WO2017210562A1 - Compositions and methods for tumor vaccination using prostate cancer-associated antigens - Google Patents
Compositions and methods for tumor vaccination using prostate cancer-associated antigens Download PDFInfo
- Publication number
- WO2017210562A1 WO2017210562A1 PCT/US2017/035694 US2017035694W WO2017210562A1 WO 2017210562 A1 WO2017210562 A1 WO 2017210562A1 US 2017035694 W US2017035694 W US 2017035694W WO 2017210562 A1 WO2017210562 A1 WO 2017210562A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antigen
- composition
- seq
- nucleic acid
- acid sequence
- Prior art date
Links
- 239000000427 antigen Substances 0.000 title claims abstract description 236
- 108091007433 antigens Proteins 0.000 title claims abstract description 234
- 102000036639 antigens Human genes 0.000 title claims abstract description 234
- 239000000203 mixture Substances 0.000 title claims abstract description 148
- 238000000034 method Methods 0.000 title claims abstract description 105
- 206010028980 Neoplasm Diseases 0.000 title claims description 106
- 208000000236 Prostatic Neoplasms Diseases 0.000 title claims description 33
- 206010060862 Prostate cancer Diseases 0.000 title claims description 29
- 238000002255 vaccination Methods 0.000 title abstract description 23
- 239000013598 vector Substances 0.000 claims abstract description 287
- 108010072866 Prostate-Specific Antigen Proteins 0.000 claims abstract description 144
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 126
- 241000701161 unidentified adenovirus Species 0.000 claims abstract description 114
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims abstract description 95
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims abstract description 87
- 230000036039 immunity Effects 0.000 claims abstract description 17
- 230000000139 costimulatory effect Effects 0.000 claims abstract description 14
- 102000007066 Prostate-Specific Antigen Human genes 0.000 claims abstract 16
- 210000004027 cell Anatomy 0.000 claims description 164
- 150000007523 nucleic acids Chemical group 0.000 claims description 131
- -1 GplOO Proteins 0.000 claims description 113
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 85
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims description 83
- 238000012217 deletion Methods 0.000 claims description 60
- 230000037430 deletion Effects 0.000 claims description 60
- 230000014509 gene expression Effects 0.000 claims description 59
- 102100034256 Mucin-1 Human genes 0.000 claims description 57
- 230000028993 immune response Effects 0.000 claims description 57
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 55
- 241000700605 Viruses Species 0.000 claims description 47
- 241001068295 Replication defective viruses Species 0.000 claims description 44
- 229960005486 vaccine Drugs 0.000 claims description 43
- 241000282414 Homo sapiens Species 0.000 claims description 42
- 201000011510 cancer Diseases 0.000 claims description 40
- 230000004927 fusion Effects 0.000 claims description 40
- 230000001900 immune effect Effects 0.000 claims description 36
- 238000009169 immunotherapy Methods 0.000 claims description 36
- 108010074328 Interferon-gamma Proteins 0.000 claims description 35
- 230000003053 immunization Effects 0.000 claims description 35
- 210000000822 natural killer cell Anatomy 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 102000003812 Interleukin-15 Human genes 0.000 claims description 32
- 108090000172 Interleukin-15 Proteins 0.000 claims description 32
- 102100037850 Interferon gamma Human genes 0.000 claims description 31
- 238000002649 immunization Methods 0.000 claims description 31
- 239000002245 particle Substances 0.000 claims description 31
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 28
- 239000002773 nucleotide Substances 0.000 claims description 20
- 125000003729 nucleotide group Chemical group 0.000 claims description 20
- 108010029485 Protein Isoforms Proteins 0.000 claims description 16
- 102000001708 Protein Isoforms Human genes 0.000 claims description 16
- 230000002950 deficient Effects 0.000 claims description 16
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 15
- 230000001404 mediated effect Effects 0.000 claims description 14
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 13
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 13
- 102000046689 human FOLH1 Human genes 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 claims description 11
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims description 11
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 11
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 11
- 102000002698 KIR Receptors Human genes 0.000 claims description 11
- 108010043610 KIR Receptors Proteins 0.000 claims description 11
- 102100031413 L-dopachrome tautomerase Human genes 0.000 claims description 11
- 101710093778 L-dopachrome tautomerase Proteins 0.000 claims description 11
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 claims description 11
- 238000002512 chemotherapy Methods 0.000 claims description 11
- 102000015735 Beta-catenin Human genes 0.000 claims description 10
- 108060000903 Beta-catenin Proteins 0.000 claims description 10
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 10
- 210000004443 dendritic cell Anatomy 0.000 claims description 10
- 230000003612 virological effect Effects 0.000 claims description 10
- 108010029697 CD40 Ligand Proteins 0.000 claims description 9
- 102100032937 CD40 ligand Human genes 0.000 claims description 9
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims description 9
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 9
- 230000002708 enhancing effect Effects 0.000 claims description 9
- 101150029707 ERBB2 gene Proteins 0.000 claims description 8
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 claims description 8
- 108700020467 WT1 Proteins 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- 108010084313 CD58 Antigens Proteins 0.000 claims description 7
- 108010074032 HLA-A2 Antigen Proteins 0.000 claims description 7
- 102000025850 HLA-A2 Antigen Human genes 0.000 claims description 7
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 claims description 7
- 102100036735 Prostate stem cell antigen Human genes 0.000 claims description 7
- 102100023635 Alpha-fetoprotein Human genes 0.000 claims description 6
- 101000719121 Arabidopsis thaliana Protein MEI2-like 1 Proteins 0.000 claims description 6
- 102100038078 CD276 antigen Human genes 0.000 claims description 6
- 101150108242 CDC27 gene Proteins 0.000 claims description 6
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 6
- 102100039510 Cancer/testis antigen 2 Human genes 0.000 claims description 6
- 102100026548 Caspase-8 Human genes 0.000 claims description 6
- 108090000538 Caspase-8 Proteins 0.000 claims description 6
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims description 6
- 102100039717 G antigen 1 Human genes 0.000 claims description 6
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 6
- 101000889345 Homo sapiens Cancer/testis antigen 2 Proteins 0.000 claims description 6
- 101000886137 Homo sapiens G antigen 1 Proteins 0.000 claims description 6
- 101000614481 Homo sapiens Kidney-associated antigen 1 Proteins 0.000 claims description 6
- 101000857677 Homo sapiens Runt-related transcription factor 1 Proteins 0.000 claims description 6
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 claims description 6
- 102000003505 Myosin Human genes 0.000 claims description 6
- 108060008487 Myosin Proteins 0.000 claims description 6
- 108060006580 PRAME Proteins 0.000 claims description 6
- 102000036673 PRAME Human genes 0.000 claims description 6
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 6
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 claims description 6
- 102000003425 Tyrosinase Human genes 0.000 claims description 6
- 108060008724 Tyrosinase Proteins 0.000 claims description 6
- 230000004663 cell proliferation Effects 0.000 claims description 6
- 102000052587 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Human genes 0.000 claims description 5
- 108700004606 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Proteins 0.000 claims description 5
- 102000004149 Annexin A2 Human genes 0.000 claims description 5
- 108090000668 Annexin A2 Proteins 0.000 claims description 5
- 102100035526 B melanoma antigen 1 Human genes 0.000 claims description 5
- 101000653197 Beet necrotic yellow vein virus (isolate Japan/S) Movement protein TGB3 Proteins 0.000 claims description 5
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 claims description 5
- 241000282836 Camelus dromedarius Species 0.000 claims description 5
- 102100024462 Cyclin-dependent kinase 4 inhibitor B Human genes 0.000 claims description 5
- 102100040606 Dermatan-sulfate epimerase Human genes 0.000 claims description 5
- 101710127030 Dermatan-sulfate epimerase Proteins 0.000 claims description 5
- 101100216227 Dictyostelium discoideum anapc3 gene Proteins 0.000 claims description 5
- 102100028043 Fibroblast growth factor 3 Human genes 0.000 claims description 5
- 108090000382 Fibroblast growth factor 6 Proteins 0.000 claims description 5
- 102100028075 Fibroblast growth factor 6 Human genes 0.000 claims description 5
- 108050001931 Folate receptor alpha Proteins 0.000 claims description 5
- 102000010451 Folate receptor alpha Human genes 0.000 claims description 5
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 5
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 claims description 5
- 101000980919 Homo sapiens Cyclin-dependent kinase 4 inhibitor B Proteins 0.000 claims description 5
- 101000954709 Homo sapiens Doublecortin domain-containing protein 2 Proteins 0.000 claims description 5
- 101000985516 Homo sapiens Hermansky-Pudlak syndrome 5 protein Proteins 0.000 claims description 5
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 claims description 5
- 101001134060 Homo sapiens Melanocyte-stimulating hormone receptor Proteins 0.000 claims description 5
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 claims description 5
- 101000721712 Homo sapiens NTF2-related export protein 1 Proteins 0.000 claims description 5
- 101001109419 Homo sapiens RNA-binding protein NOB1 Proteins 0.000 claims description 5
- 101000648075 Homo sapiens Trafficking protein particle complex subunit 1 Proteins 0.000 claims description 5
- 101000813738 Homo sapiens Transcription factor ETV6 Proteins 0.000 claims description 5
- 101710123134 Ice-binding protein Proteins 0.000 claims description 5
- 101710082837 Ice-structuring protein Proteins 0.000 claims description 5
- 108050002021 Integrator complex subunit 2 Proteins 0.000 claims description 5
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 claims description 5
- 102100034216 Melanocyte-stimulating hormone receptor Human genes 0.000 claims description 5
- 102100034263 Mucin-2 Human genes 0.000 claims description 5
- 101001062862 Mus musculus Fatty acid-binding protein, adipocyte Proteins 0.000 claims description 5
- 101000621505 Peanut clump virus (isolate 87/TGTA2) Suppressor of RNA silencing Proteins 0.000 claims description 5
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 5
- 102100022491 RNA-binding protein NOB1 Human genes 0.000 claims description 5
- 102100035748 Squamous cell carcinoma antigen recognized by T-cells 3 Human genes 0.000 claims description 5
- 101710185775 Squamous cell carcinoma antigen recognized by T-cells 3 Proteins 0.000 claims description 5
- 102100025256 Trafficking protein particle complex subunit 1 Human genes 0.000 claims description 5
- 102100039580 Transcription factor ETV6 Human genes 0.000 claims description 5
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 claims description 5
- 101710107540 Type-2 ice-structuring protein Proteins 0.000 claims description 5
- 102000040856 WT1 Human genes 0.000 claims description 5
- 101150084041 WT1 gene Proteins 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 5
- 230000001580 bacterial effect Effects 0.000 claims description 5
- 239000003550 marker Substances 0.000 claims description 5
- 102100021305 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 Human genes 0.000 claims description 4
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 claims description 4
- 108700020463 BRCA1 Proteins 0.000 claims description 4
- 101150072950 BRCA1 gene Proteins 0.000 claims description 4
- 102100025401 Breast cancer type 1 susceptibility protein Human genes 0.000 claims description 4
- 108010013476 HLA-A24 Antigen Proteins 0.000 claims description 4
- 108010086377 HLA-A3 Antigen Proteins 0.000 claims description 4
- 101001042227 Homo sapiens Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 Proteins 0.000 claims description 4
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 claims description 4
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 4
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 4
- 101000665137 Homo sapiens Scm-like with four MBT domains protein 1 Proteins 0.000 claims description 4
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 4
- 102000017578 LAG3 Human genes 0.000 claims description 4
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 4
- 102100034640 PWWP domain-containing DNA repair factor 3A Human genes 0.000 claims description 4
- 108050007154 PWWP domain-containing DNA repair factor 3A Proteins 0.000 claims description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 4
- 102100038689 Scm-like with four MBT domains protein 1 Human genes 0.000 claims description 4
- 230000006052 T cell proliferation Effects 0.000 claims description 4
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 4
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 4
- 108700015934 Triose-phosphate isomerases Proteins 0.000 claims description 4
- 102100033598 Triosephosphate isomerase Human genes 0.000 claims description 4
- 102100027244 U4/U6.U5 tri-snRNP-associated protein 1 Human genes 0.000 claims description 4
- 101710155955 U4/U6.U5 tri-snRNP-associated protein 1 Proteins 0.000 claims description 4
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 230000035755 proliferation Effects 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 claims description 3
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 claims description 3
- 108700031361 Brachyury Proteins 0.000 claims description 3
- 102100027207 CD27 antigen Human genes 0.000 claims description 3
- 101710185679 CD276 antigen Proteins 0.000 claims description 3
- 101150013553 CD40 gene Proteins 0.000 claims description 3
- 102100025221 CD70 antigen Human genes 0.000 claims description 3
- 102100031351 Galectin-9 Human genes 0.000 claims description 3
- 101100229077 Gallus gallus GAL9 gene Proteins 0.000 claims description 3
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 3
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 claims description 3
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 claims description 3
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 claims description 3
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 claims description 3
- 101000638251 Homo sapiens Tumor necrosis factor ligand superfamily member 9 Proteins 0.000 claims description 3
- 102100034980 ICOS ligand Human genes 0.000 claims description 3
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 claims description 3
- 108010042215 OX40 Ligand Proteins 0.000 claims description 3
- 102000004473 OX40 Ligand Human genes 0.000 claims description 3
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims description 3
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 3
- 101710173693 Short transient receptor potential channel 1 Proteins 0.000 claims description 3
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 claims description 3
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 3
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 3
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 claims description 3
- 206010046865 Vaccinia virus infection Diseases 0.000 claims description 3
- 230000003915 cell function Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 208000007089 vaccinia Diseases 0.000 claims description 3
- 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 claims description 2
- 102100039699 G antigen 4 Human genes 0.000 claims description 2
- 102100039698 G antigen 5 Human genes 0.000 claims description 2
- 101710092267 G antigen 5 Proteins 0.000 claims description 2
- 102100039713 G antigen 6 Human genes 0.000 claims description 2
- 101710092269 G antigen 6 Proteins 0.000 claims description 2
- 102100040578 G antigen 7 Human genes 0.000 claims description 2
- 108010007707 Hepatitis A Virus Cellular Receptor 2 Proteins 0.000 claims description 2
- 101000886136 Homo sapiens G antigen 4 Proteins 0.000 claims description 2
- 101000893968 Homo sapiens G antigen 7 Proteins 0.000 claims description 2
- 101000945351 Homo sapiens Killer cell immunoglobulin-like receptor 3DL1 Proteins 0.000 claims description 2
- 101000884270 Homo sapiens Natural killer cell receptor 2B4 Proteins 0.000 claims description 2
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 claims description 2
- 102100033627 Killer cell immunoglobulin-like receptor 3DL1 Human genes 0.000 claims description 2
- 108010008707 Mucin-1 Proteins 0.000 claims description 2
- 102100038082 Natural killer cell receptor 2B4 Human genes 0.000 claims description 2
- 108050003189 SH2B adapter protein 1 Proteins 0.000 claims description 2
- 102000006601 Thymidine Kinase Human genes 0.000 claims description 2
- 108020004440 Thymidine kinase Proteins 0.000 claims description 2
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 2
- FUHMZYWBSHTEDZ-UHFFFAOYSA-M bispyribac-sodium Chemical compound [Na+].COC1=CC(OC)=NC(OC=2C(=C(OC=3N=C(OC)C=C(OC)N=3)C=CC=2)C([O-])=O)=N1 FUHMZYWBSHTEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000002538 fungal effect Effects 0.000 claims description 2
- 230000008348 humoral response Effects 0.000 claims description 2
- 230000004073 interleukin-2 production Effects 0.000 claims description 2
- 230000002601 intratumoral effect Effects 0.000 claims description 2
- 101150066555 lacZ gene Proteins 0.000 claims description 2
- 208000037819 metastatic cancer Diseases 0.000 claims description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 claims description 2
- 239000003226 mitogen Substances 0.000 claims description 2
- 244000045947 parasite Species 0.000 claims description 2
- 102100028721 Hermansky-Pudlak syndrome 5 protein Human genes 0.000 claims 2
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 claims 2
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 claims 2
- 102100026882 Alpha-synuclein Human genes 0.000 claims 1
- 102100024003 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 Human genes 0.000 claims 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims 1
- 102100031788 E3 ubiquitin-protein ligase MYLIP Human genes 0.000 claims 1
- 101710190174 E3 ubiquitin-protein ligase MYLIP Proteins 0.000 claims 1
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims 1
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 claims 1
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims 1
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 claims 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims 1
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims 1
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 claims 1
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 claims 1
- 108040000983 polyphosphate:AMP phosphotransferase activity proteins Proteins 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 26
- 229940126580 vector vaccine Drugs 0.000 abstract description 4
- 230000005975 antitumor immune response Effects 0.000 abstract description 3
- 241001135569 Human adenovirus 5 Species 0.000 description 129
- 102100038358 Prostate-specific antigen Human genes 0.000 description 128
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 73
- 108090000765 processed proteins & peptides Proteins 0.000 description 73
- 102000004169 proteins and genes Human genes 0.000 description 64
- 235000018102 proteins Nutrition 0.000 description 57
- 102000004196 processed proteins & peptides Human genes 0.000 description 55
- 229920001184 polypeptide Polymers 0.000 description 54
- 102000040430 polynucleotide Human genes 0.000 description 42
- 108091033319 polynucleotide Proteins 0.000 description 42
- 239000002157 polynucleotide Substances 0.000 description 42
- 102000004127 Cytokines Human genes 0.000 description 35
- 108090000695 Cytokines Proteins 0.000 description 35
- 210000004988 splenocyte Anatomy 0.000 description 30
- 239000012634 fragment Substances 0.000 description 28
- 230000002163 immunogen Effects 0.000 description 28
- 201000010099 disease Diseases 0.000 description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 108010002350 Interleukin-2 Proteins 0.000 description 26
- 102000000588 Interleukin-2 Human genes 0.000 description 26
- 230000006870 function Effects 0.000 description 25
- 230000004044 response Effects 0.000 description 24
- 241000699670 Mus sp. Species 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 23
- 230000037396 body weight Effects 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 230000035772 mutation Effects 0.000 description 22
- 230000000638 stimulation Effects 0.000 description 20
- 210000001744 T-lymphocyte Anatomy 0.000 description 19
- 229940024606 amino acid Drugs 0.000 description 19
- 150000001413 amino acids Chemical class 0.000 description 19
- 230000010076 replication Effects 0.000 description 19
- 101710164463 Preterminal protein Proteins 0.000 description 18
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 17
- 230000000670 limiting effect Effects 0.000 description 17
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 16
- 102000039446 nucleic acids Human genes 0.000 description 16
- 108020004707 nucleic acids Proteins 0.000 description 16
- 108020004414 DNA Proteins 0.000 description 15
- 108050003558 Interleukin-17 Proteins 0.000 description 15
- 102000013691 Interleukin-17 Human genes 0.000 description 15
- 238000013459 approach Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 230000028327 secretion Effects 0.000 description 14
- 239000002671 adjuvant Substances 0.000 description 13
- 239000012636 effector Substances 0.000 description 13
- 108020001507 fusion proteins Proteins 0.000 description 13
- 102000037865 fusion proteins Human genes 0.000 description 13
- 230000005847 immunogenicity Effects 0.000 description 13
- 230000003248 secreting effect Effects 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- 102100030703 Interleukin-22 Human genes 0.000 description 12
- 230000008901 benefit Effects 0.000 description 12
- 210000002307 prostate Anatomy 0.000 description 12
- 238000013519 translation Methods 0.000 description 12
- 108010057840 ALT-803 Proteins 0.000 description 11
- 241000282412 Homo Species 0.000 description 11
- 239000002246 antineoplastic agent Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 238000011275 oncology therapy Methods 0.000 description 11
- 238000006467 substitution reaction Methods 0.000 description 11
- 230000008685 targeting Effects 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- 108090000978 Interleukin-4 Proteins 0.000 description 10
- 102000004388 Interleukin-4 Human genes 0.000 description 10
- 108010002616 Interleukin-5 Proteins 0.000 description 10
- 108090001005 Interleukin-6 Proteins 0.000 description 10
- 102000004889 Interleukin-6 Human genes 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 230000001413 cellular effect Effects 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 230000008088 immune pathway Effects 0.000 description 10
- 230000002147 killing effect Effects 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 238000013518 transcription Methods 0.000 description 10
- 230000035897 transcription Effects 0.000 description 10
- 239000013603 viral vector Substances 0.000 description 10
- 108091026890 Coding region Proteins 0.000 description 9
- 238000002965 ELISA Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 108010002386 Interleukin-3 Proteins 0.000 description 9
- 102000000646 Interleukin-3 Human genes 0.000 description 9
- 108090001007 Interleukin-8 Proteins 0.000 description 9
- 108010002335 Interleukin-9 Proteins 0.000 description 9
- 102000000585 Interleukin-9 Human genes 0.000 description 9
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 9
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 9
- 108010063954 Mucins Proteins 0.000 description 9
- 102000015728 Mucins Human genes 0.000 description 9
- 102100031789 Myeloid-derived growth factor Human genes 0.000 description 9
- 108700012920 TNF Proteins 0.000 description 9
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 9
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 9
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 9
- 230000000973 chemotherapeutic effect Effects 0.000 description 9
- 238000002648 combination therapy Methods 0.000 description 9
- 239000003623 enhancer Substances 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 101000998139 Homo sapiens Interleukin-32 Proteins 0.000 description 8
- 241000701806 Human papillomavirus Species 0.000 description 8
- 108010065637 Interleukin-23 Proteins 0.000 description 8
- 102100033501 Interleukin-32 Human genes 0.000 description 8
- 108010002586 Interleukin-7 Proteins 0.000 description 8
- 108091008874 T cell receptors Proteins 0.000 description 8
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 230000001939 inductive effect Effects 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 8
- 230000026731 phosphorylation Effects 0.000 description 8
- 238000006366 phosphorylation reaction Methods 0.000 description 8
- 230000003389 potentiating effect Effects 0.000 description 8
- 230000002483 superagonistic effect Effects 0.000 description 8
- 238000011725 BALB/c mouse Methods 0.000 description 7
- 108010062802 CD66 antigens Proteins 0.000 description 7
- 238000011510 Elispot assay Methods 0.000 description 7
- 108091006020 Fc-tagged proteins Proteins 0.000 description 7
- 108090000467 Interferon-beta Proteins 0.000 description 7
- 108010065805 Interleukin-12 Proteins 0.000 description 7
- 102000013462 Interleukin-12 Human genes 0.000 description 7
- 108090000171 Interleukin-18 Proteins 0.000 description 7
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 7
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 229940034982 antineoplastic agent Drugs 0.000 description 7
- 231100000433 cytotoxic Toxicity 0.000 description 7
- 239000002254 cytotoxic agent Substances 0.000 description 7
- 230000001472 cytotoxic effect Effects 0.000 description 7
- 230000001024 immunotherapeutic effect Effects 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001356 surgical procedure Methods 0.000 description 7
- 238000012384 transportation and delivery Methods 0.000 description 7
- 102000007499 CD27 Ligand Human genes 0.000 description 6
- 108010046080 CD27 Ligand Proteins 0.000 description 6
- 102000004634 CD30 Ligand Human genes 0.000 description 6
- 108010017987 CD30 Ligand Proteins 0.000 description 6
- 102100024533 Carcinoembryonic antigen-related cell adhesion molecule 1 Human genes 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 102000001398 Granzyme Human genes 0.000 description 6
- 108060005986 Granzyme Proteins 0.000 description 6
- 101001002470 Homo sapiens Interferon lambda-1 Proteins 0.000 description 6
- 101000853000 Homo sapiens Interleukin-26 Proteins 0.000 description 6
- 101000998122 Homo sapiens Interleukin-37 Proteins 0.000 description 6
- 101000845170 Homo sapiens Thymic stromal lymphopoietin Proteins 0.000 description 6
- 229940099539 IL-36 receptor antagonist Drugs 0.000 description 6
- 102100026720 Interferon beta Human genes 0.000 description 6
- 102100020990 Interferon lambda-1 Human genes 0.000 description 6
- 102100020989 Interferon lambda-2 Human genes 0.000 description 6
- 101710099622 Interferon lambda-2 Proteins 0.000 description 6
- 102000003814 Interleukin-10 Human genes 0.000 description 6
- 108090000174 Interleukin-10 Proteins 0.000 description 6
- 101800003050 Interleukin-16 Proteins 0.000 description 6
- 102000049772 Interleukin-16 Human genes 0.000 description 6
- 102000013264 Interleukin-23 Human genes 0.000 description 6
- 102100036679 Interleukin-26 Human genes 0.000 description 6
- 108010067003 Interleukin-33 Proteins 0.000 description 6
- 102100021150 Interleukin-36 receptor antagonist protein Human genes 0.000 description 6
- 101710089409 Interleukin-36 receptor antagonist protein Proteins 0.000 description 6
- 102100033502 Interleukin-37 Human genes 0.000 description 6
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 6
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 6
- 102100026894 Lymphotoxin-beta Human genes 0.000 description 6
- 108090000362 Lymphotoxin-beta Proteins 0.000 description 6
- 108090000630 Oncostatin M Proteins 0.000 description 6
- 102100031942 Oncostatin-M Human genes 0.000 description 6
- 102100031294 Thymic stromal lymphopoietin Human genes 0.000 description 6
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 6
- 210000004899 c-terminal region Anatomy 0.000 description 6
- 239000003183 carcinogenic agent Substances 0.000 description 6
- 230000036755 cellular response Effects 0.000 description 6
- 229940127089 cytotoxic agent Drugs 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000001415 gene therapy Methods 0.000 description 6
- 210000002865 immune cell Anatomy 0.000 description 6
- 108090000681 interleukin 20 Proteins 0.000 description 6
- 102000004114 interleukin 20 Human genes 0.000 description 6
- 108010074108 interleukin-21 Proteins 0.000 description 6
- 108010074109 interleukin-22 Proteins 0.000 description 6
- 108090000237 interleukin-24 Proteins 0.000 description 6
- 102000003898 interleukin-24 Human genes 0.000 description 6
- 150000002632 lipids Chemical group 0.000 description 6
- 239000002502 liposome Substances 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 108010082808 4-1BB Ligand Proteins 0.000 description 5
- 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 5
- 238000011740 C57BL/6 mouse Methods 0.000 description 5
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 5
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 5
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 108700024394 Exon Proteins 0.000 description 5
- 102000003958 Glutamate Carboxypeptidase II Human genes 0.000 description 5
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 description 5
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 5
- 101000853002 Homo sapiens Interleukin-25 Proteins 0.000 description 5
- 101001128431 Homo sapiens Myeloid-derived growth factor Proteins 0.000 description 5
- 102100039879 Interleukin-19 Human genes 0.000 description 5
- 108050009288 Interleukin-19 Proteins 0.000 description 5
- 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 5
- 101710120463 Prostate stem cell antigen Proteins 0.000 description 5
- 102100035703 Prostatic acid phosphatase Human genes 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 108700019146 Transgenes Proteins 0.000 description 5
- 108010067390 Viral Proteins Proteins 0.000 description 5
- 230000005754 cellular signaling Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 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 5
- 230000007423 decrease Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000003292 diminished effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 5
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000003780 insertion Methods 0.000 description 5
- 230000037431 insertion Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 210000001616 monocyte Anatomy 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 108010043671 prostatic acid phosphatase Proteins 0.000 description 5
- 230000004853 protein function Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000002195 synergetic effect Effects 0.000 description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 description 4
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 4
- 101001003140 Homo sapiens Interleukin-15 receptor subunit alpha Proteins 0.000 description 4
- 102000008070 Interferon-gamma Human genes 0.000 description 4
- 108090000177 Interleukin-11 Proteins 0.000 description 4
- 102000003815 Interleukin-11 Human genes 0.000 description 4
- 108090000176 Interleukin-13 Proteins 0.000 description 4
- 102000003816 Interleukin-13 Human genes 0.000 description 4
- 108010066979 Interleukin-27 Proteins 0.000 description 4
- 102100040442 Kidney-associated antigen 1 Human genes 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 4
- 101710188053 Protein D Proteins 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- 101710132893 Resolvase Proteins 0.000 description 4
- 108091081024 Start codon Proteins 0.000 description 4
- 230000024932 T cell mediated immunity Effects 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 230000004071 biological effect Effects 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
- 210000000988 bone and bone Anatomy 0.000 description 4
- 230000007969 cellular immunity Effects 0.000 description 4
- 230000004640 cellular pathway Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 238000001794 hormone therapy Methods 0.000 description 4
- 230000003463 hyperproliferative effect Effects 0.000 description 4
- 239000012642 immune effector Substances 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 230000016784 immunoglobulin production Effects 0.000 description 4
- 229940121354 immunomodulator Drugs 0.000 description 4
- 230000003308 immunostimulating effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 230000026792 palmitoylation Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000037452 priming Effects 0.000 description 4
- 229960000714 sipuleucel-t Drugs 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 108700028369 Alleles Proteins 0.000 description 3
- 108010074708 B7-H1 Antigen Proteins 0.000 description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- 108010077333 CAP1-6D Proteins 0.000 description 3
- 102100024530 Carcinoembryonic antigen-related cell adhesion molecule 20 Human genes 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 102100028914 Catenin beta-1 Human genes 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 101710183768 Glutamate carboxypeptidase 2 Proteins 0.000 description 3
- 101710155188 Hexon-interlacing protein Proteins 0.000 description 3
- 101000981108 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 20 Proteins 0.000 description 3
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 3
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 3
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 3
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 108091092195 Intron Proteins 0.000 description 3
- 101150008942 J gene Proteins 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 3
- 229930192392 Mitomycin Natural products 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- 101710172711 Structural protein Proteins 0.000 description 3
- 102100033082 TNF receptor-associated factor 3 Human genes 0.000 description 3
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- 230000000692 anti-sense effect Effects 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000021164 cell adhesion Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000012292 cell migration Effects 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
- 210000000349 chromosome Anatomy 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000011498 curative surgery Methods 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 229960000640 dactinomycin Drugs 0.000 description 3
- 229960000975 daunorubicin Drugs 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000002919 epithelial cell Anatomy 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
- 238000002474 experimental method Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 229960001438 immunostimulant agent Drugs 0.000 description 3
- 239000003022 immunostimulating agent Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 229960003130 interferon gamma Drugs 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- 229960001924 melphalan Drugs 0.000 description 3
- 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 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 3
- 239000002088 nanocapsule Substances 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 231100000590 oncogenic Toxicity 0.000 description 3
- 230000002246 oncogenic effect Effects 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 3
- 229960000624 procarbazine Drugs 0.000 description 3
- 108010031970 prostasin Proteins 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000010188 recombinant method Methods 0.000 description 3
- 230000006798 recombination Effects 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 229930182490 saponin Natural products 0.000 description 3
- 150000007949 saponins Chemical class 0.000 description 3
- 235000017709 saponins Nutrition 0.000 description 3
- 210000000582 semen Anatomy 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000009450 sialylation Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000008093 supporting effect Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- 230000002485 urinary effect Effects 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- 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 3
- 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 3
- 229960004854 viral vaccine Drugs 0.000 description 3
- 210000002845 virion Anatomy 0.000 description 3
- OTLLEIBWKHEHGU-UHFFFAOYSA-N 2-[5-[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COC1C(CO)OC(OC(C(O)C(OP(O)(O)=O)C(O)C(O)=O)C(O)=O)C(O)C1O OTLLEIBWKHEHGU-UHFFFAOYSA-N 0.000 description 2
- PCZUSAVLHNFWAD-UHFFFAOYSA-N 2-sulfanylidene-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound NP1(=S)NCCCN1 PCZUSAVLHNFWAD-UHFFFAOYSA-N 0.000 description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229940023835 Ad-based vaccine Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 102100034112 Alkyldihydroxyacetonephosphate synthase, peroxisomal Human genes 0.000 description 2
- 108700023418 Amidases Proteins 0.000 description 2
- 108091008875 B cell receptors Proteins 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 102000039968 CEA family Human genes 0.000 description 2
- 108091069214 CEA family Proteins 0.000 description 2
- 102000000905 Cadherin Human genes 0.000 description 2
- 108050007957 Cadherin Proteins 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 102100035445 Carcinoembryonic antigen-related cell adhesion molecule 16 Human genes 0.000 description 2
- 102100035440 Carcinoembryonic antigen-related cell adhesion molecule 18 Human genes 0.000 description 2
- 102100024531 Carcinoembryonic antigen-related cell adhesion molecule 21 Human genes 0.000 description 2
- 102100025466 Carcinoembryonic antigen-related cell adhesion molecule 3 Human genes 0.000 description 2
- 102100025472 Carcinoembryonic antigen-related cell adhesion molecule 4 Human genes 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 2
- 108010049048 Cholera Toxin Proteins 0.000 description 2
- 102000009016 Cholera Toxin Human genes 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 108010062580 Concanavalin A Proteins 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- 241000450599 DNA viruses Species 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- 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 2
- QRLVDLBMBULFAL-UHFFFAOYSA-N Digitonin Natural products CC1CCC2(OC1)OC3C(O)C4C5CCC6CC(OC7OC(CO)C(OC8OC(CO)C(O)C(OC9OCC(O)C(O)C9OC%10OC(CO)C(O)C(OC%11OC(CO)C(O)C(O)C%11O)C%10O)C8O)C(O)C7O)C(O)CC6(C)C5CCC4(C)C3C2C QRLVDLBMBULFAL-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 2
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 2
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 2
- 101000799143 Homo sapiens Alkyldihydroxyacetonephosphate synthase, peroxisomal Proteins 0.000 description 2
- 101000737645 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 16 Proteins 0.000 description 2
- 101000737663 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 18 Proteins 0.000 description 2
- 101000981110 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 21 Proteins 0.000 description 2
- 101000914337 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 3 Proteins 0.000 description 2
- 101000914325 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 4 Proteins 0.000 description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 2
- 101000617708 Homo sapiens Pregnancy-specific beta-1-glycoprotein 1 Proteins 0.000 description 2
- 101000620554 Homo sapiens Ras-related protein Rab-38 Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101001010819 Homo sapiens Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 2
- 241000598171 Human adenovirus sp. Species 0.000 description 2
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 2
- 102100036705 Interleukin-23 subunit alpha Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 101001019594 Mus musculus Interleukin-15 receptor subunit alpha Proteins 0.000 description 2
- 241000187488 Mycobacterium sp. Species 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 2
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 2
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 2
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 102000016979 Other receptors Human genes 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100021983 Pregnancy-specific beta-1-glycoprotein 9 Human genes 0.000 description 2
- 102100022305 Ras-related protein Rab-38 Human genes 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 101150006914 TRP1 gene Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 108091036066 Three prime untranslated region Proteins 0.000 description 2
- 241000723873 Tobacco mosaic virus Species 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- 102000005922 amidase Human genes 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 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 2
- 229960001220 amsacrine Drugs 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 230000005809 anti-tumor immunity Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 238000002725 brachytherapy Methods 0.000 description 2
- 210000004900 c-terminal fragment Anatomy 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 238000012047 cause and effect analysis Methods 0.000 description 2
- 230000004709 cell invasion Effects 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000002759 chromosomal effect Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000011220 combination immunotherapy Methods 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000012043 cost effectiveness analysis Methods 0.000 description 2
- 238000002681 cryosurgery Methods 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- UVYVLBIGDKGWPX-KUAJCENISA-N digitonin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O[C@H]5[C@@H]([C@@H](O)[C@@H](O[C@H]6[C@@H]([C@@H](O[C@H]7[C@@H]([C@@H](O)[C@H](O)CO7)O)[C@H](O)[C@@H](CO)O6)O[C@H]6[C@@H]([C@@H](O[C@H]7[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O7)O)[C@@H](O)[C@@H](CO)O6)O)[C@@H](CO)O5)O)C[C@@H]4CC[C@H]3[C@@H]2[C@@H]1O)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 UVYVLBIGDKGWPX-KUAJCENISA-N 0.000 description 2
- UVYVLBIGDKGWPX-UHFFFAOYSA-N digitonine Natural products CC1C(C2(CCC3C4(C)CC(O)C(OC5C(C(O)C(OC6C(C(OC7C(C(O)C(O)CO7)O)C(O)C(CO)O6)OC6C(C(OC7C(C(O)C(O)C(CO)O7)O)C(O)C(CO)O6)O)C(CO)O5)O)CC4CCC3C2C2O)C)C2OC11CCC(C)CO1 UVYVLBIGDKGWPX-UHFFFAOYSA-N 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 206010013990 dysuria Diseases 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 210000001163 endosome Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 231100000776 exotoxin Toxicity 0.000 description 2
- 239000002095 exotoxin Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 229930182830 galactose Chemical group 0.000 description 2
- 210000003976 gap junction Anatomy 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 102000052224 human IL15RA Human genes 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 108091008042 inhibitory receptors Proteins 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 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 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 210000004197 pelvis Anatomy 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000000644 propagated effect Effects 0.000 description 2
- 229940030749 prostate cancer vaccine Drugs 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 230000003439 radiotherapeutic effect Effects 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 102220311640 rs1382779104 Human genes 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000009747 swallowing 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
- 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 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 235000002374 tyrosine Nutrition 0.000 description 2
- 150000003668 tyrosines Chemical class 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 229960001055 uracil mustard Drugs 0.000 description 2
- 210000003708 urethra Anatomy 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
- 230000029812 viral genome replication Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- AXNVHPCVMSNXNP-IVKVKCDBSA-N (2s,3s,4s,5r,6r)-6-[[(3s,4s,4ar,6ar,6bs,8r,8ar,9r,10r,12as,14ar,14br)-9-acetyloxy-8-hydroxy-4,8a-bis(hydroxymethyl)-4,6a,6b,11,11,14b-hexamethyl-10-[(e)-2-methylbut-2-enoyl]oxy-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-4-hydroxy-3, Chemical compound O([C@@H]1[C@H](O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@]1(CO)C)C)(C)C[C@@H](O)[C@@]1(CO)[C@@H](OC(C)=O)[C@@H](C(C[C@H]14)(C)C)OC(=O)C(/C)=C/C)C(O)=O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O AXNVHPCVMSNXNP-IVKVKCDBSA-N 0.000 description 1
- SSOORFWOBGFTHL-OTEJMHTDSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SSOORFWOBGFTHL-OTEJMHTDSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 102100039583 116 kDa U5 small nuclear ribonucleoprotein component Human genes 0.000 description 1
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-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
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- OPVPGKGADVGKTG-BQBZGAKWSA-N Ac-Asp-Glu Chemical compound CC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OPVPGKGADVGKTG-BQBZGAKWSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010001258 Adenoviral infections Diseases 0.000 description 1
- 101150051188 Adora2a gene Proteins 0.000 description 1
- AXNVHPCVMSNXNP-GKTCLTPXSA-N Aescin Natural products O=C(O[C@H]1[C@@H](OC(=O)C)[C@]2(CO)[C@@H](O)C[C@@]3(C)[C@@]4(C)[C@@H]([C@]5(C)[C@H]([C@](CO)(C)[C@@H](O[C@@H]6[C@@H](O[C@H]7[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O7)[C@@H](O)[C@H](O[C@H]7[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O7)[C@@H](C(=O)O)O6)CC5)CC4)CC=C3[C@@H]2CC1(C)C)/C(=C/C)/C AXNVHPCVMSNXNP-GKTCLTPXSA-N 0.000 description 1
- 102100040069 Aldehyde dehydrogenase 1A1 Human genes 0.000 description 1
- 101710150756 Aldehyde dehydrogenase, mitochondrial Proteins 0.000 description 1
- 240000006108 Allium ampeloprasum Species 0.000 description 1
- 235000005254 Allium ampeloprasum Nutrition 0.000 description 1
- 102100032959 Alpha-actinin-4 Human genes 0.000 description 1
- 101710115256 Alpha-actinin-4 Proteins 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 241000272478 Aquila Species 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 description 1
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 102100036848 C-C motif chemokine 20 Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 108700012439 CA9 Proteins 0.000 description 1
- 101150045267 CEA gene Proteins 0.000 description 1
- 108010071134 CRM197 (non-toxic variant of diphtheria toxin) Proteins 0.000 description 1
- 101100504320 Caenorhabditis elegans mcp-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- 101710198223 Capsid fiber protein Proteins 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 102100035439 Carcinoembryonic antigen-related cell adhesion molecule 19 Human genes 0.000 description 1
- 102100025473 Carcinoembryonic antigen-related cell adhesion molecule 6 Human genes 0.000 description 1
- 102100025474 Carcinoembryonic antigen-related cell adhesion molecule 7 Human genes 0.000 description 1
- 102100025470 Carcinoembryonic antigen-related cell adhesion molecule 8 Human genes 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- 241000701489 Cauliflower mosaic virus Species 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 240000006162 Chenopodium quinoa Species 0.000 description 1
- 235000015493 Chenopodium quinoa Nutrition 0.000 description 1
- 102100039361 Chondrosarcoma-associated gene 2/3 protein Human genes 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 102000011591 Cleavage And Polyadenylation Specificity Factor Human genes 0.000 description 1
- 108010076130 Cleavage And Polyadenylation Specificity Factor Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 102100032368 Coiled-coil domain-containing protein 110 Human genes 0.000 description 1
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 229940046168 CpG oligodeoxynucleotide Drugs 0.000 description 1
- 108091029430 CpG site Proteins 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 102100030074 Dickkopf-related protein 1 Human genes 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 101100181139 Drosophila melanogaster Pkcdelta gene Proteins 0.000 description 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 1
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 1
- 102100026245 E3 ubiquitin-protein ligase RNF43 Human genes 0.000 description 1
- 102100037238 E3 ubiquitin-protein ligase UBR4 Human genes 0.000 description 1
- 102100031334 Elongation factor 2 Human genes 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 108010055191 EphA3 Receptor Proteins 0.000 description 1
- 102100030324 Ephrin type-A receptor 3 Human genes 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 208000034347 Faecal incontinence Diseases 0.000 description 1
- 102100031517 Fc receptor-like protein 1 Human genes 0.000 description 1
- 101150051800 Fcrl1 gene Proteins 0.000 description 1
- 101150032412 Fcrla gene Proteins 0.000 description 1
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 description 1
- 208000000666 Fowlpox Diseases 0.000 description 1
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100024405 GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1 Human genes 0.000 description 1
- 101710144640 GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1 Proteins 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 241001316290 Gypsophila Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 1
- 101000608799 Homo sapiens 116 kDa U5 small nuclear ribonucleoprotein component Proteins 0.000 description 1
- 101000765923 Homo sapiens Bcl-2-like protein 1 Proteins 0.000 description 1
- 101000713099 Homo sapiens C-C motif chemokine 20 Proteins 0.000 description 1
- 101100165850 Homo sapiens CA9 gene Proteins 0.000 description 1
- 101000737655 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 19 Proteins 0.000 description 1
- 101000914326 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 6 Proteins 0.000 description 1
- 101000914320 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 8 Proteins 0.000 description 1
- 101000741072 Homo sapiens Caspase-5 Proteins 0.000 description 1
- 101000916489 Homo sapiens Chondroitin sulfate proteoglycan 4 Proteins 0.000 description 1
- 101000745414 Homo sapiens Chondrosarcoma-associated gene 2/3 protein Proteins 0.000 description 1
- 101000868824 Homo sapiens Coiled-coil domain-containing protein 110 Proteins 0.000 description 1
- 101000864646 Homo sapiens Dickkopf-related protein 1 Proteins 0.000 description 1
- 101000692702 Homo sapiens E3 ubiquitin-protein ligase RNF43 Proteins 0.000 description 1
- 101000807547 Homo sapiens E3 ubiquitin-protein ligase UBR4 Proteins 0.000 description 1
- 101001060267 Homo sapiens Fibroblast growth factor 5 Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 1
- 101100179540 Homo sapiens IL15 gene Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 1
- 101000893526 Homo sapiens Leucine-rich repeat transmembrane protein FLRT2 Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101001057156 Homo sapiens Melanoma-associated antigen C2 Proteins 0.000 description 1
- 101001133088 Homo sapiens Mucin-21 Proteins 0.000 description 1
- 101000588345 Homo sapiens Nuclear transcription factor Y subunit gamma Proteins 0.000 description 1
- 101000619805 Homo sapiens Peroxiredoxin-5, mitochondrial Proteins 0.000 description 1
- 101000829725 Homo sapiens Phospholipid hydroperoxide glutathione peroxidase Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000610208 Homo sapiens Poly(A) polymerase gamma Proteins 0.000 description 1
- 101000617726 Homo sapiens Pregnancy-specific beta-1-glycoprotein 3 Proteins 0.000 description 1
- 101000617727 Homo sapiens Pregnancy-specific beta-1-glycoprotein 4 Proteins 0.000 description 1
- 101000617720 Homo sapiens Pregnancy-specific beta-1-glycoprotein 5 Proteins 0.000 description 1
- 101000617721 Homo sapiens Pregnancy-specific beta-1-glycoprotein 6 Proteins 0.000 description 1
- 101000617723 Homo sapiens Pregnancy-specific beta-1-glycoprotein 8 Proteins 0.000 description 1
- 101000617728 Homo sapiens Pregnancy-specific beta-1-glycoprotein 9 Proteins 0.000 description 1
- 101000605534 Homo sapiens Prostate-specific antigen Proteins 0.000 description 1
- 101000877404 Homo sapiens Protein enabled homolog Proteins 0.000 description 1
- 101000842302 Homo sapiens Protein-cysteine N-palmitoyltransferase HHAT Proteins 0.000 description 1
- 101000848199 Homo sapiens Protocadherin Fat 4 Proteins 0.000 description 1
- 101000592517 Homo sapiens Puromycin-sensitive aminopeptidase Proteins 0.000 description 1
- 101000591201 Homo sapiens Receptor-type tyrosine-protein phosphatase kappa Proteins 0.000 description 1
- 101001073409 Homo sapiens Retrotransposon-derived protein PEG10 Proteins 0.000 description 1
- 101000709473 Homo sapiens Sialic acid-binding Ig-like lectin 14 Proteins 0.000 description 1
- 101000665150 Homo sapiens Small nuclear ribonucleoprotein Sm D1 Proteins 0.000 description 1
- 101000665250 Homo sapiens Small nuclear ribonucleoprotein Sm D2 Proteins 0.000 description 1
- 101001056234 Homo sapiens Sperm mitochondrial-associated cysteine-rich protein Proteins 0.000 description 1
- 101000664703 Homo sapiens Transcription factor SOX-10 Proteins 0.000 description 1
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 description 1
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 description 1
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 1
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 1
- 108020005350 Initiator Codon Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010066719 Interleukin Receptor Common gamma Subunit Proteins 0.000 description 1
- 102000018682 Interleukin Receptor Common gamma Subunit Human genes 0.000 description 1
- 102000007482 Interleukin-13 Receptor alpha2 Subunit Human genes 0.000 description 1
- 108010085418 Interleukin-13 Receptor alpha2 Subunit Proteins 0.000 description 1
- 108010017535 Interleukin-15 Receptors Proteins 0.000 description 1
- 102000004556 Interleukin-15 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 101150003872 KLK3 gene Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102100034872 Kallikrein-4 Human genes 0.000 description 1
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical group C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 102100040899 Leucine-rich repeat transmembrane protein FLRT2 Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- 102000005727 Mammaglobin A Human genes 0.000 description 1
- 108010031030 Mammaglobin A Proteins 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 102100027252 Melanoma-associated antigen C2 Human genes 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 102100026262 Metalloproteinase inhibitor 2 Human genes 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 102100034260 Mucin-21 Human genes 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- DWAICOVNOFPYLS-OSMVPFSASA-N N-acetyl-D-galactosaminitol Chemical compound CC(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)CO DWAICOVNOFPYLS-OSMVPFSASA-N 0.000 description 1
- KTHDTJVBEPMMGL-VKHMYHEASA-N N-acetyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(C)=O KTHDTJVBEPMMGL-VKHMYHEASA-N 0.000 description 1
- KTHDTJVBEPMMGL-UHFFFAOYSA-N N-acetyl-L-alanine Natural products OC(=O)C(C)NC(C)=O KTHDTJVBEPMMGL-UHFFFAOYSA-N 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 102100022913 NAD-dependent protein deacetylase sirtuin-2 Human genes 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 102100031719 Nuclear transcription factor Y subunit gamma Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010072353 Painful ejaculation Diseases 0.000 description 1
- 108091081548 Palindromic sequence Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010077519 Peptide Elongation Factor 2 Proteins 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 1
- 108010067163 Perilipin-2 Proteins 0.000 description 1
- 102000017794 Perilipin-2 Human genes 0.000 description 1
- 102100022078 Peroxiredoxin-5, mitochondrial Human genes 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 102100037419 Pituitary tumor-transforming gene 1 protein-interacting protein Human genes 0.000 description 1
- 101710199379 Pituitary tumor-transforming gene 1 protein-interacting protein Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 102100040153 Poly(A) polymerase gamma Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100022020 Pregnancy-specific beta-1-glycoprotein 3 Human genes 0.000 description 1
- 102100022021 Pregnancy-specific beta-1-glycoprotein 4 Human genes 0.000 description 1
- 102100022025 Pregnancy-specific beta-1-glycoprotein 5 Human genes 0.000 description 1
- 102100022026 Pregnancy-specific beta-1-glycoprotein 6 Human genes 0.000 description 1
- 102100022018 Pregnancy-specific beta-1-glycoprotein 8 Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 102100035093 Protein enabled homolog Human genes 0.000 description 1
- 101710150114 Protein rep Proteins 0.000 description 1
- 102000018471 Proto-Oncogene Proteins B-raf Human genes 0.000 description 1
- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 1
- 102100034547 Protocadherin Fat 4 Human genes 0.000 description 1
- 108091008109 Pseudogenes Proteins 0.000 description 1
- 102000057361 Pseudogenes Human genes 0.000 description 1
- 102100034089 Receptor-type tyrosine-protein phosphatase kappa Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 102100037421 Regulator of G-protein signaling 5 Human genes 0.000 description 1
- 101710140403 Regulator of G-protein signaling 5 Proteins 0.000 description 1
- 101710152114 Replication protein Proteins 0.000 description 1
- 102100035844 Retrotransposon-derived protein PEG10 Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 102000016681 SLC4A Proteins Human genes 0.000 description 1
- 108091006267 SLC4A11 Proteins 0.000 description 1
- 102100031312 Secernin-1 Human genes 0.000 description 1
- 101710186590 Secernin-1 Proteins 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 108010079723 Shiga Toxin Proteins 0.000 description 1
- 102100034370 Sialic acid-binding Ig-like lectin 14 Human genes 0.000 description 1
- 108010041216 Sirtuin 2 Proteins 0.000 description 1
- 102100038685 Small nuclear ribonucleoprotein Sm D2 Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102100026503 Sperm mitochondrial-associated cysteine-rich protein Human genes 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 101150050863 T gene Proteins 0.000 description 1
- 102000052935 T-box transcription factor Human genes 0.000 description 1
- 108700035811 T-box transcription factor Proteins 0.000 description 1
- 101710086566 T-box transcription factor T Proteins 0.000 description 1
- 102100033130 T-box transcription factor T Human genes 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- 108010031372 Tissue Inhibitor of Metalloproteinase-2 Proteins 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 102100038808 Transcription factor SOX-10 Human genes 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 description 1
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 102100038286 Vasoactive intestinal polypeptide receptor 2 Human genes 0.000 description 1
- 101710137651 Vasoactive intestinal polypeptide receptor 2 Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 108010087302 Viral Structural Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 229940021704 adenovirus vaccine Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001295 alanines Chemical class 0.000 description 1
- 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 1
- 230000000172 allergic effect Effects 0.000 description 1
- 239000012637 allosteric effector Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical group OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000007416 antiviral immune response Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 101150036080 at gene Proteins 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 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 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 229940093314 beta-escin Drugs 0.000 description 1
- AXNVHPCVMSNXNP-BEJCRFBNSA-N beta-escin Natural products CC=C(/C)C(=O)O[C@H]1[C@H](OC(=O)C)[C@]2(CO)[C@H](O)C[C@@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O[C@H]6O[C@@H]([C@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@@H]6O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)C(=O)O)[C@](C)(CO)[C@@H]5CC[C@@]34C)[C@@H]2CC1(C)C AXNVHPCVMSNXNP-BEJCRFBNSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- RAURUSFBVQLAPW-DNIKMYEQSA-N clocinnamox Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)NC(=O)\C=C\C=2C=CC(Cl)=CC=2)CC1)O)CC1CC1 RAURUSFBVQLAPW-DNIKMYEQSA-N 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000002089 crippling effect Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000006334 disulfide bridging Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229940011399 escin Drugs 0.000 description 1
- 229930186222 escin Natural products 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000001808 exosome Anatomy 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000002710 external beam radiation therapy Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 210000001703 glandular epithelial cell Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 229940032219 immunotherapy vaccine Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 238000002743 insertional mutagenesis Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 108040002039 interleukin-15 receptor activity proteins Proteins 0.000 description 1
- 102000008616 interleukin-15 receptor activity proteins Human genes 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 1
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 108010024383 kallikrein 4 Proteins 0.000 description 1
- 238000002430 laser surgery Methods 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 208000027906 leg weakness Diseases 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 238000002624 low-dose chemotherapy Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000001589 lymphoproliferative effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 210000004995 male reproductive system Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 101150110704 melC2 gene Proteins 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 231100000324 minimal toxicity Toxicity 0.000 description 1
- CPTIBDHUFVHUJK-NZYDNVMFSA-N mitopodozide Chemical compound C1([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(=O)NNCC)=CC(OC)=C(OC)C(OC)=C1 CPTIBDHUFVHUJK-NZYDNVMFSA-N 0.000 description 1
- 229950010088 mitopodozide Drugs 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940051875 mucins Drugs 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 206010029446 nocturia Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000011499 palliative surgery Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 108010054442 polyalanine Proteins 0.000 description 1
- 108010094020 polyglycine Proteins 0.000 description 1
- 229920000232 polyglycine polymer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 108010000627 pregnancy-specific beta-1-glycoprotein 7 Proteins 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 208000017497 prostate disease Diseases 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 229940034080 provenge Drugs 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000011472 radical prostatectomy Methods 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 102200108188 rs587782423 Human genes 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 230000035936 sexual power Effects 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- MWFOPMKUGZLPQA-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)propane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCCN(CC)C1=CC=CC(OC)=C1 MWFOPMKUGZLPQA-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- UGODCLHJOJPPHP-AZGWGOJFSA-J tetralithium;[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-4-hydroxy-2-[[oxido(sulfonatooxy)phosphoryl]oxymethyl]oxolan-3-yl] phosphate;hydrate Chemical compound [Li+].[Li+].[Li+].[Li+].O.C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OS([O-])(=O)=O)[C@@H](OP([O-])([O-])=O)[C@H]1O UGODCLHJOJPPHP-AZGWGOJFSA-J 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 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
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940125575 vaccine candidate Drugs 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine 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-CFWMRBGOSA-N 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
- GBABOYUKABKIAF-IELIFDKJSA-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-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.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 CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 229940023147 viral vector vaccine Drugs 0.000 description 1
Classifications
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2086—IL-13 to IL-16
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001103—Receptors for growth factors
- A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001148—Regulators of development
- A61K39/00115—Apoptosis related proteins, e.g. survivin or livin
- A61K39/001151—Apoptosis related proteins, e.g. survivin or livin p53
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001152—Transcription factors, e.g. SOX or c-MYC
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001152—Transcription factors, e.g. SOX or c-MYC
- A61K39/001153—Wilms tumor 1 [WT1]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001156—Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001157—Telomerase or TERT [telomerase reverse transcriptase]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001158—Proteinases
- A61K39/001161—Caspases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001169—Tumor associated carbohydrates
- A61K39/00117—Mucins, e.g. MUC-1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001176—Heat shock proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00118—Cancer antigens from embryonic or fetal origin
- A61K39/001182—Carcinoembryonic antigen [CEA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001186—MAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001188—NY-ESO
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001189—PRAME
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001191—Melan-A/MART
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001192—Glycoprotein 100 [Gp100]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
- A61K39/001194—Prostate specific antigen [PSA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
- A61K39/001195—Prostate specific membrane antigen [PSMA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- 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
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5156—Animal cells expressing foreign proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5256—Virus expressing foreign proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55516—Proteins; Peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
- A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/70—Multivalent vaccine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/884—Vaccine for a specifically defined cancer prostate
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10321—Viruses as such, e.g. new isolates, mutants or their genomic sequences
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10334—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10341—Use of virus, viral particle or viral elements as a vector
- C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10361—Methods of inactivation or attenuation
- C12N2710/10362—Methods of inactivation or attenuation by genetic engineering
Definitions
- Vaccines help the body fight disease by training the immune system to recognize and destroy harmful substances and diseased cells.
- Vaccines can be largely grouped into two types, preventive and treatment vaccines.
- Prevention vaccines are given to healthy people to prevent the development of specific diseases, while treatment vaccines, also referred to as immunotherapies, are given to a person who has been diagnosed with disease to help stop the disease from growing and spreading or as a preventive measure.
- Viral vaccines are currently being developed to help fight infectious diseases and cancers. These viral vaccines work by inducing expression of a small fraction of genes associated with a disease within the host's cells, which in turn, enhance the host's immune system to identify and destroy diseased cells. As such, clinical response of a viral vaccine can depend on the ability of the vaccine to obtain a high-level immunogenicity and have sustained long-term expression.
- the present disclosure provides a composition comprising a replication-defective virus vector comprising a nucleic acid sequence encoding a prostate specific antigen (PSA) and/or a nucleic acid sequence encoding prostate-specific membrane antigen (PSMA), wherein the PSA has an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical with SEQ ID NO: 1 or SEQ ID NO: 34 or the PSMA has an amino acid sequence at least 80% identical with SEQ ID NO: 11.
- PSA prostate specific antigen
- PSMA prostate-specific membrane antigen
- the vector comprises a nucleic acid sequence encoding a PSA having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical with SEQ ID NO: 35 or the nucleic acid sequence encoding PSA has at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical with SEQ ID NO: 2.
- the vector comprises a nucleic acid sequence encoding a PSMA having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical with SEQ ID NO: 36.
- the composition further comprises a second replication-defective virus vector comprising a second nucleic acid sequence encoding a Brachyury antigen, a third replication-defective virus vector comprising a third nucleic acid sequence encoding a MUC1 antigen, or a combination thereof.
- the Brachyury antigen binds to HLA-A2, HLA-A3, HLA-A24, or a combination thereof.
- the Brachyury antigen is a modified Brachyury antigen comprising an amino acid sequence set forth in WLLPGTSTV (SEQ ID NO: 7).
- the Brachyury antigen is a modified Brachyury antigen comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 42
- the second replication-defective vector comprises a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical with SEQ ID NO: 3, SEQ ID NO: 4, positions 13 to 1242 of SEQ ID NO: 4, SEQ ID NO: 42.
- the second replication-defective vector comprises a nucleotide sequence at least 80% identical, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% to SEQ ID NO: 12 (Ad vector with sequence encoding ma modifided Brachyury antigen), positions 1033-2083 of SEQ ID NO: 12, or SEQ ID NO: 42.
- the MUC1 antigen comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 10 or SEQ ID NO: 41.
- the third nucleic acid sequence encoding a MUC1 antigen comprises at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identity to SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 41.
- the MUC-1 antigen binds to HLA-A2, HLA-A3, HLA-A24, or a combination thereof.
- the replication-defective virus vector, the second replication- defective virus vector, and/or the third replication-defective virus vector is an adenovirus vector.
- the adenovirus vector comprises a deletion in an El region, an E2b region, an E3 region, an E4 region, or a combination thereof.
- the adenovirus vector comprises a deletion in an E2b region.
- the adenovirus vector comprises a deletion in an El region, an E2b region, and an E3 region.
- the composition comprises from at least lxlO 9 virus particles to at least 5xl0 12 virus particles.
- the composition comprises at least 5xl0 9 virus particles.
- the composition comprises at least 5xl0'° virus particles.
- the composition comprises at least 5x10" virus particles.
- the composition comprises at least 5xl0 12 virus particles.
- the composition or the replication-defective virus vector further comprises a nucleic acid sequences encoding a costimulatory molecule.
- the costimulatory molecule comprises B7, ICAM-1, LFA-3, or a combination thereof. In some aspects, the costimulatory molecule comprises a combination of B7, ICAM-1, and LFA-3.
- the composition further comprises a plurality of nucleic acid sequences encoding a plurality of costimulatory molecules positioned in the same replication- defective virus vector. In some aspects, the composition further comprises a plurality of nucleic acid sequences encoding a plurality of costimulatory molecules positioned in separate replication-defective virus vectors.
- the composition further comprises a nucleic acid sequence encoding one or more additional target antigens or immunological epitopes thereof.
- the replication-defective virus vector further comprises a nucleic acid sequence encoding one or more additional target antigens or immunological epitopes thereof.
- the one or more additional target antigens is a tumor neo-antigen, tumor neo-epitope, tumor-specific antigen, tumor-associated antigen, tissue- specific antigen, bacterial antigen, viral antigen, yeast antigen, fungal antigen, protozoan antigen, parasite antigen, mitogen, or a combination thereof.
- the one or more additional target antigens is CEA, folate receptor alpha, WT1, HPV E6, HPV E7, p53, MAGE-A1, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, BAGE, DAM-6, -10, GAGE-1, -2, -8, GAGE-3, -4, -5, -6, -7B, NA88-A, NY-ESO-1, MART-1, MC1R, GplOO, PSCA, PSMA, PAP, Tyrosinase, TRP- 1, TRP-2, ART-4, CAMEL, Cyp-B, Her2/neu, BRCA1 , BRACHYURY, BRACHYURY(TIVS7-2, polymorphism), BRACHYURY (IVS7 T/C polymorphism), T BRACHYURY, T, hTERT, hTRT, iCE, MUCl, MUCl (V
- the one or more additional target antigens is CEA
- the one or more additional target antigens is CEA, Brachyury, and MUC1.
- CEA is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 37 or SEQ ID NO: 38.
- the one or more additional target antigens is HER.3.
- the one or more additional target antigens is HPV E6 or HPV E7.
- the replication-defective virus vector further comprises a selectable marker.
- the selectable marker is a lacZ gene, thymidine kinase, gpt, GUS, or a vaccinia K1L host range gene, or a combination thereof.
- the present disclosure provides a composition comprising one or more replication-defective virus vectors comprising a nucleic acid sequence encoding a prostate specific antigen (PSA), a nucleic acid sequence encoding prostate-specific membrane antigen (PSMA), a nucleic acid sequence encoding a Brachyury antigen, a nucleic acid sequence encoding a MUC1 antigen, or a combination thereof.
- PSA prostate specific antigen
- PSMA prostate-specific membrane antigen
- Brachyury antigen a nucleic acid sequence encoding a Brachyury antigen
- MUC1 antigen a combination thereof.
- the present disclosure provides a composition comprising one or more replication-defective virus vectors comprising a nucleic acid sequence encoding a prostate specific antigen (PSA), a nucleic acid sequence encoding a Brachyury antigen, and a nucleic acid sequence encoding a MUC1 antigen.
- PSA prostate specific antigen
- Brachyury antigen a nucleic acid sequence encoding a Brachyury antigen
- MUC1 antigen a nucleic acid sequence encoding a MUC1 antigen
- the present disclosure provides a composition comprising one or more replication-defective virus vectors comprising a nucleic acid sequence encoding prostate-specific membrane antigen (PSMA), a nucleic acid sequence encoding a Brachyury antigen, and a nucleic acid sequence encoding a MUC1 antigen.
- PSMA prostate-specific membrane antigen
- MUC1 antigen MUC1 antigen
- the present disclosure provides a composition comprising one or more replication-defective virus vectors comprising a nucleic acid sequence encoding a prostate specific antigen (PSA), a nucleic acid sequence encoding prostate-specific membrane antigen (PSMA), a nucleic acid sequence encoding a Brachyury antigen, a nucleic acid sequence encoding a MUC1 antigen, and a nucleic acid sequence encoding a CEA antigen.
- PSA prostate specific antigen
- PSMA prostate-specific membrane antigen
- Brachyury antigen a nucleic acid sequence encoding a Brachyury antigen
- MUC1 antigen a nucleic acid sequence encoding a MUC1 antigen
- CEA antigen a nucleic acid sequence encoding a CEA antigen
- the replication-defective virus vector of any of the above compositions further comprises a nucleic acid sequence encoding an immunological fusion partner.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising the composition according any composition described herein and a pharmaceutically acceptable carrier.
- the present disclosure provides a host cell comprising the composition according to any composition described herein.
- the present disclosure provides a method of preparing a tumor vaccine, the method comprising preparing a pharmaceutical composition according to claim 42.
- the present disclosure provides a method of enhancing an immune response in a subject in need thereof, the method comprising administering a therapeutically effective amount of any composition described herein or the pharmaceutical composition as described herein to the subject.
- the present disclosure provides a method of treating a PSA-expressing or PSMA-expressing cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of any composition described herein or the pharmaceutical composition as described herein to the subject.
- the method further comprises readministering the pharmaceutical composition to the subject.
- the method further comprises administering an immune checkpoint inhibitor to the subject.
- the immune checkpoint inhibitor inhibits PD 1 , PDL1 , PDL2, CD28, CD80, CD86, CTLA4, B7RP1 , ICOS, B7RPI, B7-H3, B7-H4, BTLA, HVEM, KIR, TCR, LAG3, CD 137, CD137L, OX40, OX40L, CD27, CD70, CD40, CD40L, TIM3, GAL9, ADORA, CD276, VTCNl , IDO l , KIR3DL1 , HAVCR2, VISTA, or CD244
- the immune checkpoint inhibitor inhibits PD1 or PDL1
- the immune checkpoint inhibitor is an anti-PDl or anti-PDLl antibody.
- the immune checkpoint inhibitor is an anti-PDLl antibody.
- a route of administration is intravenous, subcutaneous, intralymphatic, intratumoral, intradermal, intramuscular, intraperitoneal, intrarectal, intravaginal, intranasal, oral, via bladder instillation, or via scarification.
- the enhanced immune response is a cell-mediated or humoral response.
- the enhanced immune response is an enhancement of B-cell proliferation, CD4+ T cell proliferation, CD8+ T cell proliferation, or a combination thereof
- the enhanced immune response is an enhancement of IL-2 production, IFN- ⁇ production or combination thereof.
- the enhanced immune response is an enhancement of antigen presenting cell proliferation, function or combination thereof.
- the subject has been previously administered an adenovirus vector. In some aspects, the subject has pre-existing immunity to adenovirus vectors. In some aspects, the subject is determined to have pre-existing immunity to adenovirus vectors.
- the method further comprises administering to the subject a chemotherapy, radiation, a different immunotherapy, or a combination thereof.
- the subject is a human or a non-human animal. In some aspects, the subject has previously been treated for cancer. [0030] In some aspects, the administering the therapeutically effective amount is repeated at least three times. In some aspects, the administering the therapeutically effective amount comprises lxlO 9 to 5xl0 12 virus particles per dose. In some aspects, the administering the therapeutically effective amount comprises 5xl0 9 virus particles per dose. In some aspects, the administering the therapeutically effective amount comprises 5xl0 10 virus particles per dose. In some aspects, the administering the therapeutically effective amount comprises 5xl0" virus particles per dose. In some aspects, the administering the therapeutically effective amount comprises 5xl0 12 virus particles per dose. In some aspects, the administering the therapeutically effective amount is repeated every one, two, or three weeks.
- he administering the therapeutically effective amount is followed by one or more booster immunizations comprising the same composition or pharmaceutical composition.
- the booster immunization is administered every one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve months or more.
- the booster immunization is repeated three four, five, six, seven, eight, nine, ten, eleven, or twelve or more times.
- the administering the therapeutically effective amount is a primary immunization repeated every one, two, or three weeks for three four, five, six, seven, eight, nine, ten, eleven, or twelve or more times followed by a booster immunization repeated every one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve or more months for three or more times.
- the method further comprises administering to the subject a pharmaceutical composition comprising a population of engineered nature killer (NK) cells.
- the engineered NK cells comprise one or more NK cells that have been modified as essentially lacking the expression of KIR (killer inhibitory receptors), one or more NK cells that have been modified to express a high affinity CD 16 variant, and one or more NK cells that have been modified to express one or more CARs (chimeric antigen receptors), or any combinations thereof.
- the engineered NK cells comprise one or more NK cells that have been modified as essentially lacking the expression KIR.
- the engineered NK cells comprise one or more NK cells that have been modified to express a high affinity CD 16 variant.
- the engineered NK cells comprise one or more NK cells that have been modified to express one or more CARs.
- the CAR is a CAR for a tumor neo-antigen, tumor neo-epitope, WT1 , HPV- E6, HPV-E7, p53, MAGE-A1 , MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE- A10, MAGE-A12, BAGE, DAM-6, DAM-10, Folate receptor alpha, GAGE-1 , GAGE-2, GAGE- 8, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7B, NA88-A, NY-ESO-1, MART- 1, MC1R, GplOO, PSA, PSM, Tyrosinase, TRP- 1, TRP-2, ART-4, CAMEL, CEA, Cyp-B, Her2/neu, Her3, BRCA1 , Brachyury, Brachy
- a cell comprises the replication-defective adenovirus vector.
- the cell is a dendritic cells (DC).
- DC dendritic cells
- the method further comprises administering a pharmaceutical composition comprises a therapeutically effective amount of IL-15 or a replication-defective vector comprising a nucleic acid sequence encoding IL-15.
- the subject has prostate cancer. In some aspects, the subject has advanced stage prostate cancer. In some aspects, the subject has unresectable, locally advanced, or metastatic cancer.
- the administering the therapeutically effective amount of any composition described herein or the pharmaceutical composition as described herein comprises a first replication-defective virus vector comprising a first nucleic acid sequence encoding a PSA antigen, a second replication-defective virus vector comprising a second nucleic acid sequence encoding a PSMA antigen, a third replication-defective virus vector comprising a third nucleic acid sequence encoding a Brachyury antigen, a fourth replication- defective virus vector comprising a fourth nucleic acid sequence encoding a MUC1 antigen at a 1 : 1 : 1 : 1 ratio.
- FIG. 1 illustrates induction of PSA specific cellular immunity in mice after homologous immunizations.
- FIG. 1A illustrates IFN- ⁇ cellular mediated immune (CMI) response in Ad5 immune BALB/c mice immunized three times with either an injection buffer (control group) or 10 10 Virus Particles (VP) of Ad5[El-, E2b-]-PSA at 7 day intervals.
- FIG. IB illustrates IL-2 cellular mediated immune (CMI) response in Ad5 immune BALB/c mice immunized three times with either an injection buffer (control group) or lO 10 Virus Particles (VP) of Ad5[El-, E2b-]-PSA at 7 day intervals.
- FIG. 2 illustrate specificity of PSA cellular mediated immunity following immunizations with Ad5 [E1-, E2b-]-PSA.
- FIG. 2A illustrates IFN- ⁇ spot forming cells (SFC) per 10 6 splenocytes after ex vivo exposure to PSA or control antigens (HIV-gag, CMV).
- SFC spot forming cells
- FIG. 2B illustrates IL-2 spot forming cells (SFC) per 10 6 splenocytes after ex vivo exposure to PSA or control antigens (HIV-gag, CMV).
- SFC spot forming cells
- FIG. 3 illustrates PSA directed antibody (anti-PSA Ab) responses using a quantitative ELISA.
- FIG. 4 illustrates tumor growth in mice immunized with Ad5 [E1-, E2b-]-PSA compared to mice immunized with Ad5 [E1-, E2b-]-null following implantation of PSA expressing tumor cells.
- FIG. 5 illustrates PSA secretion from cells after infection with Ad5 [El-]-PSA or Ad5 [E1-, E2b-]-PSA.
- RM- 11 murine prostate tumor cells or HEK-293 cells were infected with Ad5 [El-]-PSA or Ad5 [E1-, E2b-]-PSA, respectively.
- Levels of PSA secreted into medium were assessed at various time points. Note the greater secretion of PSA by cells infected with Ad5 [E1-, E2b-]-PSA as compared to cells infected with Ad5 [E l -]-PSA.
- FIG. 6 illustrates PSA specific cellular immunity in naive mice after immunizing with Ad5 [E1-, E2b-]-PSA three times or Ad5-immune mice after immunizing with Ad5 [E1-, E2b-]-PSA three times.
- Naive or Ad5-immune BALB/c mice were immunized three times with either injection buffer (control group) or 10 10 VP of Ad5 [E1-, E2b-]-PSA at 7 day intervals.
- Splenocytes were assessed 14 days after the final immunization for the secretion of IFN- ⁇ in an ELISpot assay. Cells were exposed to 2 ⁇ g of PSA antigen.
- FIG. 7 illustrates PSA specific cellular immunity in naive mice after immunizing with Ad5 [E1-, E2b-]-PSA three times or Ad5-immune mice mice after immunizing with Ad5 [El- , E2b-]-PSA three times.
- Naive or Ad5-immune BALB/c mice were immunized three time with either injection buffer (control group) or 10 10 VP of Ad5 [E1-, E2b-]-PSA at 7 day intervals.
- Splenocytes were assessed 14 days after the final immunization for the secretion of IL-2 in an ELISpot assay. Cells were exposed to 2 ⁇ g of PSA antigen.
- FIG. 8 illustrates specificity of PSA cellular mediated immunity following immunization with Ad5 [E1-, E2b-]-PSA in Ad5-immune mice.
- Ad5-immune BALB/c mice were immunized two times with 10 10 VP of Ad5 [El -]-null at a 14 day interval.
- Two weeks after the last immunization of Ad5 [El-]-null the mice were immunized three times with 10 10 VP of Ad5 [E1-, E2b-]-PSA at 7 day intervals.
- Splenocytes were assessed by ELISpot assay 14 days after the final immunization for the secretion of both IFN- ⁇ and IL-2 after ex vivo exposure to PSA or control antigens (HIV-gag, CMV).
- FIG. 8A illustrates the frequency of IFN- ⁇ secreting cells after ex vivo exposure of splenocytes to PSA or control antigen peptide pools (HIV-gag, CMV).
- FIG. 8B illustrates the frequency of IL-2 secreting cells after ex vivo exposure of splenocytes to PSA or control antigen peptide pools (HIV-gag, CMV).
- FIG. 9 illustrates anti-PSA antibody (Ab) activity in naive mice after immunizing with Ad5 [E1-, E2b-]-PSA three times.
- BALB/c mice were immunized three time with either injection buffer (control group) or 10 10 VP of Ad5 [E1-, E2b-]-PSA at 7 day intervals.
- Sera were assessed 14 days after the final immunization for the presence of anti-PSA Ab in a quantitative ELISA using purified PSA as an antibody capture antigen target.
- FIG. 10 illustrates possible prostate cancer multi-antigen gene construct for insertion into Ad5[El-, E2b-].
- FIG. 10A illustrates a triple gene insert for a prostate cancer vaccine.
- FIG. 10B illustrates the products after translation of FIG. 10A.
- FIG. 11 illustrates analysis of IFN- ⁇ -, IL-2- and Granzyme B-expressing splenocytes following vaccination of mice with Ad5 [E1-, E2b-]-PSMA.
- Splenocytes were collected 7 days after the final vaccination and ex vivo exposure to a PSMA peptide pool, a negative control antigen (Nef peptide pool), or a positive control (ConA).
- ELISPOT assay was used to evaluate IFN- ⁇ secretion, IL-2 secretion, and Granzyme B secretion after exposure to PSMA peptide pools, a negative control antigen (Nef peptide pool), or ConA, respectively. Data are reported as the number of spot forming cells (SFs) per 10 6 splenocytes. The error bars depict the SEM.
- FIG. 11A illustrates the frequency of IFN-y-secreting cells after ex vivo stimulation.
- FIG. 11B illustrates the frequency of IL-2-secreting cells after ex vivo stimulation.
- FIG. llC illustrates the frequency of Granzyme B-secreting cells after ex vivo stimulation.
- FIG. 12 illustrates analysis of CD8+ splenocytes and CD4+ splenocytes and multifunctional cellular populations following vaccination with Ad5 [E1-, E2b-]-PSMA.
- Splenocytes were collected 7 days after the final vaccination and were stimulated ex vivo with a PSMA peptide pool or a negative control (plain media or SIV nef peptide pool).
- Cells were assessed by flow cytometry for phenoytype and inflammatory cytokine secretion. For positive controls, splenocytes were exposed to PMA/ionomycin (data not shown). Error bars depict the SEM.
- FIG. 12A illustrates the percentage of CD8P+ splenocytes secreting IFN- ⁇ after ex vivo stimulation.
- FIG. 12B illustrates the percentage of CD4+ splenocytes secreting IFN- ⁇ after ex vivo stimulation.
- FIG. 12C illustrates the percentage of CD8P+ splenocytes secreting IFN- ⁇ and TNF-a after ex vivo stimulation.
- FIG. 12D illustrates the percentage of CD4+ splenocytes secreting IFN- ⁇ and TNF-a after ex vivo stimulation.
- FIG. 13 illustrates antibody responses in mice following vaccination with Ad5 [E1-, E2b-]-PSMA.
- Sera were collected 7 days after the final vaccination and assessed by ELISA for antigen specific antibodies against PSMA protein.
- FIG. 14 illustrates analysis of IFN- ⁇ -, IL-2- and Granzyme B- expressing splenocytes following vaccination of mice with Ad5 [E1-, E2b-]-PSA.
- mice Two weeks after the final vaccination, mice were injected with 5xl0 5 D2F2 tumorgenic cells that express PSA, into the right hind side of mice.
- Splenocytes were collected at the end of the experiment (37 days post-tumor implant) and stimulated ex vivo with a PSA peptide pool, a negative control (SIV-Nef peptide pool), or a positive control (Concanavalin A (Con A)). Cytokine secretion was measured after ex vivo stimulation using an ELISPOT assay. Data are reported as the number of spot forming cells (SFC) per 10 6 splenocytes and error bars show the SEM.
- SFC spot forming cells
- FIG. 14A illustrates IFN- ⁇ spot forming cells (SFC) per 10 6 splenocytes after ex vivo exposure stimulation.
- FIG. 14B illustrates IL-2 spot forming cells (SFC) per 10 6 splenocytes aftere vivo stimulation.
- FIG. 14C illustrates Granzyme B spot forming cells (SFC) per 10 6 splenocytes after ex vivo stimulation.
- FIG. 15 illustrates analysis of CD8+ splenocytes and CD4+ splenoctyes and multifunctional cellular populations following vaccination with Ad5 [E1-, E2b-]-PSA.
- mice Two weeks after the final vaccination, mice were injected with 5xl0 5 D2F2 tumorgenic cells that express PSA, into the right hind side of mice.
- Splenocytes were collected at the end of the experiment (37 days post-tumor inoculation) and exposed ex vivo to a PSA peptide pool or a negative control antigen (media or SIV-Nef peptide pool). Cells were stained for surface markers and for intracellular cytokine secretion and analyzed by flow cytometry.
- FIG. 15A illustrates the percent of CD8p+ splenocytes secreting IFN- ⁇ .
- FIG. 15B illustrates the percent of CD4+ splenocytes secreting IFN- ⁇ .
- FIG. 15C illustrates the percent of CD8P+ splenocytes secreting IFN- ⁇ and TNF-a.
- FIG. 15D illustrates the percent of CD4+ splenocytes secreting IFN- ⁇ and TNF-a.
- mice Two weeks after the final vaccination, mice were injected with 5xl0 5 D2F2 tumorgenic cells that express PSA, into the right hind side of mice.
- Sera was collected at the end of the experiment (37 days post-tumor inoculation) and analyzed for the presence of antibodies using an enzyme-linked immunosorbent assay (ELISA).
- ELISA enzyme-linked immunosorbent assay
- FIG. 16A illustrates the mass of IgG specific antibodies against PSA.
- FIG. 16B illustrates the mass of IgG 1 specific antibodies against PSA.
- any embodiment can be combined with any other embodiment.
- a variety of aspects can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range as if explicitly written out. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. When ranges are present, the ranges include the range endpoints. I. Target Antigens
- expression constructs or vectors comprising nucleic acid sequences that encode one or more target proteins of interest or target antigens, such as PSA, PSMA, CEA, MUC1 , Brachyury, or a combination thereof as described herein.
- expression constructs or vectors may contain nucleic acid encoding at least, at most or about one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 different target antigens of interest or any number or ranges derived therefrom.
- the expression constructs or vectors may contain nucleic acid sequences encoding multiple fragments or epitopes from one or more target antigens or may contain one or more fragments or epitopes from numerous different target antigens.
- the target antigens may be a full-length protein or may be an immunogenic fragment (e.g., an epitope) thereof.
- Immunogenic fragments may be identified using available techniques, such as those summarized in Paul, Fundamental Immunology, 3rd ed., 243-247 (Raven Press, 1993) and references cited therein. Representative techniques for identifying immunogenic fragments include screening polypeptides for the ability to react with antigen- specific antisera and/or T-cell lines or clones.
- An immunogenic fragment of a particular target polypeptide may be a fragment that reacts with such antisera and/or T-cells at a level that is not substantially less than the reactivity of the full-length target polypeptide (e.g., in an ELISA and/or T-cell reactivity assay). In other words, an immunogenic fragment may react within such assays at a level that is similar to or greater than the reactivity of the full-length polypeptide.
- Such screens may generally be performed using methods available to those of ordinary skill in the art, such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988.
- a target antigen can be an immunogenic epitope, for example, an epitope of 8 to 10 amino acids long. In some cases, a target antigen is four to ten amino acids long or over 10 amino acids long.
- a target antigen can comprise a length of or can comprise a length of at least, about, or at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 amino acids, or any number or ranges derived therefrom.
- a target antigen can be any length of amino acids.
- target antigens include carcinoembryonic antigen (CEA), folate receptor alpha, WT1, brachyury (TIVS7-2, polymorphism), brachyury (IVS7 T/C polymorphism), T brachyury, T, hTERT, hTRT, iCE, HPV E6, HPV E7, BAGE, DAM- 6, -10, GAGE-1 , -2, -8, GAGE-3, -4, -5, -6, -7B, NA88-A, NY-ESO-1, MART-1 , MC1R, GplOO, PSA, PSMA, PSCA, STEAP, PAP, Tyrosinase, TRP-1 , TRP-2, ART-4, CAMEL, Cyp-B, EGFR, Her2/neu, Her3, MUC1 , MUC1 (VNTR polymorphism), MUCl-c, MUCl-n, MUC1
- tumor neo-epitopes as used herein are tumor- specific epitopes, such as EQVWGMAVR (SEQ ID NO: 13) or CQGPEQVWGMAVREL (SEQ ID NO: 14) (R346W mutation of FLRT2), GETVTMPCP (SEQ ID NO: 15) or NVGETVTMPCPKVFS (SEQ ID NO: 16) (V73M mutation of VIPR2), GLGAQCSEA (SEQ ID NO: 17) or NNGLGAQCSEAVTLN (SEQ ID NO: 18) (R286C mutation of FCRL1), RKLTTELTI (SEQ ID NO: 19), LGPERRKLTTELTII (SEQ ID NO: 20), or PERRKLTTE (SEQ ID NO: 21) (S 1613L mutation of FAT4), MDWVWMDTT (SEQ ID NO: 22), AVMDWVWMDTTLSLS (SEQ ID NO: 23), or VWMDTTLSL (
- Tumor-associated antigens may be antigens not normally expressed by the host; they can be mutated, truncated, misfolded, or otherwise abnormal manifestations of molecules normally expressed by the host; they can be identical to molecules normally expressed but expressed at abnormally high levels; or they can be expressed in a context or environment that is abnormal.
- Tumor-associated antigens may be, for example, proteins or protein fragments, complex carbohydrates, gangliosides, haptens, nucleic acids, other biological molecules or any combinations thereof.
- compositions comprising replication-defective vectors comprising one or more nucleic acid sequences encoding PSA and/or PSMA antigen, and/or one or more nucleic acid sequences encoding mucin family antigen such as MUCl, and/or one or more nucleic acid sequences encoding Brachyury, and/or one or more nucleic acid sequences encoding CEA in the same or separate replication-defective vectors.
- PSA Prostate-specific antigen
- KLK3 gamma- seminoprotein or kallikrein-3
- PSA is a glycoprotein enzyme encoded in humans by the KLK3 gene.
- PSA is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely. It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus.
- PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders. PSA is not a unique indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia. Thirty percent of patients with high PSA have prostate cancer diagnosed after biopsy.
- PSA is considered to be attractive antigenic target for tumor specific immunotherapy because the prostate cancer cells over express this antigen and elevated levels of PSA are associated with a diagnosis of prostate cancer.
- PSA induced immune responses are effective at inducing anti-tumor CMI responses in humans and in experimental animal models of PSA expressing cancer.
- Ad5 [E1-, E2b-]-based vector platform to insert the human PSA gene as a new immunotherapy vaccine (referred to as Ad5 [E1-, E2b-]-PSA) to treat PSA expressing prostate cancers.
- Ad5 [E1-, E2b-]-PSA a new immunotherapy vaccine
- this vaccine induced anti-tumor cell mediated immune (CMI) responses in a mouse model of PSA expressing cancer and provides us with a strong rationale for using the Ad5 [E1-, E2b-]-PSA as an immunotherapeutic vaccine to treat PSA expressing prostate cancers.
- CMI vaccine induced anti-tumor cell mediated immune
- a PSA antigen of this disclosure can have an amino sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 34.
- a PSA antigen of this disclosure can have an amino acid sequence as set forth in SEQ ID NO: 34.
- a PSA antigen of this disclosure can have a nucleotidesequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 35.
- a PSA antigen of this disclosure can have a nucleotide acid sequence as set forth in SEQ ID NO: 35.
- compositions comprising replication-defective vectors comprising one or more nucleic acid sequences encoding PSA and/or PSMA antigen, and/or one or more nucleic acid sequences encoding mucin family antigen such as MUCl, and/or one or more nucleic acid sequences encoding Brachyury, and/or one or more nucleic acid sequences encoding CEA in the same or separate replication-defective vectors,
- Glutamate carboxypeptidase II also known as N-acetyl-L-aspartyl-L- glutamate peptidase I (NAALADase I), NAAG peptidase, or prostate-specific membrane antigen (PSMA) is an enzyme that in humans is encoded by the FOLH1 (folate hydrolase 1) gene.
- FOLH1 farnesoid alpha 1
- Human GCPII contains 750 amino acids and weighs approximately 84 kDa.
- GCPII is a zinc metalloenzyme that resides in membranes. Most of the enzyme resides in the extracellular space. GCPII is a class II membrane glycoprotein. It catalyzes the hydrolysis of N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartate (NAA) according to the reaction scheme to the right.
- NAAG N-acetylaspartylglutamate
- NAA N-acetylaspartate
- a PSMA antigen of this disclosure can have an amino sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 1 1.
- a PSMA antigen of this disclosure can have an amino acid sequence as set forth in SEQ ID NO: 1 1.
- a PSMA antigen of this disclosure can have a nucleotidesequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 36.
- a PSMA antigen of this disclosure can have a nucleotide acid sequence as set forth in SEQ ID NO: 36.
- compositions comprising replication-defective vectors comprising one or more nucleic acid sequences encoding PSA and/or PSMA antigen, and/or one or more nucleic acid sequences encoding mucin family antigen such as MUCl, and/or one or more nucleic acid sequences encoding Brachyury, and/or one or more nucleic acid sequences encoding CEA in the same or separate replication-defective vectors.
- the human mucin family (MUCl to MUC21) includes secreted and transmembrane mucins that play a role in forming protective mucous barriers on epithelial surfaces in the body. These proteins function in to protecting the epithelia lining the respiratory, gastrointestinal tracts, and lining ducts in important organs such as, for example the mammary gland, liver, stomach, pancreas, and kidneys.
- MUCl (CD227) is a TAA that is over-expressed on a majority of human carcinomas and several hematologic malignancies. MUCl (GenBank: X80761.1, NCBI: NM_001204285.1) and activates many important cellular pathways known to be involved in human disease. MUCl is a heterodimeric protein formed by two subunits that is commonly overexpressed in several human cancers. MUCl undergoes autoproteolysis to generate two subunits MUCln and MUClc that, in turn, form a stable noncovalent heterodimer.
- the MUCl C-terminal subunit can comprise a 58 aa extracellular domain (ED), a 28 aa transmembrane domain (TM) and a 72 aa cytoplasmic domain (CD).
- the MUClc also can contain a "CQC" motif that can allow for dimerization of MUCl and it can also impart oncogenic function to a cell.
- MUCl can in part oncogenic function through inducing cellular signaling via MUClc.
- MUClc can interact with EGFR, ErbB2 and other receptor tyrosine kinases and contributing to the activation of the PI3K- ⁇ AKT and MEK ⁇ ERK cellular pathways.
- MUClc activates the Wnt/p-catenin, STAT, and NF-KB RelA cellular pathways.
- MUCl can impart oncogenic function through inducing cellular signaling via MUCln.
- the MUCl N-terminal subunit (MUCln) can comprise variable numbers of 20 amino acid tandem repeats that can be glycosylated.
- MUCl is normally expressed at the surface of glandular epithelial cells and is over-expressed and aberrantly glycosylated in carcinomas.
- MUCl is a TAA that can be utilized as a target for tumor immunotherapy.
- Several clinical trials have been and are being performed to evaluate the use of MUCl in immunotherapeutic vaccines. Importantly, these trials indicate that immunotherapy with MUCl targeting is safe and may provide survival benefit.
- MUCl is a relatively poor immunogen.
- MUCl-C or MUClc T lymphocyte immune enhancer peptide sequence in the C terminus region of the MUCl oncoprotein.
- the agonist in their modified MUCl -C (a) bound HLA-A2 at lower peptide concentrations, (b) demonstrated a higher avidity for HLA-A2, (c) when used with antigen-presenting cells, induced the production of more IFN- ⁇ by T-cells than with the use of the native peptide, and (d) was capable of more efficiently generating MUCl-specific human T-cell lines from cancer patients.
- T-cell lines generated using the agonist epitope were more efficient than those generated with the native epitope for the lysis of targets pulsed with the native epitope and in the lysis of HLA-A2 human tumor cells expressing MUCl .
- the inventors have identified additional CD8+ cytotoxic T lymphocyte immune enhancer agonist sequence epitopes of MUCl-C.
- a potent MUCl-C modified for immune enhancer capability (mMUCl-C or MUCl -C or MUClc).
- the present disclosure provides a potent MUCl-C modified for immune enhancer capability incorporated it into a recombinant Ad5 [E1-, E2b-] platform to produce a new and more potent immunotherapeutic vaccine.
- the immunotherapeutic vaccine can be Ad5 [E1-, E2b-]-mMUCl-C for treating MUCl expressing cancers or infectious diseases.
- Post-translational modifications play an important role in controlling protein function in the body and in human disease.
- MUCl can have several post-translational modifications such as glycosylation, sialylation, palmitoylation, or a combination thereof at specific amino acid residues.
- immunotherapies targeting glycosylation, sialylation, phosphorylation, or palmitoylation modifications of MUCl.
- MUCl can be highly glycosylated (N- and O-linked carbohydrates and sialic acid at varying degrees on serine and threonine residues within each tandem repeat, ranging from mono- to penta-glycosylation).
- N-glycosylation consists of high-mannose, acidic complex-type and hybrid glycans in the secreted form MUC1/SEC, and neutral complex-type in the transmembrane form, MUC1/TM.4.
- the present disclosure provides for immunotherapies targeting differentially O-glycosylated forms of MUCl .
- MUCl can be sialylated.
- Membrane-shed glycoproteins from kidney and breast cancer cells have preferentially sialyated core 1 structures, while secreted forms from the same tissues display mainly core 2 structures.
- the O-glycosylated content is overlapping in both these tissues with terminal fucose and galactose, 2- and 3-linked galactose, 3- and 3,6- linked GalNAc-ol and 4-linked GlcNAc predominating.
- the present disclosure provides for immunotherapies targeting various sialylation forms of MUCl . Dual palmitoylation on cysteine residues in the CQC motif is required for recycling from endosomes back to the plasma membrane.
- the present disclosure provides for immunotherapies targeting various palmitoylation forms of MUCl .
- Phosphorylation can affect MUCl 's ability to induce specific cell signaling responses that are important for human health.
- the present disclosure provides for immunotherapies targeting various phosphorylated forms of MUCl .
- MUCl can be phosphorylated on tyrosine and serine residues in the C-terminal domain.
- Phosphorylation on tyrosines in the C-terminal domain can increase nuclear location of MUCl and ⁇ -catenin.
- Phosphorylation by PKC delta can induce binding of MUCl to ⁇ -catenin/CTNNB 1 and decrease formation of ⁇ -catenin/E-cadherin complexes.
- Src-mediated phosphorylation of MUCl can inhibit interaction with GSK3B.
- Src- and EGFR-mediated phosphorylation of MUCl on Tyr-1229 can increase binding to ⁇ -catenin/CTNNB l.
- GSK3B-mediated phosphorylation of MUCl on Ser-1227 can decrease this interaction, but restores the formation of the ⁇ -cadherin E-cadherin complex.
- PDGFR-mediated phosphorylation of MUCl can increase nuclear colocalization of MUC1CT and CTNNB 1.
- the present disclosure provides for immunotherapies targeting different phosphorylated forms of MUCl, MUClc, and MUCln known to regulate its cell signaling abilities.
- the disclosure provides for immunotherapies that modulate MUClc cytoplasmic domain and its functions in the cell.
- the disclosure provides for immunotherapies that comprise modulating a CQC motif in MUClc.
- the disclosure provides for immunotherapies that comprise modulating the extracellular domain (ED), the transmembrane domain (TM), the cytoplasmic domain (CD) of MUClc, or a combination thereof.
- the disclosure provides for immunotherapies that comprise modulating MUClc's ability to induce cellular signaling through EGFR, ErbB2, or other receptor tyrosine kinases.
- the disclosure provides for immunotherapies that comprise modulating MUClc's ability to induce PI3K ⁇ AKT, MEK ⁇ ERK, Wnt ⁇ -catenin, STAT, NF- ⁇ RelA cellular pathways, or combination thereof.
- the MUClc immunotherapy can further comprise PSA, PSMA, CEA, or Brachyury immunotherapy in the same replication-defective virus vectors or separate replication-defective virus vectors.
- the disclosure also provides for immunotherapies that modulate MUCln and its cellular functions.
- the disclosure also provides for immunotherapies comprising tandem repeats of MUCln, the glycosylation sites on the tandem repeats of MUCln, or a combination thereof.
- the MUCl n immunotherapy further comprises PSA, PSMA, CEA, or Brachyury immunotherapy in the same replication-defective virus vectors or separate replication-defective virus vectors.
- the disclosure also provides vaccines comprising MUCln, MUClc, PSA, brachyury, CEA, or a combination thereof.
- the disclosure provides vaccines comprising MUClc and PSA, PSMA, brachyury, CEA, or a combination thereof.
- the disclosure also provides vaccines targeting MUCln and PSA, Brachyury, CEA, or a combination thereof.
- the antigen combination is contained in one vector as provided herein. In some embodiments, the antigen combination is contained in a separate vector as provided herein.
- the present invention relates to a replication defective adenovirus vector of serotype 5 comprising a sequence encoding an immunogenic polypeptide.
- the immunogenic polypeptide may be an isoform of MUCl or a subunit or a fragment thereof.
- the replication defective adenovirus vector comprises a sequence encoding a polypeptide with at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% identity to the immunogenic polypeptide.
- the immunogenic polypeptide encoded by the adenovirus vectors described herein comprising up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or more point mutations, such as single amino acid substitutions or deletions, as compared to a wild-type human MUCl sequence.
- a MUCl-c antigen of this disclosure can be a modified MUCl and can have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 10.
- a MUCl-c antigen of this disclosure can have an amino acid sequence as set forth in SEQ ID NO: 10.
- a MUCl-c antigen of this disclosure can be a modified MUCl and can have a nucleotide sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 41.
- a MUCl-c antigen of this disclosure can have a nucleotide sequence as set forth in SEQ ID NO: 41.
- compositions comprising replication-defective vectors comprising one or more nucleic acid sequences encoding PSA and/or PSMA antigen, and/or one or more nucleic acid sequences encoding mucin family antigen such as MUCl, and/or one or more nucleic acid sequences encoding Brachyury, and/or one or more nucleic acid sequences encoding CEA in the same or separate replication-defective vectors.
- the disclosure provides for immunotherapies that comprise one or more antigens to Brachyury.
- Brachyury also known as the "T" protein in humans
- T-box family of transcription factors that play key roles during early development, mostly in the formation and differentiation of normal mesoderm and is characterized by a highly conserved DNA-binding domain designated as T-domain.
- the epithelial to mesenchymal transition (EMT) is a key step during the progression of primary tumors into a metastatic state in which Brachyury plays a crucial role.
- EMT epithelial to mesenchymal transition
- the expression of Brachyury in human carcinoma cells induces changes characteristic of EMT, including up-regulation of mesenchymal markers, down-regulation of epithelial markers, and an increase in cell migration and invasion.
- Brachyury Conversely, inhibition of Brachyury resulted in down-regulation of mesenchymal markers and loss of cell migration and invasion and diminished the ability of human tumor cells to form metastases. Brachyury can function to mediate epithelial-mesenchymal transition and promotes invasion.
- the disclosure also provides for immunotherapies that modulate Brachyury effect on epithelial-mesenchymal transition function in cell proliferation diseases, such as cancer.
- the disclosure also provides immunotherapies that modulate Brachyury's ability to promote invasion in cell proliferation diseases, such as cancer.
- the disclosure also provides for immunotherapies that modulate the DNA binding function of T-box domain of Brachyury.
- the Brachyury immunotherapy can further comprise one or more antigens to PSA, PSMA, CEA, or MUC1 , MUClc or MUCln.
- Brachyury expression is nearly undetectable in most normal human tissues and is highly restricted to human tumors and often overexpressed making it an attractive target antigen for immunotherapy.
- Brachyury is encoded by the T gene (GenBank: AJ001699.1, NCBI: NM_003181.3).
- T gene GeneBank: AJ001699.1, NCBI: NM_003181.3.
- isoforms produced by alternative splicing found in humans. Each isoform has a number of natural variants.
- Brachyury is immunogenic and Brachyury-specific CD8+ T-cells expanded in vitro can lyse Brachyury expressing tumor cells. These features of Brachyury make it an attractive tumor associated antigen (TAA) for immunotherapy.
- the Brachyury protein is a T-box transcription factor. It can bind to a specific DNA element, a near palindromic sequence "TCACACCT" through a region in its N-terminus, called the T-box to activate gene transcription when bound to such a site.
- the disclosure also provides vaccines comprising Brachyury, PSA, PSMA, MUC1 , CEA, or a combination thereof.
- the antigen combination is contained in one vector as provided herein.
- the antigen combination is contained in a separate vector as provided herein.
- the present invention relates to a replication defective adenovirus vector of serotype 5 comprising a sequence encoding an immunogenic polypeptide.
- the immunogenic polypeptide may be an isoform of Brachyury or a subunit or a fragment thereof.
- the replication defective adenovirus vector comprises a sequence encoding a polypeptide with at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% identity to the immunogenic polypeptide.
- the immunogenic polypeptide encoded by the adenovirus vectors described herein comprising up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or more point mutations, such as single amino acid substitutions or deletions, as compared to a wild- type human Brachyury sequence.
- a Brachyury antigen of this disclosure can have an amino sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 42.
- a Brachyury antigen of this disclosure can have an amino acid sequence as set forth in SEQ ID NO: 42.
- compositions comprising replication-defective vectors comprising one or more nucleic acid sequences encoding PSA and/or PSMA antigen, and/or one or more nucleic acid sequences encoding mucin family antigen such as MUCl, and/or one or more nucleic acid sequences encoding Brachyury, and/or one or more nucleic acid sequences encoding CEA in the same or separate replication-defective vectors.
- CEA represents an attractive target antigen for immunotherapy since it is over-expressed in nearly all colorectal cancers and pancreatic cancers, and is also expressed by some lung and breast cancers, and uncommon tumors such as medullary thyroid cancer, but is not expressed in other cells of the body except for low-level expression in gastrointestinal epithelium.
- CEA contains epitopes that may be recognized in an MHC restricted fashion by T-cells.
- CEA antigen specific CMI can be, for example, greater than 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 5000, 10000, or more IFN- ⁇ spot forming cells (SFC) per 10 6 peripheral blood mononuclear cells (PBMC).
- the immune response is raised in a human subject with a preexisting inverse Ad5 neutralizing antibody titer of greater than 50, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000, 1000, 12000, 15000, or higher.
- the immune response may comprise a cell-mediated immunity and/or a humoral immunity as described herein.
- the immune response may be measured by one or more of intracellular cytokine staining (ICS), ELISpot, proliferation assays, cytotoxic T-cell assays including chromium release or equivalent assays, and gene expression analysis using any number of polymerase chain reaction (PCR) or RT-PCR based assays, as described herein and to the extent they are available to a person skilled in the art, as well as any other suitable assays known in the art for measuring immune response.
- ICS intracellular cytokine staining
- ELISpot ELISpot
- proliferation assays proliferation assays
- cytotoxic T-cell assays including chromium release or equivalent assays
- gene expression analysis using any number of polymerase chain reaction (PCR) or RT-PCR based assays, as described herein and to the extent they are available to a person skilled in the art, as well as any other suitable assays
- the replication defective adenovirus vector comprises a modified sequence encoding a subunit with at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% identity to a wild-type subunit of the polypeptide.
- the immunogenic polypeptide may be a mutant CEA or a fragment thereof.
- the immunogenic polypeptide comprises a mutant CEA with an Asn->Asp substitution at position 610.
- the replication defective adenovirus vector comprises a sequence encoding a polypeptide with at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% identity to the immunogenic polypeptide.
- the sequence encoding the immunogenic polypeptide comprises the sequence of SEQ ID NO: 37 (nucleic acid sequence for CEA-CAP1(6D)) or SEQ ID NO: 38 (amino acid sequence for the mutated CAP1 (6D) epitope).
- the sequence encoding the immunogenic polypeptide comprises a sequence with at least 70% 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% identity to SEQ ID NO: 37 or SEQ ID NO: 38 or a sequence generated from SEQ ID NO: 37 or SEQ ID NO: 38 by alternative codon replacements.
- the immunogenic polypeptide encoded by the adenovirus vectors comprise up to 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or more point mutations, such as single amino acid substitutions or deletions, as compared to a wild-type human CEA sequence.
- the immunogenic polypeptide comprises a sequence from SEQ ID NO: 37 or a modified version, e.g., comprising up to 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or more point mutations, such as single amino acid substitutions or deletions, of SEQ ID NO: 37 or SEQ ID NO: 38.
- CEACAM CEA-related Cell Adhesion Molecule
- PSG Pregnancy Specific Glycoprotein
- PSG11 Pregnancy Specific Glycoprotein subgroup containing eleven closely related genes
- CEACAMP1-CEACAMP11 a subgroup of eleven pseudogenes
- CEACAM16 contains two Ig-like V-type domains at its N and C termini and CEACAM20 contains a truncated Ig-like V-type 1 domain.
- CEACAM molecules can be anchored to the cell surface via their transmembrane domains (CEACAMS thought CEACAMS) or directly linked to glycophosphatidylinositol (GPI) lipid moiety (CEACAM5, CEACAM18 thought CEACAM21).
- CEACAMS transmembrane domains
- GPI glycophosphatidylinositol
- CEA family members are expressed in different cell types and have a wide range of biological functions.
- CEACAMs are found prominently on most epithelial cells and are present on different leucocytes.
- CEACAM1 the ancestor member of CEA family, is expressed on the apical side of epithelial and endothelial cells as well as on lymphoid and myeloid cells.
- CEACAM1 mediates cell-cell adhesion through hemophilic (CEACAM] to CEACAM1) as well as heterothallic (e.g., CEACAM1 to CEACAMS) interactions.
- CEACAM1 is involved in many other biological processes, such as angiogenesis, cell migration, and immune functions.
- CEACAM3 and CEACAM4 expression is largely restricted to granulocytes, and they are able to convey uptake and destruction of several bacterial pathogens including Neisseria, Moraxella, and Haemophilus species.
- compositions and methods relate to raising an immune response against a CEA, selected from the group consisting of CEACAM 1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEACAM 16, CEACAM18, CEACAM19, CEACAM20, CEACAM21 , PSG1, PSG2, PSG3, PSG4, PSG5, PSG6, PSG7, PSG8, PSG9, and PSG1 1.
- An immune response may be raised against cells, e.g. cancer cells, expressing or overexpressing one or more of the CEAs, using the methods and compositions.
- the overexpression of the one or more CEAs in such cancer cells is over 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 fold or more compared to non-cancer cells.
- the CEA antigen used herein is a wild-type CEA antigen or a modified CEA antigen having a least a mutation in YLSGANLNL (SEQ ID NO: 39), a CAP1 epitope of CEA.
- the mutation can be conservative or non-conservative, substitution, addition, or deletion.
- the CEA antigen used herein has an amino acid sequence set forth in YLSGADLNL (SEQ ID NO: 38), a mutated CAP1 epitope.
- the first replication-defective vector or a replication-defective vectors that express CEA has a nucleotide sequence at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9%, or 100% identical to any portion of SEQ ID NO: 40 (the predicted sequence of an adenovirus vector expressing a modified CEA antigen), such as positions 1057 to 3165 of SEQ ID NO: 40 or full-length SEQ ID NO: 40.
- compositions comprising replication-defective vectors comprising one or more nucleic acid sequences encoding PSA family antigen (e.g., PSA and/or PSMA), and/or one or more nucleic acid sequences encoding mucin family antigen such as MUC1 , and/or one or more nucleic acid sequences encoding Brachyury, and/or one or more nucleic acid sequences encoding CEA in same or separate replication- defective vectors.
- PSA family antigen e.g., PSA and/or PSMA
- Prostate cancer also known as carcinoma of the prostate, is the development of cancer in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, some grow relatively quickly. The cancer cells may spread from the prostate to other parts of the body, particularly the bones and lymph nodes. It may initially cause no symptoms. In later stages it can lead to difficulty urinating, blood in the urine, or pain in the pelvis, back or when urinating. A disease known as benign prostatic hyperplasia may produce similar symptoms. Other late symptoms may include feeling tired due to low levels of red blood cells.
- prostate cancer usually has no clear symptoms. Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hyperplasia. These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), and dysuria (painful urination).
- diseases such as benign prostatic hyperplasia. These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), and dysuria (painful urination).
- Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds the prostatic urethra. Changes within the gland, therefore, directly affect urinary function. Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the prostate gland itself are included in semen content, prostate cancer may also cause problems with sexual function and performance, such as difficulty achieving erection or painful ejaculation.
- advanced prostate cancer can spread to other parts of the body, possibly causing additional symptoms.
- the most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis, or ribs.
- the spread of cancer into other bones, such as the femur, is usually a result of spreading to the proximal or nearby part of the bone.
- Prostate cancer in the spine can also compress the spinal cord, causing tingling, leg weakness and urinary and fecal incontinence.
- Prostate cancer is an ideal candidate for immunotherapy for several reasons.
- the slow growing nature of cancer within the prostate allows sufficient time to generate an anti-tumor immune response following a prime/boost or multiple immunization strategies.
- prostate cancer expresses numerous tumor associated antigens (TAAs) that include the Prostate Specific Antigen (PSA), Prostatic Acid Phosphatase (PAP), Prostate Specific Membrane Antigen (PSMA), Prostate Stem Cell Antigen (PSCA) and Six Transmembrane Epithelial Antigen of the Prostate (STEAP). All of these TAAs provide multiple potential immunological anti-tumor targets and the ideal combination of antigens to target has yet to be fully determined.
- TAAs tumor associated antigens
- PSA Prostate Specific Antigen
- PAP Prostatic Acid Phosphatase
- PSMA Prostate Specific Membrane Antigen
- PSCA Prostate Stem Cell Antigen
- STEAP Six Transmembrane Epithelial Antigen of the Prostate
- Sipuleucel-T consists of autologous peripheral blood mononuclear cells with antigen presenting dendritic cells that have been activated ex vivo with a recombinant fusion protein (PA2024) consisting of PAP linked to granulocyte-macrophage colony stimulating factor (GM-CSF).
- PA2024 recombinant fusion protein
- GM-CSF granulocyte-macrophage colony stimulating factor
- OS median overall survival
- PSA has been incorporated into a replication incompetent early generation Ad5 [El -]-based vector platform and tested in a phase 1 trial. Sequential cohorts of subjects had increasing doses of a single injection of Ad5-PSA. Most subjects developed detectable cellular mediated anti-PSA responses 18/32 (67%). This approach is being evaluated in a phase 2 trial using multiple doses (3 injections) at 1 month intervals.
- PSA based vaccination approaches have preliminary evidence of clinical activity as well as an ability to induce anti-PSA directed cellular immunity.
- Improved vectors such as the new Etubics Ad5
- Non-replicating adenoviral vectors should improve the safety of this approach, and the ability to circumvent neutralizing anti-viral immune responses would enable sustained boosting to maximize immune responses.
- Standard treatment of aggressive prostate cancers may involve surgery (i.e., radical prostatectomy), radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation therapy, high-intensity focused ultrasound (HIFU), chemotherapy, oral chemotherapeutic drugs (Temozolomide/TMZ), cryosurgery, hormonal therapy, or some combination.
- the Ad5 [E1 -, E2b-]-PSA- and/or -PSMA-based vaccination approaches as used herein can be combined with any available prostate cancer therapy, such as the examples described above.
- Certain aspects include transferring into a cell an expression construct comprising one or more nucleic acid sequences encoding one or more target antigens such as PSA, MUC1, Brachyury, PSMA, CEA, or a combination thereof.
- transfer of an expression construct into a cell may be accomplished using a viral vector.
- a viral vector may be used to include those constructs containing viral sequences sufficient to express a recombinant gene construct that has been cloned therein.
- the viral vector is an adenovirus vector.
- Adenoviruses are a family of DNA viruses characterized by an icosahedral, non-enveloped capsid containing a linear double-stranded genome. Of the human adenoviruses, none are associated with any neoplastic disease, and only cause relatively mild, self-limiting illness in immunocompetent individuals.
- Adenovirus vectors may have low capacity for integration into genomic DNA. Adenovirus vectors may result in highly efficient gene transfer. Additional advantages of adenovirus vectors include that they are efficient at gene delivery to both nondividing and dividing cells and can be produced in large quantities.
- adenoviral infection of host cells may not result in chromosomal integration because adenoviral DNA can replicate in an episomal manner without potential genotoxicity.
- adenovirus vectors may be structurally stable, and no genome rearrangement has been detected after extensive amplification.
- Adenovirus is particularly suitable for use as a gene transfer vector because of its mid- sized genome, ease of manipulation, high titer, wide target-cell range and high infectivity.
- the first genes expressed by the virus are the El genes, which act to initiate high- level gene expression from the other Ad5 gene promoters present in the wild type genome.
- Viral DNA replication and assembly of progeny virions occur within the nucleus of infected cells, and the entire life cycle takes about 36 hr with an output of approximately 10 4 virions per cell.
- the wild type Ad5 genome is approximately 36 kb, and encodes genes that are divided into early and late viral functions, depending on whether they are expressed before or after DNA replication.
- the early/late delineation is nearly absolute, since it has been demonstrated that super-infection of cells previously infected with an Ad5 results in lack of late gene expression from the super-infecting virus until after it has replicated its own genome. Without being bound by theory, this is likely due to a replication dependent cis- activation of the Ad5 major late promoter (MLP), preventing late gene expression (primarily the Ad5 capsid proteins) until replicated genomes are present to be encapsulated.
- MLP Ad5 major late promoter
- the composition and methods may take advantage of these features in the development of advanced generation Ad vectors/vaccines.
- the adenovirus vector may be replication defective, or at least conditionally defective.
- the adenovirus may be of any of the 42 different known serotypes or subgroups A- F and other serotypes or subgroups are envisioned.
- Adenovirus type 5 of subgroup C may be used in particular embodiments in order to obtain a replication- defective adenovirus vector. This is because Adenovirus type 5 is a human adenovirus about which a great deal of biochemical and genetic information is known, and it has historically been used for most constructions employing adenovirus as a vector.
- Adenovirus growth and manipulation is known to those of skill in the art, and exhibits broad host range in vitro and in vivo. Modified viruses, such as adenoviruses with alteration of the CAR domain, may also be used. Methods for enhancing delivery or evading an immune response, such as liposome encapsulation of the virus, are also envisioned.
- the vector may comprise a genetically engineered form of adenovirus, such as an E2 deleted adenoviral vector, or more specifically, an E2b deleted adenoviral vector.
- E2b deleted refers to a specific DNA sequence that is mutated in such a way so as to prevent expression and/or function of at least one E2b gene product.
- E2b deleted refers to a specific DNA sequence that is deleted (removed) from the Ad genome.
- E2b deleted or "containing a deletion within the E2b region” refers to a deletion of at least one base pair within the E2b region of the Ad genome.
- more than one base pair is deleted and in further embodiments, at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, or 150 base pairs are deleted.
- the deletion is of more than 150, 160, 170, 180, 190, 200, 250, or 300 base pairs within the E2b region of the Ad genome.
- An E2b deletion may be a deletion that prevents expression and/or function of at least one E2b gene product and therefore, encompasses deletions within exons encoding portions of E2b-specific proteins as well as deletions within promoter and leader sequences.
- an E2b deletion is a deletion that prevents expression and/or function of one or both of the DNA polymerase and the preterminal protein of the E2b region.
- "E2b deleted” refers to one or more point mutations in the DNA sequence of this region of an Ad genome such that one or more encoded proteins is non-functional. Such mutations include residues that are replaced with a different residue leading to a change in the amino acid sequence that result in a nonfunctional protein.
- regions of the Ad genome can be deleted.
- “deleted” in a particular region of the Ad genome refers to a specific DNA sequence that is mutated in such a way so as to prevent expression and/or function of at least one gene product encoded by that region.
- to be “deleted” in a particular region refers to a specific DNA sequence that is deleted (removed) from the Ad genome in such a way so as to prevent the expression and/or the function encoded by that region (e.g., E2b functions of DNA polymerase or preterminal protein function).
- "Deleted" or "containing a deletion" within a particular region refers to a deletion of at least one base pair within that region of the Ad genome.
- more than one base pair is deleted and in further embodiments, at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 base pairs are deleted from a particular region.
- the deletion is more than 150, 160, 170, 180, 190, 200, 250, or 300 base pairs within a particular region of the Ad genome.
- "deleted" in a particular region of the Ad genome refers to one or more point mutations in the DNA sequence of this region of an Ad genome such that one or more encoded proteins is non-functional. Such mutations include residues that are replaced with a different residue leading to a change in the amino acid sequence that result in a nonfunctional protein.
- the adenovirus vectors contemplated for use include E2b deleted adenovirus vectors that have a deletion in the E2b region of the Ad genome and, optionally, the El region. In some cases, such vectors do not have any other regions of the Ad genome deleted.
- the adenovirus vectors contemplated for use include E2b deleted adenovirus vectors that have a deletion in the E2b region of the Ad genome and, optionally, deletions in the El and E3 regions. In some cases, such vectors have no other regions deleted.
- the adenovirus vectors contemplated for use include adenovirus vectors that have a deletion in the E2b region of the Ad genome and, optionally, deletions in the El, E3, and also optionally, partial or complete removal of the E4 regions. In some cases, such vectors have no other deletions.
- the adenovirus vectors contemplated for use include adenovirus vectors that have a deletion in the E2b region of the Ad genome and, optionally, deletions in the El and/or E4 regions. In some cases, such vectors contain no other deletions.
- the adenovirus vectors contemplated for use include adenovirus vectors that have a deletion in the E2a, E2b, and/or E4 regions of the Ad genome. In some cases, such vectors have no other deletions.
- the adenovirus vectors for use herein comprise vectors having the El and/or DNA polymerase functions of the E2b region deleted. In some cases, such vectors have no other deletions.
- the adenovirus vectors for use herein have the El and/or the preterminal protein functions of the E2b region deleted. In some cases, such vectors have no other deletions.
- the adenovirus vectors for use herein have the El , DNA polymerase and/or the preterminal protein functions deleted. In some cases, such vectors have no other deletions. In one particular embodiment, the adenovirus vectors contemplated for use herein are deleted for at least a portion of the E2b region and/or the El region.
- such vectors are not "gutted" adenovirus vectors.
- the vectors may be deleted for both the DNA polymerase and the preterminal protein functions of the E2b region.
- the adenovirus vectors for use include adenovirus vectors that have a deletion in the El, E2b, and/or 100K regions of the adenovirus genome.
- the adenovirus vector may be a "gutted" adenovirus vector.
- the adenovirus vectors for use herein comprise vectors having the El , E2b, and/or protease functions deleted. In some cases, such vectors have no other deletions.
- the adenovirus vectors for use herein have the El and/or the E2b regions deleted, while the fiber genes have been modified by mutation or other alterations (e.g., to alter Ad tropism). Removal of genes from the E3 or E4 regions may be added to any of the mentioned adenovirus vectors.
- the deleted adenovirus vectors can be generated using recombinant techniques known in the art (see e.g., Amalfitano, et al. J. Virol. 1998; 72:926-33; Hodges, et al. J Gene Med 2000; 2:250-59).
- the adenovirus vectors for use in certain aspects can be successfully grown to high titers using an appropriate packaging cell line that constitutively expresses E2b gene products and products of any of the necessary genes that may have been deleted.
- HEK-293 -derived cells that not only constitutively express the El and DNA polymerase proteins, but also the Ad-preterminal protein, can be used.
- E.C7 cells are used to successfully grow high titer stocks of the adenovirus vectors (see e.g., Amalfitano, et al. J. Virol. 1998; 72:926-33; Hodges, et al. J Gene Med 2000; 2:250-59) [0167]
- the proteins encoded by the targeted genes may be coexpressed in HEK-293 cells, or similar, along with the El proteins. Therefore, only those proteins which are non-toxic when coexpressed constitutively (or toxic proteins inducibly- expressed) can be utilized.
- El and 100k genes have been successfully expressed in transcomplementing cell lines, as have El and protease genes (Oualikene, et al. Hum Gene Ther 2000; 11 : 1341-53; Hodges, et al. J. Virol 2001 ; 75:5913-20).
- Cell lines coexpressing El and E2b gene products for use in growing high titers of E2b deleted Ad particles are described in U.S. Patent No. 6,063,622.
- the E2b region encodes the viral replication proteins which are absolutely required for Ad genome replication (Doerfler, et al. Chromosoma 1992; 102:S39-S45).
- Useful cell lines constitutively express the approximately 140 kDa Ad-DNA polymerase and/or the approximately 90 kDa preterminal protein.
- cell lines that have high-level, constitutive coexpression of the El, DNA polymerase, and preterminal proteins, without toxicity (e.g., E.C7), are desirable for use in propagating Ad for use in multiple vaccinations. These cell lines permit the propagation of adenovirus vectors deleted for the El, DNA polymerase, and preterminal proteins.
- the recombinant adenovirus vector can be propagated using techniques available in the art. For example, in certain embodiments, tissue culture plates containing E.C7 cells are infected with the adenovirus vector virus stocks at an appropriate MOI (e.g., 5) and incubated at 37.0 °C for 40-96 hrs. The infected cells are harvested, resuspended in 10 mM Tris-CI (pH 8.0), and sonicated, and the virus is purified by two rounds of cesium chloride density centrifugation.
- MOI e.g. 5
- 10 mM Tris-CI pH 8.0
- the virus containing band is desalted over a Sephadex CL-6B column (Pharmacia Biotech, Piscataway, NJ.), sucrose or glycerol is added, and aliquots are stored at -80 °C.
- the virus vector is placed in a solution designed to enhance its stability, such as A195 (Evans, et al. J Pharm Sci 2004; 93:2458-75). The titer of the stock is measured (e.g., by measurement of the optical density at 260 nm of an aliquot of the virus after SDS lysis).
- plasmid DNA can be transfected into E.C7, or similar cells, and incubated at 37.0 °C until evidence of viral production is present (e.g., the cytopathic effect).
- the conditioned media from these cells can then be used to infect more E.C7, or similar cells, to expand the amount of virus produced, before purification. Purification can be accomplished by two rounds of cesium chloride density centrifugation or selective filtration.
- the virus may be purified by column chromatography, using commercially available products (e.g., Adenopure from Puresyn, Inc., Malvern, PA) or custom made chromatographic columns.
- the recombinant adenovirus vector may comprise enough of the virus to ensure that the cells to be infected are confronted with a certain number of viruses.
- a stock of recombinant Ad particularly an RCA-free stock of recombinant Ad.
- the preparation and analysis of Ad stocks can use any methods available in the art. Viral stocks vary considerably in titer, depending largely on viral genotype and the protocol and cell lines used to prepare them.
- the viral stocks can have a titer of at least about 10 6 , 10 7 , or 10 8 virus particles (VPs)/ml, and many such stocks can have higher titers, such as at least about 10 9 , 10 10 , 10 u , or 10 12 VPs/ml.
- VPs virus particles
- E2b deleted adenovirus vectors such as those described in U.S. Pat. Nos. 6,063,622; 6,451,596; 6,057,158; 6,083,750; and 8,298,549.
- the vectors with deletions in the E2b regions in many cases cripple viral protein expression and/or decrease the frequency of generating replication competent Ad (RCA).
- Propagation of these E2b deleted adenovirus vectors can be done utilizing cell lines that express the deleted E2b gene products. Certain aspects also provide such packaging cell lines; for example E.C7 (formally called C-7), derived from the HEK-293 cell line.
- E.C7 (formally called C-7), derived from the HEK-293 cell line.
- the E2b gene products, DNA polymerase and preterminal protein can be constitutively expressed in E.C7, or similar cells along with the El gene products. Transfer of gene segments from the Ad genome to the production cell line has immediate benefits: (1) increased carrying capacity; and, (2) a decreased potential of RCA generation, typically requiring two or more independent recombination events to generate RCA.
- the El, Ad DNA polymerase and/or preterminal protein expressing cell lines used herein can enable the propagation of adenovirus vectors with a carrying capacity approaching 13 kb, without the need for a contaminating helper virus.
- genes critical to the viral life cycle are deleted (e.g., the E2b genes)
- a further crippling of Ad to replicate or express other viral gene proteins occurs. This can decrease immune recognition of virally infected cells, and allow for extended durations of foreign transgene expression.
- El, DNA polymerase, and preterminal protein deleted vectors are typically unable to express the respective proteins from the El and E2b regions. Further, they may show a lack of expression of most of the viral structural proteins.
- MLP major late promoter
- the highly toxic Ad late genes are primarily transcribed and translated from the MLP only after viral genome replication has occurred. This cis-dependent activation of late gene transcription is a feature of DNA viruses in general, such as in the growth of polyoma and SV-40.
- the DNA polymerase and preterminal proteins are important for Ad replication (unlike the E4 or protein IX proteins). Their deletion can be extremely detrimental to adenovirus vector late gene expression, and the toxic effects of that expression in cells such as APCs.El-deleted adenovirus vectors
- Ad5 [E1 -] are constructed such that a transgene replaces only the El region of genes. Typically, about 90% of the wild-type Ad5 genome is retained in the vector.
- Ad5 [E1-] vectors have a decreased ability to replicate and cannot produce infectious virus after infection of cells not expressing the Ad5 El genes.
- the recombinant Ad5 [E1-] vectors are propagated in human cells (typically 293 cells) allowing for Ad5 [E1-] vector replication and packaging.
- Ad5 [E1 -] vectors have a number of positive attributes; one of the most important is their relative ease for scale up and cGMP production.
- Ad5 [E 1-] vectors are well over 220 human clinical trials, with more than two thousand subjects given the virus subcutaneously, intramuscularly, or intravenously.
- Ad5 vectors do not integrate; their genomes remain episomal. Generally, for vectors that do not integrate into the host genome, the risk for insertional mutagenesis and/or germ-line transmission is extremely low if at all. Conventional Ad5 [E1-] vectors have a carrying capacity that approaches 7 kb.
- pre-existing immunity against Ad5 can be an inhibitory factor to commercial use of Ad-based vaccines.
- the preponderance of humans have antibody against Ad5, the most widely used subtype for human vaccines, with two-thirds of humans studied having lympho-proliferative responses against Ad5.
- This pre-existing immunity can inhibit immunization or re-immunization using typical Ad5 vaccines and may preclude the immunization of a vaccine against a second antigen, using an Ad5 vector, at a later time.
- Overcoming the problem of pre-existing anti- vector immunity has been a subject of intense investigation. Investigations using alternative human (non-Ad5 based) Ad5 subtypes or even non-human forms of Ad5 have been examined.
- next generation Ad5 vector based vaccine platform has additional deletions in the E2b region, removing the DNA polymerase and the preterminal protein genes.
- the Ad5 [E1-, E2b-] platform has an expanded cloning capacity that is sufficient to allow inclusion of many possible genes.
- Ad5 [E1-, E2b-] vectors have up to about 12 kb gene-carrying capacity as compared to the 7 kb capacity of Ad5 [E1-] vectors, providing space for multiple genes if needed.
- an insert of more than 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or 1 1 kb is introduced into an Ad5 vector, such as the Ad5 [E1-, E2b-] vector.
- Deletion of the E2b region may confer advantageous immune properties on the Ad5 vectors, often eliciting potent immune responses to target antigens, such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, while minimizing the immune responses to Ad viral proteins.
- target antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof.
- Ad5 [E1-, E2b-] vectors may induce a potent CMI, as well as antibodies against the vector expressed target antigens, such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, even in the presence of Ad immunity.
- Ad5 [E1-, E2b-] vectors also have reduced adverse reactions as compared to Ad5 [E1-] vectors, in particular the appearance of hepatotoxicity and tissue damage.
- Ad5 vectors Certain aspects of these Ad5 vectors are that expression of Ad late genes is greatly reduced. For example, production of the capsid fiber proteins could be detected in vivo for Ad5 [E1-] vectors, while fiber expression was ablated from Ad5 [E1-, E2b-] vector vaccines. The innate immune response to wild type Ad is complex. Proteins deleted from the Ad5 [E1-, E2b-] vectors generally play an important role. Specifically, Ad5 [E1-, E2b-] vectors with deletions of preterminal protein or DNA polymerase display reduced inflammation during the first 24 to 72 hours following injection compared to Ad5 [E1-] vectors. In various embodiments, the lack of Ad5 gene expression renders infected cells invisible to anti-Ad activity and permits infected cells to express the transgene for extended periods of time, which develops immunity to the target.
- Various embodiments contemplate increasing the capability for the Ad5 [E1-, E2b-] vectors to transduce dendritic cells, improving antigen specific immune responses in the vaccine by taking advantage of the reduced inflammatory response against Ad5 [E1-, E2b-] vector viral proteins and the resulting evasion of pre-existing Ad immunity.
- Ad5 [E1 -, E2b-] vectors not only are safer than, but appear to be superior to Ad5 [E1-] vectors in regard to induction of antigen specific immune responses, making them much better suitable as a platform to deliver tumor vaccines that can result in a clinical response.
- methods and compositions are provided by taking advantage of an Ad5 [E1-, E2b-] vector system for developing a therapeutic tumor vaccine that overcomes barriers found with other Ad5 systems and permits the immunization of people who have previously been exposed to Ad5.
- E2b deleted vectors may have up to a 13 kb gene-carrying capacity as compared to the 5 to 6 kb capacity of First Generation adenovirus vectors, easily providing space for nucleic acid sequences encoding any of a variety of target antigens, such as PSA, PSMA, MUCl , Brachyury, or a combination thereof.
- E2b deleted adenovirus vectors also have reduced adverse reactions as compared to First Generation adenovirus vectors. E2b deleted vectors have reduced expression of viral genes, and this characteristic leads to extended transgene expression in vivo.
- certain embodiments of the Second Generation E2b deleted adenovirus vectors contain additional deletions in the DNA polymerase gene (pol) and deletions of the pre-terminal protein (pTP).
- Ad proteins expressed from adenovirus vectors play an important role. Specifically, the deletions of pre-terminal protein and DNA polymerase in the E2b deleted vectors appear to reduce inflammation during the first 24 to 72 hours following injection, whereas First Generation adenovirus vectors stimulate inflammation during this period.
- second generation E2b deleted vectors results in increased potential for the vectors to express desired vaccine antigens, such as PSA, PSMA, MUCl , Brachyury, CEA, or a combination thereof, during the infection of antigen presenting cells (i.e., dendritic cells), decreasing the potential for antigenic competition, resulting in greater immunization of the vaccine to the desired antigen relative to identical attempts with First Generation adenovirus vectors.
- desired vaccine antigens such as PSA, PSMA, MUCl , Brachyury, CEA, or a combination thereof
- E2b deleted adenovirus vectors provide an improved Ad-based vaccine candidate that is safer, more effective, and more versatile than previously described vaccine candidates using First Generation adenovirus vectors.
- first generation, El -deleted Adenovirus subtype 5 (Ad5)-based vectors although promising platforms for use as vaccines, may be impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies.
- Ad5-based vectors with deletions of the El and the E2b regions may avoid immunological clearance and induce more potent immune responses against the encoded antigen transgene, such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, in Ad-immune hosts.
- vectors such as adenovirus vectors, may comprise heterologous nucleic acid sequences that encode one or more tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, fusions thereof or fragments thereof, which can modulate the immune response.
- tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof
- fusions thereof or fragments thereof which can modulate the immune response.
- a Second Generation E2b deleted adenovirus vectors that comprise a heterologous nucleic acid sequence encoding one or more tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof.
- polynucleotides that encode PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof from any source as described further herein, vectors or constructs comprising such polynucleotides and host cells transformed or transfected with such vectors or expression constructs.
- nucleic acid and “polynucleotide” are used essentially interchangeably herein.
- polynucleotides used herein may be single- stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules.
- RNA molecules may include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns.
- Additional coding or non-coding sequences may, but need not, be present within a polynucleotide as disclosed herein, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.
- An isolated polynucleotide means that a polynucleotide is substantially away from other coding sequences.
- an isolated DNA molecule as used herein does not contain large portions of unrelated coding DNA, such as large chromosomal fragments or other functional genes or polypeptide coding regions. Of course, this refers to the DNA molecule as originally isolated, and does not exclude genes or coding regions later added to the segment through recombination in the laboratory.
- the polynucleotides can include genomic sequences, extra-genomic and plasmid-encoded sequences and smaller engineered gene segments that express, or may be adapted to express target antigens as described herein, fragments of antigens, peptides and the like. Such segments may be naturally isolated, or modified synthetically by the hand of man.
- Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof or a portion thereof) or may comprise a sequence that encodes a variant or derivative of such a sequence.
- the polynucleotide sequences set forth herein encode one or more mutated tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof.
- polynucleotides represent a novel gene sequence that has been optimized for expression in specific cell types (i.e., human cell lines) that may substantially vary from the native nucleotide sequence or variant but encode a similar protein antigen.
- polynucleotide variants having substantial identity to native sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, for example those comprising at least 70, 80, 90, 95, 96, 97, 98, or 99% sequence identity or any derivable range or value thereof, particularly at least 75% up to 99% or higher, sequence identity compared to a native polynucleotide sequence encoding one or more tumor antigens such as PSA, MUC1, Brachyury, CEA, or a combination thereof using the methods described herein, (e.g., BLAST analysis using standard parameters, as described below).
- BLAST analysis using standard parameters, as described below.
- polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions, particularly such that the immunogenicity of the epitope of the polypeptide encoded by the variant polynucleotide or such that the immunogenicity of the heterologous target protein is not substantially diminished relative to a polypeptide encoded by the native polynucleotide sequence.
- the polynucleotide variants preferably encode a variant of one or more tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, or a fragment (e.g., an epitope) thereof wherein the propensity of the variant polypeptide or fragment (e.g., epitope) thereof to react with antigen- specific antisera and/or T-cell lines or clones is not substantially diminished relative to the native polypeptide.
- tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof
- a fragment e.g., an epitope
- the term "variants” should also be understood to encompass homologous genes of xenogenic origin.
- polynucleotides that comprise or consist of at least about 5 up to a 1000 or more contiguous nucleotides encoding a polypeptide, including target protein antigens, as described herein, as well as all intermediate lengths there between.
- intermediate lengths means any length between the quoted values, such as 16, 17, 18, 19, etc.; 21, 22, 23, etc.; 30, 31, 32, etc.; 50, 51, 52, 53, etc.; 100, 101, 102, 103, etc.; 150, 151, 152, 153, etc.; including all integers through 200-500; 500-1,000, and the like.
- a polynucleotide sequence as described herein may be extended at one or both ends by additional nucleotides not found in the native sequence encoding a polypeptide as described herein, such as an epitope or heterologous target protein.
- This additional sequence may consist of 1 up 20 nucleotides or more, at either end of the disclosed sequence or at both ends of the disclosed sequence.
- polynucleotides or fragments thereof regardless of the length of the coding sequence itself, may be combined with other DNA sequences, such as promoters, expression control sequences, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length may vary considerably. It is therefore contemplated that a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant DNA protocol.
- illustrative polynucleotide segments with total lengths of about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000, about 500, about 200, about 100, about 50 base pairs in length, and the like, (including all intermediate lengths) are contemplated to be useful in certain aspects.
- two sequences are said to be “identical” if the sequence of nucleotides in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity.
- a “comparison window” as used herein refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
- Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters.
- This program embodies several alignment schemes described in the following references: Dayhoff MO (1978) A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff MO (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345- 358; Hein J Unified Approach to Alignment and Phylogenes, pp. 626-645 (1990); Methods in Enzymology vol.183, Academic Press, Inc., San Diego, CA; Higgins, et al.
- optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith, et al. Add. APL. Math 1981 ; 2:482, by the identity alignment algorithm of Needleman, et al. Mol. Biol. 1970 48:443, by the search for similarity methods of Pearson and Lipman, Proc. Natl. Acad. Sci. USA 1988; 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, Wl), or by inspection.
- BLAST and BLAST 2.0 are described in Altschul et al, Nucl. Acids Res. 1977 25:3389-3402, and Altschul et al. J. Mol. Biol. 1990 215:403-10, respectively.
- BLAST and BLAST 2.0 can be used, for example with the parameters described herein, to determine percent sequence identity for the polynucleotides.
- Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.
- cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always ⁇ 0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
- the BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.
- the "percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences.
- the percentage is calculated by determining the number of positions at which the identical nucleic acid bases occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.
- alleles of the genes comprising the polynucleotide sequences provided herein may also be contemplated. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).
- a mutagenesis approach such as site-specific mutagenesis, is employed for the preparation of variants and/or derivatives of nucleic acid sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, or fragments thereof, as described herein.
- tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, or fragments thereof, as described herein.
- Site-specific mutagenesis allows the production of mutants through the use of specific oligonucleotide sequences which encode the DNA sequence of the desired mutation, as well as a sufficient number of adjacent nucleotides, to provide a primer sequence of sufficient size and sequence complexity to form a stable duplex on both sides of the deletion junction being traversed. Mutations may be employed in a selected polynucleotide sequence to improve, alter, decrease, modify, or otherwise change the properties of the polynucleotide itself, and/or alter the properties, activity, composition, stability, or primary sequence of the encoded polypeptide.
- Polynucleotide segments or fragments encoding the polypeptides may be readily prepared by, for example, directly synthesizing the fragment by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer. Also, fragments may be obtained by application of nucleic acid reproduction technology, such as the PCRTM technology of U.S. Patent 4,683,202, by introducing selected sequences into recombinant vectors for recombinant production, and by other recombinant DNA techniques generally known to those of skill in the art of molecular biology (see for example, Current Protocols in Molecular Biology, John Wiley and Sons, NY, NY).
- nucleotide sequences encoding the polypeptide, or functional equivalents are inserted into an appropriate vector such as a replication-defective adenovirus vector as described herein using recombinant techniques known in the art.
- the appropriate vector contains the necessary elements for the transcription and translation of the inserted coding sequence and any desired linkers.
- Methods that are available to those skilled in the art may be used to construct these vectors containing sequences encoding one or more tumor antigens such as PSA, MUC1, Brachyury, CEA, or a combination thereof and appropriate transcriptional and translational control elements.
- tumor antigens such as PSA, MUC1, Brachyury, CEA, or a combination thereof
- methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Such techniques are described, for example, in Amalfitano, et al. J. Virol. 1998; 72:926-33; Hodges, et al. J Gene Med 2000; 2:250-259; Sambrook J, et al.
- a variety of vector/host systems may be utilized to contain and produce polynucleotide sequences. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA vectors; yeast transformed with yeast vectors; insect cell systems infected with virus vectors (e.g., baculovirus); plant cell systems transformed with virus vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or with bacterial vectors (e.g., Ti or pBR322 plasmids); or animal cell systems.
- microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA vectors
- yeast transformed with yeast vectors insect cell systems infected with virus vectors (e.g., baculovirus)
- plant cell systems transformed with virus vectors e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV
- virus vectors
- control elements or "regulatory sequences” present in a vector, such as an adenovirus vector, are those non-translated regions of the vector— enhancers, promoters, 5' and 3' untranslated regions — which interact with host cellular proteins to carry out transcription and translation. Such elements may vary in their strength and specificity. Depending on the vector system and host utilized, any number of suitable transcription and translation elements, including constitutive and inducible promoters, may be used. For example, sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof may be ligated into an Ad transcription/translation complex consisting of the late promoter and tripartite leader sequence.
- tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof may be ligated into an Ad transcription/translation complex consisting of the late promoter and tripartite leader sequence.
- Insertion in a nonessential El or E3 region of the viral genome may be used to obtain a viable virus that is capable of expressing the polypeptide in infected host cells (Logan J, et al. Proc. Natl. Acad. Sci 1984; 87:3655-59).
- transcription enhancers such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells.
- RSV Rous sarcoma virus
- Specific initiation signals may also be used to achieve more efficient translation of sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof.
- Such signals include the ATG initiation codon and adjacent sequences.
- sequences encoding the polypeptide, its initiation codon, and upstream sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed.
- exogenous translational control signals including the ATG initiation codon should be provided.
- the initiation codon should be in the correct reading frame to ensure translation of the entire insert.
- Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic.
- the efficiency of expression may be enhanced by the inclusion of enhancers that are appropriate for the particular cell system which is used, such as those described in the literature (Scharf D., et al. Results Probl. Cell Differ. 1994; 20: 125-62).
- Specific termination sequences, either for transcription or translation, may also be incorporated in order to achieve efficient translation of the sequence encoding the polypeptide of choice.
- a variety of protocols for detecting and measuring the expression of polynucleotide- encoded products e.g., one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof
- polynucleotide- encoded products e.g., one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof
- examples include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence activated cell sorting (FACS).
- ELISA enzyme-linked immunosorbent assay
- RIA radioimmunoassay
- FACS fluorescence activated cell sorting
- a two- site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non- interfering epitopes on a given polypeptide may be preferred for some applications, but a competitive binding assay may also be employed.
- elements that increase the expression of the desired tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof may be incorporated into the nucleic acid sequence of expression constructs or vectors such as adenovirus vectors described herein.
- Such elements include internal ribosome binding sites (IRES; Wang, et al. Curr. Top. Microbiol. Immunol 1995; 203:99; Ehrenfeld, et al. Curr. Top. Microbiol. Immunol. 1995; 203:65; Rees, et al. Biotechniques 1996; 20: 102; Sugimoto, et al. Biotechnology 1994; 2:694).
- IRES increase translation efficiency.
- sequences may enhance expression.
- sequences especially at the 5' end inhibit transcription and/or translation. These sequences are usually palindromes that can form hairpin structures. Any such sequences in the nucleic acid to be delivered are generally deleted.
- Expression levels of the transcript or translated product are assayed to confirm or ascertain which sequences affect expression. Transcript levels may be assayed by any known method, including Northern blot hybridization, RNase probe protection, and the like. Protein levels may be assayed by any known method, including ELISA.
- vectors such as adenovirus vectors described herein, that comprise heterologous nucleic acid sequences can be generated using recombinant techniques known in the art, such as those described in Maione, et al. Proc Natl Acad Sci USA 2001 ; 98:5986-91 ; Maione, et al. Hum Gene Ther 2000 1 :859-68; Sandig, et al. Proc Natl Acad Sci USA, 2000; 97: 1002-07; Harui, et al. Gene Therapy 2004; 11 : 1617- 26; Parks et al.
- compositions that comprise nucleic acid sequences encoding one or more one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof against which an immune response is to be generated.
- tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof against which an immune response is to be generated.
- the adenovirus vector stock described herein may be combined with an appropriate buffer, physiologically acceptable carrier, excipient, or the like.
- an appropriate number of adenovirus vector particles are administered in an appropriate buffer, such as, sterile PBS.
- an appropriate buffer such as, sterile PBS.
- solutions of the pharmaceutical compositions as free base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
- Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
- E2b deleted adenovirus vectors may be delivered in pill form, delivered by swallowing or by suppository.
- Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent 5,466,468).
- the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria, molds and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, lipids, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
- Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants.
- the prevention of the action of microorganisms can be facilitated by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- the solution may be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.
- a sterile aqueous medium that can be employed will be known to those of skill in the art in light of the present disclosure.
- one dosage may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. Moreover, for human administration, preparations will of course suitably meet sterility, pyrogenicity, and the general safety and purity standards as required by FDA Office of Biology standards.
- the carriers can further comprise any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
- the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- pharmaceutically- acceptable refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human.
- compositions described herein, as well as dosage will vary from individual to individual, and from disease to disease, and may be readily established using standard techniques.
- the pharmaceutical compositions and vaccines may be administered by injection (e.g., intracutaneous, intramuscular, intravenous or subcutaneous), intranasally (e.g., by aspiration), in pill form (e.g., swallowing, suppository for vaginal or rectal delivery).
- injection e.g., intracutaneous, intramuscular, intravenous or subcutaneous
- intranasally e.g., by aspiration
- pill form e.g., swallowing, suppository for vaginal or rectal delivery
- from 1 to 3 doses may be administered over a 6 week period and further booster vaccinations may be given periodically thereafter.
- a suitable dose is an amount of an adenovirus vector that, when administered as described above, is capable of promoting a target antigen immune response as described elsewhere herein.
- the immune response is at least 10- 50% above the basal (i.e., untreated) level.
- Such response can be monitored by measuring the target antigen antibodies in a patient or by vaccine-dependent generation of cytolytic effector cells capable of killing target antigen-expressing cells in vitro, or other methods known in the art for monitoring immune responses.
- the target antigens are PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof.
- an appropriate dosage and treatment regimen provides the adenovirus vectors in an amount sufficient to provide prophylactic benefit.
- Protective immune responses may generally be evaluated using standard proliferation, cytotoxicity or cytokine assays, which may be performed using samples obtained from a patient before and after immunization (vaccination).
- the actual dosage amount of a composition administered to a patient or subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration.
- the practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
- compositions and methods described herein are the capability to administer multiple vaccinations with the same adenovirus vectors, particularly in individuals with preexisting immunity to Ad, the adenoviral vaccines described herein may also be administered as part of a prime and boost regimen.
- a mixed modality priming and booster inoculation scheme may result in an enhanced immune response.
- one aspect is a method of priming a subject with a plasmid vaccine, such as a plasmid vector comprising nucleic acid sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, by administering the plasmid vaccine at least one time, allowing a predetermined length of time to pass, and then boosting by administering the adenovirus vector described herein.
- a plasmid vaccine such as a plasmid vector comprising nucleic acid sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof
- primings e.g., 1-3, may be employed, although more may be used.
- the length of time between priming and boost may typically vary from about six months to a year, but other time frames may be used.
- compositions may comprise, for example, at least about 0.1 % of therapeutic agents, such as the expression constructs or vectors used herein as vaccine, a related lipid nanovesicle, or an exosome or nanovesicle loaded with therapeutic agents.
- therapeutic agents such as the expression constructs or vectors used herein as vaccine, a related lipid nanovesicle, or an exosome or nanovesicle loaded with therapeutic agents.
- the therapeutic agent may comprise from about 2% to about 75% of the weight of the unit, or from about 25% to about 60%, for example, and any range derivable therein.
- a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligrarn/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
- a range of about 5 microgram/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligrarn/kg/body weight, etc. can be administered.
- An effective amount of the pharmaceutical composition is determined based on the intended goal.
- the term "unit dose” or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined-quantity of the pharmaceutical composition calculated to produce the desired responses discussed above in association with its administration, i.e., the appropriate route and treatment regimen.
- the quantity to be administered, both according to number of treatments and unit dose depends on the protection or effect desired.
- Precise amounts of the pharmaceutical composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment (e.g., alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance.
- compositions comprising a vaccination regime as described herein can be administered either alone or together with a pharmaceutically acceptable carrier or exqipient, by any routes, and such administration can be carried out in both single and multiple dosages.
- the pharmaceutical composition can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hand candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
- Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
- compositions described throughout can be formulated into a pharmaceutical medicament and be used to treat a human or mammal, in need thereof, diagnosed with a disease, e.g., cancer, or to enhances an immune response.
- a disease e.g., cancer
- the viral vectors or compositions described herein may be administered in conjunction with one or more immunostimulants, such as an adjuvant.
- An immunostimulant refers to essentially any substance that enhances or potentiates an immune response (antibody and/or cell-mediated) to an antigen.
- One type of immunostimulant comprises an adjuvant.
- Many adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a stimulator of immune responses, such as lipid A, Bortadella pertussis or Mycobacterium tuberculosis derived proteins.
- adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories); Merck Adjuvant 65 (Merck and Company, Inc.) AS-2 (SmithKline Beecham); aluminum salts such as aluminum hydroxide gel (alum) or aluminum phosphate; salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and quil A.
- Cytokines such as GM-CSF, IFN- ⁇ , TNFa, IL-2, IL-8, IL- 12, IL- 18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL- 10, IL- 13, IL- 15, IL-16, IL-23, and/or IL-32, and others, like growth factors, may also be used as adjuvants.
- the adjuvant composition can be one that induces an immune response predominantly of the Thl type.
- High levels of Thl -type cytokines e.g., IFN- ⁇ , TNFa, IL-2 and IL- 12
- Th2-type cytokines e.g., IL-4, IL-5, IL-6 and IL- 10.
- a patient may support an immune response that includes Thl - and/or Th2-type responses.
- Thl -type cytokines in which a response is predominantly Thl -type, the level of Thl -type cytokines will increase to a greater extent than the level of Th2-type cytokines.
- the levels of these cytokines may be readily assessed using standard assays.
- various embodiments relate to therapies raising an immune response against a target antigen, for example PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, using cytokines, e.g., IFN- ⁇ , TNFa, IL-2, IL-8, IL- 12, IL- 18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL- 10, IL- 13 and/or IL-15 supplied concurrently with a replication defective viral vector treatment.
- cytokines e.g., IFN- ⁇ , TNFa, IL-2, IL-8, IL- 12, IL- 18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL- 10, IL- 13 and/or IL-15 supplied concurrently with a replication defective viral vector treatment.
- cytokine or a nucleic acid encoding a cytokine is administered together with a replication defective viral described herein.
- cytokine administration is performed prior or subsequent to viral vector administration.
- a replication defective viral vector capable of raising an immune response against a target antigen for example PSA, PSMA, MUCl , Brachyury, CEA, or a combination thereof, further comprises a sequence encoding a cytokine.
- Certain illustrative adjuvants for eliciting a predominantly Thl -type response include, for example, a combination of monophosphoryl lipid A, such as 3-de-O-acylated monophosphoryl lipid A, together with an aluminum salt.
- MPL® adjuvants are commercially available (see, e.g., U.S. Pat. Nos. 4,436,727; 4,877,61 1 ; 4,866,034; and 4,912,094).
- CpG- containing oligonucleotides in which the CpG dinucleotide is unmethylated
- Immunostimulatory DNA sequences can also be used.
- Another adjuvant for use in some embodiments comprises a saponin, such as Quil A, or derivatives thereof, including QS21 and QS7 (Aquila Biopharmaceuticals Inc.), Escin; Digitonin; or Gypsophila or Chenopodium quinoa saponins.
- Other formulations may include more than one saponin in the adjuvant combinations, e.g., combinations of at least two of the following group comprising QS21 , QS7, Quil A, ⁇ -escin, or digitonin.
- the compositions may be delivered by intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
- the delivery of drugs using intranasal microparticle resins and lysophosphatidyl-glycerol compounds can be employed (see, e.g., U.S. Pat. No. 5,725,871).
- illustrative transmucosal drug delivery in the form of a polytetrafluoroetheylene support matrix can be employed (see, e.g., U.S. Pat. No. 5,780,045).
- compositions as described herein can be used for the introduction of the compositions as described herein into suitable hot cells/organisms.
- Compositions as described herein may be formulated for delivery either encapsulated in a lipid particle, a liposome, a vesicle, a nanosphere, or a nanoparticle or the like.
- compositions as described herein can be bound, either covalently or non- covalently, to the surface of such carrier vehicles.
- Liposomes can be used effectively to introduce genes, various drugs, radiotherapeutic agents, enzymes, viruses, transcription factors, allosteric effectors and the like, into a variety of cultured cell lines and animals. Furthermore, the use of liposomes does not appear to be associated with autoimmune responses or unacceptable toxicity after systemic delivery.
- liposomes are formed from phospholipids dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (i.e., multilamellar vesicles (MLVs)).
- Nanocapsules can generally entrap pharmaceutical compositions in a stable and reproducible way.
- ultrafme particles sized around 0.1 ⁇
- a pharmaceutical composition comprising IL-15 may be administered to an individual in need thereof, in combination with one or more therapy provided herein, particularly one or more adenoviral vectors comprising nucleic acid sequences encoding one or more tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof.
- Interleukin 15 is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD 122) and the common gamma chain (gamma-C, CD132). IL-15 is secreted by mononuclear phagocytes (and some other cells) following infection by virus(es). This cytokine induces cell proliferation of natural killer cells; cells of the innate immune system whose principal role is to kill virally infected cells. [0248] IL- 15 can enhance the anti-tumor immunity of CD8+ T cells in pre-clinical models. A phase I clinical trial to evaluate the safety, dosing, and anti-tumor efficacy of IL- 15 in patients with metastatic melanoma and renal cell carcinoma(kidney cancer) has begun to enroll patients at the National Institutes of Health.
- IL- 15 disclosed herein may also include mutants of IL- 15 that are modified to maintain the function of its native form.
- IL - 15 is 14- 15 kDa glycoprotein encoded by the 34 kb region 4q31 of chromosome 4, and by the central region of chromosome 8 in mice.
- the human IL- 15 gene comprises nine exons ( 1 - 8 and 4A) and eight introns, four of which (exons 5 through 8) code for the mature protein.
- Two alternatively spliced transcript variants of this gene encoding the same protein have been reported.
- the originally identified isoform, with long signal peptide of 48 amino acids (IL- 15 LSP) consisted of a 316 bp 5 '-untranslated region (UTR), 486 bp coding sequence and the C-terminus 400 bp 3 '-UTR region.
- the other isoform (IL- 15 SSP) has a short signal peptide of 21 amino acids encoded by exons 4A and 5. Both isoforms shared 1 1 amino acids between signal sequences of the N-terminus. Although both isoforms produce the same mature protein, they differ in their cellular trafficking. IL- 15 LSP isoform was identified in Golgi apparatus (GC), early endosomes and in the endoplasmic reticulum (ER). It exists in two forms, secreted and membrane-bound particularly on dendritic cells. On the other hand, IL- 15 SSP isoform is not secreted and it appears to be restricted to the cytoplasm and nucleus where it plays an important role in the regulation of cell cycle.
- GC Golgi apparatus
- ER endoplasmic reticulum
- IL- 15 mRNA can be found in many cells and tissues including mast cells, cancer cells or fibroblasts, this cytokine is produce as a mature protein mainly by dendritic cells, monocytes and macrophages. This discrepancy between the wide appearance of IL- 15 mRNA and limited production of protein might be explained by the presence of the twelve in humans and five in mice upstream initiating codons, which can repress translation of IL- 15 mRNA. Translational inactive mRNA is stored within the cell and can be induced upon specific signal.
- IL- 15 can be stimulated by cytokine such as GM-CSF, double- strand mRNA, unmethylated CpG oligonucleotides, lipopolysaccharide (LPS) through Toll- like receptors(TLR), interferon gamma (IFN- ⁇ ) or after infection of monocytes herpes virus, Mycobacterium tuberculosis and Candida albicans.
- cytokine such as GM-CSF, double- strand mRNA, unmethylated CpG oligonucleotides, lipopolysaccharide (LPS) through Toll- like receptors(TLR), interferon gamma (IFN- ⁇ ) or after infection of monocytes herpes virus, Mycobacterium tuberculosis and Candida albicans.
- cytokine such as GM-CSF, double- strand mRNA, unmethylated CpG oligonucleotides, lipopolysacc
- native or engineered NK cells may be provided to be administered to a subject in need thereof, in combination with adenoviral vector-based compositions or immunotherapy as described herein.
- the immune system is a tapestry of diverse families of immune cells each with its own distinct role in protecting from infections and diseases.
- immune cells include the natural killer, or NK, cells as the body's first line of defense.
- NK cells have the innate ability to rapidly seek and destroy abnormal cells, such as cancer or vi ally- infected cells, without prior exposure or activation by other support molecules.
- NK cells have been utilized as a cell-based "off-the-shelf treatment in phase 1 clinical trials, and have demonstrated tumor killing abilities for cancer.
- NK cells for administering to a patient that has do not express Killer Inhibitory Receptors (KIR), which diseased cells often exploit to evade the killing function of NK cells.
- KIR Killer Inhibitory Receptors
- This unique activated NK, or aNK, cell lack these inhibitory receptors while retaining the broad array of activating receptors which enable the selective targeting and killing of diseased cells.
- aNK cells also carry a larger pay load of granzyme and perforin containing granules, thereby enabling them to deliver a far greater payload of lethal enzymes to multiple targets.
- CAR Chimeric antigen receptor
- ADCC antibody dependent cell-mediated cytotoxicity
- effector immune cells attach to antibodies, which are in turn bound to the target cancer cell, thereby facilitating killing of the cancer by the effector cell.
- NK cells are the key effector cell in the body for ADCC and utilize a specialized receptor (CD 16) to bind antibodies.
- NK cells are modified to express high-affinity CD16 (haNK cells).
- haNK cells may potentiate the therapeutic efficacy of a broad spectrum of antibodies directed against cancer cells.
- compositions comprising an adenoviral vector-based vaccination comprising a nucleic acid sequence encoding tumor antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof described throughout can be formulated into a pharmaceutical medicament and be used to treat a human or mammal in need thereof or diagnosed with a disease, e.g., cancer.
- These medicaments can be co-administered with one or more additional vaccines to a human or mammal, or together with one or more conventional cancer therapies or alternative cancer therapies, cytokines such as IL-15 or nucleic acid sequences encoding such cytokines, engineered natural killer cells, or immune pathway checkpoint modulators as described herein.
- Conventional cancer therapies include one or more selected from the group of chemical or radiation based treatments and surgery.
- Chemotherapies include, for example, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camplothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate, or any analog or derivative variant of the foregoing.
- CDDP cisplatin
- carboplatin carboplatin
- any vaccine described herein can be combined with low dose chemotherapy or low dose radiation.
- any vaccine described herein e.g., Ad5[El-, E2b-]-HER3
- the chemotherapy can be cyclophosphamide.
- the cyclophasmade can administered at a dose that is lower than the clinical standard of care dosing.
- the chemotherapy can be administered at 50 mg twice a day (BID) on days 1 -5 and 8-12 every 2 weeks for a total of 8 weeks.
- any vaccine described herein can be combined with radiation, such that the dose of radiation administered is lower than the clinical standard of care.
- concurrent sterotactic body radiotherapy (SBRT) at 8 Gy can be given on day 8, 22, 36, 50 (every 2 weeks for 4 doses). Radiation can be administered to all feasible tumor sites using SBRT.
- Radioisotopes Radiation therapy that causes DNA damage and have been used extensively include what are commonly known as ⁇ -rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors effect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
- contacted and “exposed,” when applied to a cell are used herein to , describe the process by which a therapeutic construct and a chemotherapeutic or radiotherapeutic agent are delivered to a target cell or are placed in direct juxtaposition with the target cell. To achieve cell killing or stasis, both agents are delivered to a cell in a combined amount effective to kill the cell or prevent it from dividing.
- Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment described herein, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies.
- Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed.
- Tumor resection refers to physical removal of at least part of a tumor.
- treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). It is further contemplated that treatment methods described herein may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.
- a cavity may be formed in the body. Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy.
- Such treatment may be repeated, for example, every 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, or 14 days, or every 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or every 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 18, 20, 22, 23, or 24 months.
- These treatments may be of varying dosages as well.
- Alternative cancer therapies include any cancer therapy other than surgery, chemotherapy and radiation therapy, such as immunotherapy, gene therapy, hormonal therapy or a combination thereof.
- Subjects identified with poor prognosis using the present methods may not have favorable response to conventional treatment(s) alone and may be prescribed or administered one or more alternative cancer therapy per se or in combination with one or more conventional treatments.
- Immunotherapeutics generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
- the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
- the antibody alone may serve as an effector of therapy or it may recruit other cells to actually effect cell killing.
- the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent.
- the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
- Various effector cells include cytotoxic T cells and NK cells.
- Gene therapy is the insertion of polynucleotides, including DNA or RNA, into a subject's cells and tissues to treat a disease.
- Antisense therapy is also a form of gene therapy.
- a therapeutic polynucleotide may be administered before, after, or at the same time of a first cancer therapy. Delivery of a vector encoding a variety of proteins is provided in some embodiments. For example, cellular expression of the exogenous tumor suppressor oncogenes would exert their function to inhibit excessive cellular proliferation, such as p53, pl6 and C-CAM.
- Additional agents to be used to improve the therapeutic efficacy of treatment include immunomodulatory agents, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, or agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers.
- Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or ⁇ - 1 , MIP- lbeta, MCP- 1 , RANTES, and other chemokines.
- cytostatic or differentiation agents can be used in combination with pharmaceutical compositions described herein to improve the anti-hyperproliferative efficacy of the treatments.
- Inhibitors of cell adhesion are contemplated to improve the efficacy of pharmaceutical compositions described herein.
- cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with pharmaceutical compositions described herein to improve the treatment efficacy.
- FAKs focal adhesion kinase
- Lovastatin Lovastatin
- Hormonal therapy may also be used in combination with any other cancer therapy previously described.
- the use of hormones may be employed in the treatment of certain cancers such as breast, prostate, ovarian, or cervical cancer to lower the level or block the effects of certain hormones such as testosterone or estrogen. This treatment is often used in combination with at least one other cancer therapy as a treatment option or to reduce the risk of metastases.
- a "Chemotherapeutic agent” or “chemotherapeutic compound” and their grammatical equivalents as used herein, can be a chemical compound useful in the treatment of cancer.
- the chemotherapeutic cancer agents that can be used in combination with the disclosed T cell include, but are not limited to, mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, vindesine and NavelbineTM (vinorelbine,5'-noranhydroblastine).
- chemotherapeutic cancer agents include topoisomerase I inhibitors, such as camptothecin compounds.
- camptothecin compounds include CamptosarTM (irinotecan HCL), HycamtinTM (topotecan HCL) and other compounds derived from camptothecin and its analogues.
- CamptosarTM irinotecan HCL
- HycamtinTM topotecan HCL
- Another category of chemotherapeutic cancer agents that can be used in the methods and compositions disclosed herein are podophyllotoxin derivatives, such as etoposide, teniposide and mitopodozide.
- methods or compositions described herein further encompass the use of other chemotherapeutic cancer agents known as alkylating agents, which alkylate the genetic material in tumor cells.
- alkylating agents include without limitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacarbazine.
- alkylating agents include without limitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacarbazine.
- the disclosure encompasses antimetabolites as chemotherapeutic agents. Examples of these types of agents include cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprime, and
- chemotherapeutic cancer agents that may be used in the methods and compositions disclosed herein includes antibiotics. Examples include without limitation doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. In certain aspects, methods or compositions described herein further encompass the use of other chemotherapeutic cancer agents including without limitation anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, ifosfamide and mitoxantrone.
- the disclosed adenovirus vaccine herein can be administered in combination with other anti-tumor agents, including cytotoxic/antineoplastic agents and anti-angiogenic agents.
- Cytotoxic/anti-neoplastic agents can be defined as agents who attack and kill cancer cells.
- Some cytotoxic/anti-neoplastic agents can be alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine.
- cytotoxic/anti-neoplastic agents can be antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine.
- Other cytotoxic/anti-neoplastic agents can be antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
- doxorubicin e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
- mitotic inhibitors (vinca alkaloids).
- cytotoxic/anti-neoplastic agents include taxol and its derivatives, L- asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindcsine.
- Additional formulations comprising population(s) of CAR T cells, T cell receptor engineered T cells, B cell receptor engineered cells, can be administered to a subject in conjunction, before, or after the administration of the pharmaceutical compositions described herein.
- a therapeutically-effective population of adoptively transferred cells can be administered to subjects when the methods described herein are practiced.
- formulations are administered that comprise from about 1 x 10 4 to about 1 x 10 10 CAR T cells, T cell receptor engineered cells, or B cell receptor engineered cells.
- the formulation comprises from about 1 x 10 5 to about 1 x 10 9 engineered cells, from about 5 x 10 s to about 5 x 10 8 engineered cells, or from about 1 x 10 6 to about 1 x 10 7 engineered cells.
- the number of engineered cells administered to a subject will vary between wide limits, depending upon the location, source, identity, extent and severity of the cancer, the age and condition of the subject to be treated etc. A physician will ultimately determine appropriate dosages to be used.
- Anti-angiogenic agents can also be used. Suitable anti-angiogenic agents for use in the disclosed methods and compositions include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including a and ⁇ ) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.
- the unit dosage of the composition or formulation administered can be 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.
- the total amount of the composition or formulation administered can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 g.
- the viral vectors or composition described herein may further comprise nucleic acid sequences that encode proteins, or an "immunological fusion partner," that can increase the immunogenicity of the target antigen such as PSA and/or PSMA, or wherein the target antigen is any target antigen disclosed herein.
- the protein produced following immunization with the viral vector containing such a protein may be a fusion protein comprising the target antigen of interest fused to a protein that increases the immunogenicity of the target antigen of interest.
- combination therapy with Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and an immunological fusion partner can result in boosting the immune response, such that the combination of both therapeutic moieties acts to synergistically boost the immune response than either the Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA alone, or the immunological fusion partner alone.
- combination therapy with Ad5lEl-, E2b-] vectors encoding for PSA and/or PSMA and an immunological fusion partner can result in synergistic enhancement of stimulation of antigen- specific effector CD4+ and CD8+ T cells, stimulation of NK cell response directed towards killing infected cells, stimulation of neutrophils or monocyte cell responses directed towards killing infected cells via antibody dependent cell-mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) mechanisms, or any combination thereof.
- ADCC antibody dependent cell-mediated cytotoxicity
- ADCP antibody dependent cellular phagocytosis
- combination therapy with Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and an immunological fusion partner can result in generating an immune response comprises an increase in target antigen-specific CTL activity of about 1.5 to 20, or more fold in a subject administered the adenovirus vectors as compared to a control.
- generating an immune response comprises an increase in target-specific CTL activity of about 1.5 to 20, or more fold in a subject administered the Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and an immunological fusion partner as compared to a control.
- generating an immune response that comprises an increase in target antigen-specific cell-mediated immunity activity as measured by ELISpot assays measuring cytokine secretion, such as interferon-gamma (IFN- ⁇ ), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-a), or other cytokines, of about 1.5 to 20, or more fold as compared to a control.
- generating an immune response comprises an increase in target-specific antibody production of between 1.5 and 5 fold in a subject administered the Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and an immunological fusion partner as described herein as compared to an appropriate control.
- generating an immune response comprises an increase in target-specific antibody production of about 1.5 to 20, or more fold in a subject administered the adenovirus vector as compared to a control.
- combination therapy with Ad5[El-, E2b-] vectors encoding for target epitope antigens and an immunological fusion partner can result in synergistic enhancement of stimulation of antigen-specific effector CD4+ and CD8+ T cells, stimulation of NK cell response directed towards killing infected cells, stimulation of neutrophils or monocyte cell responses directed towards killing infected cells via antibody dependent cell- mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) mechanisms, or any combination thereof.
- ADCC antibody dependent cell- mediated cytotoxicity
- ADCP antibody dependent cellular phagocytosis
- combination therapy with Ad5[El-, E2b-] vectors encoding for target epitope antigens and an immunological fusion partner can result in generating an immune response comprises an increase in target antigen-specific CTL activity of about 1.5 to 20, or more fold in a subject administered the adenovirus vectors as compared to a control.
- generating an immune response comprises an increase in target-specific CTL activity of about 1.5 to 20, or more fold in a subject administered the Ad5[El-, E2b-] vectors encoding for target epitope antigens and an immunological fusion partner as compared to a control.
- generating an immune response that comprises an increase in target antigen-specific cell- mediated immunity activity as measured by ELISpot assays measuring cytokine secretion, such as interferon-gamma (IFN- ⁇ ), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-a), or other cytokines, of about 1.5 to 20, or more fold as compared to a control.
- cytokine secretion such as interferon-gamma (IFN- ⁇ ), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-a), or other cytokines
- generating an immune response comprises an increase in target-specific antibody production of between 1.5 and 5 fold in a subject administered the adenovirus vectors as described herein as compared to an appropriate control.
- generating an immune response comprises an increase in target-specific antibody production of about 1.5 to 20, or more fold in a subject administered the adenovirus vector as compared to a control.
- such an immunological fusion partner is derived from a Mycobacterium sp., such as a Mycobacterium tuberculosis-dctwed Ral2 fragment.
- the immunological fusion partner derived from Mycobacterium sp. can be any one of the sequences set forth in SEQ ID NO: 43 - SEQ ID NO: 51.
- Ral2 compositions and methods for their use in enhancing the expression and/or immunogenicity of heterologous polynucleotide/polypeptide sequences are described in U.S. Patent No. 7,009,042, which is herein incorporated by reference in its entirety.
- Ral2 refers to a polynucleotide region that is a subsequence of a Mycobacterium tuberculosis MTB32A nucleic acid.
- MTB32A is a serine protease of 32 kDa encoded by a gene in virulent and avirulent strains of M. tuberculosis.
- the nucleotide sequence and amino acid sequence of MTB32A have been described (see, e.g., U.S. Patent No. 7,009,042; Skeiky et al., Infection and Immun. 67:3998- 4007 (1999), incorporated herein by reference in their entirety).
- Ral2 may enhance the immunogenicity of heterologous immunogenic polypeptides with which it is fused.
- a Ral2 fusion polypeptide can comprise a 14 kDa C-terminal fragment corresponding to amino acid residues 192 to 323 of MTB32A.
- Other Ral2 polynucleotides generally can comprise at least about 15, 30, 60, 100, 200, 300, or more nucleotides that encode a portion of a Ral2 polypeptide.
- Ral2 polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes a Ral2 polypeptide or a portion thereof) or may comprise a variant of such a sequence.
- Ral2 polynucleotide variants may contain one or more substitutions, additions, deletions and/or insertions such that the biological activity of the encoded fusion polypeptide is not substantially diminished, relative to a fusion polypeptide comprising a native Ral2 polypeptide.
- Variants can have at least about 70%, 80%, or 90% identity, or more, to a polynucleotide sequence that encodes a native Ral2 polypeptide or a portion thereof.
- an immunological fusion partner can be derived from protein D, a surface protein of the gram-negative bacterium Haemophilus influenzae B.
- the immunological fusion partner derived from protein D can be the sequence set forth in SEQ ID NO: 52.
- a protein D derivative comprises approximately the first third of the protein (e.g., the first N-terminal 100- 110 amino acids).
- a protein D derivative may be lipidated.
- the first 109 residues of a Lipoprotein D fusion partner is included on the N-terminus to provide the polypeptide with additional exogenous T-cell epitopes, which may increase the expression level in E. coli and may function as an expression enhancer.
- the lipid tail may ensure optimal presentation of the antigen to antigen presenting cells.
- Other fusion partners can include the non-structural protein from influenza virus, NS 1 (hemagglutinin). Typically, the N-terminal 81 amino acids are used, although different fragments that include T-helper epitopes may be used.
- the immunological fusion partner can be the protein known as LYTA, or a portion thereof (particularly a C-terminal portion).
- the immunological fusion partner derived from LYTA can the sequence set forth in SEQ ID NO: 53.
- LYTA is derived from Streptococcus pneumoniae, which synthesizes an N-acetyl-L-alanine amidase known as amidase LYTA (encoded by the LytA gene).
- LYTA is an autolysin that specifically degrades certain bonds in the peptidoglycan backbone.
- the C-terminal domain of the LYTA protein is responsible for the affinity to the choline or to some choline analogues such as DEAE.
- LYTA E. coli C-LYTA expressing plasmids useful for expression of fusion proteins.
- Purification of hybrid proteins containing the C- LYTA fragment at the amino terminus can be employed.
- a repeat portion of LYTA may be incorporated into a fusion polypeptide.
- a repeat portion can, for example, be found in the C-terminal region starting at residue 178.
- One particular repeat portion incorporates residues 188-305.
- the target antigen is fused to an immunological fusion partner, also referred to herein as an "immunogenic component,” comprising a cytokine selected from the group of IFN- ⁇ , TNFct, IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL- 13, IL-15, IL-16, IL-17, IL-23, IL-32, M-CSF (CSF-1), IFN-a, IFN- ⁇ , IL-la, IL- ⁇ , IL- 1RA, IL-11 , IL-17A, IL-17F, IL-19, IL-20, IL-21, IL-22, IL-24, IL-25, IL-26, IL-27, IL-28A, B, IL-29, IL-30, IL-31 , IL-33, IL-34, IL-35,
- the target antigen fusion can produce a protein with substantial identity to one or more of IFN- ⁇ , TNFa IL-2, IL-8, IL- 12, IL-18, IL- 7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-15, IL-16, IL-17, IL-23, IL-32, M-CSF (CSF- 1), IFN-a, IFN- ⁇ , IL-la, IL- ⁇ , IL- 1RA, IL-11, IL-17A, IL-17F, IL-19, IL-20, IL-21 , IL-22, IL-24, IL-25, IL-26, IL-27, IL-28A, B, IL-29, IL-30, IL-31 , IL-33, IL-34, IL-35, ⁇ .-36 ⁇ , ⁇ , ⁇ , IL-36Ra, IL-37, TSLP, LIF, OSM,
- the target antigen fusion can encode a nucleic acid encoding a protein with substantial identity to one or more of IFN- ⁇ , TNFa, IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL- 10, IL-13, IL-15, IL- 16, IL- 17, IL-23, IL-32, M-CSF (CSF- 1), IFN-a, IFN- ⁇ , IL- la, IL- ⁇ ⁇ , IL-1RA, IL-11, IL-17A, IL-17F, IL-19, IL-20, IL-21, IL-22, IL-24, IL-25, IL-26, IL- 27, IL-28A, B, IL-29, IL-30, IL-31, IL-33, IL-34, IL-35, ⁇ -36 ⁇ , ⁇ , ⁇ , IL-36Ra, IL-37, TSLP,
- the target antigen fusion further comprises one or more immunological fusion partner, also referred to herein as an "immunogenic components," comprising a cytokine selected from the group of IFN- ⁇ , TNFa, IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL- 13, IL- 15, IL- 16, IL- 17, IL-23, IL-32, M-CSF (CSF- 1), IFN-a, IFN- ⁇ , IL- la, IL- ⁇ , IL- 1RA, IL-1 1 , IL-17A, IL-17F, IL-19, IL-20, IL-21, IL-22, IL-24, IL-25, IL-26, IL-27, IL-28A, B, IL-29, IL-30, IL-31, IL-33, IL-34, IL-35, ⁇
- the sequence of IFN- ⁇ can be, but is not limited to, a sequence as set forth in SEQ ID NO: 54.
- the sequence of TNFa can be, but is not limited to, a sequence as set forth in SEQ ID NO: 55.
- the sequence of IL-2 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 56.
- the sequence of IL-8 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 57.
- the sequence of IL-12 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 58.
- the sequence of IL-18 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 59.
- the sequence of IL-7 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 60.
- the sequence of IL-3 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 61.
- the sequence of IL-4 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 62.
- the sequence of IL-5 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 63.
- the sequence of IL-6 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 64.
- the sequence of IL-9 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 65.
- the sequence of IL-10 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 66.
- the sequence of IL- 13 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 67.
- the sequence of IL-15 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 68.
- the sequence of IL-16 can be, but is not limted to, a sequence as set forth in SEQ ID NO: 95.
- the sequence of IL-17 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 96.
- the sequence of IL-23 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 97.
- the sequence of IL-32 can be, but is not limited to, a sequence as set forth in SEQ ID NO: 98.
- the target antigen is fused or linked to an immunological fusion partner, also referred to herein as an "immunogenic component,” comprising a cytokine selected from the group of IFN- ⁇ , TNFa IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-15, , IL-16, IL-17, IL-23, IL-32, M-CSF (CSF-1), IFN-a, IFN- ⁇ , IL-la, IL- ⁇ , IL-1RA, IL-11 , IL-17A, IL-17F, IL-19, IL-20, IL-21 , IL-22, IL-24, IL- 25, IL-26, IL-27, IL-28A, B, IL-29, IL-30, IL-31, IL-33, IL-34, IL-35,
- an immunological fusion partner
- the target antigen is co-expressed in a cell with an immunological fusion partner, also referred to herein as an "immunogenic component," comprising a cytokine selected from the group of IFN- ⁇ , TNFa IL-2, IL-8, IL-12, IL-18, IL-7, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL- 15, IL-16, IL-17, IL-23, IL-32, M-CSF (CSF-1), IFN-a, IFN- ⁇ , IL-la, IL- ⁇ , IL-1RA, IL- 1 1, IL- 17 A, IL- 17F, IL- 19, IL-20, IL-21, IL-22, IL-24, IL-25, IL-26, IL- 27, IL-28A, B, IL-29, IL-30, IL-31, IL-33, IL-34, IL-35,
- the target antigen is fused or linked to an immunological fusion partner, comprising CpG ODN (a non-limiting example sequence is shown in SEQ ID NO: 69), cholera toxin (a non-limiting example sequence is shown in SEQ ID NO: 70), a truncated A subunit coding region derived from a bacterial ADP-ribosylating exotoxin (a non-limiting example sequence is shown in (a non-limiting example sequence is shown in SEQ ID NO: 71), a truncated B subunit coding region derived from a bacterial ADP- ribosylating exotoxin (a non-limiting example sequence is shown in SEQ ID NO: 72), Hp91 (a non-limiting example sequence is shown in SEQ ID NO: 73), CCL20 (a non-limiting example sequence is shown in SEQ ID NO: 74), CCL3 (a non-limiting example sequence is shown in SEQ ID NO: 75), GM-CSF
- the target antigen is fused or linked to an immunological fusion partner, comprising an IL-15 superagonist.
- Interleukin 15 IL-15
- IL-15 is a naturally occurring inflammatory cytokine secreted after viral infections. Secreted IL-15 can carry out its function by signaling via the its cognate receptor on effector immune cells, and thus, can lead to overall enhancement of effector immune cell activity.
- IL-15 Based on IL- 15's broad ability to stimulate and maintain cellular immune responses, it is believed to be a promising immunotherapeutic drug that could potentially cure certain cancers.
- major limitations in clinical development of IL-15 can include low production yields in standard mammalian cell expression systems and short serum half-life.
- the IL-15:IL-15Ra complex comprising proteins co-expressed by the same cell, rather than the free IL-15 cytokine, can be responsible for stimulating immune effector cells bearing IL- 15 ⁇ receptor.
- IL-15N72D IL-15 15 superagonist mutant
- Addition of either mouse or human IL-15Ra and Fc fusion protein (the Fc region of immunoglobulin) to equal molar concentrations of IL-15N72D can provide a further increase in IL-15 biologic activity, such that IL- 15N72D:IL-15Rct/Fc super-agonist complex exhibits a median effective concentration (EC50) for supporting IL-15-dependent cell growth that was greater thanlO-fold lower than that of free IL-15 cytokine.
- EC50 median effective concentration
- the IL- 15 superagonist can be a novel IL-15 superagonist mutant (IL-15N72D).
- addition of either mouse or human IL-15Ra and Fc fusion protein (the Fc region of immunoglobulin) to equal molar concentrations of IL- 15N72D can provide a further increase in IL- 15 biologic activity, such that IL-15N72D:IL- 15Rot/Fc super-agonist complex exhibits a median effective concentration (EC50) for supporting IL- 15-dependent cell growth that can be greater thanlO-fold lower than that of free IL-15 cytokine
- EC50 median effective concentration
- the present disclosure provides a IL-15N72D:IL- 15Ra/Fc super-agonist complex with an EC50 for supporting IL-15 -dependent cell growth that is greater than 2-fold lower, greater than 3-fold lower, greater than 4-fold lower, greater than 5-fold lower, greater than 6-fold lower, greater than 7-fold lower, greater than 8-fold lower, greater than 9-fold lower, greater than 10-fold lower, greater than 15-fold lower, greater than 20-fold lower, greater than 25-fold lower, greater than 30-fold lower, greater than 35-fold lower, greater than 40-fold lower, greater than 45-fold lower, greater than 50- fold lower, greater than 55-fold lower, greater than 60-fold lower, greater than 65-fold lower, greater than 70-fold lower, greater than 75-fold lower, greater than 80-fold lower, greater than 85-fold lower, greater than 90-fold lower, greater than 95-fold lower, or greater than 100-fold lower than that of free IL-15 cytokine.
- the IL-15 super agonist is a biologically active protein complex of two IL-15N72D molecules and a dimer of soluble IL- 15Ra/Fc fusion protein, also known as ALT-803.
- ALT-803 a dimer of soluble IL- 15Ra/Fc fusion protein
- the composition of ALT-803 and methods of producing and using ALT-803 are described in U.S. Patent Application Publication 2015/0374790, which is herein incorporated by reference. It is known that a soluble IL-15Ra fragment, containing the so- called "sushi" domain at the N terminus (Su), can bear most of the structural elements responsible for high affinity cytokine binding.
- a soluble fusion protein can be generated by linking the human IL- 15RaSu domain (amino acids 1 -65 of the mature human IL-15Ra protein) with the human IgGl CH2-CH3 region containing the Fc domain (232 amino acids).
- This IL-15RaSu/IgGl Fc fusion protein can have the advantages of dimer formation through disulfide bonding via IgGl domains and ease of purification using standard Protein A affinity chromatography methods.
- ALT-803 can have a soluble complex consisting of 2 protein subunits of a human IL-1 variant associated with high affinity to a dimeric IL-15Ra sushi domain/human IgGl Fc fusion protein.
- the IL-15 variant is a 114 amino acid polypeptide comprising the mature human IL- 15 cytokine sequence with an Asn to Asp substitution at position 72 of helix C N72D).
- the human IL-15R sushi domain/human IgGl Fc fusion protein comprises the sushi domain of the IL- 15R subunit (amino acids 1- 65 of the mature human IL-15Ra protein) linked with the human IgGl CH2-CH3 region containing the Fc domain (232 amino acids).
- the protein sequences are human. Based on the amino acid sequence of the subunits, the calculated molecular weight of the complex comprising two IL-15N72D polypeptides (an example IL-15N72D sequence is shown in SEQ ID NO: 92) and a disulfide linked homodimeric IL- 15RaSu/IgGl Fc protein (an example IL-15RaSu/Fc domain is shown in SEQ ID NO: 93) is 92.4 kDa.
- a recombinant vector encoding for a target antigen and for ALT-803 can have any sequence described herein to encode for the target antigen and can have SEQ ID NO: 92, SEQ ID NO: 92, SEQ ID NO: 93, and SEQ ID NO: 93 in any order, to encode for ALT-803.
- Each IL-15N720 polypeptide has a calculated molecular weight of approximately 12.8 kDa and the IL- 15RaSu/IgG 1 Fc fusion protein has a calculated molecular weight of approximately 33.4 kDa.
- Both the IL-15N72D and IL- 15RaSu/IgG 1 Fc proteins can be glycosylated resulting in an apparent molecular weight of ALT- 803 of approximately 114 kDa by size exclusion chromatography.
- the isoelectric point (pi) determined for ALT-803 can range from approximately 5.6 to 6.5.
- the fusion protein can be negatively charged at pH 7.
- Combination therapy with Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and ALT-803 can result in boosting the immune response, such that the combination of both therapeutic moieties acts to synergistically boost the immune response than either therapy alone.
- combination therapy with Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and ALT-803 can result in synergistic enhancement of stimulation of antigen- specific effector CD4+ and CD8+ T cells, stimulation of NK cell response directed towards killing infected cells, stimulation of neutrophils or monocyte cell responses directed towards killing infected cells via antibody dependent cell-mediated cytotoxicity (ADCC), or antibody dependent cellular phagocytosis (ADCP) mechanisms.
- ADCC antibody dependent cell-mediated cytotoxicity
- ADCP antibody dependent cellular phagocytosis
- Combination therapy with Ad5[El-, E2b-] vectors encoding for PSA and/or PSMA and ALT-803 can synergistically boost any one of the above responses, or a combination of the above responses, to vastly improve survival outcomes after administration to a subject in need thereof.
- any of the immunogenicity enhancing agents described herein can be fused or linked to a target antigen by expressing the immunogenicity enhancing agents and the target antigen in the same recombinant vector, using any recombinant vector described herein.
- Nucleic acid sequences that encode for such immunogenicity enhancing agents can be any one of SEQ ID NO: 43 - SEQ ID NO: 98 and are summarized in TABLE 1.
- the nucleic acid sequences for the target antigen and the immunological fusion partner are not separated by any nucleic acids.
- a nucleic acid sequence that encodes for a linker can be inserted between the nucleic acid sequence encoding for any target antigen described herein and the nucleic acid sequence encoding for any immunological fusion partner described herein.
- the protein produced following immunization with the viral vector containing a target antigen, a linker, and an immunological fusion partner can be a fusion protein comprising the target antigen of interest followed by the linker and ending with the immunological fusion partner, thus linking the target antigen to an immunological fusion partner that increases the immunogenicity of the target antigen of interest via a linker.
- the sequence of linker nucleic acids can be from about 1 to about 150 nucleic acids long, from about 5 to about 100 nucleic acids along, or from about 10 to about 50 nucleic acids in length.
- the nucleic acid sequences may encode one or more amino acid residues.
- the amino acid sequence of the linker can be from about 1 to about 50, or about 5 to about 25 amino acid residues in length. In some embodiments, the sequence of the linker comprises less than 10 amino acids. In some embodiments, the linker can be a polyalanine linker, a polyglycine linker, or a linker with both alanines and glycines.
- Nucleic acid sequences that encode for such linkers can be any one of SEQ ID NO: 99 - SEQ ID NO: 1 13 and are summarized in TABLE 2.
- co-stimulatory molecules can be incorporated into said vaccine to increase immunogenicity. Initiation of an immune response requires at least two signals for the activation of naive T cells by APCs (Damle, et al. J Immunol 148: 1985-92 (1992); Guinan, et al. Blood 84:3261-82 (1994); Hellstrom, et al. Cancer Chemother Pharmacol 38:S40-44 (1996); Hodge, et al.
- An antigen specific first signal is delivered through the T cell receptor (TCR) via the peptide/major histocompatability complex (MHC) and causes the T cell to enter the cell cycle.
- a second, or costimulatory, signal may be delivered for cytokine production and proliferation.
- TCR T cell receptor
- MHC peptide/major histocompatability complex
- a second, or costimulatory, signal may be delivered for cytokine production and proliferation.
- APCs professional antigen presenting cells
- B7-1 interacts with the CD28 and CTLA-4 molecules
- ICAM-1 interacts with the CDl la/CD18 (LFA-i 2 integrin) complex
- LFA-3 interacts with the CD2 (LFA-2) molecules.
- a recombinant adenovirus vector that contains B7- 1, ICAM- 1, and LFA-3, respectively, that, when combined with a recombinant adenovirus- based vector vaccine containing one or more nucleic acids encoding target antigens such as PSA, MUC1, Brachyury, CEA, or a combination thereof, will further increase/enhance antitumor immune responses directed to specific target antigens.
- target antigens such as PSA, MUC1, Brachyury, CEA, or a combination thereof
- immune pathway checkpoint inhibitors i.e., immune checkpoint inhibitors
- compositions comprising adenoviral vectors disclosed herein.
- a patient received an immune pathway checkpoint inhibitor in conjunction with a vaccine or pharmaceutical compositions described herein.
- compositions are administered with one or more immune pathway checkpoint modulators.
- a balance between activation and inhibitory signals regulates the interaction between T lymphocytes and disease cells, wherein T-cell responses are initiated through antigen recognition by the T-cell receptor (TCR).
- TCR T-cell receptor
- the inhibitory pathways and signals are referred to as immune pathway checkpoints.
- immune pathway checkpoints play a critical role in control and prevention of autoimmunity and also protect from tissue damage in response to pathogenic infection.
- Certain embodiments provide combination immunotherapies comprising viral vector- based vaccines and compositions for modulating immune pathway checkpoint inhibitory pathways for the prevention and/or treatment of cancer and infectious diseases.
- modulating is increasing expression or activity of a gene or protein.
- modulating is decreasing expression or activity of a gene or protein.
- modulating affects a family of genes or proteins.
- the immune inhibitory pathways are initiated by ligand-receptor interactions. It is now clear that in diseases, the disease can co-opt immune-checkpoint pathways as mechanism for inducing immune resistance in a subject.
- the induction of immune resistance or immune inhibitory pathways in a subject by a given disease can be blocked by molecular compositions such as siRNAs, antisense, small molecules, mimic, a recombinant form of Iigand, receptor or protein, or antibodies (which can be an Ig fusion protein) that are known to modulate one or more of the Immune Inhibitory Pathways.
- molecular compositions such as siRNAs, antisense, small molecules, mimic, a recombinant form of Iigand, receptor or protein, or antibodies (which can be an Ig fusion protein) that are known to modulate one or more of the Immune Inhibitory Pathways.
- CTL4 Cytotoxic T- lymphocyte-associated antigen 4
- PDl programmed cell death protein 1
- Combination immunotherapies as provide herein can comprise one or more compositions comprising an immune pathway checkpoint modulator that targets one or more of the following immune- checkpoint proteins: PDl , PDL1, PDL2, CD28, CD80, CD86, CTLA4, B7RP1, ICOS, B7RPI, B7-H3 (also known as CD276), B7-H4 (also known as B7-S1, B7x and VCTN1), BTLA (also known as CD272), HVEM, KIR, TCR, LAG3 (also known as CD223), CD 137, CD137L, OX40, OX40L, CD27, CD70, CD40, CD40L, TIM3 (also known as HAVcr2), GAL9, A2aR, and Aden
- the molecular composition comprises a siRNAs. In some embodiments, the molecular composition comprises a small molecule. In some embodiments, the molecular composition comprises a recombinant form of a ligand. In some embodiments, the molecular composition comprises a recombinant form of a receptor. In some embodiments, the molecular composition comprises an antibody. In some embodiments, the combination therapy comprises more than one molecular composition and/or more than one type of molecular composition. As it will be appreciated by those in the art, future discovered proteins of the immune checkpoint inhibitory pathways are also envisioned to be encompassed by the present disclosure.
- combination immunotherapies comprise molecular compositions for the modulation of CTLA4. In some embodiments, combination immunotherapies comprise molecular compositions for the modulation of PDl . In some embodiments, combination immunotherapies comprise molecular compositions for the modulation of PDL1. In some embodiments, combination immunotherapies comprise molecular compositions for the modulation of LAG3. In some embodiments, combination immunotherapies comprise molecular compositions for the modulation of B7-H3. In some embodiments, combination immunotherapies comprise molecular compositions for the modulation of B7-H4. In some embodiments, combination immunotherapies comprise molecular compositions for the modulation of TIM3. In some embodiments, modulation is an increase or enhancement of expression. In other embodiments, modulation is the decrease of absence of expression.
- Two non-limiting exemplary immune pathway checkpoint inhibitors include the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and the programmed cell death protein- 1 (PDl).
- CTLA-4 can be expressed exclusively on T-cells where it regulates early stages of T-cell activation.
- CTLA-4 interacts with the co-stimulatory T-cell receptor CD28 which can result in signaling that inhibits T-cell activity. Once TCR antigen recognition occurs, CD28 signaling may enhances TCR signaling, in some cases leading to activated T- cells and CTLA-4 inhibits the signaling activity of CD28.
- the present disclosure provides immunotherapies as provided herein in combination with anti-CTLA-4 monoclonal antibody for the prevention and/or treatment of cancer and infectious diseases.
- the present disclosure provides vaccine or immunotherapies as provided herein in combination with CTLA-4 molecular compositions for the prevention and/or treatment of cancer and infectious diseases.
- PDL1 Programmed death cell protein ligand-1
- PDL1 is a member of the B7 family and is distributed in various tissues and cell types. PDL1 can interact with PDl inhibiting T-cell activation and CTL mediated lysis. Significant expression of PDL1 has been demonstrated on various human tumors and PDL1 expression is one of the key mechanisms in which tumors evade host anti-tumor immune responses.
- Programmed death-ligand 1 (PDL1) and programmed cell death protein-1 (PDl) interact as immune pathway checkpoints. This interaction can be a major tolerance mechanism which results in the blunting of anti-tumor immune responses and subsequent tumor progression.
- PD 1 is present on activated T cells and PDL1 , the primary ligand of PDl, is often expressed on tumor cells and antigen-presenting cells (APC) as well as other cells, including B cells.
- APC antigen-presenting cells
- Significant expression of PDL1 has been demonstrated on various human tumors including HPV-associated head and neck cancers.
- PDL1 interacts with PDl on T cells inhibiting T cell activation and cytotoxic T lymphocyte (CTL) mediated lysis.
- CTL cytotoxic T lymphocyte
- the present disclosure provides immunotherapies as provided herein in combination with anti-PDl or anti-PDLl monoclonal antibody for the prevention and/or treatment of cancer and infectious diseases.
- Certain embodiments may provide immunotherapies as provided herein in combination with PDl or anti-PDLl molecular compositions for the prevention and/or treatment of cancer and infectious diseases. Certain embodiments may provide immunotherapies as provided herein in combination with anti-CTLA-4 and anti-PD l monoclonal antibodies for the prevention and/or treatment of cancer and infectious diseases. Certain embodiments may provide immunotherapies as provided herein in combination with anti-CTLA-4 and PDLl monoclonal antibodies. Certain embodiments may provide vaccine or immunotherapies as provided herein in combination with anti-CTLA-4, anti-PD l , anti- PDL1 monoclonal antibodies, or a combination thereof, for the treatment of cancer and infectious diseases.
- Immune pathway checkpoint molecules can be expressed by T cells. Immune pathway checkpoint molecules can effectively serve as "brakes” to down-modulate or inhibit an immune response. Immune pathway checkpoint molecules include, but are not limited to Programmed Death 1 (PD1 or PD- 1 , also known as PDCD 1 or CD279, accession number: NM_005018), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4, also known as CD 152, GenBank accession number AF414120.1), LAG3 (also known as CD223, accession number: NM_002286.5), Tim3 (also known as hepatitis A virus cellular receptor 2 (HAVCR2), GenBank accession number: JX049979.1), B and T lymphocyte associated (BTLA) (also known as CD272, accession number: NM_181780.3), BY55 (also known as CD 160, GenBank accession number: CR541888.1), TIGIT (also known as IVSTM3, accession number: NM_
- Additional immune pathway checkpoints that can be targeted can be adenosine A2a receptor (ADORA), CD276, V-set domain containing T cell activation inhibitor 1 (VTCN1), indoleamine 2,3-dioxygenase 1 (IDO l), killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 1 (KIR3DL1), V-domain immunoglobulin suppressor of T- cell activation (VISTA), cytokine inducible SH2-containing protein (CISH), hypoxanthine phosphoribosyltransferase 1 (HPRT), adeno-associated virus integration site 1 (AAVS l ), or chemokine (C-C motif) receptor 5 (gene/pseudogene) (CCR5), or any combination thereof.
- ADORA adenosine A2a receptor
- VTCN1 V-set domain containing T cell activation inhibitor 1
- IDO l indoleamine 2,3-d
- TABLE 3 shows exemplary immune pathway checkpoint genes that can be inactivated to improve the efficiency of the adenoviral vector-based composition as described herein.
- Immune pathway checkpoints gene can be selected from such genes listed in TABLE 3 and others involved in co-inhibitory receptor function, cell death, cytokine signaling, arginine tryptophan starvation, TCR signaling, Induced T-reg repression, transcription factors controlling exhaustion or anergy, and hypoxia mediated tolerance.
- the combination of an adenoviral-based composition and an immune pathway checkpoint modulator may result in reduction in infection, progression, or symptoms of a disease in treated patients, as compared to either agent alone.
- the combination of an adenoviral-based composition and an immune pathway checkpoint modulator may result in improved overall survival of treated patients, as compared to either agent alone.
- the combination of an adenoviral-based composition and an immune pathway checkpoint modulator may increase the frequency or intensity of disease- specific T cell responses in treated patients as compared to either agent alone.
- Certain embodiments may also provide the use of immune pathway checkpoint inhibition to improve performance of an adenoviral vector-based composition.
- Certain immune pathway checkpoint inhibitors may be administered at the time of an adenoviral vector-based composition.
- Certain immune pathway checkpoint inhibitors may also be administered after the administration of an adenoviral vector-based composition.
- Immune pathway checkpoint inhibition may occur simultaneously to an adenoviral vaccine administration. Immune pathway checkpoint inhibition may occur 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, or 60 minutes after vaccination. Immune pathway checkpoint inhibition may also occur 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24 hours after the administration of an adenoviral vector-based composition. In some cases, immune inhibition may occur 1 , 2, 3, 4, 5, 6, or 7 days after vaccination. Immune pathway checkpoint inhibition may occur at any time before or after the administration of an adenoviral vector-based composition.
- a vaccine comprising one or more nucleic acids encoding an antigen and an immune pathway checkpoint modulator.
- a method for treating a subject having a condition that would benefit from downregulation of an immune pathway checkpoint protein, PD1 or PDL1 for example, and its natural binding partner(s) on cells of the subject are provided.
- An immune pathway checkpoint modulator may be combined with an adenoviral vector-based composition comprising one or more nucleic acids encoding any antigen.
- an antigen can be a tumor antigen, such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, or any antigen described herein.
- An immune pathway checkpoint modulator may produce a synergistic effect when combined with an adenoviral vector-based composition, such as a vaccine.
- An immune pathway checkpoint modulator may also produce a beneficial effect when combined with an adenoviral vector-based composition.
- compositions comprising adenoviral vectors described herein can be used to evaluate or treat stages of disease, such as between hyperplasia, dysplasia, neoplasia, pre-cancer and cancer, or between a primary tumor and a metastasized tumor.
- Neoplastic cells and “neoplasia” may be used interchangeably and refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
- Neoplastic cells can be malignant or benign.
- a neoplasia includes both dysplasia and cancer.
- Neoplasms may be benign, pre-malignant (carcinoma in situ or dysplasia) or malignant (cancer).
- Neoplastic cells may form a lump (i.e., a tumor) or not.
- Dysplasia may be used when the cellular abnormality is restricted to the originating tissue, as in the case of an early, in-situ neoplasm. Dysplasia may be indicative of an early neoplastic process.
- cancer may refer to a malignant neoplasm, including a broad group of various diseases involving unregulated cell growth.
- Metastasis may refer to the spread of a cancer from one organ or part to another non-adjacent organ or part. The new occurrences of disease thus generated may be referred to as metastases.
- Cancers that may be evaluated or treated by the disclosed methods and compositions include cancer cells particularly from the pancreas, including pancreatic ductal adenocarcinoma (PDAC), but may also include cells and cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
- PDAC pancreatic ductal adenocarcinoma
- the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acid
- the adenovirus vectors described herein can be used in a number of vaccine settings for generating an immune response against one or more target antigens as described herein.
- methods of generating an immune response against any target antigen such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof.
- the adenovirus vectors are of particular importance because of the unexpected finding that they can be used to generate immune responses in subjects who have preexisting immunity to Ad and can be used in vaccination regimens that include multiple rounds of immunization using the adenovirus vectors, regimens not possible using previous generation adenovirus vectors.
- generating an immune response comprises an induction of a humoral response and/or a cell-mediated response. It may be desirable to increase an immune response against a target antigen of interest.
- Generating an immune response may involve a decrease in the activity and/or number of certain cells of the immune system or a decrease in the level and/or activity of certain cytokines or other effector molecules.
- a variety of methods for detecting alterations in an immune response e.g., cell numbers, cytokine expression, cell activity
- Illustrative methods useful in this context include intracellular cytokine staining (ICS), ELISpot, proliferation assays, cytotoxic T-cell assays including chromium release or equivalent assays, and gene expression analysis using any number of polymerase chain reaction (PCR) or RT-PCR based assays.
- Generating an immune response can comprise an increase in target antigen-specific CTL activity of from 1.5 to 5 fold in a subject administered the adenovirus vectors as described herein as compared to a control.
- generating an immune response comprises an increase in target-specific CTL activity of about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1 , 1 1.5, 12, 12.5, 15, 16, 17, 18, 19, 20, or more fold in a subject administered the adenovirus vectors as compared to a control.
- Generating an immune response can comprise an increase in target antigen-specific HTL activity, such as proliferation of helper T-cells, of from 1.5 to 5 fold in a subject administered the adenovirus vectors as described herein that comprise nucleic acid encoding the target antigen as compared to an appropriate control.
- generating an immune response comprises an increase in target- specific HTL activity of about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 15, 16, 17, 18, 19, 20, or more fold as compared lo a control.
- HTL activity may comprise an increase as described above, or decrease, in production of a particular cytokine, such as interferon- ⁇ (IFN- ⁇ ), interleukin- 1 (IL- 1), IL-2, IL-3, IL-6, IL-7, IL-12, IL-15, tumor necrosis factor-a (TNF-a), granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), or other cytokine.
- generating an immune response may comprise a shift from a Th2 type response to a Thl type response or in certain embodiments a shift from a Thl type response to a Th2 type response.
- generating an immune response may comprise the stimulation of a predominantly Thl or a Th2 type response.
- Generating an immune response can comprise an increase in target-specific antibody production of between 1.5 and 5 fold in a subject administered the adenovirus vectors as described herein as compared to an appropriate control.
- generating an immune response comprises an increase in target-specific antibody production of about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1 , 11.5, 12, 12.5, 15, 16, 17, 18, 19, 20, or more fold in a subject administered the adenovirus vector as compared to a control.
- a target antigen of interest such as PSA, PSMA, MUCl , Brachyury, CEA, or a combination thereof
- administering to the individual an adenovirus vector comprising: a) a replication defective adenovirus vector, wherein the adenovirus vector has a deletion in the E2b region, and b) a nucleic acid encoding the target antigen such as PSA, PSMA, MUCl , Brachyury, CEA, or a combination thereof; and readministering the adenovirus vector at least once to the individual; thereby generating an immune response against the target antigen.
- the target antigen may be a wild-type protein, a fragment, a variant, or a variant fragment thereof.
- the target antigen comprises a tumor antigen such as PSA, MUCl, Brachyury, CEA, or a combination thereof, a fragment, a variant, or a variant fragment thereof.
- adenovirus vector comprising: a) a replication defective adenovirus vector, wherein the adenovirus vector has a deletion in the E2b region, and b) a nucleic acid encoding the target antigen; and readministering the adenovirus vector at least once to the individual; thereby generating an immune response against the target antigen.
- the target antigen may be a wild-type protein, a fragment, a variant, or a variant fragment thereof.
- the target antigen comprises such as PSA, PSMA, MUCl , Brachyury, CEA, or a combination thereof, a fragment, a variant, or a variant fragment thereof.
- preexisting immunity to Ad this can be determined using methods known in the art, such as antibody-based assays to test for the presence of Ad antibodies. Further, in certain embodiments, the methods as described herein include first determining that an individual has preexisting immunity to Ad then administering the E2b deleted adenovirus vectors as described herein.
- One embodiment provides a method of generating an immune response against one or more target antigens in an individual comprising administering to the individual a first adenovirus vector comprising a replication defective adenovirus vector, wherein the adenovirus vector has a deletion in the E2b region, and a nucleic acid encoding at least one target antigen; administering to the individual a second adenovirus vector comprising a replication defective adenovirus vector, wherein the adenovirus vector has a deletion in the E2b region, and a nucleic acid encoding at least one target antigen, wherein the at least one target antigen of the second adenovirus vector is the same or different from the at least one target antigen of the first adenovirus vector.
- the target antigen may be a wild-type protein, a fragment, a variant, or a variant fragment thereof.
- the target antigen comprises a tumor antigen such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, a fragment, a variant, or a variant fragment thereof.
- certain embodiments contemplate multiple immunizations with the same E2b deleted adenovirus vector or multiple immunizations with different E2b deleted adenovirus vectors.
- the adenovirus vectors may comprise nucleic acid sequences that encode one or more target antigens as described elsewhere herein.
- the methods comprise multiple immunizations with an E2b deleted adenovirus encoding one target antigen, and re-administration of the same adenovirus vector multiple times, thereby inducing an immune response against the target antigen.
- the target antigen comprises a tumor antigen such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof, a fragment, a variant, or a variant fragment thereof.
- the methods comprise immunization with a first adenovirus vector that encodes one or more target antigens, and then administration with a second adenovirus vector that encodes one or more target antigens that may be the same or different from those antigens encoded by the first adenovirus vector.
- one of the encoded target antigens may be different or all of the encoded antigens may be different, or some may be the same and some may be different.
- the methods include administering the first adenovirus vector multiple times and administering the second adenovirus multiple times.
- the methods comprise administering the first adenovirus vector 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, or more times and administering the second adenovirus vector 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more times.
- the order of administration may comprise administering the first adenovirus one or multiple times in a row followed by administering the second adenovirus vector one or multiple times in a row.
- the methods include alternating administration of the first and the second adenovirus vectors as one administration each, two administrations each, three administrations each, and so on.
- the first and the second adenovirus vectors are administered simultaneously.
- the first and the second adenovirus vectors are administered sequentially.
- the target antigen comprises a tumor antigen such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, a fragment, a variant, or a variant fragment thereof.
- adenovirus vectors may be used in the methods as described herein.
- Three, 4, 5, 6, 7, 8, 9, 10, or more different adenovirus vectors may be used in the methods as described herein.
- the methods comprise administering more than one E2b deleted adenovirus vector at a time.
- immune responses against multiple target antigens of interest can be generated by administering multiple different adenovirus vectors simultaneously, each comprising nucleic acid sequences encoding one or more target antigens.
- the adenovirus vectors can be used to generate an immune response against a cancer, such as carcinomas or sarcomas (e.g., solid tumors, lymphomas and leukemia).
- the adenovirus vectors can be used to generate an immune response against a cancer, such as neurologic cancers, melanoma, non-Hodgkin's lymphoma, Hodgkin's disease, leukemia, plasmocytomas, adenomas, gliomas, thymomas, breast cancer, prostate cancer, colorectal cancer, kidney cancer, renal cell carcinoma, uterine cancer, pancreatic cancer, esophageal cancer, lung cancer, ovarian cancer, cervical cancer, testicular cancer, gastric cancer, multiple myeloma, hepatoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia
- Methods are also provided for treating or ameliorating the symptoms of any of the infectious diseases or cancers as described herein.
- the methods of treatment comprise administering the adenovirus vectors one or more times to individuals suffering from or at risk from suffering from an infectious disease or cancer as described herein.
- certain embodiments provide methods for vaccinating against infectious diseases or cancers in individuals who are at risk of developing such a disease.
- Individuals at risk may be individuals who may be exposed to an infectious agent at some time or have been previously exposed but do not yet have symptoms of infection or individuals having a genetic predisposition to developing a cancer or being particularly susceptible to an infectious agent.
- Individuals suffering from an infectious disease or cancer described herein may be determined to express and/or present a target antigen, which may be use to guide the therapies herein.
- a target antigen which may be use to guide the therapies herein.
- an example can be found to express and/or present a target antigen and an adenovirus vector encoding the target antigen, a variant, a fragment or a variant fragment thereof may be administered subsequently.
- adenovirus vectors for the in vivo delivery of nucleic acids encoding a target antigen, or a fragment, a variant, or a variant fragment thereof.
- the nucleic acid sequence is expressed resulting in an immune response against the antigen encoded by the sequence.
- the adenovirus vector vaccine can be administered in an "effective amount," that is, an amount of adenovirus vector that is effective in a selected route or routes of administration to elicit an immune response as described elsewhere herein.
- An effective amount can induce an immune response effective to facilitate protection or treatment of the host against the target infectious agent or cancer.
- the amount of vector in each vaccine dose is selected as an amount which induces an immune, immunoprotective or other immunotherapeutic response without significant adverse effects generally associated with typical vaccines.
- subjects may be monitored to determine the efficacy of the vaccine treatment. Monitoring the efficacy of vaccination may be performed by any method known to a person of ordinary skill in the art.
- blood or fluid samples may be assayed to detect levels of antibodies.
- ELISpot assays may be performed to detect a cell- mediated immune response from circulating blood cells or from lymphoid tissue cells.
- from 1 to 10 doses may be administered over a 52 week period.
- 6 doses are administered, at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 1, 12, 13; 14, 15, 16, 17, 18, 20, 22, 23, or 24 months or any range or value derivable therefrom, and further booster vaccinations may be given periodically thereafter, at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 22, 23, or 24 months or any range or value derivable therefrom.
- Alternate protocols may be appropriate for individual patients.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more doses may be administered over a 1 year period or over shorter or longer periods, such as over 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 week periods. Doses may be administered at 1, 2, 3, 4, 5, or 6 week intervals or longer intervals.
- a vaccine can be infused over a period of less than about 4 hours, and more preferably, over a period of less than about 3 hours.
- the first 25-50 mg could be infused within 30 minutes, preferably even 15 min, and the remainder infused over the next 2-3 hrs.
- the dosage of an administered vaccine construct may be administered as one dosage every 2 or 3 weeks, repeated for a total of at least 3 dosages.
- the construct may be administered twice per week for 4-6 weeks.
- the dosing schedule can optionally be repeated at other intervals and dosage may be given through various parenteral routes, with appropriate adjustment of the dose and schedule.
- Compositions as described herein can be administered to a patient in conjunction with (e.g., before, simultaneously, or following) any number of relevant treatment modalities.
- a suitable dose is an amount of an adenovirus vector that, when administered as described above, is capable of promoting a target antigen immune response as described elsewhere herein.
- the immune response is at least 10-50% above the basal (i.e., untreated) level.
- the immune response is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 110, 125, 150, 200, 250, 300, 400, 500, or more over the basal level.
- Such response can be monitored by measuring the target antigen(s) antibodies in a patient or by vaccine-dependent generation of cytolytic effector cells capable of killing patient tumor or infected cells in vitro, or other methods known in the art for monitoring immune responses.
- Such vaccines should also be capable of causing an immune response that leads to an improved clinical outcome of the disease in question in vaccinated patients as compared to non-vaccinated patients.
- the improved clinical outcome comprises treating disease, reducing the symptoms of a disease, changing the progression of a disease, or extending life.
- compositions provided herein may be administered to an individual.
- “Individual” may be used interchangeably with “subject” or "patient.”
- An individual may be a mammal, for example a human or animal such as a non-human primate, a rodent, a rabbit, a rat, a mouse, a horse, a donkey, a goat, a cat, a dog, a cow, a pig, or a sheep.
- the individual is a human.
- the individual is a fetus, an embryo, or a child.
- the compositions provided herein are administered to a cell ex vivo.
- compositions provided herein are administered to an individual as a method of treating a disease or disorder.
- the individual has a genetic disease.
- the individual is at risk of having the disease, such as any of the diseases described herein.
- the individual is at increased risk of having a disease or disorder caused by insufficient amount of a protein or insufficient activity of a protein. If an individual is "at an increased risk" of having a disease or disorder, the method involves preventative or prophylactic treatment. For example, an individual can be at an increased risk of having such a disease or disorder because of family history of the disease.
- a subject does not have a disease.
- the treatment as described herein is administered before onset of a disease.
- a subject may have undetected disease.
- a subject may have a low disease burden.
- a subject may also have a high disease burden.
- a subject may be administered a treatment as described herein according to a grading scale.
- a grading scale can be a Gleason classification.
- a Gleason classification reflects how different tumor tissue is from normal prostate tissue. It uses a scale from 1 to 5.
- a physician gives a cancer a number based on the patterns and growth of the cancer cells. The lower the number, the more normal the cancer cells look and the lower the grade. The higher the number, the less normal the cancer cells look and the higher the grade.
- a treatment may be administered to a patient with a low Gleason score.
- a patient with a Gleason score of 3 or below may be administered a treatment as described herein.
- compositions and methods for raising an immune response against one or more particular target antigens such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof in selected patient populations.
- methods and compositions as described herein may target patients with a cancer including but not limited to prostate cancer, carcinomas or sarcomas such as neurologic cancers, melanoma, non-Hodgkin's lymphoma, Hodgkin's disease, leukemia, plasmocytomas, adenomas, gliomas, thymomas, breast cancer, colorectal cancer, kidney cancer, renal cell carcinoma, uterine cancer, pancreatic cancer, esophageal cancer, lung cancer, ovarian cancer, cervical cancer, testicular cancer, gastric cancer, multiple myeloma, hepatoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia
- ALL acute lymphoblastic leuk
- the targeted patient population may be limited to individuals having colorectal adenocarcinoma, metastatic colorectal cancer, advanced PSA, PSMA, MUC1 , MUClc, MUCln, T, or CEA expressing cancer, prostate cancer, colorectal cancer, head and neck cancer, liver cancer, breast cancer, lung cancer, bladder cancer, or pancreas cancer.
- a histologically confirmed diagnosis of a selected cancer for example colorectal adenocarcinoma, may be used.
- a particular disease stage or progression may be selected, for example, patients with one or more of a metastatic, recurrent, stage III, or stage IV cancer may be selected for therapy with the methods and compositions as described herein.
- patients may be required to have received and, optionally, progressed through other therapies including but not limited to fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, cetuximab, or panitumumab containing therapies.
- individual' s refusal to accept such therapies may allow the patient to be included in a therapy eligible pool with methods and compositions as described herein.
- individuals to receive therapy using the methods and compositions as described herein may be required to have an estimated life expectancy of at least, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 18, 21, or 24 months.
- the patient pool to receive a therapy using the methods and compositions as described herein may be limited by age.
- individuals who are older than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 25, 30, 35, 40, 50, 60, or more years old can be eligible for therapy with methods and compositions as described herein.
- individuals who are younger than 75, 70, 65, 60, 55, 50, 40, 35, 30, 25, 20, or fewer years old can be eligible for therapy with methods and compositions as described herein.
- patients receiving therapy using the methods and compositions as described herein are limited to individuals with adequate hematologic function, for example with one or more of a white blood cell (WBC) count of at least 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more per microliter, a hemoglobin level of at least 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or higher g/dL, a platelet count of at least 50,000; 60,000; 70,000; 75,000; 90,000; 100,000; 110,000; 120,000; 130,000; 140,000; 150,000 or more per microliter; with a PT-INR value of less than or equal to 0.8, 1.0, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8,
- WBC white blood cell
- hematologic function indicator limits are chosen differently for individuals in different gender and age groups, for example 0-5, 5-10, 10-15, 15- 18, 18-21 , 21-30, 30-40, 40-50, 50-60, 60-70, 70-80, or older than 80.
- patients receiving therapy using the methods and compositions as described herein are limited to individuals with adequate renal and/or hepatic function, for example with one or more of a serum creatinine level of less than or equal to 0.8, 0.9, 1.0,
- renal or hepatic function indicator limits are chosen differently for individuals in different gender and age groups, for example 0-5, 5-10, 10- 15, 15-18, 18-21, 21-30, 30-40, 40-50, 50-60, 60-70, 70-80, or older than 80.
- the K-ras mutation status of individuals who are candidates for a therapy using the methods and compositions as described herein can be determined. Individuals with a preselected K-ras mutational status can be included in an eligible patient pool for therapies using the methods and compositions as described herein.
- patients receiving therapy using the methods and compositions as described herein are limited to individuals without concurrent cytotoxic chemotherapy or radiation therapy, a history of, or current, brain metastases, a history of autoimmune disease, such as but not restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, multiple sclerosis, thyroid disease and vitiligo, serious intercurrent chronic or acute illness, such as cardiac disease (NYHA class III or IV), or hepatic disease, a medical or psychological impediment to probable compliance with the protocol, concurrent (or within the last 5 years) second malignancy other than non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial bladder cancer, or other carcinoma in situ that has been treated, an active acute or chronic infection including: a urinary tract infection, HIV (e.g., as determined by ELISA and confirmed by Western Blot), and chronic hepatitis, or concurrent steroid therapy (or other immuno
- patients with at least 3, 4, 5, 6, 7, 8, 9, or 10 weeks of discontinuation of any steroid therapy may be included in a pool of eligible individuals for therapy using the methods and compositions as described herein.
- patients receiving therapy using the methods and compositions o as described herein include individuals with thyroid disease and vitiligo.
- samples for example serum or urine samples, from the individuals or candidate individuals for a therapy using the methods and compositions as described herein may be collected.
- Samples may be collected before, during, and/or after the therapy for example, within 2, 4, 6, 8, 10 weeks prior to the start of the therapy, within 1 week, 10 day, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks from the start of the therapy, within 2, 4, 6, 8, 10 weeks prior to the start of the therapy, within 1 week, 10 day, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, or 12 weeks from the start of the therapy, in 1 week, 10 day, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, or 12 weeks intervals during the therapy, in 1 month, 3 month, 6 month, 1 year, 2 year intervals after the therapy, within 1 month, 3 months, 6 months, 1 year, 2 years, or longer after the therapy, for a duration of 6 months, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years, or
- the samples may be tested for any of the hematologic, renal, or hepatic function indicators described herein as well as suitable others known in the art, for example a ⁇ -HCG for women with childbearing potential.
- hematologic and biochemical tests including cell blood counts with differential, PT, INR and PTT, tests measuring Na, K, CI, C0 2 , BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT and glucose are contemplated in certain aspects.
- the presence or the amount of HIV antibody, Hepatitis BsAg, or Hepatitis C antibody are determined in a sample from individuals or candidate individuals for a therapy using the methods and compositions described herein.
- Biological markers such as antibodies to target antigens or the neutralizing antibodies to Ad5 vector can be tested in a sample, such as serum, from individuals or candidate individuals for a therapy using the methods and compositions described herein.
- a sample such as serum
- one or more samples such as a blood sample can be collected and archived from an individuals or candidate individuals for a therapy using the methods and compositions described herein. Collected samples can be assayed for immunologic evaluation.
- Individuals or candidate individuals for a therapy using the methods and compositions described herein can be evaluated in imaging studies, for example using CT scans or MRI of the chest, abdomen, or pelvis.
- Imaging studies can be performed before, during, or after therapy using the methods and compositions described herein, during, and/or after the therapy, for example, within 2, 4, 6, 8, 10 weeks prior to the start of the therapy, within 1 week, 10 day, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks from the start of the therapy, within 2, 4, 6, 8, 10 weeks prior to the start of the therapy, within 1 week, 10 day, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, or 12 weeks from the start of the therapy, in 1 week, 10 day, 2 week, 3 week, 4 week, 6 week, 8 week, 9 week, or 12 week intervals during the therapy, in 1 month, 3 month, 6 month, 1 year, 2 year intervals after the therapy, within 1 month, 3 months, 6 months, 1 year, 2 years, or longer after the therapy, for a duration of 6 months, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 years, or longer.
- compositions and methods described herein contemplate various dosage and administration regimens during therapy.
- Patients may receive one or more replication defective adenovirus or adenovirus vector, for example, Ad5 [E1-, E2B-]-vectors comprising a target antigen that is capable of raising an immune response in an individual against a target antigen described herein.
- the replication defective adenovirus is administered at a dose that suitable for effecting such immune response. In some embodiments, the replication defective adenovirus is administered at a dose from about lxlO 8 virus particles to about 5xl0 13 virus particles per immunization. In some cases, the replication defective adenovirus is administered at a dose that is from about lxlO 9 to about 5xl0 12 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about lxlO 8 virus particles to about 5xl0 8 virus particles per immunization.
- the replication defective adenovirus is administered at a dose from about 5xl0 8 virus particles to about lxlO 9 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about l xlO 9 virus particles to about 5xl0 9 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about 5x l 0 9 virus particles to about lxlO 10 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about lxl O 10 virus particles to about 5xl 0 10 virus particles per immunization.
- the replication defective adenovirus is administered at a dose from about 5xl0 10 virus particles to about lxlO 1 1 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about 1x10" virus particles to about 5x10" virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about 5xl0" virus particles to about lxlO 12 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about lxlO 12 virus particles to about 5xl0 12 virus particles per immunization.
- the replication defective adenovirus is administered at a dose from about 5xl0 12 virus particles to about lxlO 13 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about lxlO 13 virus particles to about 5xl0 13 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about l xlO 8 virus particles to about 5xl0 10 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about l xlO 10 virus particles to about 5xl0 12 virus particles per immunization.
- the replication defective adenovirus is administered at a dose from about lxlO 1 1 virus particles to about 5xl0 13 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about lxlO 8 virus particles to about lxlO 10 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about lxlO 10 virus particles to about lxlO 12 virus particles per immunization. In some embodiments, the replication defective adenovirus is administered at a dose from about 1x10" virus particles to about 5xl0 13 virus particles per immunization.
- the replication defective adenovirus is administered at a dose that is greater than or equal to lxlO 9 , 2 xlO 9 , 3 x lO 9 , 4 xlO 9 , 5 xlO 9 , 6 xlO 9 , 7 xlO 9 , 8 xlO 9 , 9 xlO 9 , lxlO 10 , 2 xlO 10 , 3 xlO 10 , 4 xlO 10 , 5 xlO 10 , 6 xlO 10 , 7 xlO 10 , 8 xlO 10 , 9 xlO 10 , 1 xlO 1 1 , 2 xlO 1 1 , 3 xlO 1 1 , 4 xlO" , 5x10" , 6 xlO 1 1 , 7 xlO 1 1 , 8 xlO 1 1 , 9 xlO 1 1 , lxlO 12 ,
- the replication defective adenovirus is administered at a dose that is less than or equal to lxlO 9 , 2 xlO 9 , 3 xlO 9 , 4 xlO 9 , 5 xlO 9 , 6 xlO 9 , 7 xlO 9 , 8 xlO 9 , 9 xlO 9 , lxlO 10 , 2 xlO 10 , 3 xlO 10 , 4 xlO 10 , 5 xlO 10 , 6 xlO 10 , 7 xlO 10 , 8 xlO 10 , 9 xlO 10 , 1 xlO", 2 xlO", 3 xlO 1 1 , 4 xlO 1 1 , 5x10" , 6 xlO 1 1 , 7 xlO 1 1 , 8 xlO 1 1 , 9 xlO 1 1 ,
- a desired dose described herein is administered in a suitable volume of formulation buffer, for example a volume of about 0.1-10 mL, 0.2-8mL, 0.3-7mL, 0.4-6 mL, 0.5-5 mL, 0.6-4 mL, 0.7-3 mL, 0.8-2 mL, 0.9- 1.5 mL, 0.95- 1.2 mL, or 1.0-1.1 mL.
- a suitable volume of formulation buffer for example a volume of about 0.1-10 mL, 0.2-8mL, 0.3-7mL, 0.4-6 mL, 0.5-5 mL, 0.6-4 mL, 0.7-3 mL, 0.8-2 mL, 0.9- 1.5 mL, 0.95- 1.2 mL, or 1.0-1.1 mL.
- the volume may fall within any range bounded by any of these values (e.g., about 0.5 mL to about 1.1 mL).
- virus particles can be through a variety of suitable paths for delivery, for example it can be by injection (e.g., intracutaneously, intramuscularly, intravenously or subcutaneously), intranasally (e.g., by aspiration), in pill form (e.g., swallowing, suppository for vaginal or rectal delivery.
- a subcutaneous delivery may be preferred and can offer greater access to dendritic cells.
- virus particles to an individual may be repeated. Repeated deliveries of virus particles may follow a schedule or alternatively, may be performed on an as needed basis. For example, an individual's immunity against a target antigen, for example, a tumor antigen such as PSA, PSMA, MUC1 , Brachyury, CEA, or a combination thereof, a fragment, a variant, or a variant fragment thereof, may be tested and replenished as necessary with additional deliveries.
- schedules for delivery include administrations of virus particles at regular intervals. Joint delivery regimens may be designed comprising one or more of a period with a schedule and/or a period of need based administration assessed prior to administration.
- a therapy regimen may include an administration, such as subcutaneous administration once every three weeks then another immunotherapy treatment every three months until removed from therapy for any reason including death. Another example regimen comprises three administrations every three weeks then another set of three immunotherapy treatments every three months.
- Another example regimen comprises a first period with a first number of administrations at a first frequency, a second period with a second number of administrations at a second frequency, a third period with a third number of administrations at a third frequency, etc., and optionally one or more periods with undetermined number of administrations on an as needed basis.
- the number of administrations in each period can be independently selected and can for example be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more.
- the frequency of the administration in each period can also be independently selected, can for example be about every day, every other day, every third day, twice a week, once a week, once every other week, every three weeks, every month, every six weeks, every other month, every third month, every fourth month, every fifth month, every sixth month, once a year etc.
- the therapy can take a total period of up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36 months, or more.
- the scheduled interval between immunizations may be modified so that the interval between immunizations is revised by up to a fifth, a fourth, a third, or half of the interval.
- an immunization may be repeated from 20 to 28 days (3 weeks - 1 day to 3 weeks +7 days).
- the subsequent immunizations may be shifted allowing a minimum amount of buffer between immunizations.
- the subsequent immunization may be scheduled to occur no earlier than 17, 18, 19, or 20 days after the previous immunization.
- compositions described herein can be provided in various states, for example, at room temperature, on ice, or frozen.
- Compositions may be provided in a container of a suitable size, for example a vial of 2 mL vial.
- a 2ml vial with 1.0 mL of extractable vaccine contains 5x10" total virus particles/mL.
- Storage conditions including temperature and humidity may vary.
- compositions for use in therapy may be stored at room temperature, 4 °C, -20 °C, or lower.
- general evaluations are performed on the individuals receiving treatment according to the methods and compositions as described herein.
- One or more of any tests may be performed as needed or in a scheduled basis, such as on weeks 0, 3, 6, etc.
- a different set of tests may be performed concurrent with immunization vs. at time points without immunization.
- General evaluations may include one or more of medical history, ECOG Performance Score, Karnofsky performance status, and complete physical examination with weight by the attending physician. Any other treatments, medications, biologies, or blood products that the patient is receiving or has received since the last visit may be recorded. Patients may be followed at the clinic for a suitable period, for example approximately 30 minutes, following receipt of vaccine to monitor for any adverse reactions.
- local and systemic reactogenicity after each dose of vaccine may be assessed daily for a selected time, for example for 3 days (on the day of immunization and 2 days thereafter).
- Diary cards may be used to report symptoms and a ruler may be used to measure local reactogenicity.
- Immunization injection sites may be assessed.
- CT scans or MRI of the chest, abdomen, and pelvis may be performed.
- hematological and biochemical evaluations are performed on the individuals receiving treatment according to the methods and compositions as described herein. One or more of any tests may be performed as needed or in a scheduled basis, such as on weeks 0, 3, 6, etc. A different set of tests may be performed concurrent with immunization vs. at time points without immunization.
- Hematological and biochemical evaluations may include one or more of blood test for chemistry and hematology, CBC with differential, Na, K, CI, C0 2 , BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, glucose, and ANA.
- biological markers are evaluated on individuals receiving treatment according to the methods and compositions as described herein.
- One or more of any tests may be performed as needed or in a scheduled basis, such as on weeks 0, 3, 6, etc.
- a different set of tests may be performed concurrent with immunization vs. at time points without immunization.
- Biomarkers evaluations may include one or more of measuring antibodies to target antigens or viral vectors described herein, from a serum sample of adequate volume, for example about 5ml Biomarkers may be reviewed if determined and available.
- an immunological assessment is performed on individuals receiving treatment according to the methods and compositions as described herein.
- One or more of any tests may be performed as needed or in a scheduled basis, such as on weeks 0, 3, 6, etc.
- a different set of tests may be performed concurrent with immunization vs. at time points without immunization.
- Peripheral blood for example about 90mL may be drawn prior to each immunization and at a time after at least some of the immunizations, to determine whether there is an effect on the immune response at specific time points during the study and/or after a specific number of immunizations.
- Immunological assessment may include one or more of assaying peripheral blood mononuclear cells (PBMC) for T-cell responses to target antigens using ELISpot, proliferation assays, multi-parameter flow cytometric analysis, and cytoxicity assays. Serum from each blood draw may be archived and sent and determined.
- PBMC peripheral blood mononuclear cells
- a tumor assessment is performed on individuals receiving treatment according to the methods and compositions as described herein.
- One or more of any tests may be performed as needed or in a scheduled basis, such as prior to treatment, on weeks 0, 3, 6, etc.
- a different set of tests may be performed concurrent with immunization vs. at time points without immunization.
- Tumor assessment may include one or more of CT or MRI scans of chest, abdomen, or pelvis performed prior to treatment, at a time after at least some of the immunizations and at approximately every three months following the completion of a selected number, for example 2, 3, or 4, of first treatments and for example until removal from treatment.
- Immune responses against a target antigen such as PSA, PSMA, MUC1, Brachyury, CEA, or a combination thereof may be evaluated from a sample, such as a peripheral blood sample of an individual using one or more suitable tests for immune response, such as ELISpot, cytokine flow cytometry, or antibody response.
- a positive immune response can be determined by measuring a T-cell response.
- a T-cell response can be considered positive if the mean number of spots adjusted for background in six wells with antigen exceeds the number of spots in six control wells by 10 and the difference between single values of the six wells containing antigen and the six control wells is statistically significant at a level of p ⁇ 0.05 using the Student's t-test.
- Immunogenicity assays may occur prior to each immunization and at scheduled time points during the period of the treatment. For example, a time point for an immunogenicity assay at around week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 18, 20 , 24, 30, 36, or 48 of a treatment may be scheduled even without a scheduled immunization at this time. In some cases, an individual may be considered evaluable for immune response if they receive at least a minimum number of immunizations, for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, or more immunizations.
- disease progression or clinical response determination is made according to the RECIST 1.1 criteria among patients with measurable/evaluable disease.
- therapies using the methods and compositions as described herein affect a Complete Response (CR; disappearance of all target lesions for target lesions or disappearance of all non-target lesions and normalization of tumor marker level for non- target lesions) in an individual receiving the therapy.
- therapies using the methods and compositions as described herein affect a Partial Response (PR; at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD for target lesions) in an individual receiving the therapy.
- PR Partial Response
- therapies using the methods and compositions as described herein affect a Stable Disease (SD; neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started for target lesions) in an individual receiving the therapy.
- therapies using the methods and compositions described herein affect an Incomplete Response/ Stable Disease (SD; persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits for non-target lesions) in an individual receiving the therapy.
- therapies using the methods and compositions as described herein affect a Progressive Disease (PD; at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions for target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits for non-target lesions) in an individual receiving the therapy.
- PD Progressive Disease
- compositions, immunotherapy or vaccines described herein may be supplied in the form of a kit.
- kits of the present disclosure may further comprise instructions regarding the dosage and or administration including treatment regimen information.
- kits comprise the compositions and methods for providing immunotherapy or vaccines described.
- kits may further comprise components useful in administering the kit components and instructions on how to prepare the components.
- the kit can further comprise software for conducting monitoring patient before and after treatment with appropriate laboratory tests, or communicating results and patient data with medical staff.
- the components comprising the kit may be in dry or liquid form. If they are in dry form, the kit may include a solution to solubilize the dried material.
- the kit may also include transfer factor in liquid or dry form. In some embodiments, if the transfer factor is in dry form, the kit includes a solution to solubilize the transfer factor.
- the kit may also include containers for mixing and preparing the components.
- the kit may also include instrument for assisting with the administration such for example needles, tubing, applicator, inhalant, syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle.
- the kits or drug delivery systems as described herein also will typically include a means for containing compositions of the present disclosure in close confinement for commercial sale and distribution.
- This example describes pre-clinical testing of the Ad5 [E1-, E2b-]-PSA vaccine in a mouse model. Studies were performed to assess the use of Ad5 [E1-, E2b-]-PSA as a cancer vaccine in a BALB/c mouse model. Ad5 [E1-, E2b-]-PSA induced potent CMI against PSA in mice. Studies were also performed to show anti-tumor activity of the vaccine in a murine model of PSA expressing cancer. These data indicate that in vivo delivery of Ad5 [E1-, E2b- ]-PSA can induce PSA directed anti-tumor immunity against PSA expressing cancers.
- PSA directed CMI responses were induced in vaccinated but not control mice (FIGS. 1A and IB). Specificity of the CMI responses was demonstrated in ELISpot assays using irrelevant HIV-gag or cytomegalovirus virus (CMV) antigens (FIGS. 2A and 2B). Antibody responses were also tested and PSA directed antibody responses were detected in immunized but not control mice (FIG. 3).
- CMV cytomegalovirus virus
- infected human DC could stimulate human antigen-specific T cell lines to secrete IFN- ⁇
- specifically infected DC were incubated with antigen-specific T cell lines and tested for IFN- ⁇ secreting activity as a measure of stimulation.
- Human DC were infected with Ad5 vector, incubated for 48 hours, washed, and used for stimulation of human antigen-specific T cells.
- infection of human dendritic cells (from a HLA-A2 donor) with recombinant Ad5-PSA vectors encoding transgenes can activate PSA- specific T cell lines to produce IFN- ⁇ .
- mice were immunized three times subcutaneously (SC) at two-week intervals with l xlO 10 VP of Ad5 [E1-, E2b-]-null (empty vector controls) or lxlO 10 VP of Ad5 [E1-, E2b-]-PSA vaccine. Two weeks after the last immunization (vaccination), mice were implanted with 5xl0 5 PSA expressing murine tumor cells.
- FIG. 14A illustrates IFN- ⁇ secreting cells after ex vivo stimulation.
- FIG. 14B illustrates IL-2 secreting cells after ex vivo stimulation.
- FIG. 14C illustrates Granzyme B secreting cells after ex vivo stimulation.
- FIG. 15A illustrates the percent of CD8p+ splenocytes secreting IFN- ⁇ .
- FIG. 15B illustrates the percent of CD4+ splenocytes secreting IFN- ⁇ .
- FIG. 15C illustrates the percent of CD8 + splenocytes secreting IFN- ⁇ and TNF-a.
- FIG. 15D illustrates the percent of CD4+ splenocytes secreting IFN- ⁇ and TNF-a.
- FIG. 16A illustrates the mass of IgG specific antibodies against PSA.
- FIG. 16B illustrates the mass of IgG 1 specific anitbodies against PSA.
- Ad5 [E1-, E2b-]-PSA is a therapeutic vaccine targeting PSA that induces robust immune responses.
- Ad5 [E1 -, E2b-]-PSA induced potent CMI against PSA in mice as assessed in ELISpot assays for IFN- ⁇ and IL-2 secreting splenocytes.
- human antigen-specific T cell lines were stimulated by human DC infected with Ad5 [E1-, E2b-]- PSA.
- Ad5 [E1-, E2b-]-PSA vaccine generated anti-tumor activity in a preclinical murine model of PSA expressing cancer.
- This example describes a Phase I/IIa study of the Ad5 [E1-, E2b-]-PSA vaccine in individuals with advanced prostate cancer.
- the goal is to clinically test this therapeutic vaccine against PSA which utilizes an Ad5 vector system that overcomes barriers found with other Ad5 systems.
- the results of the clinical studies can establish the safety and immunogenicity of using this Ad5 [E1-, E2b-]-PSA vaccine as an immunotherapeutic agent.
- Ad5 [E1-, E2b-]-PSA immunotheraputic agent in patients with advanced stage prostate cancer.
- Ad5 [E1-, E2b-]-PSA is designed to induce anti-tumor T cell-mediated immune responses.
- Ad5 [E1-, E2b-]-PSA is an adenovirus serotype 5 (Ad5) vector that has been modified by removal of early 1 (El), early 2b (E2b) and early 3 (E3) gene regions and insertion of the human prostate specific antigen (PSA) gene.
- the resulting recombinant replication-defective vector is propagated in the newly engineered, proprietary human 293 based cell line (E.C7) that supplies the El and E2b gene functions in trans required for vector production. No gene transfer insertion is proposed for this protocol; the product functions and remains episomal.
- An open-label, dose-escalation, Phase I/IIa study is conducted with a total of up to 24 patients with PSA expressing prostate cancer. 5xl0 9 , 5xl0 10 and 5x10" adenovirus VP dosage levels are evaluated.
- patients are enrolled into successive dosage level cohorts of 3 or 6 patients and monitored for dose-limiting toxicity (DLT). Each patient is given Ad5 [E1-, E2b-]-PSA by SC injection every 3 weeks for 3 immunizations. Assessment of DLT for dose escalation is made after all patients in a cohort have had a study visit at least 3 weeks after receiving their last dose of vaccine. Patients with a history of allergic reactions to any component of this vaccine are not included in the trial.
- Ad5 [E 1-, E2b-]-PSA vaccine is a clear colorless liquid filled in a 2-mL amber vial containing 1 mL of extractable vaccine. There are total of 5.0x10" total VP in 1 mL of the product.
- Each vial is sealed with a rubber stopper and has a white flip off seal. End user of the product flips the white plastic portion of the cap up/off with their thumb to expose the rubber stopper, and then puncture the stopper with an injection needle to withdraw the liquid. The rubber stopper is secured to the vial with an aluminum crimped seal.
- Ad5 [E1-, E2b-]-PSA is characterized by high-level expression of PSA within transfected cells.
- Ad5 [E1-, E2b-]-PSA is 5xl0 9 , 5xl0 10 , or 5x10" VP depending on which cohort the patient is enrolled.
- the maximum tolerated dose is determined in a dose escalation study.
- the Ad5 [E1-, E2b-]-PSA vaccine is stored at ⁇ -20 °C. Prior to injection, the appropriate vial is removed from the freezer and allowed to thaw at controlled room temperature (20-25 °C, 68-77 °F) for at least 20 minutes and not more than 30 minutes, after which it is kept at 2-8 °C (35-46 °F). The vaccine is stable for at least 8 hours after removal from the freezer when kept refrigerated at 2-8 °C (35-46 °F).
- the thawed vial is swirled and then, using aseptic technique, the pharmacist withdraws the appropriate volume (lmL) from the vial using a 1 mL syringe.
- the vaccine is injected as soon as possible using a 1 to 1/2 inch, 20 to 25-gauge needle. If the vaccine cannot be injected immediately, the syringe is stored at 2-8°C (35-46°F).
- All injections of vaccine are given as a volume of lmL by subcutaneous injection in the upper arm after preparation of the site with alcohol. Either arm is used for each injection.
- Ad5 [E1-, E2b-]-PSA vaccine is supplied as a sterile, clear solution in a 2-mL single- dose vial. Each vial contains a single dose of vaccine provided at 5xl0 u VP per mL. Each vial contains a 1.3 mL total volume. The product is stored at ⁇ -20 ⁇ 10 °C until use. [0406] Individual vials (in the desired number) of Ad5 [E1-, E2b-]-PSA are be packaged in a cardboard box and are shipped over dry ice ( ⁇ -20 °C) by overnight courier with a temperature monitoring device included. Upon receipt, one inspects contents of package for any noticeable damages or defects.
- This example describes production of a multi-targeted vaccine comprising more than one antigen target.
- Ad5 [E1-, E2b-]-brachyury, Ad5 [E1-, E2b-]-PSA (and/or PSMA) and Ad5 [E1-, E2b-]-MUCl are constructed and produced. Briefly, the transgenes are sub-cloned into the El region of the Ad5 [E1-, E2b-] vector using a homologous recombination-based approach. The replication deficient virus is propagated in the E.C7 packaging cell line, CsCk purified, and titered. Viral infectious titer is determined as plaque-forming units (PFUs) on an E.C7 cell monolayer. The VP concentration is determined by sodium dodecyl sulfate (SDS) disruption and spectrophotometry at 260 nm and 280 nm.
- SDS sodium dodecyl sulfate
- sequence encoding for a human PSA antigen as in SEQ ID NO: 1 or SEQ ID NO: 35 is constructed and subsequently cloned into the Ad5 vector to generate the Ad5 [E1-, E2b- ]-PSA construct.
- sequence encoding for a human PSMA antigen as in SEQ ID NO: 11 is constructed and subsequently cloned into the Ad5 vector to generate the Ad5 [E1-, E2b-]-PSMA construct.
- the sequence encoding for the human Brachyury protein (T, NM_003181.3) is modified by introducing the enhancer T-cell HLA-A2 epitope (WLLPGTSTV; SEQ ID NO: 7) and removal of a 25 amino acid fragment involved in DNA binding.
- WLLPGTSTV enhancer T-cell HLA-A2 epitope
- the resulting construct is subsequently subcloned into the Ad5 vector to generate the Ad5 [E1-, E2b-]- Brachyury construct.
- the MUCl molecule consisted of two regions: the N-terminus (MUCl -n), which is the large extracellular domain of MUCl, and the C-terminus (MUCl -c), which has three regions: a small extracellular domain, a single transmembrane domain, and a cytoplasmic tail.
- the cytoplasmic tail contained sites for interaction with signaling proteins and acts as an oncogene and a driver of cancer motility, invasiveness and metastasis.
- the entire MUCl transgene including eight agonist epitopes, will be subcloned into the Ad5 vector.
- the agonist epitopes included in the Ad5 [E1-, E2b-]-MUCl vector bind to HLA-A2 (epitope P93L in the N-terminus, VIA and V2A in the VNTR region, and CIA, C2A and C3A in the C-terminus), HLA-A3 (epitope C5A), and HLA-A24 (epitope C6A in the C-terminus).
- the Tri-Ad5 vaccine is produced by combining of 1 ⁇ '° VP of Ad5 [E1-, E2b-]- Brachyury, Ad5 [E1-, E2b-]-PSA (or alternatively Ad5 [E1-, E2b-]-PSMA) and Ad5 [E1-, E2b-]-MUCl at a ratio of 1 : 1 : 1 (3xl0 10 VP total).
- Ad5 [E1-, E2b-]-PSA (and/or PSMA), Ad5 [E1-, E2b-]-MUCl and the Ad5 [E1-, E2b-]-Brachyury products can be produced in a 5 L Cell Bioreactor.
- vials of the E.C7 manufacturing cell line are thawed, transferred into a T225 flask, and initially cultured at 37 °C in 5% C0 2 in DMEM containing 10% FBS/4 mM L- glutamine. After expansion, the E.C7 cells are expanded using 10-layered CellSTACKS (CS- 10) and transitioned to FreeStyle serum-free medium (SFM). The E.C7 cells are cultured in SFM for 24 hours at 37 °C in 5% C0 2 to a target density of 5xl0 5 cells/mL in the Cell Bioreactor.
- CS- 10 10-layered CellSTACKS
- SFM FreeStyle serum-free medium
- the E.C7 cells will then be infected with the Ad5 [E1 -, E2b-]-PSA, Ad5 [E1 -, E2b-]- MUC1 or Ad5 [E1-, E2b-]-Brachyury, respectively, and cultured for 48 hours.
- a two-column anion exchange procedure is performed.
- a first column is packed with Q Sepharose XL resin, sanitized, and equilibrated with loading buffer.
- the clarified lysate is loaded onto the column and washed with loading buffer.
- the vaccine product is eluted and the main elution peak (eluate) containing the Ad5 [E 1 -, E2b-]-PSA (and/or PSMA), Ad5 [E1 -, E2b-]- MUC1 or Ad5 [E1 -, E2b-]-Brachyury carried forward to the next step.
- a second column is packed with Source 15Q resin, sanitized, and equilibrated with loading buffer.
- the eluate from the first anion exchange column is loaded onto the second column and the vaccine product eluted with a gradient starting at 100% Buffer A (20 mM Tris, 1 mM MgCl 2 , pH 8.0) running to 50% Buffer B (20 mM Tris, 1 mM MgCl 2 , 2M NaCl, pH 8.0).
- Buffer A (20 mM Tris, 1 mM MgCl 2 , pH 8.0
- Buffer B 20 mM Tris, 1 mM MgCl 2 , 2M NaCl, pH 8.0.
- the elution peaks containing the Ad5 [E1 -, E2b-]-PSA (and/or PSMA), Ad5 [E1-, E2b-]- MUC1 or Ad5 [E1-, E2b-]-Brachyury are collected and stored overnight at 2-8 °C.
- the peak elution fractions are processed through a tangential flow filtration (TFF) system for concentration and diafiltration against formulation buffer (20 mM Tris, 25 mM NaCl, 2.5% (v/v) glycerol, pH 8.0). After processing, the final vaccine products are sterile filtered, dispensed into aliquots, and stored at ⁇ -60 °C. A highly purified product approaching 100% purity is typically produced and similar results for these products are predicted.
- TMF tangential flow filtration
- the concentration and total number of VP product produced are determined spectrophotometrically. Product purity is assessed by HPLC. Infectious activity is determined by performing an Ad5 hexon-staining assay for infectious particles using kits.
- This example describes immunogenicity results using a multi-targeted vaccine against PSA (and/or PSMA), MUC1 and T (i.e., Brachyury). Each viral vector product is tested for purity, infectivity, and antigen expression, as described herein and each passed these criteria.
- mice are administered in 25 ⁇ of injection buffer (20 mM HEPES with 3% sucrose) and mice are vaccinated three times at 14-day intervals. Fourteen days after the final injection spleens and sera are collected. Sera are frozen at -20 C. Splenocyte suspensions are generated by gently crushing the spleens through a 70 ⁇ nylon cell strainer (BD Falcon, San Jose, CA). Red cells are removed by the addition of red cell lysis buffer (Sigma-Aldrich, St.
- splenocytes are washed twice and resuspended in R10 (RPMI 1640 supplemented with L- glutamine (2 mM), HEPES (20 mM), penicillin 100 U/ml and streptomycin 100 ⁇ g/ml, and 10% fetal bovine serum.
- Splenocytes are assayed for cytokine production by ELISPOT and flow cytometry.
- C57B1/6 mice are injected subcutaneously 3 times at one-week intervals or 2-week intervals with tri-immunization comprising lxlO 10 virus particles (VP) Ad5 [E1-, E2b-]-null (empty vector controls) or with lxlO 10 VP containing a 1 : 1 : 1 mixture of Ad5 [E1-, E2b-]-PSA (and/or PSMA), Ad5 [E1-, E2b-]-MUCl, and Ad5 [E1-, E2b-] -Brachyury.
- VP lxlO 10 virus particles
- Ad5 [E1-, E2b-]-null empty vector controls
- lxlO 10 VP containing a 1 : 1 : 1 mixture of Ad5 [E1-, E2b-]-PSA (and/or PSMA), Ad5 [E1-, E2b-]-MUCl, and Ad5 [E1-, E2
- CMI responses against PSA, PSMA, MUCl , and Brachyury as assessed by ELISpot assays for IFN- ⁇ secreting splenocytes (SFC) are detected in multi-targeted immunized mice but not control mice (injected with Ad5-Null empty vector). Specificity of the ELISpot assay responses is confirmed by lack of reactivity to irrelevant SIV-nef or SIV- vif peptide antigens.
- a positive control includes cells exposed to concanavalin A (Con A).
- Ad5 [E1 -, E2b-]-based tri- vaccines Tri-Ad5, i.e., Ad5 [E1 -, E2b-]-PSA (and/or PSMA), Ad5 [E1-, E2b-]-MUCl , and/or Ad5 [E1 -, E2b-] -Brachyury) in immunotherapy studies in mice with established PSA, MUC l , or Brachyury expressing tumors, respectively.
- the anti-tumor activity of the individual components of the Ad5 [E1-, E2b-]-based tri-vaccine are assessed.
- mice are injected subcutaneously in the right flank with 5xl0 5 PSA (and/or PSMA), MUCl , and/or Brachyury expressing murine tumor cells.
- mice are treated by 3 subcutaneous injections at a weekly interval with lxlO 10 VP each of Ad5 [E1-, E2b-]-null (no transgene, e.g., empty vector), Ad5 [E 1 -, E2b-]-PSA (and/or PSMA), Ad5 [E1-, E2b-]- MUC1 , and/or Ad5 [E 1-, E2b-] -Brachyury, respectively.
- Control mice are injected with 3 x 10 10 VP of Adeno-null. Tumor volumes are calculated and tumor growth curves are plotted. 7- 10 mice/group are sufficient for statistical evaluation of treatment. Tumor studies are terminated when tumors reached 1 00 m 3 or became severely ulcerated.
- mice Larger numbers of mice are treated to show significant anti-tumor activity and to combine immunotherapy with immune pathway checkpoint modulators, such as anti- checkpoint inhibitor antibodies, to determine if anti-tumor activity is enhanced.
- immune pathway checkpoint modulators such as anti- checkpoint inhibitor antibodies
- PSA antibody activity is assessed from sera of mice vaccinated with Ad5 [E 1-, E2b-]- PSA/B7- 1/ICAM- 1/LFA-3.
- PSA IgG levels as determined by ELISA in mice that are vaccinated three times with Ad5 [E1 -, E2b-]-PSA/B7- l/ICAM-l/LFA-3.
- CDC Complement-dependent cellular cytotoxicity
- This example describes a clinical trial of Ad5 [E1-, E2b-]-PSA/B7-l/ICAM-l/LFA-3 as a combination therapy.
- a clinical trial employs a combination of an Ad5 [E1-, E2b-]- PSA/B7-1/ICAM-1/LFA-3 vaccine and anti-PDLl antibody for immunotherapy in prostate cancer patients.
- the phase I portion of the study determines the safety of immunization with Ad5 [E1-, E2B-]-PSA/B7- l/ICAM-l/LFA-3 in patients with prostate cancer.
- the Phase II portion of the study evaluates patient immune responses to the immunizations and the clinical feasibility of treating prostate cancer with an Ad5 [E1-, E2b-]-PSA/B7- l/ICAM-l/LFA-3 vaccine in combination with an anti-PDLl antibody.
- the study population consists of patients with a histologically confirmed diagnosis of prostate cancer that is PSA positive.
- the safety of three dosage levels of Ad5 [E1-, E2B-]- PSA/B7-1/ICAM-1/LFA-3 vaccine (phase I component), and the safety and suitability of using an Ad5 [E1-, E2B-]-PSA/B7-l/ICAM-l/LFA-3 vaccine in combination with an anti- PDLl antibody for the treatment of prostate cancer (phase II component) are determined by the study.
- the phase I study drug is Ad5 [E1-, E2B-]-PSA/B7-l/ICAM-l/LFA-3 given by subcutaneous (SC) injection every 3 weeks for 3 immunizations.
- the phase II study drug is Ad5 [E1 -, E2B-]-PSA/B7-l/ICAM-l/LFA-3 in combination with an anti-PDLl antibody given by subcutaneous (SC) injection every 3 weeks for 3 immunizations.
- Safety is evaluated in each cohort at least 3 weeks after the last patient in the previous cohort has received their first injection.
- a dosing scheme is considered safe if ⁇ 33 of patients treated at a dosage level experience DLT (e.g., 0 of 3, ⁇ 1 of 6, ⁇ 3 of 12 or ⁇ 5 of 18 patients).
- This example describes a clinical trial of Ad5 [E1 -, E2b-]-PSA/B7-l/ICAM-l/LFA-3, Ad5 [E1-, E2b-]-PSMA B7- l ICAM- l LFA-3, Ad5 [E 1-, E2b-]-MUCl/B7- l/ICAM- l LFA- 3, Ad5 [E1-, E2b-]-Brachyury/B7-l/ICAM-l/LFA-3, and an anti-PDLl antibody as a combination therapy.
- a clinical trial employs a combination of: an Ad5 [E1-, E2b-]-PSA/B7- l/ICAM-l/LFA-3 vaccine, an Ad5 [E1-, E2b-]-PSMA/B7-l/ICAM-l/LFA-3 vaccine, an Ad5 [E1-, E2b-]-MUCl/B7-l/ICAM-l LFA-3 vaccine, an Ad5 [E1-, E2b-]-Brachyury/B7- l/ICAM-l/LFA-3 vaccine, and anti-PDLl antibody for immunotherapy in advanced stage PSA-expressing prostate cancer patients.
- the phase I portion of the study determines the safety of immunization with Ad5 [E1-, E2b-]-PSA/B7-l/ICAM-l/LFA-3, an Ad5 [E1-, E2b- J-PSMA/B7-1/ICAM-1/LFA-3 vaccine, an Ad5 [E1-, E2b-]-MUCl/B7-l/ICAM-l/LFA-3, an Ad5 [E1-, E2b-]-Brachyury/B7-l/ICAM-l/LFA-3 vaccines in patients with prostate cancer.
- the Phase II portion of the study evaluates patient immune responses to the immunizations and the clinical feasibility of treating prostate cancer with Ad5 [E1-, E2b-]-PSA/B7-l/ICAM- l/LFA-3, an Ad5 [E1-, E2b-]-PSMA/B7-l/ICAM-l/LFA-3 vaccine, an Ad5 [E1-, E2b-]- MUC1/B7-1/ICAM-1/LFA-3, an Ad5 [E1-, E2b-]-Brachyury/B7-l/ICAM-l/LFA-3 vaccines in combination with an anti-PDLl antibody.
- the study population consists of patients with a histologically confirmed diagnosis of prostate cancer that is PSA positive.
- the phase I study drug is a combination of Ad5 [E1-, E2b-]-PSA/B7-l/ICAM-l/LFA- 3, an Ad5 [E1-, E2b-]-PSMA/B7-l/ICAM-l/LFA-3 vaccine, an Ad5 [E1-, E2b-]-MUCl/B7- l/ICAM-l/LFA-3, an Ad5 [E1-, E2b-]-Brachyury/B7-l/ICAM-l/LFA-3 vaccines given by subcutaneous (SC) injection every 3 weeks for 3 immunizations.
- SC subcutaneous
- the phase II study drug is Ad5 [E1-, E2b-]-PSA/B7-l/ICAM-l/LFA-3, an Ad5 [E1-, E2b-]-PSMA/B7-l/ICAM-l/LFA- 3 vaccine , an Ad5 [E1-, E2b-]-MUCl/B7-l/ICAM-l/LFA-3, an Ad5 [E1-, E2b-]- Brachyury/B7-l/ICAM-l/LFA-3 vaccines in combination with an anti-PDLl antibody given by subcutaneous (SC) injection every 3 weeks for 3 immunizations.
- SC subcutaneous
- This example describes treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5x10' 1 virus particles (VPs) subcutaneously.
- Vaccines are administered a total of 3-times and each vaccination is separated by a 3 week interval. Thereafter, a booster injection is given every two months (bi-monthly).
- the subject is any animal, for example a mammal, such as a mouse, human, or non-human primate.
- the cellular and humoral responses are initiated against the PSA-expressing or PSMA expressing cancer and the cancer is eliminated.
- This example describes combination treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5xl0" virus particles (VPs) subcutaneously in combination with a costimulatory molecule.
- VPs virus particles
- Vaccines are administered a total of 3 times and each vaccination is separated by a 3 week interval. Thereafter, bi-monthly booster injections are administered.
- the co-stimulatory molecule is B7-1, ICAM- 1 , or LFA-3.
- the subject is any animal, for example a mammal, such as a mouse, human, or non-human primate.
- a mammal such as a mouse, human, or non-human primate.
- the vaccine and co- stimulatory molecule Upon administration of the vaccine and co- stimulatory molecule, the cellular and humoral responses are initiated against the PSA- expressing or PSMA-expressing cancer and the cancer is eliminated.
- This example describes treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA and/or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5x10" virus particles (VPs) subcutaneously in combination with a checkpoint inhibitor.
- VPs virus particles
- Vaccines are administered a total of 3 times and each vaccination is separated by a 3-week interval. Thereafter, bi-monthly booster injections are administered.
- the checkpoint inhibitor is an anti-PDLl antibody, such as Avelumab. Avelumab is dosed and administered as per package insert labeling at 10 mg/kg.
- the subject is any animal, for example a mammal, such as a mouse, human, or non-human primate.
- a mammal such as a mouse, human, or non-human primate.
- the vaccine and the checkpoint inhibitor Upon administration of the vaccine and the checkpoint inhibitor, the cellular and humoral responses are initiated against the PSA- expressing or PSMA-expressing cancer and the cancer is eliminated.
- This example describes combination treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA and/or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5x10" virus particles (VPs) subcutaneously in combination with a costimulatory molecule.
- VPs virus particles
- Vaccines are administered a total of 3 times and each vaccination is separated by a 3-week interval. Thereafter, bi-monthly booster injections are administered.
- Subjects are additionally administered engineered NK cells, specifically activated NK cells (aNK cells).
- aNK cells are infused on days -2, 12, 26, and 40 at a dose of 2 x 10 9 cells per treatment.
- Subjects in need thereof have CEA-expressing cancer cells, such as colorectal cancer.
- Subjects are any mammal, such as a human or a non-human primate.
- This example describes combination treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA and/or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5xl0" virus particles (VPs) subcutaneously in combination with a costimulatory molecule.
- VPs virus particles
- Vaccines are administered a total of 3 times and each vaccination is separated by a 3-week interval. Thereafter, bi-monthly booster injections are administered.
- Subjects are also administered a super-agonist/super-agonist complex, such as ALT-803, at a dose of 10 Mg/kg SC on weeks 1 , 2, 4, 5, 7, and 8, respectively.
- Subjects in need thereof have CEA-expressing cancer cells, such as colorectal cancer.
- Subjects are any mammal, such as a human or a non- human animal.
- This example describes combination treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA and/or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5xl0" virus particles (VPs) subcutaneously in combination with a costimulatory molecule.
- VPs virus particles
- Vaccines are administered a total of 3 times and each vaccination is separated by a 3-week interval. Thereafter, bi-monthly booster injections are administered.
- Subjects are also administered low dose chemotherapy.
- the chemotherapy is cyclophosphamide.
- the chemotherapy is administered at a dose that is lower than the clinical standard of care dosing.
- the chemotherapy is administered at 50 mg twice a day (BID) on days 1-5 and 8-12 every 2 weeks for a total of 8 weeks.
- Subjects in need thereof have CEA-expressing cancer cells, such as colorectal cancer.
- Subjects are any mammal, such as a human or a non-human animal.
- This example describes combination treatment of cancer, including a PSA-expressing and/or PSMA-expressing cancer, in a subject in need thereof.
- Ad5 [E1-, E2b-] vectors encoding for PSA and/or PSMA are administered to a subject in need thereof at a dose of lxlO 9 - 5x10" virus particles (VPs) subcutaneously in combination with a costimulatory molecule.
- VPs virus particles
- Vaccines are administered a total of 3 times and each vaccination is separated by a 3-week interval. Thereafter, bi-monthly booster injections are administered.
- Subjects are also administered low dose radiation.
- the low dose radiation is administered at a dose that is lower than the clinical standard of care dosing.
- Concurrent sterotactic body radiotherapy (SBRT) at 8 Gy is given on day 8, 22, 36, 50 (every 2 weeks for 4 doses). Radiation is administered to all feasible tumor sites using SBRT.
- Subjects in need thereof have CEA-expressing cancer cells, such as colorectal cancer.
- Subjects are any mammal, such as a human or a non-human animal.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Gynecology & Obstetrics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Pregnancy & Childbirth (AREA)
- Reproductive Health (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Gastroenterology & Hepatology (AREA)
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201780046603.7A CN110114086A (en) | 2016-06-03 | 2017-06-02 | For using the composition and method of prostate cancer related antigen tumor vaccination |
KR1020187037612A KR20190034503A (en) | 2016-06-03 | 2017-06-02 | Composition and method for tumor vaccination using prostate cancer-associated antigen |
JP2018563446A JP6983819B2 (en) | 2016-06-03 | 2017-06-02 | Compositions and Methods for Tumor Vaccination Using Prostate Cancer-Related Antigens |
MX2018014898A MX2018014898A (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens. |
EP17807571.9A EP3463450A4 (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
US16/306,097 US20190125852A1 (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
CA3026342A CA3026342A1 (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
SG11201810631SA SG11201810631SA (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
AU2017274540A AU2017274540B2 (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
IL263383A IL263383A (en) | 2016-06-03 | 2018-11-29 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662345582P | 2016-06-03 | 2016-06-03 | |
US62/345,582 | 2016-06-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017210562A1 true WO2017210562A1 (en) | 2017-12-07 |
Family
ID=60477952
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2017/035694 WO2017210562A1 (en) | 2016-06-03 | 2017-06-02 | Compositions and methods for tumor vaccination using prostate cancer-associated antigens |
Country Status (12)
Country | Link |
---|---|
US (1) | US20190125852A1 (en) |
EP (1) | EP3463450A4 (en) |
JP (2) | JP6983819B2 (en) |
KR (1) | KR20190034503A (en) |
CN (1) | CN110114086A (en) |
AU (1) | AU2017274540B2 (en) |
CA (1) | CA3026342A1 (en) |
IL (1) | IL263383A (en) |
MX (1) | MX2018014898A (en) |
SG (1) | SG11201810631SA (en) |
TW (1) | TWI731095B (en) |
WO (1) | WO2017210562A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018223103A1 (en) * | 2017-06-02 | 2018-12-06 | Etubics Corporation | Compositions and methods for tumor vaccination and immunotherapy involving her antigens |
US10676516B2 (en) | 2017-05-24 | 2020-06-09 | Pandion Therapeutics, Inc. | Targeted immunotolerance |
US10946068B2 (en) | 2017-12-06 | 2021-03-16 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US10961310B2 (en) | 2017-03-15 | 2021-03-30 | Pandion Operations, Inc. | Targeted immunotolerance |
US11091526B2 (en) | 2017-12-06 | 2021-08-17 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
WO2021209897A1 (en) * | 2020-04-13 | 2021-10-21 | Janssen Biotech, Inc. | Psma and steap1 vaccines and their uses |
US11739146B2 (en) | 2019-05-20 | 2023-08-29 | Pandion Operations, Inc. | MAdCAM targeted immunotolerance |
US11981715B2 (en) | 2020-02-21 | 2024-05-14 | Pandion Operations, Inc. | Tissue targeted immunotolerance with a CD39 effector |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW202345890A (en) * | 2018-04-23 | 2023-12-01 | 美商南特細胞公司 | Neoepitope vaccine and immune stimulant combinations and methods |
US11564980B2 (en) | 2018-04-23 | 2023-01-31 | Nantcell, Inc. | Tumor treatment method with an individualized peptide vaccine |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050261213A1 (en) * | 2001-10-10 | 2005-11-24 | Patrick Branigan | Nucleic acid compositions and methods for use |
US20140004135A1 (en) * | 2011-03-17 | 2014-01-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Yeast-brachyury immunotherapeutic compositions |
WO2015024664A1 (en) * | 2013-08-21 | 2015-02-26 | Curevac Gmbh | Composition and vaccine for treating prostate cancer |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150037297A1 (en) * | 1999-08-30 | 2015-02-05 | David S Terman | Sickled Erythrocytes and Progenitors Target Cytotoxics to Tumors |
WO2002040059A2 (en) * | 2000-11-01 | 2002-05-23 | American Foundation For Biological Research, Inc. | Methods and compositions for inducing cell-mediated immune responses |
EP2125868B1 (en) * | 2007-02-28 | 2015-06-10 | The Govt. Of U.S.A. As Represented By The Secretary Of The Department Of Health And Human Services | Brachyury polypeptides and methods for use |
EP3061462B1 (en) * | 2007-07-02 | 2019-02-27 | Etubics Corporation | Methods and compositions for producing an adenovirus vector for use with multiple vaccinations |
NZ601827A (en) * | 2007-10-18 | 2014-01-31 | Bavarian Nordic Inc | Use of mva to treat prostate cancer |
US8927692B2 (en) * | 2010-11-12 | 2015-01-06 | The Trustees Of The University Of Pennsylvania | Consensus prostate antigens, nucleic acid molecule encoding the same and vaccine and uses comprising the same |
NZ703411A (en) * | 2012-06-27 | 2017-09-29 | Berg Llc | Use of markers in the diagnosis and treatment of prostate cancer |
KR102196884B1 (en) * | 2013-11-01 | 2020-12-30 | 화이자 인코포레이티드 | Vectors for expression of prostate-associated antigens |
-
2017
- 2017-06-02 KR KR1020187037612A patent/KR20190034503A/en not_active IP Right Cessation
- 2017-06-02 SG SG11201810631SA patent/SG11201810631SA/en unknown
- 2017-06-02 EP EP17807571.9A patent/EP3463450A4/en not_active Withdrawn
- 2017-06-02 US US16/306,097 patent/US20190125852A1/en not_active Abandoned
- 2017-06-02 CA CA3026342A patent/CA3026342A1/en not_active Abandoned
- 2017-06-02 CN CN201780046603.7A patent/CN110114086A/en active Pending
- 2017-06-02 MX MX2018014898A patent/MX2018014898A/en unknown
- 2017-06-02 TW TW106118357A patent/TWI731095B/en not_active IP Right Cessation
- 2017-06-02 WO PCT/US2017/035694 patent/WO2017210562A1/en unknown
- 2017-06-02 JP JP2018563446A patent/JP6983819B2/en active Active
- 2017-06-02 AU AU2017274540A patent/AU2017274540B2/en not_active Ceased
-
2018
- 2018-11-29 IL IL263383A patent/IL263383A/en unknown
-
2021
- 2021-09-15 JP JP2021150043A patent/JP2022003050A/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050261213A1 (en) * | 2001-10-10 | 2005-11-24 | Patrick Branigan | Nucleic acid compositions and methods for use |
US20140004135A1 (en) * | 2011-03-17 | 2014-01-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Yeast-brachyury immunotherapeutic compositions |
WO2015024664A1 (en) * | 2013-08-21 | 2015-02-26 | Curevac Gmbh | Composition and vaccine for treating prostate cancer |
Non-Patent Citations (1)
Title |
---|
See also references of EP3463450A4 * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10961310B2 (en) | 2017-03-15 | 2021-03-30 | Pandion Operations, Inc. | Targeted immunotolerance |
US10676516B2 (en) | 2017-05-24 | 2020-06-09 | Pandion Therapeutics, Inc. | Targeted immunotolerance |
US11466068B2 (en) | 2017-05-24 | 2022-10-11 | Pandion Operations, Inc. | Targeted immunotolerance |
US11116827B2 (en) | 2017-06-02 | 2021-09-14 | Etubics Corporation | Compositions and methods for tumor vaccination and immunotherapy involving HER antigens |
AU2018275147B2 (en) * | 2017-06-02 | 2021-01-28 | Etubics Corporation | Compositions and methods for tumor vaccination and immunotherapy involving HER antigens |
WO2018223103A1 (en) * | 2017-06-02 | 2018-12-06 | Etubics Corporation | Compositions and methods for tumor vaccination and immunotherapy involving her antigens |
US10946068B2 (en) | 2017-12-06 | 2021-03-16 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US11091527B2 (en) | 2017-12-06 | 2021-08-17 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US11091526B2 (en) | 2017-12-06 | 2021-08-17 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US11779632B2 (en) | 2017-12-06 | 2023-10-10 | Pandion Operation, Inc. | IL-2 muteins and uses thereof |
US11945852B2 (en) | 2017-12-06 | 2024-04-02 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US11965008B2 (en) | 2017-12-06 | 2024-04-23 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
US11739146B2 (en) | 2019-05-20 | 2023-08-29 | Pandion Operations, Inc. | MAdCAM targeted immunotolerance |
US11981715B2 (en) | 2020-02-21 | 2024-05-14 | Pandion Operations, Inc. | Tissue targeted immunotolerance with a CD39 effector |
WO2021209897A1 (en) * | 2020-04-13 | 2021-10-21 | Janssen Biotech, Inc. | Psma and steap1 vaccines and their uses |
Also Published As
Publication number | Publication date |
---|---|
TW201805012A (en) | 2018-02-16 |
IL263383A (en) | 2018-12-31 |
CA3026342A1 (en) | 2017-12-07 |
EP3463450A4 (en) | 2020-07-29 |
TWI731095B (en) | 2021-06-21 |
KR20190034503A (en) | 2019-04-02 |
MX2018014898A (en) | 2019-06-06 |
JP2019517521A (en) | 2019-06-24 |
US20190125852A1 (en) | 2019-05-02 |
SG11201810631SA (en) | 2018-12-28 |
JP2022003050A (en) | 2022-01-11 |
CN110114086A (en) | 2019-08-09 |
AU2017274540A1 (en) | 2019-01-03 |
JP6983819B2 (en) | 2021-12-17 |
AU2017274540B2 (en) | 2020-04-16 |
EP3463450A1 (en) | 2019-04-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017274540B2 (en) | Compositions and methods for tumor vaccination using prostate cancer-associated antigens | |
US20190134174A1 (en) | Compositions and methods for tumor vaccination and immunotherapy involving her2/neu | |
JP2020169177A (en) | Neoepitope vaccine compositions and methods of use thereof | |
US20190134195A1 (en) | Compositions and methods for the treatment of human papillomavirus (hpv)-associated diseases | |
US11304998B2 (en) | Combination immunotherapies comprising IL-15 superagonists | |
CA3063747C (en) | Compositions and methods for tumor vaccination and immunotherapy involving her antigens | |
US20210046177A1 (en) | Compositions and methods for combination cancer vaccine and immunologic adjuvant therapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17807571 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3026342 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2018563446 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20187037612 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017274540 Country of ref document: AU Date of ref document: 20170602 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017807571 Country of ref document: EP Effective date: 20190103 |