CN111315885A - 增强肿瘤免疫原性的方法和组合物 - Google Patents
增强肿瘤免疫原性的方法和组合物 Download PDFInfo
- Publication number
- CN111315885A CN111315885A CN201880072494.0A CN201880072494A CN111315885A CN 111315885 A CN111315885 A CN 111315885A CN 201880072494 A CN201880072494 A CN 201880072494A CN 111315885 A CN111315885 A CN 111315885A
- Authority
- CN
- China
- Prior art keywords
- complement
- cfh
- cfhr3
- cfhr1
- cathepsin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 105
- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 230000002708 enhancing effect Effects 0.000 title claims abstract description 8
- 230000005851 tumor immunogenicity Effects 0.000 title description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 122
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 96
- 230000014509 gene expression Effects 0.000 claims abstract description 81
- 102000000989 Complement System Proteins Human genes 0.000 claims abstract description 27
- 108010069112 Complement System Proteins Proteins 0.000 claims abstract description 27
- 230000005847 immunogenicity Effects 0.000 claims abstract description 9
- 230000000295 complement effect Effects 0.000 claims description 183
- 239000003795 chemical substances by application Substances 0.000 claims description 116
- 108090000623 proteins and genes Proteins 0.000 claims description 100
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 72
- 102100025680 Complement decay-accelerating factor Human genes 0.000 claims description 63
- 102100035432 Complement factor H Human genes 0.000 claims description 63
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 claims description 63
- 241000282414 Homo sapiens Species 0.000 claims description 62
- 101000737574 Homo sapiens Complement factor H Proteins 0.000 claims description 62
- 102100035321 Complement factor H-related protein 3 Human genes 0.000 claims description 59
- 101000878136 Homo sapiens Complement factor H-related protein 3 Proteins 0.000 claims description 59
- 102000006834 complement receptors Human genes 0.000 claims description 59
- 108010047295 complement receptors Proteins 0.000 claims description 58
- 102100035436 Complement factor D Human genes 0.000 claims description 57
- 102100040132 Complement factor H-related protein 1 Human genes 0.000 claims description 57
- 102100035326 Complement factor H-related protein 2 Human genes 0.000 claims description 57
- 102100035324 Complement factor H-related protein 4 Human genes 0.000 claims description 57
- 102100035431 Complement factor I Human genes 0.000 claims description 57
- 101000890732 Homo sapiens Complement factor H-related protein 1 Proteins 0.000 claims description 57
- 101000878135 Homo sapiens Complement factor H-related protein 2 Proteins 0.000 claims description 57
- 101000878133 Homo sapiens Complement factor H-related protein 4 Proteins 0.000 claims description 57
- 101000741544 Homo sapiens Properdin Proteins 0.000 claims description 57
- 102100038567 Properdin Human genes 0.000 claims description 57
- 102100021633 Cathepsin B Human genes 0.000 claims description 56
- 102000005600 Cathepsins Human genes 0.000 claims description 56
- 108010084457 Cathepsins Proteins 0.000 claims description 56
- 102100034622 Complement factor B Human genes 0.000 claims description 56
- 102100035325 Complement factor H-related protein 5 Human genes 0.000 claims description 56
- 101000710032 Homo sapiens Complement factor B Proteins 0.000 claims description 56
- 101000737554 Homo sapiens Complement factor D Proteins 0.000 claims description 56
- 101000878134 Homo sapiens Complement factor H-related protein 5 Proteins 0.000 claims description 56
- 108010059385 chemotactic factor inactivator Proteins 0.000 claims description 56
- 102100032219 Cathepsin D Human genes 0.000 claims description 55
- 102100035654 Cathepsin S Human genes 0.000 claims description 55
- 102100030149 Complement C1r subcomponent Human genes 0.000 claims description 55
- 102100037078 Complement component 1 Q subcomponent-binding protein, mitochondrial Human genes 0.000 claims description 55
- 102100032768 Complement receptor type 2 Human genes 0.000 claims description 55
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 claims description 55
- 101000898449 Homo sapiens Cathepsin B Proteins 0.000 claims description 55
- 101000869010 Homo sapiens Cathepsin D Proteins 0.000 claims description 55
- 101000793922 Homo sapiens Dipeptidyl peptidase 1 Proteins 0.000 claims description 55
- 101000961414 Homo sapiens Membrane cofactor protein Proteins 0.000 claims description 55
- 102100039373 Membrane cofactor protein Human genes 0.000 claims description 55
- 238000004519 manufacturing process Methods 0.000 claims description 55
- 101150060120 C1qbp gene Proteins 0.000 claims description 54
- 102100030152 Complement C1r subcomponent-like protein Human genes 0.000 claims description 54
- 101000794267 Homo sapiens Complement C1r subcomponent-like protein Proteins 0.000 claims description 54
- 201000011510 cancer Diseases 0.000 claims description 54
- 210000004027 cell Anatomy 0.000 claims description 54
- 230000000694 effects Effects 0.000 claims description 47
- 230000003308 immunostimulating effect Effects 0.000 claims description 39
- 238000010362 genome editing Methods 0.000 claims description 36
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 36
- 102000004169 proteins and genes Human genes 0.000 claims description 33
- 239000013598 vector Substances 0.000 claims description 33
- 150000007523 nucleic acids Chemical group 0.000 claims description 23
- 239000013603 viral vector Substances 0.000 claims description 23
- 108020004707 nucleic acids Proteins 0.000 claims description 16
- 102000039446 nucleic acids Human genes 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 14
- 102000005962 receptors Human genes 0.000 claims description 12
- 108020003175 receptors Proteins 0.000 claims description 12
- 108091027967 Small hairpin RNA Proteins 0.000 claims description 11
- 230000009368 gene silencing by RNA Effects 0.000 claims description 10
- 102100022002 CD59 glycoprotein Human genes 0.000 claims description 9
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 230000004614 tumor growth Effects 0.000 claims description 9
- 241000702421 Dependoparvovirus Species 0.000 claims description 8
- 108091030071 RNAI Proteins 0.000 claims description 8
- 238000013518 transcription Methods 0.000 claims description 8
- 230000035897 transcription Effects 0.000 claims description 8
- 108020005544 Antisense RNA Proteins 0.000 claims description 7
- 206010027476 Metastases Diseases 0.000 claims description 7
- 238000010459 TALEN Methods 0.000 claims description 7
- 239000003184 complementary RNA Substances 0.000 claims description 7
- 108020001507 fusion proteins Proteins 0.000 claims description 7
- 102000037865 fusion proteins Human genes 0.000 claims description 7
- 230000009401 metastasis Effects 0.000 claims description 7
- 108091070501 miRNA Proteins 0.000 claims description 7
- 239000002679 microRNA Substances 0.000 claims description 7
- 241000700618 Vaccinia virus Species 0.000 claims description 6
- 239000013604 expression vector Substances 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000004055 small Interfering RNA Substances 0.000 claims description 6
- 241000701161 unidentified adenovirus Species 0.000 claims description 6
- 241001529453 unidentified herpesvirus Species 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 claims description 5
- 210000001808 exosome Anatomy 0.000 claims description 5
- 239000002502 liposome Substances 0.000 claims description 5
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 4
- 230000006801 homologous recombination Effects 0.000 claims description 4
- 238000002744 homologous recombination Methods 0.000 claims description 4
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 4
- 102100032957 C5a anaphylatoxin chemotactic receptor 1 Human genes 0.000 claims description 3
- 101710098483 C5a anaphylatoxin chemotactic receptor 1 Proteins 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 2
- 239000002105 nanoparticle Substances 0.000 claims description 2
- 239000003207 proteasome inhibitor Substances 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 claims description 2
- 238000009169 immunotherapy Methods 0.000 claims 1
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 12
- 206010062016 Immunosuppression Diseases 0.000 abstract description 4
- 235000018102 proteins Nutrition 0.000 description 24
- 101100275686 Homo sapiens CR2 gene Proteins 0.000 description 18
- 101100275687 Mus musculus Cr2 gene Proteins 0.000 description 18
- 101000794279 Homo sapiens Complement C1r subcomponent Proteins 0.000 description 17
- 230000003211 malignant effect Effects 0.000 description 17
- 230000028993 immune response Effects 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- -1 meturedpa Chemical compound 0.000 description 14
- 230000027455 binding Effects 0.000 description 13
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 12
- 108091028043 Nucleic acid sequence Proteins 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 102100022133 Complement C3 Human genes 0.000 description 11
- 102000035195 Peptidases Human genes 0.000 description 11
- 108091005804 Peptidases Proteins 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 11
- 108010078015 Complement C3b Proteins 0.000 description 10
- 108010052926 complement C3d,g Proteins 0.000 description 10
- 150000001413 amino acids Chemical group 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 201000009030 Carcinoma Diseases 0.000 description 8
- 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
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 8
- 239000013612 plasmid Substances 0.000 description 8
- 230000002797 proteolythic effect Effects 0.000 description 8
- 101150071258 C3 gene Proteins 0.000 description 7
- 230000004927 fusion Effects 0.000 description 7
- 230000014616 translation Effects 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- 108020005004 Guide RNA Proteins 0.000 description 6
- 239000004365 Protease Substances 0.000 description 6
- 208000009956 adenocarcinoma Diseases 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000007857 degradation product Substances 0.000 description 6
- 210000000987 immune system Anatomy 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 201000001441 melanoma Diseases 0.000 description 6
- 239000002773 nucleotide Substances 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 241000283690 Bos taurus Species 0.000 description 5
- 102000016574 Complement C3-C5 Convertases Human genes 0.000 description 5
- 108010067641 Complement C3-C5 Convertases Proteins 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 206010039491 Sarcoma Diseases 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 102000040430 polynucleotide Human genes 0.000 description 5
- 108091033319 polynucleotide Proteins 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 238000013519 translation Methods 0.000 description 5
- 108700028369 Alleles Proteins 0.000 description 4
- 102000005590 Anaphylatoxin C5a Receptor Human genes 0.000 description 4
- 108010059426 Anaphylatoxin C5a Receptor Proteins 0.000 description 4
- 108010092160 Dactinomycin Proteins 0.000 description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 4
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 4
- 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 4
- 102000005741 Metalloproteases Human genes 0.000 description 4
- 108010006035 Metalloproteases Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 241000282887 Suidae Species 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 230000000340 anti-metabolite Effects 0.000 description 4
- 229940100197 antimetabolite Drugs 0.000 description 4
- 239000002256 antimetabolite Substances 0.000 description 4
- 229940034982 antineoplastic agent Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 230000024203 complement activation Effects 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229940126864 fibroblast growth factor Drugs 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 238000011275 oncology therapy Methods 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000001177 retroviral effect Effects 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010003571 Astrocytoma Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 201000000274 Carcinosarcoma Diseases 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 description 3
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 3
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- 241000192656 Nostoc Species 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 229930183665 actinomycin Natural products 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 229930195731 calicheamicin Natural products 0.000 description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 3
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 3
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 3
- 229950001725 carubicin Drugs 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 238000003197 gene knockdown Methods 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 230000002611 ovarian Effects 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000003362 replicative effect Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 2
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 2
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 241000283725 Bos Species 0.000 description 2
- 241000219198 Brassica Species 0.000 description 2
- 235000003351 Brassica cretica Nutrition 0.000 description 2
- 235000003343 Brassica rupestris Nutrition 0.000 description 2
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 2
- 101150073986 C3AR1 gene Proteins 0.000 description 2
- 108091033409 CRISPR Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 208000005243 Chondrosarcoma Diseases 0.000 description 2
- 108010078044 Complement C1r Proteins 0.000 description 2
- 108010028780 Complement C3 Proteins 0.000 description 2
- 102100030886 Complement receptor type 1 Human genes 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 2
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 2
- 108010013198 Daptomycin Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- 208000005234 Granulosa Cell Tumor Diseases 0.000 description 2
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 2
- 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 102000043129 MHC class I family Human genes 0.000 description 2
- 108091054437 MHC class I family Proteins 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 208000010357 Mullerian Mixed Tumor Diseases 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 2
- 201000010133 Oligodendroglioma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 2
- 108010009736 Protein Hydrolysates Proteins 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 101710142969 Somatoliberin Proteins 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 102000019197 Superoxide Dismutase Human genes 0.000 description 2
- 108010012715 Superoxide dismutase Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 2
- 229950004955 adozelesin Drugs 0.000 description 2
- 230000003305 autocrine Effects 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 2
- 229950006844 bizelesin Drugs 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 2
- 229960005484 daptomycin Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 108091006104 gene-regulatory proteins Proteins 0.000 description 2
- 102000034356 gene-regulatory proteins Human genes 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 229960001438 immunostimulant agent Drugs 0.000 description 2
- 239000003022 immunostimulating agent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 235000010460 mustard Nutrition 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 208000029974 neurofibrosarcoma Diseases 0.000 description 2
- 229950009266 nogalamycin Drugs 0.000 description 2
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 208000007312 paraganglioma Diseases 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229960004694 prednimustine Drugs 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000003531 protein hydrolysate Substances 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000000153 supplemental effect Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 1
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- OQWKEEOHDMUXEO-UHFFFAOYSA-N (6)-shogaol Natural products CCCCCC=CC(=O)CCC1=CC=C(O)C(OC)=C1 OQWKEEOHDMUXEO-UHFFFAOYSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- OZDGMOYKSFPLSE-UHFFFAOYSA-N 2-Methylaziridine Chemical compound CC1CN1 OZDGMOYKSFPLSE-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- 101710131943 40S ribosomal protein S3a Proteins 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 239000013607 AAV vector Substances 0.000 description 1
- 208000016557 Acute basophilic leukemia Diseases 0.000 description 1
- 208000004804 Adenomatous Polyps Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102100022987 Angiogenin Human genes 0.000 description 1
- 208000031873 Animal Disease Models Diseases 0.000 description 1
- XFOUAXMJRHNTOP-UHFFFAOYSA-N Bacilysin Natural products CC(N)C(=O)NC(C(O)=O)CC1CCC(=O)C2OC12 XFOUAXMJRHNTOP-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 208000007690 Brenner tumor Diseases 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- KHCHRGKQDGMNEI-AXIMARPXSA-N C(CC)(=O)O.CC1[C@@H]2[C@](CC1)(C)CC[C@H]1[C@H]2CC[C@H]2C(CCC[C@]12C)=O Chemical compound C(CC)(=O)O.CC1[C@@H]2[C@](CC1)(C)CC[C@H]1[C@H]2CC[C@H]2C(CCC[C@]12C)=O KHCHRGKQDGMNEI-AXIMARPXSA-N 0.000 description 1
- 102100032996 C5a anaphylatoxin chemotactic receptor 2 Human genes 0.000 description 1
- 238000010356 CRISPR-Cas9 genome editing Methods 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 101100434927 Caenorhabditis elegans prmt-5 gene Proteins 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000003902 Cathepsin C Human genes 0.000 description 1
- 108090000267 Cathepsin C Proteins 0.000 description 1
- 102000003908 Cathepsin D Human genes 0.000 description 1
- 108090000258 Cathepsin D Proteins 0.000 description 1
- 102100024940 Cathepsin K Human genes 0.000 description 1
- 108090000624 Cathepsin L Proteins 0.000 description 1
- 101710177066 Cathepsin O Proteins 0.000 description 1
- 108090000613 Cathepsin S Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 206010008583 Chloroma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108010023729 Complement 3d Receptors Proteins 0.000 description 1
- 102000011412 Complement 3d Receptors Human genes 0.000 description 1
- 108010028773 Complement C5 Proteins 0.000 description 1
- 102100031506 Complement C5 Human genes 0.000 description 1
- 108010053085 Complement Factor H Proteins 0.000 description 1
- 108090000044 Complement Factor I Proteins 0.000 description 1
- 102000003712 Complement factor B Human genes 0.000 description 1
- 108090000056 Complement factor B Proteins 0.000 description 1
- 108090000059 Complement factor D Proteins 0.000 description 1
- 241000222511 Coprinus Species 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- UYUXSRADSPPKRZ-SKNVOMKLSA-N D-glucurono-6,3-lactone Chemical compound O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O UYUXSRADSPPKRZ-SKNVOMKLSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- 102100035102 E3 ubiquitin-protein ligase MYCBP2 Human genes 0.000 description 1
- 208000005431 Endometrioid Carcinoma Diseases 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000283070 Equus zebra Species 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 description 1
- 108010043685 GPI-Linked Proteins Proteins 0.000 description 1
- 102000002702 GPI-Linked Proteins Human genes 0.000 description 1
- 208000002966 Giant Cell Tumor of Bone Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 102000001398 Granzyme Human genes 0.000 description 1
- 108060005986 Granzyme Proteins 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 208000002125 Hemangioendothelioma Diseases 0.000 description 1
- 208000002291 Histiocytic Sarcoma Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000868001 Homo sapiens C5a anaphylatoxin chemotactic receptor 2 Proteins 0.000 description 1
- 101000941598 Homo sapiens Complement C5 Proteins 0.000 description 1
- 101000727061 Homo sapiens Complement receptor type 1 Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 241000282596 Hylobatidae Species 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 241000283986 Lepus Species 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 208000000265 Lobular Carcinoma Diseases 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 208000007369 Malignant Mixed Tumor Diseases 0.000 description 1
- 206010072448 Malignant blue naevus Diseases 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 229920000877 Melamine resin Polymers 0.000 description 1
- 206010027145 Melanocytic naevus Diseases 0.000 description 1
- 206010027193 Meningioma malignant Diseases 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 201000009574 Mesenchymal Chondrosarcoma Diseases 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 208000007871 Odontogenic Tumors Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 108700022034 Opsonin Proteins Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 108010056995 Perforin Proteins 0.000 description 1
- 102000004503 Perforin Human genes 0.000 description 1
- 208000009077 Pigmented Nevus Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000139306 Platt Species 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- 241000282405 Pongo abelii Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100026534 Procathepsin L Human genes 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 108091030066 RNAIII Proteins 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- NSFWWJIQIKBZMJ-YKNYLIOZSA-N Roridin A Chemical compound C([C@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-YKNYLIOZSA-N 0.000 description 1
- 240000004274 Sarcandra glabra Species 0.000 description 1
- 235000010842 Sarcandra glabra Nutrition 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 229930192786 Sisomicin Natural products 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 201000009365 Thymic carcinoma Diseases 0.000 description 1
- 108010046075 Thymosin Proteins 0.000 description 1
- 102000007501 Thymosin Human genes 0.000 description 1
- 102400000800 Thymosin alpha-1 Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 108020004417 Untranslated RNA Proteins 0.000 description 1
- 102000039634 Untranslated RNA Human genes 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- OQWKEEOHDMUXEO-BQYQJAHWSA-N [6]-Shogaol Chemical compound CCCCC\C=C\C(=O)CCC1=CC=C(O)C(OC)=C1 OQWKEEOHDMUXEO-BQYQJAHWSA-N 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 201000000452 adenoid squamous cell carcinoma Diseases 0.000 description 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 206010065867 alveolar rhabdomyosarcoma Diseases 0.000 description 1
- 230000002707 ameloblastic effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 108010072788 angiogenin Proteins 0.000 description 1
- 238000011558 animal model by disease Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940045713 antineoplastic alkylating drug ethylene imines Drugs 0.000 description 1
- 239000003101 antineoplastic hormone agonist and antagonist Substances 0.000 description 1
- 201000007436 apocrine adenocarcinoma Diseases 0.000 description 1
- 208000019493 atypical carcinoid tumor Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- XFOUAXMJRHNTOP-PFQXTLEHSA-N bacilysin Chemical compound C[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)C[C@@H]1CCC(=O)[C@@H]2O[C@H]12 XFOUAXMJRHNTOP-PFQXTLEHSA-N 0.000 description 1
- 108700023668 bacilysin Proteins 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 201000007551 basophilic adenocarcinoma Diseases 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000007622 bioinformatic analysis Methods 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000011143 bone giant cell tumor Diseases 0.000 description 1
- 201000003714 breast lobular carcinoma Diseases 0.000 description 1
- 108010049223 bryodin Proteins 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000002939 cerumen Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 208000011588 combined hepatocellular carcinoma and cholangiocarcinoma Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 210000001840 diploid cell Anatomy 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 208000028730 endometrioid adenocarcinoma Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010213 eniluracil Drugs 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin 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[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 201000008825 fibrosarcoma of bone Diseases 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229960002687 ganciclovir sodium Drugs 0.000 description 1
- 230000000574 ganglionic effect Effects 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229950002441 glucurolactone Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 208000030316 grade III meningioma Diseases 0.000 description 1
- 201000007574 granular cell carcinoma Diseases 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 201000006812 malignant histiocytosis Diseases 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 208000021810 malignant mixed neoplasm Diseases 0.000 description 1
- 208000028676 malignant spindle cell neoplasm Diseases 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 201000008749 mast-cell sarcoma Diseases 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 150000007974 melamines Chemical class 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 208000010569 mesonephric adenocarcinoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 229960005189 methadone hydrochloride Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 201000005987 myeloid sarcoma Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- BRZOTEHEMOQUOY-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NP(=O)(N1CC1)N1CC1 BRZOTEHEMOQUOY-UHFFFAOYSA-N 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 olivomycin Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229940045681 other alkylating agent in atc Drugs 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 201000010210 papillary cystadenocarcinoma Diseases 0.000 description 1
- 208000024641 papillary serous cystadenocarcinoma Diseases 0.000 description 1
- 201000001494 papillary transitional carcinoma Diseases 0.000 description 1
- 208000031101 papillary transitional cell carcinoma Diseases 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920001197 polyacetylene Polymers 0.000 description 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 208000013368 pseudoglandular squamous cell carcinoma Diseases 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 229960001520 ranitidine hydrochloride Drugs 0.000 description 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- IMUQLZLGWJSVMV-UOBFQKKOSA-N roridin A Natural products CC(O)C1OCCC(C)C(O)C(=O)OCC2CC(=CC3OC4CC(OC(=O)C=C/C=C/1)C(C)(C23)C45CO5)C IMUQLZLGWJSVMV-UOBFQKKOSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000018964 sebaceous gland cancer Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 229960005456 sisomicin Drugs 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008866 synergistic binding Effects 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 208000015191 thyroid gland papillary and follicular carcinoma Diseases 0.000 description 1
- 208000013076 thyroid tumor Diseases 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 208000029335 trabecular adenocarcinoma Diseases 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 150000003327 trichothecene derivatives Chemical class 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000007502 viral entry Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Images
Classifications
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/472—Complement proteins, e.g. anaphylatoxin, C3a, C5a
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- A61K38/1725—Complement proteins, e.g. anaphylatoxin, C3a or C5a
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
- C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPRs]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Marine Sciences & Fisheries (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Mycology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本文描述了通过调节/改变与肿瘤/肿瘤细胞的免疫抑制有关的特异性补体蛋白和补体蛋白受体的表达来增强目的肿瘤的免疫原性的方法和组合物。
Description
相关应用
根据35U.S.C.§119(e),本申请要求以下美国临时申请号的权益:2017年9月11日提交的62/556,836、2017年11月7日提交的62/582,365和2018年4月12日提交的62/656,495,其全部内容通过引用整体并入本文。
通过引用将材料并入ASCII文本文件中
本申请包含序列表,该序列表已经以ASCII格式电子提交,并且通过引用整体并入本文。所述ASCII副本创建于2018年9月10日,命名为0371_0001WO1_SL.txt,大小为22,560字节。
背景技术
癌性肿瘤会形成隐形的屏障,以保护自身免受身体免疫驱动的防御机制。已经开发出各种方法来增强对这种肿瘤的免疫应答,包括接种细菌感染、病毒、由肿瘤细胞制备的疫苗、免疫刺激剂或佐剂、增强免疫应答的免疫调节剂和抑制免疫应答的代谢酶抑制剂。这些方法的基本原理是,一旦不再隐藏肿瘤并接合免疫系统,肿瘤细胞将像其他病原体一样容易被身体的免疫应答消除。然而,尽管取得了进展,但仍需要特异性靶向肿瘤细胞并增强肿瘤免疫原性的免疫调节方法,以作为有效抑制肿瘤生长和转移并提供治疗或预防癌症的新选择的手段。
发明内容
本发明包括用于调节肿瘤细胞中补体蛋白产生和/或表达以抑制补体驱动的肿瘤细胞生长和转移的方法和组合物。本发明进一步包括激活或增强针对肿瘤细胞的免疫应答的方法。如本文所述,本发明的方法使全部或部分肿瘤脱离隐形模式,将被治疗的肿瘤从具有有限免疫应答和低水平溶细胞酶如颗粒酶B和穿孔素1的“冷”模式转变为“热”模式,其中所述“热”模式中肿瘤诱导使肿瘤的所有部分都容易受到身体免疫系统的攻击的应答。
已经研究了与补体激活途径相关的补体蛋白、补体蛋白受体和蛋白水解酶在癌症以及肿瘤生长和转移中的作用。特别地,补体蛋白C3,C5(及其降解/蛋白水解片段,例如iC3b)以及补体细胞表面受体C3aR和C5aR是与肿瘤的免疫抑制相关的分子。补体蛋白C3d或C3dg是C3蛋白的分解产物,并与肿瘤的免疫刺激活性有关,即,使肿瘤对免疫应答更敏感。因此,如本发明所提供的,降低补体蛋白C3、C3a、C5和C5a的表达或活性以防止产生免疫抑制性分解降解(break down degradation)产物如iC3b,同时在肿瘤细胞表面或局部肿瘤微环境中提高免疫刺激性降解产物如C3d或C3dg或其他免疫刺激性肽的表达(或过表达)、产生或提高其活性,为大大增强肿瘤的免疫原性提供了基础。
肿瘤表面附近或表面上的C3免疫抑制性降解产物的产生也可以使用由肿瘤或从诸如CFH的组分合成的途径组分进行扩增,所述组分从微环境中捕获C3并将其再循环到肿瘤中的肿瘤表面处理(Martin,Leffler等人,2016;Elvington,Liszewski等人,2017)。C3降解可能通过细胞外部的蛋白酶发生,也可能使用内部蛋白酶,例如属于组织蛋白酶家族的蛋白酶(Liszewski,Kolev等人,2013;Martin,Leffler等人,2016;Elvington,Liszewski等人,2017)。在任一种情况下,肿瘤细胞分泌的C3b可通过肿瘤外部的途径进一步扩增,以增加抑制性C3降解产物在肿瘤表面上的沉积。CFH与C3b的结合还通过阻断对产生C3d所必需的C3b上蛋白水解位点的接近来抑制免疫刺激性产物(如C3d)的产生(Xue等人,2017,图1)。
本文描述了通过调节与肿瘤细胞的免疫抑制有关的特异性补体蛋白和/或补体因子和/或补体蛋白受体和/或补体相关蛋白水解酶的产生或改变其表达来增强目的肿瘤或癌症或肿瘤细胞的免疫原性的方法。本文所述的特定靶标可以是补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
特别地,目的肿瘤包括表达补体成分(例如补体蛋白C3或C5)的肿瘤细胞。或者,肿瘤细胞也可以表达补体受体,例如补体蛋白受体C3aR1或C5aR1。可以出于本发明的目的而被调节的其他补体受体或与补体相关的受体包括例如C5aR2、C1R、C1RL、CR2、C1QBP、CD46、CD55、CD59和LAIR1,以及例如补体因子诸如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP。也可以调节由肿瘤细胞产生的某些蛋白水解酶,例如组织蛋白酶(例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合)。参见例如Chauhan,S.等人,CancerRes.51.1478-1481(1991年3月1日)。
目的肿瘤或癌细胞可以表达上述补体蛋白、补体受体、补体因子、补体调节剂或组织蛋白酶中的一种或任意组合。因此,补体成分C3、C5或它们各自的蛋白水解降解产物或它们各自的细胞表面受体中的任一个均适用于本文所述的方法。
如本文所述,增强目的肿瘤的免疫原性的一个方面涉及使用作为治疗剂施用的组合药剂降低或抑制(部分或完全消除)补体蛋白C3、C5的表达或活性,或补体受体或补体调节蛋白的表达或信号传导活性,例如补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,它们会导致C3的免疫抑制性降解产物,同时还通过肿瘤细胞或肿瘤微环境中的其他细胞来增加免疫刺激性补体降解产物C3d或C3dg或其他免疫刺激性肽的表达/产生或活性。蛋白质产生、活性或表达的这种调节可以基本上同时或顺序地进行。
本文所述的方法包括使肿瘤细胞与第一药剂接触的步骤,其中所述第一药剂降低以下各项在肿瘤细胞中的表达或产生,例如补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,以及使肿瘤细胞与第二药剂接触的步骤,其中第二药剂增加补体蛋白C3d在肿瘤细胞中的表达、活性或产生或其他免疫刺激性肽的表达、活性或产生。使肿瘤细胞与第一药剂接触可以在使肿瘤细胞与第二药剂接触之前,基本上同时或之后发生。
在一个实施方案中,第一药剂包括降低或抑制以下各项在肿瘤细胞内的表达的基因编辑剂:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。基因编辑剂可以包含CRISPR(成簇的规律间隔的短回文重复序列)系统构建体,其降低或抑制以下一项或更多项在肿瘤细胞内的表达:补体成分例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。或者,基因编辑剂可包含TALEN(转录激活因子样效应物核酸酶)构建体,所述构建体降低或抑制以下各项在肿瘤细胞内的表达:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,大范围核酸酶,同源重组或碱基编辑。如本文所述,可以构建基因编辑剂,以降低或抑制以下各项的表达:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,但不降低或抑制C3d或其他免疫刺激性肽在肿瘤细胞中的表达、活性或产生。
在本发明的另一个实施方案中,第一药剂是包含RNAi、shRNA、miRNA或反义RNA的核酸构建体,其降低或抑制以下一项或更多项在肿瘤细胞内的表达:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。在又一个实施方案中,第一药剂是核酸构建体,其表达降低或抑制以下一项或更多项在肿瘤细胞中的转录的蛋白质:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。可以使用已知的递送媒介物将该药剂靶向递送至肿瘤细胞,包括但不限于病毒载体、纳米颗粒、脂质体或外来体。如果通过病毒载体递送构建体,则病毒载体可包含用于将构建体靶向和递送至肿瘤细胞的任何合适的复制或非复制病毒载体,并且可以是例如腺病毒、腺相关病毒、慢病毒载体、牛痘病毒、疱疹病毒载体、副粘病毒(paromxyovirus)或任何病毒载体或任何病毒样颗粒。
本发明的另一个实施方案是通过经典的,替代性的或凝集素途径或通过能够产生C3转化酶复合物的其他蛋白水解酶产生的C3转化酶复合物的抑制剂的用途。抑制C3转化酶复合物抑制了C3酶分解为C3a和C3b。转化酶抑制剂可包含例如可溶性补体受体1,在本文中称为sCR1(“Soluble human complement receptor type 1:in vivo inhibitor ofcomplement suppressing post-ischemic myocardial inflammation and necrosis”Weisman等人Science 1990 Jul 13:249(4965):146-51;sCR1的核酸序列参见图6)。另一种C3转化酶转化复合物抑制剂可以包含补体激活阻断剂2(CAB-2;“A soluble chimericcomplement inhibitory protein that possesses both decay-accelerating andfactor I cofactor activities”Higgins等人,J Immunol.1997Mar 15;158(6):2872-81和“Modulation and repletion/enhancement of the complement system fortreatment of trauma”US 20110190221 A1)。另外的C3转化酶复合物抑制剂可以包含由已知补体受体的组合制成的融合蛋白。参见,例如“Design and development of TT30,anovel C3d-targeted C3/C5 convertase inhibitor for treatment of humancomplement alternative pathway-mediated diseases”,Fridkis-Harel等人,Blood,27October 2011,vol.118,number 17;“Regional Engineering of a Minimized Inhibitorwith Unique Triple-Targeting Properties”,Schmidt,等人,J.Immonol.,2013,190:5712-5721(描述了补体调节因子H“mini-FH”构建体)和“Polypeptides for Inhibitingcomplement Activation”WO 2017/109208。该方法特别涉及将这些抑制剂编码为核酸,然后使用本领域技术人员已知的技术在肿瘤微环境中表达所述核酸,例如重组腺病毒、腺相关病毒、慢病毒载体、牛痘病毒、疱疹病毒载体、副粘病毒或任何病毒载体或任何病毒样颗粒,或使用质粒或微环(mini-circles)。设计载体以不影响C3d或其他免疫刺激性肽在肿瘤细胞或其微环境中的表达、产生或活性但降低C3的免疫抑制性分解产物的产生。
可选地,如本文所述,补体因子(CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFI、CFP)也是本文所述疗法的合适靶标。其中降低一种或更多种这些因子的表达或抑制其活性,可通过增加免疫刺激性产物(如C3d)的产生来增强肿瘤的免疫原性(图1)。C3和CFH的产生在侵袭性癌症模型中均失调(上调)(参见,例如JnBaptiste,Gurtan等人(2017),其中补充表S6说明这些基因是预测生存不良的部分特征)。结合C3d的序列在补体因子例如CFH和CFHR3之间是保守的。CFHR3可以抑制B细胞的刺激(Fritsche,Lauer等人,2010)。CFH和CFHR3之间的保守性处于核苷酸水平,这允许利用单个gRNA对两个转录物的翻译进行RNA干扰。这种RNAi序列的实例是AUGUUCAUCACAGUAAUAGGAG(SEQ ID NO:1)和AGUAUGGUCUACGCAUAUUCUC(SEQ ID NO:2)。还可以使用针对这些保守序列的向导,使用基因编辑方法同时敲除这两种成分的基因。这两种蛋白质的丢失将增加肿瘤细胞的免疫原性,因为C3d的产生和活性将不再被肿瘤抑制。
本发明的方法进一步包括在与第一药剂接触之前、同时、基本同时或之后,使肿瘤或癌细胞与第二药剂接触。第二药剂增加、启动或刺激与肿瘤的免疫刺激或增加的免疫监视有关的补体成分或其他免疫刺激性肽的产生或表达。特别地,第二药剂包含靶向肿瘤细胞的表达载体,其中该载体包含核酸构建体,在包括增加与I类或II类主要组织相容性(MHC)抗原的结合并去除C3d结构域中硫酯位点的半胱氨酸的突变体的肿瘤细胞中,该核酸构建体表达C3d或源自C3d的肽或其生物活性变体,或编码激活C3d表达的蛋白质。通过使肿瘤细胞与两种试剂的组合接触,肿瘤细胞的免疫原性增强,并且肿瘤细胞变得更容易受到免疫系统的攻击。
在本发明的另一个实施方案中,第二药剂可以包含免疫刺激性蛋白质或肽,所述蛋白质或肽可以与多个I类和/或II类MHC等位基因结合以在具有不同遗传背景的个体中刺激针对广泛肿瘤的免疫应答。这种肽的实例是PADRE或泛HLA-DR表位肽(例如参见,Alexander,J.等人.Immunity,vol.1,751-761,Dec.1994;Song,L.等人.PloS ONE 9(12)2014.)特别地,泛刺激性肽PADRE(AKFVAAWTLKAAA(SEQ ID NO:3))可用作C3d的替代品,作为本文所述方法中的第二药剂,与敲减或敲除C3和/或如本文所述的其他补体或补体相关蛋白的第一药剂结合使用。
本发明还包括抑制受试者中的肿瘤生长的方法,其中所述肿瘤包含表达以下各项的细胞:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS,或上述蛋白质或其受体的任何组合,该方法包括向受试者施用治疗有效量的第一药剂,其中第一药剂降低以下各项在肿瘤细胞中的表达:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,并向受试者施用治疗有效量的第二药剂,其中第二药剂可增加补体蛋白C3d或C3d衍生肽或其他免疫刺激性肽在肿瘤细胞或肿瘤微环境中的表达,从而抑制受试者中的肿瘤生长。可以在施用第二药剂之前、基本上同时或之后施用第一药剂。
在特定的实施方案中,本发明方法中的受试者是哺乳动物,更特别地,该哺乳动物是人。该方法的第一和第二药剂如上所述。
本发明的特定实施方案包括在受试者(在人类受试者的情况下,在本文中也称为个体或患者)中治疗癌症或预防癌症转移的方法,其中癌症的肿瘤细胞表达补体蛋白补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或上述蛋白或其受体的任意组合,该方法包括向个体施用治疗有效量的第一药剂,其中第一药剂降低以下各项在癌细胞中的表达:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,并向个体施用治疗有效量的第二药剂,其中第二药剂可提高补体蛋白C3d或C3d衍生肽或其他免疫刺激性肽在肿瘤细胞或肿瘤微环境中的表达、活性或产生,从而在受试者中治疗癌症或预防癌症的转移。可以在施用第二药剂之前、基本上同时或之后施用第一药剂。该方法的第一和第二药剂如上所述。
只要癌症的肿瘤细胞与自分泌补体途径相关(图5A-C),并且特别是表达如本文所述的一种或更多种补体成分,就可以通过本文所述的方法治疗受试者的任何癌症。例如,癌症可以是卵巢癌、乳腺癌、肾癌、前列腺癌、肺癌、结肠癌或肺癌。
治疗癌症的方法可以进一步包括在至少一种或更多种适合于治疗该特定癌症的另外或补充的癌症治疗的同时、或之前或之后、或与之联合施用第一和/或第二药剂。例如但不限于,补充癌症治疗可以选自包含检查点抑制剂、蛋白酶体抑制剂、免疫治疗剂、放射疗法或化学疗法的疗法。其他合适的另外或补充癌症疗法是本领域技术人员已知的。
本发明还包括一种或多种药物组合物,所述药物组合物包含如本文所述的治疗有效量的第一药剂和治疗有效量的第二药剂。尽管该组合物可以包含第一和第二药剂二者,但是替代实施方案包括可以基本上同时或顺序施用的两种组合物(一种包含第一药剂,而另一种包含第二药剂)。在药物组合物的两个实施方案中,第一药剂降低以下各项在肿瘤细胞中的表达:补体成分,如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,第二药剂增加补体蛋白C3d或源自C3d的或其他免疫刺激性的生物活性肽在肿瘤细胞中或在肿瘤微环境中的表达。所述组合物还可以包括药学上可接受的、适合作为第一和第二药剂的载体的介质。所述组合物还可包含靶向剂以将所述组合物递送至特定的肿瘤部位。
现在将参考附图更具体地描述并在权利要求书中指出包括构造和部件组合的各种新颖细节的本发明的上述和其他特征以及其他优点。应当理解,在附图和实施例中通过举例说明而非限制本发明的方式示出了体现本发明的特定方法和组合物。在不脱离本发明的范围的情况下,本发明的原理和特征可以用于不同的各种实施方式。
附图说明
在附图中,贯穿不同的视图,附图标记指代相同的部分。附图不一定按比例绘制,相反,重点放在说明本发明的原理上。该专利或申请文件包含至少一张彩色附图。将根据要求并支付必要的费用,专利局将提供带有彩色附图的该专利或申请公开的副本。在附图中:
图1是描述通过辅因子的结合位点调节iC3b和C3dg生成的示意图。该途径的上分支产生免疫抑制性产物,例如iC3b,而下分支产生免疫刺激性产物,例如C3d。在此描述中,CFH阻止接近导致C3dg形成的蛋白水解位点,这有利于免疫抑制性iC3b的沉积,而CR1使该位点暴露,这有利于C3d的形成和免疫刺激(Nature Structural&Molecular Biology 24,643-651(2017))。
图2A描绘了适用于所述方法的构建体。腺相关病毒(AAV)构建体用于将CRISPR递送至细胞以敲除C3基因。sgRNA不包含C3d序列(载体1)。C3d或工程变体或其他免疫刺激性肽的多个拷贝被递送到相同的细胞,以指导这些肽的产生(载体2)。用控制向肿瘤细胞的递送的衣壳蛋白假型化AAV载体。
图2B描绘了适用于所述方法的构建体。腺相关病毒(AAV)构建体用于将AGO核酸酶递送至细胞以敲除C3基因(构建体1)。gRNA不包含C3d序列(构建体2)。C3d或工程变体或其他免疫刺激性肽被递送至同一细胞的膜,以指导这些肽的产生(构建体3)。尽管单独显示,但在某些情况下可以将构建体组合并用于能够容纳大尺寸插入物的病毒中。
图3描绘了补体成分C3及其活化产物的结构转变。Nishida N1,Walz T,SpringerTA.Proc Natl Acad Sci U S A.2006Dec 26;103(52):19737-42。C3b被蛋白水解剪切以产生许多不同的片段,包括C3d。硫酯键的位点由彩色圆圈表示。
图4A-B描述了智人补体C3b/C4b受体1(sCR1)转录物变体F,mRNA-胞外结构域的核酸序列(SEQ ID NO:4)。NCBI参考序列:NM-000573.3(Weisman等人.Science,1990年7月13日:249(4965):145-51)。
图5A-C描绘了由肿瘤细胞产生(A)或从微环境吸收(B)的补体成分的实例。两种途径都可以使用肿瘤外部的成分进行扩增(C)。加号表示正反馈自分泌循环,而减号表示负反馈。
图6描绘了C3野生型氨基酸序列(SEQ ID NO:6、8、10、12和14)及其相关的突变序列(SEQ ID NO:7、9、11、13和15)。
图7描绘了用于CRISPR的示例性向导RNA序列(SEQ ID NO:16、17和18)。
图8描绘了编码融合蛋白的Cd3/CD55构建体的核酸序列(SEQ ID NO:22)。
具体实施方式
现在将在下文中参考附图更全面地描述本发明,在附图中示出了本发明的说明性实施方案。然而,本发明可以以许多不同的形式来体现,并且不应被解释为限于本文阐述的实施方案;相反,提供这些实施方案是为了使本公开透彻和完整,并将本发明的范围充分传达给本领域技术人员。
提供了贯穿全文讨论的出版物仅仅是因为它们的公开内容早于本申请的申请日。本文中的任何内容均不应被解释为承认本发明人由于在先公开而没有资格先于这样的公开内容。
如本文所使用的,术语“和/或”包括一个或更多个相关联的所列项目的任何和所有组合。此外,单数形式和冠词“一”(a),“一个”(an)和“该”(the)也意图包括复数形式,除非另有明确说明。还将理解,术语“包括”(include),“包含”(comprise),“包括”(including)和/或“包含”(comprising)在本说明书中使用时,指定存在所述特征、整数、步骤、操作、元件和/或成分,但不排除存在或添加一个或更多个其他特征、整数、步骤、操作、元件、成分和/或其组合。此外,应当理解,当将包括成分或子系统的元件称为和/或示出为与另一元件连接或耦接时,该元件可以直接与另一元件连接或耦接,或者可以存在中间元件。
除非另有定义,否则本文中使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常理解的相同含义。尽管与本文描述的那些类似或等同的方法和材料可以用于所公开的方法和组合物的实践中,但是本文描述了示例性的方法和材料。
描述本文中有用的分子生物学技术(包括载体,启动子和许多其他相关主题的使用)的一般文本包括Berger和Kimmel,Guide to Molecular Cloning Techniques,Methodsin Enzymology Volume 152,(Academic Press,Inc.,San Diego,Calif.)("Berger");Sambrook等人,Molecular Cloning--A Laboratory Manual,第2版,Vol.1-3,Cold SpringHarbor Laboratory,Cold Spring Harbor,N.Y.,1989("Sambrook")和Current Protocolsin Molecular Biology,F.M.Ausubel等人编辑,Current Protocols,a joint venturebetween Greene Publishing Associates,Inc.和John Wiley&Sons,Inc.,(1999年增补)("Ausubel")。足以指导技术人员通过体外扩增方法进行操作的方案实例,包括聚合酶链反应(PCR)、连接酶链反应(LCR),Qβ-复制酶扩增和其他RNA聚合酶介导的技术(例如NASBA),例如用于产生本公开的同源核酸,可以在以下中找到:Berger,Sambrook,和Ausubel,以及Mullis等人(1987)美国专利号4,683,202;Innis等人编辑(1990)PCR Protocols:A Guideto Methods and Applications(Academic Press Inc.San Diego,Calif.)("Innis");Arnheim&Levinson(1990年10月1日)C&EN 36-47;The Journal Of NIH Research(1991)3:81-94;Kwoh等人(1989)Proc.Natl.Acad.Sci.USA 86:1173;Guatelli等人(1990)Proc.Nat'l.Acad.Sci.USA 87:1874;Lomell等人(1989)J.Clin.Chem 35:1826;Landegren等人(1988)Science 241:1077-1080;Van Brunt(1990)Biotechnology 8:291-294;Wu和Wallace(1989)Gene 4:560;Barringer等人(1990)Gene 89:117;以及Sooknanan和Malek(1995)Biotechnology 13:563-564。在Wallace等人的美国专利号5,426,039中描述了在体外克隆扩增的核酸的改进方法。Cheng等人(1994)Nature 369:684-685和其中引用的参考文献综述了通过PCR扩增大核酸的改进方法,其中产生了高达40kb的PCR扩增子。
术语“载体”,“载体构建体”和“表达载体”是指可以将DNA或RNA序列(例如外源基因)引入宿主细胞以转化宿主并促进所引入序列的表达(例如转录和翻译)的媒介物。载体通常包含可传递剂的DNA,通过限制酶技术将编码蛋白质的外源DNA插入其中。载体的常见类型是“质粒”,其通常是自包含的双链DNA分子,其可以容易地接受另外的(外源)DNA并且可以容易地引入合适的宿主细胞中。已经描述了用于在各种真核和原核宿主中复制和/或表达的大量载体,包括质粒和真菌载体。非限制性实例包括pKK质粒(Clonetech)、pUC质粒、pET质粒(Novagen,Inc.,Madison,Wis.)、pRSET或pREP质粒(Invitrogen,San Diego,Calif.)或pMAL质粒(New England Biolabs,Beverly,Mass.),和许多合适的宿主细胞,其使用本文公开或引用的方法或相关领域技术人员已知的方法。重组克隆载体通常将包括一个或更多个用于克隆或表达的复制系统,一个或更多个用于在宿主中进行选择(例如抗生素抗性)的标志物,以及一个或更多个表达盒。
在一个实施方案中,病毒载体可以是具有复制能力的逆转录病毒载体,其能够仅感染具有特定突变的复制肿瘤细胞。在一个实施方案中,具有复制能力的逆转录病毒载体包含内部核糖体进入位点(IRES),其位于编码例如胞嘧啶脱氨酶、miRNA、siRNA、细胞因子、受体、抗体等的异源多核苷酸的5'端。当异源多核苷酸编码非翻译的RNA(例如siRNA、miRNA或RNAi)时,则不需要IRES,但对于另一翻译基因可以将其包含在内,并且可以使用任何种类的逆转录病毒(见下文)。在一个实施方案中,该多核苷酸位于逆转录病毒载体的ENV多核苷酸的3'端。在一个实施方案中,病毒载体是逆转录病毒载体,其能够多次感染靶向的肿瘤细胞(每个二倍体细胞5次或更多次)。
术语“表达”(express)和“表达”(expression)是指允许或引起基因或DNA序列中的信息变得明显,例如通过激活涉及相应基因或DNA序列的转录和翻译的细胞功能来产生蛋白质。DNA序列在细胞中或由细胞表达以形成“表达产物”例如蛋白质。表达产品本身,例如所得的蛋白质,也可以说被细胞“表达”了。例如,当多核苷酸或多肽在外源或天然启动子的控制下在外源宿主细胞中或在外源启动子的控制下在天然宿主细胞中表达或产生时,多核苷酸或多肽被重组表达了。
本文所述的术语“基因编辑”或“基因编辑技术”可包括RNA介导的干扰(本文称为RNAi或干扰RNA分子),或短发夹RNA(shRNA)或CRISPR-Cas9和TALEN。参见例如Agrawal.N.等人,Microbiol Mol Biol Rev.2003年12月;67(4):657–685;Moore,C.B.,等人.MethodsMol Biol.2010;629:141–158;Doudna,J.A.和Charpentier,E.Science vo.346,2014年11月28日;Sander,J.D.和Joung,K.Nature Biotech 32,347-355(2014);U.S.Pat 8,697,359;Nemudryo,A.A.ACTA Naturae vol.6,No.3(22)2014。也可以使用反义RNA(Gleave,M.和Monia,B.,Nature Reviews Cancer 5,468-479(2005年6月))。术语“基因疗法”通常是指一种治疗方法,其中将所需的基因/遗传序列(与表达特定基因所需的其他序列一起)插入细胞或组织中。有关基因治疗技术的描述请参见例如genetherapynet.com。
如本文所用,术语“受试者”可包括出于医学目的的人类受试者,例如用于现有疾病、病症、病况的治疗或用于预防疾病、病症或病况的发作的预防性治疗,或用于医学、兽医目的或发育目的的动物受试者。合适的动物受试者包括哺乳动物,包括但不限于灵长类,例如人、猴子、猿、长臂猿、黑猩猩、猩猩、猕猴等;牛科(bovine),例如牛(cattle)、公牛(oxen)等;绵羊(ovine),例如绵羊(sheep)等;山羊(caprine),例如山羊(goat)等;猪(porcine),例如猪(pig)、猪(hog)等;马科(equine),例如马、驴、斑马等;猫科,包括野猫和家猫;犬科,包括狗;兔类动物,包括兔子、野兔等;啮齿动物,包括小鼠、大鼠、豚鼠等。动物可以是转基因动物。在一些实施方案中,受试者是人类,包括但不限于胎儿、新生儿、婴儿、青少年和成人受试者。此外,“受试者”可包括患有或怀疑患有疾病、病症或病况的患者。因此,术语“受试者”和“患者”在本文可互换使用。受试者还包括动物疾病模型(例如,实验中使用的大鼠或小鼠等)。
术语“癌症”或“肿瘤”包括但不限于实体瘤和血源性肿瘤。这些术语包括皮肤、组织、器官、骨骼、软骨、血液和血管的疾病。这些术语进一步涵盖原发性和转移性癌症。识别以下各项在肿瘤中的表达的生物标记物提供了一种选择患者用于治疗的方式:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,无论该生物标记物是通过RNA表达、抗体还是其他可定量这些分子的试剂检测到的。
本发明的方法和组合物可以用于治疗任何类型的癌性肿瘤或癌细胞。此类肿瘤/癌症可能位于身体的任何位置,包括但不限于选自脑、结肠、泌尿生殖系统、肺、肾、前列腺、胰腺、肝脏、食道、胃、造血组织、乳腺、胸腺、睾丸、卵巢、皮肤、骨髓和/或子宫组织的组织中。可以通过本发明的方法和组合物治疗的癌症包括但不限于来自以下器官的癌细胞:膀胱、血液、骨、骨髓、脑、乳腺、结肠、食道、胃肠道、牙龈、头、肾、肝、肺、鼻咽、颈、卵巢、前列腺、皮肤、胃、睾丸、舌头或子宫。另外,癌症可以具体地是以下组织类型,尽管其不限于这些:恶性肿瘤;癌;未分化癌;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌(pilomatrix carcinoma);移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;合并肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤息肉中的腺癌;家族性息肉腺癌;实体癌;恶性类癌瘤;细支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡状腺癌;乳头状和滤泡状腺癌;非包膜硬化性癌(nonencapsulating sclerosing carcinoma);肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;顶泌腺癌;皮脂腺癌;耵聍腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特氏病,乳腺;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;恶性胸腺瘤;恶性卵巢间质瘤;恶性泡膜细胞瘤;恶性颗粒细胞瘤;恶性母细胞瘤;塞尔托利细胞癌;恶性莱迪希氏细胞瘤;恶性脂质细胞瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;血管肉瘤;恶性黑色素瘤;无黑素性黑色素瘤;浅表扩散性黑色素瘤;巨大色素痣内恶性黑色素瘤;上皮样细胞黑色素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;黏液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;恶性混合瘤;缪勒混合瘤(mullerian mixed tumor);肾母细胞瘤;肝母细胞瘤;癌肉瘤;恶性间叶瘤;恶性布伦纳瘤;恶性叶状瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎癌;恶性畸胎瘤;恶性卵巢甲状腺瘤;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西氏肉瘤(kaposi's sarcoma);恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁成骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间叶性软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤(ewing'ssarcoma);恶性牙源性肿瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;恶性松果体瘤;脊索瘤;恶性胶质瘤;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;成少突胶质细胞瘤;原始神经外胚层瘤;小脑肉瘤;神经节神经母细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤;恶性脑膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性颗粒细胞瘤;恶性淋巴瘤;霍奇金氏病(Hodgkin'sdisease);霍奇金氏淋巴瘤;副肉芽肿;小淋巴细胞性恶性淋巴瘤;大细胞弥漫性恶性淋巴瘤;滤泡性恶性淋巴瘤;蕈样真菌病;其他指定的非霍奇金氏淋巴瘤(otherspecified non-Hodgkin's lymphomas);恶性组织细胞增多病;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓样白血病;嗜碱细胞性白血病;嗜酸粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;骨髓肉瘤;和毛细胞白血病。
如本文所用,“治疗有效”量是指足以具有所需生物学效应的量(例如,足以降低以下各项的表达的量:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合),或者,以适用于任何医学治疗的合理的收益/风险比,在受试者的至少一个亚组细胞中对潜在疾病状态的所需效果(例如,足以抑制受试者肿瘤生长的量)。本领域技术人员可以通过使用已知技术并通过观察在类似情况下获得的结果来容易地确定用于本发明的药剂的治疗有效量。量/剂量可根据治疗临床医生判断的受试者的需求;所治疗疾病的严重程度和所使用的特定组合物而变化。在确定治疗有效量时,治疗临床医生考虑许多因素,包括但不限于:特定的疾病状态;特定药剂的药效学特性及其施用方式和途径;所需的治疗时间;被治疗的物种;物种的大小,年龄和总体健康状况;涉及的特定疾病;疾病的程度或介入(involvement)或严重程度;个别患者的反应;所施用的特定药剂;施用方式;所施用制剂的生物利用度特征;选择的剂量方案;并行治疗的种类(即药剂与其他共同施用药剂的相互作用);和其他相关情况。
例如,如本文所述,C3d蛋白的氨基酸序列可以被截短/突变/改变以产生生物活性肽或变体。可以合成或以其他方式产生源自C3d蛋白的此类肽,并评估其生物学活性。生物活性可以包括C3d或C3d肽与MHC的结合,或蛋白酶(例如金属蛋白酶)引起的蛋白水解位点的改变。突变可以特异性地增加MHC的结合从而增加免疫刺激。备选地,可以使用其他免疫刺激性肽。
在某些实施方案中,可以根据本文提供的方法和组合物,将用于本发明描述的试剂与本领域已知的其他药理活性化合物(“另外的活性药剂”)组合。另外的活性药剂可以是大分子(例如蛋白质、脂质、碳水化合物)或其他免疫刺激性肽或小分子(例如合成的无机、有机金属或有机分子)。在一个实施方案中,另外的活性药剂独立地或协同地有助于治疗癌症。
例如,某些另外的活性药剂是抗癌化学治疗剂。术语化学治疗剂包括但不限于铂基药剂,例如卡铂和顺铂;氮芥烷化剂;亚硝基脲烷基化剂,例如卡莫司汀(BCNU)和其他烷基化剂;抗代谢物,例如甲氨蝶呤;嘌呤类似物抗代谢物;嘧啶类似物抗代谢物,例如氟尿嘧啶(5-FU)和吉西他滨;激素抗肿瘤药,例如戈舍瑞林、亮丙瑞林和他莫昔芬;天然抗肿瘤药,例如紫杉烷类药物(例如多西紫杉醇和紫杉醇)、阿地白介素、白介素-2、依托泊苷(VP-16)、α干扰素和维甲酸(ATRA);抗生素天然抗肿瘤药,例如博来霉素、放线菌素、柔红霉素、阿霉素和丝裂霉素;和长春花生物碱天然抗肿瘤药,例如长春碱和长春新碱或靶向肿瘤细胞内特定突变的药剂。
此外,即使本身不被认为是抗肿瘤剂,以下药物也可以与抗肿瘤剂组合使用:放线菌素、盐酸柔红霉素、多西他赛、盐酸阿霉素、阿法依泊汀、依托泊苷(VP-16)、更昔洛韦钠、硫酸庆大霉素、α干扰素、醋酸亮丙瑞林、盐酸哌替啶、盐酸美沙酮、盐酸雷尼替丁、硫酸长春碱和齐多夫定(AZT)。例如,最近已经将氟尿嘧啶与肾上腺素和牛胶原蛋白一起配制以形成特别有效的组合。
此外,以下氨基酸、肽、多肽、蛋白质、多糖和其他大分子的列表也可以与本发明结合使用:靶向例如PD-1和CTLA-4的检查点抑制剂;白介素1至37,包括突变体和类似物;干扰素或细胞因子,例如α、β和γ干扰素;激素,如促黄体生成激素释放激素(LHRH)及其类似物,以及促性腺激素释放激素(GnRH);生长因子,例如转化生长因子-β(TGF-β)、成纤维细胞生长因子(FGF)、神经生长因子(NGF)、生长激素释放因子(GHRF)、表皮生长因子(EGF)、成纤维细胞生长因子同源因子(FGFHF)、肝细胞生长因子(HGF)和胰岛素生长因子(IGF);肿瘤坏死因子-α和β(TNF-α和β);侵袭抑制因子2(IIF-2);骨形态发生蛋白1-7(BMP 1-7);生长抑素;胸腺素-α-1;γ-球蛋白;超氧化物歧化酶(SOD);补体因子;抗血管生成因子;抗原物质;和前药。
与本文所述的组合物和治疗方法一起使用的化学治疗剂包括但不限于烷基化剂,例如噻替帕和环磷酰胺;烷基磺酸盐,例如白消安、英丙舒凡和哌泊舒凡;氮丙啶,例如苯佐替派(benzodopa)、卡波醌、美妥替哌(meturedopa)和乌瑞替派(uredopa);乙撑亚胺类和甲基蜜胺类(methylamelamine),包括六甲蜜胺、曲他胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺(trimethylolomelamine);多聚乙酰(acetogenin)(特别是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成的类似物拓扑替康);苔藓虫素;callystatin;CC-1065(包括其阿多来新(adozelesin),卡折来新(Carzelesin)和比折来新(bizelesin)合成类似物);念珠藻素(尤其是念珠藻素1和念珠藻素8);多拉司他汀;多卡米星(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素(spongistatin);氮芥,例如苯丁酸氮芥、萘氮芥(chlomaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、氮芥(mechlorethamine)、氧化氮芥盐酸盐(mechlorethamine oxide hydrochloride)、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀(prednimustine)、曲磷胺、尿嘧啶氮芥;亚硝基尿,例如卡莫司汀,氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素,例如烯二炔类抗生素(例如,加利车霉素(calicheamicin),特别是加利车霉素γlI和加利车霉素ωl1;达尼霉素(dynemicin),包括达尼霉素A;双膦酸酯,如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新制癌菌素发色团和相关色蛋白烯二炔类抗生素生色团)、阿克拉霉素、放线菌素、蒽霉素(authramycin)、偶氮丝氨酸、博莱霉素、放线菌素C、卡柔比星(carabicin)、洋红霉素、嗜癌霉素、色霉素、放线菌素D、柔红霉素、地托比星、6-重氮-5-氧-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星,氰基吗啉代-多柔比星,2-吡咯啉代-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素类例如丝裂霉素C、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素类、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链脲菌素、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢药,例如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,例如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,例如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷;雄激素,例如卡普睾酮、丙酸甲雄烷酮、环硫雄醇、美雄烷、睾内酯;抗肾上腺素,例如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,例如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;比曲比新(bestrabucil);比生群(bisantrene);依达曲沙;地佛法明(defofamine);秋水仙胺;地吖醌;依氟鸟氨酸(elformithine);依利醋铵(elliptiniumacetate);埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登醇,例如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;nitraerine;喷司他丁;蛋氨氮芥(phenamet);吡柔比星;洛索蒽醌;鬼臼酸(podophyllinic acid);2-乙酰肼;丙卡巴肼;PSK多糖复合物;丙亚胺;根霉素;西咗喃(sizofuran);锗螺胺;细交链孢菌酮酸(tenuazonic acid);三亚胺醌;2,2′,2″-三氯三乙胺;单端孢霉烯(特别是T-2毒素、verracurin A、杆孢菌素A(roridin A)和蛇形菌素(anguidine));乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷,例如紫杉醇和多西他赛;苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂复合物,例如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊甙(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺安托(novantrone);替尼泊苷;依达曲沙;道诺霉素;氨蝶呤;希罗达;伊班膦酸盐;依立替康(例如CPT--11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视色素,例如视黄酸;卡培他滨;以上任一种的药学上可接受的盐、酸或衍生物。
本发明的组合物和方法可以包含或包括使用其他生物活性物质,包括治疗药物或前药,例如,用于癌症疫苗应用的其他化学治疗剂或抗原。可以使用各种形式的化学治疗剂和/或另外的活性药剂。这些包括但不限于具有生物活性的不带电荷分子、分子复合物、盐、醚、酯、酰胺等形式。
本文所述的药剂和物质可以用药学上合适的或可接受的或生物相容的载体递送给受试者。术语“药学上合适的/可接受的”或“生物相容的”是指适合用于药物用途(例如,对于所述目的而言足够的安全界限,并且如果合适的话,具有足够的功效),特别是如本发明的组合物和方法中所使用的。
本文所述的组合物可以通过任何合适的用于治疗癌症的施用途径来递送,包括口服,经鼻,经粘膜,经眼,经直肠,阴道内,肠道外,包括肌肉内,皮下,髓内注射以及鞘内,直接注射心室内,静脉内,关节内,胸骨内,滑膜内,肝内,通过吸入喷雾或本领域已知的其他递送方式。
先前已经报道,卵巢癌小鼠模型中缺乏补体成分C3与肿瘤生长降低有关。肿瘤中缺乏C3a和C5a受体也减慢了肿瘤的生长。癌症基因组图谱–NIH(TCGA)数据的分析证实,人类肿瘤中C3表达的降低与更好的存活率相关,从而支持了小鼠数据。该机制的生物信息学分析确定C3是免疫系统的开启/关闭开关,其中一种分解产物iC3b促进了免疫抑制,而另一种蛋白水解产物C3dg/C3d是一种免疫刺激剂。C3dg和C3d是由iC3b蛋白水解产生的,其产生受到隐藏蛋白水解发生位点的调节蛋白的抑制。不希望受到理论的束缚,有理由相信,通过去除iC3b免疫抑制屏障,用其C3dg或C3d产物或源自C3d的生物活性肽或其他免疫刺激性肽替代肿瘤产生的全长C3可使肿瘤具有免疫原性,从而使免疫系统看到独特的肿瘤相关抗原,同时通过C3dg、C3d或源自C3d的肽或其他免疫刺激性肽的作用刺激免疫应答。这种组合方法将免疫应答转移到肿瘤被排斥的状态。它使肿瘤从没有免疫应答的“冷”模式转移到免疫系统攻击肿瘤的“热”模式。在“热”模式下,可以使用临床认可的其他免疫调节剂来增强反应。
如本文所述,可以使用各种方法来敲低(部分抑制或降低)或敲除(完全抑制或消除)C3基因或C3基因的片段在肿瘤细胞中的表达、活性或产生,其结果,其生物活性分解产物iC3b无法为肿瘤提供免疫抑制屏障。适用于本发明中的敲低或敲除靶向的基因的列表及其序列如下。
C3的核酸序列,包括片段C3d和C3dg,可以在例如“Proc.Natl.Acad.Sci.USA,vol.82,pp.708-712,1985年2月”中找到。本文所用的术语“C3d”旨在涵盖C3d和C3dg。C3aR的核酸序列可以在“C3AR1 complement C3a receptor 1[智人(人)]”中找到,基因ID:719,ncbi.nlm.nih.gov/gene,更新于2017年8月6日。C5a受体的核酸序列可在“C5AR1complement C5a receptor 1[智人(人)]”中找到,基因ID:728,ncbi.nlm.nih.gov/gene,更新于2017年8月29日。C1R补体C1r[智人(人)],基因ID:715,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,C1RL补体C1r子组分样蛋白[智人(人),基因ID:51279,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,C5AR2补体成分5a受体2[智人(人)],基因ID:27202,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,C1QBP补体C1q结合蛋白[智人(人)],基因ID:708,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,CR2补体C3d受体2[智人(人)],基因ID:1380,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,CD46分子[智人(人)],基因ID:4179,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,CD55分子(Cromer血型)[智人(人)],基因ID:1604,ncbi.nlm.nih.gov/gene,更新于2017年9月6日,CD59分子(CD59血型)[智人(人)],基因ID:966,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,LAIR1白细胞相关的免疫球蛋白样受体1[智人(人)],基因ID:3903,ncbi.nlm.nih.gov/gene,更新于2017年9月3日,补体因子B,CFB[智人(人)],基因ID:629,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子D,CFD,[智人(人)],ID:1675,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子H,CFH,[智人(人)],基因ID:3075,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子H相关1,CFHR1,[智人(人)],基因ID:3078,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子H相关2,CFHR2,[智人(人)],基因ID:3080,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子H相关3,CFHR3,[智人(人)],基因ID:10878,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子H相关4,CFHR4,[智人(人)],基因ID:10877,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子H相关5,CFHR5,[智人(人)],基因ID:81494,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子I,CFI,[智人(人)],基因ID:3426,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;补体因子备解素,CFP,[智人(人)],基因ID:5199,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;组织蛋白酶B,CTSB,[智人(人)],基因ID:1508,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;组织蛋白酶C,CTSC,[智人(人)],基因ID:1075,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;组织蛋白酶D,CTSD[智人(人)],基因ID:1509,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;组织蛋白酶L,CSTL,[智人(人)],基因ID:1514,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;组织蛋白酶O,CSTO,[智人(人)],基因ID:1519,ncbi.nlm.nih.gov/gene,更新于2017年9月3日;组织蛋白酶S,CSTS,[智人(人)],基因ID:1520,ncbi.nlm.nih.gov/gene,更新于2017年9月3日。例如,可以使用使肿瘤内的C3基因失活的基因编辑技术(参见例如美国专利8,697,359对CRISPR技术的描述)。可以通过使用病毒载体,将具有针对C3(不包括C3d序列)的sgRNA的CRISPR/CAS9和C3d或C3d衍生肽或其他免疫刺激性肽的核酸序列递送至肿瘤细胞。许多病毒载体已经用于人类,这些病毒载体可用于在不同细胞类型中转导遗传物质。这样的方法是本领域技术人员已知的。靶向载体以将构建体特异性递送至目的肿瘤细胞的手段也是本领域技术人员已知的。例如,存在经基因工程改造的载体,其中衣壳被修饰以包含受体的配体,其促进病毒进入特定细胞类型。在图1中给出了一个实例。该构建体还包括报告基因,该报告基因允许将病毒转导到肿瘤中的效率定量。
这些基因在肿瘤细胞中的细胞内表达可以通过表达抑制C3基因转录的蛋白质来抑制,而不是敲除C3(补体成分,例如C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合)。或者,可以在细胞中导入并表达与C3结合并导致其破坏或抑制C3加工的另一种蛋白质。这包括细胞内抗体、纳米抗体或其他工程改造的蛋白质以及细胞蛋白水解机制的抑制剂(例如泛素连接酶或蛋白水解酶)。可以表达阻止C3翻译的微小RNA。由使C3RNA不稳定或抑制其翻译的核糖核苷酸、脱氧核糖核苷酸或经修饰碱基的混合物组成的寡核苷酸可被表达或引入肿瘤中,以阻止C3产生。这样的方法是本领域技术人员已知的。
为了刺激免疫应答,C3d可以表达为最小结构域、扩展结构域、由核心C3d序列的重复单元(其具有或不具有对C3d氨基酸的修饰,旨在增强其辅助作用)组成的单体或多聚体。源自C3d的免疫刺激性肽(即生物活性肽)或其他免疫刺激性肽可以表达为最小结构域、扩展结构域、由核心肽序列的重复单元(其具有或不具有对肽氨基酸的修饰,旨在增强其辅助作用,改善稳定性或改善药理特性(例如在肿瘤中的半衰期))组成的单体或多聚体。对C3d或由其衍生的生物活性肽的修饰包括与其他序列融合,该序列将其引导至特定细胞或细胞外位置或特定结合配偶体,或还起到刺激免疫应答的作用。对硫酯键形成残基的修饰可用于使C3d可溶而不是膜结合。C3d也可以作为包含已列出的修饰的肽或肽融合体添加。
上述方法可以与其他癌症疗法组合,包括免疫调节剂,例如PD-1CTLA-4,ICOS,OX40的检查点抑制剂配体;针对C3a和C5a受体的试剂;淋巴因子、细胞因子及其受体以及旨在增加主要和次要组织相容性抗原的策略。另外,本发明的方法可以与其他标准的癌症疗法例如放射疗法和化学疗法相结合。
实施例
实施例1:从C3d选择免疫活性肽的方法
本文和实施例2中所述的方法基于Knopf,P.M.等人,Immunol.Cell Biol.(2008)86,221-225,和De Groot,A.S.,Immunol.Cell Biol.(2014)1-9的方法,以鉴定存在于C3d中的免疫刺激性II类MHC结合肽。该方法可以扩展为鉴定适用于本发明的其他肽。这些扩展的目的是:
1.使用非专有算法鉴定C3d衍生肽的高亲和性I类和II类主要组织相容性复合体(MHC)结合位点;
2.确保肿瘤环境中的金属蛋白酶可以将它们消化成与MHC蛋白结合的合适大小。
步骤
1.将人C3d氨基酸序列:(SEQ ID NO:5)
与来自狗、猪、牛、小鼠和大鼠的序列进行比对,以鉴定保守区。
2.还将人序列输入到以下网址的网络服务器中:
a.tools.immuneepeepitope.org/mhci/
b.tools.immuneepeepitope.org/mhcii/
并筛选与以下I类和II类MHC等位基因的预测结合:
1、将所有I类等位基因以及所有II类等位基因的每个C3d序列的百分等级进行求和,以鉴定混杂结合的肽,以增加它们在广泛的个体中有活性的可能性。
2、然后进一步筛选低得分的泛MHC C3d序列,以鉴定跨物种保守的序列。
3、选择保守的泛MHC序列用于进一步分析,然后在以下网站上筛选受到金属蛋白酶(MMP)2、9、14、15、16、24和25蛋白水解的位点:
protease.burnham.org/www/tools/cgi-bin/specdb/
4、在必要时,将保守的突变引入保守的泛MHC序列中,以在每个MHC结合序列的末端产生高效的蛋白水解位点,或去除序列中存在的蛋白水解位点。在以下网址筛选每个突变:
protease.burnham.org/www/tools/cgi-bin/specdb/
5、这种方法使多个I类和II类MHC序列能够组合在一个肽中。
6、重新筛选用于MHC结合的突变序列,以确保保留亲和性。
7、针对非冗余人类蛋白数据库筛选了突变序列,以确保它们不与C3以外的蛋白比对,从而降低了无意地诱导针对这些其他蛋白的自身免疫应答的风险:
blast.ncbi.nlm.nih.gov/
实施例2:C3 MHC肽
图6列出了C3野生型氨基酸序列(SEQ ID NO:6、8、10、12和14)及其相关的突变序列(SEQ ID NO:7、9、11、13和15),所述突变序列已被优化以改善MHC结合并改变金属蛋白酶的蛋白水解位点。突变的肽合理地提高了MHC结合并提高了免疫刺激。
实施例3:用于CRISPR的向导RNA序列的设计
对于使用CRISPR技术进行基因编辑的方法,需要向导RNA序列,其合理地编辑/切出C3基因但不编辑/切出C3d基因序列。参见例如portals.broadinstitute.org/gpp/public/analysis-tools/sgrna-design。示例性的向导RNA序列(SEQ ID NO:16-18)以及相应的PAM序列在图7中示出。
实施例4:反义RNA
如本文所述的基因编辑方法也可以使用干扰RNA序列来完成。这样的序列可以是例如:
5'ACAUUCUGAUUCCUUCCGG 3'(SEQ ID NO:19)
5'ACUUUCUGCACUCCUUCAC 3'(SEQ ID NO:20)
可以由单个DNA插入物合成RNA,在该插入物的任一侧带有RNA III启动子(例如U6、7SL)。DNA插入物具有以下序列作为其上链,反义链标有下划线:
实施例5:C3d/CD55或CD59融合构建体
C3d通常通过补体蛋白C3的蛋白水解切割产生。在此过程中,C3d通过主要与细胞表面碳水化合物的羟基形成的硫酯键锚定到细胞膜上(Law,S.K.和A.W.Dodds,"Theinternal thioester and the covalent binding properties of the complementproteins C3 and C4."Protein Science:a publication of the Protein Society 6(2):263-274(1997))。C3d与补体受体2(CR2)结合并刺激适应性免疫应答(Ricklin等人."The renaissance of complement therapeutics."Nature Reviews.Nephrology 14(1):26-47(2018))。
本文描述了使用通过糖基磷脂酰肌醇(GPI)锚与细胞膜结合的C3d融合蛋白来提高抗原的免疫原性的方法。在该实施例中,制备了可以在细胞膜上表达Cd3的Cd3/CD55融合构建体(参见图8,SEQ ID NO:22)。或者,可以以类似方式制备Cd3/CD59融合构建体。
融合体有三个部分:
(1)指导输出到细胞表面膜的信号序列;
(2)C3d序列;
(3)指导GPI标签附着的序列。
自然加工了超过150种蛋白质以添加GPI锚,并且可以如本文所述用作融合蛋白的部分1和部分3的来源(Kinoshita,T.和M.Fujita"Biosynthesis of GPI-anchoredproteins:special emphasis on GPI lipid remodeling."Journal of Lipid Research57(1):6-24(2016))。
本发明使用了来自CD55的部分1和部分3的序列,同时去除了CD55中存在的所有其他序列信息,这些信息对于CD55作为补体激活调节剂的功能是必需的(Coyne,Crisci等人"Construction of synthetic signals for glycosyl-phosphatidylinositol anchorattachment.Analysis of amino acid sequence requirements for anchoring."TheJournal of biological chemistry268(9):6689-6693(1993))。融合体包含以下序列,以单字母氨基酸代码给出,用于每个部分:
MTVARPSVPA ALPLLGELPR LLLLVLLCLP AVWG(SEQ ID NO:23)
(信号序列)
(C3d序列)
SG TTSGTTRLLS GHTCFTLTGL LGTLVTMGLL T(SEQ ID NO:25)(GPI锚)
使用来自CD59的部分1和3构建融合蛋白也是可能的,如下:
MGIQGGSVLF GLLLVLAVFC HSGHS(SEQ ID NO:26)(信号序列)
ENGGTSLSEK TVLLLVTPFL AAAWSLHP(SEQ ID NO:27)(GPI锚)
一种替代方法是用以下描述的经加工的GPI锚序列替换部分3:Nagarathinam,A.,P.Hoflinger,等人"Membrane-anchored Abeta accelerates amyloid formation andexacerbates amyloid-associated toxicity in mice."The Journal of neuroscience:the official journal of the Society for Neuroscience 33(49):19284-19294。在这种情况下,部分3的序列为:
SRDGRRS(SEQ ID NO:28)。
参考文献(其教导通过引用并入本文):
1.Neoplasia.2012 Nov;14(11):994–1004.DOI 10.1593/neo.121262“Geneticand Pharmacologic Inhibition of Complement Impairs Endothelial Cell Functionand Ablates Ovarian Cancer Neovascularization”Nunez-Cruz S,Gimotty PA,GuerraMW,Connolly DC,Wu YQ,DeAngelis RA,Lambris JD,Coukos G,Scholler N.
2.Cell Rep.2014 Mar 27(6):1085-95.doi:10.1016/j.celrep.2014.02.014“Autocrine effects of tumor-derived complement.”Cho MS,Vasquez HG,RupaimooleR,Pradeep S,Wu S,Zand B,Han HD,Rodriguez-Aguayo C,Bottsford-Miller J,Huang J,Miyake T,Choi HJ,Dalton HJ,Ivan C,Baggerly K,Lopez-Berestein G,Sood AK,Afshar-Kharghan V.
3.JCI Insight.2017;2(9):e90201.doi:10.1172/jci.insight.90201“C3dregulates immune checkpoint blockade and enhances antitumor immunity”PlattJL,Silva I,Balin SJ,Lefferts AR,Farkash E,Ross TM,Carroll MC,Cascalho M.
4.Nat Struct Mol Biol.2017 Jul 3.doi:10.1038/nsmb.3427 Regulator-dependent mechanisms of C3b processing by factor I allow differentiation ofimmune responses.Xue X,Wu J,Ricklin D,Forneris F,Di Crescenzio P,Schmidt CQ,Granneman J,Sharp TH,Lambris JD,Gros P.
5.Cascalho and Platt:eurekalert.org/pub_releases/2017-05/mmu-fcr051117.php
6.Vaccine compositions and methods of modulating immune responses US20030133942.
7.Opsonin-enhanced cells,and methods of modulating an immune responseto an antigenWO 1997035619 A1.
8.Mutable vaccines US 7776321 B2.
9.Dempsrey et al.(1996)Nature 271:348-350.
10.Compositions and methods for generating an immune response US20150231227 A1.
11.Antibody targeting cell surface deposited complement protein C3dand use thereof WO2015105973 A1.
12.Antibodies to the C3d fragment of complement component 3 US20130129728 A1.
13.Modulating the immune response CA 2207000 A1.
14.Gene editing for immunological destruction of neoplasia US20170020922 A1.
15.Methods and compositions for selectively eliminating cells ofinterest WO 2016094888 A1.
16.Crispr/cas-mediated genome editing to treat egfr-mutant lungcancer US 20170145405 A1.
17.Cancer therapy US 9603912 B2.
18.Prmt5 inhibitors for the treatment of cancer with reduced mtapactivity WO 2016145150 A3.
19.Fritsche,L.G.,N.Lauer,et al.(2010)."An imbalance of humancomplement regulatory proteins CFHR1,CFHR3 and factor H influences risk forage-related macular degeneration(AMD)."Human molecular genetics 19(23):4694-4704.
20.JnBaptiste,C.K.,A.M.Gurtan,et al.(2017)."Dicer loss and recoveryinduce an oncogenic switch driven by transcriptional activation of theoncofetal Imp1-3 family."Genes&development 31(7):674-687.
21.Liszewski,M.K.,M.Kolev,et al.(2013)."Intracellular complementactivation sustains T cell homeostasis and mediates effectordifferentiation."Immunity 39(6):1143-1157.
22.Martin,M.,J.Leffler,et al.(2016)."Factor H uptake regulatesintracellular C3 activation during apoptosis and decreases the inflammatorypotential of nucleosomes."Cell death and differentiation 23(5):903-911.
23.Elvington,M.,M.K.Liszewski,et al.(2017),“A C3(H20)recyclingpathway is a component of the intracellular complement system.”The Journal ofClinical Investigation 127(3):970-981.
尽管已经参考本发明的优选实施方案具体示出并描述了本发明,但是本领域技术人员将理解,在不脱离本发明所附权利要求所涵盖的范围的情况下,可以在形式和细节上进行各种改变。
Claims (55)
1.增强肿瘤细胞免疫原性的方法,其中所述肿瘤细胞表达补体蛋白C3和/或C5,或补体蛋白受体C3aR和/或C5aR,或所述蛋白或其受体的任意组合,所述方法包括:
a)使所述肿瘤细胞与第一药剂接触,其中所述第一药剂降低以下各项在肿瘤细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,以及
b)使所述肿瘤细胞与第二药剂接触,其中所述第二药剂提高补体蛋白C3d或包括源自C3d的肽的其生物活性变体或其他免疫刺激性肽在肿瘤细胞或肿瘤细胞微环境中的表达或活性。
2.权利要求1所述的方法,其中所述第一药剂包括基因编辑剂,所述基因编辑剂降低或抑制以下一项或更多项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
3.权利要求2所述的方法,其中所述基因编辑剂包括CRISPR-Cas系统构建体,所述CRISPR-Cas系统构建体降低或抑制以下一项或更多项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
4.权利要求2所述的方法,其中所述基因编辑剂包括TALEN构建体,所述TALEN构建体降低或抑制以下一项或更多项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
5.权利要求3或4所述的方法,其中所述基因编辑剂不降低或抑制肿瘤细胞中的C3d或源自C3d的肽或其他免疫刺激性肽的表达。
6.权利要求1所述的方法,其中所述第一药剂是包括RNAi、shRNA、miRNA或反义RNA的核酸构建体,所述核酸构建体降低或抑制以下一项或更多项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
7.权利要求1所述的方法,其中所述第一药剂是表达如下蛋白质的核酸构建体,所述蛋白质降低或抑制以下一项或更多项在肿瘤细胞内的转录:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS,或其任意组合。
8.权利要求2至7中任一项所述的方法,其中使用病毒载体、纳米颗粒、脂质体或外来体将所述药剂靶向递送至所述肿瘤细胞。
9.权利要求8所述的方法,其中所述病毒载体包括腺病毒、腺相关病毒、慢病毒载体、牛痘病毒、疱疹病毒载体、副粘病毒或任何病毒载体或任何病毒样颗粒。
10.权利要求1所述的方法,其中所述第二药剂包括靶向所述肿瘤细胞的表达载体,其中所述载体包括核酸构建体,所述核酸构建体表达C3d或包括源自C3d的肽的其生物活性变体,或编码激活肿瘤细胞中的C3d或其他免疫刺激性肽的表达的蛋白质。
11.抑制受试者中肿瘤生长的方法,其中所述肿瘤包括肿瘤细胞,所述肿瘤细胞表达补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,或所述蛋白或其受体的任意组合,所述方法包括:
a)向所述受试者施用治疗有效量的第一药剂,其中所述第一药剂降低以下各项在肿瘤细胞中的表达:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,以及
b)向所述受试者施用治疗有效量的第二药剂,所述第二药剂增加补体蛋白C3d或包括源自C3d的肽的其生物活性变体或其他免疫刺激性肽在肿瘤细胞或肿瘤细胞微环境中的表达、活性或产生,从而抑制所述受试者中的肿瘤生长。
12.权利要求11所述的方法,其中所述受试者是哺乳动物。
13.权利要求12所述的方法,其中所述哺乳动物是人。
14.权利要求11所述的方法,其中所述第一药剂包括基因编辑剂,所述基因编辑剂降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
15.权利要求14所述的方法,其中所述基因编辑剂包括CRISPR-Cas系统构建体,所述CRISPR-Cas系统构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
16.权利要求14所述的方法,其中所述基因编辑剂包括TALEN构建体,所述TALEN构建体降低或抑制以下各项在肿瘤细胞内的表达或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
17.权利要求14所述的方法,其中所述基因编辑剂包括大范围核酸酶构建体,所述大范围核酸酶构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
18.权利要求14所述的方法,其中所述基因编辑剂包括同源重组构建体,所述同源重组构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
19.权利要求14所述的方法,其中所述基因编辑剂包括碱基编辑构建体,所述碱基编辑构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
20.权利要求15至19所述的方法,其中所述基因编辑剂不降低或抑制C3d或C3d衍生肽或其他免疫刺激性肽在肿瘤细胞中的表达、活性或产生。
21.权利要求11所述的方法,其中所述第一药剂是包括RNAi、shRNA、miRNA或反义RNA的核酸构建体,所述核酸构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
22.权利要求11所述的方法,其中所述第一药剂是表达如下蛋白质的核酸构建体,所述蛋白质降低或抑制以下各项在肿瘤细胞内的转录:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
23.权利要求14至22中任一项所述的方法,其中使用病毒载体、脂质体或外来体将所述药剂靶向递送至所述肿瘤细胞。
24.权利要求23所述的方法,其中所述病毒载体包括腺病毒、腺相关病毒、慢病毒载体、牛痘病毒、疱疹病毒载体、副粘病毒或任何病毒载体或任何病毒样颗粒。
25.权利要求11所述的方法,其中所述第二药剂包括靶向所述肿瘤细胞的表达载体,其中所述载体包括在所述肿瘤细胞中表达C3d或其生物活性变体或其他免疫刺激性肽的核酸构建体。
26.在受试者中治疗癌症或预防癌症转移的方法,其中所述癌细胞表达补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,所述方法包括:
a)向所述受试者施用治疗有效量的第一药剂,其中所述第一药剂降低以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,以及
b)向所述受试者施用治疗有效量的第二药剂,其中所述第二药剂增加补体蛋白C3d或源自C3d的肽或其他免疫刺激性肽在所述受试者的癌细胞或肿瘤微环境中的表达,从而治疗癌症或预防癌症的转移。
27.权利要求26所述的方法,其中所述第一药剂包括基因编辑剂,所述基因编辑剂降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
28.权利要求26所述的方法,其中所述基因编辑剂包括CRISPR-Cas系统构建体,所述CRISPR-Cas系统构建体降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
29.权利要求26所述的方法,其中所述基因编辑剂包括TALEN构建体,所述TALEN构建体降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
30.权利要求26所述的方法,其中所述基因编辑剂包括大范围核酸酶构建体,所述大范围核酸酶构建体降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
31.权利要求26所述的方法,其中,所述基因编辑剂包括同源重组构建体,所述同源重组构建体降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
32.权利要求26所述的方法,其中所述基因编辑剂包括碱基编辑构建体,所述碱基编辑构建体降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
33.权利要求27至32所述的方法,其中所述基因编辑剂不降低或抑制C3d或包括源自C3d的肽的其生物活性变体或其他免疫刺激性肽在癌细胞中的表达、活性或产生。
34.权利要求33所述的方法,其中所述第一药剂是包括RNAi、shRNA、miRNA或反义RNA的核酸构建体,所述核酸构建体降低或抑制以下各项在癌细胞中的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
35.权利要求33所述的方法,其中所述第一药剂是表达如下蛋白质的核酸构建体,所述蛋白质降低或抑制以下各项在癌细胞中的转录:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
36.权利要求26至35中任一项所述的方法,其中使用病毒载体、脂质体或外来体将所述药剂靶向递送至癌细胞。
37.权利要求36所述的方法,其中所述病毒载体包括腺病毒、腺相关病毒、慢病毒载体、牛痘病毒、疱疹病毒载体、副粘病毒或任何病毒载体或任何病毒样颗粒。
38.权利要求26所述的方法,其中所述第二药剂包括靶向所述肿瘤细胞的表达载体,其中所述载体包括在所述癌细胞中表达C3d或源自C3d的肽或其生物活性变体或其他免疫刺激性肽的核酸构建体。
39.权利要求26所述的方法,其中所述第一和/或第二药剂与至少一种其他癌症治疗同时或在其之前或之后顺序施用。
40.权利要求39所述的方法,其中所述癌症治疗是施用选自由以下各项组成的组的治疗:检查点抑制剂、蛋白酶体抑制剂、免疫疗法、放射疗法、化学疗法。
41.药物组合物,其包括药学上可接受的介质中的治疗有效量的第一药剂和治疗有效量的第二药剂,所述第一药剂降低以下各项在肿瘤细胞内的表达、产生或活性:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合,所述第二药剂增加补体蛋白C3d或包括源自C3d的肽的其生物活性变体或其他免疫刺激性肽在肿瘤细胞或肿瘤细胞微环境中的表达或活性。
42.权利要求41所述的组合物,其中所述第一药剂包括基因编辑剂,所述基因编辑剂降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
43.权利要求41所述的组合物,其中所述基因编辑剂包括CRISPR-Cas系统构建体,所述CRISPR-Cas系统构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
44.权利要求41所述的组合物,其中所述基因编辑剂包括TALEN构建体,所述TALEN构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
45.权利要求41所述的组合物,其中所述基因编辑剂包括大范围核酸酶构建体,所述大范围核酸酶构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
46.权利要求41所述的组合物,其中所述基因编辑剂包括同源重组构建体,所述同源重组构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
47.权利要求41所述的组合物,其中所述基因编辑剂包括碱基编辑构建体,所述碱基编辑构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
48.权利要求41所述的组合物,其中所述第一药剂是包括RNAi、shRNA、miRNA或反义RNA的核酸构建体,所述核酸构建体降低或抑制以下各项在肿瘤细胞内的表达、活性或产生:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
49.权利要求41所述的组合物,其中所述第一药剂是表达如下蛋白质的核酸构建体,所述蛋白质降低或抑制以下各项在肿瘤细胞内的转录:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
50.权利要求41至49中任一项所述的组合物,其中使用病毒载体、脂质体或外来体将所述药剂靶向递送至肿瘤细胞。
51.权利要求50所述的组合物,其中所述病毒载体包括腺病毒、腺相关病毒、慢病毒载体、牛痘病毒、疱疹病毒载体、副粘病毒或任何病毒载体或任何病毒样颗粒。
52.权利要求41所述的组合物,其中所述第二药剂包括靶向所述肿瘤细胞的表达载体,其中所述载体包括在肿瘤细胞中表达C3d或包括源自C3d的肽的其生物活性变体或其他免疫刺激性肽的核酸构建体。
53.权利要求41所述的组合物,其中所述第一药剂包括小分子,所述小分子降低或抑制以下各项在肿瘤细胞内的表达、产生或活性:补体成分,例如C3和C5;补体受体,例如C3aR1、C5aR1、C5aR2、C1R、C1RL、CR2和LAIR1;补体因子,例如CFB、CFD、CFH、CFHR1、CFHR2、CFHR3、CFHR4、CFHR5、CFI和CFP;补体调节剂,例如C1QBP、CD46、CD55和CD59;或组织蛋白酶,例如CTSB、CTSC、CTSD、CSTL、CSTO或CTSS或其任意组合。
54.权利要求1、10、11、25、26或38中任一项所述的方法,其中所述第二药剂是包括C3d和CD 55或C3d和CD 59蛋白质的融合蛋白构建体。
55.权利要求41或52所述的组合物,其中所述第二药剂是包括C3d和CD 55或C3d和CD59蛋白质的融合蛋白构建体。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762556836P | 2017-09-11 | 2017-09-11 | |
US62/556,836 | 2017-09-11 | ||
US201762582365P | 2017-11-07 | 2017-11-07 | |
US62/582,365 | 2017-11-07 | ||
US201862656495P | 2018-04-12 | 2018-04-12 | |
US62/656,495 | 2018-04-12 | ||
PCT/US2018/050330 WO2019051443A1 (en) | 2017-09-11 | 2018-09-11 | METHODS AND COMPOSITIONS FOR IMPROVING IMMUNOGENICITY OF TUMORS |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111315885A true CN111315885A (zh) | 2020-06-19 |
Family
ID=63762991
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880072494.0A Pending CN111315885A (zh) | 2017-09-11 | 2018-09-11 | 增强肿瘤免疫原性的方法和组合物 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20200262879A1 (zh) |
EP (1) | EP3682006A1 (zh) |
JP (1) | JP2020533414A (zh) |
CN (1) | CN111315885A (zh) |
MA (1) | MA50280A (zh) |
WO (1) | WO2019051443A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109666693A (zh) * | 2018-12-29 | 2019-04-23 | 北京市农林科学院 | Mg132在碱基编辑系统编辑受体基因组中的应用 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210403519A1 (en) * | 2018-11-02 | 2021-12-30 | Insideoutbio, Inc. | Methods and compositions to induce or suppress immune responses through the use of membrane bound complement split products |
WO2021072031A1 (en) * | 2019-10-11 | 2021-04-15 | Insideoutbio, Inc. | Methods and compositions for the manufacture and use of circular dna encoded therapeutics for genetic disorders and other diseases |
CN114686481B (zh) * | 2020-12-31 | 2023-08-15 | 北京键凯科技股份有限公司 | 一种抑制cfd表达的干扰rna及其制备方法和应用 |
GB202107586D0 (en) | 2021-05-27 | 2021-07-14 | Complement Therapeutics Ltd | Inhibitory nucleic acids for Factor H family proteins |
US20240035033A1 (en) * | 2022-07-29 | 2024-02-01 | Chung-Ang University Industry-Academic Cooperation Foundation | Prevention and treatment of age-related macular degeneration through suppression of cathepsin s expression |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110236455A1 (en) * | 2008-09-26 | 2011-09-29 | Peter Zipfel | Novel Regulators of the Innate Immune System |
US20150361183A1 (en) * | 2013-01-30 | 2015-12-17 | Imperial Innovations Limited | Inhibition of the complement system |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US5426039A (en) | 1993-09-08 | 1995-06-20 | Bio-Rad Laboratories, Inc. | Direct molecular cloning of primer extended DNA containing an alkane diol |
GB9424631D0 (en) | 1994-12-06 | 1995-01-25 | Lynxvale Ltd | Modulating the immune response |
EP0921816A4 (en) | 1996-03-28 | 2004-09-22 | Whitehead Biomedical Inst | CELLS WITH INCREASED OPSONINE CONTENT AND METHOD FOR REGULATING AN IMMUNE RESPONSE TO ANTIQUE |
US20030103984A1 (en) * | 1998-05-04 | 2003-06-05 | Heinz Kohler | Fusion proteins of biologically active peptides and antibodies |
US20150231227A1 (en) | 2000-03-02 | 2015-08-20 | Emory University | Compositions and methods for generating an immune response |
US7371387B2 (en) | 2001-02-21 | 2008-05-13 | Genitrix Llc | Vaccine compositions and methods of modulating immune responses |
AU2002336760A1 (en) | 2001-09-26 | 2003-06-10 | Mayo Foundation For Medical Education And Research | Mutable vaccines |
WO2009121065A2 (en) | 2008-03-28 | 2009-10-01 | Apellis Ag | Modulation and repletion/enhancement of the complement system for treatment of trauma |
GB0916997D0 (en) | 2009-09-28 | 2009-11-11 | Ark Therapeutics Ltd | Combination therapy |
KR20130036276A (ko) | 2010-06-22 | 2013-04-11 | 더 리젠츠 오브 더 유니버시티 오브 콜로라도, 어 바디 코포레이트 | 보체 결합 3의 C3d 조각에 대한 항체들 |
CA2843684A1 (en) * | 2010-08-13 | 2012-02-16 | Tufts University | Compositions, kits and methods for treatment of macular degeneration using soluble membrane-independent cd59 protein |
WO2013110064A1 (en) * | 2012-01-19 | 2013-07-25 | Albany Medical College | Fusion protein for enhancing immunogenicity of bacterial antigen/immunogen |
US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
WO2014197885A2 (en) * | 2013-06-07 | 2014-12-11 | Duke University | Inhibitors of complement factor h |
US10035848B2 (en) | 2014-01-08 | 2018-07-31 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibody targeting cell surface deposited complement protein C3d and use thereof |
CN107249645A (zh) | 2014-12-12 | 2017-10-13 | 朱坚 | 用于选择性消除所关注细胞的方法和组合物 |
EP3268044A2 (en) | 2015-03-11 | 2018-01-17 | The Broad Institute Inc. | Prmt5 inhibitors for the treatment of cancer with reduced mtap activty |
US20170020922A1 (en) | 2015-07-16 | 2017-01-26 | Batu Biologics Inc. | Gene editing for immunological destruction of neoplasia |
US10240145B2 (en) | 2015-11-25 | 2019-03-26 | The Board Of Trustees Of The Leland Stanford Junior University | CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer |
HUE056019T2 (hu) | 2015-12-23 | 2022-01-28 | eleva GmbH | Polipeptidek komplement aktiváció gátlására |
-
2018
- 2018-09-11 WO PCT/US2018/050330 patent/WO2019051443A1/en unknown
- 2018-09-11 MA MA050280A patent/MA50280A/fr unknown
- 2018-09-11 EP EP18782582.3A patent/EP3682006A1/en not_active Withdrawn
- 2018-09-11 CN CN201880072494.0A patent/CN111315885A/zh active Pending
- 2018-09-11 JP JP2020536719A patent/JP2020533414A/ja active Pending
- 2018-09-11 US US16/645,646 patent/US20200262879A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110236455A1 (en) * | 2008-09-26 | 2011-09-29 | Peter Zipfel | Novel Regulators of the Innate Immune System |
US20150361183A1 (en) * | 2013-01-30 | 2015-12-17 | Imperial Innovations Limited | Inhibition of the complement system |
Non-Patent Citations (3)
Title |
---|
PEI-HE LIANG等: "Construction of a DNA vaccine encoding Flk-1 extracellular domain and C3d fusion gene and investigation of its suppressing eVect on tumor growth", 《CANCER IMMUNOL IMMUNOTHER》 * |
SRINIVAS MAMIDI等: "Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab", 《MOLECULAR ONCOLOGY》 * |
WEI ZHANG等: "Generation of complement protein C3 deficient pigs by CRISPR/Cas9- mediated gene targeting", 《SCIENTIFIC REPORTS》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109666693A (zh) * | 2018-12-29 | 2019-04-23 | 北京市农林科学院 | Mg132在碱基编辑系统编辑受体基因组中的应用 |
CN109666693B (zh) * | 2018-12-29 | 2022-08-16 | 北京市农林科学院 | Mg132在碱基编辑系统编辑受体基因组中的应用 |
Also Published As
Publication number | Publication date |
---|---|
MA50280A (fr) | 2020-07-22 |
US20200262879A1 (en) | 2020-08-20 |
EP3682006A1 (en) | 2020-07-22 |
WO2019051443A1 (en) | 2019-03-14 |
JP2020533414A (ja) | 2020-11-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111315885A (zh) | 增强肿瘤免疫原性的方法和组合物 | |
US20220220506A1 (en) | Compositions and processes for targeted delivery, expression and modulation of coding ribonucleic acids in tissue | |
US20200376142A1 (en) | Compositions and methods for organ-protective expression and modulation of coding ribonucleic acids | |
JP2024059816A (ja) | エキソソーム関連遺伝子編集を用いてがんを処置するための方法および組成物 | |
KR20200136978A (ko) | 치료제의 표적화된 전달을 위한 엑소좀의 용도 | |
CN113227384B (zh) | 用于治疗肿瘤的药物组合物、药盒和方法 | |
US20220220169A1 (en) | Modular Therapeutics for the Treatment of Inflammatory Diseases and Cancer | |
JP2022539779A (ja) | 腫瘍を治療するための医薬組成物、キット及び方法 | |
US20210403519A1 (en) | Methods and compositions to induce or suppress immune responses through the use of membrane bound complement split products | |
WO2021072031A1 (en) | Methods and compositions for the manufacture and use of circular dna encoded therapeutics for genetic disorders and other diseases | |
US11497772B2 (en) | Targeting of SRC-3 in immune cells as an immunomodulatory therapeutic for the treatment of cancer | |
US20230346901A1 (en) | Methods and vaccine compositions to treat cancers | |
WO2021118927A1 (en) | Methods and compositions for targeted delivery of nucleic acid therapeutics | |
JP2016023182A (ja) | がんを処置するための医薬 | |
WO2013086433A1 (en) | Sirna compositions and methods for inhibiting gene expression in tumor initiating cells of breast cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200619 |
|
WD01 | Invention patent application deemed withdrawn after publication |