WO2022244792A1 - 骨軟部腫瘍の治療用医薬組成物 - Google Patents
骨軟部腫瘍の治療用医薬組成物 Download PDFInfo
- Publication number
- WO2022244792A1 WO2022244792A1 PCT/JP2022/020609 JP2022020609W WO2022244792A1 WO 2022244792 A1 WO2022244792 A1 WO 2022244792A1 JP 2022020609 W JP2022020609 W JP 2022020609W WO 2022244792 A1 WO2022244792 A1 WO 2022244792A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tumor
- promoter
- bone
- restricted
- adenovirus
- Prior art date
Links
- 206010068771 Soft tissue neoplasm Diseases 0.000 title claims abstract description 83
- 208000018084 Bone neoplasm Diseases 0.000 title claims abstract description 63
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 48
- 230000001225 therapeutic effect Effects 0.000 title abstract description 31
- 241000701161 unidentified adenovirus Species 0.000 claims abstract description 132
- 108010002687 Survivin Proteins 0.000 claims abstract description 39
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 35
- 102000000763 Survivin Human genes 0.000 claims abstract 3
- 206010028980 Neoplasm Diseases 0.000 claims description 185
- 210000000988 bone and bone Anatomy 0.000 claims description 37
- 201000009047 Chordoma Diseases 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 29
- 230000001394 metastastic effect Effects 0.000 claims description 28
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 28
- 230000014509 gene expression Effects 0.000 claims description 24
- 230000000306 recurrent effect Effects 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 7
- 230000009452 underexpressoin Effects 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 230000003362 replicative effect Effects 0.000 abstract description 3
- 238000011282 treatment Methods 0.000 description 53
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 36
- 230000003902 lesion Effects 0.000 description 33
- 238000000034 method Methods 0.000 description 27
- 238000002512 chemotherapy Methods 0.000 description 25
- 206010005949 Bone cancer Diseases 0.000 description 21
- 230000004044 response Effects 0.000 description 20
- 230000000694 effects Effects 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 239000003814 drug Substances 0.000 description 17
- 201000011510 cancer Diseases 0.000 description 16
- 241000700605 Viruses Species 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 201000008968 osteosarcoma Diseases 0.000 description 12
- 208000005243 Chondrosarcoma Diseases 0.000 description 11
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- 208000021644 malignant soft tissue neoplasm Diseases 0.000 description 10
- 238000002271 resection Methods 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- 206010027476 Metastases Diseases 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 230000009401 metastasis Effects 0.000 description 9
- 238000001959 radiotherapy Methods 0.000 description 9
- 210000004872 soft tissue Anatomy 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 8
- 239000013612 plasmid Substances 0.000 description 8
- 238000004393 prognosis Methods 0.000 description 8
- 238000011272 standard treatment Methods 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 238000001356 surgical procedure Methods 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 208000006168 Ewing Sarcoma Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000003296 saliva Anatomy 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 238000011144 upstream manufacturing Methods 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- 230000005727 virus proliferation Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 230000002147 killing effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 210000000115 thoracic cavity Anatomy 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000007717 exclusion Effects 0.000 description 4
- 210000001624 hip Anatomy 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 3
- 206010067482 No adverse event Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000005250 Spontaneous Fractures Diseases 0.000 description 3
- 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 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003433 contraceptive agent Substances 0.000 description 3
- 230000002254 contraceptive effect Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- 230000002601 intratumoral effect Effects 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 244000309459 oncolytic virus Species 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 210000002640 perineum Anatomy 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 102100026656 Actin, alpha skeletal muscle Human genes 0.000 description 2
- 102100021253 Antileukoproteinase Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 101150008656 COL1A1 gene Proteins 0.000 description 2
- 101150082216 COL2A1 gene Proteins 0.000 description 2
- 101150069920 Camk2a gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 description 2
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 101100481404 Danio rerio tie1 gene Proteins 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
- 102100030801 Elongation factor 1-alpha 1 Human genes 0.000 description 2
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 2
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 2
- 101150036925 HCN4 gene Proteins 0.000 description 2
- 101000834207 Homo sapiens Actin, alpha skeletal muscle Proteins 0.000 description 2
- 101000615334 Homo sapiens Antileukoproteinase Proteins 0.000 description 2
- 101000920078 Homo sapiens Elongation factor 1-alpha 1 Proteins 0.000 description 2
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 2
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 2
- 101000595193 Homo sapiens Podocin Proteins 0.000 description 2
- 101000821100 Homo sapiens Synapsin-1 Proteins 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 101150089655 Ins2 gene Proteins 0.000 description 2
- 102100022338 Integrin alpha-M Human genes 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- 206010025327 Lymphopenia Diseases 0.000 description 2
- 101150094019 MYOG gene Proteins 0.000 description 2
- 102100025136 Macrosialin Human genes 0.000 description 2
- 241000713333 Mouse mammary tumor virus Species 0.000 description 2
- 101100481406 Mus musculus Tie1 gene Proteins 0.000 description 2
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 2
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 2
- 101150044568 PRNP gene Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102100036037 Podocin Human genes 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 101710183548 Pyridoxal 5'-phosphate synthase subunit PdxS Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000713880 Spleen focus-forming virus Species 0.000 description 2
- 101000879712 Streptomyces lividans Protease inhibitor Proteins 0.000 description 2
- 102100021905 Synapsin-1 Human genes 0.000 description 2
- 101150027463 TUBA1A gene Proteins 0.000 description 2
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 102100026893 Troponin T, cardiac muscle Human genes 0.000 description 2
- 101710165323 Troponin T, cardiac muscle Proteins 0.000 description 2
- 102000003425 Tyrosinase Human genes 0.000 description 2
- 108060008724 Tyrosinase Proteins 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000011226 adjuvant chemotherapy Methods 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 238000002266 amputation Methods 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000010072 bone remodeling Effects 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000001370 mediastinum Anatomy 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 238000009806 oophorectomy Methods 0.000 description 2
- 229940127234 oral contraceptive Drugs 0.000 description 2
- 239000003539 oral contraceptive agent Substances 0.000 description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 2
- 229960000639 pazopanib Drugs 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 208000018417 undifferentiated high grade pleomorphic sarcoma of bone Diseases 0.000 description 2
- 238000007879 vasectomy Methods 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 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
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 101710197337 Adenovirus death protein Proteins 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000002817 Clear Cell Chondrosarcoma Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 1
- 208000013186 Extra-osseous Ewing sarcoma Diseases 0.000 description 1
- 208000016803 Extraskeletal Ewing sarcoma Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 241001135569 Human adenovirus 5 Species 0.000 description 1
- 241000598171 Human adenovirus sp. Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000007433 Lymphatic Metastasis Diseases 0.000 description 1
- 201000009574 Mesenchymal Chondrosarcoma Diseases 0.000 description 1
- 229920013643 Mirel Polymers 0.000 description 1
- 101100494126 Mus musculus Birc5 gene Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010034156 Pathological fracture Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 208000037323 Rare tumor Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 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
- 206010049590 Upper respiratory tract inflammation Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003263 anti-adenoviral effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 206010003883 azoospermia Diseases 0.000 description 1
- 229960002903 benzyl benzoate Drugs 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
- 238000004820 blood count Methods 0.000 description 1
- 201000008791 bone leiomyosarcoma Diseases 0.000 description 1
- 201000008873 bone osteosarcoma Diseases 0.000 description 1
- 230000010478 bone regeneration Effects 0.000 description 1
- 201000009613 breast lymphoma Diseases 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 235000020247 cow milk Nutrition 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 208000030347 dedifferentiated chondrosarcoma Diseases 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 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
- 229960003649 eribulin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 201000000844 fibrous synovial sarcoma Diseases 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000002594 fluoroscopy Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 210000001621 ilium bone Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 231100001023 lymphopenia Toxicity 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000014441 malignancy in giant cell tumor of bone Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 208000022084 motor paralysis Diseases 0.000 description 1
- 238000013059 nephrectomy Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000002727 particle therapy Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 201000003434 periosteal osteogenic sarcoma Diseases 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000009597 pregnancy test Methods 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000000954 sacrococcygeal region Anatomy 0.000 description 1
- 208000011571 secondary malignant neoplasm Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 210000001154 skull base Anatomy 0.000 description 1
- 201000008864 small cell osteogenic sarcoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000000273 spinal nerve root Anatomy 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 208000014794 superficial urinary bladder carcinoma Diseases 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000011080 telangiectatic osteogenic sarcoma Diseases 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 208000030218 transient fever Diseases 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/761—Adenovirus
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10032—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10071—Demonstrated in vivo effect
Definitions
- Bone and soft tissue tumors are a combination of "bone” tumors and “soft tissue” tumors, and malignant bone and soft tissue tumors are classified into primary bone and soft tissue tumors and metastatic bone and soft tissue tumors.
- Primary malignant bone tumor (a general term for malignant tumors occurring in the bone) is a rare disease, and the incidence is estimated to be 4 out of 1 million people.
- About 40% of the histologic types of primary malignant bone tumors are osteosarcoma, followed by chondrosarcoma and Ewing's sarcoma. Osteosarcoma and Ewing's sarcoma are more common in children, accounting for 40% and 43%, respectively, of those aged 10-19 years.
- the 5-year disease-free survival rate is about 60-70% and the overall survival rate is about 70-80% in extremity-free cases without metastasis.
- the prognosis of chondrosarcoma is that recurrence may occur even after 5 or 10 years, and the 5-year survival rate is 59%, while the 20-year overall survival rate is reported to be 35%.
- Ewing's sarcoma has a 5-year disease-free survival rate of 69% and a 5-year overall survival rate of 72%.
- the prognosis differs depending on the site of occurrence, and the 5-year disease-free survival rate for cases with distal extremities is 68%, while 61% for proximal extremities and 50% for pelvic lesions.
- doxorubicin, cisplatin, and high-dose methotrexate (MTX) therapy are performed as standard preoperative chemotherapy, and surgical resection of the tumor is performed after the tumor shrinks due to preoperative chemotherapy.
- adjuvant chemotherapy is recommended based on the histological effect of preoperative chemotherapy.
- the response to chemotherapy is good, but it is difficult to expect cure with chemotherapy alone, and in cases of pelvic or trunk tumors, the treatment is mainly aimed at improving symptoms and prolonging life because the tumor cannot be removed. .
- the response rate of chemotherapy is only 29% (Non-Patent Document 1).
- Non-Patent Document 1 there are problems that chemotherapy cannot be performed sufficiently in elderly people and patients with severe complications, chemotherapy is ineffective, and there are no other treatment options in recurrent cases.
- Non-Patent Document 2 Patients with extensively resectable extremities can be cured by amputation and amputation, but in cases where extensive resection is not possible, such as cases with trunk lesions, repeated recurrences occur as a result of incomplete resection, and ultimately tumor death. There are many. In some cases, the degree of malignancy increases during repeated recurrences, and distant metastasis occurs.
- Chemotherapy standard is a combination therapy that includes vincristine, doxorubicin, ifosfamide, and etoposide.
- the response rate of chemotherapy is only 35% (Non-Patent Document 3).
- the prognosis of recurrent/metastatic cases after chemotherapy is poor, and there is no chemotherapy that has been confirmed to be effective and recommended for recurrent/metastatic cases.
- curative surgical excision is very rare in spinal lesions, and the prognosis is poorer than in other site lesions.
- radiotherapy as an alternative therapy for inoperable cases has the problem of secondary cancer, and the development of new treatment methods is desired.
- Chordoma is a low-grade but locally destructive bone tumor that occurs most frequently in the sacrum (50%), followed by the base of the skull (30%), and other spines (20%).
- the median age of onset is 60 years, and cases of skull base onset are common in children.
- surgical resection is the main treatment for chordoma. Local control in recurrent cases is difficult, and long-term survival is unlikely (Non-Patent Document 4).
- Non-Patent Document 5 In recent years, it has been reported that heavy ion radiation is effective, and the 5-year local control rate of heavy ion radiation for chordoma is reported to be 77.2% (Non-Patent Document 5).
- chordomas are complicated by distant metastasis, usually occurring in cases after local recurrence.
- chemotherapy for advanced chordoma the response rate of chemotherapy in chordoma is only 0-2%
- Non-Patent Documents 4, 6 the treatment of chordoma is similar to that of chondrosarcoma.
- chordoma If local recurrence can be prevented by reliably treating chordoma, it is highly possible that the prognosis, including distant metastasis, can be improved. This is a big advantage for patients. In other words, when the unresectable recurrent/metastatic lesion increases, pain and dysfunction appear, and when the tumor increases and penetrates the skin, it leads to serious symptoms such as infection and bleeding. In addition, in the case of chordoma, the sacral and cervical vertebrae are the most frequent sites, and neuropathic pain and motor paralysis may occur due to pressure on the spinal cord and nerve roots, which is painful for the patient. It would be a great advantage if such symptoms could be alleviated even a little. However, there is currently no method for reliably shrinking and treating chordoma, and thus chordoma is a typical malignant bone tumor with unmet medical needs for which there is no existing treatment.
- primary malignant soft tissue tumors (a general term for malignant tumors that occur in soft tissue) are estimated to occur in 2 to 3 cases per 100,000 people, which is slightly more common than primary malignant bone tumors, but is a rare tumor.
- malignant fibrous histiocytoma (MFH) was the most frequent histological type, but in 2013 the WHO diagnostic criteria for soft tissue sarcoma were revised, and MFH is no longer used.
- liposarcoma, undifferentiated pleomorphic sarcoma (MFH in the narrow sense), and leiomyosarcoma are common.
- Chemotherapy and radiation therapy for primary malignant soft tissue tumors have been established as standard treatments only for round cell sarcoma, such as extraosseous Ewing's sarcoma and rhabdomyosarcoma. is mainly surgical treatment.
- pazopanib which targets vascular endothelial growth factor (VEGF)
- VEGF vascular endothelial growth factor
- Non-round cell sarcoma is a soft tissue tumor such as leiomyosarcoma, malignant fibrous histiocytoma, and synovial sarcoma, which consists of spindle-shaped or pleomorphic cells. Although it is much more common than round cell sarcoma, it is less sensitive to chemotherapy and its efficacy has not been established. Surgery is the standard treatment worldwide for resectable non-progressive cases, but recent meta-analyses have shown the efficacy of adjuvant chemotherapy with doxorubicin and ifosfamide. However, it is necessary to pay attention to adverse events during chemotherapy, and indications should be determined in consideration of the patient's age and general condition. It is said that there is
- Survivin-reactive restricted-growth adenovirus was aimed at killing infected tumor cells by propagating the virus specifically in malignant tumor cells expressing survivin. It is an "oncolytic virus” or another name “conditionally-replicating adenovirus (CRA)” (Patent Document 1, Non-Patent Document 4). This virus uses gene recombination technology to introduce the survivin promoter, which is abnormally highly activated in tumor cells, upstream of the E1A gene, which is necessary for adenovirus proliferation, to promote tumor-specific viral proliferation.
- CRA conditionally-replicating adenovirus
- Non-Patent Document 7, Patent Document 2 is positioned as a next-generation CRA (Non-Patent Document 7, Patent Document 2).
- Survivin is reported to be strongly expressed in lung cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, and lymphoma, while its expression is not observed in normal tissues.
- the present inventors have so far found that expression of survivin mRNA is observed in gastric cancer, colon cancer, liver cancer, cervical cancer and osteosarcoma cell lines, whereas it is hardly expressed in fibroblasts and osteoblasts. has been reported (Non-Patent Document 8).
- the survivin promoter exhibits tumor-specific high activity in malignant bone and soft tissue tumors such as chordoma.
- An object of the present invention is to provide a novel restricted-growth adenovirus and a novel therapeutic method for bone and soft tissue tumors using the same.
- the present inventors have made intensive studies to provide a method for treating bone and soft tissue tumors.
- the efficacy of this product against bone and soft tissue tumors is markedly superior to that of restricted-growth adenoviruses reported so far.
- the present invention has been completed by discovering that it exhibits a clear effect and safety.
- the present inventors searched for a more effective therapeutic method using a restricted-growth adenovirus having the E1A gene under the expression control of the Survivin promoter. developed.
- the present inventors found that by retaining the E3 region of adenovirus, Surv. It was found that the tumor specificity of m-CRA (Kamizono et al., supra) is further improved, and the side effect of damaging normal cells is reduced while maintaining the tumor cell-killing effect.
- the present invention provides the following [1] to [15].
- Bone and soft tissue tumors preferably malignant bone and soft tissue tumors such as primary malignant bone tumors, metastatic bone tumors, A pharmaceutical composition for the treatment of primary malignant soft tissue tumors, metastatic soft tissue tumors), wherein the restricted-growth adenovirus does not lack the E3 region.
- the pharmaceutical composition of [1] wherein the bone and soft tissue tumor is a primary bone and soft tissue tumor.
- the pharmaceutical composition of [1], wherein the bone and soft tissue tumor is a recurrent primary bone and soft tissue tumor or a recurrent metastatic bone and soft tissue tumor.
- the pharmaceutical composition of [1] wherein the volume of the administered liquid is changed according to the tumor volume of the administration target.
- the pharmaceutical composition of [1] which is administered to up to 3 tumors when there are multiple tumors, and each dose is divided according to the tumor volume.
- the pharmaceutical composition of [1], which is administered to only one site when the volume of one tumor is 30 cm 3 or more.
- the pharmaceutical composition contains 1 x 10 11 vp of restricted adenovirus for either dose volume. contains When administered to multiple tumors, each combined dose contains 1 ⁇ 10 11 vp of restricted adenovirus.
- Promoters in which the E1B region of the restricted-replication adenovirus is different from the E1A region e.g., CMV promoter, RSV promoter, CA promoter, E2F promoter, EF1A promoter, EFS promoter, CAG promoter, CBh promoter, CBA promoter, SFFV promoter, MSCV promoter, SV40 promoter, mPGK promoter, hPGK promoter, UBC promoter, Nanog promoter, Nes promoter, Tuba1a promoter, Camk2a promoter, SYN1 promoter, Hb9 promoter, Th promoter, NSE promoter, GFAP promoter, iba1 promoter, ProA1 promoter, hRHO promoter, hBEST1 promoter, Prnp promoter, Cnp promoter, K14 promoter, BK5 promoter, mTyr promoter, cTnT promoter, ⁇ MHC promoter, Myog promoter,
- the present invention provides the following [16] to [20].
- Each of the requirements defined in [1] to [15] of the first mode above can also be applied to [16] to [20] below.
- [16] A pharmaceutical composition for treating recurrent bone and soft tissue tumors, comprising a restricted-growth adenovirus having the E1A gene under the expression control of the Survivin promoter.
- a pharmaceutical composition for the treatment of bone and soft tissue tumors containing a restricted-growth adenovirus having the E1A gene under the expression control of the survivin promoter, wherein the dosage is changed according to the tumor volume.
- pharmaceutical compositions pharmaceutical compositions.
- a pharmaceutical composition for treating bone and soft tissue tumors comprising a restricted-growth adenovirus having an E1A gene under expression control by a Survivin promoter, wherein the restricted-growth adenovirus is administered to the subject per dose
- the present invention provides the following [1] to [19].
- Bone and soft tissue tumors preferably, malignant bone and soft tissue tumors, e.g., primary malignant bone tumors, including administering to a subject a restricted-growth adenovirus having the E1A gene under the expression control of a survivin promoter
- metastatic bone tumors preferably, primary malignant soft tissue tumors, including administering to a subject a restricted-growth adenovirus having the E1A gene under the expression control of a survivin promoter
- metastatic bone tumors e.g., primary malignant bone tumors, including administering to a subject a restricted-growth adenovirus having the E1A gene under the expression control of a survivin promoter
- metastatic bone tumors e.g., primary malignant bone tumors, including administering to a subject a restricted-growth adenovirus having the E1A gene under the expression control of a survivin promoter
- metastatic bone tumors e
- the total dose of restricted adenovirus to a subject per dose is 1 x 10 11 vp
- 1 x 10 11 vp of restricted adenovirus is administered for either dose volume.
- a total volume of 1 ⁇ 10 11 vp restricted adenovirus is administered.
- the present invention provides the following [1] to [15].
- [1] Survivin for use in the treatment of bone and soft tissue tumors (preferably malignant bone and soft tissue tumors, such as primary malignant bone tumors, metastatic bone tumors, primary malignant soft tissue tumors, metastatic soft tissue tumors) A composition comprising a restricted-growth adenovirus having an E1A gene under the expression control of a promoter, wherein the restricted-growth adenovirus is not defective in the E3 region (retains the E3 region).
- the bone and soft tissue tumor is recurrent primary bone and soft tissue tumor (e.g., primary malignant bone tumor, primary malignant soft tissue tumor) or recurrent metastatic bone and soft tissue tumor (e.g., metastatic bone tumor, metastatic soft tissue tumor ), the composition for use according to [1] or [2].
- the composition for use according to [4], wherein the bone tumor is chordoma.
- the total dosage of restricted-growth adenovirus to the patient per dose is 1 ⁇ 10 10 vp to 1 ⁇ 10 12 vp. composition.
- [7] For the use according to any one of [1] to [6], which is administered in a single dose or repeated doses once every 4 weeks, preferably once every 4 weeks for a total of 3 to 5 doses Composition.
- Any of [1] to [9] wherein when tumors are present in multiple locations, the administration is administered to a maximum of 3 tumors, and each dose is divided according to the tumor volume.
- composition for use in [11] The composition for use according to any one of [1] to [9], which is administered to only one site when one tumor has a volume of 30 cm 3 or more.
- the composition will contain 1 x 10 11 v
- each combined dose contains. When administered to multiple tumors, each combined dose contains 1 ⁇ 10 11 vp of restricted adenovirus.
- a restricted-growth adenovirus having an E1A gene under expression control by a Survivin promoter wherein the restricted-growth adenovirus is not deficient in the E3 region, preferably the E1B region is E1B ⁇ 55K
- a restricted-growth adenovirus according to [14] wherein preferably the E1B region is controlled by a different promoter (as described in the first aspect) than the E1A region, eg the CMV promoter.
- the present invention provides the following [16] to [20].
- Each of the requirements specified in [1] to [15] of the third mode can also be applied to [16] to [20] below.
- [16] A composition comprising a restricted replication adenovirus having the E1A gene under the expression control of the Survivin promoter for use in the treatment of recurrent bone and soft tissue tumors.
- [17] A composition comprising a restricted replication adenovirus having the E1A gene under the expression control of the Survivin promoter for use in the treatment of bone and soft tissue tumors, wherein the composition is administered once or repeated once every 4 weeks
- a composition containing a restricted-growth adenovirus having an E1A gene under the expression control of a survivin promoter which is used in the treatment of bone and soft tissue tumors, wherein the dosage is changed according to the tumor volume composition.
- a composition comprising a restricted-growth adenovirus having the E1A gene under expression control by the Survivin promoter for use in the treatment of bone and soft tissue tumors, wherein the adenovirus is restricted-growth to a subject per dose
- FIG. 4 shows the treatment course of a patient (45 years old, female) with low-dose sacral chordoma. This patient developed sacral chordoma in 2007, recurrence in the soft tissue of the right hip in 2013, no indication for chemotherapy or radiotherapy, and in August 2016, Surv. m-CRA-1 was administered.
- the table in the middle shows the RECIST-based response determination (upper) and the Choi-based response determination (lower) from pre-administration to 114 weeks after administration.
- the photographs shown at the bottom show, from the left, CT images of lesions before administration, 12 weeks after administration, 28 weeks after administration, and 100 weeks after administration.
- PR partial response
- SD stable disease
- the middle table shows the treatment course from pre-dose to 135 weeks post-dose.
- the table shows, from top to bottom, major axis (mm) and its rate of change (%), CT value (HU) and its rate of change (%), RECIST criteria response determination, Choi criteria response determination, non-enhanced CT value and The rate of change (%) is shown.
- the photographs shown at the bottom show, from the left, CT images of lesions before administration, 4 weeks after administration, 12 weeks after administration, and 56 weeks after administration.
- FIG. 4 is a graph showing the cell viability of a liver cancer cell line (HepG2) and a normal cell fibroblast (WI-38) infected in vitro with m-CRA-1.
- the vertical axis indicates Ad. of the control under each condition.
- the ratio (%) of viable cell number of m-CRA (without E3) is shown.
- the horizontal axis indicates the multiplicity of infection (MOI). * indicates statistically significant difference from control (P ⁇ 0.05).
- the present invention relates to a pharmaceutical composition for the treatment of bone and soft tissue tumors containing, as an active ingredient, a restricted-growth adenovirus having the E1A gene under the expression control of the Survivin promoter.
- CRA Conditionally-replicating adenovirus
- Restricted-growth adenovirus is also called an oncolytic virus, the meaning of which is well known in the art.
- the survivin promoter is bound upstream of the E1A gene so that the expression of the E1A gene can be directly regulated.
- the survivin promoter may be bound 10-200 bp upstream of the transcription initiation region of the E1A gene.
- the E1B region of the restricted-growth adenovirus is E1B ⁇ 55K.
- E1B ⁇ 55K is an adenoviral E1B protein lacking the p53 binding region (JAMES R. BISCHOFF et al., SCIENCE 18 OCT 1996: 373-376), and is also called E1B19K. Viruses carrying E1B ⁇ 55K are known to be able to grow in tumor cells lacking p53, but not in normal cells with p53.
- the E1A region and the E1B region are preferably controlled by different promoters. This allows separate control of E1A expression and E1B ⁇ 55K expression (Nagano et al., WO2005/012536, supra). Such adenoviruses are referred to herein as "regulated with multiple tumor-specific factors” (CRA) (m-CRA).
- CRA tumor-specific factors
- a promoter controlling the E1B region is not particularly limited as long as it is different from the E1A region.
- CMV promoter For example, CMV promoter, RSV promoter, CA promoter, E2F promoter, EF1A promoter, EFS promoter, CAG promoter, CBh promoter, CBA promoter, SFFV promoter, MSCV promoter, SV40 promoter, mPGK promoter, hPGK promoter, UBC promoter, Nanog promoter, Nes promoter, Tuba1a promoter, Camk2a promoter, SYN1 promoter, Hb9 promoter, Th promoter, NSE promoter, GFAP promoter, iba1 promoter, ProA1 promoter, hRHO promoter, hBEST1 promoter, Prnp promoter, Cnp promoter, K14 promoter, BK5 promoter, mTyr promoter , cTnT promoter, ⁇ MHC promoter, Myog promoter, ACTA1 promoter, MHCK7 promoter, SM22a promoter, EnSM22a promoter, Runx
- multifactor restricted-growth adenoviruses examples include the adenoviruses described in International Publication No. WO2005/115476 or Junichi Kamizono et al., Cancer Res June 15 2005 (65) (12) 5284-5291.
- This adenovirus is a multifactor-restricted growth type adenovirus in which the endogenous promoter of the E1A region and the endogenous promoter of the E1B region (preferably E1B ⁇ 55K) in the adenovirus genome are replaced with the survivin promoter and the CMV promoter, respectively. It's a virus.
- the restricted-growth adenovirus has no foreign gene inserted into the E3 region of the adenovirus.
- a restricted-growth adenovirus is a restricted-growth adenovirus that is not deficient in the E3 region (ie, has the E3 region of a wild-type adenovirus).
- the E3 region contains a region that encodes a gene called Adenovirus Death Protein that induces tumor cell death, it was generally believed that having the E3 region would have a higher therapeutic effect (Fanny Georgi, et al., FEBS Letters 594 (2020) 1861-1878). Contrary to such conventional wisdom, however, restricted-growth adenoviruses retaining the E3 region are more tumor-specific in vitro than restricted-growth adenoviruses lacking the E3 region. It was found that the cytotoxic effect was high. In the clinical trials shown in Examples, it was confirmed that the restricted replication adenovirus (Surv.m-CRA-1) retaining the E3 region has sufficient therapeutic efficacy and safety.
- a restricted-growth adenovirus that retains the E3 region maintains a tumor-cell-killing effect that can be clinically expected to have a sufficient therapeutic effect, while at the same time affecting normal cells.
- the non-specific killing effect is greatly reduced, thus making it a safer and more effective therapeutic agent.
- the restricted-growth adenovirus of the present invention is useful as a pharmaceutical composition for the treatment of bone and soft tissue tumors.
- bone and soft tissue tumors means tumors that develop in bones and soft tissues (muscle, fat, nerves, blood vessels, etc.), and includes common osteosarcoma, chondroblast-type, fibroblast-type, bone Osteosarcoma, including blastic, telangiectatic osteosarcoma, small cell osteosarcoma, secondary osteosarcoma, parabone osteosarcoma, periosteal osteosarcoma, and high-grade superficial osteosarcoma; , dedifferentiated chondrosarcoma, mesenchymal chondrosarcoma, clear cell chondrosarcoma, bone myxochondrosarcoma; Ewing sarcoma; undifferentiated high-grade pleomorphic sarcoma of bone (so-called MFH); malignant giant cell tumor of bone; angiosarcoma of bone; leiomyosarcoma of bone; "Bone and soft tissue tumor” includes bone
- Bone and soft tissue tumors are preferably malignant bone and soft tissue tumors, which are divided into primary bone and soft tissue tumors and metastatic bone and soft tissue tumors.
- Primary bone and soft tissue tumor means a malignant tumor in which cancer originates from the bone and soft tissue itself.
- a “metastatic bone and soft tissue tumor” means a malignant tumor caused by cancer of other organs such as internal organs metastasizing to bone and soft tissue.
- the restricted-growth adenovirus of the present invention is also effective for recurrent primary bone and soft tissue tumors and metastatic bone and soft tissue tumors.
- “Recurrent primary bone and soft tissue tumor” refers to a primary bone and soft tissue tumor that has already been treated with radiotherapy or chemotherapy and/or has undergone surgical treatment such as resection, and the tumor exacerbation or metastasis of Similarly, a “recurrent primary bone and soft tissue tumor” refers to a metastatic bone and soft tissue tumor that has already been treated and which has aggravated or metastasized after the treatment.
- the restricted-growth adenovirus of the present invention may be used in combination with conventionally known therapeutic methods for bone and soft tissue tumors.
- Treatment methods for bone and soft tissue tumors are based on the Japanese Orthopedic Association (JOA) Clinical Practice Guidelines on the Management of Soft Tissue Tumors, NCCN guidelines, ESMO clinical practice guidelines, EURACAN guidelines, and other countries' guidelines. Guidelines (Cancer Chemother Pharmacol. 2016 Jan; 77(1): 133-46. etc.).
- chemotherapeutic agents include vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, pazopanib, trabectedin, or eribulin, or combinations thereof.
- the present invention provides a method for treating a patient with bone and soft tissue tumors, which comprises administering an effective amount of a restricted-growth adenovirus having the E1A gene under the expression control of the Survivin promoter.
- a restricted-growth adenovirus having the E1A gene under expression control by the Survivin promoter for the use of a restricted-growth adenovirus having the E1A gene under expression control by the Survivin promoter.
- the growth-restrictive adenovirus referred to above is a restricted-reproduction adenovirus that retains the wild-type E3 region and preferably has E1B ⁇ 55K as the E1B region.
- the restricted-replication adenovirus of the present invention or a pharmaceutical composition comprising the same as an active ingredient is administered, for example, on a schedule of administration once every four weeks, 1 to 10 times, 2 to 8 times, 3 to 5 times, Or 4-5 doses.
- Administration is by injection and may be blood administration or intratumoral administration, preferably intratumoral administration.
- the dosage of the pharmaceutical composition of the present invention may be changed according to the tumor volume.
- the dosage volume of the pharmaceutical compositions described herein may be determined as follows: 1 mL if the tumor volume to be administered is less than 5 cm 3 ; 2 mL when the tumor volume to be administered is 5 cm 3 or more and less than 9 cm 3 ; 3 mL when the tumor volume of the administration target is 9 cm 3 or more and less than 15 cm 3 ; 5 mL when the tumor volume of the administration target is 15 cm 3 or more and less than 21 cm 3 ; 7 mL when the target tumor volume is 21 cm 3 or more and less than 30 cm 3 ; and 10 mL when the target tumor volume is 30 cm 3 or more.
- the virus can spread more widely within the tumor.
- the restricted adenovirus is administered, for example, to up to 3 tumors (preferably 3 tumors with large tumor sizes). Alternatively, each dose may be divided according to tumor volume. Alternatively, if the volume of one tumor is 30 cm 3 or more, it may be administered to only one tumor without dividing. In addition, in the case of multiple administrations, if the volume of the tumor that has been administered up to the previous time has decreased at the time of the second and subsequent administrations, the restricted growth type adenovirus is administered at the time of the second and subsequent administrations. It may be administered to three tumors with large tumor diameters among the lesions administered in .
- the three tumors with the largest tumor diameter mean the tumor with the largest tumor diameter, the tumor with the second largest tumor diameter, and the tumor with the third largest tumor diameter.
- the restricted growth adenovirus is the first administration. It may be administered to the tumor with the fourth largest tumor size among the treated lesions at the time point.
- the restrictive adenovirus is the fourth largest tumor in the administered lesion at the time of the first administration. and the fifth largest tumor.
- the restricted growth adenovirus is the fourth largest tumor in the administered lesion at the time of the first administration, May be administered to the 5th largest tumor and the 6th largest tumor.
- a single dose of restricted-growth adenovirus can be 1 ⁇ 10 10 vp to 1 ⁇ 10 12 vp, preferably 1 ⁇ 10 11 vp.
- Administration of restricted-growth adenovirus can be single or multiple doses, but the total dose can be 1 ⁇ 10 10 vp to 1 ⁇ 10 12 vp, preferably 1 ⁇ 10 11 to 5 ⁇ 10 vp. 10 11 vp or 3 ⁇ 10 11 to 5 ⁇ 10 11 vp.
- the form of the pharmaceutical composition of the present invention is not particularly limited as long as it is suitable for administration to the tumor site, and may contain pharmacologically acceptable carriers and additives.
- carriers and additives include solvents, solubilizers, suspending agents, emulsifiers, tonicity agents, stabilizers, soothing agents, preservatives, antioxidants, buffers and the like. be done.
- Solvents include purified water, physiological saline, phosphate buffer and the like.
- solubilizing agents include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.
- Suspending or emulsifying agents include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, celluloses such as sodium carboxymethylcellulose, polysorbates, and polyoxyethylene hydrogenated castor oil. mentioned.
- Tonicity agents include sodium chloride, potassium chloride, sugars, glycerin, urea and the like.
- Stabilizers include polyethylene glycol, sodium dextran sulfate, and other amino acids.
- Analgesics include glucose, calcium gluconate, procaine hydrochloride and the like.
- Preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
- Antioxidants include water-soluble antioxidants ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, fat-soluble antioxidants ascorbyl palmitate, and butylated hydroxyanisole (BHA). , butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the metal chelating agents citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid.
- BHA butylated hydroxyanisole
- the pharmaceutical composition of the present invention contains, for example, restricted-growth adenovirus in a glycerinized Tris-buffered saline buffer (containing 2.5% (v/v) glycerin, 25 mM NaCl, 20 mM Tris, pH 8.0). It can be an injectable formulation containing The amount of the restricted-growth adenovirus to be contained can be appropriately selected according to the purpose and dosage and administration, but is preferably 1 ⁇ 10 11 vp/mL.
- the drug used is a multifactor-restricted growth human adenovirus whose E1 region has been modified to express the E1A gene under the control of the survivin promoter and the E1B19K gene under the control of the CMV promoter.
- Virus type 5 is used as an active ingredient.
- This adenovirus has m-CRA as a basic framework in which the endogenous promoters of the E1A and E1B regions necessary for viral replication are removed from the type 5 adenovirus genome, and does not have a therapeutic gene.
- the final formulation of this drug was an injection formulation.
- One formulation contains 0.6 mL/vial of virus at a concentration of 1 ⁇ 10 11 vp/mL.
- the composition of the base is a buffer consisting of GTS buffer (25 mM NaCl, 20 mM Tris, pH 8.0 containing 2.5% glycerol (v/v)).
- Selection criteria 1) Histologically diagnosed with any of the following. Primary malignant bone tumor Metastatic bone tumor Primary malignant soft-tissue tumor Metastatic soft-tissue tumor 2) If standard treatment was given as prior treatment, 4 weeks or more have passed since treatment at the time of enrollment. 3) not amenable to generally accepted standard treatments that may prolong life or provide symptomatic relief; 4) Has a lesion that allows measurement of the minor axis, major axis, and height of the tumor and administration of investigational products into the tumor. 5) Age at the time of consent acquisition is 10 years old or more and less than 85 years old.
- One tumor site to be administered was selected based on the following criteria based on the anatomical location. No distinction was made between primary tumors and metastatic lesions.
- the administration target is selected from the viewpoint of ease of administration procedures. 1) The size of the tumor is large and the administration procedure is easy 2) The site is not adjacent to large blood vessels and the thoracic cavity 3) The site is not presumed to be related to symptoms such as pain
- the medicine is diluted to 10 mL and administered.
- the low dose group and medium dose group if the tumor volume was 3.4 cm 3 or less, the drug was administered without dilution, and if the tumor volume was 3.5 cm 3 to 33.3 cm 3 or less, the drug was administered after dilution to 30% of the tumor volume.
- the high-dose group if the tumor volume was 33.3 cm 3 or less, the drug was administered in its entirety without dilution.
- the amount of liquid to be administered to one lesion site to be administered is evenly distributed within the same tumor while changing the direction of the needle tip. It was administered so that it was divided into a total of about 5 to 10 sites.
- Table 1 shows the treatment efficacy of subjects in the Phase I trial. Among them, a patient (45 years old, female) with low-dose sacral chordoma metastasized to the liver and lungs 6 years after the onset of sacral chordoma, and recurred in the soft tissue of the right hip. He had no response to chemotherapeutic agents or radiotherapy, and resection of recurrent tumors was not possible. This drug was able to achieve partial response (PR) with only a single administration even in such cases of recurrence (and in failure cases of chemotherapeutic agents and radiotherapy). In particular, both therapeutic efficacy and safety were noteworthy.
- PR partial response
- thoracic chordoma patient (61 years old, male) underwent resection of thoracic chordoma from the right mediastinum, and 11 years later, a fourth recurrence in the adjacent vertebral bodies was observed, and standard This is a case in which the effect of treatment was not observed. This drug was able to achieve PR even in such recurrent cases. More notably, therapeutic effects were seen 4 weeks after treatment, and evidence of bone remodeling was seen 12 weeks after treatment. Bone remodeling is a phenomenon of healing and regeneration that is induced only after bone tumors are killed, and clinically demonstrates a high therapeutic effect.
- the tumor was formed in the bone, so even if the tumor had undergone cell death, even if there was bone regeneration, it would not block the entire site where the tumor existed, so the tumor diameter was evaluated. Since the RECIST does not fully evaluate the tumor shrinkage effect, it is presumed that a more dramatic therapeutic effect was originally observed. Furthermore, in Choi evaluated by contrast-enhanced CT, the rate of increase in CT value was shown, that is, very good results were shown in which bone modeling of regenerative healing occurred remarkably. Therefore, considering these results together, it is considered that this patient is actually in a state close to obtaining a strong therapeutic effect of complete response.
- Table 1 shows a summary of the therapeutic effects in all 9 patients who underwent clinical trials.
- the therapeutic effect was determined by the tumor reduction effect according to Choi criteria and RECIST criteria.
- PD is progressive disease
- SD is stable disease
- PR is partial response.
- Safety (adverse events and side effects) was analyzed for all adverse events that occurred from the date of administration of the investigational product to the end of the observation period.
- Common Terminology Criteria for Adverse Events CCAE ver.
- JCOG Japanese translation Japanese Clinical Oncology Group version
- lymphocytes in the peripheral blood decreased due to temporary mobilization of spheres to the tumor and lymph nodes. Therefore, in a sense, it can be said that this is the evidence that this medicine is functioning properly. No subjects died within 28 days after administration of the study product. There were no adverse events leading to discontinuation or DLT (dose limiting toxicity). No clinically significant changes were observed in laboratory test values and vital signs, except for abnormalities reported as adverse events.
- Virus was quantified in body fluids after administration. Table 2 shows the results. At the low dose, virus in saliva was positive only on the day of administration (Day 1 only) in one case, negative in blood and urine, and negative in blood, saliva and urine in other cases. At the middle dose, 2 cases were positive in blood until 7 days (Day 8), 1 case was positive in saliva after 7 days (Day 8), the other was positive after 21 days (positive until Day 22, but after 14 days ( After Day 15), the concentration was as low as 20 copies/ ⁇ L or less.At the high dose, blood was positive in all three cases until 7 days later (Day 8), saliva was positive in 2 cases until 7 days later (Day 8), and urine was positive. All 3 subjects were negative, although some subjects became positive transiently after administration of the investigational product, but became negative by the end of the study treatment/evaluation period (Day 29).
- lesions in which the investigational product can be administered into the tumor are lesions that meet all of the following conditions.
- Main site is bone or soft tissue (metastatic lesion of bone tumor) Injection from the body surface into the tumor is possible No lymph node lesion Minimal diameter of the tumor is 10mm or more If the entire tumor is a cystic lesion No For the volume of the drug to be administered to one lesion, calculate the volume of the tumor to be administered and determine the volume of the drug to be administered according to the following criteria. If dilution is required, dilute with physiological saline according to the volume of administration.
- Tumor volume and dose volume (after dilution) Tumor volume (cm 3 ) Administered volume (mL) Less than 5 1 5 or more and less than 9 2 9 or more and less than 15 3 15 or more and less than 21 5 21 or more and less than 30 7 30 or more 10
- the volume of the administered liquid is calculated according to the above criteria using the total tumor volume. A maximum of 3 tumors can be administered at each dose. When administered to multiple tumors, the total dose should be 1 ⁇ 10 11 vp, divided according to tumor volume. However, if the volume of one tumor is 30 cm 3 or more, it should be administered to only one site and not to the next tumor. When there are multiple lesions that can be administered, the selection of lesions to be administered will be determined by the investigator or subinvestigator according to the following criteria. Tumor diameter should be large Can be approached from the body surface Safe administration without important nerves and blood vessels in the vicinity
- m-CRA-1 was produced by a new improved method based on m-CRA production technology (Patent Document 2, Non-Patent Document 7) as follows. Also, Surv. The structure of m-CRA-1 has not been previously reported. First, the mouse survivin promoter (-173 to -19) was inserted upstream of E1A and the CMV promoter was inserted upstream of E1B ⁇ 55K into a vector plasmid (P1 plasmid: replication-controllable plasmid) containing a growth control unit. E1A-CMV. A 19K plasmid was constructed by the method described in US Pat. Next, pSurv. E1A-CMV.
- the 19K plasmid was digested with restriction enzyme I-Ceul and then with restriction enzyme PI-Seel, and a DNA sequence having survivin promoter/E1A/CMV promoter/E1B ⁇ 55K was isolated and purified from the upstream.
- restriction enzyme I-Ceul restriction enzyme I-Ceul
- PI-Seel restriction enzyme PI-Seel
- 342-3523 bp of human adenovirus type 5 containing the E1 region is deleted, and the I-Ceul and PI-Seel recognition sequences are added to subclone the P1 plasmid gene at that site, while the E3 region is The adenoviral genome plasmid harboring pAd. HM3 (provided by Dr. Mark A.
- Fig. 3 shows the results of comparing the 3 groups for each MOI and each Day (day after infection).
- m-CRA In m-CRA (without E3), significant cell death was induced in HepG2 tumor cells, and no significant cell death occurred in WI-38 normal cells at MOI 3. All survivin-reactive multifactorially restricted growth adenoviruses exhibit tumor-specific cytotoxic effects and have excellent and reliable performance as cancer therapeutic agents, but Surv. m-CRA-1 (with E3) is superior in tumor specificity (safety).
- m-CRA-1 (with E3) is an even better restricted-growth adenovirus.
- Surv. Surv. Although it was found to be less cytotoxic under certain conditions of in vitro experiments than m-CRA (and importantly, this finding completely contradicts the conventional wisdom), the actual clinical treatment In moderate doses, as in pharmaceutical use, and in long-term (that is, not hours or days as in vitro) clinical therapeutic effects that benefit the patient, Surv. m-CRA-1 (with E3) produces a sufficiently potent therapeutic effect (comparable to without E3). This demonstrates a strong therapeutic effect (exceeding conventional restricted-growth adenoviruses) and an extremely high safety (severe no significant side effects).
- the Surv. m-CRA-1 is the first restricted-growth adenovirus that has the potential to become a cancer therapeutic agent by itself, which greatly surpasses conventional restricted-growth adenoviruses in terms of both therapeutic efficacy and safety. .
- Table 4 shows the RECIST-based response determination and Choi-based response determination from before administration to 32 weeks after administration at the administration site (sacrum), and at the non-administration site (right iliac wing) from before administration. RECIST-based response evaluation up to 32 weeks after administration is shown.
- tumors increased at non-administration sites, whereas lesions were suppressed and tumor volumes decreased at administration sites.
- the effect of SD was recognized 8 months (32 weeks) after the start of administration. No adverse events were observed during the dosing period.
- the tumor volume was 22.8 cm 3 perineum and 14.95 cm 3 subcutaneously at the sacrum. From the 1st to the 3rd time, 5 ⁇ 10 11 vp of Surv. m-CRA-1 was administered in divided doses as follows. Surv. The dose of m-CRA-1 was adjusted to 3.5 ⁇ 10 11 vp (7 ml), and the 4th and 5th doses were administered. Dosing was done every 4 weeks. 1-3 times 4 or 5 times Perineum: 7ml 4 places 5ml 3 places Sacrum subcutaneous: 3ml 2 places 2ml 1 place Injection
- Table 5 shows the efficacy determination based on RECIST criteria and the efficacy determination based on Choi criteria from before administration to 140 days after administration at the administration sites (perineum, subcutaneous sacral region), and non-administration sites (left rectum, right rectum, RECIST-based response assessment from pre-administration to 84 days post-administration in left gluteal muscle, right iliac bone).
- the tumor increased at the non-administration site, whereas the lesion was suppressed at the administration site. A clear shrinkage was observed. No adverse events other than lymphopenia (750/ ⁇ l) were observed during the dosing period.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Oncology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本出願は、日本特許出願2021-084823(2021年5月19日出願)に基づく優先権を主張しており、この内容は本明細書に参照として取り込まれる。
技術分野
本発明は骨軟部腫瘍の治療分野に関する。
[1] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む、骨軟部腫瘍(好ましくは、悪性骨軟部腫瘍、例えば、原発性悪性骨腫瘍、転移性骨腫瘍、原発性悪性軟部腫瘍、転移性軟部腫瘍)の治療用医薬組成物であって、前記制限増殖型アデノウイルスがE3領域を欠損していない、医薬組成物。
[2] 骨軟部腫瘍が、原発性骨軟部腫瘍である、[1]に記載の医薬組成物。
[3] 骨軟部腫瘍が、再発した原発性骨軟部腫瘍または再発した転移性骨軟部腫瘍である、[1]に記載の医薬組成物。
[4] 骨軟部腫瘍が骨腫瘍である、[1]~[3]のいずれかに記載の医薬組成物。
[5] 骨腫瘍が脊索腫である、[4]に記載の医薬組成物。
[6] 1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1010vp~1×1012vpである、[1]に記載の医薬組成物。
[7] 単回投与または4週に1回反復投与、好ましくは4週に1回投与の計3~5回投与される、[1]に記載の医薬組成物。
[8] 投与対象の腫瘍体積に応じて投与液量が変更される、[1]に記載の医薬組成物。
[9] 1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpである、[1]に記載の医薬組成物。
[10] 複数の箇所に腫瘍が存在する場合には、最大3か所の腫瘍に投与され、各投与量が腫瘍体積に応じて分割される、[1]に記載の医薬組成物。
[11] 一つの腫瘍体積が30cm3以上の場合は、1か所のみに投与される、[1]に記載の医薬組成物。
[12] 投与液量が以下のように決定される、[8]または[10]に記載の医薬組成物:
投与対象の腫瘍体積が5cm3未満の場合1mL;
投与対象の腫瘍体積が5cm3以上9cm3未満の場合2mL;
投与対象の腫瘍体積が9cm3以上15cm3未満の場合3mL;
投与対象の腫瘍体積が15cm3以上21cm3未満の場合5mL;
投与対象の腫瘍体積が21cm3以上30cm3未満の場合7mL;かつ
投与対象の腫瘍体積が30cm3以上の場合10mL。
例えば、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpの場合、医薬組成物はいずれの投与液量の場合も1×1011vpの制限増殖型アデノウイルスを含有する。複数の腫瘍に投与される場合は、各投与液量を合わせて1×1011vpの制限増殖型アデノウイルスを含有する。
[13] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスであって、E3領域を欠損していない制限増殖型アデノウイルス。
[14] 制限増殖型アデノウイルスのE1B領域がE1BΔ55Kである、[1]に記載の医薬組成物、または[13]に記載の制限増殖型アデノウイルス。
[15] 制限増殖型アデノウイルスのE1B領域が、E1A領域とは異なるプロモーター、例えば、CMVプロモーター、RSVプロモーター、CAプロモーター、E2Fプロモーター、EF1Aプロモーター、EFSプロモーター、CAGプロモーター、CBhプロモーター、CBAプロモーター、SFFVプロモーター、MSCVプロモーター、SV40プロモーター、mPGKプロモーター、hPGKプロモーター、UBCプロモーター、Nanogプロモーター、Nesプロモーター、Tuba1aプロモーター、Camk2aプロモーター、SYN1プロモーター、Hb9プロモーター、Thプロモーター、NSEプロモーター、GFAPプロモーター、iba1プロモーター、ProA1プロモーター、hRHOプロモーター、hBEST1プロモーター、Prnpプロモーター、Cnpプロモーター、K14プロモーター、BK5プロモーター、mTyrプロモーター、cTnTプロモーター、αMHCプロモーター、Myogプロモーター、ACTA1プロモーター、MHCK7プロモーター、SM22aプロモーター、EnSM22aプロモーター、Runx2プロモーター、OCプロモーター、Col1a1プロモーター、Col2a1プロモーター、aP2プロモーター、Adipoqプロモーター、Tie1プロモーター、Cd144プロモーター、CD68プロモーター、CD11bプロモーター、Afpプロモーター、Albプロモーター、TBGプロモーター、MMTVプロモーター、Wapプロモーター、HIPプロモーター、Pdx1プロモーター、Ins2プロモーター、Hcn4プロモーター、NPHS2プロモーター、SPBプロモーター、CD144プロモーター、TERTプロモーター、TREプロモーターFLK-1プロモーター、VEGFプロモーター、c-Mycプロモーター、SLPIプロモーター、PSAプロモーター、チロシナーゼプロモーター、から選ばれるいずれかのプロモーター、好ましくはCMVプロモーターによって制御される、[14]に記載の医薬組成物または制限増殖型アデノウイルス。
[16] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む、再発した骨軟部腫瘍の治療用医薬組成物。
[17] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む、骨軟部腫瘍の治療用医薬組成物であって、単回投与または4週に1回反復投与、好ましくは4週に1回投与の計3~5回投与される、医薬組成物。
[18] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む、骨軟部腫瘍の治療用医薬組成物であって、腫瘍体積に応じて投与液量が変更される、医薬組成物。
[19] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む、骨軟部腫瘍の治療用医薬組成物であって、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1010vp~1×1012vpの範囲において安全な治療が可能である、医薬組成物。
[20] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む、骨軟部腫瘍の治療用医薬組成物であって、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpである、医薬組成物。
[1] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを対象に投与することを含む、骨軟部腫瘍(好ましくは、悪性骨軟部腫瘍、例えば、原発性悪性骨腫瘍、転移性骨腫瘍、原発性悪性軟部腫瘍、転移性軟部腫瘍)を(安全に)治療する方法。
[2] 骨軟部腫瘍が、原発性骨軟部腫瘍である、[1]に記載の方法。
[3] 骨軟部腫瘍が、再発した原発性骨軟部腫瘍または再発した転移性骨軟部腫瘍である、[1]に記載の方法。
[4] 骨軟部腫瘍が骨腫瘍である、[1]に記載の方法。
[5] 骨腫瘍が脊索腫である、[4]に記載の方法。
[6] 1回あたりの患者への制限増殖型アデノウイルスの総投与量が1×1010vp~1×1012vpである、[1]に記載の方法。
[7] 制限増殖型アデノウイルスが、単回投与または4週に1回反復投与、好ましくは4週に1回投与の計3~5回投与される、[1]に記載の方法。
[8] 投与対象の腫瘍体積に応じて制限増殖型アデノウイルスの投与液量が変更される、[1]に記載の方法。
[9] 1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpである、[1]に記載の方法。
[10] 複数の箇所に腫瘍が存在する場合には、最大3か所の腫瘍に制限増殖型アデノウイルスが投与され、各投与量が腫瘍体積に応じて分割される、[1]に記載の方法。
[11] 一つの腫瘍体積が30cm3以上の場合は、1か所のみに制限増殖型アデノウイルスが投与される、[1]に記載の方法。
[12] 制限増殖型アデノウイルスの投与液量が以下のように決定される、[8]または[10]に記載の方法:
投与対象の腫瘍体積が5cm3未満の場合1mL;
投与対象の腫瘍体積が5cm3以上9cm3未満の場合2mL;
投与対象の腫瘍体積が9cm3以上15cm3未満の場合3mL;
投与対象の腫瘍体積が15cm3以上21cm3未満の場合5mL;
投与対象の腫瘍体積が21cm3以上30cm3未満の場合7mL;かつ
投与対象の腫瘍体積が30cm3以上の場合10mL。
例えば、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpの場合、いずれの投与液量の場合も1×1011vpの制限増殖型アデノウイルスが投与される。複数の腫瘍に投与される場合は、各投与液量を合わせて1×1011vpの制限増殖型アデノウイルスが投与される。
[13] 制限増殖型アデノウイルスのE3領域が欠損していない、[1]に記載の方法。
[14] 制限増殖型アデノウイルスのE1B領域がE1BΔ55Kである、[1]に記載の方法。
[15] 制限増殖型アデノウイルスのE1B領域が、E1A領域とは異なるプロモーター(第1の態様に記載のとおり)によって制御される、[1]に記載の方法。
[16] 制限増殖型アデノウイルスのE1B領域が、CMVプロモーターによって制御される、[1]に記載の方法。
[1] 骨軟部腫瘍(好ましくは、悪性骨軟部腫瘍、例えば、原発性悪性骨腫瘍、転移性骨腫瘍、原発性悪性軟部腫瘍、転移性軟部腫瘍)の治療において使用される、サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む組成物であって、前記制限増殖型アデノウイルスがE3領域を欠損していない(E3領域を保持している)、組成物。
[2] 骨軟部腫瘍が、原発性骨軟部腫瘍(例えば、原発性悪性骨腫瘍、原発性悪性軟部腫瘍)である、[1]に記載の使用のための組成物。
[3] 骨軟部腫瘍が、再発した原発性骨軟部腫瘍(例えば、原発性悪性骨腫瘍、原発性悪性軟部腫瘍)または再発した転移性骨軟部腫瘍(例えば、転移性骨腫瘍、転移性軟部腫瘍)である、[1]または[2]に記載の使用のための組成物。
[4] 骨軟部腫瘍が骨腫瘍である、[1]~[3]のいずれかに記載の使用のための組成物。
[5] 骨腫瘍が脊索腫である、[4]に記載の使用のための組成物。
[6] 1回あたりの患者への制限増殖型アデノウイルスの総投与量が1×1010vp~1×1012vpである、[1]~[5]のいずれかに記載の使用のための組成物。
[7] 単回投与または4週に1回反復投与、好ましくは4週に1回投与の計3~5回投与される、[1]~[6]のいずれかに記載の使用のための組成物。
[8] 投与対象の腫瘍体積に応じて投与液量が変更される、[1]~[7]のいずれかに記載の使用のための組成物。
[9] 1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpである、[1]~[8]のいずれかに記載の使用のための組成物。
[10] 複数の箇所に腫瘍が存在する場合には、最大3か所の腫瘍に投与され、各投与量が腫瘍体積に応じて分割される、[1]~[9]のいずれかに記載の使用のための組成物。
[11] 一つの腫瘍体積が30cm3以上の場合は、1か所のみに投与される、[1]~[9]のいずれかに記載の使用のための組成物。
[12] 投与液量が以下のように決定される、[1]~[11]のいずれかに記載の使用のための組成物:
投与対象の腫瘍体積が5cm3未満の場合1mL;
投与対象の腫瘍体積が5cm3以上9cm3未満の場合2mL;
投与対象の腫瘍体積が9cm3以上15cm3未満の場合3mL;
投与対象の腫瘍体積が15cm3以上21cm3未満の場合5mL;
投与対象の腫瘍体積が21cm3以上30cm3未満の場合7mL;かつ
投与対象の腫瘍体積が30cm3以上の場合10mL
例えば、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpの場合、組成物はいずれの投与液量の場合も1×1011vpの制限増殖型アデノウイルスを含有する。複数の腫瘍に投与される場合は、各投与液量を合わせて1×1011vpの制限増殖型アデノウイルスを含有する。[13] 制限増殖型アデノウイルスのE1B領域がE1BΔ55Kである、[1]~[12]のいずれかに記載の使用のための組成物。
[14] 制限増殖型アデノウイルスのE1B領域が、E1A領域とは異なるプロモーター(第1の形態に記載のとおり)、例えば、CMVプロモーターによって制御される、[1]~[13]のいずれかに記載の使用のための組成物。
[15] サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスであって、E3領域を欠損していない制限増殖型アデノウイルス、好ましくは、E1B領域がE1BΔ55Kであり、さらに好ましくはE1B領域が、E1A領域とは異なるプロモーター(第1の形態に記載のとおり)、例えばCMVプロモーターによって制御される、[14]に記載の制限増殖型アデノウイルス。
[16] 再発した骨軟部腫瘍の治療において使用される、サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む組成物。
[17] 骨軟部腫瘍の治療において使用される、サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む組成物であって、単回投与または4週に1回反復投与、好ましくは4週に1回投与の計3~5回投与される、組成物。
[18] 骨軟部腫瘍の治療において使用される、サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む組成物であって、腫瘍体積に応じて投与液量が変更される、組成物。
[19] 骨軟部腫瘍の治療において使用される、サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む組成物であって、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1010vp~1×1012vpの範囲において安全な治療が可能である、組成物。
[20] 骨軟部腫瘍の治療において使用される、サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む組成物であって、1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpである、組成物。
投与対象の腫瘍体積が5cm3未満の場合1mL;
投与対象の腫瘍体積が5cm3以上9cm3未満の場合2mL;
投与対象の腫瘍体積が9cm3以上15cm3未満の場合3mL;
投与対象の腫瘍体積が15cm3以上21cm3未満の場合5mL;
投与対象の腫瘍体積が21cm3以上30cm3未満の場合7mL;かつ
投与対象の腫瘍体積が30cm3以上の場合10mL。
このように、腫瘍の体積に応じて投与液量を変えることにより、腫瘍内でより広くウイルスをいきわたらせることができる。
溶解補助剤としては、ポリエチレングリコール、プロピレングリコール、トレハロース、安息香酸ベンジル、エタノール、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸ナトリウムなどが挙げられる。
安定化剤としては、ポリエチレングリコール、デキストラン硫酸ナトリウム、その他のアミノ酸類などが挙げられる。
防腐剤としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。
以下の選択基準をすべてみたし、除外基準のいずれにも該当しない患者を適格として登録した。
(選択基準)
1)組織学的に下記のいずれかと診断されている。
原発性悪性骨腫瘍
転移性骨腫瘍
原発性悪性軟部腫瘍
転移性軟部腫瘍
2)前治療として標準的治療が行われている場合、登録時に、治療後4週間以上が経過している。
3)延命や症状緩和が得られる可能性のある、一般的に認められた標準的治療法の対象にならない。
4)腫瘍の短径・長径・高さの計測および腫瘍内への治験製品投与が可能な病変を有する。
5)同意取得時年齢が10歳以上85歳未満である。
6)ECOG PSが0~2である。
7)3ヶ月以上の生存が期待される。
8)主要臓器機能が保持されている。(登録前2週間以内の最新の検査)
ヘモグロビン≧8g/dL
白血球数≧2,000/μL
血小板数≧70,000/μL
AST(GOT)≦100U/L
ALT(GPT)≦100U/L
総ビリルビン≦1.5mg/dL
血清クレアチニン≦2.0mg/dL
9)男性の場合、以下のいずれかを満たす。
無精子症である。
精管切除術等の外科的避妊手術後である。
同意取得時から治験製品投与後、治験製品Surv.m-CRA-1が体内から消失するまでの間、コンドームの適切な使用、又は禁欲にて避妊することに同意している。
女性パートナーが、閉経後1年以上経過している、または両側卵巣摘出術等の手術後、または同意取得時から治験製品投与後、治験製品Surv.m-CRA-1が体内から消失するまでの間、経口避妊薬(避妊用ピル)、子宮内避妊用具(ペッサリー)にて避妊することに同意している。
10)女性の場合、以下のいずれかを満たす。
閉経後1年以上経過している。
両側卵巣摘出術等の外科的避妊手術後である。
同意取得時から治験製品投与後、治験製品Surv.m-CRA-1が体内から消失するまでの間、経口避妊薬(避妊用ピル)、子宮内避妊用具(ペッサリー)、又は禁欲にて避妊することに同意している。
男性パートナーが、無精子症である、または精管切除術等の外科的避妊手術後である、または同意取得時から治験製品投与後、治験製品Surv.m-CRA-1が体内から消失するまでの間、コンドームの適切な使用にて避妊することに同意している。
11)本治験への参加について、被験者本人または代諾者からの同意が文書で得られている。
1)以下のいずれかの合併症を有する。
重篤な心疾患、呼吸器疾患、消化器疾患、肝疾患
コントロール不良の糖尿病
継続的な治療を必要とする感染症
2)ペニシリンまたはブタ、ウシ(牛乳を含む)アレルギーの既往を有する。
3)免疫抑制剤またはステロイドの全身投与を必要とする疾患を有する(造影剤アレルギー予防のためのステロイド使用は許容されるが、使用した場合、治験製品投与まで1週間程度間隔をあけ、感染予防策などを考慮する)。
4)活動性の重複がんを有する。(適切に治療された基底細胞癌、上皮内癌、表在膀胱癌、または5年間以上の転移・再発が認められない悪性腫瘍は不適格としない)
5)原疾患に伴う発熱・疼痛のコントロールができない。
6)妊娠中、授乳中の女性、閉経前または閉経後1年以内で妊娠検査が陽性の女性。
7)同意取得前4週間以内に他の未承認薬の投与を受けている。
8)その他、治験責任医師/治験分担医師が本治験への参加は不適当と判断している。
1)腫瘍の大きさが大きく、投与手技が容易であること
2)大血管および胸腔に隣接しない部位であること
3)疼痛などの症状に関係すると推測される部位ではないこと
<腫瘍体積算出>
腫瘍体積(cm3)=短径(cm)×長径(cm)×高さ(cm)×1/2
第I相試験の被験者の治療効果を表1に示す。このうち、低用量の仙骨脊索腫の患者(45歳、女性)は、仙骨脊索腫発症から6年後に肝臓及び肺に転移し、右臀部軟部組織が再発した事例である。化学療法剤や放射線治療による効果が見られず、再発腫瘍の切除も不能であった。本医薬は、このような再発事例(かつ化学療法剤や放射線治療不奏効事例)においても、単回投与のみで部分奏効(Partial Response: PR)を達成することができた。特に治療効果と安全性は、いずれも特筆するものであった。つまり、これまで報告された制限増殖型アデノウイルスの臨床試験は反復投与されたにも関わらず、このような低用量で治療効果がみられたことは報告されていない。さらに制限増殖型アデノウイルスの臨床試験で、投与後、2年以上に渡って治療効果がみられた例も報告されていない。治療経過を図1に表す。
主たる部位が骨または軟部組織(骨腫瘍の転移病変)である
体表から腫瘍内への注射が可能である
リンパ節病変ではない
腫瘍の最小径が10mm以上である
腫瘍の全体が嚢胞性病変ではない
1つの病変に対する医薬の液量については、投与対象の腫瘍体積を算出し、以下の基準に従い、投与液量を決定する。希釈が必要な場合は、投与液量に合わせて生理食塩水で希釈して投与する。
腫瘍体積(cm3) 投与液量(mL)
5未満 1
5以上9未満 2
9以上15未満 3
15以上21未満 5
21以上30未満 7
30以上 10
腫瘍径が大きい
体表からアプローチが可能であること
近傍に重要な神経や血管などがなく安全に投与できること
<腫瘍体積算出>
腫瘍体積(cm3)=短径(cm)×長径(cm)×高さ(cm)×1/2
[症例1]
仙骨再発脊索腫(60歳、男性)に対する、Surv.m-CRA-1による治療経過を示す。患者は、2014年に仙骨脊索腫を発症し、粒子線治療を開始した。2019年に左腎に転移により腎摘出。2020年12月に仙骨脊索腫の増大を認め、2021年5月にSurv.m-CRA-1の投与を開始した。患者は、実施例1の選択基準を満たし、除外基準に該当しない。腫瘍体積は315cm3(30cm3以上)であったため、1×1011vpのSurv.m-CRA-1を9か所に分けて、4週ごとに全5回(合計5×1
仙骨再発脊索腫(73歳、男性)に対する、Surv.m-CRA-1による治療経過を示す。患者は、2016年に仙骨脊索腫を発症し、S3レベルで腫瘍切除した。2018年に重粒子線治療(2回)を実施。2020年10月に右腓腹筋転移切除し、2021年化学療法(ADR)3コース施行した。2021年左大腿骨転子部病的骨折、2021年10月に会陰部、仙骨部皮下の腫瘍増大(仙骨再発脊索腫)を認め、2021年11月にSurv.m-CRA-1の投与を開始した。患者は、実施例1の選択基準を満たし、除外基準に該当しない。
腫瘍体積は、会陰部が22.8cm3、仙骨部皮下が14.95cm3であった。1~3回目までは、5×1011vpのSurv.m-CRA-1を下記のように分割して投与した。3回投与後に縮小した腫瘍体積に応じてSurv.m-CRA-1の投与量を3.5×1011vp(7ml)に調整し、4,5回目を投与した。投与は4週間毎に行った。
1-3回 4,5回
会陰部: 7ml 4か所 5ml 3か所
仙骨部皮下: 3ml 2か所 2ml 1か所 注入
Claims (15)
- サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスを含む骨軟部腫瘍の治療用医薬組成物であって、前記制限増殖型アデノウイルスがE3領域を欠損していない、医薬組成物。
- 骨軟部腫瘍が、原発性骨軟部腫瘍である、請求項1に記載の医薬組成物。
- 骨軟部腫瘍が、再発した原発性骨軟部腫瘍または再発した転移性骨軟部腫瘍である、請求項1に記載の医薬組成物。
- 骨軟部腫瘍が骨腫瘍である、請求項1~3のいずれか1項に記載の医薬組成物。
- 骨腫瘍が脊索腫である、請求項4に記載の医薬組成物。
- 1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1010vp~1×1012vpである、請求項1に記載の医薬組成物。
- 単回投与または4週に1回反復投与される、請求項1に記載の医薬組成物。
- 投与対象の腫瘍体積に応じて投与液量が変更される、請求項1に記載の医薬組成物。
- 1回あたりの対象への制限増殖型アデノウイルスの総投与量が1×1011vpである、請求項1に記載の医薬組成物。
- 複数の箇所に腫瘍が存在する場合には、最大3か所の腫瘍に投与され、各投与量が腫瘍体積に応じて分割される、請求項1に記載の医薬組成物。
- 一つの腫瘍体積が30cm3以上の場合は、1か所のみに投与される、請求項1に記載の医薬組成物。
- 医薬組成物の投与液量が以下のように決定される、請求項8または10に記載の医薬組成物:
投与対象の腫瘍体積が5cm3未満の場合1mL;
投与対象の腫瘍体積が5cm3以上9cm3未満の場合2mL;
投与対象の腫瘍体積が9cm3以上15cm3未満の場合3mL;
投与対象の腫瘍体積が15cm3以上21cm3未満の場合5mL;
投与対象の腫瘍体積が21cm3以上30cm3未満の場合7mL;かつ
投与対象の腫瘍体積が30cm3以上の場合10mL。 - サバイビン(Survivin)プロモーターによる発現制御下にE1A遺伝子を有する制限増殖型アデノウイルスであって、E3領域を欠損していない制限増殖型アデノウイルス。
- 制限増殖型アデノウイルスのE1B領域がE1BΔ55Kである、請求項1に記載の医薬組成物、または請求項13に記載の制限増殖型アデノウイルス。
- 制限増殖型アデノウイルスのE1B領域が、E1A領域とは異なるプロモーターによって制御される、請求項14に記載の医薬組成物または制限増殖型アデノウイルス。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL308585A IL308585A (en) | 2021-05-19 | 2022-05-18 | A therapeutic pharmaceutical preparation for bone and soft tissue tumors |
CA3220640A CA3220640A1 (en) | 2021-05-19 | 2022-05-18 | Therapeutic pharmaceutical composition for bone and soft tissue tumors |
EP22804703.1A EP4342480A1 (en) | 2021-05-19 | 2022-05-18 | Therapeutic pharmaceutical composition for bone and soft tissue tumors |
JP2023522687A JP7536364B2 (ja) | 2021-05-19 | 2022-05-18 | 骨軟部腫瘍の治療用医薬組成物 |
MX2023013501A MX2023013501A (es) | 2021-05-19 | 2022-05-18 | Composicion farmaceutica terapeutica para tumores oseos y de tejido blando. |
US18/560,539 US20240252561A1 (en) | 2021-05-19 | 2022-05-18 | Therapeutic pharmaceutical composition for bone and soft tissue tumors |
KR1020237043448A KR20240016988A (ko) | 2021-05-19 | 2022-05-18 | 골연부 종양의 치료용 의약 조성물 |
AU2022278285A AU2022278285A1 (en) | 2021-05-19 | 2022-05-18 | Therapeutic pharmaceutical composition for bone and soft tissue tumors |
BR112023024147A BR112023024147A2 (pt) | 2021-05-19 | 2022-05-18 | Composição farmacêutica, adenovírus de replicação condicional, e, uso do mesmo |
CN202280043672.3A CN117651561A (zh) | 2021-05-19 | 2022-05-18 | 用于治疗骨与软组织肿瘤的药物组合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021084823 | 2021-05-19 | ||
JP2021-084823 | 2021-05-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022244792A1 true WO2022244792A1 (ja) | 2022-11-24 |
Family
ID=84141371
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2022/020609 WO2022244792A1 (ja) | 2021-05-19 | 2022-05-18 | 骨軟部腫瘍の治療用医薬組成物 |
Country Status (11)
Country | Link |
---|---|
US (1) | US20240252561A1 (ja) |
EP (1) | EP4342480A1 (ja) |
JP (1) | JP7536364B2 (ja) |
KR (1) | KR20240016988A (ja) |
CN (1) | CN117651561A (ja) |
AU (1) | AU2022278285A1 (ja) |
BR (1) | BR112023024147A2 (ja) |
CA (1) | CA3220640A1 (ja) |
IL (1) | IL308585A (ja) |
MX (1) | MX2023013501A (ja) |
WO (1) | WO2022244792A1 (ja) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005012536A1 (ja) | 2003-07-31 | 2005-02-10 | Nagoya Industrial Science Research Institute | 増殖制御型組換えアデノウイルスベクターの効率的な作製方法及びその作製用キット |
WO2005115476A1 (ja) | 2004-05-25 | 2005-12-08 | Univ Kurume | サービビン(Survivin)プロモーターを含む増殖型ベクターを有効成分とする医薬 |
JP2021084823A (ja) | 2019-11-26 | 2021-06-03 | デンカ株式会社 | 粉体急結剤 |
-
2022
- 2022-05-18 WO PCT/JP2022/020609 patent/WO2022244792A1/ja active Application Filing
- 2022-05-18 JP JP2023522687A patent/JP7536364B2/ja active Active
- 2022-05-18 AU AU2022278285A patent/AU2022278285A1/en active Pending
- 2022-05-18 KR KR1020237043448A patent/KR20240016988A/ko unknown
- 2022-05-18 EP EP22804703.1A patent/EP4342480A1/en active Pending
- 2022-05-18 IL IL308585A patent/IL308585A/en unknown
- 2022-05-18 CA CA3220640A patent/CA3220640A1/en active Pending
- 2022-05-18 CN CN202280043672.3A patent/CN117651561A/zh active Pending
- 2022-05-18 BR BR112023024147A patent/BR112023024147A2/pt unknown
- 2022-05-18 US US18/560,539 patent/US20240252561A1/en active Pending
- 2022-05-18 MX MX2023013501A patent/MX2023013501A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005012536A1 (ja) | 2003-07-31 | 2005-02-10 | Nagoya Industrial Science Research Institute | 増殖制御型組換えアデノウイルスベクターの効率的な作製方法及びその作製用キット |
WO2005115476A1 (ja) | 2004-05-25 | 2005-12-08 | Univ Kurume | サービビン(Survivin)プロモーターを含む増殖型ベクターを有効成分とする医薬 |
JP2021084823A (ja) | 2019-11-26 | 2021-06-03 | デンカ株式会社 | 粉体急結剤 |
Non-Patent Citations (19)
Title |
---|
A. ITALIANO. ET AL., ANNALS OF ONCOLOGY, vol. 24, 2013, pages 2916 - 2922 |
CANCER CHEMOTHER PHARMACOL, vol. 77, no. 1, January 2016 (2016-01-01), pages 133 - 46 |
ELIZABETH FOX. ET AL., THE ONCOLOGIST, vol. 17, 2012, pages 321 |
FANNY GEORGI ET AL., FEBS LETTERS, vol. 594, 2020, pages 1861 - 1878 |
FANNY GEORGI; URS F. GREBER: "The Adenovirus Death Protein – a small membrane protein controls cell lysis and disease", FEBS LETTERS, ELSEVIER, AMSTERDAM., NL, vol. 594, no. 12, 19 June 2020 (2020-06-19), NL , pages 1861 - 1878, XP071257033, ISSN: 0014-5793, DOI: 10.1002/1873-3468.13848 * |
FARIBA NAVID ET AL., CANCER, vol. 113, no. 2, 2008, pages 419 - 425 |
FARRERA-SAL MARTÍ, DE SOSTOA JANA, NUÑEZ-MANCHÓN ESTELA, MORENO RAFAEL, FILLAT CRISTINA, BAZAN-PEREGRINO MIRIAM, ALEMANY RAMON: "Arming Oncolytic Adenoviruses: Effect of Insertion Site and Splice Acceptor on Transgene Expression and Viral Fitness", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 14, 21 July 2020 (2020-07-21), pages 5158, XP093006520, DOI: 10.3390/ijms21145158 * |
IMAI R. ET AL., INT J RADIATION ONCOL BIOL PHYS, vol. 95, no. 1, 2016, pages 322 - 327 |
JAMES R. BISCHOFF ET AL., SCIENCE, 18 October 1996 (1996-10-18), pages 373 - 376 |
KAMIZONO ET AL., CANCER RES, vol. 65, no. 12, 15 June 2005 (2005-06-15), pages 5284 - 5291 |
KAMIZONO J ET AL., CANCER RES, vol. 65, 2005, pages 5284 - 5291 |
KAMIZONO J, ET AL.: "Survivin-responsive conditionally replicating adenovirus exhibits cancer-specific and efficient viral replication.", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 65, no. 12, 15 June 2005 (2005-06-15), US, pages 5284 - 5291, XP002997036, ISSN: 0008-5472, DOI: 10.1158/0008-5472.CAN-04-2657 * |
LOIC LEBELLEC ET AL., HEMATOLOGY, vol. 95, 2015, pages 125 - 131 |
MURALI V. K., ORNELLES D. A., GOODING L. R., WILMS H. T., HUANG W., TOLLEFSON A. E., WOLD W. S. M., GARNETT-BENSON C.: "Adenovirus Death Protein (ADP) Is Required for Lytic Infection of Human Lymphocytes", JOURNAL OF VIROLOGY, THE AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 88, no. 2, 15 January 2014 (2014-01-15), US , pages 903 - 912, XP093006519, ISSN: 0022-538X, DOI: 10.1128/JVI.01675-13 * |
NAGANO S ET AL: "An efficient construction of conditionally replicating adenoviruses that target tumor cells with multiple factors", GENE THERAPY, NATURE PUBLISHING GROUP, LONDON, GB, vol. 12, no. 18, 1 September 2005 (2005-09-01), GB , pages 1385 - 1393, XP002409299, ISSN: 0969-7128, DOI: 10.1038/sj.gt.3302540 * |
NAGANO S. ET AL., GENE THER., vol. 12, no. 18, 2005, pages 1385 - 1393 |
STACCHIOTTI S. ET AL., LANCET ONCOL., vol. 16, no. 2, February 2015 (2015-02-01), pages e71 - 83 |
SUZUKI KAORI, ALEMANY RAMÓN, YAMAMOTO MASATO, CURIEL DAVID T: "The Presence of the Adenovirus E3 Region Improves the Oncolytic Potency of Conditionally Replicative Adenoviruses ", CLINICAL CANCER RESEARCH, vol. 8, 30 November 2002 (2002-11-30), pages 3348 - 3359, XP093006526 * |
THANINDRATARN PICHAYA; DEAN DYLAN C.; FENG WENLONG; WEI RAN; NELSON SCOTT D.; HORNICEK FRANCIS J.; DUAN ZHENFENG: "Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value", EUROPEAN SPINE JOURNAL, SPRINGER BERLIN HEIDELBERG, BERLIN/HEIDELBERG, vol. 29, no. 12, 1 January 1900 (1900-01-01), Berlin/Heidelberg, pages 3214 - 3228, XP037312988, ISSN: 0940-6719, DOI: 10.1007/s00586-020-06543-z * |
Also Published As
Publication number | Publication date |
---|---|
JPWO2022244792A1 (ja) | 2022-11-24 |
IL308585A (en) | 2024-01-01 |
BR112023024147A2 (pt) | 2024-01-30 |
CN117651561A (zh) | 2024-03-05 |
CA3220640A1 (en) | 2022-11-24 |
MX2023013501A (es) | 2023-12-12 |
AU2022278285A1 (en) | 2023-11-30 |
US20240252561A1 (en) | 2024-08-01 |
KR20240016988A (ko) | 2024-02-06 |
EP4342480A1 (en) | 2024-03-27 |
JP7536364B2 (ja) | 2024-08-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20060257369A1 (en) | Therapeutic regimen for treating cancer | |
US10874716B2 (en) | Methods and compositions for treatment of bone, skin, subcutaneous, mucosal and/or submucosal cancer by percutaneous and/or transmucosal administration of interferon | |
US20070166284A1 (en) | Therapeutic regimen for treating cancer | |
JP2004505009A (ja) | 新生物を処置するための組合せ | |
WO2008034346A1 (fr) | Composition et méthode de traitement de tumeurs | |
EP3436073B1 (en) | A composition comprising pic for treatment of cancer | |
WO2022244792A1 (ja) | 骨軟部腫瘍の治療用医薬組成物 | |
KR20180052761A (ko) | T-dm1 불응성 암 환자의 syd985 치료 | |
JP2022512903A (ja) | Ad-REIC/Dkk-3とチェックポイント阻害剤とを用いた胸部がんの治療のための併用療法 | |
Nakamura et al. | Amiodarone-induced hyponatremia masked by tolvaptan in a patient with an implantable left ventricular assist device | |
Williams et al. | Targeting multiple angiogenic pathways for the treatment of neuroblastoma | |
Hanssen et al. | Extended Experience with Recombinant a-2b Interferon with OR Without Hepatic Artery Embolization in the Treatment OF Midgut Carcinoid Tumours A preliminary report | |
Niwas et al. | Revisiting bronchoscopic intratumoral chemotherapy in malignant central airway obstruction via EUS-B approach and its review of literature | |
Poedjomartono et al. | Transcatheter Arterial Chemo Infusion (TACI) for Squamous Cell Carcinoma of the Tongue: A Case Report | |
TW200908997A (en) | Treatment of cellular proliferative disorders | |
Panke et al. | S80 Tuesday, October 26, 2004 Proffered papers | |
Jiang et al. | Application of Immunoenhancing Radiotherapy in Treating Unresectable Intrahepatic Cholangiocarcinoma: A Case Report | |
CN116637181A (zh) | 溶瘤病毒和抗pd-1单抗在协同抑制黑色素瘤中的应用 | |
CN113521087A (zh) | 特女贞苷在制备治疗慢性肾功能不全或肾性骨病的药物中的用途 | |
Hanssen et al. | EXTENDED EXPERIENCE WITH RECOMBINANT a-2b INTERFERON WITH OR WITHOUT HEPATIC ARTERY EMBOLIZATION IN THE TREATMENT OF MIDGUT CARCINOID TUMOURS | |
WO2019104429A1 (en) | Methods for regulating endogenous production of checkpoint molecule antagonists | |
JP2008528522A (ja) | 腫瘍患者の治療における組み換えアデノウイルスp53薬剤の新規な使用 | |
AU2002342263A1 (en) | Treatment of human cancer with adenoviral vector expressing TNF-alpha |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22804703 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023522687 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 18560539 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2023/013501 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022278285 Country of ref document: AU Ref document number: 308585 Country of ref document: IL Ref document number: AU2022278285 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 3220640 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2301007522 Country of ref document: TH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3220640 Country of ref document: CA |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112023024147 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2022278285 Country of ref document: AU Date of ref document: 20220518 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202347084676 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 20237043448 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12023553417 Country of ref document: PH Ref document number: 1020237043448 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202280043672.3 Country of ref document: CN Ref document number: 2023133582 Country of ref document: RU Ref document number: 2022804703 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022804703 Country of ref document: EP Effective date: 20231219 |
|
ENP | Entry into the national phase |
Ref document number: 112023024147 Country of ref document: BR Kind code of ref document: A2 Effective date: 20231117 |