6或两者的组合治疗的实体瘤包括但不限于乳腺癌、肺癌、胰腺癌、食道癌、甲状腺髓样癌、卵巢癌、结肠癌、直肠癌、膀胱癌、口腔癌和胃癌。大多数癌,包括胃肠癌、呼吸道癌、泌尿生殖系统癌和乳腺癌表达CEACAM5并且可用主题ADC治疗。hMN-14抗体是包含轻链可变区CDR序列CDR1(KASQDVGTSVA;SEQ ID NO:9)、CDR2(WTSTRHT;SEQ ID NO:10)和CDR3(QQYSLYRS;SEQ ID NO:11)以及重链可变区CDR序列CDR1(TYWMS;SEQ ID NO:12)、CDR2(EIHPDSSTINYAPSLKD;SEQ ID NO:13)和CDR3(LYFGFPWFAY;SEQ ID NO:14)的人源化抗体。hMN-3抗体是包含轻链可变区CDR序列CDR1(RSSQSIVHSNGNTYLE,SEQ ID NO:15)、CDR2(KVSNRFS,SEQ ID NO:16)和CDR3(FQGSHVPPT,SEQ ID NO:17)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:18)、CDR2(WINTYTGEPTYADDFKG,SEQ ID NO:19)和CDR3(KGWMDFNSSLDY,SEQ ID NO:20)的人源化抗体。hMN-15抗体是包含轻链可变区CDR序列SASSRVSYIH(SEQ IDNO:21)、GTSTLAS(SEQ ID NO:22)和QQWSYNPPT(SEQ ID NO:23)以及重链可变区CDR序列DYYMS(SEQ ID NO:24)、FIANKANGHTTDYSPSVKG(SEQ ID NO:25)和DMGIRWNFDV(SEQ ID NO:26)的人源化抗体。
尽管优选使用MN-14、MN-15或MN-3,但是针对CEACAM5或CEACAM6的其他抗体是本领域已知的,并且可用作ADC,如SN-38缀合物。针对CEACAM5的另一种示例性抗体是抗CEACAM5 CC4抗体(例如,Zheng等人,2011,PLoS One 6:e21146)。针对CEACAM5或CEACAM6的抗体可从许多商业来源获得,包括LS-C6031、LS-B7292、LS-C338757(LSBio,Seattle,WA);SAB1307198、GW22478、HPA019758(Sigma-Aldrich,St.Louis,MO);sc-23928、sc-59872、sc-52390(Santa Cruz Biotechnology,Santa Cruz,CA);以及ab78029(Cambridge,MA)。任何这种已知的抗CEACAM5或抗CEACAM6抗体可用于本文公开的ADC中。
抗HLA-DR抗体
人白细胞抗原-DR(HLA-DR)是主要组织相容性复合物(MHC)II类抗原的三种同种型之一。HLA-DR在多种血液恶性肿瘤中高度表达,并且已经积极地用于基于抗体的淋巴瘤治疗(Brown等人,2001,Clin Lymphoma 2:188-90;DeNardo等人,2005,Clin CancerRes11:7075s-9s;Stein等人,2006,Bloood 108:2736-44)。人HLA-DR抗原以比典型B细胞标志物(包括CD20)显著更高的水平在非霍奇金淋巴瘤(NHL)、慢性淋巴细胞性白血病(CLL)和其他B细胞恶性肿瘤中表达。初步研究表明,抗HLA-DR mAb在淋巴瘤、白血病和多发性骨髓瘤的体外和体内实验中明显比目前临床上感兴趣的其他裸mAb更有效(Stein等人,未发表的结果)。
HLA-DR也在正常免疫细胞的亚群上表达,所述免疫细胞包括B细胞、单核细胞/巨噬细胞、朗格汉斯细胞、树突细胞和活化的T细胞(Dechant等人,2003,Semin Oncol 30:465-75)。因此,也许并不出人意料,开发抗HLA-DR抗体的先前尝试一直受到毒性的阻碍,特别是可能与补体活化有关的输注相关的毒性(Lin等人,2009,Leuk L ymphoma 50:1958-63;Shi等人,2002,Leuk Lymphoma 43:1303-12)。
在优选的实施方案中,主题抗HLA-DR抗体可以是人源化L243抗体。此类抗体与亲本鼠L243抗体结合至HLA-DR上的相同表位,但具有降低的免疫原性。mL243已经保藏在美国典型培养物保藏中心,Rockville,MD,登录号为ATCC HB55。
人源化L243抗体可包含附接至人抗体FR和恒定区序列的重链CDR序列CDR1(NYGMN,SEQ ID NO:27)、CDR2(WINTYTREPTYADDFKG,SEQ ID NO:28)和CDR3(DITAVVPTGFDY,SEQ ID NO:29)以及轻链CDR序列CDR1(RASENIYSNLA,SEQ ID NO:30)、CDR2(AASNLAD,SEQID NO:31)和CDR3(QHFWTTPWA,SEQ ID NO:32)。在更优选的实施方案中,一个或多个鼠FR氨基酸残基被相应的人FR残基取代,特别是在邻近CDR残基或CDR残基附近的位置。可在人源化设计中被取代的示例性鼠VH残基是在位置:F27、K38、K46、A68和F91。可在人源化设计中被取代的示例性鼠VL残基是在位置R37、K39、V48、F49和G1。
人源化抗体分子的轻链和重链可变结构域可与人轻链或重链恒定结构域融合。可关于所提出的抗体功能选择人恒定结构域。在一个实施方案中,可基于缺乏效应子功能来选择人恒定结构域。与重链可变区融合的重链恒定结构域可以是人IgA(αl或α2链)、IgG(γ1、γ2、γ3或γ4链)或IgM(μ链)的那些。可与轻链可变区融合的轻链恒定结构域包括人λ和κ链。
在本发明的一个特定实施方案中,使用γ1链。在又一个特定实施方案中,使用γ4链。使用γ4链可在一些情况下增加受试者对hL243的耐受性(减少的副作用和输注反应等)。
各种实施方案可涉及主题抗HLA-DR抗体或其片段用于治疗或诊断疾病的用途,所述疾病包括但不限于:B细胞非霍奇金淋巴瘤、B细胞急性和慢性淋巴性白血病、伯基特淋巴瘤、霍奇金淋巴瘤、毛细胞白血病、急性和慢性骨髓性白血病、T细胞淋巴瘤和白血病、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、癌、黑素瘤、肉瘤、神经胶质瘤以及皮肤癌。癌可选自由以下组成的组:口腔癌、胃肠道癌、肺道癌、乳腺癌、卵巢癌、前列腺癌、子宫癌、膀胱癌、胰腺癌、肝癌、胆囊癌、皮肤癌和睾丸癌。
喜树碱缀合物
用于制备包含附接至抗体或抗原结合抗体片段的喜树碱治疗剂的免疫缀合物的非限制性方法和组合物在下文进行了描述。在优选的实施方案中,通过在药物与抗体之间放置限定的聚乙二醇(PEG)部分(即,含有限定数量的单体单元的PEG)来增强药物的溶解度,其中限定的PEG是优选含有1-30个单体单元、更优选含有1-12个单体单元、最优选含有6-8个单体单元的低分子量PEG。
优选地,第一接头在一端连接药物,并且可在另一端用乙炔或叠氮化物基团终止。这种第一接头可包含在一端具有叠氮化物或乙炔基团并且在另一端具有不同的反应性基团(如羧酸或羟基)的限定的PEG部分。所述双官能限定的PEG可附接至氨基醇的胺基团上,并且后者的羟基可附接至呈碳酸酯形式的药物上的羟基。或者,所述限定的双官能PEG的非叠氮化物(或乙炔)部分任选地附接至L-氨基酸或多肽的N-末端,其C-末端附接至氨基醇的氨基,并且后者的羟基附接至分别呈碳酸酯或氨基甲酸酯形式的药物的羟基。
包含抗体偶联基团和与第一接头的叠氮化物(或乙炔)基团互补的反应性基团(即乙炔(或叠氮化物))的第二接头可经由乙炔-叠氮化物环加成反应与药物-(第一接头)缀合物反应以提供最终的双官能药物产品,其可用于缀合至靶向疾病的抗体。抗体偶联基团优选地是硫醇或硫醇反应性基团。
下文提供了在涉及CPT类似物如SN-38的药物-接头前体制剂中在C-20碳酸酯存在下选择性再生10-羟基的方法。也可使用药物中的反应性羟基的其他保护基团,如SN-38中的酚羟基,例如叔丁基二甲基甲硅烷基或叔丁基二苯基甲硅烷基,并且在将衍生化的药物连接至抗体偶联部分之前通过四丁基氟化铵对这些进行脱保护。除了‘BOC’之外,CPT类似物的10-羟基可替代地被保护为酯或碳酸酯,以使得双官能CPT与抗体缀合而没有这种保护基团的先前脱保护。在施用生物缀合物后,保护基团在生理pH条件下容易地脱保护。
在称为‘点击化学’的乙炔-叠氮化物偶联中,叠氮化物部分可在L2上,乙炔部分在L3上。或者,L2可含有乙炔,L3含有叠氮化物。‘点击化学’是指乙炔部分与叠氮化物部分之间的铜(+1)催化的环加成反应(Kolb HC和Sharpless KB,Drug Discov Today 2003;8:1128-37),尽管已知并且可使用替代形式的点击化学。点击化学在近中性pH条件下在水溶液中发生,并且因此适合于药物缀合。点击化学的优点在于它是化学选择性的,并且补充其他众所周知的缀合化学如硫醇-马来酰亚胺反应。
示例性的优选实施方案涉及药物衍生物和抗体的具有以下所示的通式(1)的缀合物。
MAb-[L2]-[L1]-[AA]m-[A’]-药物(1)
其中MAb是靶向疾病的抗体;L2是包含抗体偶联部分和一个或多个乙炔(或叠氮化物)基团的交联剂的组分;L1包含在一端具有与L2中的乙炔(或叠氮化物)部分互补的叠氮化物(或乙炔)的限定的PEG以及在另一端的反应性基团如羧酸或羟基;AA是L-氨基酸;m是值为0、1、2、3或4的整数;并且A'是选自乙醇胺、4-羟基苄醇、4-氨基苄醇或取代的或未取代的乙二胺的组的另外的间隔基。‘AA’的L氨基酸选自丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸以及缬氨酸。如果A'基团含有羟基,则它连接至分别呈碳酸酯或氨基甲酸酯形式的药物的羟基或氨基。
在式1的优选实施方案中,A'是衍生自L-氨基酸的取代的乙醇胺,其中所述氨基酸的羧酸基团被羟甲基部分置换。A'可衍生自以下L-氨基酸中的任一种:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸以及缬氨酸。
在式1的优选实施方案的缀合物的实例中,m是0,A'是L-缬氨醇,并且药物由SN-38例示。在式1的另一个实例中,m是1并且由衍生化的L-赖氨酸代表,A'是L-缬氨醇,并且药物由SN-38例示。在此实施方案中,使用赖氨酸氨基的正交保护基团首先在氨基酸如赖氨酸的羧酸与缬氨醇的氨基之间形成酰胺键。除去赖氨酸的N-末端上的保护基团,从而保持赖氨酸的侧链上的保护基团完整,并且N-末端与在另一端具有叠氮化物(或乙炔)的限定的PEG上的羧基偶联。缬氨醇的羟基然后附接至10-羟基保护的SN-38的20-氯甲酸酯衍生物,并且此中间体与携带抗体结合部分的L2组分以及参与点击环加成化学的互补的乙炔(或叠氮化物)基团偶联。最后,除去赖氨酸侧链和SN-38两者处的保护基团得到此实施例的产物。
虽然不希望受理论束缚,但在细胞内蛋白水解后产生的小MW SN-38产物(即缬氨醇-SN-38碳酸酯)具有通过涉及缬氨醇的氨基和碳酸酯的羰基的分子内环化释放完整SN-38的额外途径。
在另一个优选的实施方案中,具有通式1的A'是A-OH,其中A-OH是可塌缩的部分,如4-氨基苄醇或在苄基位置被C1-C10烷基取代的取代的4-氨基苄醇,并且后者经由其氨基附接至L-氨基酸或包含至多4个L-氨基酸部分的多肽;其中N-末端附接至终止于抗体结合基团中的交联剂。
在优选实施方案的另一个实例中,具有通式1的A'的A-OH衍生自取代的4-氨基苄醇,并且‘AA’由通式1中m=1情况下的单个L-氨基酸组成,并且药物以SN-38例示。AA的单个氨基酸可选自以下L-氨基酸中的任一种:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸以及缬氨酸。4-氨基苄醇部分上的取代基R(A'的A-OH实施方案)是氢或选自C1-C10烷基的烷基。此式的实例(其中单个氨基酸AA是L-赖氨酸并且R=H,并且药物由SN-38例示)被称为MAb-CL2A-SN-38(下文所示)。所述结构与接头MAb-CL2-SN-38的区别在于单个赖氨酸残基取代CL2接头中发现的Phe-Lys二肽。将Phe-Lys二肽设计为溶酶体酶的组织蛋白酶B裂解位点,其被认为对于结合的药物的细胞内释放是重要的。出人意料地,尽管消除组织蛋白酶裂解位点,但包含CL2A接头的免疫缀合物在体内显然比包含CL2接头的那些更有效。
在另一个优选的实施方案中,缀合物的L1组分含有具有1-30个重复单体单元的限定的聚乙二醇(PEG)间隔基。在进一步优选的实施方案中,PEG是具有1-12个重复单体单元的限定的PEG。PEG的引入可涉及使用可商购的异双官能化PEG衍生物。异双官能PEG可含有叠氮化物或乙炔基团。
在优选的实施方案中,L2具有在2-40个、但优选2-20个、并且更优选2-5个范围内的多个乙炔(或叠氮化物)基团和单个抗体结合部分。在代表性实例中,‘L2’组分附加至2个炔属基团,从而导致附接附加两个叠氮化物的SN-38分子。与MAb的键合可涉及琥珀酰亚胺。
在优选的实施方案中,当双官能药物含有硫醇反应性部分作为抗体结合基团时,使用硫醇化试剂在抗体的赖氨酸基团上产生抗体上的硫醇。用于通过修饰MAb的赖氨酸基团将硫醇基团引入到抗体上的方法是本领域熟知的(Wong于Chemistry of proteinconjugation and cross-linking,CRC Press,Inc.,Boca Raton,FL(1991),第20-22页中)。或者,使用还原剂如二硫苏糖醇(DTT)轻微还原抗体上的链间二硫键(Willner等人,Bioconjugate Chem.4:521-527(1993))可在抗体上产生7至10个硫醇;其具有在MAb的远离抗原结合区的链间区域中并入多个药物部分的优点。在更优选的实施方案中,SN-38附接至还原的二硫化物巯基导致形成抗体-SN-38免疫缀合物,其中每个抗体分子共价附接有6至8个SN-38部分。提供用于附接药物或其他治疗剂的半胱氨酸残基的其他方法是已知的,如使用半胱氨酸工程化的抗体(参见美国专利号7,521,541,其实施例部分以引用的方式并入本文)。
在替代优选的实施方案中,化学治疗部分是选自由以下组成的组:阿霉素(DOX)、表柔比星、吗啉代阿霉素(吗啉代-DOX)、氰基吗啉代-阿霉素(氰基吗啉代-DOX)、CPT、10-羟基喜树碱、SN-38、托泊替康、勒托替康(lurtotecan)、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素、安莎霉素和埃博霉素。在更优选的实施方案中,化学治疗部分是SN-38。优选地,在优选实施方案的缀合物中,抗体连接至至少一个化学治疗部分;优选1至约12个化学治疗部分;最优选约6至约8个化学治疗部分。
此外,在优选的实施方案中,接头组分‘L2’包含硫醇基团,所述硫醇基团与在所述抗体的一个或多个赖氨酸侧链氨基处引入的硫醇反应性残基反应。在此类情况下,通过本领域充分描述的程序,将抗体用硫醇反应性基团如马来酰亚胺、乙烯基砜、溴乙酰胺或碘乙酰胺预衍生化。
在这种工作的背景下,出人意料地发现了一种方法,通过所述方法可制备CPT药物-接头,其中CPT另外具有10-羟基。这种方法包括但不限于保护10-羟基作为叔丁氧基羰基(BOC)衍生物,随后制备药物-接头缀合物的倒数第二个中间体。通常,除去BOC基团需要用强酸如三氟乙酸(TFA)处理。在这些条件下,含有待除去的保护基团的CPT 20-O-接头碳酸酯也易于裂解,从而产生未修饰的CPT。事实上,如本领域所阐述的,使用可温和除去的甲氧基三苯甲基(MMT)保护基团用于接头分子的赖氨酸侧链的原理正是为了避免这种可能性(Walker等人,2002)。发现通过进行短持续时间的反应,最佳3至5分钟,可能选择性除去酚BOC保护基团。在这些条件下,主要产物是去除10-羟基位置的‘BOC’、而‘20’位置的碳酸酯为完整的产物。
替代方法涉及用除‘BOC’以外的基团保护CPT类似物的10-羟基位置,以使得最终产物准备好与抗体缀合而不需要使10-OH保护基团脱保护。将10-OH转化为酚碳酸酯或酚酯的10-羟基保护基团易容易地在体内施用缀合物后通过生理pH条件或通过酯酶脱保护。He等人已经描述了在生理条件下在10位置处的酚碳酸酯对比10-羟基喜树碱的20位置处的叔碳酸酯的更快除去(He等人,Bioorganic&Medicinal Chemistry 12:4003-4008(2004))。SN-38上的10-羟基保护基团可以是‘COR’,其中R可以是取代的烷基如“N(CH3)2-(CH2)n”,其中n是1-10并且其中末端氨基任选地呈季盐形式以增强水溶性;或简单的烷基残基如“CH3-(CH2)n”,其中n是0-10;或者它可以是烷氧基部分,如“CH3-(CH2)n-O-”,其中n是0-10,或“N(CH3)2-(CH2)n-O-”,其中n是2-10,或“R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基,并且n是具有0-10的值的整数。如果最终衍生物将是碳酸酯,则通过用所选试剂的氯甲酸酯处理容易地制备这些10-羟基衍生物。通常,使用三乙胺作为碱,用摩尔当量的二甲基甲酰胺中的氯甲酸酯处理含有10-羟基的喜树碱如SN-38。在这些条件下,20-OH位置不受影响。为了形成10-O-酯,使用所选试剂的酰基氯。
在制备药物衍生物和抗体的具有通式1的缀合物的优选方法中,其中描述符L2、L1、AA和AX如前面部分中所描述,首先制备双官能药物部分[L2]-[L1]-[AA]m-[A-X]-药物,随后将双官能药物部分缀合至抗体(在本文中表示为“MAb”)。
在制备药物衍生物和抗体的具有通式1的缀合物的优选方法中,其中描述符L2、L1、AA和A-OH如前面部分中所描述,通过首先经由酰胺键将A-OH连接至AA的C-末端、随后将AA的胺末端偶联至L1的羧酸基团来制备双官能药物部分。如果AA不存在(即m=0),则A-OH经由酰胺键直接附接至L1。交联剂[L1]-[AA]m-[A-OH]附接至药物的羟基或氨基,并且其随后经由点击化学通过借助于L1和L2中叠氮化物(或乙炔)与乙炔(或叠氮化物)基团之间的反应而附接至L1部分。
在一个实施方案中,所述抗体是单克隆抗体(MAb)。在其他实施方案中,所述抗体可以是多价和/或多特异性MAb。抗体可以是鼠、嵌合、人源化或人单克隆抗体,并且所述抗体可以是完整、片段(Fab、Fab’、F(ab)2、F(ab’)2)或亚片段(单链构建体)、或具有IgG1、IgG2a、IgG3、IgG4、IgA同种型或来自其的亚分子。
抗体制备
用于制备实际上抗任何靶抗原如Trop-2的单克隆抗体的技术是本领域熟知的。参见例如,和Milstein,Nature 256:495(1975)和Coligan等人(编辑),CURRENTPROTOCOLS IN IMMUNOLOGY,第1卷,第2.5.1-2.6.7页(John Wiley&Sons 1991)。简言之,单克隆抗体可通过以下步骤获得:用包含抗原的组合物注射小鼠,移除脾脏以获得B淋巴细胞,使B淋巴细胞与骨髓瘤细胞融合以产生杂交瘤,克隆所述杂交瘤,选择产生针对所述抗原的抗体的阳性克隆,培养产生针对所述抗原的抗体的克隆,以及从所述杂交瘤培养物分离所述抗体。
MAb可通过许多广泛接受的技术从所述杂交瘤培养物分离和纯化。此类分离技术包括使用蛋白-A或蛋白-G Sepharose的亲和色谱法、尺寸排阻色谱法和离子交换色谱法。参见例如,Coligan第2.7.1-2.7.12页和第2.9.1-2.9.3页。此外,参见Baines等人,“Purification of Immunoglobulin G(IgG),”于METHODS IN MOLECULAR BIOLOGY,第10卷,第79-104页(The Humana Press,Inc.1992)。
在针对免疫原的抗体的初始产生之后,可对抗体进行测序,并且随后通过重组技术制备。鼠抗体和抗体片段的人源化和嵌合是本领域的技术人员已知的,如下文所讨论。
各种技术,诸如制备嵌合或人源化抗体,可涉及抗体克隆和构建的工序。目标抗体的抗原结合Vκ(可变轻链)和VH(可变重链)序列可通过各种分子克隆工序,如RT-PCR、5’-RACE和cDNA文库筛选获得。可通过PCR扩增克隆表达鼠MAb的细胞的MAb的V基因并测序。为确认其保真性,可在细胞培养中以嵌合Ab表达克隆的VL和VH基因,如Orlandi等人所述(Proc.Natl.Acad.Sci.,USA,86:3833(1989))。然后可根据V基因序列设计和构建人源化MAb,如Leung等人所述(Mol.Immunol.,32:1413(1995))。
cDNA可从任何已知的杂交瘤系或产生鼠MAb的转染细胞系通过一般分子克隆技术制备(Sambrook等人,Molecular Cloning,Alaboratory manual,第2版(1989))。MAb的Vκ序列可使用引物VK1BACK和VK1FOR(Orlandi等人,1989)或由Leung等人(BioTechniques,15:286(1993))描述的延伸引物组扩增。VH序列可使用引物对VH1BACK/VH1FOR(Orlandi等人,1989)或由Leung等人(Hybridoma,13:469(1994))描述的与鼠IgG的恒定区退火的引物进行扩增。人源化V基因可通过长寡核苷酸模板合成和PCR扩增的组合构建,如Leung等人(Mol.Immunol.,32:1413(1995))所述。
Vκ的PCR产物可亚克隆至分期载体,诸如基于pBR327的包含Ig启动子、信号肽序列和简便限制性位点的分期载体VKpBR。VH的PCR产物可亚克隆至类似的分期载体,诸如基于pBluescript的VHpBS。可分别从VKpBR和VHpBS切下含有Vκ和VH序列以及启动子和信号肽序列的表达盒,并连接至适当的表达载体,诸如pKh和pG1g中(Leung等人,Hybridoma,13:469(1994))。表达载体可共转染至适当的细胞,并监测上清液流体中嵌合人源化或人MAb的生成。或者,可切下Vκ和VH表达盒并亚克隆至单个表达载体,如pdHL2中,如Gillies等人(J.Immunol.Methods 125:191(1989)并且还在Losman等人,Cancer,80:2660(1997)中示出)所描述。
在替代实施方案中,表达载体可转染至宿主细胞,所述宿主细胞预先改造为在无血清培养基中进行转染、生长和表达。可使用的示例性细胞系包括Sp/EEE、Sp/ESF和Sp/ESF-X细胞系(参见例如,美国专利号7,531,327;7,537,930和7,608,425,其各自的实施例部分以引用的方式并入本文)。这些示例性细胞系基于Sp2/0骨髓瘤细胞系,转染有突变的Bcl-EEE基因,暴露至甲氨蝶呤以扩增转染基因序列,并且预先改造为用于蛋白质表达的无血清细胞系。
嵌合抗体
嵌合抗体是其中人抗体的可变区被例如小鼠抗体的可变区,包括小鼠抗体的互补决定区(CDR)置换的重组蛋白。当施用至受试者时,嵌合抗体表现出降低的免疫原性和增加的稳定性。用于克隆鼠免疫球蛋白可变区的一般技术已公开于例如Orlandi等人,Proc.Nat'l Acad.Sci.USA 6:3833(1989)中。用于构建嵌合抗体的技术是本领域的技术人员熟知的。作为实例,Leung等人,Hybridoma 13:469(1994)通过将编码鼠LL2(抗CD22单克隆抗体)的Vκ和VH结构域的DNA序列与相应的人κ和IgG1恒定区结构域组合生成LL2嵌合体。
人源化抗体
用于产生人源化MAb的技术是本领域熟知的(参见例如,Jones等人,Nature 321:522(1986);Riechmann等人,Nature 332:323(1988);Verhoeyen等人,Science 239:1534(1988);Carter等人,Proc.Nat'l Acad.Sci.USA 89:4285(1992),Sandhu,Crit.Rev.Biotech.12:437(1992)以及Singer等人,J.Immun.150:2844(1993))。嵌合或鼠单克隆抗体可通过将来自小鼠免疫球蛋白的可变重链和轻链的小鼠CDR转移到人抗体的相应可变结构域中来进行人源化。嵌合单克隆抗体中的小鼠框架区(FR)也被人FR序列置换。由于简单地将小鼠CDR转移到人FR通常会导致抗体亲和力的减少或甚至丧失,另外的修饰对于恢复鼠抗体的初始亲和力可为必须的。这可通过将FR区中的一个或多个人残基取代为其鼠对应部分,以获得对其表位具有良好的结合亲和力的抗体来实现。参见例如Tempest等人,Biotechnology 9:266(1991)和Verhoeyen等人,Science 239:1534(1988)。用于取代的优选残基包括位于CDR残基侧链的1、2或3埃内,位于CDR序列附近,或预期与CDR残基相互作用的FR残基。
人抗体
使用组合方法或用人免疫球蛋白基因座转化的转基因动物来产生完全人抗体的方法是本领域已知的(例如,Mancini等人,2004,New Microbiol.27:315-28;Conrad和Scheller,2005,Comb.Chem.High Throughput Screen.8:117-26;Brekke和Loset,2003,Curr.Opin.Pharmacol.3:544-50)。完全人抗体也可通过基因或染色体转染方法以及噬菌体展示技术构建,所有技术都是本领域已知的。参见例如,McCafferty等人,Nature 348:552-553(1990)。预期此类完全人抗体表现出比嵌合或人源化抗体甚至更少的副作用并且在体内起基本上内源性人抗体的作用。
在一个替代方案中,可使用噬菌体展示技术来产生人抗体(例如,Dantas-Barbosa等人,2005,Genet.Mol.Res.4:126-40)。人抗体可从正常人或从表现出特定疾病状态如癌症的人产生(Dantas-Barbosa等人,2005)。从患病个体构建人抗体的优点在于循环抗体谱系可偏向针对疾病相关抗原的抗体。
在这种方法的一个非限制性实例中,Dantas-Barbosa等人(2005)构建了来自骨肉瘤患者的人Fab抗体片段的噬菌体展示库。一般来说,从循环血液淋巴细胞获得总RNA(同上)。从μ、γ和κ链抗体谱系克隆重组Fab并插入噬菌体展示文库中(同上)。将RNA转化成cDNA并用于使用针对重链和轻链免疫球蛋白序列的特异性引物制备Fab cDNA文库(Marks等人,1991,J.Mol.Biol.222:581-97)。根据Andris-Widhopf等人(2000,于:Phage DisplayLaboratory Manual,Barbas等人(编辑),第1版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY第9.1至9.22页中)进行文库构建。将最终Fab片段用限制性核酸内切酶消化,并插入噬菌体基因组中,以制备噬菌体展示库。此类文库可使用本领域已知的标准噬菌体展示方法筛选。可以各种形式进行噬菌体展示,对于它们的综述,参见例如Johnson和Chiswell,Current Opinion in Structural Biology 3:5564-571(1993)。
人抗体也可通过体外活化的B细胞来生成。参见美国专利号5,567,610和5,229,275,所述专利以引用的方式整体并入本文。熟练技术人员将认识到,这些技术是示例性的,并且可使用用于制备和筛选人抗体或抗体片段的任何已知方法。
在另一个替代方案中,使用标准免疫实验方案,已进行遗传工程化以产生人抗体的转基因动物可用来产生针对基本上任何免疫原性靶标的抗体。用于从转基因小鼠获得人抗体的方法由Green等人et al.,Nature Genet.7:13(1994);Lonberg等人,Nature 368:856(1994)和Taylor等人,Int.Immun.6:579(1994)公开。这种系统的非限制性实例是来自(Fremont,CA)的(例如,Green等人,1999,J.Immunol.Methods 231:11-23,以引用的方式并入本文)。在和类似动物中,已使小鼠抗体基因失活并置换为功能性人抗体基因,而小鼠免疫系统的其余部分保持完整。
用含有人IgH和Igκ基因座的部分的种系构型YAC(酵母人工染色体)转化所述基因座部分包括大部分可变区序列连同辅助基因和调控序列。人可变区谱系可用于获得产生抗体的B细胞,所述B细胞可通过已知的技术加工成杂交瘤。用靶抗原免疫的将通过正常免疫应答产生人抗体,其可通过上文论述的标准技术收获和/或产生。可获得的多种品系,所述品系各自能够产生不同类别的抗体。转基因产生的人抗体已证明具有治疗潜能,同时保留正常人抗体的药物动力学性质(Green等人,1999)。熟练的技术人员将认识到,所要求保护的组合物和方法不限于使用系统,而是可利用已进行遗传工程化以产生人抗体的任何转基因动物。
已知抗体和靶标抗原
如上所述,在优选的实施方案中,ADC用于治疗癌症。在某些实施方案中,靶癌症可表达一种或多种靶肿瘤相关抗原(TAA)。可用于治疗癌症的具体抗体包括但不限于LL1(抗CD74)、LL2或RFB4(抗CD22)、维妥珠单抗(hA20,抗CD20)、利妥昔单抗(抗CD20)、奥比妥珠单抗(GA101,抗CD20)、兰布罗利珠单抗(抗PD-1受体)、纳武单抗(抗PD-1受体)、伊匹单抗(抗CTLA-4)、RS7(抗上皮糖蛋白-1(EGP-1,也称为Trop-2))、PAM4或KC4(两者均为抗粘蛋白)、MN-14(抗癌胚抗原(CEA,也称为CD66e或CEACAM5)、MN-15或MN-3(抗CEACAM6)、Mu-9(抗结肠特异性抗原-p)、Immu 31(抗α-胎蛋白)、R1(抗IGF-1R)、A19(抗CD19)、TAG-72(例如,CC49)、Tn、J591或HuJ591(抗PSMA(前列腺特异性膜抗原))、AB-PG1-XG1-026(抗PSMA二聚体)、D2/B(抗PSMA)、G250(抗碳酸酐酶IX MAb)、L243(抗HLA-DR)、阿仑单抗(抗CD52)、贝伐单抗(抗VEGF)、西妥昔单抗(抗EGFR)、吉妥珠单抗(抗CD33)、替伊莫单抗(抗CD20)、帕尼单抗(抗EGFR)、托西莫单抗(抗CD20)、PAM4(又名克伐珠单抗,抗粘蛋白)和曲妥珠单抗(抗ErbB2)。此类抗体是本领域已知的(例如,美国专利号5,686,072;5,874,540;6,107,090;6,183,744;6,306,393;6,653,104;6,730.300;6,899,864;6,926,893;6,962,702;7,074,403;7,230,084;7,238,785;7,238,786;7,256,004;7,282,567;7,300,655;7,312,318;7,585,491;7,612,180;7,642,239;以及美国专利申请公布号20050271671;20060193865;20060210475;20070087001;各自的实施例部分以引用的方式并入本文)。所用的具体已知的抗体包括hPAM4(美国专利号7,282,567)、hA20(美国专利号7,151,164)、hA19(美国专利号7,109,304)、hIMMU-31(美国专利号7,300,655)、hLL1(美国专利号7,312,318)、hLL2(美国专利号5.789.554)、hMu-9(美国专利号7,387,772)、hL243(美国专利号7,612,180)、hMN-14(美国专利号6,676,924)、hMN-15(美国专利号8,287,865)、hR1(美国专利号9,441,043)、hRS7(美国专利号7,238,785)、hMN-3(美国专利号7,541,440)、AB-PG1-XG1-026(美国专利申请11/983,372,其保藏为ATCC PTA-4405和PTA-4406)以及D2/B(WO 2009/130575),关于附图和实施例部分,每一个列举的专利或申请的文本以引用的方式并入本文。
可被靶向的其他可用肿瘤相关抗原包括碳酸酐酶IX、B7、CCL19、CCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20(例如,C2B8、hA20、1F5 MAb)、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD47、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM6、CTLA-4、α-胎蛋白(AFP)、VEGF(例如,纤连蛋白剪接变体)、ED-B纤连蛋白(例如,L19)、EGP-1(Trop-2)、EGP-2(例如,17-1A)、EGF受体(ErbB1)(例如,)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GRO-β、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、组蛋白H2B、组蛋白H3、组蛋白H4、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节苷脂、HCG、L243所结合的HLA-DR抗原、CD66抗原即CD66a-d或它们的组合、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞迁移抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5ac、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PAM4抗原、PD-1受体、PD-L1、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、汤姆森-弗里德里希抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、Trop-2、VEGFR、RANTES、T101以及癌症干细胞抗原、补体因子C3、C3a、C3b、C5a、C5和致癌基因产物。
归因于更具治疗耐受性前体恶性细胞群体的癌症干细胞(Hill和Perris,J.Natl.Cancer Inst.2007;99:1435-40)具有可在某些癌症类型中靶向的抗原,诸如前列腺癌(Maitland等人,Ernst Schering Found.Sympos.Proc.2006;5:155-79)、非小细胞肺癌(Donnenberg等人,J.Control Release 2007;122(3):385-91)和成胶质细胞瘤(Beier等人,Cancer Res.2007;67(9):4010-5)中的CD133,以及结肠直肠癌(Dalerba等人,Proc.Natl.Acad.Sci.USA 2007;104(24)10158-63)、胰腺癌(Li等人,Cancer Res.2007;67(3):1030-7)和头颈部鳞状细胞癌(Prince等人,Proc.Natl.Acad.Sci.USA 2007;104(3)973-8)中的CD44。乳腺癌治疗的另一个有用靶标是Taylor等人(Biochem.J.2003;375:51-9)描述的LIV-1抗原。
检查点抑制剂抗体已用于癌症治疗。免疫检查点是指在免疫系统中负责维持自身耐受性和调节免疫系统应答的程度,以尽量减少外周组织损伤的抑制途径。然而,肿瘤细胞也可活化免疫系统检查点,以减少针对肿瘤组织的免疫应答的有效性。针对细胞毒性T-淋巴细胞抗原4(CTLA4,也称为CD152)、程序性细胞死亡蛋白1(PD1,也称为CD279)和程序性细胞死亡1配体1(PD-L1,也称为CD274)的示例性检查点抑制剂抗体可与一种或多种其他剂组合使用,以增加针对患病细胞、组织或病原体的免疫应答的有效性。示例性抗PD1抗体包括兰布罗利珠单抗(MK-3475,MERCK)、纳武单抗(BMS-936558,BRISTOL-MYERS SQUIBB)、AMP-224(MERCK)和匹地利珠单抗(CT-011,CURETECH LTD.)。抗PD1抗体可例如从(AB137132)、(EH12.2H7、RMP1-14)和AFFYMETRIXEBIOSCIENCE(J105、J116、MIH4)商购获得。示例性抗PD-L1抗体包括MDX-1105(MEDAREX)、MEDI4736(MEDIMMUNE)、MPDL3280A(GENENTECH)和BMS-936559(BRISTOL-MYERSSQUIBB)。抗PD-L1抗体也可例如从AFFYMETRIX EBIOSCIENCE(MIH1)商购获得。示例性抗CTLA4抗体包括伊匹单抗(Bristol-Myers Squibb)和曲美木单抗(PFIZER)。抗PD1抗体可例如从(AB134090),SINO BIOLOGICAL INC.(11159-H03H,11159-H08H)和THERMO SCIENTIFICPIERCE(PA5-29572,PA5-23967,PA5-26465,MA1-12205,MA1-35914)商购获得。伊匹单抗最近被FDA批准用于转移性黑素瘤的治疗(Wada等人,2013,J Transl Med 11:89)。
巨噬细胞迁移抑制因子(MIF)是先天性和适应性免疫和细胞凋亡的重要调控因子。据报道,CD74是MIF的内源性受体(Leng等人,2003,JExpMed 197:1467-76)。拮抗性抗CD74抗体对MIF介导的细胞内途径的治疗作用可用于治疗一系列广泛的疾病状态,如膀胱癌、前列腺癌、乳腺癌、肺癌和结肠癌(例如,Meyer-Siegler等人,2004,BMC Cancer 12:34;Shachar&Haran,2011,Leuk Lymphoma 52:1446-54)。米拉珠单抗(hLL1)是具有用于治疗MIF介导的疾病的治疗用途的示例性抗CD74抗体。
所用的各种其他抗体是本领域已知的(例如,美国专利号5,686,072;5,874,540;6,107,090;6,183,744;6,306,393;6,653,104;6,730.300;6,899,864;6,926,893;6,962,702;7,074,403;7,230,084;7,238,785;7,238,786;7,256,004;7,282,567;7,300,655;7,312,318;7,585,491;7,612,180;7,642,239以及美国专利申请公布号20060193865,所述专利各自以引用的方式并入本文)。
所用的抗体可从广泛的已知来源商购获得。例如,许多分泌抗体的杂交瘤系可自美国典型培养物保藏中心(American Type Culture Collection(ATCC,Manassas,VA))获得。大量针对各种疾病靶标(包括肿瘤相关抗原)的抗体已保藏于ATCC和/或已公布可变区序列并且可获得以用于所要求保护的方法和组合物中。参见例如,美国专利号7,312,318;7,282,567;7,151,164;7,074,403;7,060,802;7,056,509;7,049,060;7,045,132;7,041,803;7,041,802;7,041,293;7,038,018;7,037,498;7,012,133;7,001,598;6,998,468;6,994,976;6,994,852;6,989,241;6,974,863;6,965,018;6,964,854;6,962,981;6,962,813;6,956,107;6,951,924;6,949,244;6,946,129;6,943,020;6,939,547;6,921,645;6,921,645;6,921,533;6,919,433;6,919,078;6,916,475;6,905,681;6,899,879;6,893,625;6,887,468;6,887,466;6,884,594;6,881,405;6,878,812;6,875,580;6,872,568;6,867,006;6,864,062;6,861,511;6,861,227;6,861,226;6,838,282;6,835,549;6,835,370;6,824,780;6,824,778;6,812,206;6,793,924;6,783,758;6,770,450;6,767,711;6,764,688;6,764,681;6,764,679;6,743,898;6,733,981;6,730,307;6,720,155;6,716,966;6,709,653;6,693,176;6,692,908;6,689,607;6,689,362;6,689,355;6,682,737;6,682,736;6,682,734;6,673,344;6,653,104;6,652,852;6,635,482;6,630,144;6,610,833;6,610,294;6,605,441;6,605,279;6,596,852;6,592,868;6,576,745;6,572;856;6,566,076;6,562,618;6,545,130;6,544,749;6,534,058;6,528,625;6,528,269;6,521,227;6,518,404;6,511,665;6,491,915;6,488,930;6,482,598;6,482,408;6,479,247;6,468,531;6,468,529;6,465,173;6,461,823;6,458,356;6,455,044;6,455,040,6,451,310;6,444,206’6,441,143;6,432,404;6,432,402;6,419,928;6,413,726;6,406,694;6,403,770;6,403,091;6,395,276;6,395,274;6,387,350;6,383,759;6,383,484;6,376,654;6,372,215;6,359,126;6,355,481;6,355,444;6,355,245;6,355,244;6,346,246;6,344,198;6,340,571;6,340,459;6,331,175;6,306,393;6,254,868;6,187,287;6,183,744;6,129,914;6,120,767;6,096,289;6,077,499;5,922,302;5,874,540;5,814,440;5,798,229;5,789,554;5,776,456;5,736,119;5,716,595;5,677,136;5,587,459;5,443,953;5,525,338。这些仅仅是示例性的,并且许多其他抗体及其杂交瘤是本领域已知的。熟练技术人员将认识到,针对几乎任何疾病相关抗原的抗体序列或分泌抗体的杂交瘤可通过在ATCC、NCBI和/或USPTO数据库中简单搜索针对目标选定疾病相关靶标的抗体来获得。可使用本领域熟知的标准技术扩增、切除克隆的抗体的抗原结合结构域,连接至表达载体中,转染到适应宿主细胞中并用于蛋白质产生。
抗体同种异型
治疗性抗体的免疫原性与输注反应的风险增加和治疗性应答的持续时间减少相关(Baert等人,2003,N Engl J Med 348:602-08)。治疗性抗体在宿主中诱导免疫应答的程度可部分地通过抗体的同种异型来确定(Stickler等人,2011,Genes and Immunity 12:213-21)。抗体同种异型涉及抗体的恒定区序列中特定位置处的氨基酸序列变型。含有重链γ-型恒定区的IgG抗体的同种异型被命名为Gm同种异型(1976,J Immunol 117:1056-59)。
对于常见的IgG1人抗体而言,最普遍的同种异型是G1m1(Stickler等人,2011,Genes and Immunity 12:213-21)。然而,G1m3同种异型在白种人(Caucasians)中也是常见的(Stickler等人,2011)。已经报告了当向非G1m1(nG1m1)接受者(如G1m3患者)施用时,G1m1抗体含有倾向于诱导免疫应答的同种异型序列(Stickler等人,2011)。当向G1m1患者施用时,非G1m1同种异型抗体不是作为免疫原性的(Stickler等人,2011)。
人G1m1同种异型包含重链IgG1的CH3序列中Kabat位置356处的氨基酸天冬氨酸和Kabat位置358处的氨基酸亮氨酸。nG1m1同种异型包含Kabat位置356处的氨基酸谷氨酸和Kabat位置358处的氨基酸甲硫氨酸。G1ml和nG1ml同种异型二者包含Kabat位置357处的谷氨酸残基,并且所述同种异型有时称为DEL和EEM同种异型。针对示例性抗体利妥昔单抗(SEQ ID NO:7)和维妥珠单抗(SEQ ID NO:8),以下示出G1m1和nG1m1同种异型抗体的重链恒定区序列的非限制性实例。
利妥昔单抗重链可变区序列(SEQ ID NO:7)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
维妥珠单抗重链可变区(SEQ ID NO:8)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Jefferis和Lefranc(2009,mAbs 1:1-7)综述了为IgG同种异型的特征的序列变型和它们对免疫原性的影响。他们报道了与G1m17同种异型中的Kabat 214处的赖氨酸残基相比,G1m3同种异型的特征在于Kabat位置214处的精氨酸残基。nG1m1,2同种异型的特征在于Kabat位置356处的谷氨酸、Kabat位置358处的甲硫氨酸和Kabat位置431处的丙氨酸。G1m1,2同种异型的特征在于Kabat位置356处的天冬氨酸、Kabat位置358处的亮氨酸和Kabat位置431处的甘氨酸。除重链恒定区序列变体之外,Jefferis和Lefranc(2009)报告了κ轻链恒定区中的同种异型变体,其中Km1同种异型的特征在于Kabat位置153处的缬氨酸和Kabat位置191处的亮氨酸,Km1,2同种异型的特征在于Kabat位置153处上的丙氨酸和Kabat位置191处的亮氨酸,并且Km3同种异型的特征在于Kabat位置153处的丙氨酸和Kabat位置191处的缬氨酸。
关于治疗性抗体,维妥珠单抗和利妥昔单抗分别是对治疗各种各样的血液恶性肿瘤和/或自身免疫疾病有用的、针对CD20的人源化和嵌合IgG1抗体。表1比较了利妥昔单抗与维妥珠单抗的同种异型序列。如在表1中所示,利妥昔单抗(G1m17,1)是DEL同种异型IgG1,在利妥昔单抗中的赖氨酸相对维妥珠单抗中的精氨酸在Kabat位置214(重链CH1)处具有额外序列变化。已经报告了在受试者中维妥珠单抗比利妥昔单抗的免疫原性小(参见例如,Morchhauser等人,2009,J Clin Oncol 27:3346-53;Goldenberg等人,2009,Blood113:1062-70;Robak&Robak,2011,BioDrugs 25:13-25),所述作用已经被归因于人源化抗体与嵌合抗体之间的差异。然而,EEM与DEL同种异型之间的同种异型的差异可能也解释了维妥珠单抗的较低免疫原性。
表1利妥昔单抗与维妥珠单抗的同种异型
为了减小治疗性抗体在nG1m1基因型个体中的免疫原性,希望选择的抗体同种异型对应于G1m3同种异型,其特征在于Kabat 214处的精氨酸;和nG1m1,2无效同种异型,其特征在于Kabat位置356处的谷氨酸、Kabat位置358处的甲硫氨酸以及Kabat位置431处的丙氨酸。出人意料地,发现在长时间段内重复皮下施用G1m3抗体不会产生显著免疫应答。在替代实施方案中,与G1m3同种异型有共同之处的人IgG4重链具有Kabat 214处的精氨酸、Kabat356处的谷氨酸、Kabat 359处的甲硫氨酸和Kabat431处的丙氨酸。由于免疫原性似乎至少部分与这些位置处的残基相关,人IgG4重链恒定区序列用于治疗抗体也是优选的实施方案。G1m3 IgG1抗体与IgG4抗体的组合也可用于治疗剂施用。
纳米抗体
纳米抗体是大小为约12-15kDa(长度为约110个氨基酸)的单结构域抗体。纳米抗体可选择性地结合至靶标抗原,如完整大小的抗体,并且具有类似的抗原亲和力。然而,由于其大小较小,因此能够更好地穿透实体肿瘤。较小的大小也有助于稳定纳米抗体,其比完整大小的抗体更耐pH和极端温度(Van Der Linden等人,1999,Biochim Biophys Act1431:37-46)。单结构域抗体最初根据如下发现开发:骆驼科(骆驼、羊驼、美洲驼)具有无轻链的完全功能抗体(例如,Hamsen等人,2007,Appl Microbiol Biotechnol 77:13-22)。重链抗体由单个可变结构域(VHH)和两个恒定结构域(CH2和CH3)组成。像抗体那样,纳米抗体可开发和用作多价和/或双特异性构建体。纳米抗体的人源化形式正在商业开发中,其靶向许多靶抗原,如IL-6R、vWF、TNF、RSV、RANKL、IL-17A&F和IgE(例如,Ghent、Belgium),在癌症和其他疾病中具有潜在临床用途(例如,Saerens等人,2008,Curr OpinPharmacol 8:600-8;Muyldermans,2013,Ann Rev Biochem 82:775-97;Ibanez等人,2011,J Infect Dis 203:1063-72)。
纳米抗体的血浆半衰期小于完全大小的抗体,主要通过肾脏途径消除。因为它们缺乏Fc区,所以不表现出补体依赖性细胞毒性。
纳米抗体可通过以下步骤制备:用靶抗原免疫骆驼、美洲驼、羊驼或鲨鱼,然后分离mRNA,克隆至文库并筛选抗原结合。纳米抗体序列可通过标准技术人源化(例如,Jones等人,1986,Nature 321:522;Riechmann等人,1988,Nature 332:323;Verhoeyen等人,1988,Science 239:1534;Carter等人,1992,Proc.Nat'l Acad.Sci.USA 89:4285,Sandhu,1992,Crit.Rev.Biotech.12:437;Singer等人,1993,J.Immun.150:2844)。由于骆驼科与人FR序列之间的高同源性,人源化相对直接。
在各种实施方案中,主题ADC可包括用于将缀合的药物靶向递送至靶标癌细胞的纳米抗体。所用的纳米抗体公开于例如美国专利号7,807,162;7,939,277;8,188,223;8,217,140;8,372,398;8,557,965;8,623,361和8,629,244,所述专利各自的实施例部分以引用的方式并入本文)。
抗体片段
抗体片段是抗体的抗原结合部分,诸如F(ab’)2、Fab’、F(ab)2、Fab、Fv、sFv、scFv等。识别特定表位的抗体片段可通过已知技术制备。F(ab’)2片段,例如可通过胃蛋白酶消化抗体分子来制备。这些和其他方法例如由Goldenberg,美国专利号4,036,945和4,331,647以及其中包含的参考文献描述。还可参见Nisonoff等人,Arch Biochem.Biophys.89:230(1960);Porter,Biochem.J.73:119(1959);Edelman等人,于METHODS IN ENZYMOLOGY第1卷,第422页(Academic Press 1967)和Coligan,第2.8.1-2.8.10和2.10.-2.10.4页中。或者,可构建Fab’表达文库(Huse等人,1989,Science,246:1274-1281),以使快速和简易鉴定具有所需特异性的单克隆Fab’片段。
单链Fv分子(scFv)包括VL结构域和VH结构域。VL和VH结构域缔合形成靶标结合位点。这两个结构域还通过肽接头(L)共价连接。如果VL结构域是scFv分子的N-末端部分,则scFv分子表示为VL-L-VH,或如果VH结构域是scFv分子的N-末端部分,则表示为VH-L-VL。用于制备scFv分子和设计合适的肽接头的方法描述于美国专利号4,704,692、美国专利号4,946,778、R.Raag和M.Whitlow,"Single Chain Fvs."FASEB第9卷:73-80(1995)以及R.E.Bird和B.W.Walker,Single Chain Antibody Variable Regions,TIBTECH,第9卷:132-137(1991)。
其他抗体片段,例如单结构域抗体片段,是本领域已知的并且可用于受权利要求书保护的构建体。单结构域抗体(VHH)可例如通过标准免疫技术从骆驼、羊驼或美洲驼获得。(参见例如,Muyldermans等人,TIBS 26:230-235,2001;Yau等人,J Immunol Methods281:161-75,2003;Maass等人,J Immunol Methods 324:13-25,2007)。VHH可具有强大的抗原结合能力,并且可与传统VH-VL对无法触及的新表位相互作用(Muyldermans等人,2001)。羊驼血清IgG含有约50%的骆驼科仅重链IgG抗体(HCAb)(Maass等人,2007)。可使用已知的抗原诸如TNF-α免疫羊驼,并且可分离结合至以及中和靶抗原的VHH(Maass等人,2007)。已鉴定扩增几乎所有编码羊驼VHH的序列的PCR引物,并且可用于构建羊驼VHH噬菌体展示文库,所述文库可用于通过本领域熟知的标准生物淘选技术进行抗体片段分离(Maass等人,2007)。
抗体片段也可通过全长抗体的蛋白水解或通过在大肠杆菌或另一种宿主中表达编码该片段的DNA来制备。抗体片段可通过常规方法使用胃蛋白酶或木瓜蛋白酶消化全长抗体来获得。例如,抗体片段可通过使用胃蛋白酶来酶切抗体来制备,从而得到大约100kD以F(ab’)2表示的片段。此片段可使用硫醇还原剂和任选地由二硫键联的裂解产生的巯基基团的封端基团进一步裂解,以产生大约50kd Fab’单价片段。或者,使用木瓜蛋白酶进行酶促裂解直接产生两个单价Fab片段和一个Fc片段。
还可使用裂解抗体的其他方法,如分离重链以形成单价轻链-重链片段、进一步裂解片段,或其他酶促、化学或遗传技术,只要所述片段结合至由完整抗体识别的抗原即可。
双特异性和多特异性抗体
双特异性抗体可用于许多生物医学应用中。例如,具有用于肿瘤细胞表面抗原和用于T细胞表面受体的结合位点的双特异性抗体可指导通过T细胞的特异性肿瘤细胞的溶解。识别神经胶质瘤和T细胞上的CD3表位的双特异性抗体已经成功用于治疗人患者的脑肿瘤(Nitta,等人Lancet.1990;355:368-371)。优选的双特异性抗体是抗CD3 X抗Trop-2抗体。在替代实施方案中,抗CD3抗体或其片段可附接至针对B细胞相关抗原的抗体或片段,如抗CD3 X抗CD19、抗CD3 X抗CD20、抗CD3 X抗CD22、抗CD3 X抗HLA-DR或抗CD3 X抗CD74。在某些实施方案中,本文公开的用于治疗剂递送的技术和组合物可与作为靶向部分的双特异性或多特异性抗体一起使用。
用于产生双特异性或多特异性抗体的许多方法是已知的,如例如美国专利号7,405,320所公开,所述专利的实施例部分以引用的方式并入本文。双特异性抗体可通过四源杂交瘤方法产生,所述方法包括使各自产生识别不同抗原位点的单克隆抗体的两种不同杂交瘤的融合(Milstein和Cuello,Nature,1983;305:537-540)。
用于产生双特异性抗体的另一种方法使用异双官能交联剂来化学系栓两种不同的单克隆抗体(Staerz,等人Nature,1985;314:628-631;Perez,等人Nature,1985;316:354-356)。双特异性抗体也可通过将两种亲本单克隆抗体中的每种还原成相应半分子,然后将其混合并使其再氧化以获得杂合体结构(Staerz和Bevan.Proc Natl Acad Sci U SA.1986;83:1453-1457)。另一替代方案涉及使用适当接头使两种或三种单独纯化的Fab'片段化学交联。(参见例如,欧洲专利申请0453082)。
其他方法包括通过经由逆转录病毒来源的穿梭载体将独特的选择性标记基因转移至相应的亲本杂交瘤中,随后将它们融合(DeMonte,等人Proc Natl Acad Sci U SA.1990,87:2941-2945);或使用含有不同抗体的重链和轻链基因的表达质粒转染杂交瘤细胞系来提高产生杂合体杂交瘤的效率。
可将同源VH和VL结构域与具有适当组成和长度(通常由多于12个氨基酸残基组成)的肽接头接合以形成具有结合活性的单链Fv(scFv)。制造scFv的方法公开于美国专利号4,946,778和美国专利号5,132,405中,所述专利各自的实施例部分以引用的方式并入本文。肽接头长度减小至小于12个氨基酸残基防止了相同链上VH和VL结构域的配对,并且迫使VH和VL结构域与其他链上的互补结构域的配对,从而形成功能多聚体。与3与12个氨基酸残基之间的接头接合的VH和VL结构域的多肽链主要形成二聚体(称为双抗体)。使用0与2个氨基酸残基之间的接头,有助于形成三聚体(称为三抗体)和四聚体(称为四抗体),但除接头长度之外,寡聚化的准确模式似乎取决于V结构域(VH-接头-VL或VL-接头-VH)的组成以及取向。
用于产生多特异性或双特异性抗体的这些技术就低收率、纯化的必要性、低稳定性或技术的劳动密集性而言表现出许多困难。最近,已经利用称为“对接锁定(dock andlock)”(DNL)的技术来产生几乎任何所需抗体、抗体片段和其他效应分子的组合(参见例如,美国专利号7,521,056;7,527,787;7,534,866;7,550,143;7,666,400;7,858,070;7,871,622;7,906,121;7,906,118;8,163,291;7,901,680;7,981,398;8,003,111以及8,034,352,所述专利各自的实施例部分以引用的方式并入本文。所述技术利用称为锚定结构域(AD)和二聚化与对接结构域(DDD)的互补蛋白质结合结构域,其彼此结合并且允许组装范围为二聚体、三聚体、四聚体、五聚体和六聚体的复杂分子。这些以高产率形成稳定复合物而不需要广泛纯化。DNL技术允许组装单特异性、双特异性或多特异性抗体。本领域已知的用于制备双特异性或多特异性抗体的任何技术可用于实施本发明要求保护的方法。
缀合方案
在某些实施方案中,细胞毒性药物或其他治疗剂或诊断剂可共价附接至抗体或抗体片段以形成免疫缀合物。在一些实施方案中,药物或其他剂可经由载体部分附接至抗体或其片段。载体部分可例如附接至还原的SH基团和/或碳水化合物侧链。载体部分可经由二硫键形成附接至还原抗体组分的铰链区。或者,此类剂可使用异双官能交联剂,如3-(2-吡啶基二硫代)丙酸N-琥珀酰基酯(SPDP)附接。Yu等人,Int.J.Cancer 56:244(1994)。这种缀合的一般技术是本领域熟知的。参见例如,Wong,CHEMISTRY OF PROTEIN CONJUGATION ANDCROSS-LINKING(CRC Press 1991);Upeslacis等人,“Modification of Antibodies byChemical Methods,”于MONOCLONAL ANTIBODIES:PRINCIPLES AND APPLICATIONS,Birch等人(编辑),第187-230页(Wiley-Liss,Inc.1995)中;Price,“Production andCharacterization of Synthetic Peptide-Derived Antibodies,”于MONOCLONALANTIBODIES:PRODUCTION,ENGINEERING AND CLINICAL APPLICATION,Ritter等人(编辑),第60-84页(Cambridge University Press 1995)中。或者,载体部分可经由抗体的Fc区中的碳水化合物部分缀合。
用于经由抗体碳水化合物部分将官能团缀合至抗体的方法是本领域的技术人员熟知的。参见例如,Shih等人,Int.J.Cancer 41:832(1988);Shih等人,Int.J.Cancer 46:1101(1990);以及Shih等人,美国专利号5,057,313,其实施例部分以引用的方式并入本文。一般方法涉及使具有氧化的碳水化合物部分的抗体与具有至少一个游离胺官能团的载体聚合物反应。这种反应产生初始席夫碱(亚胺)键联,所述键联可通过还原成仲胺来稳定,以形成最终缀合物。
如果ADC的抗体组分是抗体片段,则可能不存在Fc区。然而,有可能将碳水化合物部分引入全长抗体或抗体片段的轻链可变区中。参见例如,Leung等人,J.Immunol.154:5919(1995);美国专利号5,443,953和6,254,868,所述专利的实施例部分以引用的方式并入本文。使用工程化的碳水化合物部分来附接治疗剂或诊断剂。
用于将载体部分附接至靶向分子的替代方法涉及使用点击化学反应。点击化学方法最初构想为通过将小亚基以模组方式连接在一起来快速生成复合物的方法。(参见例如,Kolb等人,2004,Angew Chem Int Ed 40:3004-31;Evans,2007,Aust J Chem 60:384-95。)各种形式的点击化学反应是本领域已知的,如胡伊斯根(Huisgen)1,3-偶极环加成铜催化反应(Tornoe等人,2002,J Organic Chem 67:3057-64),其通常称为“点击反应”。其他替代方案包括环加成反应,诸如Diels-Alder、亲核取代反应(特别是小张力环如环氧基和氮丙啶化合物)、脲化合物的羰基化学形成以及涉及碳-碳双键的反应,诸如硫醇-炔反应中的炔烃。
叠氮化物炔烃胡伊斯根环加成反应使用铜催化剂在存在还原剂的情况下催化末端炔烃基附接至第一分子的反应。在存在包含叠氮化物部分的第二分子的情况下,叠氮化物与活化的炔烃反应以形成1,4-二取代的1,2,3-三唑。铜催化反应在室温下进行,并且具有足够的特异性,以使得反应产物的纯化通常不是必须的。(Rostovstev等人,2002,AngewChem Int Ed 41:2596;Tornoe等人,2002,J Org Chem 67:3057。)叠氮化物和炔烃官能团对水介质中的生物分子为基本上惰性的,从而使反应在复合物溶液中进行。所形成的三唑在化学上是稳定的,未经受酶裂解,从而使得点击化学产物在生物系统中是高度稳定的。虽然铜催化剂对活细胞是有毒的,但基于铜的点击化学反应可在体外用于免疫缀合物形成。
已提出用于生物分子的共价修饰的无铜点击反应。(参见例如,Agard等人,2004,JAm Chem Soc 126:15046-47。)无铜反应使用环张力代替铜催化剂来促进[3+2]叠氮化物-炔烃环加成反应(同上)。例如,环辛炔是包含内部炔烃键的8碳环结构。闭环结构诱导了乙炔的显著键角变形,乙炔与叠氮化物基团反应形成三唑具有高度反应性。因此,环辛炔衍生物可用于无铜点击反应(同上)。
Ning等人(2010,Angew Chem Int Ed 49:3065-68)报告了另一种类型的无铜点击反应,涉及张力促进的炔烃-硝酮环加成反应。为解决初始环辛炔反应的缓慢速率,将吸电子基团邻近附接至三键(同上)。此类取代环辛炔的实例包括二氟化环辛炔、4-二苯并环辛炔醇和氮杂环辛炔(同上)。替代无铜反应涉及张力促进的炔烃-硝酮环加成反应,得到N-烷基化异噁唑啉(同上)。据报告,所述反应具有特别快的反应动力学,并且用于肽和蛋白质的位点特异性修饰的一锅三步骤方案(同上)。硝酮通过适当的醛与N-甲基羟胺的缩合反应制备,并且环加成反应在乙腈和水的混合物中进行(同上)。这些和其他已知的点击化学反应可用于在体外将载体部分附接至抗体。
Agard等人(2004,J Am Chem Soc 126:15046-47)显示,在存在全乙酰化N-叠氮基乙酰基甘露糖胺的情况下在CHO细胞中表达重组糖蛋白的结果是将N-叠氮基乙酰基唾液酸生物掺入糖蛋白的碳水化合物。叠氮基衍生化的糖蛋白与生物素化环辛炔特异性反应以形成生物素化糖蛋白,而无叠氮基部分的对照糖蛋白仍然未标记(同上)。Laughlin等人(2008,Science 320:664-667)使用类似的技术来代谢标记与全乙酰化N-叠氮基乙酰半乳糖胺一起孵育的斑马鱼胚胎中的细胞表面聚糖。叠氮基衍生化的聚糖与二氟化环辛炔(DIFO)试剂反应以使聚糖在体内可视化。
Diels-Alder反应也用于分子的体内标记。Rossin等人(2010,Angew Chem Int Ed49:3375-78)报道了携带反式环辛烯(TCO)反应性部分和111In标记的四嗪DOTA衍生物的肿瘤定位的抗TAG72(CC49)抗体之间的体内收率为52%。将TCO标记的CC49抗体施用至携带结肠癌异种移植物的小鼠,在1天后注射111In标记的四嗪探针(同上)。放射性标记的探针与肿瘤定位的抗体的反应的结果是在肿瘤中产生显著的放射性定位,如在注射放射性标记探针三小时后活小鼠的SPECT成像所示,肿瘤与肌肉的比率为13:1(同上)。结果确认了TCO和四嗪标记分子的体内化学反应。
点击化学反应的修饰适用于体外或体内。反应性靶向分子可通过化学缀合或通过生物掺入形成。靶向分子,诸如抗体或抗体片段,可使用叠氮基部分、取代环辛炔或炔烃基或硝酮部分活化。在靶向分子包含叠氮基或硝酮基的情况下,对应的可靶向构建体将包含取代环辛炔或炔烃基,反之亦然。此类活化分子可通过活细胞中的代谢掺入制备,如上文所讨论。
或者,此类部分化学缀合至生物分子的方法是本领域熟知的,并且可利用任何此类已知的方法。免疫缀合物形成的一般方法公开于例如美国专利号4,699,784、4,824,659、5,525,338、5,677,427、5,697,902、5,716,595、6,071,490、6,187,284、6,306,393、6,548,275、6,653,104、6,962,702、7,033,572、7,147,856和7,259,240,其各自的实施例部分以引用的方式并入本文。
其他治疗剂
多种治疗性试剂可与主题ADC同时或依序施用。或者,此类剂可与本发明的抗体缀合,例如,药物、毒素、寡核苷酸、免疫调节剂、激素、激素拮抗剂、酶、酶抑制剂、放射性核素、血管生成抑制剂等。在此列举的治疗剂是对于如上所述的ADC单独施用也是有用的那些剂。治疗剂包括例如化学治疗药物,如长春花生物碱、蒽环类药物如阿霉素、吉西他滨、表鬼臼毒素、紫杉烷、抗代谢物、烷基化剂、抗生素、SN-38、COX-2抑制剂、抗有丝分裂剂、抗血管生成剂和促凋亡剂,特别是阿霉素、甲氨蝶呤、紫杉酚、CPT-11、喜树碱、蛋白酶体抑制剂、mTOR抑制剂、HDAC抑制剂、酪氨酸激酶抑制剂和其他药物。用于同时或依序施用或用于制备ADC的其他有用的抗癌细胞毒性药物包括氮芥、烷基磺酸盐、亚硝基脲、三氮烯、叶酸类似物、COX-2抑制剂、抗代谢物、嘧啶类似物、嘌呤类似物、铂配位络合物、mTOR抑制剂、酪氨酸激酶抑制剂、蛋白酶体抑制剂、HDAC抑制剂、喜树碱、激素等。合适的细胞毒性剂描述于REMINGTON'S PHARMACEUTICAL SCIENCES,第19版(Mack Publishing Co.1995)和GOODMANAND GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,第7版(MacMillanPublishing Co.1985)以及这些出版物的修订版所述。其他合适的细胞毒性剂诸如实验药物是本领域的技术人员已知的。在一个优选的实施方案中,喜树碱和相关化合物的缀合物诸如SN-38可缀合至hRS7或其他抗Trop-2抗体。
毒素可以是动物、植物或微生物来源的。所用的毒素包括蓖麻毒素、相思豆毒素、核糖核酸酶(RNA酶)、DNA酶I、葡萄球菌肠毒素A、美洲商陆抗病毒蛋白、豹蛙抗瘤酶(onconase)、白树毒素(gelonin)、白喉毒素、假单胞菌外毒素和假单胞菌内毒素。参见例如,Pastan等人,Cell 47:641(1986),Goldenberg,CA--A Cancer Journal forClinicians 44:43(1994);Sharkey和Goldenberg,CA--A Cancer Journal forClinicians 56:226(2006)。适合使用的另外毒素是本领域的技术人员已知的,并且如美国专利号6,077,499所公开,所述专利的实施例部分以引用的方式并入本文。
如本文所用,术语“免疫调节剂”包括细胞因子、淋巴因子、单核因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素(IFN)、甲状旁腺激素、甲状腺素、胰岛素、胰岛素原、松弛素、松弛素原、促卵泡激素(FSH)、促甲状腺激素(TSH)、促黄体激素(LH)、肝生长因子、前列腺素、成纤维细胞生长因子、促乳素、胎盘催乳素、OB蛋白、转化生长因子(TGF)、TGF-α、TGF-β、胰岛素样生长因子(ILGF)、促红细胞生成素、促血小板生成素、肿瘤坏死因子(TNF)、TNF-α、TNF-β、苗勒管抑制物质、小鼠促性腺激素相关肽、抑制素、活化素、血管内皮生长因子、整联蛋白、白介素(IL)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、干扰素-α、干扰素-β、干扰素-γ、干扰素-λ、S1因子、IL-1、IL-1cc、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21和IL-25、LIF、kit配体、FLT-3、血管抑素、血小板反应蛋白、内皮他丁、淋巴毒素等等。
特别有用的治疗性放射性核素包括但不限于111In、177Lu、212Bi、213Bi、211At、62Cu、64Cu、67Cu、90Y、125I、131I、32P、33P、47Sc、111Ag、67Ga、142Pr、153Sm、161Tb、166Dy、166Ho、186Re、188Re、189Re、212Pb、223Ra、225Ac、59Fe、75Se、77As、89Sr、99Mo、105Rh、109Pd、143Pr、149Pm、169Er、194Ir、198Au、199Au以及211Pb。治疗性放射性核素优选地具有在20至6,000keV范围内、优选地在60至200keV的范围内(对于俄歇发射体)、在100-2,500keV的范围内(对于β发射体)和在4,000-6,000keV的范围内(对于α发射体)的衰变能。可用的β粒子发射核素的最大衰变能为优选地20-5,000keV、更优选地100-4,000keV以及最优选地500-2,500keV。另外优选的是基本上随俄歇发射粒子而衰变的放射性核素。例如,Co-58、Ga-67、Br-80m、Tc-99m、Rh-103m、Pt-109、In-111、Sb-119、I-125、Ho-161、Os-189m和Ir-192。可用的β粒子发射核素的衰变能为优选地1,000keV、更优选地100keV以及最优选地70keV。另外优选的是基本上随α粒子的产生而衰变的放射性核素。此类放射性核素包括但不限于:Dy-152、At-211、Bi-212、Ra-223、Rn-219、Po-215、Bi-211、Ac-225、Fr-221、At-217、Bi-213、Fm-255和Th-227。可用的α粒子发射放射性核素的衰变能优选地是2,000-10,000keV、更优选地3,000-8,000keV并且最优选地4,000-7,000keV。
例如,可使用二亚乙基三胺五乙酸(DTPA)或更优选地使用DOTA将发射高能β粒子的90Y偶联至抗体、抗体片段或融合蛋白。将90Y缀合至抗体或可靶向构建体的方法是本领域已知的,并且可使用任何此类已知的方法。(参见例如,美国专利号7,259,249,所述专利的实施例部分以引用的方式并入本文。还可参见Lindén等人,Clin Cancer Res.11:5215-22,2005;Sharkey等人,J Nucl Med.46:620-33,2005;Sharkey等人,JNucl Med.44:2000-18,2003。)
另外可能的治疗性放射性同位素包括11C、13N、15O、75Br、198Au、224Ac、126I、133I、77Br、113mIn、95Ru、97Ru、103Ru、105Ru、107Hg、203Hg、121mTe、122mTe、125mTe、165Tm、167Tm、168Tm、197Pt、109Pd、105Rh、142Pr、143Pr、161Tb、166Ho、199Au、57Co、58Co、51Cr、59Fe、75Se、201Tl、225Ac、76Br、169Yb等。
在另一个实施方案中,放射致敏剂可与裸的或缀合抗体或抗体片段组合使用。例如,放射致敏剂可与放射性标记的抗体或抗体片段组合使用。与单独使用放射性标记的抗体或抗体片段治疗相比,加入放射致敏剂可产生增强功效。放射致敏剂如D.M.Goldenberg(编),CANCER THERAPY WITH RADIOLABELED ANTIBODIES,CRC Press(1995)所述。与这种技术一起使用的目标其他典型放射致敏剂包括吉西他滨、5-氟尿苷和顺铂,并且与各种癌症治疗中的外部照射组合使用。
制剂和施用
ADC的合适施用途径包括但不限于口服、肠胃外、皮下、直肠、经粘膜、肠内施用、髓内、鞘内、直接心室内、静脉内、玻璃体内、腔内、腹膜内或肿瘤内注射。优选的施用途径是肠胃外,更优选地是皮下。或者,可以局部而非全身方式施用化合物,例如经由将化合物直接注射到实体瘤或血液肿瘤中。
ADC可根据已知方法进行配制以制备药学上有用的组合物,由此将所述ADC与药学上合适的赋形剂组合成混合物。无菌磷酸盐缓冲盐水是药学上合适的赋形剂的一个实例。其他合适的赋形剂是本领域熟知的。参见例如,Ansel等人,PHARMACEUTICAL DOSAGE FORMSAND DRUG DELIVERY SYSTEMS,第5版(Lea&Febiger 1990);和Gennaro(编辑),REMINGTON’SPHARMACEUTICAL SCIENCES,第18版(Mack Publishing Company 1990)以及它们的修订版。
在一个优选的实施方案中,在Good氏生物缓冲液(pH 6-7)中,使用选自由以下组成的组的缓冲液配制ADC:N-(2-乙酰胺基)-2-氨基乙磺酸(ACES)、N-(2-乙酰胺基)亚氨基二乙酸(ADA)、N,N-双(2-羟乙基)-2-氨基乙磺酸(BES)、4-(2-羟乙基)哌嗪-1-乙磺酸(HEPES)、2-(N-吗啉代)乙磺酸(MES)、3-(N-吗啉代)丙磺酸(MOPS)、3-(N-吗啉基)-2-羟基丙磺酸(MOPSO)以及哌嗪-N,N’-双(2-乙磺酸)[Pipes]。更优选的缓冲液是MES或MOPS,优选地在20至100mM的浓度范围内,更优选地约25mM。最优选的是25mM MES,pH 6.5。制剂还可包含25mM海藻糖和0.01%v/v聚山梨醇酯80作为赋形剂,由于添加的赋形剂而使最终缓冲液浓度变为22.25mM。优选的储存方法是以缀合物的冻干制剂储存在-20℃至2℃的温度范围内,最优选地储存在2℃至8℃的温度范围下。
主题ADC可被配制用于经由例如推注、缓慢输注或连续输注进行静脉内施用。所述ADC可在少于约4小时的时间内,并且更优选地在少于约3小时的时间内输注。例如,前25-50mg可在30分钟,优选地甚至15分钟内输注,并且其余的部分在接下来的2-3小时内输注。
或者,ADC可被配制用于通过浓缩以用于低体积注射而进行皮下施用(参见,例如,美国专利号8,658,773、9,180,205和9,468,689;其各自的实施例部分以引用的方式并入本文)。低体积施用可以是1、2或3mL或其任何部分。
用于注射的制剂可以单位剂型提供,例如在安瓿瓶或多剂量容器中,并添加防腐剂。组合物可采取诸如悬浮液、溶液或于油性或水性媒介物中的乳液的形式,并且可含有配制剂,如悬浮剂、稳定剂和/或分散剂。或者,活性成分可以是在使用前与合适的媒介物(例如不含热原的无菌水)一起复原的粉末形式。
另外的制药方法可用于控制治疗缀合物的作用持续时间。可通过使用聚合物来复合或吸附ADC来制备控释制剂。例如,生物相容性聚合物包括聚(乙烯-共-乙酸乙烯酯)的基质以及硬脂酸二聚体和癸二酸的聚酸酐共聚物的基质。Sherwood等人,Bio/Technology10:1446(1992)。从这种基质释放ADC的速率取决于ADC的分子量、基质内的ADC的量以及分散颗粒的大小。Saltzman等人,Biophys.J.55:163(1989);Sherwood等人,同上。其他固体剂型在Ansel等人,PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS,第5版(Lea&Febiger 1990),和Gennaro(编辑),REMINGTON’S PHARMACEUTICAL SCIENCES,第18版(Mack Publishing Company 1990)以及它们的修订版中描述。
一般而言,用于人的施用的ADC的剂量将根据诸如患者年龄、体重、身高、性别、一般医学病状和先前病史的因素而变化。如上所述,通过静脉内或其他肠胃外施用递送的抗体-SN-38缀合物的剂量可从3至18、更优选4至16、更优选6至12、更优选8至10mg/kg变化。可根据需要重复剂量,例如,每周一次持续2-10周、每周一次持续8周或每周一次持续4周。还可根据维持治疗的需要以更低的频率给与,诸如每隔一周一次持续若干个月或每月一次或每季度一次持续许多个月。所述剂量优选地多次、每周一次或两次施用。可使用4周、更优选地8周、更优选地16周或更长的最小剂量时间表,其中剂量频率取决于大部分与血液毒性有关的毒性副作用以及由此的恢复。施用时间表可包括按选自由以下组成的组的周期每周一次或两次施用:(i)每周;(ii)每隔一周;(iii)治疗一周,随后停药两周、三周或四周;(iv)治疗两周,随后停药一周、两周、三周或四周;(v)治疗三周,然后停药一周、两周、三周、四周或五周;(vi)治疗四周,随后停药一周、两周、三周、四周或五周;(vii)治疗五周,随后停药一周、两周、三周、四周或五周;以及(viii)每月。所述周期可重复2、4、6、8、10或12次或更多次。
或者,可每2周或3周一次剂量施用ADC,总共重复至少3次剂量。或者,每周两次,持续4-6周。剂量可每隔一周一次或甚至更低的频率施用,使患者可从任何药物相关毒性恢复。或者,可减少剂量时程,即每2周或每3周持续2-3个月。给药时程可任选地以其他时间间隔重复,并且剂量可在对剂量和时程进行适当调整下通过各种胃肠外途径给与。
对于皮下施用,诸如沙西妥珠单抗戈维替康(IMMU-132)、IMMU-130或IMMU-140的ADC的剂量可能受限于在没有沉淀或聚集的情况下浓缩ADC的能力,以及可皮下给与的施用体积(优选1、2或3ml或更少)。因此,对于皮下施用,ADC可以2至4mg/kg给与,每天给予持续1周或每周3次持续2周、或每周两次持续2周,然后停药。可在诱导后每两到三周或每月静脉内或皮下施用维持剂量的ADC。或者,可在以8-10mg/kg静脉内施用的二至四个周期发生诱导(每个周期,在两个21天周期的第1天和第8天施用ADC,其间一周停药期),然后作为每周一次或多次活性给药或作为维持疗法皮下施用。可基于中期肿瘤扫描和/或通过分析Trop-2阳性循环肿瘤细胞来调整剂量。
本文所述和要求保护的方法和组合物可用于治疗恶性或癌变前疾患,并且用于预防进展为赘生性或恶性状态,包括但不限于上述那些病症。此类用途表明了已知或怀疑先前进展为赘瘤或癌症的疾患,特别是在已发生包括增生、化生或最特别地发育异常的非赘生性细胞生长的情况下(关于此类异常生长疾患的综述,参见Robbins和Angell,BasicPathology,第2版,W.B.Saunders Co.,Philadelphia,第68-79页(1976))。
发育异常通常是癌症的预兆,并且主要可见于上皮中。其是非赘生性细胞生长的最无序形式,涉及个别细胞一致性和细胞结构取向的丧失。在存在慢性刺激或炎症的情况下,发育异常特征性地发生。在优选的实施方案中,本发明的方法用于抑制癌症,特别是上文列出的那些癌症的生长、进展和/或转移。
药盒
各种实施方案可涉及药盒,所述药盒含有适用于治疗患者的癌组织的组分。示例性药盒可含有至少一种如本文所述的ADC。如果含有用于施用的组分的组合物未配制成经由消化道递送,如通过口服递送,那么可包括能够通过一些其他途径递送药盒部件的装置。用于诸如胃肠外递送的应用的一种类型的装置是注射器,其用于将组合物注射至受试者体内。还可使用吸入装置。在某些实施方案中,抗体或其抗原结合片段可以含有抗体的无菌液体制剂或冻干制品的预填充注射器或自动注射笔形式提供(例如,Kivitz等人,Clin.Ther.2006,28:1619-29)。
药盒部件可包装在一起或分成两个或更多个容器。在一些实施方案中,所述容器可以是含有适用于复原的组合物的无菌冻干制剂的小瓶。药盒也可含有一种或多种适用于其他试剂的复原和/或稀释的缓冲液。可使用的其他容器包括但不限于小袋、托盘、盒、管等。药盒部件可包装并且无菌保持在容器内。可包括的另一个部件是试剂盒的使用说明。
实施例
以下实施例是本发明的实施方案的展示,并且不限制权利要求的范围。
实施例1.用IMMU-132(沙西妥珠单抗戈维替康)(一种抗Trop-2-SN-38抗体药物缀合物(ADC))靶向治疗胃肠(GI)癌
Trop-2是在许多上皮癌中非常普遍的肿瘤相关糖蛋。其升高的表达一直与更具侵袭性的疾病和不良预后有关。结合至Trop-2的细胞外结构域的人源化mAb与SN-38(IMMU-132;平均药物:mAb比率=7.6)(CPT-11的活性成分)缀合。在人肿瘤异种移植物中的有效活性之后,在患有各种实体瘤(包括胃肠癌)的患者(pt)中开始I/II期试验。
方法:患有转移性癌症的患者在用标准疗法治疗失败后招募,以在3周周期的第1天和第8天给与的8.0mg/kg的剂量开始。MTD被确定为12mg/kg;选择8和10mg/kg的剂量水平用于II期测试。
结果:六十名患有晚期胃肠癌的患者被招募在I/II期试验中。在29例CRC患者中(9例以10mg/kg治疗,20例以8mg/kg治疗),1例具有PR(部分应答)并且14例具有SD(稳定疾病)作为RECIST的最佳应答,其中进展时间(TTP)对于PR(-65%)为50+周,并且对于SD患者(5例持续)中值为21+周。十三例CRC患者具有KRAS突变,7例显示SD,中值TTP为19.1+周(范围,12.0-34.0;3例持续)。在所治疗的15例胰腺癌患者中(5例以8mg/kg,7例以10mg/kg,并且3例以12mg/kg),7例具有SD作为最佳应答,中值TTP为15.0周。在11例食道癌患者中(9例以8mg/kg开始,1例一10mg/kg,并且1例以18mg/kg),8例进行了CT评估,显示1例PR,TTP为30+周;并且4例具有17.4+、21.9、26.3和29.9周的SD。在5例胃癌患者中(2例以8mg/kg,并且3例以10mg/kg),仅3例进行了CT评估,都具有SD(1例靶病灶减少19%且持续TTP为29+周)。
嗜中性粒细胞减少症是主要的剂量限制性毒性,伴有疲劳、腹泻、恶心和呕吐等作为其他通常报告的毒性。然而,在完整试验中来自75例患者的毒性概况分别显示仅17.3%和2.7%的3级和4级嗜中性粒细胞减少症,以及仅6.7%的3级腹泻。
结论:IMMU-132在患有各种复发性转移性胃肠癌的患者中显示高治疗指数。它具有与内化的癌症选择性mAb缀合的中等毒性药物,其可在21天周期内每周一次x 2在数月内重复给与。
实施例2.抗CEACAM5-SN-38抗体药物缀合物(IMMU-130)在转移性结肠直肠癌(mCRC)中的活性
IMMU-130是CEACAM5靶向ADC、拉贝珠单抗-SN-38,其中药物是拓扑异构酶I抑制剂CPT-11的活性形式,并且以7-8摩尔/摩尔IgG替代。这种剂正处于患有复发性mCRC的患者的I/II期临床试验中。
方法:实验在4周或更大的携带皮下LS174T人结肠癌异种移植物(约0.2cm3大小)或通过静脉内注射GW-39人结肠癌细胞产生肺转移后2周的雌性无胸腺裸鼠中进行。包括未处理的对照,包括非靶向ADC。使用单一12.5mg/kg剂量的ADC或未缀合的拉贝珠单抗(各自掺有111In标记的底物)在皮下模型中检查生物分布。在新西兰白兔中进行耐受性研究。
结果:在转移模型(n=8)中,21天周期治疗的2个周期的分次给药、固定总剂量为50mg/kg ADC显示每周两次×2周和每周一次×2周时间表与未处理的小鼠相比,使中值存活期加倍,并且优于两周一次时间表(P 0.0474;对数秩)。在转移模型(n=10)中,预先给药多达两倍剂量的拉贝珠单抗作为ADC剂量,不影响中值存活期(P>0.15)。皮下模型中的治疗实验表明,IMMU-130中的接头(在约20小时内释放50%的药物)优于具有超稳定接头的缀合物(n=5),所述ADC优于5FU/甲酰四氢叶酸化学疗法的MTD(n=10;P 0.0001),并且所述ADC可与贝伐单抗组合以获得改善的功效(n=8-10;P 0.031)。观察到特异性ADC对比非特异性ADC的显著更好的功效。小鼠的药代动力学表明MAb对比ADC的约25%更长的半衰期,但对肿瘤摄取的影响最小。兔中的耐受性研究表明,NOAEL是作为两个剂量给与的40-60mg/kg的人类等效剂量。
结论:临床前数据表明这种ADC的优异治疗窗口,其似乎转化为迄今为止的临床经验。还指示了组合疗法的潜力。
实施例3.抗Trop-2-SN-38抗体-药物缀合物的产生和使用
如美国专利号7,238,785中所描述产生人源化RS7(hRS7)抗Trop-2抗体,所述专利的附图和实施例部分以引用的方式并入本文。根据美国专利7,999,083(其实施例10和12以引用的方式并入本文)产生附接至CL2A接头的SN-38并与hRS7(抗Trop-2)、hPAM4(抗MUC5ac)、hA20(抗CD20)或hMN-14(抗CEACAM5)抗体缀合。缀合方案使得每个抗体分子附接约6个SN-38分子的比例。
将携带皮下人胰腺或结肠肿瘤异种移植物的免疫受损的无胸腺裸鼠(雌性)用特异性CL2A-SN-38缀合物或对照缀合物进行处理或不进行处理。观察特异性缀合物的治疗功效。图1示出Capan 1胰腺肿瘤模型,其中hRS7(抗Trop-2)、hPAM4(抗MUC-5ac)和hMN-14(抗CEACAM5)抗体的特异性CL2A-SN-38缀合物显示出比对照hA20-CL2A-SN-38缀合物(抗CD20)和未处理的对照更好的功效。类似地,在人胰腺癌的BXPC3模型中,特异性hRS7-CL2A-SN-38显示出比对照处理更好的治疗功效(图2)。
实施例4.抗Trop-2-SN-38 ADC针对各种上皮癌的体内功效
摘要
此研究的目的是评价SN-38-抗Trop-2(hRS7)ADC针对几种人实体瘤类型的功效,并且评估其在小鼠和猴中的耐受性,后者与人相似,具有hRS7的组织交叉反应性。将两种SN-38衍生物CL2-SN-38和CL2A-SN-38与抗Trop-2-人源化抗体hRS7缀合。将所述ADC在体外针对稳定性、结合和细胞毒性进行了表征。在表达Trop-2抗原的五种不同的人实体瘤-异种移植物模型中测试功效。在小鼠和食蟹猴中评估毒性。
两种SN-38衍生物的hRS7缀合物在药物替代(约6)、细胞结合(Kd约1.2nmol/L)、细胞毒性(IC50约2.2nmol/L)、体外血清稳定性(t/1/2约20个小时)方面是等效的。将细胞暴露于ADC展示出导致PARP裂解的信号传导途径,但注意到在p53和p21上调中对比游离SN-38的差异。当与非靶向对照ADC相比时,hRS7-SN-38在无毒剂量下在携带Calu(P≤0.05)、Capan-1(P 0.018)、BxPC-3(P 0.005)和COLO 205肿瘤(P 0.033)的小鼠中产生显著抗肿瘤作用。小鼠耐受2×12mg/kg的剂量(SN-38当量),仅具有ALT和AST肝酶水平的短暂升高。输注2×0.96mg/kg的食蟹猴仅表现出血细胞计数的瞬时下降,但重要的是,所述值不会低于正常范围。
总之,抗Trop-2hRS7-CL2A-SN-38 ADC针对一系列人实体瘤类型提供了显著且特异性的抗肿瘤作用。它在临床相关剂量下,在猴中良好耐受,其中组织Trop-2表达与人相似。
引言
对实体瘤患者的成功伊立替康治疗受到限制,这在很大程度上是由于CPT-11前药转化为活性SN-38代谢物的转化率低。其他人已经检查了非靶向形式的SN-38,作为绕过这种转化需求并将SN-38被动地递送至肿瘤的手段。将SN-38与人源化抗Trop-2抗体hRS7共价缀合。这种抗体-药物缀合物在一系列皮下人癌症异种移植物模型(包括非小细胞肺癌、胰腺癌、结肠直肠癌和鳞状细胞肺癌)中具有特异性抗肿瘤作用,全部在无毒剂量下(例如,≤3.2mg/kg累积SN-38当量剂量)。Trop-2在许多上皮癌中广泛表达,但也在一些正常组织中表达,并且因此在食蟹猴中进行剂量递增研究以评估这种缀合物的临床安全性。猴耐受24mg SN-38当量/kg,只有轻微的、可逆的毒性。鉴于其肿瘤靶向和安全性概况,hRS7-SN-38在对伊立替康有反应的实体瘤的管理方面提供显著改善。
材料和方法
细胞系、抗体和化学治疗剂-本研究中使用的所有人癌细胞系均购自美国典型培养物保藏中心。这些包括Calu-3(非小细胞肺癌)、SK-MES-1(鳞状细胞肺癌)、COLO 205(结肠腺癌)、Capan-1和BxPC-3(胰腺癌)和PC-3(前列腺腺癌)。在Immunomedics,Inc.制备人源化RS7 IgG和对照人源化抗CD20(hA20 IgG,维妥珠单抗)和抗CD22(hLL2 IgG,依帕珠单抗)抗体。伊立替康(20mg/mL)从Hospira,Inc.获得。
SN-38 ADC和体外方面-先前已经描述了CL2-SN-38的合成(Moon等人,2008,J MedChem 51:6916-26)。如所述(Moon等人,2008,J Med Chem 51:6916-26;Govindan等人,2009,Clin Chem Res 15:6052-61)进行其与hRS7 IgG的缀合和血清稳定性。如前述实施例中所述进行CL2A-SN-38(M.W.1480)及其hRS7缀合物的制备,以及稳定性、结合和细胞毒性研究。
体内治疗研究-对于所有动物研究,SN-38 ADC和伊立替康的剂量以SN-38当量显示。基于6的平均SN-38/IgG替代比,至20-g小鼠的500μg ADC的剂量(25mg/kg)含有0.4mg/kg的SN-38。伊立替康剂量同样显示为SN-38当量(即,40mg伊立替康/kg相当于24mg/kg的SN-38)。
4至8周龄的NCr雌性无胸腺裸鼠(nu/nu)和10周龄的雄性Swiss-Webster小鼠购自Taconic Farms。由SNBL USA,Ltd在食蟹猴(食蟹猕猴(Macaca fascicularis);2.5–4kg雄性和雌性)中进行耐受性研究。
用不同的人癌细胞系皮下植入动物。肿瘤体积(TV)通过使用卡尺在二维空间测量来确定,并且体积定义为:L×w2/2,其中L是肿瘤的最长尺寸并且w是最短的。当治疗开始时,肿瘤的大小范围在0.10与0.47cm3之间。每个实验中的处理方案、剂量和动物数目描述于结果中。将冻干的hRS7-CL2A-SN-38和对照ADC重构并根据需要在无菌盐水中稀释。除伊立替康(其静脉内施用)外,所有试剂均腹膜内施用(0.1mL)。给药方案受到之前调查的影响,其中ADC每4天或每周两次给与持续不同时间长度(Moon等人,2008,J Med Chem 51:6916-26;Govindan等人,2009,Clin Chem Res 15:6052-61)。这种给药频率反映了缀合物的体外血清半衰期的考虑,以允许更连续地暴露于ADC。
统计数据-生长曲线显示为初始TV随时间推移的变化百分比。肿瘤生长的统计分析是基于曲线下面积(AUC)。通过线性曲线建模获得个体肿瘤生长的概况。f检验用于在生长曲线的统计分析之前确定组之间的方差齐性。双尾t检验用于评估各种处理组与对照之间的统计显著性,除了盐水对照,其中使用单尾t检验(显著性在P≤0.05)。AUC的统计学比较仅进行直至组内第一只动物由于进展而被安乐死的时间。
药代动力学和生物分布-将111In放射性标记的hRS7-CL2A-SN-38和hRS7 IgG注射到携带皮下SK-MES-1肿瘤(约0.3cm3)的裸鼠中。将一组静脉内注射20μCi(250-μg蛋白质)的111In-hRS7-CL2A-SN-38,而另一组接受20μCi(250-μg蛋白质)的111In-hRS7 IgG。在不同的时间点,将小鼠(每个时间点5只)麻醉,经由心脏内穿刺术放血,且然后实施安乐死。取出肿瘤和各种组织,称重并通过γ闪烁计数以确定每克组织的注射剂量百分比(%ID/g)。第三组在施用111In-hRS7-CL2A-SN-38之前3天注射250μg未标记的hRS7-CL2A-SN-38且同样进行了尸检。双尾t检验用于在使用f检验确定方差齐性之后比较hRS7-CL2A-SN-38和hRS7IgG摄取。使用WinNonLin软件(Parsight Corp.)进行关于血液清除的药代动力学分析。
在Swiss-Webster小鼠和食蟹猴中的耐受性-简言之,将小鼠分成4组,每组在第0天和第3天接受2-mL腹膜内注射乙酸钠缓冲液对照或3种不同剂量的hRS7-CL2A-SN-38(4、8或12mg/kg SN-38),然后进行血液和血清收集,如结果中所述。向食蟹猴(3只雄性和3只雌性;2.5-4.0kg)施用2种不同剂量的hRS7-CL2A-SN-38。结果中描述了被取血以用于评价可能的血液学毒性和血清化学的猴的剂量、时间和数量。
结果
hRS7-CL2A-SN-38的稳定性和效力-使用两种不同的键联来将SN-38缀合至hRS7IgG(图3A)。第一种称为CL2-SN-38,并且先前已有描述(Moon等人,2008,J Med Chem 51:6916-26;Govindan等人,2009,Clin Chem Res 15:6052-61)。使用CL2合成的变化来除去接头内的苯丙氨酸部分来产生CL2A接头。这种变化简化了合成,但不影响缀合结果(例如,CL2-SN-38和CL2A-SN-38两者均每个IgG分子并入约6个SN-38)。并排比较发现血清稳定性、抗原结合或体外细胞毒性无显著差异。这一结果是令人惊讶的,因为CL2中的苯丙氨酸残基是组织蛋白酶B(一种溶酶体蛋白酶)的设计的裂解位点的一部分。
为了确认SN-38接头从CL2至CL2A的变化不会影响体内效力,在携带COLO 205(图3B)或Capan-1肿瘤(图3C)的小鼠中分别使用每周两次×4周的0.4mg或0.2mg/kg SN-38对hRS7-CL2A和hRS7-CL2-SN-38进行了比较,并且在两项研究中起始肿瘤大小均为0.25cm3。与未处理(在COLO 205模型中对比盐水AUC14天P 0.002;在Capan-1模型中对比盐水AUC21天P0.001)和非靶向抗CD20对照ADC,hA20-CL2A-SN-38(在COLO-205模型中AUC14天P 0.003;在Capan-1模型中AUC35天:P 0.002)的相比,hRS7-CL2A和CL2-SN-38缀合物两者均显著抑制肿瘤生长。在Capan-1模型中研究结束时(第140天),50%的用hRS7-CL2A-SN-38处理的小鼠和40%的hRS7-CL2-SN-38小鼠无肿瘤,而只有20%的hA20-ADC处理的动物没有明显疾病迹象。如图3所示,与CL2相比,CL2A接头产生稍微更高的功效。
作用机制-体外细胞毒性研究证明hRS7-CL2A-SN-38针对几种不同的实体瘤系具有在nmol/L范围内的IC50值(表2)。游离SN-38情况下的IC50在所有细胞系中低于缀合物。尽管Trop-2表达与对hRS7-CL2A-SN-38的敏感性之间没有明显相关性,但ADC对比游离SN-38的IC50比率在较高Trop-2表达细胞中较低,最可能反映出当存在更多抗原时内化药物的能力增强。
已知SN-38活化细胞中的若干信号传导途径,从而导致细胞凋亡(Cusack等人,2001,Cancer Res 61:3535-40;Liu等人2009,Cancer Lett 274:47-53;Lagadec等人,2008,Br J Cancer 98:335-44)。初始研究在体外检查了参与早期信号传导事件和1个晚期凋亡事件[聚-ADP-核糖聚合酶(PARP)的裂解)]的2种蛋白质(p21Waf1/Cip1和p53)的表达(未示出)。在BxPC-3中,SN-38导致p21Waf1/Cip1表达增加20倍(未示出),而hRS7-CL2A-SN-38仅产生10倍增加(未示出),这一发现与此细胞系中游离SN-38情况下的较高活性一致(表2)。然而,hRS7-CL2A-SN-38使Calu-3中的p21Waf1/Cip1表达相对于游离SN-38增加超过2倍(未示出)。
在p53表达中观察到hRS7-CL2A-SN-38-与游离SN-38介导的信号传导事件之间的更大差异(未示出)。在BxPC-3和Calu-3中,在游离SN-38情况下p53的上调直到48小时才明显,而hRS7-CL2A-SN-38在24小时内上调p53(未示出)。另外,与SN-38相比,暴露于ADC的细胞中的p53表达在两种细胞系中均更高(未示出)。令人感兴趣的是,尽管hRS7 IgG对p21Waf1 /Cip1表达没有明显影响,但它确实诱导BxPC-3和Calu-3两者中p53的上调,但仅在暴露48小时后(未示出)。就后来的细胞凋亡事件而言,当与SN-38或缀合物一起孵育时,PARP的裂解在两种细胞系中都是明显的(未示出)。裂解的PARP的存在在BxPC-3中24小时较高(未示出),这与p21的高表达及其较低的IC50相关。与ADC相比,游离SN-38情况下的更高裂解程度与细胞毒性结果一致。
hRS7-SN-38的功效-由于Trop-2在若干人癌症中广泛表达,因此在若干不同的人癌症模型中进行了研究,所述模型使用hRS7-CL2-SN-38键联开始,但稍后使用了具有CL2A键联的缀合物。与施用等量非靶向hLL2-CL2-SN-38的动物相比,每4天×4给与0.04mg SN-38/kg hRS7-CL2-SN-38的携带Calu-3的裸鼠具有显著改善的反应(相应地TV=0.14±0.22cm3对比0.80±0.91cm3;AUC42天P0.026;图4A)。当剂量增加至0.4mg/kg SN-38时,观察到剂量反应(图4A)。在这种较高剂量水平下,给与特异性hRS7缀合物的所有小鼠在28天内“治愈”,并且在第147天保持无肿瘤直至研究结束,而肿瘤在用不相关的ADC处理的动物中重新生长(特异性对比不相关的AUC98天:P=0.05)。在接受hRS7 IgG和SN-38的混合物的小鼠中,到第56天肿瘤进展>4.5倍(TV=1.10±0.88cm3;对比hRS7-CL2-SN-38 AUC56天P 0.006)(图4A)。
还在人结肠(COLO 205)和胰腺(Capan-1)肿瘤异种移植物中检查了功效。在携带COLO 205肿瘤的动物中(图4B),与对照抗CD20 ADC(hA20-CL2-SN-38)或hRS7 IgG相比,hRS7-CL2-SN-38(0.4mg/kg,q4dx8)在28天处理期内阻止肿瘤生长,肿瘤显著更小(TV分别=0.16±0.09cm3、1.19±0.59cm3和1.77±0.93cm3;AUC28天P 0.016)。
表2.在各种实体瘤系中SN-38和hRS7-SN-38的Trop-2表达和体外细胞毒性
伊立替康(24mg SN-38/kg,q2dx5)的MTD在COLO 205细胞中与hRS7-CL2-SN-38一样有效,因为小鼠血清可比人血清更有效地将伊立替康转化为SN-38(Morton等人,2000,Cancer Res 60:4206-10),但伊立替康中的SN-38剂量(2,400μg累积)比在缀合物(总计64μg)情况下高37.5倍。
当以等效于hRS7-CL2-SN-38缀合物的SN-38剂量给与时,携带Capan-1的动物(图4C)对单独伊立替康未显示显著反应(例如,在第35天,在给与0.4mg SN-38/kg hRS7-SN-38的动物中平均肿瘤大小是0.04±0.05cm3,对比在给与0.4mg/kg SN-38的伊立替康处理的动物中1.78±0.62cm3;AUC第35天P 0.001;图4C)。当伊立替康剂量增加10倍至4mg/kg SN-38时,反应得到改善,但仍不如0.4mg/kg SN-38剂量水平的缀合物显著(TV=0.17±0.18cm3对比1.69±0.47cm3,AUC第49天P 0.001)(图4C)。与伊立替康处理的动物相比,相等剂量的非靶向hA20-CL2-SN-38也具有显著抗肿瘤作用,但特异性hRS7缀合物显著优于不相关的ADC(TV=0.17±0.18cm3对比0.80±0.68cm3,AUC第49天P 0.018)(图4C)。
然后将使用hRS7-CL2A-SN-38 ADC的研究扩展至2种其他人上皮癌模型。在携带BxPC-3人胰腺肿瘤的小鼠中图4D),与用盐水或等量非靶向hA20-CL2A-SN-38处理的对照小鼠(相应地TV=0.24±0.11cm3对比1.17±0.45cm3和1.05±0.73cm3;AUC第21天P 0.001)或以高10倍的SN-38等效剂量给与的伊立替康(相应地TV=0.27±0.18cm3对比0.90±0.62cm3;AUC第25天P 0.004)(图4D)相比,hRS7-CL2A-SN-38再次显著抑制肿瘤生长。令人感兴趣的是,在用0.4mg/kg的ADC处理的携带SK-MES-1人鳞状细胞肺肿瘤的小鼠中(图4E),肿瘤生长抑制优于盐水或未缀合的hRS7 IgG(相应地TV=0.36±0.25cm3对比1.02±0.70cm3和1.30±1.08cm3;AUC28天,P0.043),但非靶向hA20-CL2A-SN-38或伊立替康的MTD提供与特异性hRS7-SN-38缀合物相同的抗肿瘤作用(图4E)。
在所有鼠类研究中,hRS7-SN-38 ADC在体重减轻方面良好地耐受(未示出)。
hRS7-CL2A-SN-38的生物分布-使用相应的111In标记的底物,在携带SK-MES-1人鳞状细胞肺癌异种移植物的小鼠中比较hRS7-CL2A-SN-38或未缀合的hRS7 IgG的生物分布(未示出)。进行药代动力学分析以确定hRS7-CL2A-SN-38相对于未缀合的hRS7的清除率(未示出)。ADC比等量的未缀合的hRS7更快地清除,其中ADC表现出短约40%的半衰期和平均停留时间。尽管如此,这对肿瘤摄取具有最小影响(未示出)。虽然在24小时和48小时时间点存在显著差异,但到72小时(峰值摄取),肿瘤中两种剂的量相似。在正常组织中,肝和脾差异最显著(未示出)。在注射后24小时,在肝脏中hRS7-CL2A-SN-38比hRS7 IgG多>2倍(未示出)。相反,在脾脏中,在峰值摄取(48小时时间点)处存在比hRS7-CL2A-SN-38多3倍的亲本hRS7 IgG(未示出)。剩余组织中的摄取和清除通常反映血液浓度的差异(未示出)。
因为给与治疗的每周两次剂量,所以检查了在注射111In标记的抗体之前3天首先接受0.2mg/kg(250μg蛋白质)预剂量的hRS7 ADC的一组动物中的肿瘤摄取。与未接受预剂量的动物相比,预先给药的小鼠中的111In-hRS7-CL2A-SN-38在每个时间点显著降低(例如,在72小时,预先给药的肿瘤摄取是12.5%±3.8%ID/g,对比在未给与预剂量的动物中25.4%±8.1%ID/g;P=0.0123;未示出)。预给药对血液清除或组织摄取没有明显影响(未示出)。这些研究表明,在一些肿瘤模型中,特异性抗体的肿瘤增积可通过一个或多个前面的剂量减少,这可能解释了治疗反应的特异性可随着ADC剂量增加而减少的原因以及未指示进一步剂量递增的原因。
hRS7-CL2A-SN-38在Swiss-Webster小鼠和食蟹猴中的耐受性Swiss-Webster小鼠在3天内耐受2个剂量,4、8和12mg SN-38/kg的hRS7-CL2A-SN-38中的每一个,具有最小的瞬时体重减轻(未示出)。未发生造血毒性,并且血清化学仅揭示升高的天冬氨酸转氨酶(AST,图5A)和丙氨酸转氨酶(ALT,图5B)。在处理后七天,所有3个处理组中的AST均升至正常水平(>298U/L)(图5A),最大比例的小鼠处于2×8mg/kg组中。然而,到处理后15天,大多数动物都在正常范围内。在处理的7天内ALT水平也高于正常范围(>77U/L)(图5B)并且到第15天具有正常化的证据。来自所有这些小鼠的肝脏未显示组织损伤的组织学证据(未示出)。就肾功能而言,仅葡萄糖和氯化物水平在处理组中略微升高。在2×8mg/kg下,7只小鼠中的5只具有略微升高的葡萄糖水平(273–320mg/dL的范围,正常上限263mg/dL),其到注射后15天恢复正常。类似地,氯化物水平略有升高,在2个最高剂量组中在116至127mmol/L的范围内(正常范围上限115mmol/L)(在2×8mg/kg组中57%,并且在2×12mg/kg组中100%),并在注射后保持升高至15天。这也可指示胃肠毒性,因为大多数氯化物是通过肠道吸收获得的;然而,在终止时,在所检查的任何器官系统中不存在组织损伤的组织学证据(未示出)。
因为小鼠不表达由hRS7鉴定的Trop-2,所以需要更合适的模型来确定hRS7缀合物用于临床用途的潜力。免疫组织学研究揭示人和食蟹猴中的多种组织中的结合(乳腺、眼、胃肠道、肾、肺、卵巢、输卵管、胰腺、甲状旁腺、前列腺、唾液腺、皮肤、胸腺、甲状腺、扁桃体、输尿管、膀胱和子宫;未示出)。基于这种交叉反应性,在猴中进行耐受性研究。
接受2×0.96mg SN-38/kg的hRS7-CL2A-SN-38的组在输注后和直到研究结束没有显著临床事件。体重减轻不超过7.3%,并且到第15天恢复至适应重量。在大多数血细胞计数数据中注意到短暂下降(嗜中性粒细胞和血小板数据显示在图5C和图5D中),但值未下降到正常范围以下。在血清化学中未发现异常值。在第11天(最后一次注射后8天)尸检的动物的组织病理学显示造血器官(胸腺、下颌和肠系膜淋巴结、脾和骨髓)、胃肠器官(胃、十二指肠、空肠、回肠、盲肠、结肠和直肠)、女性生殖器官(卵巢、子宫和阴道)中以及注射部位处的微观变化。这些变化在从最小至中等的范围内,并且在所有组织中在恢复期(第32天)结束时完全逆转,除了在胸腺和胃肠道中之外,其在此后的时间点趋向于完全恢复(未示出)。
在缀合物的2×1.92mg SN-38/kg剂量水平下,存在1例因胃肠道并发症和骨髓抑制引起的死亡,并且此组中的其他动物显示出与2×0.96mg/kg组相似但更严重的不良事件(未示出)。这些数据表明剂量限制毒性与伊立替康相同;即肠道和血液学。因此,hRS7-CL2A-SN-38的MTD介于2×0.96与1.92mg SN-38/kg之间,其代表2×0.3至0.6mg/kg SN-38的人等效剂量。
论述
Trop-2是在许多上皮肿瘤(包括肺癌、乳腺癌、结肠直肠癌、胰腺癌、前列腺癌和卵巢癌)上表达的蛋白质,从而使其成为递送细胞毒性剂的潜在重要靶标(Ohmachi等人,2006,Clin Cancer Res 12:3057-63;Fong等人,2008,Br J Cancer 99:1290-95;Cubas等人,2009,Biochim Biophys Acta 1796:309-14)。当与Trop-2结合时,RS7抗体内化(Shih等人,1995,Cancer Res 55:5857s-63s),其能够直接细胞内递送细胞毒素。
SN-38是有效的拓扑异构酶-I抑制剂,在几种细胞系中具有在纳摩尔范围内的IC50值。它是用于治疗结肠直肠癌并且还在肺癌、乳腺癌和脑癌中具有活性的前药伊立替康的活性形式。推断呈ADC的形式的直接靶向的SN-38将通过克服后者的低和患者可变的生物转化为活性SN-38而相对于CPT-11显著改善治疗(Mathijssen等人,2001,Clin Cancer Res7:2182-94)。
插入原始CL2衍生物中的Phe-Lys肽允许经由组织蛋白酶B裂解。为了简化合成过程,在CL2A中消除了苯丙氨酸,且因此除去了组织蛋白酶B裂解位点。令人感兴趣的是,与用CL2获得的宽概况相比,这种产物具有更好定义的色谱概况(未示出),但更重要的是,这种改变对并排测试中缀合物的结合、稳定性或效力没有影响。这些数据表明CL2中的SN-38主要通过在pH敏感的碳酸苄酯键处裂解成SN-38的内酯环而不是组织蛋白酶B裂解位点而从缀合物释放。
hRS7 ADC针对一系列实体瘤细胞系的体外细胞毒性始终具有在nmol/L范围内的IC50值。然而,暴露于游离SN-38的细胞表现出与ADC相比较低的IC50值。还报告了ENZ-2208(Sapra等人,2008,Clin Cancer Res 14:1888-96;Zhao等人,2008,Bioconjug Chem 19:849-59)和NK012(Koizumi等人,2006,Cancer Res 66:10048-56)的游离与缀合的SN-38之间的这种差异。ENZ-2208利用支化PEG连接每个PEG约3.5至4个SN-38分子,而NK012是含有20重量%SN-38的胶束纳米颗粒。使用我们的ADC,随着Trop-2表达水平在肿瘤细胞中增加,这种差异(即,游离对比缀合的SN-38的效力比)降低,从而表明靶向递送药物的优点。就体外血清稳定性而言,hRS7-SN-38的CL2和CL2A-SN-38形式产生约20个小时的t/1/2,这与对于ENZ-2208报告的12.3分钟的短t/1/2形成对比(Zhao等人,2008,Bioconjug Chem 19:849-59),但是与24小时后在生理条件下从NK012 57%释放SN-38相似(Koizumi等人,2006,Cancer Res 66:10048-56)。
用hRS7-SN-38(CL2-SN-38或CL2A-SN-38)处理携带肿瘤的小鼠显著抑制5种不同肿瘤模型中的肿瘤生长。在其中4个中,观察到肿瘤消退,并且在Calu-3的情况下,所有接受最高剂量的hRS7-SN-38的小鼠在研究结束时是无肿瘤的。与人不同,伊立替康通过小鼠中的血浆酯酶非常有效地转化为SN-38,具有大于50%转化率,并且在小鼠中比在人中产生更高的效力(Morton等人,2000,Cancer Res 60:4206-10;Furman等人,1999,J Clin Oncol17:1815-24)。当伊立替康以高10倍或等效SN-38水平施用时,hRS7-SN-38在控制肿瘤生长方面显著更好。只有当伊立替康以24mg/kg q2dx5(多37.5倍的SN-38)的其MTD施用时,它才与hRS7-SN-38的有效性相当。在患者中,我们期望这种优势更有利于hRS7-CL2A-SN-38,因为伊立替康的生物转化将大大降低。
还在一些抗原表达细胞系(如SK-MES-1)中显示,使用抗原结合ADC不能保证比非结合的不相关的缀合物更好的治疗反应。这不是不寻常或出人意料的发现。实际上,当与伊立替康相比时,前面提到的非结合SN-38缀合物增强治疗活性,并且因此预期不相关的IgG-SN-38缀合物具有一些活性。这与肿瘤具有不成熟的渗漏血管的事实有关,所述血管允许大分子比正常组织更好地通过(Jain,1994,Sci Am271:58-61)。使用我们的缀合物,50%的SN-38将在约13小时内释放,此时pH降低至模拟溶酶体水平的水平(例如,在37℃下pH 5.3;数据未示出),而在血清的中性pH下,释放速率降低近2倍。如果不相关的缀合物进入酸性肿瘤微环境,则预期局部释放一些SN-38。其他因素,如肿瘤生理学和对药物的先天敏感性,也将在定义这种“基线”活性中发挥作用。然而,只要存在足够的抗原来捕获特异性抗体,具有较长停留时间的特异性缀合物应该具有相对于这种基线反应增强的效力。SK-MES-1模型中的生物分布研究还表明,如果肿瘤抗原由于连续给药而变得饱和,则特异性缀合物的肿瘤摄取减少,这产生类似于用不相关的缀合物发现的治疗结果。
尽管我们的ADC与其他SN-38递送剂的已公开报告之间进行直接比较具有挑战性,但可进行一些一般性观察。在我们的治疗研究中,最高个体剂量是0.4mg/kg的SN-38。在Calu-3模型中,在20g小鼠中仅给予4次注射,总累积剂量为1.6mg/kg SN-38或32μg SN-38。使用其10mg/kg×5的MTD进行ENZ-2208的多项研究(Sapra等人,2008,Clin Cancer Res14:1888-96;Pastorini等人,2010,Clin Cancer Res 16:4809-21),并且用NK012进行的临床前研究涉及其30mg/kg×3的MTD(Koizumi等人,2006,Cancer Res 66:10048-56)。因此,使用hRS7-SN-38以分别比ENZ-2208和NK012中报告的剂量少30倍和55倍的SN-38当量获得显著抗肿瘤作用。即使hRS7 ADC(0.04mg/kg)少10倍,也观察到显著抗肿瘤作用,而较低剂量的ENZ-2208未呈现,并且当NK012剂量降低4倍至7.5mg/kg时,效力丧失(Koizumi等人,2006,Cancer Res 66:10048-56)。正常小鼠未显示急性毒性,累积剂量超过1周24mg/kgSN-38(1,500mg/kg缀合物),从而表明MTD更高。因此,用7.5至15倍低量的SN-38当量有效地处理携带肿瘤的动物。
生物分布研究揭示hRS7-CL2A-SN-38具有与亲本hRS7 IgG相似的肿瘤摄取,但是在肝脏摄取高2倍的情况下清除显著更快,这可能是由于SN-38的疏水性。随着ADC通过肝脏清除,预期肝脏和胃肠道毒性将是剂量限制性的。尽管小鼠具有肝转氨酶升高的证据,但胃肠道毒性最好是轻微的,只有短暂的体重减轻,并且在组织病理学检查时未注意到异常。令人感兴趣的是,未注意到血液学毒性。然而,猴显示出与针对伊立替康所预期相同的毒性概况,其中胃肠道和血液学毒性是剂量限制性的。
因为由hRS7识别的Trop-2不在小鼠中表达,所以在具有与人类相似的Trop-2组织表达的猴中进行毒性研究是重要的。耐受0.96mg/kg/剂量(约12mg/m2)的猴具有轻微和可逆的毒性,其外推为约0.3mg/kg/剂量(约11mg/m2)的人剂量。在NK012的I期临床试验中,实体瘤患者耐受每3周一次28mg/m2的SN-38,具有4级嗜中性粒细胞减少症作为剂量限制性毒性(DLT;Hamaguchi等人,2010,Clin Cancer Res 16:5058-66)。类似地,使用ENZ-2208的I期临床试验揭示剂量限制性发热性嗜中性粒细胞减少症,建议施用10mg/m2每3周或16mg/m2(如果向患者施用G-CSF)(Kurzrock等人,AACR-NCI-EORTC International Conference onMolecular Targets and Cancer Therapeutics;2009年11月15–19日;Boston,MA;PosterNo C216;Patnaik等人,AACR-NCI-EORTC International Conference on MolecularTargets and Cancer Therapeutics;2009年11月15–19日;Boston,MA;Poster No C221)。因为猴耐受22mg/m2的累积人等效剂量,所以似乎即使hRS7与许多正常组织结合,但单次hRS7 ADC处理的MTD可能与其他非靶向SN-38剂相似。实际上,抗Trop-2抗体的特异性似乎在定义DLT中不起作用,因为毒性概况与伊立替康相似。更重要的是,如果可如在用刚好0.03mg SN-38当量/kg/剂量的人等效剂量响应的小鼠中那样在人中实现抗肿瘤活性,那么可在临床上实现显著抗肿瘤反应。
总之,猴中的毒理学研究与小鼠中的体内人癌症异种移植物模型组合已经表明,这种靶向Trop-2的ADC在若干不同上皮起源的肿瘤中是有效的治疗剂。
实施例5.包含hRS7和紫杉醇的抗Trop-2 ADC
通过将紫杉醇缀合至hRS7抗人Trop-2抗体(hRS7-紫杉醇)来制备新的抗体-药物缀合物(ADC)。最终产物的平均药物与抗体替代比为2.2。使用两种不同的Trop-2阳性细胞系作为靶标在体外对这种ADC进行测试:BxPC-3(人胰腺癌)和MDA-MB-468(人三阴性乳腺癌)。在添加ADC之前一天,从组织培养物收获细胞,并以每孔2000个细胞接种到96孔板中。第二天将细胞暴露于游离紫杉醇(6.1x 10-11至4x 10-6M)或hRS7-紫杉醇的药物等效物。为了比较,还在3.84x 10-12至2.5x 10-7M的范围下测试了hRS7-SN-38和游离SN-38。将板在37℃下孵育96小时。在此孵育期后,将MTS底物添加至所有板,并以半小时间隔读取显色,直至未处理的对照孔具有大约1.0的OD492nm读数。使用Microsoft Excel和Prism软件作为相对于未处理细胞的生长百分比测量生长抑制(非线性回归以产生S形剂量反应曲线,其产生IC50值)。
hRS7-紫杉醇ADC在MDA-MB-468乳腺细胞系中表现出细胞毒活性(图6),其中IC50值比hRS7-SN-38高大约4.5倍。游离紫杉醇比游离SN-38更有效(图6)。而游离SN-38的IC50为1.54x10-9M,游离紫杉醇的IC50小于6.1x10-11M。对于BxPC-3胰腺细胞系获得类似的结果(图7),其中hRS7-紫杉醇ADC具有比hRS7-SN-38 ADC高大约2.8倍的IC50值。这些结果表明抗Trop-2缀合的紫杉醇的体外功效,IC50值在纳摩尔范围内,类似于hRS7-SN-38 ADC。
实施例6.抗Trop-2抗体的细胞结合测定
获得针对人Trop-2的两种不同鼠单克隆抗体用于ADC缀合。从滚瓶中生长的杂交瘤(ATCC,HB-187)纯化第一抗体162-46.2。第二抗体MAB650购自R&D Systems(Minneapolis,MN)。对于结合的比较,Trop-2阳性人胃癌NCI-N87用作靶标。在结合测定前一天,将细胞(1.5×105/孔)接种到96孔板中。第二天早上,使用162-46.2、MAB650和鼠RS7(0.03至66nM)生成剂量/反应曲线。将这些第一抗体在4℃下与细胞一起孵育1.5小时。冲洗孔,并且在4℃下将抗小鼠HRP第二抗体添加至所有孔持续1小时。再次洗涤孔,然后添加发光底物。使用Envision板阅读器读取板,并且值被报告为相对发光单位。
全部三种抗体具有类似的KD值,对于RS7为0.57nM,对于162-46.2为0.52nM并且对于MAB650为0.49nM。然而,当比较162-46.2和MAB650与RS7的最大结合(Bmax)时,它们分别减少25%和50%(BMax对于RS7为11,250,对于162-46.2为8,471并且对于MAB650为6,018),从而表明与RS7相比具有不同的结合性质。
实施例7.抗Trop-2 ADC(MAB650-SN-38)的细胞毒性
用SN-38和MAB650制备新颖的抗Trop-2 ADC,从而产生6.89的平均药物与抗体替代比。使用两种不同的人胰腺癌细胞系(BxPC-3和Capan-1)和人三阴性乳腺癌细胞系(MDA-MB-468)作为靶标进行细胞毒性测定以比较MAB650-SN-38和hRS7-SN-38 ADC。
在添加ADC之前一天,从组织培养物收获细胞并接种到96孔板中。在第二天将细胞以3.84x 10-12至2.5x 10-7M的药物范围暴露于hRS7-SN-38、MAB650-SN-38和游离SN-38。未缀合的MAB650用作与MAB650-SN-38蛋白质等效剂量下的对照。将板在37℃下孵育96小时。在此孵育期后,将MTS底物添加至所有板,并以半小时间隔读取显色直至对于未处理的细胞达到大约1.0的OD492nm。使用Microsoft Excel和Prism软件作为相对于未处理细胞的生长百分比测量生长抑制(非线性回归以产生S形剂量反应曲线,其产生IC50值。
如图8所示,hRS7-SN-38和MAB650-SN-38具有相似的生长抑制作用,其中IC50值在低nM范围内,这对于这些细胞系中的SN-38-ADC是典型的。在人Capan-1胰腺癌细胞系中(图8A),与MAB650-SN-38 ADC的4.1nM和游离SN-38的1.0nM相比,hRS7-SN-38 ADC显示3.5nM的IC50。在人BxPC-3胰腺癌细胞系中(图8B),与MAB650-SN-38 ADC的3.0nM和游离SN-38的1.0nM相比,hRS7-SN-38 ADC显示2.6nM的IC50。在人NCI-N87胃腺癌细胞系中(图8C),与MAB650-SN-38 ADC的4.1nM和游离SN-38的4.3nM相比,hRS7-SN-38 ADC显示3.6nM的IC50。
总之,在这些体外测定中,两种抗Trop-2抗体hRS7和MAB650的SN-38缀合物显示出针对几种肿瘤细胞系的相同功效,这与游离SN-38的功效相似。因为抗Trop-2抗体的靶向功能在体内将是比在体外更重要的因素,所以数据支持抗Trop-2-SN-38 ADC作为将在体内非常有效的一类,如上述实施例中针对hRS7-SN-38所证明的。
实施例8.抗Trop-2 ADC(162-46.2-SN-38)的细胞毒性
用SN-38和162-46.2制备新颖的抗Trop-2 ADC,从而产生6.14的药物与抗体替代比。使用两种不同的Trop-2阳性细胞系(BxPC-3人胰腺癌和MDA-MB-468人三阴性乳腺癌)作为靶标进行细胞毒性测定以比较162-46.2-SN-38和hRS7-SN-38 ADC。
在添加ADC之前一天,从组织培养物收获细胞,并以每孔2000个细胞接种到96孔板中。在第二天将细胞以3.84x 10-12至2.5x 10-7 M的药物范围暴露于hRS7-SN-38、162-46.2-SN-38或游离SN-38。未缀合的162-46.2和hRS7分别用作与162-46.2-SN-38和hRS7-SN-38相同的蛋白质等效剂量下的对照。将板在37℃下孵育96小时。在此孵育期后,将MTS底物添加至所有板,并以半小时间隔读取显色,直至未处理的对照孔具有大约1.0的OD492nm读数。使用Microsoft Excel和Prism软件作为相对于未处理细胞的生长百分比测量生长抑制(非线性回归以产生S形剂量反应曲线,其产生IC50值)。
如图9A和图9B所示,当与hRS7-SN-38相比时,162-46.2-SN-38 ADC具有相似的IC50值。当针对BxPC-3人胰腺癌细胞系进行测试时(图9A),与162-46.2-SN-38的10.6nM和游离SN-38的1.6nM相比,hRS7-SN-38具有5.8nM的IC50。当针对MDA-MB-468人乳腺癌细胞系进行测试时(图9B),与162-46.2-SN-38的6.1nM和游离SN-38的0.8nM相比,hRS7-SN-38具有3.9nM的IC50。单独游离抗体对任一Trop-2阳性癌细胞系显示很小的细胞毒性。
总之,比较与相同的细胞毒性药物缀合的三种不同抗Trop-2抗体的体外功效,所有三种ADC针对多种Trop-2阳性癌细胞系都表现出等效的细胞毒性作用。这些数据支持并入药物缀合的ADC中的一类抗Trop-2抗体是表达Trop-2的实体瘤的有效抗癌治疗剂。
实施例9.使用包含缀合至SN-38的hRS7抗体的IMMU-132抗Trop-2 ADC进行临床试验
概述
本实施例报告来自I期临床试验和正在进行的IMMU-132的II期扩展的结果,IMMU-132是通过pH敏感接头缀合至SN-38的内化人源化hRS7抗Trop-2抗体的ADC(平均药物-抗体比率=7.6)。Trop-2是由许多人癌症以高密度(约1×105)、频率和特异性表达的I型跨膜钙转导蛋白,而正常组织表达有限。携带Capan-1人胰腺肿瘤异种移植物的裸小鼠的临床前研究揭示,IMMU-132能够将比来源于最大耐受的伊立替康疗法多120倍的SN-38递送至肿瘤。
本实施例报告了多次先前疗法治疗失败的25名患者的初始I期试验(一些包括拓扑异构酶-I/II抑制性药物)过程期间获得,并且正在进行的II期扩展现在报告69名患者,包括结肠直肠癌(CRC)、小细胞和非小细胞肺癌(分别为SCLC、NSCLC)、三阴性乳腺癌(TNBC)、胰腺癌(PDC)、食道癌和其他癌症。
如下文所详细讨论,血清中未检测到Trop-2,但在大部分存档的肿瘤中强烈表达(≥2+)。在3+3试验设计中,在重复21天周期的第1天和第8天给与IMMU-132,以8mg/kg/剂量开始,然后12和18mg/kg,直到剂量限制性嗜中性粒细胞减少症。为优化最小延迟的累积处理,II期集中于8和10mg/kg(n分别=30和14)。此时在49名报告相关AE的患者中,28%中出现嗜中性粒细胞减少症≥G3(4%G4)。最初在这些患者中的最常见的非血液毒性是疲劳(55%;≥G3=9%)、恶心(53%;≥G3=0%)、痢疾(47%;≥G3=9%)、脱发(40%)和呕吐(32%;≥G3=2%)。在6名患者中发现纯合UGT1A1*28/*28,其中2名具有较严重的血液和胃肠毒性。在I期和扩展期中,目前有48名患者(不包括PDC)可根据RECIST/CT评估为最佳反应。七名(15%)患者具有部分应答(PR),包括CRC患者(N=1)、TNBC患者(N=2)、SCLC患者(N=2)、NSCLC患者(N=1)和食道癌患者(N=1),并且另外27名患者(56%)患有稳定的疾病(SD),总共38名患者(79%)具有疾病应答;13名CT可评估的PDC患者中的8名(62%)患有SD,在他们最后一次先前治疗中,与8.0周相比,中值进展时间(TTP)为12.7周。剩余48名患者的TTP为12.6+周(6.0至51.4周的范围)。血浆CEA和CA19-9与反应相关。尽管给药达数月,但未检测到抗hRS7或抗SN-38抗体。在3天内从血清清除缀合物,符合其中每天释放50%的SN-38的体内动物研究,血清中>95%的SN-38结合至非葡萄糖醛酸形式的IgG,并且浓度比给与伊立替康的患者中报告的SN-38高100倍。这些结果显示,含有hRS7-SN-38的ADC在转移性实体癌中具有治疗活性,具有可控制的痢疾和嗜中性粒细胞减少。
药代动力学
将两种ELISA方法用于测量IgG(使用抗hRS7个体基因型抗体捕获)和完整的缀合物(使用抗SN-38 IgG/具有抗hRS7个体基因型抗体的探针捕获)的清除。通过HPLC测量SN-38。总IMMU-132级分(完整的缀合物)的清除比IgG(未示出)更快,从而反映SN-38从缀合物的已知逐渐释放。SN-38(未结合和总体)的HPLC测定显示出血清中>95%的SN-38结合至IgG。低浓度的SN-38G暗示,结合至IgG的SN-38受到保护,免于葡萄糖醛酸化。缀合物的ELISA和SN-38 HPLC的比较揭示二者重叠,从而暗示ELISA是用于监测SN-38清除的替代。
给药方案和患者池的总结提供于表3中。
表3.临床试验参数
临床试验状态
报告了总共69名各种转移性癌症患者(包括25名I期患者),它们具有3次先前疗法的中值。八名患者在CT评估之前具有临床进展和撤除。十三名CT可评估的胰腺癌患者单独报告。PDC患者中的中值TTP(进展时间)是11.9周(2至21.4周的范围),相比之下之前最后治疗的中值TTP为8周。
总共48名患有各种癌症的患者具有至少1次CT评估,由此确定最佳应答(图10)和进展时间(TTP;图11)。为了总结最佳应答数据,在8名可评估TNBC(三阴性乳腺癌)患者中,有2例PR(部分应答)、4例SD(稳定疾病)和2例PD(进行性疾病),总计应答[PR+SD]为6/8(75%)。对于SCLC(小细胞肺癌),在4名可评估患者中,有2例PR、0例SD和2例PD,总计应答为2/4(50%)。对于CRC(结肠直肠癌),在18名可评估患者中,有1例PR、11例SD和6例PD,总计应答为12/18(67%)。对于食道癌,在4名可评估患者中,有1例PR、2例SD和1例PD,总计应答为3/4(75%)。对于NSCLC(非小细胞肺癌),在5名可评估患者中,有1例PR、3例SD和1例PD,总计应答为4/5(80%)。在所有治疗的患者内,在48名可评估患者中,有7例PR、27例SD和14例PD,总计应答为34/48(71%)。这些结果证明,抗Trop-2 ADC(hRS7-SN-38)显示出针对一系列广泛的人患者实体瘤的显著临床功效。
所报告的治疗副作用(不良事件)总结于表4中。如从表4的数据显而易见,hRS7-SN-38的治疗功效以ADC的剂量实现,显示可接受的低水平的不利副作用。
表4.
对抗Trop-2 ADC的示例性部分应答通过CT数据(未示出)确认。作为CRC的示例性PR,初诊为CRC的62岁妇女经历初次半结肠切除。四个月后,由于肝脏转移她经历了肝脏切除,并接受7个月的FOLFOX治疗和1个月的5FU。她出现多个病灶,主要位于肝脏中(通过免疫组织分析3+Trop-2)在初始诊断后,以8mg/kg的起始剂量进入hRS7-SN-38试验约1年。在她首次CT评估时,实现PR,靶病灶减少37%(未示出)。患者继续治疗,在10个月治疗后实现最大减少65%(未示出),CEA从781ng/mL减少至26.5ng/mL,之后稍后进展3个月。
作为NSCLC的示例性PR,65岁男性被诊断为IIIB级NSCLC(鳞状细胞癌)。碳铂/依托泊苷(3mo)以及7000cGy XRT的初始治疗使得应答持续10mo。然后除经历腰椎板切除术之外,他从Tarceva维持治疗开始,继续直到他被考虑进入IMMU-132试验。他在5个月的Tarceva之后接受第一剂量的IMMU-132,此时右肺出现5.6cm病灶以及大量胸膜腔积液。他在两个月后完成第6剂,此时首次CT显示主要目标病灶减小至3.2cm(未示出)。
作为SCLC的示例性PR,65岁妇女被诊断为低分化SCLC。在2个月之后终止的接受卡铂/依托泊苷(Topo-II抑制剂)后,无应答,然后是2个月之后终止的托泊替康(Topo-I抑制剂),也无应答,她接受1个月后终止的局部XRT(3000cGy)。然而,在接下来一个月内进展继续。患者下个月从IMMU-132开始(12mg/kg;减少至6.8mg/kg;Trop-2表达3+),并且在两个月的IMMU-132之后,靶病灶减少38%,包括主要肺病灶中出现大量减少(未示出)。在接受12个剂量之后,患者进展3个月。
这些结果的意义在于,它们显示抗Trop-2 ADC是有效的,即使在多次先前治疗之后失效或进展的患者中也是如此。
总之,在所用的剂量下,主要毒性是可控制的嗜中性粒细胞减少症,3级毒性很少。IMMU-132显示了三阴性乳腺癌、小细胞肺癌、非小细胞肺癌、结肠直肠癌和食道癌的复发/难治患者中活性(PR和持久性SD)的证据,包括具有拓扑异构酶-I抑制剂治疗的复发既往史的患者。这些结果示出抗Trop-2 ADC在一系列广泛的耐受现有疗法的癌症中的功效。
实施例10.三阴性乳腺癌(TNBC)中IMMU-132的皮下施用
沙西妥珠单抗戈维替康(IMMU-132)ADC如上文实施例中所述制备。用至少两种标准疗法治疗失败的患有三阴性乳腺癌的患者接受2至4mg/kg的沙西妥珠单抗戈维替康,每日给与持续1周、或每周3次持续2周、或每周两次持续2周,且然后停药。在诱导后每两到三周或每月静脉内或皮下施用维持剂量的ADC。或者,可在以8-10mg/kg静脉内施用的二至四个周期发生诱导(每个周期,在两个21天周期的第1天和第8天施用ADC,其间一周停药期),然后作为每周一次或多次活性给药或作为维持疗法皮下施用。可基于中期肿瘤扫描和/或通过分析Trop-2阳性循环肿瘤细胞来调整剂量。
在两个治疗周期后,在所有剂量水平和IMMU-132的施用方案中观察到目标应答,肿瘤体积平均减少35%。针对人抗hRS7抗体(HAHA)评价的所有血清样品均为阴性,并且在施用部位未观察到不利的局部反应。
实施例11.在转移性结肠癌中IMMU-130的皮下施用
患有左和右肝叶的转移性结肠癌(直径3-5cm)以及右肺的5cm转移以及130ng/mL的升高的血液CEA值的52岁男性用以4mg/kg的剂量皮下施用的抗CEACAM-5 ADC IMMU-130(hMN-14-CL2A-SN-38)进行治疗,每周给与3次持续2周,然后停药,进行3个周期的药物施用。在治疗开始8周的CT评估后,测量到3个靶病灶的总平均直径减少25%,从而根据RECIST1.1标准构成良好的稳定疾病应答。随着他的嗜中性粒细胞减少症正常化,重复疗程继续。
实施例12.双功能SN-38产物与轻度还原的抗体的缀合
使用CL2A接头将抗CEACAM5人源化MAb,hMN-14(也称为拉贝珠单抗);抗CD22人源化MAb,hLL2(也称为依帕珠单抗);抗CD20人源化MAb,hA20(也称为维妥珠单抗);抗EGP-1人源化MAb,hRS7和抗粘蛋白人源化MAb,hPAM4(也称为克伐珠单抗)缀合至SN-38。用含有5.4mM EDTA的40mM PBS(pH 7.4)中的以50-70倍摩尔过量使用的二硫苏糖醇(DTT)还原每种抗体,在37℃(浴)下45分钟。通过尺寸排阻色谱法和/或渗滤法纯化还原的产物,并缓冲液交换至pH 6.5的合适缓冲液中。通过Ellman测定确定硫醇含量,并且在6.5至8.5 SH/IgG范围内。或者,用在5-7范围内的pH的磷酸盐缓冲液中的三(2-羧乙基)膦(TCEP)还原抗体,随后原位缀合。使用7%-15%v/v的DMSO作为共溶剂使还原的MAb与约10至15倍摩尔过量的CL2A-SN-38反应,并在环境温度下孵育20分钟。通过离心SEC纯化缀合物,通过疏水性柱,且最后通过超滤-渗滤。通过366nm处的吸光度测定产物的SN-38并与标准值相关联,而蛋白质浓度由280nm处的吸光度推断,校正在此波长下SN-38吸光度的溢出。以这种方式,确定了SN-38/MAb替代比。将纯化的缀合物作为冻干制剂储存在玻璃小瓶中,在真空下加盖并储存在-20℃的冰箱中。对于这些缀合物获得的SN-38摩尔替代比(MSR)通常在5-7的范围内。
实施例13.仅使用IMMU-130(拉贝珠单抗-SN-38)治疗先前化学-免疫疗法难治的晚期结肠癌患者
患者是50岁男性,具有IV期转移性结肠癌病史,于2008年首次诊断且分别给与针对原发性和转移性结肠癌的结肠切除术和部分肝切除术。然后他接受了化学疗法,其包括伊立替康、奥沙利铂、FOLFIRINOX(5-氟尿嘧啶、甲酰四氢叶酸、伊立替康、奥沙利铂)和贝伐单抗,以及贝伐单抗与5-氟尿嘧啶/甲酰四氢叶酸组合,持续近2年。此后,他在下一年或或更长时间期间接受了单独或与FOLFIRI(甲酰四氢叶酸、5-氟尿嘧啶、伊立替康)化学疗法组合的西妥昔单抗疗程。在2009年,他在化学-免疫治疗同时接受了肝转移的射频消融治疗,并于2010年底进行了他的肺转移的楔形切除术,并在几个月后在2011年初重复进行。尽管2011年进行了化学-免疫治疗,但2011年底出现了新的肺转移,并且在2012年,肺转移和肝转移均可见。在进行使用IMMU-130的抗体-药物治疗之前,他的基线血浆癌胚抗原(CEA)滴度为12.5ng/mL。放射科医师通过计算机断层摄影术测量肿瘤大小变化所选择的指数病变是右肺中叶和肝转移,两者总计91mm作为IMMU-130(抗CEACAM5-SN-38)疗法之前基线的最长直径的总和。
此患者每隔一周通过缓慢静脉内输注接受10mg/kg IMMU-130的剂量,总计17个治疗剂量。患者对治疗耐受良好,在第一次治疗后仅具有1级恶心、腹泻和疲劳,这在治疗4和5之后发生,但之后没有,因为他接受这些副作用的药物治疗。在治疗3之后,他确实显示出在随后的治疗期间存在的脱发(2级)。恶心、腹泻和偶尔呕吐仅持续2-3天,并且在第一次输注后的疲劳持续2周。否则,患者良好地耐受治疗。由于接受与SN-38缀合的这种人源化(CDR-移植的)抗体的持续时间长,因此测量了他的血液中的抗拉贝珠单抗抗体,并且即使在16个剂量后也未检测到。
在4次治疗后进行第一次计算机断层摄影术(CT)测量,并且在这种治疗之前,在指数病灶中,显示从基线处进行的测量的总和的28.6%变化。在8次治疗后,这种减少变为40.6%,因此根据RECIST标准构成部分缓解。这种反应维持了另外2个月,当时他的CT测量值表明指数病灶比基线测量值低31.9%,但略高于之前测量的40.6%的下降。因此,基于对肺和肝脏中指数病灶的仔细CT测量,在包括(SN-38的母体分子)的之前用化学疗法和免疫疗法治疗失败的此患者显示出当经由抗CEACAM5人源化抗体拉贝珠单抗(hMN-14)靶向时,对伊立替康(或喜树碱)的活性代谢物SN-38的目标应答。令人惊讶的是,虽然伊立替康(CPT-11)通过在体内释放SN-38起作用,但SN-38缀合的抗CEACAM5抗体在结肠直肠癌患者中通过在患者早期未能对其最后一次含伊立替康的疗法作出反应后诱导部分应答而被证实有效。患者的血浆CEA滴度降低也证实了CT结果:在第三次治疗剂量后它从12.6ng/mL的基线水平下降至2.1ng/mL,并且在剂量8与12之间介于1.7与3.6ng/mL之间。CEA的正常血浆滴度通常被认为介于2.5与5.0ng/mL之间,因此这种疗法实现了他的血液中的CEA滴度的正常化。鉴于这种应答,患者接受IMMU-130的SC制剂的维持治疗,每三周每周两次以2.5mg/kg的剂量施用,持续9个月的时间。在此期间,重复扫描和血液CEA滴度保持稳定,并且患者仅具有2级嗜中性粒细胞减少症,其在每个疗程后10天内消退。
实施例14.用皮下IMMU-140治疗患有晚期结肠癌的患者
此患者是最初被诊断患有转移性结肠癌的75岁女性(IV期)。她具有右部分半结肠切除术和她的小肠切除,且然后接受FOLFOX、FOLFOX+贝伐单抗、FOLFIRI+雷莫芦单抗以及FOLFIRI+西妥昔单抗治疗持续一年半,此时她显示疾病进展,疾病传播至后穹窿、网膜,在她的骨盆中具有腹水以及她的胸腔右侧的胸膜积液。
每周两次皮下施用3mg/kg IMMU-140(抗HLA-DR-SN-38)连续2周,且然后停药一周(3周周期)持续超过20个剂量,其被非常良好地耐受,没有任何重大的血液学或非血液学毒性。在8周的评价中,她显示指数肿瘤病灶缩小21%,其在13周时增加至27%收缩。令人惊讶的是,此时患者的腹水和胸膜积液均减少(后者消失),从而显著改善患者的整体状况。患者继续她的研究治疗。
实施例15.用IMMU-130的静脉内和皮下疗法治疗的患有IV期转移性疾病的胃癌患者
患者是52岁男性,由于胃部不适和与进食有关的疼痛持续约6年而寻求医疗看护,并且在过去12个月内体重减轻。胃区的触诊显示出坚硬的肿块,然后进行胃镜检查,在胃的下部显示溃疡性肿块。将其进行活组织检查并诊断为胃腺癌。实验室测试显示无特异性异常变化,除了肝功能测试LDH和CEA升高,后者为10.2ng/mL。然后患者进行全身PET扫描,除了胃肿瘤外,其还公开了左腋窝和肝右叶中的转移性疾病(2个小转移灶)。患者切除胃肿瘤,且然后对他的转移性肿瘤进行基线CT测量。在手术后4周,他接受3个疗程的由顺铂和5-氟尿嘧啶(CF)的方案组成的组合化学疗法,但不能很好地耐受,因此转用多西他赛治疗。基于CT扫描,所述疾病似乎稳定了约4个月,但随后患者对进一步体重减轻、腹痛、食欲不振和极度疲劳的抱怨引起反复CT研究,其显示在原始胃切除部位转移灶的大小增加总和为20%和可疑病灶。
然后以8mg/kg静脉内的每周时间表给与患者IMMU-130(抗CEACAM5-SN-38)的实验性治疗。他对此耐受良好,但3周后显示2级嗜中性粒细胞减少症和1级腹泻。他的第四次输注被推迟一周,且然后每周输注重新开始,在接下来的4次注射没有腹泻或嗜中性粒细胞减少症的迹象。然后患者进行CT研究以测量他的转移性肿瘤大小并观察胃切除的原始区域。根据RECIST标准,放射科医师测量转移病灶的总和与IMMU-130治疗前的基线相比减少23%。在原始胃切除术区域似乎没有任何明显的病灶。此时患者的CEA滴度为7.2ng/mL,从IMMU-130前的基线值14.5ng/mL远远降低。患者以8.0mg/kg静脉内的相同剂量继续每周IMMU-130治疗,并且在总计13次输注后,他的CT研究显示,一个肝转移消失,并且所有转移病灶的总和减少41%,从而根据RECIST构成部分应答。患者的一般状况有所改善,并且他恢复常规活动,同时继续接受每6周每周两次皮下施用IMMU-130的3mg/kg的维持治疗持续另外4个疗程。在血液CEA的最后一次测量中,值为4.8ng/mL,这在吸烟者的正常范围内,这是此患者的情况。
实施例16.用皮下抗CEACAM5免疫缀合物治疗晚期转移性结肠癌
患者是用针对转移性结肠癌的先前疗法治疗失败的50岁男性。一线治疗是在第一个周期中以IROX(伊立替康+奥沙利铂)开始的(以逐步方式建立)。在开始这种治疗后,患者的CT显示肝转移灶的大小减小。然后进行手术切除肿瘤组织。辅助化学疗法是一线方案(没有IROX部分)的延续,其导致短暂的无复发期。在间隔约1年后,CT显示肝转移复发。这导致二线方案(FOLFIRI+西妥昔单抗)的开始。另一次CT显示肝转移的应答。然后进行肝转移的RF消融,然后继续用FOLFIRINOX+西妥昔单抗进行辅助化疗,随后维持西妥昔单抗约一年。另一次CT扫描显示没有疾病迹象。进一步扫描显示可能的肺结节,其得到证实。这导致肺结节的楔形切除。随后FOLFIRI+西妥昔单抗重新开始并继续。稍后的CT扫描显示肺和肝转移。
在施用hMN-14-SN-38 ADC时,患者患有晚期转移性结肠癌,具有肺和肝的转移,其对伊立替康(喜树碱)无反应。hMN-14-SN-38 ADC以2mg/kg皮下的剂量施用,每周两次,其每隔一周重复持续4个月。在3个月的CT评估中,患者根据RECIST标准显示出转移性肿瘤减少的部分应答。
值得注意的是,这2mg/kg皮下(每周两次给与)组中仅一名患者显示2级血液学(嗜中性粒细胞减少症),并且大多数患者具有1级或2级恶心、呕吐或秃头症-这些都是抗体-药物缀合物的活性的迹,但耐受良好。抗体部分在改善喜树碱靶向中的作用解释了SN-38部分在先前已经对未缀合的伊立替康具有耐药性的癌症中的功效。未注意到注射部位不耐受,只有在一周或更长时间内消退的一些局部红斑。
实施例17.多次皮下注射IMMU-132的耐受性
方法
在4周的时间内,用IMMU-132重复皮下注射天然雌性裸鼠。一组两只小鼠接受2mg注射(HED=8mg/kg),而第二组两只动物接受500μg(HED=2mg/kg)。为了比较,一只小鼠仅接受盐水注射。每次注射(100μL)在相同位置(即右后侧腹)施用,每周两次持续四周。在注射当天对小鼠称重,并检查注射部位是否有任何毒性迹象(即皮疹、溃疡等)。如果发生任何情况,则将通过对所述区域拍照来记录。最后一次注射后一天,将小鼠麻醉并对注射部位拍照(图12)。在最后一次注射后一周重复这一过程(图13)。
结果
在最后一次注射后一天,对小鼠进行拍照以记录注射部位(图12)。同样,在最后一次注射后一周,对他们再次拍照以记录注射部位的状况(图13)。这些照片表明,在多次注射部位没有皮肤刺激的迹象。即使在4周内注射2mg IMMU-132(总共16mg)的小鼠看起来与仅注射盐水的小鼠也没有什么不同。这些数据表明在这些小鼠中多次皮下注射IMMU-132的部位没有脱靶毒性。
实施例18.皮下IMMU-132的体内功效
实验设计
在实验性人膀胱癌中评价作为静脉内注射(i.v.)对比皮下注射(s.c.)施用的IMMU-132(沙西妥珠单抗戈维替康)的治疗功效(5637)。
将5637细胞在组织培养中扩增并用胰蛋白酶/EDTA收获。将雌性无胸腺裸鼠皮下注射200μL的与基质胶1:1混合的5637细胞悬浮液,以使得1x107个细胞被施用于每只小鼠。一旦肿瘤达到大约0.25cm3的大小(15天后),就将动物分成三个不同的处理组,每组4-5只小鼠。对于静脉内注射(N=5),小鼠接受静脉内500μg每周两次,持续四周。同样地,向接受皮下注射(N=5)的小鼠施用500μg IMMU-132每周两次,持续四周。最后一组小鼠仅接受盐水(N=4)并用作未处理的对照。测量肿瘤并且小鼠每周称重两次。如果其肿瘤体积超过1.0cm3大小,就将小鼠安乐死以获得疾病进展。
结果.
处理的小鼠的平均肿瘤体积在图14中示出。盐水对照组中的肿瘤在治疗开始后47.5天的中值存活时间(MST)进展。通过任一注射途径用IMMU-132处理的小鼠显示显著肿瘤消退,两组的MST>67天(对比盐水对照P=0.0221,对数秩检验)。当实验在第82天(治疗开始后67天)结束时,两个IMMU-132处理组中的所有5只小鼠仍然存活(图14)。这些结果表明,皮下施用ADC与静脉内施用一样有效。
* * *
本领域的技术人员将显而易见的是,可对本发明的产物、组合物、方法和工序进行各种修改和变型。因此,本发明旨在涵盖此类修改和变型,前提条件是它们在所附权利要求书的范围及其等同形式内。
Claims (36)
1.一种治疗癌症的方法,所述方法包括向患有癌症的人患者皮下施用抗体-药物缀合物(ADC)。
2.如权利要求1所述的方法,其中所述抗体结合至选自由以下组成的组的抗原:碳酸酐酶IX、B7、CCL19、CCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD47、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM6、CTLA-4、DLL2(远端缺失2)、DLL3、DLL4、α-胎蛋白(AFP)、VEGF、ED-B、纤连蛋白、EGP-1(Trop-2)、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GRO-β、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、组蛋白H2B、组蛋白H3、组蛋白H4、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节苷脂、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞迁移抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5ac、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PD-1受体、PD-L1、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、汤姆森-弗里德里希抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体R1、TRAIL受体R2)、VEGFR、RANTES、T101、补体因子C3、C3a、C3b、C5a、C5和致癌基因产物。
3.如权利要求1所述的方法,其中所述抗体结合至选自由以下组成的组的抗原:Trop-2、CEACAM5、CEACAM6、CD20、CD22、CD74、CD30、HER2/neu、AFP、叶酸受体、DLL2(远端缺失2)、DLL3、DLL4、HLA-DR。
4.如权利要求1所述的方法,其中所述抗体选自由以下组成的组:hL243、hRS7 hMN-14、hMN-15、维妥珠单抗、依帕珠单抗和米拉珠单抗。
5.如权利要求1所述的方法,其中所述药物是SN-38。
6.如权利要求5所述的方法,其中用CL2A接头将所述SN-38附接至所述抗体,并且所述ADC的结构是MAb-CL2A-SN-38
7.如权利要求1所述的方法,其中所述ADC以1.5至4mg/kg的剂量施用。
8.如权利要求7所述的方法,其中在单一注射部位皮下施用所述1.5至4mg/kg剂量。
9.如权利要求1所述的方法,其中皮下施用发生在所述患者的多个部位,并且每个部位接受1.5至4mg/kg的剂量。
10.如权利要求1所述的方法,其中以4至16mg/kg向所述患者施用一个或多个静脉内剂量的所述ADC,随后以1.5至4mg/kg施用一个或多个皮下剂量。
11.如权利要求1所述的方法,其中所述ADC以1ml、2ml、3ml或更小的体积皮下施用。
12.如权利要求1所述的方法,其中所述ADC每日一次施用持续1周,或每周3次施用持续2周,或每周两次施用持续两周,随后停药。
13.如权利要求12所述的方法,其中维持剂量的ADC可在初始治疗后每两到三周或每月静脉内或皮下施用。
14.如权利要求1所述的方法,其中基于中期肿瘤扫描或通过循环肿瘤细胞的分析来调整所述ADC剂量。
15.如权利要求1所述的方法,其中所述药物选自由以下组成的组:5-氟尿嘧啶、阿法替尼、阿普利啶、阿扎立平、阿那曲唑、蒽环类药物、阿西替尼、AVL-101、AVL-291、苯达莫司汀、博来霉素、硼替佐米、博舒替尼、苔藓虫素-1、白消安、刺孢霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、塞来昔布、苯丁酸氮芥、顺铂、COX-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、喜树碱、克唑替尼、环磷酰胺、阿糖胞苷、达卡巴嗪、达沙替尼、地尼西宝、多西他赛、更生霉素、柔红霉素、DM1、DM3、DM4、阿霉素、阿霉素葡糖苷酸、内皮抑素、表柔比星葡糖苷酸、埃罗替尼、雌莫司汀、表鬼臼毒素、埃罗替尼、恩替诺特、雌激素受体结合剂、依托泊苷(VP16)、依托泊苷葡糖苷酸、磷酸依托泊苷、依西美坦、芬戈莫德、氟尿苷(FUdR)、3’,5’-O-二油酰基-FudR(FUdR-dO)、氟达拉滨、氟他胺、法尼基-蛋白转移酶抑制剂、夫拉平度、福他替尼、吉尼替彼、GDC-0834、GS-1101、吉非替尼、吉西他滨、羟基脲、依鲁替尼、伊达比星、伊德利塞、异环磷酰胺、伊马替尼、拉帕替尼、来那度胺、亚叶酸、LFM-A13、洛莫司汀、氮芥、美法仑、巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、光辉霉素、丝裂霉素、米托坦、单甲基奥瑞斯他汀F(MMAF)、单甲基奥瑞斯他汀D(MMAD)、单甲基奥瑞斯他汀E(MMAE)、诺维本、来那替尼、尼洛替尼、亚硝基脲、奥拉帕尼、普卡霉素、丙卡巴肼、紫杉醇、PCI-32765、喷司他丁、PSI-341、雷洛昔芬、司莫司汀、SN-38、索拉非尼、链脲霉素、SU11248、舒尼替尼、他莫昔芬、替莫唑胺、反铂、沙利度胺、硫鸟嘌呤、塞替哌、替尼泊苷、托泊替康、乌拉莫司汀、瓦他拉尼、长春瑞滨、长春碱、长春新碱、长春花生物碱以及ZD1839。
16.如权利要求1所述的方法,其中所述药物是蒽环类药物或喜树碱。
17.如权利要求1所述的方法,其中所述药物选自由以下组成的组:SN-38、紫杉醇和阿霉素。
18.如权利要求1所述的方法,其中所述癌症对用至少一种抗癌剂的先前治疗具有耐药性或从用至少一种抗癌剂的先前治疗复发。
19.如权利要求1所述的方法,其中所述癌症对用伊立替康或托泊替康治疗具有耐药性或从用伊立替康或托泊替康治疗复发。
20.如权利要求1所述的方法,其中所述癌症是转移性的。
21.如权利要求1所述的方法,其中所述癌症是实体瘤,并且所述治疗使得肿瘤大小减小至少15%、至少20%、至少30%或至少40%。
22.如权利要求20所述的方法,其还包括减小大小或消除转移。
23.如权利要求1所述的方法,其中所述癌症是其他疗法难治的,但对所述ADC有反应。
24.如权利要求1所述的方法,其中所述癌症选自由以下组成的组:三阴性乳腺癌、转移性胰腺癌、转移性胃肠癌、转移性尿路上皮癌和转移性结肠直肠癌。
25.如权利要求1所述的方法,其中所述癌症选自由以下组成的组:B细胞非霍奇金淋巴瘤、B细胞急性淋巴性白血病、B细胞慢性淋巴性白血病、伯基特淋巴瘤、霍奇金淋巴瘤、毛细胞白血病、急性骨髓性白血病、慢性骨髓性白血病、T细胞淋巴瘤、T细胞白血病、边缘区淋巴瘤、DLBCL(弥漫性大B细胞淋巴瘤)、滤泡性淋巴瘤、SLL(小淋巴细胞性淋巴瘤)、套细胞淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、癌、黑素瘤、肉瘤、神经胶质瘤、口腔癌、胃肠道癌、肺道癌、乳腺癌、卵巢癌、前列腺癌、子宫癌、膀胱癌、胰腺癌、肝癌、胆囊癌、皮肤癌、睾丸癌、宫颈癌、子宫内膜癌、肺癌、结肠癌、胃癌、食道癌、肾癌、甲状腺癌、上皮癌、尿路上皮癌以及头颈癌。
26.如权利要求5所述的方法,其中每个抗体分子上附接有6个或更多个SN-38分子。
27.如权利要求5所述的方法,其中每个抗体分子上附接有6-8个SN-38分子。
28.如权利要求5所述的方法,其中每个抗体分子上附接有7-8个SN-38分子。
29.如权利要求1所述的方法,其中所述抗体是IgG1或IgG4抗体。
30.如权利要求1所述的方法,其中所述抗体具有选自由以下组成的组的同种异型:G1m3、G1m3,1、G1m3,2、G1m3,1,2、nG1m1、nG1m1,2以及Km3同种异型。
31.如权利要求1所述的方法,其中所述ADC剂量以具有选自由以下组成的组的周期的时间表每周一次或两次施用至所述人受试者:(i)每周;(ii)每隔一周;(iii)治疗一周,随后停药两周、三周或四周;(iv)治疗两周,随后停药一周、两周、三周或四周;(v)治疗三周,随后停药一周、两周、三周、四周或五周;(vi)治疗四周,随后停药一周、两周、三周、四周或五周;(vii)治疗五周,随后停药一周、两周、三周、四周或五周;以及(viii)每月。
32.如权利要求31所述的方法,其中所述周期重复4次、6次、8次、10次、12次、16次或20次。
33.如权利要求1所述的方法,其中所述ADC与选自由以下组成的组的一种或多种治疗方式组合施用:未缀合的抗体、免疫缀合物、抗原结合抗体片段、药物、毒素、放射性核素、基因疗法、化学疗法、治疗性肽、细胞因子疗法、寡核苷酸、局部放射疗法、外科手术以及干扰RNA疗法。
34.如权利要求33所述的方法,其中所述药物或毒素选自由以下组成的组:5-氟尿嘧啶、阿法替尼、阿普立定、阿扎立平、阿那曲唑、蒽环类药物、阿西替尼、AVL-101、AVL-291、苯达莫司汀、博来霉素、硼替佐米、博舒替尼、苔藓抑素-1、白消安、刺孢霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、西乐葆、苯丁酸氮芥、顺铂(CDDP)、Cox-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、喜树碱、环磷酰胺、克唑替尼、阿糖胞苷、达卡巴嗪、达沙替尼、地尼西宝、多西他赛、更生霉素、柔红霉素、阿霉素、2-吡咯啉子基阿霉素(2P-DOX)、氰基-吗啉代阿霉素、阿霉素葡糖苷酸、表柔比星葡糖苷酸、埃罗替尼、雌莫司汀、表鬼臼毒素、埃罗替尼、恩替诺特、雌激素受体结合剂、依托泊苷(VP16)、依托泊苷葡糖苷酸、磷酸依托泊苷、依西美坦、芬戈莫德、夫拉平度、氟尿苷(FUdR)、3',5'-O-二油酰基-FudR(FUdR-dO)、氟达拉滨、氟他胺、法尼基-蛋白转移酶抑制剂、福他替尼、吉尼替彼、GDC-0834、GS-1101、吉非替尼、吉西他滨、羟基脲、依鲁替尼、伊达比星、伊德利塞、异环磷酰胺、伊马替尼、L-天冬酰胺酶、拉帕替尼、来那度胺、亚叶酸、LFM-A13、洛莫司汀、氮芥、美法仑、巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、光辉霉素、丝裂霉素、米托坦、诺维本、来那替尼、尼洛替尼、亚硝基脲、奥拉帕尼、普卡霉素、丙卡巴肼、紫杉醇、PCI-32765、喷司他丁、PSI-341、雷洛昔芬、司莫司汀、索拉非尼、链脲霉素、SU11248、舒尼替尼、它莫西芬、替莫唑胺(DTIC的水性形式)、反铂、沙利度胺、硫鸟嘌呤、塞替派、替尼泊苷、托泊替康、乌拉莫司汀、瓦他拉尼、长春瑞滨、长春碱、长春新碱、长春花生物碱以及ZD1839。
35.如权利要求34所述的方法,其中所述药物是:
a)PARP抑制剂,所述PARP抑制剂选自由以下组成的组:奥拉帕尼、他拉唑帕尼(BMN-673)、鲁卡帕尼、维利帕尼、CEP 9722、MK 4827、BGB-290、ABT-888、AG014699、BSI-201、CEP-8983以及3-氨基苯甲酰胺;或
b)布鲁顿激酶抑制剂,所述布鲁顿激酶抑制剂选自由以下组成的组:依鲁替尼(PCI-32765)、PCI-45292、CC-292(AVL-292)、ONO-4059、GDC-0834、LFM-A13以及RN486;或
c)PI3K抑制剂,所述PI3K抑制剂选自由以下组成的组:伊德利塞、渥曼青霉素、去甲氧基绿胶霉素、哌立福辛、PX-866、IPI-145(度维利塞)、BAY 80-6946、BEZ235、RP6530、TGR1202、SF1126、INK1117、GDC-0941、BKM120、XL147、XL765、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、PI-103、GNE477、CUDC-907、AEZS-136以及LY294002。
36.如权利要求1所述的方法,其中所述癌症是转移性结肠癌,并且所述患者在施用所述ADC之前用FOLFIRI或FOLFOX化学疗法治疗失败。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762480789P | 2017-04-03 | 2017-04-03 | |
US62/480789 | 2017-04-03 | ||
PCT/US2018/024332 WO2018187074A1 (en) | 2017-04-03 | 2018-03-26 | Subcutaneous administration of antibody-drug conjugates for cancer therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110352201A true CN110352201A (zh) | 2019-10-18 |
Family
ID=63672752
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880010028.XA Pending CN110352201A (zh) | 2017-04-03 | 2018-03-26 | 用于癌症疗法的抗体药物缀合物的皮下施用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US10799597B2 (zh) |
EP (1) | EP3606964A4 (zh) |
CN (1) | CN110352201A (zh) |
CA (1) | CA3044082A1 (zh) |
WO (1) | WO2018187074A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022001710A1 (zh) * | 2020-06-28 | 2022-01-06 | 达石药业(广东)有限公司 | 用于抗体与药物偶联体(adc)制备的中间体及其制备方法和应用 |
CN114599392A (zh) * | 2019-10-31 | 2022-06-07 | 四十七公司 | 基于抗cd47和抗cd20的血癌治疗 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004054622A1 (en) * | 2002-12-13 | 2004-07-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US20160355591A1 (en) * | 2011-05-02 | 2016-12-08 | Immunomedics, Inc. | Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies |
DK3903829T3 (da) * | 2009-02-13 | 2023-06-26 | Immunomedics Inc | Immunkonjugater med en intracellulær spaltelig binding |
SG11201408161RA (en) | 2012-06-08 | 2015-01-29 | Sutro Biopharma Inc | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
WO2015006555A2 (en) | 2013-07-10 | 2015-01-15 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
US11253606B2 (en) * | 2013-07-23 | 2022-02-22 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
KR20180104106A (ko) | 2016-01-27 | 2018-09-19 | 서트로 바이오파마, 인크. | anti-CD74 항체 접합체, anti-CD74 항체 접합체를 포함하는 조성물 및 anti-CD74 항체 접합체의 이용 방법 |
CN111001012A (zh) * | 2018-10-19 | 2020-04-14 | 四川百利药业有限责任公司 | 一种亲水碳酸酯型抗体偶联药物 |
CN110331200A (zh) * | 2019-06-28 | 2019-10-15 | 中山大学附属第六医院 | Cd47检测试剂在制备结直肠癌对抗egfr单抗耐药诊断剂方面的应用 |
EP4079761A4 (en) * | 2019-12-16 | 2024-02-07 | Jiangsu Hengrui Medicine Co | ANTI-CEA ANTIBODIES EXATECAN ANALOG CONJUGATE AND ITS PHARMACEUTICAL USE |
GB202011993D0 (en) | 2020-07-31 | 2020-09-16 | Adc Therapeutics Sa | ANTI-IL 13Ra2 antibodies |
US11484604B2 (en) | 2020-08-07 | 2022-11-01 | Fortis Therapeutics, Inc. | Immunoconjugates targeting CD46 and methods of use thereof |
CA3228080A1 (en) * | 2021-08-06 | 2023-02-09 | Mary M. Chen | Radioconjugates targeting cd33 in the treatment of cancers |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080025989A1 (en) * | 2003-02-20 | 2008-01-31 | Seattle Genetics, Inc. | Anti-cd70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders |
US20140227180A1 (en) * | 2012-12-13 | 2014-08-14 | Immunomedics, Inc. | Antibody-sn-38 immunoconjugates with a cl2a linker |
CN109562172A (zh) * | 2016-08-11 | 2019-04-02 | 免疫医疗公司 | 抗HLA-DR抗体药物缀合物IMMU-140(hL243-CL2A-SN-38)在HLA-DR阳性癌症中的功效 |
Family Cites Families (215)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1541435A (en) | 1975-02-04 | 1979-02-28 | Searle & Co | Immunological materials |
US4036945A (en) | 1976-05-03 | 1977-07-19 | The Massachusetts General Hospital | Composition and method for determining the size and location of myocardial infarcts |
US4200690A (en) | 1976-12-16 | 1980-04-29 | Millipore Corporation | Immunoassay with membrane immobilized antibody |
US4331647A (en) | 1980-03-03 | 1982-05-25 | Goldenberg Milton David | Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers |
US5204095A (en) | 1980-04-09 | 1993-04-20 | National Research Development Corporation | Monoclonal antibodies against hepatitis B virus |
US4359457A (en) | 1980-09-30 | 1982-11-16 | Neville Jr David M | Anti Thy 1.2 monoclonal antibody-ricin hybrid utilized as a tumor suppressant |
US4925922A (en) | 1983-02-22 | 1990-05-15 | Xoma Corporation | Potentiation of cytotoxic conjugates |
US4916213A (en) | 1983-02-22 | 1990-04-10 | Xoma Corporation | Ribosomal inhibiting protein-immunoglobulin conjugates with specificity for tumor cell surface antigens, and mixtures thereof |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5672347A (en) | 1984-07-05 | 1997-09-30 | Genentech, Inc. | Tumor necrosis factor antagonists and their use |
US4824659A (en) | 1985-06-07 | 1989-04-25 | Immunomedics, Inc. | Antibody conjugates |
US5525338A (en) | 1992-08-21 | 1996-06-11 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin conjugates |
US5776093A (en) | 1985-07-05 | 1998-07-07 | Immunomedics, Inc. | Method for imaging and treating organs and tissues |
US4918163A (en) | 1985-09-27 | 1990-04-17 | Pfizer Inc. | Monoclonal antibodies specific for lipid-A determinants of gram negative bacteria |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4699784A (en) | 1986-02-25 | 1987-10-13 | Center For Molecular Medicine & Immunology | Tumoricidal methotrexate-antibody conjugate |
US5057313A (en) | 1986-02-25 | 1991-10-15 | The Center For Molecular Medicine And Immunology | Diagnostic and therapeutic antibody conjugates |
US4997913A (en) | 1986-06-30 | 1991-03-05 | Oncogen | pH-sensitive immunoconjugates and methods for their use in tumor therapy |
US4704692A (en) | 1986-09-02 | 1987-11-03 | Ladner Robert C | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
CA1320905C (en) | 1986-11-06 | 1993-08-03 | Joseph M. Cummins | Treatment of immuno-resistant disease |
US4932412A (en) | 1986-12-18 | 1990-06-12 | Immunomedics, Inc. | Intraoperative and endoscopic tumor detection and therapy |
WO1988007553A1 (en) | 1987-03-26 | 1988-10-06 | Teijin Limited | Process for preparing antibody complex |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US4981979A (en) | 1987-09-10 | 1991-01-01 | Neorx Corporation | Immunoconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
IL89220A (en) | 1988-02-11 | 1994-02-27 | Bristol Myers Squibb Co | Immunoconjugates of anthracycline, their production and pharmaceutical preparations containing them |
US5846534A (en) | 1988-02-12 | 1998-12-08 | British Technology Group Limited | Antibodies to the antigen campath-1 |
US5112954A (en) | 1988-02-26 | 1992-05-12 | Neorx Corporation | Method of enhancing the effect of cytotoxic agents |
US4861579A (en) | 1988-03-17 | 1989-08-29 | American Cyanamid Company | Suppression of B-lymphocytes in mammals by administration of anti-B-lymphocyte antibodies |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
GB8903021D0 (en) | 1989-02-10 | 1989-03-30 | Celltech Ltd | Chemical compounds |
US5134075A (en) | 1989-02-17 | 1992-07-28 | Oncogen Limited Partnership | Monoclonal antibody to novel antigen associated with human tumors |
US5171665A (en) | 1989-04-17 | 1992-12-15 | Oncogen | Monoclonal antibody to novel antigen associated with human tumors |
JPH02283294A (ja) | 1989-04-24 | 1990-11-20 | Sumitomo Chem Co Ltd | ヒトモノクローナル抗体 |
ATE149841T1 (de) | 1990-01-26 | 1997-03-15 | Immunomedics Inc | Impfstoffe gegen krebs und infektionskrankheiten |
AU7566991A (en) | 1990-03-14 | 1991-10-10 | Biomembrane Institute, The | Monoclonal antibody and immunoconjugates for the treatment and detection of b cell disorders |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
GB9020075D0 (en) | 1990-09-14 | 1990-10-24 | Filler Aaron G | Contrast agents for magnetic resonance imaging of axonal transport |
US5679640A (en) | 1991-02-12 | 1997-10-21 | Cytel Corporation | Immunosuppressant peptides |
JP3105629B2 (ja) | 1991-04-23 | 2000-11-06 | サングスタット メディカル コーポレイション | 特異的結合ペアのメンバーの細胞活性調節接合体 |
US5665595A (en) | 1991-06-07 | 1997-09-09 | Dowelanco | Immunoglobulins against insect tissue |
TW373023B (en) | 1991-07-15 | 1999-11-01 | Wellcome Found | Production of antibodies |
IE922437A1 (en) | 1991-07-25 | 1993-01-27 | Idec Pharma Corp | Recombinant antibodies for human therapy |
EP0861893A3 (en) | 1991-09-19 | 1999-11-10 | Genentech, Inc. | High level expression of immunoglobulin polypeptides |
US5622929A (en) | 1992-01-23 | 1997-04-22 | Bristol-Myers Squibb Company | Thioether conjugates |
US5965132A (en) | 1992-03-05 | 1999-10-12 | Board Of Regents, The University Of Texas System | Methods and compositions for targeting the vasculature of solid tumors |
US6096289A (en) | 1992-05-06 | 2000-08-01 | Immunomedics, Inc. | Intraoperative, intravascular, and endoscopic tumor and lesion detection, biopsy and therapy |
EP0643583B1 (en) | 1992-05-06 | 2000-07-26 | Immunomedics, Inc. | Intraoperative, intravascular and endoscopic tumor and lesion detection and therapy |
US5686072A (en) | 1992-06-17 | 1997-11-11 | Board Of Regents, The University Of Texas | Epitope-specific monoclonal antibodies and immunotoxins and uses thereof |
US5736137A (en) | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
DE69329503T2 (de) | 1992-11-13 | 2001-05-03 | Idec Pharma Corp | Therapeutische Verwendung von chimerischen und markierten Antikörpern, die gegen ein Differenzierung-Antigen gerichtet sind, dessen Expression auf menschliche B Lymphozyt beschränkt ist, für die Behandlung von B-Zell-Lymphoma |
EP0684814B1 (en) | 1993-02-22 | 1998-06-17 | Alza Corporation | Compositions for oral delivery of active agents |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
KR100220864B1 (ko) | 1993-05-17 | 1999-09-15 | 오트리브 데이비스 더블유 | 비오틴/아비딘-금속 단백질 콘쥬게이트로 병변을 검출 및 치료하기 위한 조성물 |
US6080407A (en) | 1993-05-17 | 2000-06-27 | The Picower Institute For Medical Research | Diagnostic assays for MIF |
US5484892A (en) | 1993-05-21 | 1996-01-16 | Dana-Farber Cancer Institute, Inc. | Monoclonal antibodies that block ligand binding to the CD22 receptor in mature B cells |
US5565215A (en) | 1993-07-23 | 1996-10-15 | Massachusettes Institute Of Technology | Biodegradable injectable particles for imaging |
US6084067A (en) | 1993-07-26 | 2000-07-04 | Dana-Farber Cancer Institute | CTLA4/CD28 ligands and uses therefor |
US5417972A (en) | 1993-08-02 | 1995-05-23 | The Board Of Trustees Of The Leland Stanford Junior University | Method of killing B-cells in a complement independent and an ADCC independent manner using antibodies which specifically bind CDIM |
GB9316989D0 (en) | 1993-08-16 | 1993-09-29 | Lynxvale Ltd | Binding molecules |
WO1995009917A1 (en) | 1993-10-07 | 1995-04-13 | The Regents Of The University Of California | Genetically engineered bispecific tetravalent antibodies |
US5824701A (en) | 1993-10-20 | 1998-10-20 | Enzon, Inc. | Taxane-based prodrugs |
US5443953A (en) | 1993-12-08 | 1995-08-22 | Immunomedics, Inc. | Preparation and use of immunoconjugates |
US5429746A (en) | 1994-02-22 | 1995-07-04 | Smith Kline Beecham Corporation | Antibody purification |
US5639725A (en) | 1994-04-26 | 1997-06-17 | Children's Hospital Medical Center Corp. | Angiostatin protein |
US5686578A (en) | 1994-08-05 | 1997-11-11 | Immunomedics, Inc. | Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype |
IL114909A (en) | 1994-08-12 | 1999-10-28 | Immunomedics Inc | Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells |
US8771694B2 (en) | 1994-08-12 | 2014-07-08 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells |
US5728369A (en) | 1994-10-05 | 1998-03-17 | Immunomedics, Inc. | Radioactive phosphorus labeling of proteins for targeted radiotherapy |
US5874540A (en) | 1994-10-05 | 1999-02-23 | Immunomedics, Inc. | CDR-grafted type III anti-CEA humanized mouse monoclonal antibodies |
US5798554A (en) | 1995-02-24 | 1998-08-25 | Consorzio Per La Ricerca Sulla Microelettronica Nel Mezzogiorno | MOS-technology power device integrated structure and manufacturing process thereof |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
AUPO591797A0 (en) | 1997-03-27 | 1997-04-24 | Commonwealth Scientific And Industrial Research Organisation | High avidity polyvalent and polyspecific reagents |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6685940B2 (en) | 1995-07-27 | 2004-02-03 | Genentech, Inc. | Protein formulation |
US6441025B2 (en) | 1996-03-12 | 2002-08-27 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
CA2249320C (en) | 1996-03-20 | 2008-12-23 | Immunomedics, Inc. | Glycosylated humanized b-cell specific antibodies |
AU717020B2 (en) | 1996-05-03 | 2000-03-16 | Immunomedics Inc. | Targeted combination immunotherapy of cancer |
GB9610992D0 (en) | 1996-05-24 | 1996-07-31 | Glaxo Group Ltd | Concentrated antibody preparation |
WO1998004281A1 (en) | 1996-07-26 | 1998-02-05 | Smithkline Beecham Corpration | Improved method of treating immune cell mediated systemic diseases |
US7521531B2 (en) | 1996-08-28 | 2009-04-21 | Immunomedics, Inc. | Methods for the purification of stable radioiodine conjugates |
DE19640207A1 (de) | 1996-09-30 | 1998-04-02 | Bayer Ag | Glycokonjugate von modifizierten Camptothecin-Derivaten (A- oder B-Ring-Verknüpfung) |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6653104B2 (en) | 1996-10-17 | 2003-11-25 | Immunomedics, Inc. | Immunotoxins, comprising an internalizing antibody, directed against malignant and normal cells |
US7122636B1 (en) | 1997-02-21 | 2006-10-17 | Genentech, Inc. | Antibody fragment-polymer conjugates and uses of same |
US6306393B1 (en) | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US6183744B1 (en) | 1997-03-24 | 2001-02-06 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
JP3835827B2 (ja) | 1997-05-02 | 2006-10-18 | ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ,アズ リプレゼンティッド バイ ザ セクレタリーオブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシーズ | 悪性細胞に対する、oncタンパク質を含む、免疫毒素 |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6991790B1 (en) | 1997-06-13 | 2006-01-31 | Genentech, Inc. | Antibody formulation |
US6368596B1 (en) | 1997-07-08 | 2002-04-09 | Board Of Regents, The University Of Texas System | Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells |
US6165440A (en) | 1997-07-09 | 2000-12-26 | Board Of Regents, The University Of Texas System | Radiation and nanoparticles for enhancement of drug delivery in solid tumors |
US6051228A (en) | 1998-02-19 | 2000-04-18 | Bristol-Myers Squibb Co. | Antibodies against human CD40 |
BRPI9909860B8 (pt) | 1998-04-21 | 2021-05-25 | Amgen Res Munich Gmbh | polipeptídeo multifuncional de cadeia simples, polinucleotídeo, vetor, célula procariótica, de levedura ou unicelular, composição, usos de polipeptídeo e polinucleotídeo e métodos para preparo do referido polipeptídeo e para identificação de ativadores ou inibidores de ativação ou estimulação das células t |
US6632926B1 (en) | 1998-11-18 | 2003-10-14 | Genentech, Inc. | Antibody variants |
US6201104B1 (en) | 1998-12-04 | 2001-03-13 | Entremed, Inc. | Angiogenesis—inhibiting protein binding peptides and proteins and methods of use |
US6914128B1 (en) | 1999-03-25 | 2005-07-05 | Abbott Gmbh & Co. Kg | Human antibodies that bind human IL-12 and methods for producing |
US6379698B1 (en) | 1999-04-06 | 2002-04-30 | Isis Pharmaceuticals, Inc. | Fusogenic lipids and vesicles |
WO2000066160A1 (fr) | 1999-04-28 | 2000-11-09 | Yamanouchi Pharmaceutical Co., Ltd. | Composition medicamenteuse parenterale a fragment d'anticorps monoclonal humanise et procede de stabilisation |
DK1176981T3 (da) | 1999-05-07 | 2006-04-10 | Genentech Inc | Behandling af autoimmune sygdomme med antagonister som binder til B celleoverflademarkörer |
US7074403B1 (en) | 1999-06-09 | 2006-07-11 | Immunomedics, Inc. | Immunotherapy of autoimmune disorders using antibodies which target B-cells |
US7666400B2 (en) | 2005-04-06 | 2010-02-23 | Ibc Pharmaceuticals, Inc. | PEGylation by the dock and lock (DNL) technique |
US7550143B2 (en) | 2005-04-06 | 2009-06-23 | Ibc Pharmaceuticals, Inc. | Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses |
US7527787B2 (en) | 2005-10-19 | 2009-05-05 | Ibc Pharmaceuticals, Inc. | Multivalent immunoglobulin-based bioactive assemblies |
US7829064B2 (en) | 1999-05-10 | 2010-11-09 | Immunomedics, Inc. | Anti-CD74 immunoconjugates and methods |
US7534866B2 (en) | 2005-10-19 | 2009-05-19 | Ibc Pharmaceuticals, Inc. | Methods and compositions for generating bioactive assemblies of increased complexity and uses |
US8119101B2 (en) | 1999-05-10 | 2012-02-21 | The Ohio State University | Anti-CD74 immunoconjugates and methods of use |
US8383081B2 (en) | 1999-05-10 | 2013-02-26 | Immunomedics, Inc. | Anti-CD74 immunoconjugates and methods of use |
DE19926154A1 (de) | 1999-06-09 | 2000-12-14 | Ktb Tumorforschungs Gmbh | Verfahren zur Herstellung einer injizierbaren Arzneimittelzubereitung |
EP2289549A3 (en) | 1999-10-01 | 2011-06-15 | Immunogen, Inc. | Immunoconjugates for treating cancer |
US6530944B2 (en) | 2000-02-08 | 2003-03-11 | Rice University | Optically-active nanoparticles for use in therapeutic and diagnostic methods |
AU8729101A (en) | 2000-03-31 | 2001-10-15 | Idec Pharma Corp | Combined use of anti-cytokine antibodies or antagonists and anti-CD20 for the treatment of B cell lymphoma |
US20030133972A1 (en) | 2000-10-11 | 2003-07-17 | Targesome, Inc. | Targeted multivalent macromolecules |
US7138496B2 (en) | 2002-02-08 | 2006-11-21 | Genetastix Corporation | Human monoclonal antibodies against human CXCR4 |
GB0028361D0 (en) | 2000-11-21 | 2001-01-03 | Glaxo Group Ltd | Method of separating extra chromosomal dna from other cellular components |
JP2004535364A (ja) | 2001-01-26 | 2004-11-25 | エモリー・ユニバーシティ | 臓器移植の免疫寛容を誘発し、異常血色素症を処置する方法 |
CA2455915C (en) | 2001-03-29 | 2013-05-14 | Cytokine Pharmasciences, Inc. | Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor |
US7101982B2 (en) | 2001-03-30 | 2006-09-05 | Immunex Corporation | Control of ph transitions during chromatography |
DE60235013D1 (de) | 2001-07-25 | 2010-02-25 | Facet Biotech Corp | Stabile lyophilisierte pharmazeutische formulierung des igg-antikörpers daclizumab |
NZ513418A (en) | 2001-08-07 | 2004-04-30 | Univ Massey | Vaccine comprising proteins from mycobacterium paratuberculosis |
GB0119665D0 (en) | 2001-08-10 | 2001-10-03 | Isis Innovation | Conjugates |
US6893639B2 (en) | 2001-10-19 | 2005-05-17 | Hemacare Corporation | Method for high yield purification of immune globulins from blood plasma and blood plasma intermediates |
US7053202B2 (en) | 2001-10-19 | 2006-05-30 | Millennium Pharmaceuticals, Inc. | Immunoglobulin DNA cassette molecules, monobody constructs, methods of production, and methods of use therefor |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
SE0104462D0 (sv) | 2001-12-29 | 2001-12-29 | Carlbiotech Ltd As | Peptide purifcation (Peptidrening) |
JP4460302B2 (ja) | 2002-02-05 | 2010-05-12 | ジェネンテック インコーポレイテッド | タンパク質精製法 |
CN101914158A (zh) | 2002-02-14 | 2010-12-15 | 免疫医疗公司 | 抗cd 20抗体及其融合蛋白和使用方法 |
US8287864B2 (en) | 2002-02-14 | 2012-10-16 | Immunomedics, Inc. | Structural variants of antibodies for improved therapeutic characteristics |
JP4364645B2 (ja) | 2002-02-14 | 2009-11-18 | 中外製薬株式会社 | 抗体含有溶液製剤 |
US8877901B2 (en) | 2002-12-13 | 2014-11-04 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US7591994B2 (en) | 2002-12-13 | 2009-09-22 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
SI3483183T1 (sl) | 2002-03-01 | 2021-08-31 | Immunomedics, Inc. | Imunokonjugat ki obsega humanizirana RS7 protitelesa |
US8361464B2 (en) | 2002-03-01 | 2013-01-29 | Immunomedics, Inc. | Anthracycline-Antibody Conjugates for Cancer Therapy |
US20160279239A1 (en) | 2011-05-02 | 2016-09-29 | Immunomedics, Inc. | Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease |
CA2478012C (en) | 2002-03-01 | 2012-06-19 | Immunomedics, Inc. | Internalizing anti-cd74 antibodies and methods of use |
AU2003217912A1 (en) | 2002-03-01 | 2003-09-16 | Xencor | Antibody optimization |
FR2840532B1 (fr) | 2002-06-11 | 2005-05-06 | Ethypharm Sa | Nanocapsules lipidiques furtives, procede de preparation et utilisation comme vecteur de principes(s) actif(s) |
US7563433B2 (en) | 2007-01-11 | 2009-07-21 | Immunomedics, Inc. | Methods and compositions for F-18 labeling of proteins, peptides and other molecules |
BR0311799A (pt) | 2002-06-14 | 2005-05-10 | Immunomedics Inc | Anticorpo monoclonal hpam4 |
US7906118B2 (en) | 2005-04-06 | 2011-03-15 | Ibc Pharmaceuticals, Inc. | Modular method to prepare tetrameric cytokines with improved pharmacokinetics by the dock-and-lock (DNL) technology |
CA2494310A1 (en) | 2002-08-01 | 2004-02-12 | Immunomedics, Inc. | Alpha-fetoprotein immu31 antibodies and fusion proteins and methods of use thereof |
US20040033228A1 (en) | 2002-08-16 | 2004-02-19 | Hans-Juergen Krause | Formulation of human antibodies for treating TNF-alpha associated disorders |
US7541440B2 (en) | 2002-09-30 | 2009-06-02 | Immunomedics, Inc. | Chimeric, human and humanized anti-granulocyte antibodies and methods of use |
US7803372B2 (en) | 2002-10-08 | 2010-09-28 | Immunomedics, Inc. | Antibody therapy |
WO2004054622A1 (en) | 2002-12-13 | 2004-07-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US8420086B2 (en) | 2002-12-13 | 2013-04-16 | Immunomedics, Inc. | Camptothecin conjugates of anti-CD22 antibodies for treatment of B cell diseases |
WO2004060343A1 (en) | 2002-12-31 | 2004-07-22 | Nektar Therapeutics | Antibody-containing particles and compositions |
US20040208870A1 (en) | 2003-01-30 | 2004-10-21 | Medimmune, Inc. | Stabilized high concentration anti-integrin alphanubeta3 antibody formulations |
ATE517638T1 (de) | 2003-01-31 | 2011-08-15 | Immunomedics Inc | Verfahren und zubereitungen zum verabreichen von therapeutischen und diagnostischen mitteln |
GB0304576D0 (en) | 2003-02-28 | 2003-04-02 | Lonza Biologics Plc | Protein a chromatography |
ZA200507757B (en) | 2003-04-04 | 2007-01-31 | Genentech Inc | High concentration antibody and protein formulations |
DE10333317A1 (de) | 2003-07-22 | 2005-02-17 | Biotecon Therapeutics Gmbh | Formulierung für Proteinarzneimittel ohne Zusatz von humanem Serumalbumin (HSA) |
EP2216342B1 (en) | 2003-07-31 | 2015-04-22 | Immunomedics, Inc. | Anti-CD19 antibodies |
ES2553987T3 (es) | 2003-12-25 | 2015-12-15 | Kyowa Hakko Kirin Co., Ltd. | Preparación farmacéutica de base acuosa estable que contiene anticuerpo |
US8551480B2 (en) | 2004-02-13 | 2013-10-08 | Immunomedics, Inc. | Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity |
SE0400501D0 (sv) | 2004-02-27 | 2004-02-27 | Amersham Biosciences Ab | Antibody purification |
WO2006029411A2 (en) | 2004-09-09 | 2006-03-16 | Yeda Research And Development Co. Ltd. | Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof |
WO2006047419A2 (en) | 2004-10-25 | 2006-05-04 | Intezyne Technologies, Incorporated | Heterobifunctional poly(ethylene glycol) and uses thereof |
US7251164B2 (en) | 2004-11-10 | 2007-07-31 | Innovative Silicon S.A. | Circuitry for and method of improving statistical distribution of integrated circuits |
ES2396555T3 (es) | 2004-12-15 | 2013-02-22 | Janssen Alzheimer Immunotherapy | Anticuerpos que reconocen péptido beta amiloide |
JP2006196065A (ja) | 2005-01-12 | 2006-07-27 | Fuji Photo Film Co Ltd | サーボライタ |
GT200600031A (es) | 2005-01-28 | 2006-08-29 | Formulacion anticuerpo anti a beta | |
DK3332808T3 (da) | 2005-03-03 | 2020-12-14 | Immunomedics Inc | Humaniserede L243-antistoffer |
US8349332B2 (en) | 2005-04-06 | 2013-01-08 | Ibc Pharmaceuticals, Inc. | Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases |
US8067006B2 (en) | 2005-04-06 | 2011-11-29 | Immunomedics, Inc. | Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites |
JP5011277B2 (ja) | 2005-04-06 | 2012-08-29 | アイビーシー・ファーマシューティカルズ・インコーポレーテッド | ホモダイマー、ホモテトラマーまたはダイマーのダイマーのからなる安定に連結された複合体を発生させるための方法および使用 |
US7785595B2 (en) | 2005-04-18 | 2010-08-31 | Yeda Research And Development Company Limited | Stabilized anti-hepatitis B (HBV) antibody formulations |
BRPI0614100A2 (pt) | 2005-08-03 | 2011-03-09 | Immunogen Inc | formulações de imunoconjugado lìquidas |
US20100226884A1 (en) | 2009-01-20 | 2010-09-09 | Immunomedics, Inc. | Novel Class of Monospecific and Bispecific Humanized Antibodies that Target the Insulin-like Growth Factor Type I Receptor (IGF-1R) |
CN101325970B (zh) | 2005-11-01 | 2013-08-14 | 诺华有限公司 | 抗cd40抗体的应用 |
US8466263B2 (en) * | 2005-12-02 | 2013-06-18 | Dana-Farber Cancer Institute, Inc. | Carbonic anhydrase IX (G250) anitbodies |
WO2007103470A2 (en) | 2006-03-06 | 2007-09-13 | Medimmune, Inc. | Humanized anti-cd22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
EP2650306A1 (en) | 2006-03-06 | 2013-10-16 | Aeres Biomedical Limited | Humanized Anti-CD22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
TW200806317A (en) | 2006-03-20 | 2008-02-01 | Wyeth Corp | Methods for reducing protein aggregation |
NZ611859A (en) | 2006-04-05 | 2014-12-24 | Abbvie Biotechnology Ltd | Antibody purification |
WO2009017467A1 (en) | 2007-07-27 | 2009-02-05 | Elan Pharma International Limited | Treatment of amyloidogenic diseases |
CA2648895C (en) | 2006-04-19 | 2015-02-10 | Bionumerik Pharmaceuticals, Inc. | Camptothecin-analog with a novel, "flipped" lactone-stable, e-ring and methods for making and using same |
ITFI20060163A1 (it) | 2006-06-29 | 2006-09-28 | Menarini Internat Operations Luxembourg Sa | Composizione farmaceutica contenente un anticorpo monoclonale anti idiotipico anti-ca-125 ed alluminio |
MY170607A (en) | 2006-09-07 | 2019-08-20 | Crucell Holland Bv | Human binding molecules capable of neutralizing influenza virus h5n1 and uses thereof |
AU2007331712A1 (en) | 2006-12-11 | 2008-06-19 | F. Hoffmann-La Roche Ag | Abeta antibody parenteral formulation |
CA2681743A1 (en) | 2007-03-22 | 2008-09-25 | Imclone Llc | Stable antibody formulations |
US20110130544A1 (en) | 2007-03-30 | 2011-06-02 | Medimmune, Llc | Antibodies with decreased deamidation profiles |
CN101861168B (zh) | 2007-05-07 | 2014-07-02 | 米迪缪尼有限公司 | 抗-icos抗体及其在治疗肿瘤、移植和自身免疫病中的应用 |
EP2170951A2 (en) | 2007-05-31 | 2010-04-07 | Genmab A/S | Recombinant non glycosylated monovalent half-antibodies obtained by molecular engineering |
WO2009006301A2 (en) | 2007-06-29 | 2009-01-08 | Battelle Memorial Institute | Protein stabilization |
UA107557C2 (xx) | 2007-07-06 | 2015-01-26 | Композиція антитіла офатумумабу | |
WO2009009406A1 (en) | 2007-07-06 | 2009-01-15 | Smithkline Beecham Corporation | Antibody formulations |
CA2693611A1 (en) | 2007-07-10 | 2009-01-15 | F. Hoffmann-La Roche Ag | Novel formulation |
ES2622107T3 (es) | 2007-08-03 | 2017-07-05 | Genentech, Inc. | Antagonistas anti-FGF19 humanizados y métodos de uso de los mismos |
EP2225275A4 (en) | 2007-11-28 | 2013-04-03 | Medimmune Llc | PROTEIN FORMULATION |
CA2904458C (en) | 2007-11-30 | 2017-07-25 | Wolfgang Fraunhofer | Protein formulations and methods of making same |
KR20100113112A (ko) | 2008-01-15 | 2010-10-20 | 아보트 러보러터리즈 | 개선된 포유동물 발현 벡터 및 이의 용도 |
TWI489994B (zh) | 2008-03-17 | 2015-07-01 | Baxter Healthcare Sa | 供免疫球蛋白及玻尿酸酶之皮下投藥之用的組合及方法 |
CN103396480A (zh) | 2008-05-15 | 2013-11-20 | 诺沃—诺迪斯克有限公司 | 抗体纯化方法 |
EP2318048B1 (en) | 2008-07-21 | 2019-05-29 | Immunomedics, Inc. | Structural variants of antibodies for improved therapeutic characteristics |
CA2734265C (en) | 2008-08-20 | 2017-12-19 | Ibc Pharmaceuticals, Inc. | Dock-and-lock (dnl) vaccines for cancer therapy |
NZ606283A (en) | 2008-11-28 | 2014-08-29 | Abbvie Inc | Stable antibody compositions and methods for stabilizing same |
DK3903829T3 (da) | 2009-02-13 | 2023-06-26 | Immunomedics Inc | Immunkonjugater med en intracellulær spaltelig binding |
NZ595694A (en) | 2009-05-04 | 2013-09-27 | Abbvie Biotechnology Ltd | Stable high protein concentration formulations of human anti-tnf-alpha-antibodies |
CA2774015A1 (en) | 2009-09-15 | 2011-03-24 | Cerulean Pharma Inc. | A cdp-camptothecin conjugate, particle or composition and uses thereof |
AU2010298264B2 (en) | 2009-09-24 | 2014-10-23 | Xbiotech Inc. | Methods, compositions, and kits for reducing anti-antibody responses |
US9198972B2 (en) | 2010-01-28 | 2015-12-01 | Alnylam Pharmaceuticals, Inc. | Monomers and oligonucleotides comprising cycloaddition adduct(s) |
CA2798778C (en) | 2010-05-17 | 2016-01-05 | Livtech, Inc. | Anti-human trop-2 antibody having anti-tumor activity in vivo |
EP2594589A1 (en) | 2010-06-10 | 2013-05-22 | Sapporo Medical University | ANTI-Trop-2 ANTIBODY |
US9772329B2 (en) | 2011-01-11 | 2017-09-26 | The Governing Council Of The University Of Toronto | Protein detection method |
EP2704751B1 (en) | 2011-05-02 | 2019-04-17 | Immunomedics, Inc. | Ultrafiltration concentration of allotype selected antibodies for small-volume administration |
US20150231241A1 (en) * | 2012-08-14 | 2015-08-20 | Ibc Pharmaceuticals, Inc. | Combination therapy for inducing immune response to disease |
US9382329B2 (en) * | 2012-08-14 | 2016-07-05 | Ibc Pharmaceuticals, Inc. | Disease therapy by inducing immune response to Trop-2 expressing cells |
US9931417B2 (en) | 2012-12-13 | 2018-04-03 | Immunomedics, Inc. | Antibody-SN-38 immunoconjugates with a CL2A linker |
CA3177936A1 (en) | 2012-12-13 | 2014-06-19 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity |
US9492566B2 (en) * | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
GB201504778D0 (en) | 2015-03-20 | 2015-05-06 | Univ Edinburgh | Optical probes for matrix metalloproteinases |
PL3313443T3 (pl) * | 2015-06-25 | 2023-11-06 | Immunomedics, Inc. | Łączenie przeciwciał anty-hla-dr lub anty-trop-2 z inhibitorami mikrotubuli, inhibitorami parp, 5 inhibitorami kinazy brutona lub inhibitorami 3-kinazy fosfoinozytydu istotnie poprawia wynik terapeutyczny nowotworu |
-
2018
- 2018-03-26 EP EP18780421.6A patent/EP3606964A4/en active Pending
- 2018-03-26 CA CA3044082A patent/CA3044082A1/en active Pending
- 2018-03-26 CN CN201880010028.XA patent/CN110352201A/zh active Pending
- 2018-03-26 US US15/935,866 patent/US10799597B2/en active Active
- 2018-03-26 WO PCT/US2018/024332 patent/WO2018187074A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080025989A1 (en) * | 2003-02-20 | 2008-01-31 | Seattle Genetics, Inc. | Anti-cd70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders |
US20140227180A1 (en) * | 2012-12-13 | 2014-08-14 | Immunomedics, Inc. | Antibody-sn-38 immunoconjugates with a cl2a linker |
CN109562172A (zh) * | 2016-08-11 | 2019-04-02 | 免疫医疗公司 | 抗HLA-DR抗体药物缀合物IMMU-140(hL243-CL2A-SN-38)在HLA-DR阳性癌症中的功效 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114599392A (zh) * | 2019-10-31 | 2022-06-07 | 四十七公司 | 基于抗cd47和抗cd20的血癌治疗 |
WO2022001710A1 (zh) * | 2020-06-28 | 2022-01-06 | 达石药业(广东)有限公司 | 用于抗体与药物偶联体(adc)制备的中间体及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2018187074A1 (en) | 2018-10-11 |
CA3044082A1 (en) | 2018-10-11 |
EP3606964A1 (en) | 2020-02-12 |
US10799597B2 (en) | 2020-10-13 |
EP3606964A4 (en) | 2020-12-09 |
US20180280532A1 (en) | 2018-10-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2758234C2 (ru) | ЛЕЧЕНИЕ ТРИЖДЫ НЕГАТИВНОГО РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ, ХАРАКТЕРИЗУЮЩЕГОСЯ ЭКСПРЕССИЕЙ Trop-2, С ПОМОЩЬЮ САЦИТУЗУМАБА ГОВИТЕКАНА И ИНГИБИТОРА Rad51 | |
CN110352201A (zh) | 用于癌症疗法的抗体药物缀合物的皮下施用 | |
US11116846B2 (en) | Antibody-drug conjugates and uses thereof | |
US10744129B2 (en) | Therapy of small-cell lung cancer (SCLC) with a topoisomerase-I inhibiting antibody-drug conjugate (ADC) targeting Trop-2 | |
AU2017257254B2 (en) | Efficacy of anti-Trop-2-SN-38 antibody drug conjugates for therapy of tumors relapsed/refractory to checkpoint inhibitors | |
ES2892525T3 (es) | Uso neoadyuvante de conjugados anticuerpo-fármaco | |
US20210046185A1 (en) | Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity | |
CN108601841A (zh) | Abcg2抑制剂与sacituzumab govitecan(immu-132)的组合克服表达trop-2的癌中对sn-38的抗性 | |
JP2018520140A (ja) | 抗hla‐drまたは抗trop‐2抗体と微小管阻害剤、parp阻害剤、ブルトンキナーゼ阻害剤またはホスホイノシチド3‐キナーゼ阻害剤との併用は癌の治療効果を有意に改善する | |
CN107735090A (zh) | 具有cl2a接头的抗体‑sn‑38免疫缀合物 | |
CN107753954A (zh) | 功效改进且毒性降低的抗体与sn‑38的免疫缀合物的剂量 | |
CN110248680A (zh) | 使用抗体-药物缀合物沙西妥珠单抗戈维替康(immu-132)的用于转移性尿路上皮癌的疗法 | |
EP3585442B1 (en) | Therapy of small-cell lung cancer (sclc) with a topoisomerase-i inhibiting antibody-drug conjugate (adc) targeting trop-2 | |
US20240139324A1 (en) | Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity | |
US20220054648A1 (en) | Antibody-drug conjugates and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40009429 Country of ref document: HK |
|
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20191018 |
|
WD01 | Invention patent application deemed withdrawn after publication |