WO2017186121A1 - Procédé d'amélioration de la fonction d'une cellule de réponse immunitaire - Google Patents
Procédé d'amélioration de la fonction d'une cellule de réponse immunitaire Download PDFInfo
- Publication number
- WO2017186121A1 WO2017186121A1 PCT/CN2017/082024 CN2017082024W WO2017186121A1 WO 2017186121 A1 WO2017186121 A1 WO 2017186121A1 CN 2017082024 W CN2017082024 W CN 2017082024W WO 2017186121 A1 WO2017186121 A1 WO 2017186121A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cells
- cell
- immune response
- antigen
- seq
- Prior art date
Links
- 230000028993 immune response Effects 0.000 title claims abstract description 156
- 238000000034 method Methods 0.000 title claims abstract description 72
- 239000000427 antigen Substances 0.000 claims abstract description 272
- 102000036639 antigens Human genes 0.000 claims abstract description 271
- 108091007433 antigens Proteins 0.000 claims abstract description 271
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 139
- 230000027455 binding Effects 0.000 claims abstract description 134
- 102000002227 Interferon Type I Human genes 0.000 claims abstract description 73
- 108010014726 Interferon Type I Proteins 0.000 claims abstract description 73
- 244000052769 pathogen Species 0.000 claims abstract description 29
- 210000004027 cell Anatomy 0.000 claims description 607
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 192
- 230000014509 gene expression Effects 0.000 claims description 84
- 102000005962 receptors Human genes 0.000 claims description 76
- 108020003175 receptors Proteins 0.000 claims description 76
- 108090000623 proteins and genes Proteins 0.000 claims description 67
- 239000013598 vector Substances 0.000 claims description 66
- -1 CLDN18.2 Proteins 0.000 claims description 53
- 241000700605 Viruses Species 0.000 claims description 45
- 230000000139 costimulatory effect Effects 0.000 claims description 36
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 32
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 32
- 230000001717 pathogenic effect Effects 0.000 claims description 30
- 208000015181 infectious disease Diseases 0.000 claims description 29
- 102000004169 proteins and genes Human genes 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 26
- 239000003446 ligand Substances 0.000 claims description 22
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 19
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 19
- 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 claims description 19
- 230000003834 intracellular effect Effects 0.000 claims description 18
- 210000005259 peripheral blood Anatomy 0.000 claims description 17
- 239000011886 peripheral blood Substances 0.000 claims description 17
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 claims description 16
- 102100028757 Chondroitin sulfate proteoglycan 4 Human genes 0.000 claims description 14
- 101000916489 Homo sapiens Chondroitin sulfate proteoglycan 4 Proteins 0.000 claims description 14
- 230000006044 T cell activation Effects 0.000 claims description 14
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 claims description 13
- 239000013603 viral vector Substances 0.000 claims description 13
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 claims description 12
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims description 12
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 12
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 12
- 206010017758 gastric cancer Diseases 0.000 claims description 12
- 210000002443 helper t lymphocyte Anatomy 0.000 claims description 12
- 230000006058 immune tolerance Effects 0.000 claims description 12
- 230000001965 increasing effect Effects 0.000 claims description 12
- 239000002773 nucleotide Substances 0.000 claims description 12
- 125000003729 nucleotide group Chemical group 0.000 claims description 12
- 201000011549 stomach cancer Diseases 0.000 claims description 12
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 11
- 102100022430 Melanocyte protein PMEL Human genes 0.000 claims description 11
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 11
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 11
- 241001430294 unidentified retrovirus Species 0.000 claims description 11
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 10
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 10
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 10
- 230000001177 retroviral effect Effects 0.000 claims description 10
- 241000701022 Cytomegalovirus Species 0.000 claims description 9
- 230000000638 stimulation Effects 0.000 claims description 9
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 8
- 102100027207 CD27 antigen Human genes 0.000 claims description 8
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 8
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 8
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 8
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 8
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 8
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 8
- 102100034256 Mucin-1 Human genes 0.000 claims description 8
- 101800001271 Surface protein Proteins 0.000 claims description 8
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 201000007270 liver cancer Diseases 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 210000000822 natural killer cell Anatomy 0.000 claims description 8
- 244000045947 parasite Species 0.000 claims description 8
- 101150047061 tag-72 gene Proteins 0.000 claims description 8
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims description 7
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 7
- 102100037362 Fibronectin Human genes 0.000 claims description 7
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 7
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 7
- 108060008724 Tyrosinase Proteins 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 6
- 102100038078 CD276 antigen Human genes 0.000 claims description 6
- 101710185679 CD276 antigen Proteins 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
- 108010067306 Fibronectins Proteins 0.000 claims description 6
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 6
- 101000829725 Homo sapiens Phospholipid hydroperoxide glutathione peroxidase Proteins 0.000 claims description 6
- 101001056234 Homo sapiens Sperm mitochondrial-associated cysteine-rich protein Proteins 0.000 claims description 6
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 6
- 241000701044 Human gammaherpesvirus 4 Species 0.000 claims description 6
- 102000014150 Interferons Human genes 0.000 claims description 6
- 108010050904 Interferons Proteins 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
- 201000010881 cervical cancer Diseases 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 230000035899 viability Effects 0.000 claims description 6
- 101150075175 Asgr1 gene Proteins 0.000 claims description 5
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims description 5
- 108700012439 CA9 Proteins 0.000 claims description 5
- 102100025221 CD70 antigen Human genes 0.000 claims description 5
- 102100024151 Cadherin-16 Human genes 0.000 claims description 5
- 102100038449 Claudin-6 Human genes 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 108010055196 EphA2 Receptor Proteins 0.000 claims description 5
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 claims description 5
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 claims description 5
- 101000762246 Homo sapiens Cadherin-16 Proteins 0.000 claims description 5
- 101001005719 Homo sapiens Melanoma-associated antigen 3 Proteins 0.000 claims description 5
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 5
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 claims description 5
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 claims description 5
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 5
- 102100025082 Melanoma-associated antigen 3 Human genes 0.000 claims description 5
- 102000003735 Mesothelin Human genes 0.000 claims description 5
- 108090000015 Mesothelin Proteins 0.000 claims description 5
- 102100023123 Mucin-16 Human genes 0.000 claims description 5
- 108060006580 PRAME Proteins 0.000 claims description 5
- 102000036673 PRAME Human genes 0.000 claims description 5
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 claims description 5
- 102100036735 Prostate stem cell antigen Human genes 0.000 claims description 5
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 5
- 108010002687 Survivin Proteins 0.000 claims description 5
- 102100035721 Syndecan-1 Human genes 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 claims description 5
- 102000006815 folate receptor Human genes 0.000 claims description 5
- 108020005243 folate receptor Proteins 0.000 claims description 5
- 229940079322 interferon Drugs 0.000 claims description 5
- 210000000581 natural killer T-cell Anatomy 0.000 claims description 5
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 5
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 4
- 102100031323 Anthrax toxin receptor 1 Human genes 0.000 claims description 4
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 102100032912 CD44 antigen Human genes 0.000 claims description 4
- 108010058905 CD44v6 antigen Proteins 0.000 claims description 4
- 102100038083 Endosialin Human genes 0.000 claims description 4
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 4
- 101000796095 Homo sapiens Anthrax toxin receptor 1 Proteins 0.000 claims description 4
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 4
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 claims description 4
- 101000910338 Homo sapiens Carbonic anhydrase 9 Proteins 0.000 claims description 4
- 101000882898 Homo sapiens Claudin-6 Proteins 0.000 claims description 4
- 101000884275 Homo sapiens Endosialin Proteins 0.000 claims description 4
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 claims description 4
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 claims description 4
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 claims description 4
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 4
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 claims description 4
- 101001051490 Homo sapiens Neural cell adhesion molecule L1 Proteins 0.000 claims description 4
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 claims description 4
- 101001076732 Homo sapiens RNA-binding protein 27 Proteins 0.000 claims description 4
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 claims description 4
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 102000000440 Melanoma-associated antigen Human genes 0.000 claims description 4
- 108050008953 Melanoma-associated antigen Proteins 0.000 claims description 4
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 4
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 claims description 4
- 102100029527 Natural cytotoxicity triggering receptor 3 ligand 1 Human genes 0.000 claims description 4
- 101710201161 Natural cytotoxicity triggering receptor 3 ligand 1 Proteins 0.000 claims description 4
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 claims description 4
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 4
- 102100024964 Neural cell adhesion molecule L1 Human genes 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 102100025873 RNA-binding protein 27 Human genes 0.000 claims description 4
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 claims description 4
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 102100038126 Tenascin Human genes 0.000 claims description 4
- 108010008125 Tenascin Proteins 0.000 claims description 4
- 108091008605 VEGF receptors Proteins 0.000 claims description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims description 4
- 230000004186 co-expression Effects 0.000 claims description 4
- 238000002591 computed tomography Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 201000010175 gallbladder cancer Diseases 0.000 claims description 4
- 102000006495 integrins Human genes 0.000 claims description 4
- 108010044426 integrins Proteins 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 238000012737 microarray-based gene expression Methods 0.000 claims description 4
- 238000012243 multiplex automated genomic engineering Methods 0.000 claims description 4
- 230000001338 necrotic effect Effects 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 241000712461 unidentified influenza virus Species 0.000 claims description 4
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 3
- 108010074032 HLA-A2 Antigen Proteins 0.000 claims description 3
- 102000025850 HLA-A2 Antigen Human genes 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 3
- 102100022132 High affinity immunoglobulin epsilon receptor subunit gamma Human genes 0.000 claims description 2
- 108091010847 High affinity immunoglobulin epsilon receptor subunit gamma Proteins 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 210000003289 regulatory T cell Anatomy 0.000 claims description 2
- 244000000010 microbial pathogen Species 0.000 claims 4
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims 1
- 102100039094 Tyrosinase Human genes 0.000 claims 1
- 201000000050 myeloid neoplasm Diseases 0.000 claims 1
- 208000035473 Communicable disease Diseases 0.000 abstract description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 107
- 239000012634 fragment Substances 0.000 description 66
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 62
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 61
- 108700019146 Transgenes Proteins 0.000 description 49
- 210000001519 tissue Anatomy 0.000 description 43
- 150000007523 nucleic acids Chemical group 0.000 description 37
- 239000013612 plasmid Substances 0.000 description 36
- 108090000765 processed proteins & peptides Proteins 0.000 description 31
- 230000006870 function Effects 0.000 description 30
- 102000004196 processed proteins & peptides Human genes 0.000 description 30
- 238000002054 transplantation Methods 0.000 description 30
- 102000004127 Cytokines Human genes 0.000 description 29
- 108090000695 Cytokines Proteins 0.000 description 29
- 102000039446 nucleic acids Human genes 0.000 description 28
- 108020004707 nucleic acids Proteins 0.000 description 28
- 201000011510 cancer Diseases 0.000 description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 230000002147 killing effect Effects 0.000 description 27
- 229920001184 polypeptide Polymers 0.000 description 27
- 235000018102 proteins Nutrition 0.000 description 26
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 25
- 102100032530 Glypican-3 Human genes 0.000 description 24
- 238000002650 immunosuppressive therapy Methods 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 23
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 23
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 23
- 238000000338 in vitro Methods 0.000 description 23
- 230000004913 activation Effects 0.000 description 21
- 230000001939 inductive effect Effects 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 20
- 201000010099 disease Diseases 0.000 description 20
- 239000012636 effector Substances 0.000 description 20
- 238000001727 in vivo Methods 0.000 description 19
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 18
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 18
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 16
- 230000004068 intracellular signaling Effects 0.000 description 15
- 239000002609 medium Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 238000007920 subcutaneous administration Methods 0.000 description 15
- 210000004881 tumor cell Anatomy 0.000 description 14
- 230000000259 anti-tumor effect Effects 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 210000000987 immune system Anatomy 0.000 description 13
- 210000000056 organ Anatomy 0.000 description 13
- 102000040430 polynucleotide Human genes 0.000 description 13
- 108091033319 polynucleotide Proteins 0.000 description 13
- 230000003612 virological effect Effects 0.000 description 13
- 102000002673 NFATC Transcription Factors Human genes 0.000 description 12
- 108010018525 NFATC Transcription Factors Proteins 0.000 description 12
- 108091028043 Nucleic acid sequence Proteins 0.000 description 12
- 238000010276 construction Methods 0.000 description 12
- 230000002269 spontaneous effect Effects 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 210000004698 lymphocyte Anatomy 0.000 description 11
- 239000006228 supernatant Substances 0.000 description 11
- 238000001890 transfection Methods 0.000 description 11
- 102100026720 Interferon beta Human genes 0.000 description 10
- 108090000467 Interferon-beta Proteins 0.000 description 10
- 241000713666 Lentivirus Species 0.000 description 10
- 108091093126 WHP Posttrascriptional Response Element Proteins 0.000 description 10
- 230000000735 allogeneic effect Effects 0.000 description 10
- 230000003013 cytotoxicity Effects 0.000 description 10
- 231100000135 cytotoxicity Toxicity 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 230000001988 toxicity Effects 0.000 description 10
- 231100000419 toxicity Toxicity 0.000 description 10
- 238000011144 upstream manufacturing Methods 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 206010052779 Transplant rejections Diseases 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 9
- 239000002157 polynucleotide Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 230000028327 secretion Effects 0.000 description 9
- 238000012546 transfer Methods 0.000 description 9
- 241000701806 Human papillomavirus Species 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 102100025390 Integrin beta-2 Human genes 0.000 description 8
- 108010002350 Interleukin-2 Proteins 0.000 description 8
- 102000000588 Interleukin-2 Human genes 0.000 description 8
- 238000011316 allogeneic transplantation Methods 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 238000000684 flow cytometry Methods 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000011081 inoculation Methods 0.000 description 8
- 238000012163 sequencing technique Methods 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- 108010082808 4-1BB Ligand Proteins 0.000 description 7
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 7
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 231100000263 cytotoxicity test Toxicity 0.000 description 7
- 230000002708 enhancing effect Effects 0.000 description 7
- 108020001507 fusion proteins Proteins 0.000 description 7
- 102000037865 fusion proteins Human genes 0.000 description 7
- 239000003018 immunosuppressive agent Substances 0.000 description 7
- 230000008595 infiltration Effects 0.000 description 7
- 238000001764 infiltration Methods 0.000 description 7
- 230000010354 integration Effects 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 230000002285 radioactive effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 108700026220 vif Genes Proteins 0.000 description 7
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 6
- 102000053602 DNA Human genes 0.000 description 6
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 6
- 101001010819 Homo sapiens Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 6
- 238000012408 PCR amplification Methods 0.000 description 6
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 6
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 6
- 102000003425 Tyrosinase Human genes 0.000 description 6
- 238000000246 agarose gel electrophoresis Methods 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- 210000002865 immune cell Anatomy 0.000 description 6
- 208000026278 immune system disease Diseases 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 238000004806 packaging method and process Methods 0.000 description 6
- 239000013600 plasmid vector Substances 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 231100000820 toxicity test Toxicity 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- 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 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 5
- 102100035932 Cocaine- and amphetamine-regulated transcript protein Human genes 0.000 description 5
- 108091026890 Coding region Proteins 0.000 description 5
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 5
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 5
- 101000715592 Homo sapiens Cocaine- and amphetamine-regulated transcript protein Proteins 0.000 description 5
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 description 5
- 102100031413 L-dopachrome tautomerase Human genes 0.000 description 5
- 101710093778 L-dopachrome tautomerase Proteins 0.000 description 5
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 101710163270 Nuclease Proteins 0.000 description 5
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 5
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 5
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 5
- 102100038358 Prostate-specific antigen Human genes 0.000 description 5
- 108010076504 Protein Sorting Signals Proteins 0.000 description 5
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 description 5
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 5
- 101150063416 add gene Proteins 0.000 description 5
- 238000000137 annealing Methods 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000004364 calculation method Methods 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229960004397 cyclophosphamide Drugs 0.000 description 5
- 206010052015 cytokine release syndrome Diseases 0.000 description 5
- 230000001086 cytosolic effect Effects 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 238000004925 denaturation Methods 0.000 description 5
- 230000036425 denaturation Effects 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 108010089193 pattern recognition receptors Proteins 0.000 description 5
- 102000007863 pattern recognition receptors Human genes 0.000 description 5
- 238000012257 pre-denaturation Methods 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 230000004936 stimulating effect Effects 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 102000055501 telomere Human genes 0.000 description 5
- 108091035539 telomere Proteins 0.000 description 5
- 210000003411 telomere Anatomy 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 102100023635 Alpha-fetoprotein Human genes 0.000 description 4
- 108060000903 Beta-catenin Proteins 0.000 description 4
- 102000015735 Beta-catenin Human genes 0.000 description 4
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 4
- 229940045513 CTLA4 antagonist Drugs 0.000 description 4
- 102000004631 Calcineurin Human genes 0.000 description 4
- 108010042955 Calcineurin Proteins 0.000 description 4
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 101000852870 Homo sapiens Interferon alpha/beta receptor 1 Proteins 0.000 description 4
- 102100036714 Interferon alpha/beta receptor 1 Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- 108010065805 Interleukin-12 Proteins 0.000 description 4
- 102000013462 Interleukin-12 Human genes 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 238000011789 NOD SCID mouse Methods 0.000 description 4
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 4
- 108700008625 Reporter Genes Proteins 0.000 description 4
- 108091008874 T cell receptors Proteins 0.000 description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 4
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 4
- 102100037906 T-cell surface glycoprotein CD3 zeta chain Human genes 0.000 description 4
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 4
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 238000004520 electroporation Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229940124589 immunosuppressive drug Drugs 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 208000021601 lentivirus infection Diseases 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 241000701161 unidentified adenovirus Species 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 3
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 3
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 3
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 3
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 3
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 3
- 241000702421 Dependoparvovirus Species 0.000 description 3
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 description 3
- 102100039717 G antigen 1 Human genes 0.000 description 3
- 101710113436 GTPase KRas Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 description 3
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 3
- 101000886137 Homo sapiens G antigen 1 Proteins 0.000 description 3
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 3
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 3
- 101000620359 Homo sapiens Melanocyte protein PMEL Proteins 0.000 description 3
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 3
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 3
- 108010092694 L-Selectin Proteins 0.000 description 3
- 102000016551 L-selectin Human genes 0.000 description 3
- 102100033467 L-selectin Human genes 0.000 description 3
- 108010010995 MART-1 Antigen Proteins 0.000 description 3
- 101001034843 Mus musculus Interferon-induced transmembrane protein 1 Proteins 0.000 description 3
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 3
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108091027981 Response element Proteins 0.000 description 3
- 101710173693 Short transient receptor potential channel 1 Proteins 0.000 description 3
- 101710156660 T-cell surface glycoprotein CD3 zeta chain Proteins 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 238000002617 apheresis Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000003501 co-culture Methods 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 108010030074 endodeoxyribonuclease MluI Proteins 0.000 description 3
- 239000012737 fresh medium Substances 0.000 description 3
- 230000008073 immune recognition Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 230000031146 intracellular signal transduction Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000021633 leukocyte mediated immunity Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 210000004986 primary T-cell Anatomy 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
- 108010056030 retronectin Proteins 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- 210000001541 thymus gland Anatomy 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 102100030840 AT-rich interactive domain-containing protein 4B Human genes 0.000 description 2
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102100035793 CD83 antigen Human genes 0.000 description 2
- 101150108242 CDC27 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000000584 Calmodulin Human genes 0.000 description 2
- 108010041952 Calmodulin 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
- 102100025466 Carcinoembryonic antigen-related cell adhesion molecule 3 Human genes 0.000 description 2
- 102100026548 Caspase-8 Human genes 0.000 description 2
- 108090000538 Caspase-8 Proteins 0.000 description 2
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 2
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 2
- 102000009410 Chemokine receptor Human genes 0.000 description 2
- 108050000299 Chemokine receptor Proteins 0.000 description 2
- 241001327965 Clonorchis sinensis Species 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 108010062580 Concanavalin A Proteins 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 241000223935 Cryptosporidium Species 0.000 description 2
- 108010072210 Cyclophilin C Proteins 0.000 description 2
- 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 2
- 238000002965 ELISA Methods 0.000 description 2
- 101150029707 ERBB2 gene Proteins 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 description 2
- 241000239183 Filaria Species 0.000 description 2
- 102100040510 Galectin-3-binding protein Human genes 0.000 description 2
- 101710197901 Galectin-3-binding protein Proteins 0.000 description 2
- 208000034951 Genetic Translocation Diseases 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000792935 Homo sapiens AT-rich interactive domain-containing protein 4B Proteins 0.000 description 2
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 2
- 101000914337 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 3 Proteins 0.000 description 2
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 2
- 101000614481 Homo sapiens Kidney-associated antigen 1 Proteins 0.000 description 2
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 2
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 2
- 101001062222 Homo sapiens Receptor-binding cancer antigen expressed on SiSo cells Proteins 0.000 description 2
- 101000973629 Homo sapiens Ribosome quality control complex subunit NEMF Proteins 0.000 description 2
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 2
- 101000671653 Homo sapiens U3 small nucleolar RNA-associated protein 14 homolog A Proteins 0.000 description 2
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 2
- 102100029098 Hypoxanthine-guanine phosphoribosyltransferase Human genes 0.000 description 2
- 101150007193 IFNB1 gene Proteins 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010030506 Integrin alpha6beta4 Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 108090000769 Isomerases Proteins 0.000 description 2
- 102000004195 Isomerases Human genes 0.000 description 2
- 102100040442 Kidney-associated antigen 1 Human genes 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241000222722 Leishmania <genus> Species 0.000 description 2
- 102000016200 MART-1 Antigen Human genes 0.000 description 2
- 102100025136 Macrosialin Human genes 0.000 description 2
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 2
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 241001631646 Papillomaviridae Species 0.000 description 2
- 102100024968 Peptidyl-prolyl cis-trans isomerase C Human genes 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 102100029165 Receptor-binding cancer antigen expressed on SiSo cells Human genes 0.000 description 2
- 241000712907 Retroviridae Species 0.000 description 2
- 102100022213 Ribosome quality control complex subunit NEMF Human genes 0.000 description 2
- 238000011579 SCID mouse model Methods 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 2
- 101150031162 TM4SF1 gene Proteins 0.000 description 2
- 102100032802 Tetraspanin-8 Human genes 0.000 description 2
- 241000223997 Toxoplasma gondii Species 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102100034902 Transmembrane 4 L6 family member 1 Human genes 0.000 description 2
- 206010060872 Transplant failure Diseases 0.000 description 2
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 2
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 2
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 2
- 206010064390 Tumour invasion Diseases 0.000 description 2
- 102100040099 U3 small nucleolar RNA-associated protein 14 homolog A Human genes 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000005809 anti-tumor immunity Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 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 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000010804 cDNA synthesis Methods 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 230000009400 cancer invasion Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution 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
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 210000003162 effector t lymphocyte Anatomy 0.000 description 2
- 244000079386 endoparasite Species 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 230000008175 fetal development Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 238000012239 gene modification Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 230000005017 genetic modification Effects 0.000 description 2
- 235000013617 genetically modified food Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000011194 good manufacturing practice Methods 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000002955 isolation Methods 0.000 description 2
- 238000001638 lipofection Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 229940072288 prograf Drugs 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 238000003153 stable transfection Methods 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 229960001967 tacrolimus Drugs 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 239000001226 triphosphate Substances 0.000 description 2
- 235000011178 triphosphate Nutrition 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-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
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- HKWJHKSHEWVOSS-OMDJCSNQSA-N 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4-bisphosphate) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@H]1[C@H](O)[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H]1O HKWJHKSHEWVOSS-OMDJCSNQSA-N 0.000 description 1
- PCZUSAVLHNFWAD-UHFFFAOYSA-N 2-sulfanylidene-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound NP1(=S)NCCCN1 PCZUSAVLHNFWAD-UHFFFAOYSA-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
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- 101710163573 5-hydroxyisourate hydrolase Proteins 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
- 241000224422 Acanthamoeba Species 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 240000000073 Achillea millefolium Species 0.000 description 1
- 235000007754 Achillea millefolium Nutrition 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 102100021305 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 Human genes 0.000 description 1
- 241000701242 Adenoviridae Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000701386 African swine fever virus Species 0.000 description 1
- 102100040069 Aldehyde dehydrogenase 1A1 Human genes 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100032959 Alpha-actinin-4 Human genes 0.000 description 1
- 101710115256 Alpha-actinin-4 Proteins 0.000 description 1
- 102000052587 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Human genes 0.000 description 1
- 108700004606 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Proteins 0.000 description 1
- 241000498253 Ancylostoma duodenale Species 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 241000359199 Angiostrongylus costaricensis Species 0.000 description 1
- 241000244023 Anisakis Species 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 102100023003 Ankyrin repeat domain-containing protein 30A Human genes 0.000 description 1
- 102000004149 Annexin A2 Human genes 0.000 description 1
- 108090000668 Annexin A2 Proteins 0.000 description 1
- 101710145634 Antigen 1 Proteins 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 206010003011 Appendicitis Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 241000700607 Archiacanthocephala Species 0.000 description 1
- 102100024003 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 Human genes 0.000 description 1
- 241000238888 Argasidae Species 0.000 description 1
- 241000244185 Ascaris lumbricoides Species 0.000 description 1
- 241001126258 Ascaris sp. Species 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241000223840 Babesia bigemina Species 0.000 description 1
- 241001455947 Babesia divergens Species 0.000 description 1
- 241001648338 Babesia duncani Species 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 101100007857 Bacillus subtilis (strain 168) cspB gene Proteins 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 241000934146 Balamuthia mandrillaris Species 0.000 description 1
- 241001235572 Balantioides coli Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 241000244183 Baylisascaris procyonis Species 0.000 description 1
- 102100026596 Bcl-2-like protein 1 Human genes 0.000 description 1
- 241001284802 Bertiella <tapeworm> Species 0.000 description 1
- 241001284800 Bertiella studeri Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000726108 Blastocystis Species 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000008720 Bone Marrow Neoplasms Diseases 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 241000244038 Brugia malayi Species 0.000 description 1
- 241000143302 Brugia timori Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 1
- 241000257161 Calliphoridae Species 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 241001327638 Cimex lectularius Species 0.000 description 1
- 241001533384 Circovirus Species 0.000 description 1
- 108091062157 Cis-regulatory element Proteins 0.000 description 1
- 102000002029 Claudin Human genes 0.000 description 1
- 108050009302 Claudin Proteins 0.000 description 1
- 102100040835 Claudin-18 Human genes 0.000 description 1
- 108090000229 Claudin-6 Proteins 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
- 241001327942 Clonorchis Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 241000193468 Clostridium perfringens Species 0.000 description 1
- 241000202814 Cochliomyia hominivorax Species 0.000 description 1
- 102100032368 Coiled-coil domain-containing protein 110 Human genes 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 1
- 102100024342 Contactin-2 Human genes 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- 241000016605 Cyclospora cayetanensis Species 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 201000003808 Cystic echinococcosis Diseases 0.000 description 1
- 241000205707 Cystoisospora belli Species 0.000 description 1
- 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 1
- 206010050685 Cytokine storm Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010011968 Decreased immune responsiveness Diseases 0.000 description 1
- 241001218273 Demodex brevis Species 0.000 description 1
- 241000193880 Demodex folliculorum Species 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 102100040606 Dermatan-sulfate epimerase Human genes 0.000 description 1
- 101710127030 Dermatan-sulfate epimerase Proteins 0.000 description 1
- 241000202828 Dermatobia hominis Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102100030074 Dickkopf-related protein 1 Human genes 0.000 description 1
- 241000577456 Dicrocoelium dendriticum Species 0.000 description 1
- 101100216227 Dictyostelium discoideum anapc3 gene Proteins 0.000 description 1
- 241000157306 Dientamoeba fragilis Species 0.000 description 1
- 241000690786 Dioctophyme renale Species 0.000 description 1
- 241000866683 Diphyllobothrium latum Species 0.000 description 1
- 241001319090 Dracunculus medinensis Species 0.000 description 1
- 101100118093 Drosophila melanogaster eEF1alpha2 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
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 241000244170 Echinococcus granulosus Species 0.000 description 1
- 241000244163 Echinococcus multilocularis Species 0.000 description 1
- 241000244162 Echinococcus oligarthrus Species 0.000 description 1
- 241000244165 Echinococcus vogeli Species 0.000 description 1
- 241001126301 Echinostoma Species 0.000 description 1
- 241001466953 Echovirus Species 0.000 description 1
- 102100031334 Elongation factor 2 Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000498256 Enterobius Species 0.000 description 1
- 241000498255 Enterobius vermicularis Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 108010055191 EphA3 Receptor Proteins 0.000 description 1
- 102100030324 Ephrin type-A receptor 3 Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000832 Equine Encephalomyelitis Diseases 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101100137785 Escherichia coli (strain K12) proX gene Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000204939 Fasciola gigantica Species 0.000 description 1
- 241000242711 Fasciola hepatica Species 0.000 description 1
- 241001126302 Fasciolopsis buski Species 0.000 description 1
- 102100028043 Fibroblast growth factor 3 Human genes 0.000 description 1
- 108090000382 Fibroblast growth factor 6 Proteins 0.000 description 1
- 102100028075 Fibroblast growth factor 6 Human genes 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102000010451 Folate receptor alpha Human genes 0.000 description 1
- 108050001931 Folate receptor alpha Proteins 0.000 description 1
- 241000605986 Fusobacterium nucleatum Species 0.000 description 1
- 102100024165 G1/S-specific cyclin-D1 Human genes 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
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 101100226596 Gallus gallus FABP gene Proteins 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 101710088083 Glomulin Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000010956 Glypican Human genes 0.000 description 1
- 108050001154 Glypican Proteins 0.000 description 1
- 108050007237 Glypican-3 Proteins 0.000 description 1
- 241000497087 Gnathostoma hispidum Species 0.000 description 1
- 241001276383 Gnathostoma spinigerum Species 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102100028967 HLA class I histocompatibility antigen, alpha chain G Human genes 0.000 description 1
- 108010024164 HLA-G Antigens Proteins 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 241000196812 Halicephalobus gingivalis Species 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000005331 Hepatitis D Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 101001042227 Homo sapiens Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 Proteins 0.000 description 1
- 101000890570 Homo sapiens Aldehyde dehydrogenase 1A1 Proteins 0.000 description 1
- 101000757191 Homo sapiens Ankyrin repeat domain-containing protein 30A Proteins 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000765923 Homo sapiens Bcl-2-like protein 1 Proteins 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000741072 Homo sapiens Caspase-5 Proteins 0.000 description 1
- 101000749329 Homo sapiens Claudin-18 Proteins 0.000 description 1
- 101000868824 Homo sapiens Coiled-coil domain-containing protein 110 Proteins 0.000 description 1
- 101000909516 Homo sapiens Contactin-2 Proteins 0.000 description 1
- 101000864646 Homo sapiens Dickkopf-related protein 1 Proteins 0.000 description 1
- 101000954709 Homo sapiens Doublecortin domain-containing protein 2 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
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101000985516 Homo sapiens Hermansky-Pudlak syndrome 5 protein Proteins 0.000 description 1
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 description 1
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 1
- 101000852865 Homo sapiens Interferon alpha/beta receptor 2 Proteins 0.000 description 1
- 101001054334 Homo sapiens Interferon beta Proteins 0.000 description 1
- 101000971605 Homo sapiens Kita-kyushu lung cancer antigen 1 Proteins 0.000 description 1
- 101000984189 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 2 Proteins 0.000 description 1
- 101000984186 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 4 Proteins 0.000 description 1
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 description 1
- 101001014223 Homo sapiens MAPK/MAK/MRK overlapping kinase Proteins 0.000 description 1
- 101000991061 Homo sapiens MHC class I polypeptide-related sequence B Proteins 0.000 description 1
- 101001008874 Homo sapiens Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 101001134060 Homo sapiens Melanocyte-stimulating hormone receptor Proteins 0.000 description 1
- 101001057156 Homo sapiens Melanoma-associated antigen C2 Proteins 0.000 description 1
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 description 1
- 101000978949 Homo sapiens NADP-dependent malic enzyme Proteins 0.000 description 1
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein 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
- 101000877404 Homo sapiens Protein enabled homolog Proteins 0.000 description 1
- 101001000998 Homo sapiens Protein phosphatase 1 regulatory subunit 12C Proteins 0.000 description 1
- 101000842302 Homo sapiens Protein-cysteine N-palmitoyltransferase HHAT Proteins 0.000 description 1
- 101000613391 Homo sapiens Protocadherin beta-16 Proteins 0.000 description 1
- 101001109419 Homo sapiens RNA-binding protein NOB1 Proteins 0.000 description 1
- 101000620554 Homo sapiens Ras-related protein Rab-38 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
- 101000821981 Homo sapiens Sarcoma antigen 1 Proteins 0.000 description 1
- 101000665137 Homo sapiens Scm-like with four MBT domains protein 1 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
- 101100207070 Homo sapiens TNFSF8 gene Proteins 0.000 description 1
- 101000648075 Homo sapiens Trafficking protein particle complex subunit 1 Proteins 0.000 description 1
- 101000813738 Homo sapiens Transcription factor ETV6 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
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 1
- 101000597785 Homo sapiens Tumor necrosis factor receptor superfamily member 6B Proteins 0.000 description 1
- 241001207270 Human enterovirus Species 0.000 description 1
- 108010052919 Hydroxyethylthiazole kinase Proteins 0.000 description 1
- 108010027436 Hydroxymethylpyrimidine kinase Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000244166 Hymenolepis diminuta Species 0.000 description 1
- 241001464384 Hymenolepis nana Species 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108050002021 Integrator complex subunit 2 Proteins 0.000 description 1
- 101710192051 Interferon alpha-1/13 Proteins 0.000 description 1
- 102100036718 Interferon alpha/beta receptor 2 Human genes 0.000 description 1
- 102100026688 Interferon epsilon Human genes 0.000 description 1
- 101710147309 Interferon epsilon Proteins 0.000 description 1
- 102100022469 Interferon kappa Human genes 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102100020793 Interleukin-13 receptor subunit alpha-2 Human genes 0.000 description 1
- 101710112634 Interleukin-13 receptor subunit alpha-2 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 108020003285 Isocitrate lyase Proteins 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- 241000238889 Ixodidae Species 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 102100034872 Kallikrein-4 Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 102100021533 Kita-kyushu lung cancer antigen 1 Human genes 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 102100025583 Leukocyte immunoglobulin-like receptor subfamily B member 2 Human genes 0.000 description 1
- 102100025578 Leukocyte immunoglobulin-like receptor subfamily B member 4 Human genes 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 241001541122 Linguatula serrata Species 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 241000255640 Loa loa Species 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 108010091221 Lymphotoxin beta Receptor Proteins 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 102100031520 MAPK/MAK/MRK overlapping kinase Human genes 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 102100030301 MHC class I polypeptide-related sequence A Human genes 0.000 description 1
- 102100030300 MHC class I polypeptide-related sequence B Human genes 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 108010031030 Mammaglobin A Proteins 0.000 description 1
- 102000005727 Mammaglobin A Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000022705 Mansonella streptocerca Species 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 102100034216 Melanocyte-stimulating hormone receptor Human genes 0.000 description 1
- 102100027252 Melanoma-associated antigen C2 Human genes 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 241001660194 Metagonimus yokogawai Species 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 241001549582 Metorchis Species 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000700602 Moniliformis moniliformis Species 0.000 description 1
- 102100034263 Mucin-2 Human genes 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 101100207071 Mus musculus Tnfsf8 gene Proteins 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000187484 Mycobacterium gordonae Species 0.000 description 1
- 241000186363 Mycobacterium kansasii Species 0.000 description 1
- 241000187488 Mycobacterium sp. Species 0.000 description 1
- 101100276041 Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) ctpD gene Proteins 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 241000713883 Myeloproliferative sarcoma virus Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- 102000016798 Myosin Type I Human genes 0.000 description 1
- 108010028277 Myosin Type I Proteins 0.000 description 1
- 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 1
- 206010028665 Myxoedema Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 102100022913 NAD-dependent protein deacetylase sirtuin-2 Human genes 0.000 description 1
- 102100023175 NADP-dependent malic enzyme Human genes 0.000 description 1
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 description 1
- 241000224438 Naegleria fowleri Species 0.000 description 1
- 241000498270 Necator americanus Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 208000009869 Neu-Laxova syndrome Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 108091092724 Noncoding DNA Proteins 0.000 description 1
- 108010077850 Nuclear Localization Signals Proteins 0.000 description 1
- 102100031719 Nuclear transcription factor Y subunit gamma Human genes 0.000 description 1
- 102000004473 OX40 Ligand Human genes 0.000 description 1
- 108010042215 OX40 Ligand Proteins 0.000 description 1
- 241000158589 Oestroidea Species 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000243985 Onchocerca volvulus Species 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 241001324821 Opisthorchis felineus Species 0.000 description 1
- 241000242726 Opisthorchis viverrini Species 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 206010030924 Optic ischaemic neuropathy Diseases 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 102100034640 PWWP domain-containing DNA repair factor 3A Human genes 0.000 description 1
- 108050007154 PWWP domain-containing DNA repair factor 3A Proteins 0.000 description 1
- 244000236658 Paeonia lactiflora Species 0.000 description 1
- 235000008598 Paeonia lactiflora Nutrition 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001480233 Paragonimus Species 0.000 description 1
- 241000057252 Paragonimus africanus Species 0.000 description 1
- 241000551217 Paragonimus caliensis Species 0.000 description 1
- 241001446258 Paragonimus kellicotti Species 0.000 description 1
- 241000610664 Paragonimus skrjabini Species 0.000 description 1
- 241001480234 Paragonimus westermani Species 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 241000606860 Pasteurella Species 0.000 description 1
- 241000606856 Pasteurella multocida Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000517307 Pediculus humanus Species 0.000 description 1
- 241000517306 Pediculus humanus corporis Species 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 108010077519 Peptide Elongation Factor 2 Proteins 0.000 description 1
- 102000017794 Perilipin-2 Human genes 0.000 description 1
- 108010067163 Perilipin-2 Proteins 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 102100022078 Peroxiredoxin-5, mitochondrial Human genes 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 241000223801 Plasmodium knowlesi Species 0.000 description 1
- 241000223821 Plasmodium malariae Species 0.000 description 1
- 241001675579 Plasmodium ovale curtisi Species 0.000 description 1
- 241001675578 Plasmodium ovale wallikeri Species 0.000 description 1
- 241000223810 Plasmodium vivax Species 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 241000233872 Pneumocystis carinii Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- 102100036691 Proliferating cell nuclear antigen Human genes 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 101710150344 Protein Rev Proteins 0.000 description 1
- 102100035093 Protein enabled homolog Human genes 0.000 description 1
- 102100035620 Protein phosphatase 1 regulatory subunit 12C Human genes 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
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 101100084022 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) lapA gene Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000517304 Pthirus pubis Species 0.000 description 1
- 241000718000 Pulex irritans Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102100022491 RNA-binding protein NOB1 Human genes 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 102100022305 Ras-related protein Rab-38 Human genes 0.000 description 1
- 102100034089 Receptor-type tyrosine-protein phosphatase kappa 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
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 241000702247 Reoviridae Species 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 1
- 102100035844 Retrotransposon-derived protein PEG10 Human genes 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 241000293824 Rhinosporidium seeberi Species 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000224003 Sarcocystis Species 0.000 description 1
- 241001473628 Sarcocystis suihominis Species 0.000 description 1
- 102100021466 Sarcoma antigen 1 Human genes 0.000 description 1
- 241000257185 Sarcophagidae Species 0.000 description 1
- 241000509427 Sarcoptes scabiei Species 0.000 description 1
- 241000242678 Schistosoma Species 0.000 description 1
- 241000242683 Schistosoma haematobium Species 0.000 description 1
- 241000242687 Schistosoma intercalatum Species 0.000 description 1
- 241000242677 Schistosoma japonicum Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- 241001520868 Schistosoma mekongi Species 0.000 description 1
- 241001442514 Schistosomatidae Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102100038689 Scm-like with four MBT domains protein 1 Human genes 0.000 description 1
- 102100031312 Secernin-1 Human genes 0.000 description 1
- 101710186590 Secernin-1 Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 108010041216 Sirtuin 2 Proteins 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108020004459 Small interfering RNA 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
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 241000422838 Spirometra erinaceieuropaei Species 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 102100035748 Squamous cell carcinoma antigen recognized by T-cells 3 Human genes 0.000 description 1
- 101710185775 Squamous cell carcinoma antigen recognized by T-cells 3 Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000194049 Streptococcus equinus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241000193990 Streptococcus sp. 'group B' Species 0.000 description 1
- 241000244177 Strongyloides stercoralis 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
- 241000282887 Suidae Species 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 108010083312 T-Cell Antigen Receptor-CD3 Complex Proteins 0.000 description 1
- 108700019889 TEL-AML1 fusion Proteins 0.000 description 1
- 108050000808 TNF receptor-associated factor TRAF Proteins 0.000 description 1
- 102000008889 TNF receptor-associated factor TRAF Human genes 0.000 description 1
- 101150006914 TRP1 gene Proteins 0.000 description 1
- 241000356560 Taenia multiceps Species 0.000 description 1
- 241000244159 Taenia saginata Species 0.000 description 1
- 241000244157 Taenia solium Species 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 244000309734 Thelazia californiensis Species 0.000 description 1
- 241001477955 Thelazia callipaeda Species 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 241000244030 Toxocara canis Species 0.000 description 1
- 241000244020 Toxocara cati Species 0.000 description 1
- 102100025256 Trafficking protein particle complex subunit 1 Human genes 0.000 description 1
- 102100039580 Transcription factor ETV6 Human genes 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
- 241000242541 Trematoda Species 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 241000194297 Trichinella britovi Species 0.000 description 1
- 241000243776 Trichinella nativa Species 0.000 description 1
- 241000243779 Trichinella nelsoni Species 0.000 description 1
- 241000243777 Trichinella spiralis Species 0.000 description 1
- 241000031115 Trichobilharzia regenti Species 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 241001489145 Trichuris trichiura Species 0.000 description 1
- 241001638368 Trichuris vulpis Species 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 102100032100 Tumor necrosis factor ligand superfamily member 8 Human genes 0.000 description 1
- 102100022156 Tumor necrosis factor receptor superfamily member 3 Human genes 0.000 description 1
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 1
- 102100035284 Tumor necrosis factor receptor superfamily member 6B Human genes 0.000 description 1
- 241001584775 Tunga penetrans Species 0.000 description 1
- 102100027244 U4/U6.U5 tri-snRNP-associated protein 1 Human genes 0.000 description 1
- 101710155955 U4/U6.U5 tri-snRNP-associated protein 1 Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 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 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 241000061220 Werneckiella equi Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 241000244005 Wuchereria bancrofti Species 0.000 description 1
- 101100476214 Xenopus laevis runx1 gene Proteins 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- SAZUGELZHZOXHB-UHFFFAOYSA-N acecarbromal Chemical compound CCC(Br)(CC)C(=O)NC(=O)NC(C)=O SAZUGELZHZOXHB-UHFFFAOYSA-N 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 229940119059 actemra Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 108700010877 adenoviridae proteins Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 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
- 231100000360 alopecia Toxicity 0.000 description 1
- 101150066984 aml gene Proteins 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000001494 anti-thymocyte effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 1
- 239000003963 antioxidant agent 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
- 244000309743 astrovirus Species 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 208000007456 balantidiasis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 101150008667 cadA gene Proteins 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000028956 calcium-mediated signaling Effects 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 101150055766 cat gene Proteins 0.000 description 1
- 230000009028 cell transition Effects 0.000 description 1
- 229940107810 cellcept Drugs 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 239000002642 cobra venom Substances 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 108010047295 complement receptors Proteins 0.000 description 1
- 102000006834 complement receptors Human genes 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000004940 costimulation Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000010580 coupled enzyme reaction Methods 0.000 description 1
- 101150110403 cspA gene Proteins 0.000 description 1
- 101150068339 cspLA gene Proteins 0.000 description 1
- 101150037603 cst-1 gene Proteins 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 244000078703 ectoparasite Species 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 1
- 229940007078 entamoeba histolytica Drugs 0.000 description 1
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000001761 ethyl methyl cellulose Substances 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 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 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 201000007487 gallbladder carcinoma Diseases 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 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
- 238000010362 genome editing Methods 0.000 description 1
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000029570 hepatitis D virus infection Diseases 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 102000048373 human GPC3 Human genes 0.000 description 1
- 102000055277 human IL2 Human genes 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 210000000428 immunological synapse Anatomy 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 108010080375 interferon kappa Proteins 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 108010024383 kallikrein 4 Proteins 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 210000001985 kidney epithelial cell Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229940115932 legionella pneumophila Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 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 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 208000003786 myxedema Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000009701 normal cell proliferation Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229950010006 olokizumab Drugs 0.000 description 1
- 210000002747 omentum Anatomy 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940051027 pasteurella multocida Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 101150009573 phoA gene Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229940118768 plasmodium malariae Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 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
- 229920001983 poloxamer Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 108040000983 polyphosphate:AMP phosphotransferase activity proteins Proteins 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009290 primary effect Effects 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 101150079601 recA gene Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 108091008726 retinoic acid receptors α Proteins 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 229950006348 sarilumab Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000018964 sebaceous gland cancer Diseases 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method 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
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000013605 shuttle vector Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940055944 soliris Drugs 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010911 splenectomy Methods 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 201000008759 sweat gland cancer Diseases 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 210000004876 tela submucosa Anatomy 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 108010020589 trehalose-6-phosphate synthase Proteins 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940116861 trichinella britovi Drugs 0.000 description 1
- 229940096911 trichinella spiralis Drugs 0.000 description 1
- 201000002311 trypanosomiasis Diseases 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 241000724775 unclassified viruses Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 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 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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 1
- 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 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 238000003142 viral transduction method Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Images
Classifications
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464436—Cytokines
- A61K39/464438—Tumor necrosis factors [TNF], CD70
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/464404—Epidermal growth factor receptors [EGFR]
-
- 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464474—Proteoglycans, e.g. glypican, brevican or CSPG4
-
- 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
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 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
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/51—Stomach
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
Definitions
- the present invention is in the field of immunology, and more particularly, the present invention relates to a method of improving the function of immune response cells.
- Chimeric antigen receptor is an artificially recombinant receptor that usually contains the antigen recognition domain of a monoclonal antibody located in the extracellular region, a transmembrane region, and an intracellular activation signal structure of an immune response cell. Domain composition.
- CAR-T CAR-modified T-cell
- Type I interferons were discovered more than half a century ago. Type I interferons contain IFN ⁇ protein (a class of identical proteins encoded by 13 human genes from IFNA1 to IFNA13), IFN ⁇ (encoded by a single individual and mouse gene IFNB1), and other less studied interferons such as IFN ⁇ , IFN ⁇ and IFN ⁇ (2. Trinchieri, G. Type Iinterferon: friend or foe? J. Exp. Med. 207, 2053-2063 (2010). 3. Kaur, S. & Platanias, LCIFN- ⁇ -specific signaling via a unique IFNAR1 interaction .Nat.Immunol. 14, 884-885 (2013)).
- IFN ⁇ protein a class of identical proteins encoded by 13 human genes from IFNA1 to IFNA13
- IFN ⁇ encoded by a single individual and mouse gene IFNB1
- other less studied interferons such as IFN ⁇ , IFN ⁇ and IFN ⁇ (2. Trinchieri, G. Type I
- Type I interferons are produced by the activation of pattern recognition receptors (PRRs) by various types of cells. PRRs respond to viral or bacterial components as well as ectopic endogenous molecules such as cytoplasmic DNA and extracellular DNA and RNA (Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11 , 373–384 (2010)).
- Type I interferon is transmitted by the same dimer IFN ⁇ / ⁇ receptor 1 (IFNAR1), which has a particularly high affinity for IFN ⁇ , or IFNAR1-IFNAR2 heterodimer (which binds to all type I interferons) signal.
- IFNAR1 dimer IFN ⁇ / ⁇ receptor 1
- IFN-stimulated genes ISGs
- immunostimulatory effects Hervas-Stubbs, S. et al. Direct effects of type I interferons on cells of the immune system. Clin. Cancer Res .17,2619er Res.es.mmde Weerd,NAet al.Structural basis of a unique interferon- ⁇ signaling axis mediated via the receptor IFNAR1.Nat.Immunol.14,901ol.nol.is oMcNab,F., Mayer-Barber,K Sher, A., Wack, A. & O A. &, A.
- Type I interferons in infectious disease Nat. Rev. Immunol. 15, 87 nol. Immun). Studies have shown that type I interferons have anticancer effects on some tumors, probably due to their immune stimulating function. However, systemic administration of type I interferons may have immunosuppressive effects (Lotrich, FEMajor depression during interferon- ⁇ treatment: vulnerability and prevention. Dialogues Clin. Neurosci. 11 , 417-425 (2009)) with major adverse events. The most common are fatigue, anorexia, hepatotoxicity, flu-like symptoms and severe depression (Kreutzer, K., Bonnekoh, B., Franke, I., Ulrich, J. & Gollnick, H.
- the present invention overcomes the aforementioned problems and has additional advantages.
- the present invention provides an immune response cell characterized in that the cell expresses an antigen-binding receptor; and an exogenous type I interferon.
- the immune response cells of the invention comprise T cells, natural killer cells, cytotoxic T lymphocytes, natural killer T cells, DNT cells, and/or regulatory T cells.
- the antigen binding receptor is endogenous. In some embodiments, the antigen binding receptor is recombinant. In some embodiments, the antigen binding receptor is a chimeric antigen receptor. In some embodiments, the antigen-binding receptor comprises a sequence-linked extracellular antigen binding region, a transmembrane region, and an intracellular signaling region. In some embodiments, the antigen binding unit is an antibody or fragment thereof that specifically binds to the antigen. In some embodiments, the intracellular signal region can contain a known signal motif for an immunoreceptor tyrosine activation motif (ITAM).
- ITAM immunoreceptor tyrosine activation motif
- examples of the ITAM comprising a cytoplasmic signaling sequence include those derived from TCR ⁇ , FcR ⁇ , FcR ⁇ , CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD5, CD22, CD79a, CD79b, and CD66d.
- the intracellular signaling region of the antigen binding receptor comprises one or more costimulatory domains.
- the costimulatory domain is selected from one or more of those listed in Table 1.
- the costimulatory domain is selected from the group consisting of CD28, OX40, CD27, CD2, CD5, ICAM-1, LFA-1 (CD11a/CD18), 4-1BBL, MyD88, and 4-1BB Or A variety.
- the costimulatory domain is selected from the group consisting of CD28, OX40, CD27, CD2, CD5, ICAM-1, LFA-1 (CD11a/CD18), 4-1BBL, MyD88, and 4-1BB .
- the amino acid sequence of the antigen-binding receptor is SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 54; SEQ ID NO: 55; :56; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63; SEQ ID NO: 64; SEQ ID NO: 65; SEQ ID NO: 66; SEQ ID NO: 67; SEQ ID NO: 68 SEQ ID NO: 69; SEQ ID NO: 70; SEQ ID NO: 71; SEQ ID NO: 72; SEQ ID NO: 73; SEQ ID NO: 74; SEQ ID NO: 75; and SEQ ID NO: 77
- the antigen-binding receptor is encoded by a nucleotide sequence that is SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60 Or SEQ ID NO: 76 has at least 90% identity.
- the immune response cell does not comprise an exogenous co-stimulatory ligand.
- the antigen capable of being bound by the antigen-binding receptor comprises a tumor antigen or a pathogen antigen.
- the tumor antigen is selected from the group consisting of prostate specific membrane antigen (PSMA), carcinoembryonic antigen (CEA), IL13Ralpha, HER-2, CD19, NY-ESO-1, HIV-1 Gag, Lewis Y, MART -1, gp100, tyrosinase, WT-I, hTERT, mesothelin, EGFR, EGFRvIII, phosphatidylinositol 3, EphA2, HER3, EpCAM, MUC1, MUC16, CLDN18.2, folate receptor , CLDN6, CD30, CD138, ASGPR1, CDH16, GD2, 5T4, 8H9, ⁇ v ⁇ 6 integrin, B cell mature antigen (BCMA), B7-H3, B7-H6, CAIX, CA9, CD20, CD22,
- B cell mature antigen BC
- the pathogen antigen comprises a viral antigen, a bacterial antigen, a fungal antigen, or a parasite antigen.
- the pathogen is a virus.
- the viruses include cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, and influenza virus.
- the expression of the Type I interferon is constitutively expressed. In some embodiments, the expression of the type I interferon is inducible expression. In some embodiments, the type I interferon is expressed on the surface of the immune response cell. In some embodiments, the Type I interferon comprises: IFN ⁇ or IFN ⁇ .
- the present invention provides an expression construct comprising: an expression cassette of the antigen-binding receptor of the present invention; and an expression cassette of type I interferon.
- the expression of the Type I interferon is constitutively expressed.
- the expression of the type I interferon is inducible expression.
- the expression of the type I interferon is inducible expression and the expression for expressing the type I interferon is an inducible promoter.
- the inducible promoter for expression of the type I interferon is the NFAT6 promoter.
- the NFAT6 promoter comprises the nucleic acid sequence set forth in SEQ ID NO:78.
- the invention provides a vector which expresses an antigen binding receptor of the invention and/or a type I interferon.
- the viral vector is a lentiviral vector, a retroviral vector, or an adenoviral vector.
- the viral vector is a retroviral vector.
- the invention provides a method of increasing the viability of an immune response cell administered to an individual, wherein said immune response cell expresses an antigen binding receptor of the invention, and wherein said The method comprises administering to the individual the immune response cell and an effective amount of an exogenous type I interferon.
- the exogenous type I interferon is administered sequentially or simultaneously with the immune response cell expressing the antigen binding receptor.
- the exogenous type I interferon is administered to a patient simultaneously with the immune response cell by co-expression in an immune response cell.
- the invention provides the use of an immune response cell of the invention in the manufacture of a pharmaceutical composition for treating a tumor, a pathogen infection, or enhancing an individual's immune tolerance in an individual in need thereof.
- the invention also provides a method of treating a tumor or pathogen infection in an individual, or for enhancing an individual's immune tolerance, comprising administering to the individual in need thereof an immune response cell of the invention.
- the methods of the invention result in cytotoxicity T in the peripheral blood of the individual after administration of the immune response cell to the individual compared to the absence of the exogenous type I interferon
- the sum of the number of cells and helper T cells is increased by at least 50%.
- the method comprises, after about 5 days of administering the immune response cell to the individual, the sum of the number of cytotoxic T cells and helper T cells in the peripheral blood of the individual is greater than 15,000/ ⁇ L; After about 5 days of the immune response cell, the sum of the number of cytotoxic T cells and helper T cells in the peripheral blood is greater than 500 / ⁇ L; or about 5 days after administration of the immune response cells, the peripheral blood in the body The sum of the number of cytotoxic T cells and helper T cells is greater than 50/ ⁇ L.
- the tumor comprises: pancreatic cancer, liver cancer, lung cancer, gastric cancer, head and neck squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, lymphoma, gallbladder cancer, renal cancer, leukemia, bone marrow Tumor, Ovarian cancer, cervical cancer, ovarian cancer, cervical cancer or glioma.
- the pathogen comprises: a virus, a bacterium, a fungus, a protozoa or a parasite; preferably, the virus comprises: a cytomegalovirus, an Epstein-Barr virus, a human immunodeficiency virus or flu virus.
- the tumor of the individual is reduced by at least 30% after treatment by the methods of the invention, according to computed tomography measurements. In some embodiments, the tumor of the individual completely disappears after treatment by the method of the invention, according to computed tomography measurements.
- the invention provides a pharmaceutical composition comprising an immune response cell of the invention and a pharmaceutically acceptable carrier or excipient.
- the invention provides a kit comprising an immune response cell of the invention and instructions for how to administer the immune response cell to an individual.
- Figure 1 shows the structure of the recombinant lentiviral vector pRRL-EF-1 ⁇ -92-CAR (Fig. 1A) and the construction of the 92-28Z-NFAT6-IFN- ⁇ plasmid (Fig. 1B).
- Figure 2 shows the detection of PBMC positive rate of lentivirus infection.
- Figure 3 shows the detection of PBMC positive rate of lentivirus infection.
- Figure 4 is a graph showing the release of cytokines from IFN-containing and IFN-free GPC3 CAR-T cells.
- Figure 4A shows the induction of IFN- ⁇ expression by GPC3-28Z-IFN and GPC3-28Z CAR T cells. The results showed that only GPC3-28Z-IFN was incubated with Huh7 cells for IFN- ⁇ expression, indicating that GPC3-28Z-IFN was successfully induced to be expressed and secreted outside the cell after activation by the target antigen.
- Figure 4B shows the comparison of INF- ⁇ -induced expression by GPC3-28Z-IFN and GPC3-28Z CAR.
- Figure 4C shows a comparison of GPC3-28Z-IFN and GPC3-28Z CAR T cells leading to IL-2 release in vitro. The results showed that GPC3-28Z-IFN was more effective in causing cytokine release, indicating that CAR T cells containing IFN ⁇ can be activated more efficiently.
- Figure 5 shows a comparison of the induction of cytokine release by 85-28Z T cells and 85-28Z-IFN T cells in vitro in different cell lines. The results show that CAR T cells containing IFN ⁇ can be activated more efficiently.
- Figure 6 shows GPC3-28Z CAR T cells containing IFN ⁇ and GPC3 CAR T cells not containing IFN ⁇ in vitro against various cell lines (Fig. 6A: Huh7; Fig. 6B: Hep3B; Fig. 6C: PLC/PRR/5; Figure 6D: Hep G2; Figure 6E: SK-hep-1) comparison of killing efficiency.
- Figure 7 is a graph showing the killing activity of CLD18A2 CAR-T cells containing IFN and no IFN.
- FIG. 8 shows that CLD18A2 CAR-T cells containing IFN ⁇ and CLD18A2 CAR-T cells not containing IFN ⁇ were shown in the peripheral blood of mice for 5 days (Fig. 8A) for 7 days (Fig. 8B) and 10 days. (Fig. 8C) Comparison of the number of viable cells after (Fig. 8C). The results showed that the number of CLD18A2 CAR-T surviving cells containing IFN ⁇ was significantly higher than that of the CLD18A2 CAR-T cell group not containing IFN ⁇ at all time points.
- Figure 9 is a comparison of the effect of GPC3-28Z CAR T cells containing IFN ⁇ and GPC3-28Z CAR T cells not containing IFN ⁇ on tumor volume over time in a mouse tumor model (Fig. 9A) and a comparison of tumor photographs (Fig. 9) Figure 9B).
- the results showed that GPC3-28Z CAR T cells containing IFN ⁇ were able to more significantly reduce tumor volume than GPC3-28Z CAR T cells not containing IFN ⁇ and the control group.
- Figure 10 is a graph showing the effect of CLD18A2 CAR-T cells containing IFN ⁇ and CLD18A2 CAR-T cells not containing IFN ⁇ on tumor volume in a mouse model of BGC-823-A2 subcutaneous transplantation in time (Fig. 10A). And a comparison of tumor photos (Fig. 10B). The results showed that CLD18A2 CAR-T cells containing IFN ⁇ were able to more significantly reduce tumor volume than CLD18A2 CAR-T cells not containing IFN ⁇ and the control group.
- Figure 11 is a graph showing the antitumor activity of CLD18A2 CAR-T cells containing IFN and no IFN in a subcutaneous xenograft of gastric cancer PDX model. The results showed that one of the mice in the treatment group containing IFN completely resolved tumors.
- Figure 12 is a graph showing tumor infiltration comparison of GPC3 CAR-T (92-28Z) cells containing IFN and no IFN in vivo.
- 12A is a histochemical picture
- FIG. 12B is a T cell number map. The results showed that there was no infiltrating CD3+ cells in the tumor tissues of the control group, and the number of CD3+ T cells in the INF ⁇ -CAR-T treatment group was higher than that in the 28Z CART group.
- Figure 13 shows an immunohistochemical comparison of tumor infiltration of CLD18A2 CAR-T cells containing IFN and no IFN in vivo.
- the results showed that Mock T cells showed almost no T cell infiltration around the tumor tissue, and 85-28Z and 85-2-28Z CAR T cells were visible at the edge of the tumor tissue, while 85-2-28Z-IFN T cells A certain infiltration can be observed inside the tumor tissue.
- Figure 14 is a schematic representation of the structure of EGFR-CAR containing IFN and no IFN.
- Figure 15 is a graph showing the positive rate of infection of T lymphocytes infected with retroviruses in mice.
- Figure 16 is a graph showing the ability of EGFR CAR T cells containing IFN and IFN to secrete mIFN ⁇ in vitro. The results showed that mCAR-806-mIFN ⁇ was successfully activated and induced to express mIFN ⁇ after stimulation by target cells, and no expression of mIFN ⁇ was detected in the control group.
- Figure 17 is a graph showing the induction of cytokine release in vitro (Figure 17A: mIL-2; Figure 17B: mIFN- ⁇ ; Figure 17C: mTNF- ⁇ ) of EGFR CAR-T cells containing IFN and no IFN.
- Figure 18 is a comparison of in vitro toxicity tests of IFN-containing and IFN-free EGFR CAR-T cells.
- the results showed that EGFR-CAR and EGFR-CAR-IFN had potent killing effect on target-positive CT26VIII cells compared with UT cells, the difference was significant (***P ⁇ 0.001), and the percentage of killing was dose-dependent.
- untransfected UT cells had no killing effect on CT26 and CT26VIII
- EGFR-CAR and EGFR-CAR-IFN two CAR-T cells had no killing effect on target-negative CT26 cells.
- Figure 19 is a graph showing the in vivo toxicity test of EGFR CAR-T cells containing IFN and no IFN. The results showed that the tumor size of EGFR-CAR-T cells was basically the same as that of the control group, and no inhibition was observed. After EGFR-CAR-IFN cells were reinfused, tumor growth inhibition began on the 7th day. The rate was 5.9%, reaching the strongest on the 10th day, 18.5%. By the 17th day, the tumor inhibition rate could still reach 12.4%, which was significantly better than the EGFR-CAR-T cell group.
- the present inventors conducted intensive studies and found that inducing expression of type I interferon by CAR-T cells can effectively increase the antitumor activity of CAR-T cells and reduce their toxic and side effects.
- the present invention provides an immune response cell which expresses at least one receptor capable of binding an antigen (such as a tumor antigen or an antigen derived from a pathogen) and a type I interferon, and is applied to treat tumors and infections.
- an antigen such as a tumor antigen or an antigen derived from a pathogen
- activated and “activated” are used interchangeably herein and they, as well as other grammatical forms thereof, may refer to the process by which a cell transitions from a quiescent state to an active state.
- the process can include a response to a phenotypic or genetic change in the antigen, migration, and/or functional activity state.
- activation can refer to the process by which T cells are gradually activated.
- T cells may require at least two signals to be fully activated. The first signal can occur after the TCR is bound by the antigen-MHC complex, while the second signal can occur by the conjugation of costimulatory molecules (see co-stimulatory molecules listed in Table 1).
- anti-CD3 can simulate the first signal and anti-CD28 can simulate the second signal.
- engineered T cells can be activated by the expressed CAR.
- T cell activation or T cell triggering can refer to the state of a T cell that has been sufficiently stimulated to induce detectable cell proliferation, cytokine production, and/or detectable effector function.
- co-stimulatory ligand includes a molecule on an antigen presenting cell (eg, aAPC, dendritic cell, B cell, etc.) that specifically binds to an identical costimulatory molecule on a T cell, thereby providing a signal,
- the first signal provided by binding of, for example, a TCR/CD3 complex to a peptide-loaded MHC molecule, mediates a T cell response including, but not limited to, proliferation, activation, differentiation, and the like.
- Costimulatory ligands can include, but are not limited to, CD7, B7-1 (CD80), B7-2 (CD86), PD-L, PD-L2, 4-1BBL, OX40L, inducible co-stimulatory ligands (ICOS-L) , intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, HVEM, binding to Toll ligand receptor An agonist or antibody and a ligand that specifically binds to B7-H3.
- Costimulatory ligands also specifically include antibodies that specifically bind to costimulatory molecules present on T cells, such as, but not limited to, CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function.
- costimulatory molecule refers to an identical binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response of a T cell, such as, but not limited to, proliferation.
- Costimulatory molecules include, but are not limited to, MHC class I molecules, BTLA and Toll ligand receptors.
- co-stimulatory signal refers to a signal that, in combination with a first signal, such as TCR/CD3, results in T cell proliferation and/or up- or down-regulation of key molecules.
- antigen binding unit refers to an immunoglobulin molecule and an immunologically active portion of an immune molecule, ie, a molecule containing an antigen binding site that specifically binds to an antigen ("immune response").
- immunoglobulin molecules of various species including invertebrates and vertebrates. Structurally, the simplest naturally occurring antibody (eg, IgG) comprises four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds.
- Immunoglobulins represent a large family of molecules including several types of molecules, such as IgD, IgG, IgA, IgM, and IgE.
- immunoglobulin molecule includes, for example, hybrid antibodies or altered antibodies and fragments thereof. It has been shown that the antigen binding function of antibodies can be carried out by fragments of naturally occurring antibodies. These fragments are collectively referred to as "antigen combining units.” Also included in the term “antigen binding unit” is any polypeptide chain-containing molecular structure having a specific shape that conforms to an epitope and recognizes an epitope, wherein one or more non-covalent binding interactions stabilize the structure between the molecule and the epitope Complex.
- An antigen binding unit “specifically binds" to an antigen or is “immunoreactive” with an antigen if the antigen binding unit binds to the antigen with greater affinity or affinity than binding to other reference antigens, including polypeptides or other substances. ".
- antigen refers to a substance that is recognized and specifically bound by an antigen binding unit.
- Antigens can include peptides, proteins, glycoproteins, polysaccharides, and lipids, portions thereof, and combinations thereof.
- Non-limiting exemplary antigens include tumor antigens or pathogen antigens.
- Antigen can also refer to a molecule that elicits an immune response. This immune response may involve antibody production or activation of specific immunologically-competent cells, or both. Those skilled in the art will appreciate that any macromolecule, including virtually all proteins or peptides, can serve as an antigen.
- immunoglobulin may refer to a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes referred to as chimeric antigen receptors or antigen receptors. The five members included in such proteins are IgA, IgG, IgM, IgD and IgE, with IgG being the most common circulating antibody. It is the most potent immunoglobulin in agglutination, complement fixation and other antibody reactions and is important in protecting against bacteria and viruses. For example, tumor cell antigens (or “tumor antigens”) or pathogen antigens can be identified by CAR.
- tumor cell antigens or "tumor antigens”
- pathogen antigens can be identified by CAR.
- a sample eg, a cell
- administered e.g, a patient
- the autologous process differs from the allogeneic process in which the donor and recipient are different individuals.
- xenograft and other grammatical forms thereof can include any procedure in which a recipient, a donor, and a donor are different species, transplanting, implanting, or infusing a cell, tissue, or organ into a recipient. Transplantation of cells, organs and/or tissues described herein can be used for xenografting into humans.
- Xenografts include, but are not limited to, vascularized xenografts, partially vascularized xenografts, non-vascularized xenografts, xenogeneic dressings, xenogeneic Bandages and heterogeneous structures.
- allogeneic transplantation may include transplantation of cells, tissues or organs in which the recipient and donor are the same species but different individuals, implanted. Or infusion to any of the recipients. Transplantation of cells, organs and/or tissues as described herein can be used for allogeneic transplantation into humans. Allografts include, but are not limited to, vascularized allografts, partially vascularized allografts, non-vascularized allografts, allogeneic dressings, allogeneic bandages, and allogeneic structures.
- autologous transplantation and other forms of grammar thereof (eg, autologous transplantation) may include transplantation, implantation or infusion of a cell, tissue or organ into a recipient in which the recipient and donor are the same individual. Any program in . Transplantation of cells, organs and/or tissues described herein can be used for autologous transplantation into the human body. Autologous transplantation includes, but is not limited to, vascular autologous transplantation, partial vascular autologous transplantation, non-vascularized autografts, autologous dressings, autologous bandages, and autologous structures.
- chimeric antigen receptor or "CAR” as used herein refers to an engineered molecule that can be expressed by immune cells including, but not limited to, T cells. CAR is expressed in T cells and T cells can be redirected to induce specific killing of target cells by a human receptor.
- the extracellular binding domain of CAR can be derived from a murine, humanized or fully human monoclonal antibody.
- epitope and its grammatical other forms as used herein may refer to a portion of an antigen that can be recognized by an antibody, B cell, T cell, or engineered cell.
- an epitope can be a tumor epitope or a pathogen epitope recognized by a TCR. Multiple epitopes within the antigen can also be identified. Epitopes can also be mutated.
- engineered and its grammatical other forms as used herein may refer to one or more changes in a nucleic acid, such as a nucleic acid within the genome of an organism.
- engineered can refer to alterations, additions, and/or deletions of genes.
- Engineered cells can also refer to cells having genes that are added, deleted, and/or altered.
- cell or "engineered cell” and its grammatical other forms as used herein may refer to a cell of human or non-human animal origin. Engineered cells can also refer to cells that express CAR.
- transfection refers to the introduction of an exogenous nucleic acid into a eukaryotic cell. Transfection can be achieved by a variety of means known in the art, including calcium phosphate-DNA co-precipitation, DEAE-dextran mediated transfection, polyamine transduce transfection, electroporation, microinjection, Liposome fusion, lipofection, protoplast fusion, retroviral infection, and biolistics.
- stable transfection or “stable transfection” refers to the introduction and integration of exogenous nucleic acids, DNA or RNA into the genome of a transfected cell.
- stable transfectant refers to a cell that stably integrates foreign DNA into genomic DNA.
- nucleic acid molecule encoding refers to the order or sequence of deoxyribonucleotides along a deoxyribonucleic acid strand. The order of these deoxyribonucleotides determines the order of the amino acids along the polypeptide (protein) chain. Thus, the nucleic acid sequence encodes an amino acid sequence.
- the term "individual” as used herein refers to any animal, such as a mammal or marsupial. Individuals of the invention include, but are not limited to, humans, non-human primates (e.g., rhesus or other types of macaques), mice, pigs, horses, donkeys, cows, sheep, rats, and poultry of any kind.
- non-human primates e.g., rhesus or other types of macaques
- mice pigs, horses, donkeys, cows, sheep, rats, and poultry of any kind.
- peripheral blood lymphocytes and other grammatical forms thereof as used herein may refer to lymphocytes circulating in blood (eg, peripheral blood).
- Peripheral blood lymphocytes can refer to lymphocytes that are not limited to organs.
- Peripheral blood lymphocytes can comprise T cells, NK cells, B cells, or any combination thereof.
- immune response cell or “immunoreactive cell” as used herein may refer to a cell that can elicit an immune response, including but not limited to T cells, B cells, and NKT cells, their respective precursor cells, and their progeny.
- An immune response cell can also refer to a cell of the lymphoid or myeloid lineage.
- T cell and its grammatical other forms as used herein may refer to T cells of any origin.
- the T cell can be a primary T cell such as an autologous T cell or the like.
- T cells can also be human or non-human.
- T cell activation or “T cell trigger” and other grammatical forms thereof as used herein may refer to a T cell that is sufficiently stimulated to induce detectable cell proliferation, cytokine production, and/or detectable effector function. status. In some embodiments, "complete T cell activation” can be similar to triggering cytotoxicity of T cells.
- T cell activation can be measured using various assays known in the art.
- the assay can be an ELISA for measuring cytokine secretion, ELISPOT, a flow cytometry assay for measuring intracellular cytokine expression (CD107), a flow cytometry assay for measuring proliferation, and for determining target cell elimination. Cytotoxicity assay (51Cr release assay).
- the assay is typically compared to engineered cells (CAR T) using controls (non-engineered cells) to determine the relative activation of engineered cells compared to controls. Furthermore, the assay can be compared to engineered cells that are incubated or contacted with target cells that do not express the target antigen. For example, the comparison can be a comparison with CD19-CART cells incubated with target cells that do not express CD19.
- sequence and its grammatical other forms as used herein, when used in reference to a nucleotide sequence, may include DNA or RNA, and may be single-stranded or double-stranded.
- the nucleic acid sequence can be mutated.
- the nucleic acid sequence can be of any length, for example, a nucleic acid having a length of from 2 to 1,000,000 or more nucleotides (or any integer value therebetween or above), for example, from about 100 to about 10,000 nucleotides in length or from about 200 to about 500. Nucleotides.
- an effective amount refers to an amount that provides a therapeutic or prophylactic benefit.
- expression vector refers to a vector comprising a recombinant polynucleotide comprising an expression control sequence operably linked to a nucleotide sequence to be expressed.
- the expression vector contains sufficient cis-acting for expression Cis-acting elements; other elements for expression can be provided by host cells or in vitro expression systems.
- Expression vectors include those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses).
- lentivirus refers to the genus of the family Retroviridae. Retroviruses are unique in retroviruses in their ability to infect non-dividing cells; they can deliver large amounts of genetic information into the DNA of host cells, making them one of the most efficient methods of gene delivery vectors. HIV, SIV and FIV are all examples of lentiviruses. Vectors derived from lentivirus provide a means to achieve significant levels of gene transfer in vivo.
- operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleic acid sequence that results in expression of the latter.
- first nucleic acid sequence when the first nucleic acid sequence is functionally related to the second nucleic acid sequence, the first nucleic acid sequence is operably linked to the second nucleic acid sequence.
- a promoter is operably linked to a coding sequence if the promoter affects transcription or expression of the coding sequence.
- the operably linked DNA sequences are contiguous and, where necessary, ligated two protein coding regions in the same reading frame.
- promoter is defined as a DNA sequence that is recognized by the synthetic machinery or the introduced synthetic machinery required to initiate specific transcription of a polynucleotide sequence.
- vector is a composition comprising an isolated nucleic acid and which can be used to deliver an isolated nucleic acid to the interior of a cell.
- vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids and viruses.
- vector includes autonomously replicating plasmids or viruses.
- the term should also be interpreted to include non-plasmid and non-viral compounds that facilitate the transfer of nucleic acids into cells, such as polylysine compounds, liposomes, and the like.
- viral vectors include, but are not limited to, adenoviral vectors, adeno-associated viral vectors, retroviral vectors, and the like.
- sequence identity determines the percent identity by comparing two best matched sequences over a comparison window (eg, at least 20 positions), wherein portions of the polynucleotide or polypeptide sequence in the comparison window can comprise Addition or deletion (ie gap), for example 20% or less gap (eg 5 to 15%, or 10 to 12) compared to the reference sequence (which does not contain additions or deletions) for the best matched two sequences %).
- a comparison window eg, at least 20 positions
- portions of the polynucleotide or polypeptide sequence in the comparison window can comprise Addition or deletion (ie gap), for example 20% or less gap (eg 5 to 15%, or 10 to 12) compared to the reference sequence (which does not contain additions or deletions) for the best matched two sequences %).
- the percentage is usually calculated by determining the number of positions in which the same nucleic acid base or amino acid residue occurs in both sequences to produce the number of correctly matched positions, dividing the number of correctly matched positions by the total number of positions in the reference sequence ( That is, the window size), and multiply the result by 100 to produce a percentage of sequence identity.
- type I interferon as used herein includes IFN ⁇ , IFN ⁇ , and IFN- ⁇ , IFN- ⁇ , and IFN- ⁇ and the like. All type I interferons bind to specific cell surface receptors (so-called IFN-[alpha]/[beta] receptors) consisting of two strands of IFNARl and IFNAR2. In some embodiments, the term “type I stem” is used herein. "Interferon" is IFN ⁇ or IFN ⁇ . In some embodiments, the term “type I interferon” as used herein is IFN ⁇ . In some embodiments, a type I interferon as used herein includes human, mouse, or synthetic type I. Interferon.
- the term "interferon alpha” as used herein may be a polypeptide having the sequence shown in NCBI aaa52724.1 or aaa52716.1 or aaa52725.1, or the sequence has at least 85% of the sequence The identity of the polypeptide.
- the term "interferon beta” (INF- ⁇ ) as used herein may be at least 85% identical to NCBI aac41702.1 or np_002167.1 or aah96152.1p41273 or NP 001552. Protein, or a fragment thereof that has the function of a tumor necrosis factor (TNF) ligand.
- TNF tumor necrosis factor
- the element or the type I interferon applied to construct the antigen-binding receptor may be naturally occurring, such as may be isolated or purified from a mammal; or may be artificially prepared.
- recombinant elements or type I interferons can be produced according to conventional genetic engineering recombination techniques.
- the present invention may employ recombinant elements or type I interferons.
- Amino acid sequences formed by substitution, deletion or addition of one or more amino acid residues are also included in the present invention on the basis of the respective elements or type I interferon polypeptide sequences.
- Proper replacement of amino acids is a technique well known in the art that can be readily implemented and ensures that the biological activity of the resulting molecule is not altered. These techniques have taught one in the art that, in general, altering a single amino acid in a non-essential region of a polypeptide does not substantially alter biological activity.
- bioactive fragments of the respective elements or polypeptides of type I interferon can be used in the present invention.
- a biologically active fragment refers to a polypeptide which, as part of a full length polypeptide, still retains all or part of the function of the full length polypeptide.
- the biologically active fragment retains at least 50% of the activity of the full length polypeptide.
- the active fragment is capable of retaining 60%, 70%, 80%, 90%, 95%, 99%, or 100% of the activity of the full length polypeptide.
- Modified or modified polypeptides can also be used in the present invention based on the various elements or type I interferon polypeptide sequences, for example, to promote their half-life, effectiveness, metabolism, and/or efficacy of the polypeptide.
- disease refers to any alteration or disorder that impairs or interferes with the normal function of a cell, tissue or organ.
- disease includes, but is not limited to, a tumor, a pathogen infection, an autoimmune disease, a T cell dysfunction disease, or a defect in immune tolerance (eg, transplant rejection).
- tumor refers to a disease characterized by pathological hyperplasia of cells or tissues, and its subsequent migration or invasion of other tissues or organs. Tumor growth is usually uncontrolled and progressive, Does not induce or inhibit normal cell proliferation.
- a tumor can affect a variety of cells, tissues or organs including, but not limited to, selected from the group consisting of bladder, bone, brain, breast, cartilage, glial cells, esophagus, fallopian tubes, gallbladder, heart, intestine, kidney, liver, lung, lymph nodes, Nerve tissue, ovary, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testis, thymus, thyroid, trachea, urethra, ureter, urethra, uterus, vaginal organs, or tissue or corresponding cells.
- Tumors include cancers such as sarcomas, carcinomas, or plasmacytomas (malignant tumors of plasma cells).
- the tumor of the present invention may include, but is not limited to, leukemia (such as acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute granulocyte-monocytic leukemia, Acute monocytic leukemia, acute leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, polycythemia vera), lymphoma (Hodgkin's disease, non-Hodgkin's disease), primary macroglobulinemia Disease, heavy chain disease, solid tumors such as sarcoma and cancer (such as fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, endotheli
- the "tumor” includes, but is not limited to, pancreatic cancer, liver cancer, lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, lymphoma, gallbladder cancer, Kidney cancer, leukemia, multiple myeloma, ovarian cancer, cervical cancer and glioma.
- the type of tumor antigen referred to in the present invention may also be a tumor specific antigen (TSA) or a tumor associated antigen (TAA).
- TSA is unique to tumor cells and does not occur on other cells in the body.
- the TAA-associated antigen is not unique to tumor cells, but is expressed on normal cells under conditions in which the immune tolerance state to the antigen cannot be induced. Expression of the antigen on the tumor can occur under conditions that enable the immune system to respond to the antigen.
- TAA may be antigens expressed on normal cells during fetal development, or they may be antigens that are normally present at very low levels on normal cells but are expressed at higher levels on tumor cells. .
- TSA or TAA antigens include the following: differentiation antigens such as MART-1/MelanA (MART-I), gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, and tumor-specific multicenter antigens Such as MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15; overexpressed embryonic resistance Originally as CEA; overexpressed oncogenes and mutant tumor suppressor genes such as p53, Ras, HER-2/neu; unique tumor antigens caused by chromosomal translocations, such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, and MYL-RAR; and viral antigens such as Epstein Barr virus antigen EBVA and human papillomavirus (HPV) antigens E6 and E7.
- differentiation antigens such as MART-1/MelanA (MART-I), gp100 (Pmel17), ty
- the "tumor antigen” includes, but is not limited to, prostate specific membrane antigen (PSMA), carcinoembryonic antigen (CEA), IL13Ralpha, HER-2, CD19, NY-ESO-1, HIV- 1Gag, Lewis Y, MART-1, gp100, tyrosinase, WT-I, hTERT, mesothelin, EGFR, EGFRvIII, phosphatidylinositol 3, EphA2, HER3, EpCAM, MUC1, MUC16, CLDN18 .2, folate receptor, CLDN6, CD30, CD138, ASGPR1, CDH16, GD2, 5T4, 8H9, ⁇ v ⁇ 6 integrin, B cell mature antigen (BCMA), B7-H3, B7-H6, CAIX, CA9, CD20, CD22 , kappa light chain, CD33, CD38, CD44, CD44v6, CD44v7/8, CD70,
- PSMA
- pathogen refers to protozoa that are capable of causing a disease, including: viruses, bacteria, fungi or parasites.
- viral antigen refers to a polypeptide expressed by a virus capable of inducing an immune response.
- Typical viruses include, but are not limited to, retroviridae (such as human immunodeficiency virus, such as HIV-1 (also known as HDTV-III, LAVE or HTLV-III/LAV, or HIV-III; and other strains, such as HIV-LP; picornavirus (such as poliovirus, hepatitis A virus; human enterovirus, coxsackie virus, rhinovirus, echovirus); calicivirus (such as gastroenteritis caused by strain); Covering viruses (such as equine encephalitis virus, rubella virus); flaviviruses (such as dengue virus, Japanese encephalitis virus, yellow fever virus); coronavirus (such as coronavirus); rhabdovirus (such as blisters) Stomatitis virus, rabies virus); filamentous virus family (such as Ebola Virus); paramyxoviridae (such as parainfluenza virus, mumps virus, measles virus, respiratory syncytial virus); Orthomyxovirus (
- Typical bacteria include, but are not limited to, Pasteurella, Staphylococcus aureus, Streptococcus, Escherichia coli, Salmonella, and Pseudomonas aeruginosa.
- infectious bacteria include, but are not limited to, Helicobacter pylori, spirochetes, Legionella pneumophila, Mycobacterium sp. (S. tuberculosis, Mycobacterium tuberculosis, Mycobacterium tuberculosis, M. Kansaii, M.
- an immune response cell of the invention is capable of recognizing and binding to a parasite antigen.
- the parasites include endoparasites and ectoparasites.
- the endoparasites include protozoa, helminths, mites, and flukes.
- the parasitic antigen is, for example, an antigen derived from a species of the following family: Entamoeba histolytica; Babesia B.divergens, B.bigemina, B.equi, B.microfti, B.duncani; Balantidium coli;Blastocystis Spp.;Trypanosoma cruzi;Cryptosporidium spp.;Cyclospora cayetanensis;Dientamoeba fragilis;Giardia lamblia;Balamuthia mandrillaris;Acanthamoeba spp.;Isospora belli;Leishmania spp.;Plasmodium falciparum,Plasmodium vivax,Plasmodium ovale curtisi,Plasmodium ovale wallikeri,Plasmodium malariae, Plasmodium knowlesi; Naegleria
- autoimmune disease as used herein is defined as a condition caused by an autoimmune response.
- Autoimmune diseases are the result of inappropriate and overreaction to autoantigens.
- autoimmune diseases include, but are not limited to, appendicitis, alopecia, ankylosing spondylitis, autoimmune hepatitis, autoimmune mumps, Crohn's disease, diabetes (type I), malnourished bullous epidermis Disorder, epididymitis, glomerulonephritis, Graves' disease, Gilanbar syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris , psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathy, thyroiditis, vasculitis, viti
- Tolerance or "immune tolerance” is the failure of the immune system to produce a defensive immune response to a particular antigen. Tolerance can be natural or self-independent, in which the body does not attack its own proteins and antigens, or can be induced by manipulation of the immune system. Central tolerance occurs during lymphocyte development and plays a role in the thymus and bone marrow. During this process, T lymphocytes and B lymphocytes that recognize autoantigens are deleted before they develop into fully immunocompetent cells. This process is most active during fetal development, but lasts for the rest of the life as immature lymphocytes are produced.
- Peripheral T cell tolerance refers to the functional anergy of autoantigens present in peripheral tissues and occurs after T and B cells mature and enter the periphery. These processes include the inhibition of autoreactive cells by "regulatory" T cells, and the generation of hyporeactivity (non-reactivity) in lymphocytes that encounter antigen without co-stimulatory signals accompanying inflammation. "Acquired” or “induced tolerance” refers to the adaptation of the immune system to external antigens, characterized by specific non-reactivity of lymphoid tissue with a given antigen, and in other cases may induce cell-mediated or humoral immunity. .
- tolerance can be clinically induced by repeated administration of very large doses of antigen or a small dose below the threshold required to stimulate an immune response (eg, by intravenous or sublingual administration of soluble antigen).
- the antigen that induces the formation of immune tolerance is called Tolerogen. Immunosuppression is also beneficial for inducing tolerance. Destruction of self-tolerance can lead to autoimmunity.
- the second case is when the tolerant state has been induced, either prior to exposure to the donor's antigen in a manner that results in immune tolerance rather than sensitization to the recipient, or after chronic rejection.
- Successful allogeneic transplantation requires a degree of immune tolerance to allogeneic antigens.
- the achievement of immune tolerance prevents host-versus graft response leading to transplant rejection and failure, and prevents graft versus host response (GVHD).
- enhancing immune response cell function includes, for example, enhancing T cell function.
- enhancing T cell function involves inducing, causing or stimulating T cells to have sustained or enhanced biological function, or to renew or reactivate depleted or inactive T cells.
- enhanced T cell function include increased levels of interferon secreted by CD8+ T cells, increased proliferation, and increased antigenic reactivity (eg, viral or pathogen clearance) relative to pre-intervention levels.
- the level of enhancement is at least 50%, or 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner in which such enhancement is measured is known to those of ordinary skill in the art.
- T cell dysfunctional disease includes a condition or disorder of a T cell characterized by a decrease in antigenic stimulatory reactivity.
- the T cell dysfunctional disorder is a disorder associated with inappropriately increased signaling specificity by PD-1.
- the T cell dysfunction disease is a disease in which T cells are incapable or secrete cytokines, proliferate, or have reduced ability to perform cytolytic activity. Examples of T cell dysfunction diseases characterized by T cell dysfunction include unabsorbed acute infection, chronic infection, and tumor immunity.
- exogenous refers to a nucleic acid molecule or polypeptide that is not endogenously expressed in a cell, or that has a level of expression insufficient to achieve overexpression.
- exogenous includes recombinant nucleic acid molecules or polypeptides expressed in a cell, such as exogenous, heterologous and overexpressed nucleic acid molecules and polypeptides.
- receptor refers to a polypeptide, or a portion thereof, that selectively binds one or more ligands on a cell membrane.
- an antigen binding receptor of the invention specifically binds to an antigen to which it binds.
- the antigen binding receptor of the invention is a chimeric antigen receptor.
- Chimeric Antigen Receptor refers to a tumor antigen binding domain fused to an intracellular signal transduction domain that activates T cells.
- the extracellular binding domain of CAR is derived from a mouse or humanized or human monoclonal antibody.
- a chimeric antigen receptor typically comprises an extracellular antigen binding region or antigen binding unit.
- the extracellular antigen binding region can be fully human. In other cases, the extracellular antigen binding region can be humanized. In other instances, the extracellular antigen binding region can be murine or the chimera in the extracellular antigen binding region consists of amino acid sequences from at least two different animals. In some embodiments, the extracellular antigen binding region can be non-human.
- antigen binding regions can be designed. Non-limiting examples include single-chain variable fragments (scFv) derived from antibodies, fragment antigen binding regions (Fabs) selected from libraries, single domain fragments, or natural ligands that bind to their cognate receptors.
- the extracellular antigen binding region can comprise an scFv, Fab, or natural ligand, as well as any derivatives thereof.
- An extracellular antigen binding region can refer to a molecule other than an intact antibody, which can comprise a portion of an intact antibody and can bind to an antigen to which the intact antibody binds.
- antibody fragments can include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') 2 ; bifunctional antibodies, linear antibodies; single-chain antibody molecules (eg, scFv); and formed from antibody fragments Multispecific antibodies.
- An extracellular antigen binding region such as a scFv, Fab or natural ligand, can be part of a CAR that determines antigen specificity.
- the extracellular antigen binding region can bind to any complementary target.
- Extracellular antigen binding regions can be derived from known An antibody to the variable region sequence.
- the extracellular antigen binding region can be obtained from antibody sequences obtained from available mouse hybridomas.
- extracellular antigen binding regions can be obtained from whole-out cleavage of tumor cells or primary cells, such as tumor infiltrating lymphocytes (TIL).
- TIL tumor infiltrating lymphocytes
- the binding specificity of the extracellular antigen binding region can be determined by a complementarity determining region or CDR, such as a light chain CDR or a heavy chain CDR.
- CDR complementarity determining region
- binding specificity can be determined by light chain CDRs and heavy chain CDRs.
- a given combination of heavy chain CDRs and light chain CDRs can provide a given binding pocket that can confer greater affinity and/or specificity to an antigen (eg, GPC3) than other reference antigens.
- an antigen eg, GPC3
- a CDR specific for Glypican-3 can be expressed in an extracellular binding region of a CAR such that a GPC3-targeting CAR can target an immune response cell to a GPC3-expressing tumor cell.
- the extracellular antigen binding region can comprise a light chain CDR specific for the antigen.
- the light chain CDR can be a complementarity determining region of an antigen binding unit, such as the scFv light chain of a CAR.
- the light chain CDRs may comprise contiguous amino acid residue sequences, or two or more contiguous sequence of amino acid residues separated by non-complementarity determining regions (eg, framework regions).
- a light chain CDR can comprise two or more light chain CDRs, which can be referred to as a light chain CDR-1, CDR-2, and the like.
- the light chain CDRs can comprise three light chain CDRs, which can be referred to as light chain CDR-1, light chain CDR-2 and light chain CDR-3, respectively.
- a set of CDRs present on a common light chain can be collectively referred to as a light chain CDR.
- the extracellular antigen binding region can comprise a heavy chain CDR that is specific for the antigen.
- the heavy chain CDRs can be heavy chain complementarity determining regions of antigen binding units such as scFv.
- the heavy chain CDRs may comprise a contiguous sequence of amino acid residues, or a contiguous sequence of two or more amino acid residues separated by a non-complementarity determining region (eg, a framework region).
- the heavy chain CDRs can comprise two or more heavy chain CDRs, which can be referred to as heavy chain CDR-1, CDR-2, and the like.
- the heavy chain CDRs can comprise three heavy chain CDRs, which can be referred to as heavy chain CDR-1, heavy chain CDR-2 and heavy chain CDR-3, respectively.
- a set of CDRs present on a common heavy chain can be collectively referred to as a heavy chain CDR.
- the extracellular antigen binding region can be modified in various ways by using genetic engineering.
- the extracellular antigen binding region can be mutated such that the extracellular antigen binding region can be selected to have a higher affinity for its target.
- the affinity of the extracellular antigen binding region for its target can be optimized for targets that can be expressed at low levels on normal tissues. This optimization can be done to minimize potential toxicity.
- a clone of an extracellular antigen binding region having a higher affinity for the membrane-bound form of the target may be A counterpart that is superior to its soluble form. This modification can be made because different levels of soluble forms of the target can also be detected and their targeting can cause undesirable toxicity.
- the extracellular antigen binding region comprises a hinge or spacer.
- the terms hinge and spacer are used interchangeably.
- the hinge can be considered as part of a CAR for providing flexibility to the extracellular antigen binding region.
- the hinge can be used to detect CAR on the cell surface of a cell, particularly when detecting antibodies to the extracellular antigen binding region are ineffective or available.
- the length of the hinge derived from an immunoglobulin may need to be optimized, depending on the location of the extracellular antigen binding region that targets the epitope on the target.
- the hinge may not belong to an immunoglobulin, but to another molecule, such as the native hinge of a CD8 alpha molecule.
- the CD8 alpha hinge may contain cysteine and proline residues known to play a role in the interaction of the CD8 co-receptor and the MHC molecule. The cysteine and proline residues can affect the performance of the CAR.
- the CAR hinge can be adjustable in size. This morphology of the immunological synapse between the immune response cell and the target cell also defines the distance that cannot be functionally bridged by the CAR due to the distal membrane epitope on the cell surface target molecule, ie, the use of a short hinge CAR does not The synaptic distance reaches an approximation of the signal's ability to conduct. Similarly, the membrane proximal CAR target epitope was only observed for signal output in the context of a long hinged CAR.
- the hinge can be adjusted depending on the extracellular antigen binding region used. The hinge can be of any length.
- the transmembrane domain can anchor the CAR to the plasma membrane of the cell.
- the natural transmembrane portion of CD28 can be used for CAR.
- the natural transmembrane portion of CD8 ⁇ can also be used in the CAR.
- CD8 may be a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to the NCBI reference number: NP_001759 or a fragment thereof having stimulatory activity.
- a “CD8 nucleic acid molecule” may be a polynucleotide encoding a CD8 polypeptide, and in some cases, the transmembrane region may be a natural transmembrane portion of CD28, and “CD28” may refer to NCBI reference number: NP_006130 or its stimulating activity.
- a fragment has a protein of at least 85, 90, 95, 96, 97, 98, 99 or 100% identity.
- a "CD28 nucleic acid molecule” can be a polynucleotide encoding a CD28 polypeptide.
- the transmembrane portion can comprise a CD8 alpha region.
- the (fine) intracellular signaling region of CAR may be responsible for activating at least one of the effector functions of the immune response cells into which the CAR has been placed.
- CAR can induce effector functions of T cells, for example, the effector function is cytolytic activity or helper activity, including secretion of cytokines.
- intracellular signaling region refers to a portion of a protein that transduces an effector function signal and directs the cell to perform a specific function. Although the entire intracellular signaling region can generally be used, in many cases it is not necessary to use the entire chain of the signal domain. In some embodiments, a truncated portion of an intracellular signaling region is used. In some embodiments, the term intracellular signaling region is therefore intended to include a cell sufficient to transduce an effector function signal. Any truncated portion of the inner signal conducting region.
- Preferred examples of signal domains for use in CAR may include cytoplasmic sequences of T cell receptors (TCRs) and co-receptors that act synergistically to initiate signal transduction after target-receptor binding, as well as any derivatives thereof or Variant sequences and any synthetic sequences of these sequences that have the same functionality.
- TCRs T cell receptors
- co-receptors that act synergistically to initiate signal transduction after target-receptor binding
- the intracellular signaling region can contain a known signal motif for an immunoreceptor tyrosine activation motif (ITAM).
- ITAMs containing cytoplasmic signaling sequences include those derived from TCR ⁇ , FcR ⁇ , FcR ⁇ , CD3 ⁇ , CD3 ⁇ , CD5, CD22, CD79a, CD79b, and CD66d.
- the intracellular signal domain is derived from a CD3 ⁇ chain.
- T cell signaling domain containing one or more ITAM motifs is the CD3 ⁇ domain, also known as the T cell receptor T3 ⁇ chain or CD247.
- This domain is part of the T cell receptor-CD3 complex and plays an important role in binding antigen recognition of several intracellular signal transduction pathways to the main effector activation of T cells.
- CD3 ⁇ primarily refers to human CD3 ⁇ and its isoforms, as known from the Swissprot entry P20963, including proteins having substantially the same sequence.
- the full T cell receptor T3 ⁇ chain is not required and that any derivative of the signal domain comprising the T cell receptor T3 ⁇ chain is suitable, including any functional equivalent thereof. .
- the intracellular signaling domain can be selected from any one of the domains of Table 1.
- the domain can be modified such that identity to the reference domain can range from about 50% to about 100%.
- Any of the domains of Table 1 can be modified such that the modified form can comprise about 50, 60, 70, 80, 90, 95, 96, 97, 98, 99 or up to about 100% identity.
- the intracellular signaling region of CAR may further comprise one or more costimulatory domains.
- the intracellular signaling region may comprise a single costimulatory domain, such as an ⁇ chain (first generation CAR) or it is with CD28 or 4-1BB (second generation CAR).
- the intracellular signaling region can comprise two costimulatory domains, such as CD28/OX40 or CD28/4-1BB (third generation).
- CD28 phosphatidylinositol-4,5-diphosphate 3-kinase
- 4-1BB/OX40 TNF-receptor-associated factor adapter protein
- signals generated by the CAR may be combined with an auxiliary or costimulatory signal.
- costimulatory signaling domains chimeric antigen receptor-like complexes can be designed to contain several possible costimulatory signal domains.
- a second co-stimulatory signal is required for complete productive T cell activation.
- receptors have been reported to provide co-stimulation for T cell activation including, but not limited to, CD28, OX40, CD27, CD2, CD5, ICAM-1, LFA-1 (CD11a/CD18), 4-1BBL, MyD88, and 4- 1BB.
- the signaling pathways used by these costimulatory molecules work synergistically with the primary T cell receptor activation signal.
- the signals provided by these costimulatory signaling regions can act synergistically with primary effect activation signals derived from one or more ITAM motifs (eg, the CD3zeta signal transduction domain) and can fulfill the requirements for T cell activation.
- the addition of a costimulatory domain to a chimeric antigen receptor-like complex can enhance the efficacy and durability of engineered cells.
- the T cell signal domain and the costimulatory domain are fused to each other to form a signaling region.
- the chimeric antigen receptor binds to the target antigen.
- the target antigen can be obtained or isolated from various sources.
- a target antigen as used herein is an antigenic epitope on an antigen or antigen that is critical in mammals for immune recognition and ultimately elimination or control of pathogenic factors or disease states.
- the immune recognition can be a cell and/or a body fluid. In the case of intracellular pathogens and cancer, the immune recognition can be, for example, a T lymphocyte reaction.
- the target antigen can be derived or isolated from an antigen such as a viral microorganism such as the virus described herein above.
- the chimeric antigen receptor binding of the invention includes, for example, HIV (Korber et al, eds HIV Molecular Immunology Database, Los Alamos National Laboratory, Los Alamos, N. Mex. 1977), influenza, herpes, herpes simplex Papillomavirus (U.S. Patent No. 5,719,054), Hepatitis B (US Patent No. 5,780,036), Hepatitis C (US Patent No. 5,709,995), EBV, cytomegalovirus (CMV) virus, and the like.
- HIV Korean et al, eds HIV Molecular Immunology Database, Los Alamos National Laboratory, Los Alamos, N. Mex. 1977
- influenza herpes
- herpes simplex Papillomavirus U.S. Patent No. 5,719,054
- Hepatitis B
- the target antigen can also be derived from or isolated from the pathogenic bacteria described herein.
- the chimeric antigen receptor binding of the invention is, for example, from Chlamydia (U.S. Patent No. 5,869,608), Mycobacterium, Legionella, Meningitis, Group A Streptococcus, Salmonella, Listeria, Haemophilus influenzae (U.S. Patent No. 5,955,596) and the like.
- the target antigen can be derived or isolated, for example, from Aspergillus, Invasive Candida (US Pat. No. 5,645,992), Nocardia, Histoplasmosis, Cryptosporidium And other pathogenic yeasts.
- the target antigen can be derived or isolated from, for example, pathogenic protozoa and pathogenic parasites including, but not limited to, Pneumocystis carinii, trypanosomiasis, Leishmania (U.S. Patent No. 5,965,242), Plasmodium (U.S. Patent No. 5,589,343) and Toxoplasma gondii.
- pathogenic protozoa and pathogenic parasites including, but not limited to, Pneumocystis carinii, trypanosomiasis, Leishmania (U.S. Patent No. 5,965,242), Plasmodium (U.S. Patent No. 5,589,343) and Toxoplasma gondii.
- the target antigen comprises an antigen associated with a pre-cancerous or proliferative state.
- Target antigens may also be associated with or caused by cancer.
- a chimeric antigen receptor of the invention recognizes and binds to a tumor antigen comprising TSA and TAA as described herein before.
- modulation refers to a positive or negative change. Modification examples include 1%, 2%, 10%, 25%, 50%, 75%, or 100% variation.
- treatment refers to the process of attempting to alter a disease caused by an individual or a cell.
- Clinical interventions can be either preventive or clinically pathologically.
- Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of any disease, preventing metastasis, slowing the progression of the disease, improving or ameliorating the condition, alleviating or improving the prognosis.
- immune dysfunction means that the subject has an immunodeficiency that is easily infected. Organisms that cause opportunistic infections usually do not cause illnesses that have a healthy immune system, but can infect people with weakened immune systems or suppressed immune systems.
- induced expression refers to expression under conditions such as when T cells bind to an antigen.
- T cells bind to an antigen.
- One skilled in the art how to perform conventional "induced expression”.
- the invention provides an immune response cell that expresses an antigen binding receptor and an exogenous type I interferon.
- an immune response cell of the invention can target an antigen expressed on a cancer. Its antigen or epitope can be expressed on cancer or cancer related tissues. In some cases, the target antigen may be overexpressed on cancer and have reduced or no expression on normal tissues. In some cases, cancer-specific antigens and epitopes thereof can be targeted using the immune response cells of the invention. Antigens can be derived from a wide variety of tumor antigens, such as tumor antigens produced by mutations, shared tumor-specific antigens, differentiation antigens, and antigens that are overexpressed in tumors.
- the antigens that can be targeted or bound by the immune response cells of the present invention may be or are derived from, by way of example only, including, but not limited to, folate receptor alpha, 707-AP, adipophilin, AFP, AIM-2, ALDH1A1.
- Tumor-associated antigens may be antigens that are not normally expressed by the host, which may be mutated, truncated, misfolded or otherwise abnormally expressed by the host; they may be identical to the normally expressed molecules but expressed at abnormally high levels; or they may Expressed in an abnormal environment.
- the tumor associated antigen can be, for example, a protein or protein fragment, a complex carbohydrate, a ganglioside, a hapten, a nucleic acid, other biomolecules, or any combination thereof.
- the antigen can be a neo-antigen.
- the new antigen can be derived from somatic mutations in cancer cells.
- the new antigen can be a mutant form of triphosphate isomerase (TPI).
- Mutated fibronectin (FN) is another example of a novel antigen that can be targeted by the immune response cells of the invention.
- the new antigen can be identified by a screening platform, such as biochemistry, whole-out cleavage sequencing, genetically targeted expression (GTE), or a combination thereof.
- a target that can be bound by an immune response cell of the invention may be associated with a cancer stroma.
- the cancer stroma may be associated with the tumor microenvironment.
- the antigen can be a matrix antigen.
- matrix antigens and epitopes can be present on, but not limited to, tumor endothelial cells, tumor vasculature, tumor fibroblasts, pericancetes, tumor stroma, and/or tumor mesenchymal cells.
- Those antigens may, for example, be selected from the group consisting of CD34, MCSP, FAP, CD31, PCNA, CD117, CD40, MMP4 and/or tenascin.
- Tissue expression of the antigen can be measured by immunohistochemistry (IHC) analysis and/or flow cytometry. Tissue expression can also be measured by quantitative copy number obtained by PCT (qPCR).
- the target antigen can be expressed on the surface of cancer cells.
- antigens that can be targeted may not be expressed in the context of MHC or HLA.
- the immune response cells of the invention can be targeted in a non-MHC restricted manner Cell surface antigen.
- antigens that can be targeted with CAR-T may be overexpressed as compared to expression on normal tissues.
- Overexpression can be about 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold expression on normal tissues as measured by IHC, qPCR or flow cytometry. 10, 20, 30, 40, 50, 60, 70, 80, 90 or up to 100 times.
- the antigen binding receptor comprises an antigen binding domain (extracellular binding region) and an intracellular signal domain capable of activating immune response cells.
- a transmembrane region is also included between the antigen binding domain and the intracellular signal domain (intracellular signal region).
- the extracellular binding region comprises an antibody to an antigen that is a tumor antigen or a pathogen antigen. Expression of the antigen-binding receptor on the surface of the immune response cell allows the immune response cell to have a highly specific cytotoxic effect on the tumor cell or pathogen expressing the antigen.
- the antigen-binding receptor of the present invention comprises an antibody that is a single-chain antibody that is linked to a transmembrane region, and a transmembrane region that is immediately followed by an intracellular signal region.
- an antigen binding domain of the invention is a binding domain that binds to a tumor antigen.
- the tumor antigen is a differentiation antigen selected from the group consisting of MART-1/MelanA (MART-I), gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, and tumor-specific multi-center antigen
- MART-1/MelanA MART-I
- gp100 Pmel17
- TRP-1, TRP-2 tumor-specific multi-center antigen
- MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15 overexpressed embryonic antigens such as CEA
- overexpressed oncogenes and mutant tumor suppressor genes such as p53, Ras, HER-2/neu Unique tumor antigens caused by chromosomal translocations, such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, and MYL-RAR
- viral antigens such as
- the tumor antigen is selected from the group consisting of prostate specific membrane antigen (PSMA), carcinoembryonic antigen (CEA), IL13Ralpha, HER-2, CD19, NY-ESO-1, HIV-1 Gag, Lewis Y, MART -1, gp100, tyrosinase, WT-I, hTERT, mesothelin, EGFR, EGFRvIII, phosphatidylinositol 3, EphA2, HER3, EpCAM, MUC1, MUC16, CLDN18.2, folate receptor , CLDN6, CD30, CD138, ASGPR1 CDH16, GD2, 5T4, 8H9, ⁇ v ⁇ 6 integrin, B cell mature antigen (BCMA), B7-H3, B7-H6, CAIX, CA9, CD20, CD22, kappa light chain, CD33, CD38, CD44 , CD44v6, CD44v7/8, CD70, CD123, CD17
- PSMA
- the tumor antigen is selected from the group consisting of prostate specific membrane antigen, carcinoembryonic antigen, IL13Ralpha, HER-2, CD19, NY-ESO-1, HIV-1 Gag, Lewis Y, MART-1, gp100, cheese Lysinase, WT-I, hTERT, mesothelin, EGFR, EGFRvIII, phosphatidylinositol 3, EphA2, HER3, EpCAM, MUC1, MUC16, claudin 18.2, folate receptor, claudin 6, CD30, CD138 One or more of MAGE3, ASGPR1 and CDH16.
- the transmembrane region of the antigen binding receptor can be selected from a transmembrane region of a protein such as CD8 or CD28.
- the human CD8 protein is a heterodimer composed of two chains, ⁇ or ⁇ .
- the transmembrane region is selected from the transmembrane region of CD8 alpha or CD28.
- the CD8 ⁇ hinge region is a flexible region, and therefore, CD8 or CD28 and a transmembrane region plus a hinge region are used to link the target recognition domain scFv of the antigen-binding receptor CAR to the intracellular signal region. .
- the intracellular signal domain of the invention may be selected from the group consisting of CD3 ⁇ , Fc ⁇ RI ⁇ , CD28 costimulatory signal domain, CD137 costimulatory signal domain, and combinations thereof.
- the CD3 molecule consists of five subunits, of which the CD3 ⁇ subunit (also known as CD3zeta, abbreviated as Z) contains three ITAM motifs, which are important signal transduction regions in the TCR-CD3 complex.
- CD28 and CD137 are costimulatory signaling molecules, and the costimulation of their intracellular signal segments after binding to their respective ligands causes sustained proliferation of immune response cells (mainly T lymphocytes), and It can increase the level of cytokines such as IL-2 and IFN- ⁇ secreted by immune response cells, and improve the survival cycle and anti-tumor effect of CAR immune response cells in vivo.
- the intracellular signal transduction domain is a combination of a CD3 ⁇ signal domain or a CD3 ⁇ signal domain with other costimulatory signals such as CD28.
- an expression construct can be included in an immune response cell of the invention, wherein the expression construct has elements that are sequentially linked as follows: antibody, CD28 costimulatory signal domain, CD3 ⁇ , and in opposition to the aforementioned elements Linked NFAT6, type I interferon expression unit.
- the antibody and the CD28 costimulatory signal domain are joined by a CD8 alpha transmembrane region and a CD8 alpha hinge region.
- the activated T cell nuclear factor of NFAT (Nuclear factor of activated T cells) Transcriptional expression of cytokines plays an important role in T cell activation.
- the inventors placed the IFN-beta coding sequence under the regulation of the NFAT6 promoter, so that IFN-beta can be expressed at a high level only when the CAR-T cells contact the antigen to induce T cell activation.
- the NFAT6 promoter is a promoter composed of a combination of six NFAT binding positions and a minimal promoter of IL2 (Hooijberg E, Bakker AQ, Ruizendaal JJ, Spits H. NFAT-controlled expression of GFP permits visualization and Isolation of antigen-stimulated primary human Tcells. Blood. 2000 Jul 15; 96(2): 459-66), which can be used to regulate the expression of cytokines such as IL12 in T lymphocytes such as TCR-T (Zhang L, Kerkar SP, Yu Z, Zheng Z, Yang S, Restifo NP, Rosenberg SA, Morgan RA. Immunity adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol Ther. 2011 Apr; 19(4): 751-9).
- the invention also encompasses a nucleic acid encoding the antigen-binding receptor.
- the invention also relates to variants of the above polynucleotides which encode fragments, analogs and derivatives of polypeptides or polypeptides having the same amino acid sequence as the invention.
- the present invention also provides a vector comprising the above nucleic acid encoding a receptor protein that binds to an antigen expressed on the surface of an immune response cell.
- the vector used in the present invention is a lentiviral plasmid vector pRRLSIN-cPPT.PGK-GFP.WPRE. It should be understood that other types of viral vectors as well as non-viral vectors are also applicable.
- the invention also includes viruses comprising the vectors described above.
- the virus of the present invention includes a packaged infectious virus, and also includes a virus to be packaged containing components necessary for packaging as an infectious virus.
- Other viruses known in the art that can be used to transduce foreign genes into immune response cells and their corresponding plasmid vectors can also be used in the present invention.
- the immune response cell of the present invention is transduced with a construct capable of expressing an antigen-binding receptor and an exogenous type I interferon, or an expression vector, or a virus comprising the plasmid.
- a construct capable of expressing an antigen-binding receptor and an exogenous type I interferon or an expression vector, or a virus comprising the plasmid.
- Conventional nucleic acid transduction methods including non-viral and viral transduction methods, can be used in the present invention.
- the immune response cell of the present invention may further carry a coding sequence of a foreign cytokine; the cytokine includes, but not limited to, IL-12, IL-15 or IL-21 and the like.
- cytokine includes, but not limited to, IL-12, IL-15 or IL-21 and the like.
- These cytokines have further immunomodulatory or anti-tumor activity, enhance the function of effector T cells and activated NK cells, or directly exert anti-tumor effects.
- cytokines will help the immune response cells to function better.
- the immune response cell of the present invention can also express another antigen in addition to the antigen-binding receptor described above.
- An antigen-binding receptor An antigen-binding receptor.
- the immune response cells of the invention may also express a chemokine receptor; the chemokine receptors include, but are not limited to, CCR2. Those skilled in the art will appreciate that the CCR2 chemokine receptors may allow CCR2 binding in vivo to compete with it, which is advantageous for blocking tumor metastasis.
- the immune response cells of the present invention can also express siRNA that reduces PD-1 expression or a protein that blocks PD-L1.
- siRNA that reduces PD-1 expression
- the immune response cells of the present invention may also express a safety switch; preferably, the safety switch comprises: iCaspase-9, Truncated EGFR or RQR8.
- the immune response cells of the invention do not express a costimulatory ligand such as 4-1BBL.
- a transgene encoding a receptor or a CAR that binds to an antigen can be incorporated into the cell.
- a transgene can be incorporated into an immune response cell, such as a T cell.
- the transgene can be a complementary DNA (cDNA) fragment that is a copy of messenger RNA (mRNA); or the gene itself (with or without introns) located in the original region of its genomic DNA.
- cDNA complementary DNA
- mRNA messenger RNA
- a nucleic acid encoding a transgene sequence, such as DNA can be randomly inserted into the chromosome of the cell. Random integration can be produced by any method that introduces a nucleic acid, such as DNA, into a cell.
- the method can include, but is not limited to, electroporation, ultrasound, use of a gene gun, lipofection, calcium phosphate transfection, use of dendrimers, microinjection, and use of viruses including adenovirus, AAV, and retroviral vectors.
- Vector, and/or type II ribozyme can be produced by any method that introduces a nucleic acid, such as DNA, into a cell.
- the method can include, but is not limited to, electroporation, ultrasound, use of a gene gun, lipofection, calcium phosphate transfection, use of dendrimers, microinjection, and use of viruses including adenovirus, AAV, and retroviral vectors.
- Vector, and/or type II ribozyme
- the DNA encoding the transgene can also be designed to include a reporter gene such that the presence of the transgene or its expression product can be detected by activation of the reporter gene. Any reporter gene can be used, such as those described above.
- the cells containing the transgene can be selected by selecting cells in the cell culture in which the reporter gene has been activated.
- Expression of CAR can be verified by expression assays such as qPCR or by measuring the level of RNA.
- the level of expression can also indicate the number of copies. For example, if the level of expression is very high, this may indicate that more than one copy of the CAR is integrated into the genome. Alternatively, high expression may indicate that the transgene is integrated in a high transcribed region, such as near a highly expressed promoter. Expression can also be verified by measuring protein levels, for example by Western blotting.
- an immune response cell of the invention may comprise one or more transgenes.
- the one or more transgenes can express a CAR protein that recognizes and binds to at least one epitope on the antigen or binds to a mutant epitope on the antigen.
- CAR can be a functional CAR.
- the immune response cells of the invention may comprise one or more CARs, or they may comprise a single CAR and two Secondary engineered receptors.
- the transgene can encode a suicide gene.
- CAR immune response cells cause tumor regression but can be associated with toxicity.
- the target antigen when the target antigen is shared in normal tissues and tumor cells, the CAR immune response cells may not be able to distinguish between tumors and normal tissues ("target/off-target toxicity").
- a systemic disturbance of the immune system called cytokine release syndrome (CRS)
- CRS may comprise a systemic inflammatory response syndrome or a cytokine storm, which may be a consequence of rapid expansion of the CAR immune response cells in vivo.
- CRS is a condition characterized by fever and hypotension, which can lead to multiple organ failure.
- the toxicity is associated with in vivo expansion of infused CAR immune response cells, which can cause an overall disturbance of the immune system, as well as release high levels of pro-inflammatory cytokines such as TNF[alpha] and IL-6.
- Suicide genes can induce the elimination of CAR immunoreactive cells.
- the suicide gene may be any gene that induces apoptosis in the CAR immunoreactive cells.
- a suicide gene can be encoded in the viral vector together with the antigen-binding receptor. The coding of the suicide gene allows for the mitigation or complete abortion of the toxicity caused by in vivo expansion of the infused CAR immune response cells under specific conditions.
- CAR immunoreactive cells that are present in antigens of normal tissues can be produced such that they transiently express CAR, eg, after electroporating the mRNA encoding the receptor.
- a major effort to further strengthen CAR immunoreactive cells by including a safety switch can substantially eliminate CAR immunoreactive cells in the case of severe target toxicity.
- the vector encoding CAR can be associated with, for example, an inducible caspase-9 gene (activated by a dimeric chemical inducer) or a truncated form of EGF receptor R (activated by the monoclonal antibody cetuximab) or RQR8. Safety switch combination.
- transgenes used herein may be from different species.
- one or more of the transgenes can comprise a human gene, a mouse gene, a rat gene, a porcine gene, a bovine gene, a dog gene, a cat gene, a monkey gene, a chimpanzee gene, or any combination thereof.
- a transgene can be from a human having a human genetic sequence.
- One or more transgenes may comprise a human gene. In some cases, one or more of the transgenes are not adenoviral genes.
- the transgene can be inserted into the genome of the immunoreactive cell in a random or site-specific manner.
- a transgene can be inserted into a random site in the genome of an immune cell.
- These transgenes can be functional, for example, fully functional when inserted into any part of the genome.
- a transgene can encode its own promoter or can be inserted into a position controlled by its internal promoter.
- the transgene can be inserted into a gene, such as an intron of a gene or an exon, promoter or non-coding region of a gene.
- a transgene can be inserted to insert a disruptive gene, such as an endogenous immune checkpoint.
- more than one copy of the transgene can be inserted into multiple random sites within the genome. For example, multiple copies can be inserted into random sites in the genome. This may result in an increase in overall expression compared to random insertion of the transgene once.
- a copy of the transgene can be inserted into the gene and another copy of the transgene can be inserted into a different gene.
- the transgene can be targeted such that it can be inserted into a specific site in the genome of the immunoreactive cell.
- a polynucleic acid comprising a receptor sequence encoding an antigen binding agent can take the form of a plasmid vector.
- the plasmid vector may comprise a promoter. In some cases, the promoter can be constitutive. In some embodiments, the promoter is inducible. The promoter may be or may be derived from CMV, U6, MND or EF1a. In some embodiments, the promoter can be adjacent to the CAR sequence. In some embodiments, the plasmid vector further comprises a splice acceptor. In some embodiments, the splice acceptor can be adjacent to the CAR sequence.
- the promoter sequence can be a PKG or MND promoter.
- the MND promoter may be a synthetic promoter of the U3 region of the MoMuLV LTR modified with myeloproliferative sarcoma virus enhancer.
- a polynucleic acid encoding a receptor of interest can be designed to be delivered to a cell by non-viral techniques.
- the polynucleic acid can be a Good Manufacturing Practice (GMP) compatible reagent.
- GMP Good Manufacturing Practice
- Promoters can be ubiquitous, constitutive (unrestricted promoters, allowing for continuous transcription of related genes), tissue-specific promoters or inducible promoters. Expression of a transgene inserted adjacent to or proximate to the promoter can be modulated. For example, a transgene can be inserted near or beside a ubiquitous promoter.
- Some ubiquitous promoters may be the CAGGS promoter, the hCMV promoter, the PGK promoter, the SV40 promoter or the ROSA26 promoter.
- Promoters can be endogenous or exogenous.
- one or more transgenes can be inserted adjacent to or proximate to the endogenous or exogenous ROSA26 promoter.
- the promoter may be specific for immunoreactive cells.
- one or more transgenes can be inserted adjacent to or proximate to the porcine ROSA26 promoter.
- Tissue-specific promoters or cell-specific promoters can be used to control the location of expression.
- one or more transgenes can be inserted into proximity or proximity of a tissue-specific promoter.
- Tissue-specific promoters may be FABP promoter, Lck promoter, CamKII promoter, CD19 promoter, keratin promoter, albumin promoter, aP2 promoter, insulin promoter, MCK promoter, MyHC promoter, WAP Promoter, or Col2A promoter.
- Inducible promoters can also be used. These inducible promoters can be turned on and off by adding or removing an inducer if necessary.
- the inducible promoter is contemplated to be, but not limited to, Lac, tac, trc, trp, araBAD, phoA, recA, proU, cst-1, tetA, cadA, nar, PL, cspA, T7, VHB, Mx, and/or Trex.
- inducible promoter is a controlled promoter which does not express or underexpress a gene operably linked thereto before the desired condition is reached, and is achieved under the expected conditions.
- a gene that is operably linked to it is expressed or expressed at a high level.
- an inducible promoter of the present application does not express or underexpress a gene operably linked thereto under normal or high oxygen content conditions in a cell, and in response to a reduced oxygen content in the cell, A gene that is operably linked thereto is expressed or overexpressed under hypoxic conditions.
- an inducible promoter for use herein includes Hypoxia-Inducible Transcription factor-1 ⁇ (HIF-1 ⁇ ).
- the term "inducible promoter” as used herein refers to an "immune cell-inducible promoter” that does not express or underexpresses an immune response cell prior to its exposure to the antigen or when the immune response cell is not activated.
- the "immune cell-inducible promoter” comprises a NFAT (activated T cell nuclear factor) type promoter.
- NFAT-type promoter refers to a class of promoters that regulate the expression of a gene to which they are operably linked based on NFAT binding activity.
- NFAT is a general term for a family of transcription factors that play an important role in immune responses. One or more members of the NFAT family are expressed in most cells of the immune system. NFAT is also involved in the development of the heart, skeletal muscle and nervous system.
- the NFAT transcription factor family consists of five members, NFAT1, NFAT2, NFAT3, NFAT4, and NFAT5.
- NFAT1 to NFAT4 are regulated by calcium signals.
- Calcium signaling is critical for NFAT activation because calmodulin (CaM) activates serine/threonine phosphatase calcineurin (CN).
- CaM calmodulin
- CN serine/threonine phosphatase calcineurin
- Activated CN rapidly dephosphorylates the amino-terminal serine-rich region (SRR) and SP repeats of the NFAT protein, resulting in a conformational change that exposes nuclear localization signals, resulting in NFAT input into the nucleus.
- NFAT in the transcriptional expression of cytokines during T cell activation, which can be used to modulate the immune cell-inducible promoters described herein, thereby expressing or expressing high levels of expression when the immune response cells are exposed to antigen activation.
- a nucleic acid of the invention may comprise any suitable nucleotide sequence encoding a NFAT type promoter (or a functional part or a functional variant thereof).
- NFAT-type promoter refers to one or more NFAT response elements linked to the minimal promoter of any gene expressed by a T cell.
- the minimal promoter of the gene expressed by T cells is the smallest human IL-2 promoter.
- the NFAT response element can include, for example, NFAT1, NFAT2, NFAT3, and/or NFAT4 response elements.
- more than one NFAT binding motif can be included in a "NFAT-type promoter" as described herein.
- the "NFAT-type promoter” can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NFAT binding motifs.
- the "NFAT-type promoter” includes up to 12 NFAT binding motifs.
- the "NFAT-type promoter” can be a promoter consisting of a plurality of the NFAT-binding motifs in series with a promoter, such as the IL2 minimal promoter.
- the NFAT type promoters described herein comprise six NFAT binding motifs, designated (NFAT) 6 .
- the (NFAT) 6 is also referred to as NFAT6.
- the NFAT6 also represents a 6-repeat NFAT binding motif (SEQ ID NO: 78) in the NFAT-type promoter.
- the transgenic sequences may also include transcriptional or translational regulatory sequences, such as promoters, enhancers, insulators, internal ribosome entry sites, sequences encoding 2A peptides and/or polyadenylation signals.
- transcriptional or translational regulatory sequences such as promoters, enhancers, insulators, internal ribosome entry sites, sequences encoding 2A peptides and/or polyadenylation signals.
- the transgene encodes a receptor or CAR that binds to the antigen, wherein the transgene is inserted into a safe harbor such that the antigen-binding receptor is expressed.
- the transgene is inserted into the PD1 and/or CTLA-4 locus.
- the transgene is delivered as a lentivirus to the cells for random insertion, while a PD1- or CTLA-4 specific nuclease can be provided as mRNA.
- the transgene is delivered by a viral vector system such as retrovirus, AAV or adenovirus, and mRNA encoding a nuclease specific for safe harbor (eg, AAVS1, CCR5, albumin, or HPRT). Cells can also be treated with mRNA encoding PD1 and/or CTLA-4 specific nucleases.
- the polynucleotide encoding the CAR is provided by a viral delivery system with an mRNA encoding a HPRT-specific nuclease and a PD1- or CTLA-4 specific nuclease.
- CARs that can be used with the methods and compositions disclosed herein can include all types of these chimeric proteins, including the first, second, and third generation designs previously described herein.
- a transgene can be introduced into an immunoreactive cell using a retroviral vector (gamma-retroviral or lentiviral vector).
- a transgene encoding a CAR or any receptor that binds an antigen, or a variant or fragment thereof can be cloned into a retroviral vector and can be derived from an endogenous promoter, a retroviral long terminal repeat, or a target Cell type-specific promoter drive.
- Non-viral vectors can also be used.
- Non-viral vector delivery systems can include DNA plasmids, naked nucleic acids, and nucleic acids complexed with delivery vehicles such as liposomes or poloxamers.
- retroviruses provide a convenient platform for gene delivery systems.
- the selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art.
- a vector derived from a retrovirus such as a lentivirus is A suitable tool for achieving long-term gene transfer because they allow long-term stable integration of the transgene and its propagation in daughter cells.
- Lentiviral vectors have the added advantage over vectors derived from retroviruses such as murine leukemia virus because they can transduce non-proliferating cells. They also have the added advantage of low immunogenicity.
- An advantage of adenoviral vectors is that they do not fuse into the genome of the target cell, thereby bypassing negative integration-related events.
- the cells can be transfected with a transgene encoding the antigen-binding receptor.
- the transgenic concentration can range from about 100 picograms to about 50 micrograms.
- the amount of nucleic acid (eg, ssDNA, dsDNA, or RNA) introduced into the cell can be altered to optimize transfection efficiency and/or cell viability. For example, 1 microgram of dsDNA can be added to each cell sample for electroporation.
- the amount of nucleic acid (eg, double stranded DNA) required for optimal transfection efficiency and/or cell viability varies depending on the cell type.
- the amount of nucleic acid (eg, dsDNA) used for each sample can directly correspond to transfection efficiency and/or cell viability. For example, a range of transfection concentrations.
- the transgene encoded by the vector can be integrated into the genome of the cell. In some embodiments, the transgene encoded by the vector is forward integrated. In other cases, the reverse integration of the transgene encoded by the vector.
- the immunoreactive cell can be a dry memory consisting of CD45RO(-), CCR7(+), CD45RA(+), CD62L+ (L-selectin), CD27+, CD28+, and/or IL-7R ⁇ + T SCM cells, which also express CD95, IL-2R ⁇ , CXCR3, and/or LFA-1, and exhibit many different functional properties from the stem memory cells.
- the immunoreactive cells may also be central memory T CM cells comprising L-selectin and CCR7, wherein the central memory cells may secrete, for example, IL-2 but not IFNy or IL-4.
- the immunoreactive cells may also be effector memory T EM cells comprising L-selectin or CCR7 and produce, for example, effector cytokines such as IFNy and IL-4.
- the vector by administration to an individual patient is typically by systemic administration (e.g., intravenous, intraperitoneal, intramuscular, subcutaneous, or intracranial infusion) or topical application, as described below.
- the vector can be delivered ex vivo to the cells, such as cells removed from an individual patient (eg, lymphocytes, T cells, bone marrow aspirate, tissue biopsy), and then typically after re-selecting the cells into which the vector is incorporated Implanted in a patient. Cells can be expanded before or after selection.
- Suitable immunoreactive cells for expression of a receptor that binds to an antigen may be cells that are autologous or non-autologous to the individual in need thereof.
- a suitable source of immune response cells can be obtained from the individual.
- T cells can be obtained.
- the T cells can be obtained from a number of sources, including PBMC, bone marrow, lymph node tissue, cord blood, thymus tissue, and tissues from infected sites, ascites, pleural effusion, spleen tissue, and tumors.
- any number of known to those skilled in the art, such as separation Ficoll TM, from one body from the collected blood T cells were obtained.
- cells from circulating blood of an individual are obtained by apheresis.
- Apheresis products typically contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets.
- lymphocytes including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets.
- cells collected by apheresis collection can be washed to remove plasma fractions and placed in a suitable buffer or medium for subsequent processing steps.
- cells can be derived from a healthy donor, from a patient diagnosed with cancer, or a patient diagnosed with an infection.
- the cells can be part of a mixed cell population with different phenotypic characteristics.
- Cell lines can also be obtained from transformed T cells according to the methods previously described.
- Cells can also be obtained from a cell therapy library.
- Modified cells that are resistant to immunosuppressive therapy can be obtained by any of the methods described herein. It is also possible to select a suitable cell population prior to modification.
- the engineered cell population can also be selected after modification.
- Engineered cells can be used for autologous transplantation.
- the cells can be used for allogeneic transplantation.
- the cells are administered to a sample for identification of the same patient of a cancer associated target sequence. In other instances, the cells are administered to a patient different from the patient whose sample is used to identify the cancer-related target sequence.
- suitable primary cells include peripheral blood mononuclear cells (PBMC), peripheral blood lymphocytes (PBL), and other blood cell subpopulations such as, but not limited to, T cells, natural killer cells, monocytes, Natural killer T cells, monocyte precursor cells, hematopoietic stem cells or non-pluripotent stem cells.
- the cell can be any immune cell, including any T cell such as a tumor infiltrating cell (TIL), such as a CD3+ T cell, a CD4+ T cell, a CD8+ T cell, or any other type of T cell.
- T cells can also include memory T cells, memory stem T cells, or effector T cells.
- T cells can also be expanded from a large population.
- T cells may also be inclined to specific populations and phenotypes.
- a T cell can be tilted to a phenotype comprising CD45RO(-), CCR7(+), CD45RA(+), CD62L(+), CD27(+), CD28(+), and/or IL-7R ⁇ (+).
- Suitable cells may be selected from one or more of the following list: CD45RO (-), CCR7 (+), CD45RA (+), CD62L (+), CD27 (+), CD28 (+) and/or IL-7R ⁇ (+).
- Suitable cells also include stem cells such as, for example, embryonic stem cells, induced pluripotent stem cells, hematopoietic stem cells, neuronal stem cells, and mesenchymal stem cells.
- stem cells such as, for example, embryonic stem cells, induced pluripotent stem cells, hematopoietic stem cells, neuronal stem cells, and mesenchymal stem cells.
- Suitable cells can comprise any number of primary cells, such as human cells, non-human cells, and/or mouse cells.
- Suitable cells can be progenitor cells.
- Suitable cells can be derived from a subject (eg, a patient) to be treated.
- the amount of therapeutically effective cells required in a patient can vary depending on the viability of the cells and the efficiency with which the cells are genetically modified (eg, the efficiency with which the transgene is integrated into one or more cells, or the level of expression of the protein encoded by the transgene) ).
- the product (eg, doubling) of the cell viability after genetic modification and the efficiency of transgene integration can correspond to a therapeutic amount of cells available for administration to a subject.
- an increase in cell viability after genetic modification may correspond to a reduction in the amount of essential cells effective to administer the treatment to the patient.
- an increase in the efficiency of integration of the transgene into one or more cells can correspond to a reduction in the number of cells necessary to administer a therapeutically effective in a patient.
- determining the amount of therapeutically effective cells required can include determining a function associated with changes in cells over time.
- determining the amount of cells that are required to be therapeutically effective can include determining a function corresponding to a change in efficiency of integrating the transgene into one or more cells according to a time-dependent variable (eg, cell culture time, electroporation time, Cell stimulation time).
- the therapeutically effective cell can be a population of cells comprising about 30% to about 100% of the expression of a receptor that binds to the antigen on the surface of the cell.
- the therapeutically effective cells can express about 30%, 35%, 40%, 45%, 50%, 55%, 60 of the antigen-binding receptor on the cell surface as measured by flow cytometry. %, 65%, 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9 % or more than about 99.9%.
- the antigen-binding receptor when the antigen-binding receptor is present on the plasma membrane of a cell, and when activated by binding to a target, it can result in a receptor having a binding antigen for its cell surface capable of binding The toxicity of the target cells.
- the cells when cells are present in the plasma membrane of a cell, the cells can be cytotoxic cells (eg, NK cells or cytotoxic T lymphocytes), antigen-binding receptors described herein, and when It can increase the cytotoxic activity of cytotoxic cells against target cells when activated by binding to their targets.
- an antigen-binding receptor described herein when activated by binding of its target, can increase cytotoxicity by at least 10 compared to cytotoxicity in the absence of cells that bind to the target. %, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 2 times, at least 2.5 times, at least 5 times, at least 10 times or more 10 times .
- the immune response cells of the invention can be used to prepare pharmaceutical compositions.
- the pharmaceutical composition may comprise a pharmaceutically acceptable carrier in addition to an effective amount of an immune response cell.
- pharmaceutically acceptable means that when the molecular body and composition are suitably administered to an animal or a human, they do not produce an adverse, allergic or other untoward reaction.
- sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives thereof such as carboxymethyl fibers Sodium, ethyl cellulose and methyl cellulose; western yellow gum powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, Sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Wetting agents, such as sodium lauryl sulfate; colorants; flavoring agents; compressed tablets, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solutions; and phosphate buffers
- composition of the present invention can be formulated into various dosage forms as needed, and can be administered by a physician in accordance with factors such as patient type, age, body weight, and general disease condition, mode of administration, and the like.
- the mode of administration can be, for example, parenteral administration (e.g., injection) or other treatment.
- parenteral administration of an immunogenic composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.) or intrasternal injection or infusion techniques.
- Formulations comprising an immunoreactive cell population administered to an individual comprise a plurality of immunoreactive cells effective to treat and/or prevent a particular indication or disease.
- a therapeutically effective population of immunoreactive cells can be administered to an individual.
- administration contain from about 1 ⁇ 10 4 to about 1 ⁇ 10 10 cells reactive immunization formulation.
- the formulation will contain from about 1 ⁇ 10 5 to about 1 ⁇ 10 9 cells reactive immunization, about 5 ⁇ 10 5 to about 5 ⁇ 10 8 cells reactive immunization, or from about 1 ⁇ 10 6 to About 1 ⁇ 10 7 immunoreactive cells.
- the number of CAR immunoreactive cells administered to the individual will vary from wide range. The doctor will finalize the appropriate dose to use.
- a chimeric antigen receptor is used to stimulate an immune cell mediated immune response.
- a T cell mediated immune response is an immune response involving T cell activation.
- Activated antigen-specific cytotoxic T cells are capable of inducing apoptosis in target cells that exhibit a foreign antigenic epitope on the surface, such as cancer cells that display tumor antigens.
- a chimeric antigen receptor is used to provide anti-tumor immunity in a mammal. Subjects will develop anti-tumor immunity due to T cell-mediated immune responses.
- a method of treating a subject having cancer can involve administering one or more immune response cells of the invention to a subject in need of treatment.
- the immune response cell binds to a tumor target molecule and induces cancer cell death.
- the invention also provides a method of treating a pathogen infection in an individual comprising administering to the individual a therapeutically effective amount of an immune response cell of the invention.
- the frequency of administration of the immunoreactive cells of the present invention will depend on factors including the disease being treated, the elements of the particular immunoreactive cells, and the mode of administration. For example, it can be administered 4 times, 3 times, 2 times a day, once a day, every other day, every three days, every four days, every five days, every six days, once a week, once every eight days, every time. Dosing once every nine days, every ten days, once a week, or twice a month.
- the immune response cells of the present application have improved viability, they can be administered not only in a therapeutically effective amount that is lower than an immune response cell that is similar but does not express exogenous type I interferon, and can Administration at a lower frequency to achieve at least a similar, and preferably more pronounced, effect.
- an immune response cell of the invention can be administered in combination with another therapeutic agent.
- the additional therapeutic agent is a chemotherapeutic agent.
- Chemotherapeutic agents that can be used in conjunction with the immune response cells of the invention include, but are not limited to, mitotic inhibitors (vinca alkaloids), including vincristine, vinblastine, vindesine, and novibin (TM) (vinorelbine) , 5'-dehydro sulfide); topoisomerase I inhibitors such as camptothecin compound, including Camptosar TM (irinotecan HCL), Hycamtin TM (topotecan HCL) and derived from camptothecin Other compounds of its analogs; podophyllotoxin derivatives such as etoposide, teniposide and midozozoz; alkylating agents cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide , carmustine, busulfan,
- chemotherapeutic agents that can be used in conjunction with the immune response cells of the invention include, but are not limited to, anti-angiogenic agents, including anti-VEGF antibodies (including humanized and chimeric antibodies, anti-VEGF aptamers, and antisense oligos) Nucleotide) and other angiogenesis inhibitors such as angiostatin, endostatin, interferon, interleukin-1 (including alpha and beta) interleukin 12, retinoic acid and metalloproteinase-1 and -2 tissue inhibition Agent.
- anti-angiogenic agents including anti-VEGF antibodies (including humanized and chimeric antibodies, anti-VEGF aptamers, and antisense oligos) Nucleotide) and other angiogenesis inhibitors such as angiostatin, endostatin, interferon, interleukin-1 (including alpha and beta) interleukin 12, retinoic acid and metalloproteinase-1 and -2 tissue inhibition Agent.
- the compositions may be isotonic, ie they may have the same osmotic pressure as blood and tears.
- the desired isotonicity of the compositions of the present invention can be achieved using sodium chloride or other pharmaceutically acceptable agents such as glucose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
- the viscosity of the composition can be maintained at a selected level using a pharmaceutically acceptable thickening agent.
- Suitable thickeners include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, and the like. The preferred concentration of thickener will depend on the reagent selected. It will be apparent that the choice of suitable carrier and other additives will depend on the exact route of administration and the nature of the particular formulation, such as a liquid dosage form.
- kits comprising the immune response cells of the invention.
- the kit can be used to treat or prevent cancer, pathogen infection, immune disorders or allogeneic transplantation.
- a kit can include a therapeutic or prophylactic composition comprising an effective amount of an immune response cell comprising one or more unit dosage forms.
- the kit comprises a sterile container that can contain a therapeutic or prophylactic composition; such a container can be a cartridge, ampule, bottle, vial, tube, bag, blister pack, or other suitable as is known in the art.
- Container form Such containers may be made of plastic, glass, laminated paper, metal foil or other materials suitable for holding the drug.
- immunoreactive cells such as CAR T cells
- instructions for administering CAR immunoreactive cells to a subject at risk of developing a cancer, a pathogen infection, an immune disorder, or an allogeneic transplant will generally include information regarding the composition used to treat or prevent cancer, pathogen infection, immune disease, or allogeneic transplantation.
- the kit can include from about 1 x 10 4 cells to about 1 x 10 6 cells.
- the kit can include at least about 1 x 10 5 cells, at least about 1 x 10 6 cells, at least about 1 x 10 7 cells, at least about 4 x 10 7 cells, at least about 5 x 10 7 cells, at least about 6 ⁇ 10 7 cells, at least about 6 ⁇ 10 7 cells, 8 ⁇ 10 7 cells, at least about 9 ⁇ 10 7 cells, at least about 1 ⁇ 10 8 cells, at least about 2 x 108 cells, at least about 3 x 10 8 cells, at least about 4 x 10 8 cells, at least about 5 x 10 8 cells, at least about 6 x 10 8 cells, at least about 6 x 10 8 cells, At least about 8 x 10 8 cells, at least about 9 x 10 8 cells, at least about 1 x 10 9 cells, at least about 2 x 10 9 cells, at least about 3 x 10 9 cells, at least about 4 x 10 9 cells, at least about 5 ⁇ 10 9 cells, at least about 6 ⁇ 10 9 cells, at least about 8 ⁇ 10 9 cells, at least about 9
- the kit can include allogeneic cells.
- a kit can include cells that can include genomic modifications.
- the kit can comprise "off the shelf" cells.
- the kit can include cells that can be expanded for clinical use. In some cases, the kit may contain content for research purposes.
- the instructions include at least one of: a description of a therapeutic agent; a dosage regimen and administration for treating or preventing a tumor, a pathogen infection, an immune disease, or an allograft or a symptom thereof; a preventive measure, a warning , contraindications, excessive information, adverse reactions, animal pharmacology, clinical studies, and/or citations.
- Instructions can be printed directly on the container (if any), or as a label on the container, or as a separate paper, booklet, card or folder in the container or in the container.
- the instructions provide methods of administering an immune response cell of the invention for treating or preventing a tumor, a pathogen infection, an immune disease, or an allograft or a symptom thereof.
- the instructions provide methods of administering an immunoreactive cell of the invention before, after or simultaneously with the administration of a chemotherapeutic agent.
- the invention also provides a method of treating a tumor or pathogen infection in an individual, Or a method for enhancing an individual's immune tolerance.
- the methods comprise administering to an individual in need thereof an immune response cell of the invention, the immune cell expressing the antigen binding receptor and an exogenous type I interferon.
- the methods comprise administering to the individual in need thereof an antigen binding receptor of the invention and an exogenous type I interferon.
- the exogenous type I interferon is administered sequentially or simultaneously with the immune response cell expressing the antigen binding receptor.
- the exogenous type I interferon is administered to a patient simultaneously with the immune response cell by co-expression in an immune response cell.
- the present invention provides a method of increasing the viability of an immune response cell administered to an individual, wherein the immune response cell expresses an antigen binding receptor of the present invention, and wherein the method comprises administering to the individual
- the immune response cell is also an effective amount of exogenous type I interferon.
- the exogenous type I interferon is administered sequentially or simultaneously with the immune response cell expressing the antigen binding receptor.
- the exogenous type I interferon is administered to a patient simultaneously with the immune response cell by co-expression in an immune response cell.
- the exogenous type I interferon is not co-expressed with the exogenous type I interferon or the immune response cell.
- the immune response cells of the invention can be administered at lower doses and/or lower frequencies.
- the invention is administered to an individual in need thereof as compared to the case where the exogenous type I interferon is not administered or the exogenous type I interferon is not co-expressed
- the amount of immune response cells is reduced by at least 10%, 20%, 30, 40, 50%, 60, 70%, 80% or 90%.
- the invention is administered to an individual in need thereof as compared to the case where the exogenous type I interferon is not administered or the exogenous type I interferon is not co-expressed
- the frequency of immune response cells is reduced by at least 10%, 20%, 30, 40, 50%, 60, 70%, 80%, or 90%.
- the present invention is required to be administered to an individual in need thereof multiple times as compared with the case where the exogenous type I interferon is not administered or the exogenous type I interferon is not co-expressed.
- the interval between each administration is extended by at least 10%, 20%, 30, 40, 50%, 60, 70%, 80%, 90%, 100%, 120%, 140%, 160 %, 180%, 200%, 500%, 750%, 1000%.
- the methods of the invention result in cytotoxicity T in the peripheral blood of the individual after administration of the immune response cell to the individual compared to the absence of the exogenous type I interferon
- the sum of the number of cells and helper T cells is increased by at least 10%, 20%, 30, 40, 50%, 60, 70%, 80%, 90%, 100%, 120%, 140%, 160%, 180%, 200%, 500%, 750%, 1000%.
- the method results in the in vitro administration of the immune response cell to the individual about 5 days later
- the sum of the number of cytotoxic T cells and helper T cells in the peripheral blood is greater than 5,000/ ⁇ L, 10,000/ ⁇ L, 15,000/ ⁇ L, 20,000/ ⁇ L, 25,000/ ⁇ L; about 7 days after administration of the immune response cells
- the sum of the number of cytotoxic T cells and helper T cells in the peripheral blood is greater than 100/ ⁇ L, 200/ ⁇ L, 300/ ⁇ L, 400/ ⁇ L, 500/ ⁇ L, 600/ ⁇ L, 700 / ⁇ L, 800 / ⁇ L, 900 / ⁇ L, 1,000 / ⁇ L, 1,500 / ⁇ L, 2,000 / ⁇ L, 2,500 / ⁇ L, 3,000 / ⁇ L, 3,500 / ⁇ L, 4,000 / ⁇ L, 4,500 / ⁇ L, or 5,000 / ⁇ L; or about 10 days after administration of the immune response cells, the sum of the number of cyto
- the invention also provides a method of modulating an immune response in an individual, the method comprising administering to the individual an effective amount of an immune response cell of any of the invention.
- the invention also provides a method of enhancing immune tolerance in a subject, the method comprising administering to the individual an effective amount of an immune response cell of the invention comprising a receptor that binds to a tumor antigen and a vector encoding a type I interferon.
- the method prevents or reduces autoimmune diseases or diseases associated with allografts.
- the invention also provides a method of treating or preventing infection by a pathogen in a subject, the method comprising administering an effective amount of an immune response cell comprising a receptor that binds to a viral antigen and a vector encoding a type I interferon.
- Autologous lymphocyte infusion can be used for treatment.
- Autologous peripheral blood mononuclear cells PBMC
- T cells can be activated and expanded using methods described herein and known in the art and then injected into a patient.
- allogeneic cells can be used to treat a patient.
- Transplantation can refer to adoptive transplantation of cellular products.
- the transplant can be autograft, allogeneic, xenograft or any other transplant.
- the transplant can be a xenograft.
- Transplantation can also be allogeneic transplantation.
- the subject can administer immunoreactive cells, wherein the immunoreactive cells that can be administered can be from about 1 to about 35 days of age.
- the cells administered may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or up to about 40 days.
- the age of CAR immunoreactive cells can be calculated from the time of stimulation.
- the age of the immunoreactive cells can be calculated from the time of blood collection.
- the age of the immunoreactive cells can be calculated from the time of transduction.
- the immunoreactive cells that can be administered to the subject are from about 10 to about 14 or about 20 days of age.
- the "age" of an immunoreactive cell can be determined by the telomere length.
- a "young" immune response cell can have a longer telomere length than "depleted” or "old” immunoreactive cells.
- immunoreactive cells lose an estimated telomere length of about 0.8 kb per week in culture, and young immunoreactive cell cultures can have telomeres that are about 1.4 kb longer than about 44 days of immunoreactive cells.
- a longer telomere length can be associated with a positive objective clinical response in a patient and persistence of cells in vivo.
- Cells can be functional before, after, and/or during transplantation.
- the transplanted cells may be at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 after transplantation. 20, 21, 22, 23, 24, 25, 6, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90 or 100 days.
- the transplanted cells can function at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months after transplantation.
- the transplanted cells can function at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30 years after transplantation.
- the transplanted cells can function during the life of the recipient.
- transplanted cells can function at 100% of their normal expected function.
- the transplanted cells can also perform their normal expected functions of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 , 96, 97, 98, or up to about 100% of the functionality.
- Transplanted cells can also perform more than 100% of their normal intended function.
- the transplanted cells can function as approximately 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000 as normal expected functions. Or up to about 5,000% of the functionality.
- Porting can be done by any type of transplant.
- Topography may include, but is not limited to, subhepatic sac space, subsplenic sac space, subcapsular space, omentum, gastric or intestinal submucosa, small intestinal vascular segment, venous sac, testis, brain, spleen, or cornea.
- the transplant can be a subcapsular transplant.
- Transplantation can also be intramuscular transplantation.
- the transplant can be a portal vein transplant.
- transplant rejection can be improved after treatment with the immune response cells of the present invention as compared to when one or more wild type cells are transplanted to the recipient.
- transplant rejection can be a hyperacute rejection.
- Transplant rejection can also be an acute rejection.
- Other types of rejection may include chronic rejection.
- Transplant rejection can also be cell-mediated rejection or T cell-mediated rejection.
- Transplant rejection can also be a natural killer cell mediated rejection.
- Improving transplantation may mean alleviating hyperacute rejection, which may include reducing, reducing or reducing malnutrition Role or symptom.
- Transplantation can refer to adoptive transplantation of cellular products.
- Another indication of successful transplantation may be the number of days the recipient does not need immunosuppressive therapy.
- the recipient may not require at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days of immunosuppressive therapy. This can indicate that the transplant was successful. This can also indicate that the transplanted cells, tissues and/or organs are not repelled.
- the recipient does not require immunosuppressive therapy for at least 1 day.
- the recipient may also not require immunosuppressive therapy for at least 7 days.
- the recipient does not require immunosuppressive therapy for at least 14 days.
- the recipient does not require immunosuppressive therapy for at least 21 days.
- the recipient does not require immunosuppressive therapy for at least 28 days.
- the recipient does not require immunosuppressive therapy for at least 60 days.
- the recipient may not require at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years of immunosuppressive therapy.
- Another sign of successful transplants may be the number of days that recipients need to reduce their immunosuppressive therapy. For example, after the treatment provided herein, the recipient may require at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days of reduced immunosuppressive therapy. This can indicate that the transplant was successful. This may also indicate that there is no or only minimal rejection of the transplanted cells, tissues and/or organs.
- a recipient may require at least 1 day of reduced immunosuppressive therapy.
- Recipients may also require at least 7 days of reduced immunosuppressive therapy.
- the recipient may require at least 14 days of reduced immunosuppressive therapy.
- Recipients require at least 21 days of reduced immunosuppressive therapy.
- Recipients require at least 28 days of reduced immunosuppressive therapy.
- Recipients require at least 60 days of reduced immunosuppressive therapy.
- the recipient may require at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years of reduced immunosuppressive therapy.
- Reduced immunosuppressive therapy can refer to less immunosuppressive therapy as compared to the immunosuppressive therapy required when transplanting one or more wild-type cells into a recipient.
- Immunosuppressive therapy can include any treatment that inhibits the immune system. Immunosuppressive therapy can help alleviate, reduce or eliminate transplant rejection in patients.
- immunosuppressants can be used before, during, and/or after transplantation, including MMF (Cellcept), ATG (anti-thymocyte globulin), anti-CD154 (CD4OL), anti-CD40 (2C10) , immunosuppressive drugs, anti-IL-6R antibodies (tocilizumab, Actemra), anti-IL-6 antibodies (sarilumab, olokizumab), CTLA4-Ig (Abatacept/Orencia), anti-IL-6 antibodies (ASKP1240, CCFZ533X2201) ), amphetamine (Campath), anti-CD20 (rituximab), bevacizumab (LEA29Y), sirolimus (Rapimune), everolimus, tacrolimus (Prograf), Zele-napax, Silimict, Remicade,
- one or more immunosuppressive agents/drugs may be used together or sequentially.
- One or more immunosuppressive agents/drugs can be used to induce therapy or to maintain treatment.
- the same or different drugs can be used in the induction and maintenance phases.
- daclizumab Zenapax
- tacrolimus Prograf
- sirolimus Rostune
- Non-pharmacological regimens can also be used to achieve immunosuppression, including but not limited to whole body irradiation, thymic irradiation, and total and/or partial splenectomy. These techniques can also be used in combination with one or more immunosuppressive drugs.
- the CD28 costimulatory signal domain is abbreviated as 28; CD3 ⁇ is abbreviated as Z; 4-1BB or CD137 is abbreviated as BB.
- a chimeric antigen receptor constructed as an intracellular signal domain with an scFv code of 85-2 and a CD3 ⁇ and a CD28 costimulatory signal domain can be designated as 85-2-28Z. This is true for the construction of CARs for different antigens.
- liver cancer cell lines SK-HEP-1 and PLC/PRF/5 were purchased from the ATCC cell bank, and Huh-7 was purchased from the Japanese RIKEN cell bank.
- PBMC is from the Shanghai Blood Center.
- AIM V medium CTS, Cat #1665773.
- FCS Fetal bovine serum
- IL-2 Shanghai Huaxin, recombinant human interleukin-2 for injection.
- PE-Streptavidin BD pharmingen, Cat #554061.
- CytoTox Non-radioactive cytotoxicity assay Promega, Cat# G1780.
- the following vector system used to construct the lentiviral plasmid vector of the present invention belongs to the third generation auto-inactivated lentiviral vector system, which has four plasmids: a packaging plasmid pMDLg RRE encoding the protein Gag/Pol (purchased from addgene).
- the packaging plasmid pRSV-REV (purchased from addgene) encoding the Rev protein
- the envelope plasmid pCMV-VSV-G (purchased from addgene) encoding the VSV-G protein
- the empty vector pRRLSIN-cPPT.PGK-GFP.WPRE A recombinant expression vector encoding the gene of interest, purchased from addgene, which is effective in reducing the risk of forming replicable lentiviral particles.
- the inventors first modified the empty vector pRRLSIN-cPPT.PGK-GFP.WPRE by a conventional molecular cloning technique, and started with elongation factor-1 ⁇ (elongation factor-1 ⁇ , EF-1 ⁇ ).
- the promoter replaces the promoter of the original vector and adds a MluI cleavage site between the promoter and the CD8 ⁇ sp signal peptide.
- a ClaI/SalI (purchased from NEB) double-digested vector pWPT-EGFP (purchased from addgene) was used to recover a 1.1 kb DNA fragment, and ligated to the ClaI/SalI double-digested vector pRRLSIN-cPPT with T4 DNA ligase. .PGK-GFP.WPRE, and transformed into the host strain TOP10, picked clones, identified positive clones by colony PCR and confirmed by sequencing to obtain recombinant plasmid pRRLSIN-cPPT.EF-1 ⁇ -EGFP.WPRE.
- a downstream primer 5'-GCGGTGTCCTCGCTCCGCAGGCTGCTCAGCTCCATGTAGGCGGTG-3' (SEQ ID NO: 2) amplifying a heavy chain variable region fragment; a plasmid comprising a fragment of the 92 light chain variable region (SEQ ID NO: 79 in patent 201510481235.1)
- a light chain variable region fragment was amplified using the upstream primer 5'-GCGGAGCGAGGACACCGCCGTGTACTACTGCGCCCGGTTCTACAGCTAC-3' (SEQ ID NO: 3) and the downstream primer 5'-CGGCGCTGGCGTCGTGGTACGTTTGATCTCCAGTTTGGTG-3' (SEQ ID NO: 4).
- the above heavy and light chain variable region primers were further amplified by a duplex PCR with a 92 scFv fragment (SEQ ID NO: 5) containing a repeat sequence with the upstream CD8 ⁇ signal peptide and the downstream hinge region, designated as fragment 1, 765 bp in size.
- the PCR amplification conditions were pre-denaturation: 94 ° C, 4 min; denaturation: 94 ° C, 40 s; annealing: 58 ° C, 40 s; extension: 68 ° C, 40 s; 25 cycles, and then extended at 68 ° C for 10 min.
- the PCR amplified bands were confirmed by agarose gel electrophoresis to match the expected fragment size.
- the vector plasmid pRRLSIN-cPPT.EF- constructed in this example was used.
- 1 ⁇ -EGFP.WPRE was used as a template to amplify the EF-1 ⁇ promoter (SEQ ID NO: 8) containing the CD8 ⁇ signal peptide (containing the MluI restriction site), and was named as fragment 2, and the size was 442 bp.
- the PCR amplification conditions were pre-denaturation: 94 ° C, 4 min; denaturation: 94 ° C, 30 s; annealing: 53 ° C, 30 s; extension: 68 ° C, 30 s; 25 cycles, then total extension 68 ° C, 10 min.
- the PCR amplified bands were confirmed by agarose gel electrophoresis to match the expected fragment size.
- the upstream primer 5'-accacgacgccagcgccg-3' (SEQ ID NO: 9) and the downstream primer 5'-aatccagaggttgattgtcgacctagcgagggggcagggcctgc-3' (SEQ ID NO: 10) were used as pWPT-eGFP-F2A-GPC3-BBZ, pWPT-eGFP, respectively.
- the PCR amplification conditions were pre-denaturation: 94 ° C, 4 min; denaturation: 94 ° C, 30 s; annealing: 60 ° C, 30 s; extension: 68 ° C, 30 s; 25 cycles, then total extension 68 ° C, 10 min.
- the PCR amplified bands were confirmed by agarose gel electrophoresis to match the expected fragment size.
- the equimolar amount of about 50 ng fragment 2, fragment 1 and fragment 3 were respectively subjected to splicing PCR.
- the splicing conditions were: pre-denaturation 94 ° C, 4 min; denaturation: 94 ° C, 40 s; annealing: 60 ° C, 40 s; extension: 68 ° C, 140 s, 5 cycles, then total extension 68 ° C, 10 min, supplement DNA polymerase and upstream primer 5'-gcaggggaaagaatagtagaca-3' (SEQ ID NO: 6) and downstream primer 5'-aatccagaggttgattgtcgacctagcgagggggggggcctgc-3' (SEQ ID NO: 10 25 cycles of PCR amplification, pre-denaturation: 94 ° C, 4 min; denaturation: 94 ° C, 40 s; annealing: 60 ° C, 40 s; extension: 68 ° C, 140 s, total
- the above vector plasmids pRRLSIN-cPPT.EF-1 ⁇ -EGFP.WPRE and fragments 92-BBZ, 92-28Z and 92-28BBZ were digested with restriction endonucleases Mlu I and SalI (purchased from NEB), respectively.
- the T4 ligase purchased from NEB was ligated, transformed into TOP10, and cloned for PCR to identify positive bacteria, which were sent to Invitrogen for sequencing to confirm the correct sequence, thereby obtaining pRRL-EF-1 ⁇ -92-BBZ, pRRL-EF- 1 ⁇ -92-28Z and pRRL-EF-1 ⁇ -92-28BBZ.
- the upstream primer 5'-gcaggggaaagaatagtagaca-3' (SEQ ID NO: 6) was used first. Fragment 6 was amplified by PCR by the downstream primer 5'-TCAGAAGGTCAAAATTCAAAGTCTGTTTCACGCGAGGGGGCAGGGCCTGCATGTGAA-3' (SEQ ID NO: 17).
- plasmid HG15693-G (purchased from Beijing Yiqiao Shenzhou Biotechnology Co., Ltd., the 562th base of the 41BBL gene contains a mutation from G to A) as a template, respectively, using the upstream primer 5' -gagacgttgagtccaaccctgggcccatggaatacgcctctgacgc-3' (SEQ ID NO: 18) and the downstream primer 5'-TCGGAGGAGGCGGGTGGCAGGTCCACGGTC-3' (SEQ ID NO: 19), fragment 7 was amplified by PCR; using the upstream primer 5'-ctgccacccgcctcctcccgaggctcggaa-3' (SEQ ID NO: 20) and the downstream primer 5'-TGATTGTCGACTTATTCCGACCTCGGTGAAGGGA-3' (SEQ ID NO: 21), fragment 8 was amplified by PCR, and
- equimolar fragments 6 and 9 were spliced and amplified with primer pairs (SEQ ID NO: 6 and SEQ ID NO: 21) to give 92-28Z-F2A-41BBL (SEQ ID NO: 22).
- This fragment was digested with Mlu I and SalI, and inserted into the same digested vector pRRLSIN-cPPT.EF-1 ⁇ -EGFP.WPRE by the same method as above, and confirmed by sequencing to obtain plasmid pRRL-EF-1 ⁇ -92. -28Z-F2A-41BBL.
- first primers SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35
- Synthetic fragment 10 followed by pWPT-EGFP plasmid as template, upstream primer (SEQ ID NO: 36) and downstream primer (SEQ ID NO: 37) ), fragment 11 was amplified.
- Fragments 10 and 11 were mixed equimolarly, by bridge PCR, and using primer pairs (SEQ ID NO: 35 and SEQ ID NO: 38) After amplification, the fragment was digested with ClaI and SalI, and inserted into the same digested vector pRRLSIN-cPPT-PGK-EGFP.WPRE by the same method as above, and confirmed by sequencing to obtain three NFATs.
- fragment 14 was amplified by primer pair (SEQ ID NO: 43 and SEQ ID NO: 44) using the vector pGMT-IFN- ⁇ (purchased from Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) as a template.
- PCR amplification was performed using primer pairs (SEQ ID NO: 43 and SEQ ID NO: 38), and the amplified product was digested with Mlu I and Cla I and ligated to the same vector pRRLSIN-NFAT6- EGFP-PA2 was confirmed by sequencing to obtain the pRRLSIN-NFAT6-huIFN ⁇ -PA2 plasmid.
- the EGFP fragment 16 carrying the NdeI restriction site was amplified by primer pair (SEQ ID NO: 45 and SEQ ID NO: 46);
- a good plasmid pRRLSIN-NFAT6-EGFP-PA2 plasmid was used as a template and amplified by primer pair (SEQ ID NO: 47 and SEQ ID NO: 48) to obtain NFAT6 fragment 17 with NdeI restriction site (requires amplification of 6 Fragments of the unit, while eliminating the restriction site of SalI).
- Fragments 16 and 17 were mixed equimolarly, amplified using primer pairs (SEQ ID NO: 45 and SEQ ID NO: 48), digested with EcoRI and KpnI, ligated into the same digested vector pRRLSIN-cPPT.EF In the -1 ⁇ -EGFP.WPRE, it was verified by sequencing that the plasmid pRRLSIN-EF1 ⁇ -EGFP-NFAT6-huIFN ⁇ -PA2 was obtained.
- the plasmid pRRL-EF-1 ⁇ -92-28Z was digested with MluI and SalI to obtain a 92-28Z fragment, which was ligated into the same double-digested pRRLSIN-EF1 ⁇ -EGFP-NFAT6-huIFN ⁇ -PA2 vector.
- the correct plasmid pRRLSIN-EF1 ⁇ -92-28Z-NFAT6-hu IFN ⁇ -PA2 was sequenced.
- pRRL-EF-1 ⁇ -92-BBZ The above five plasmids pRRL-EF-1 ⁇ -92-BBZ, pRRL-EF-1 ⁇ -92-28Z, pRRL-EF-1 ⁇ -92-28BBZ, pRRL-EF-1 ⁇ -92-28Z-F2A-41BBL and pRRL- EF-1 ⁇ -92-28Z-NFAT6-huIFN ⁇ -PA2 is commonly referred to as pRRL-EF-1 ⁇ -92-CAR (Fig. 1).
- amino acid sequences corresponding to 92-BBZ, 92-28Z, 92-28BBZ and 92-28Z-F2A-41BBL are SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, respectively.
- the amino acid sequence of -28Z-NFAT6-IFN- ⁇ expression comprises two segments, respectively, a CAR constructed as 92-28Z as shown in SEQ ID NO: 50 and IFN as shown in SEQ ID NO: 53, the vector construction of which is Figure 1B shows.
- 293T cells were seeded at a density of 4.5 ⁇ 10 6 in a 10 cm culture dish, and cultured at 37 ° C, 5% CO 2 overnight to prepare a packaged virus, the medium was containing DMEM, and 10% fetal calf serum was added;
- the plasmid mixture is added to the PEI mixture, and immediately after the addition, vortex or gently mix, incubate for 20 min at room temperature;
- the concentrated lentiviral suspension is divided into 50 ⁇ l portions, stored in the finished tube and stored at -80 °C; the monotropic retrovirus is unstable, and needs to be used as soon as possible after packaging. It is not recommended to freeze at -80 °C. .
- 293T cells were seeded in a 12-well culture plate at a number of 1 ⁇ 10 5 cells;
- the concentrated lentivirus was added to the cell suspension at 1 uL, 0.2 uL and 0.04 uL, respectively, and polybrene was added to a final concentration of 6 ug/mL;
- the 293T cells were trypsinized, and after adding the same amount of medium, the cells were evenly blown, and the cell suspension was transferred into a 1.5 mL centrifuge tube;
- T-lymphocyte activation from human PBMC Blood Center of Shanghai, medium was AIM V + 2% AB serum + IL-2 (500U / mL ) to adjust the density of PBMC 1 ⁇ 10 6 / mL, 1: 1 The ratio of anti-human CD3 and CD28 antibody-coated magnetic beads was activated for 48 h;
- Retronectin coated 48-well plates 160 ⁇ l of retronectn solution (5 ⁇ g/mL) was added to each well and incubated overnight at 4 °C;
- the target cells corresponding to 92-CAR are SK-HEP-1 (GPC3-) and Huh-7 (GPC3+);
- Effector cells CAR-T cells and control T cells were added to 96-well plates at a target-to-target ratio of 0.3:1, 1:1, and 3:1;
- Each experimental group each target cell + CTL expressing a different chimeric antigen receptor
- Control group 1 maximum release of LDH from target cells
- Control group 2 spontaneous release of LDH from target cells
- Control group 3 effector cells spontaneously release LDH
- CytoTox 96 non-radioactive cytotoxicity detection kit (Promega) was used. This method is based on the colorimetric detection method and can replace the 51 Cr release method. CytoTox The degree of cell lysis is reflected by detecting the amount of lactate dehydrogenase (LDH). LDH is a stable cytoplasmic enzyme that is released when cells are lysed and released in much the same way as 51 Cr is released in radioactive analysis. The released LDH medium supernatant can be detected by a 30 minute coupled enzyme reaction in which LDH converts a tetrazolium salt (INT) to red formazan. The amount of red product produced is directly proportional to the number of cells lysed. Refer specifically to the instructions for the CytoTox 96 non-radioactive cytotoxicity test kit.
- LDH lactate dehydrogenase
- the cytotoxicity calculation formula is:
- the T cell (GPC3-CD28Z in Figure 2) expressing 92-28Z (SEQ ID NO: 15, encoding the nucleotide sequence as shown in SEQ ID NO: 57) had an infection efficiency of 35.1% and expressed 92-28Z-NFAT6-
- the infection efficiency of IFN- ⁇ T cells (GPC3-CD28Z-IFN in Figure 2) was 19.2%, and the control vector MOCK infection efficiency was 49%, as shown in Fig. 2.
- 92-CAR T after detection of infection positive rate was detected as T lymphocytes expressing 92-28Z-NFAT6-IFN- ⁇ , 92-28Z and empty vector MOCK according to the effective target ratio of 0.3:1, 1:1, 3:1.
- the in vitro killing effect of liver cancer cell lines SK-HEP-1 (GPC3 - ) and Huh-7 (GPC3 + ) and PLC/PRF/5 (GPC3 + ) was detected after 18 hours of co-culture, and the content of LDH in the supernatant was detected.
- the present inventors further integrated 92-28Z-NFAT6-IFN- ⁇ with other GPC3-BBZ, GPC3-28BBZ and GPC3-41BBL constructed by the same extracellular antigen binding unit 92 (SEQ ID NO: 5) (on a CD28Z basis). Expression of 4-1BBL) compared to CAR-T cells.
- FACS detects the expression of various CARs (see Figure 3). The expression ratio of various CARs is about 40%.
- Example 3 In vitro induction of cytokine release assay by GPC3 CAR-T cells containing IFN and no IFN
- the cytokines released by untransfected T cells, 92-28Z T cells, and 92-28Z-IFN T cells were detected, respectively. Collect the above three T cells with good growth within 1-2 weeks after lentivirus infection, inoculate 5 ⁇ 10 4 /200 ⁇ L (positive cell number) in 24-well plates, and inoculate 5 ⁇ 10 4 /200 ⁇ L/24 wells in the same manner.
- the huh7 cells were incubated with CAR T cells for 24 hours, and the supernatant was collected to measure the concentrations of IFN- ⁇ , IFN- ⁇ , and IL-2, and the results are shown in Figures 4A-4C.
- FIG. 4A only GPC3-28Z-IFN T was incubated with Huh7 cells for IFN ⁇ expression, indicating that GPC3-28Z-IFN T cells were successfully induced to express and secreted outside the cell after being activated by the target antigen.
- the results indicate that GPC3-28Z-IFN T cells can be more effective in a variety of GPC3-positive cells, such as Huh7, PLC ⁇ PRF ⁇ 5, Hep-3B and other cells. Is activated.
- Example 4 In vitro induction of cytokine release assay by CLD18A2 CAR-T cells containing IFN and no IFN
- the second generation chimeric antigen receptors 85-28Z (SEQ ID NO: 55) and 85-2-28Z (SEQ ID NO:) expressing antibodies 85 and 85-2 were constructed using PRRLSIN-cPPT.EF-1 ⁇ as a vector. 54) Lentiviral plasmid.
- the 85-28Z sequence consists of the CD8 ⁇ signal peptide, 85scFV, CD8hinge, CD28 transmembrane and intracellular signaling domain regions, and the intracellular CD3 ⁇ of CD3; the sequence of 85-2-28Z is composed of CD8 ⁇ signal peptide, hu8E5-2IscFV, The CD8 hinge region, the CD28 transmembrane region and the intracellular signaling domain region, and the intracellular CD3 ⁇ of CD3 are composed.
- 85-28Z-IFNb CAR (encoding nucleotide sequence as shown in SEQ ID NO: 58) expressing IFNb cytokine was constructed on the basis of 85-28Z and 85-2-28Z, at 85-2-28Z CAR Based on the construction of 85-2-28Z-IFNb CAR (encoding nucleotide sequence as shown in SEQ ID NO: 59) which can express IFNb cytokines.
- Cytokines released from transfected T cells (Mock), 85-28Z T cells, and 85-28Z-IFN T cells were detected, respectively. Collect the above three T cells with good growth within 1-2 weeks after lentivirus infection, inoculate 5 ⁇ 104/200 ⁇ L (positive cell number) in 24-well plates, and inoculate 5 ⁇ 104/200 ⁇ L according to the effective target ratio of 1:1. /24 pore target cells.
- Target cells include 293T-A1, 293T-A2, AGS, AGS-A2, BGC-823, and BGC-823-A2 cells.
- the supernatant was collected after 24 hours of co-cultivation.
- the IFN- ⁇ cytokine released during the co-culture of CAR T lymphocytes with target cells in the supernatant was detected by sandwich ELISA.
- SK-HEP-1 is a GPC3-negative human hepatocellular carcinoma cell line
- PLC/PRF/5 is a GPC3-positive human hepatocellular carcinoma cell line
- HepG2 is a GPC3-positive human hepatocellular carcinoma cell line
- Hep3B is a GPC3-positive person.
- Hepatocellular carcinoma cell lines were purchased from the American Type Culture Collection (ATCC); Huh-7 (also known as Huh7) was a GPC3-positive human hepatocellular carcinoma cell line purchased from the Japanese RIKEN cell bank.
- CytoTox 96 non-radioactive cytotoxicity test kit (Promega) was used for detection (specific method can refer to CytoTox 96 non-radioactive cytotoxicity test kit instructions), and detected CAR T lymphocytes to Huh 7, Hep 3B, PLC /PRF/5, Hep G2 and SK-HEP-1 liver cancer cells in vitro toxicity killing effect.
- the untransfected T cells, 92-28Z T cells and 92-28Z-IFN T cells were co-cultured with tumor cells at a ratio of 1:3, 1:1 and 3:1 for 18 h.
- the settings of each experimental group and each control group are as follows:
- the experimental group was set up: each target cell + T lymphocytes expressing different chimeric antigen receptors;
- Control group 1 spontaneous release of LDH from effector cells
- Control group 2 spontaneous release of LDH from target cells
- Control group 3 maximum LDH release from target cells
- Control group 4 volume corrected control
- Control group 5 medium background control.
- 293T-A1 and 293T-A2 cells are human kidney epithelial cell lineages stably expressing CLD18A1 and CLD18A2 in vitro.
- AGS and BGC-823 are human gastric cancer cell lines, and on this basis, AGS-A2 and BGC-823-A2 cell lines stably expressing CLD18A2 were constructed.
- CytoTox 96 non-radioactive cytotoxicity test kit (Promega) was used for detection (refer to the CytoTox 96 non-radioactive cytotoxicity test kit for specific methods), and CAR T lymphocytes were detected for 293T-A1, 293T-A2. , AGS, AGS-A2, BGC-823, BGC-823-A2 cells in vitro toxicity killing effect.
- effector cells spontaneous LDH release correcting the spontaneous release of LDH by effector cells
- target cell spontaneous LDH release correcting the spontaneous release of LDH from target cells
- volume correction control correct volume change due to the addition of lysate (10 ⁇ );
- % cytotoxicity [(experimental group - effector cell control - target cell control) / (maximum amount of target cell lysis - target cell control)] x 100.
- the effector cell control, the target cell control, and the experimental group lost the medium control; the target cell maximum lysis amount was subtracted from the volume control.
- CAR-T GPC3-28ZT cells or GPC3-28Z-IFN T cells
- CAR-T cells GPC3-28Z cells
- T cells or GPC3-28Z-IFN T cells survive in vivo.
- Table 4 The number of T cells (CD3+) and CAR-T cells per ⁇ l of peripheral blood in the GPC3-28Z-IFN T cell group were higher than those in the GPC3-28ZT cell group and the Mock group.
- CD3+ (pieces / ⁇ L)
- CAR-T (pieces / ⁇ L) Mock 193.1453 0
- GPC3-28Z 375.802 232.2
- GPC3-28Z-IFN 1034.315 439.5
- Example 8 Determination of in vivo survival time of CLD18A2 CAR-T cells
- the gastric cancer PDX tumor of about 2 ⁇ 2 ⁇ 2 mm was inoculated subcutaneously into the right axillary part of NOD/SCID mice, and the day of tumor cell inoculation was recorded as D0 days.
- CAR-T cells 85-2-28Z T cells or 85-2-28Z-
- IFN T cells IFN T cells
- Peripheral blood was collected from mouse saphenous veins on D5, D7 and D10 after CAR-T infusion, respectively, and CAR-T cells (empty T cells (Mock), 85-2-28Z T cells or 85- were detected. Survival of 2-28Z-IFN T cells in vivo.
- Example 9 In vivo killing activity of GPC3CAR-T (92-28Z) cells containing IFN and no IFN
- Anti-tumor treatment experiments of Huh7 subcutaneous xenografts were performed on untransfected T cells (Mock), GPC3-28Z T cells and GPC3-28Z-IFN T cells.
- Huh7 cells in a logarithmic growth phase and in good growth state were collected and adjusted to a density of 1 ⁇ 10 7 /mL using physiological saline, and a mouse model was made by inoculating NOD-SCID mice, and the injection volume was about 200 ⁇ L. (2 ⁇ 10 6 /only), the day of tumor cell inoculation is the 0th day.
- Example 10 In vivo killing activity of CLD18A2 CAR-T cells containing IFN and no IFN
- BGC-823-A2 cells collected in logarithmic growth phase and grown well were adjusted to a density of 2.5 ⁇ 10 7 /mL using physiological saline, and the volume of the injected cell suspension was 200 ⁇ L ( 5 ⁇ 10 6 / only) subcutaneously in the right axilla of mice. The day of tumor cell inoculation is recorded as day 0.
- Adoptive transfer of T cells 100 mg/kg of cyclophosphamide was intraperitoneally injected at a tumor volume of 100-150 mm 3 (Day 11), and 1 ⁇ 10 7 CAR T cells were infused through the tail vein 24 hours after injection (Mock) Cells, 85-28Z T, 85-2-28Z T cells or 85-2-28Z-IFN cells), while using the untransfected T cell group (Mock group) as a control, were observed to measure the growth of subcutaneous xenografts.
- Example 11 Anti-tumor test of CLD18A2 CAR-T cells containing IFN and no IFN in subcutaneous xenografts of gastric cancer PDX model
- T cells 100 mg/kg of cyclophosphamide was intraperitoneally injected at a tumor volume of 30 mm3, and 1.0 ⁇ 107 CAR-T cells (85-2-28Z T cells or 85-) were infused through the tail vein 24 hours after the injection. 2-28Z-IFN T cells), while the untransfected T cell group was used as a control. Observe and measure the growth of subcutaneous xenografts of gastric cancer PDX.
- Example 12 Effect of GPC3CAR-T (92-28Z) cells containing IFN and no IFN on tumor invasion in vivo
- Example 13 Effect of CLD18A2 CAR-T cells containing IFN and no IFN on tumor invasion in vivo
- Mock T cells showed almost no T cell infiltration around the tumor tissue.
- 85-28Z and 85-2-28Z CAR T cells were visible at the edge of the tumor tissue, while 85-2-28Z - IFN T cells can observe some infiltration within the tumor tissue.
- mice infected with retrovirus were retroviral packaging system, which were EGFR-CAR and EGFR-CAR-IFN, respectively.
- the positive infection rates were 65.1% and 35.2%, respectively (Fig. 15).
- Example 15 Determination of in vitro secretion of mIFN ⁇ by EGFR CAR (806-28Z) T cells containing IFN and no IFN
- Example 17 in vitro toxicity test of EGFR CAR (806-28Z)-T cells containing IFN and no IFN
- Example 18 in vivo toxicity test of EGFR CAR (806-28Z)-T cells containing IFN and no IFN
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Cell Biology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Plant Pathology (AREA)
- Dermatology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
La présente invention concerne un procédé d'amélioration de la fonction d'une cellule de réponse immunitaire et une cellule de réponse immunitaire qui exprime au moins un récepteur susceptible de liaison avec un antigène et un interféron de type I. La cellule présente une capacité considérable de tuer les tumeurs ou les pathogènes et peut être utilisée pour traiter les tumeurs et les maladies infectieuses.
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201780021791.8A CN108884459B (zh) | 2016-04-26 | 2017-04-26 | 一种改善免疫应答细胞功能的方法 |
PCT/CN2017/092381 WO2018006882A1 (fr) | 2016-07-08 | 2017-07-10 | Anticorps dirigé contre la claudine 18a2 et son utilisation |
IL264144A IL264144B2 (en) | 2016-07-08 | 2017-07-10 | Antibody 18A2 against CLAUDIN and its use |
CN201780042611.4A CN109790222B (zh) | 2016-07-08 | 2017-07-10 | 抗密蛋白18a2的抗体及其应用 |
KR1020197003874A KR20190038564A (ko) | 2016-07-08 | 2017-07-10 | 항클라우딘 18a2의 항체 및 이의 응용 |
EP17823694.9A EP3483182B1 (fr) | 2016-07-08 | 2017-07-10 | Anticorps dirigé contre la claudine 18a2 et son utilisation |
CA3030257A CA3030257A1 (fr) | 2016-07-08 | 2017-07-10 | Anticorps dirige contre la claudine 18a2 et son utilisation |
BR112019000327A BR112019000327A8 (pt) | 2016-07-08 | 2017-07-10 | Anticorpo para anticlaudina 18a2 e uso do mesmo |
US16/316,331 US11111295B2 (en) | 2016-07-08 | 2017-07-10 | Antibody for anti-claudin 18A2 and use thereof |
RU2019101430A RU2793445C2 (ru) | 2016-07-08 | 2017-07-10 | Антитело против клаудина 18а2 и его применение |
SG11201900171QA SG11201900171QA (en) | 2016-07-08 | 2017-07-10 | Antibody for anti-claudin 18a2 and use thereof |
JP2019521178A JP2019531084A (ja) | 2016-07-08 | 2017-07-10 | 抗クローディンタンパク質18a2の抗体及びその応用 |
AU2017294276A AU2017294276A1 (en) | 2016-07-08 | 2017-07-10 | Antibody for anti-claudin 18A2 and use thereof |
CL2019000061A CL2019000061A1 (es) | 2016-07-08 | 2019-01-08 | Anticuerpo para anti-claudin 18a2 y su utilización. |
US17/395,223 US20220185880A1 (en) | 2016-07-08 | 2021-08-05 | Antibody for anti-claudin 18a2 and use thereof |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610265614 | 2016-04-26 | ||
CN201610265614.1 | 2016-04-26 | ||
CN201610536449.9 | 2016-07-08 | ||
CN201610536449 | 2016-07-08 | ||
CN201611148447 | 2016-12-13 | ||
CN201611148447.9 | 2016-12-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017186121A1 true WO2017186121A1 (fr) | 2017-11-02 |
Family
ID=60160697
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2017/082024 WO2017186121A1 (fr) | 2016-04-26 | 2017-04-26 | Procédé d'amélioration de la fonction d'une cellule de réponse immunitaire |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN108884459B (fr) |
WO (1) | WO2017186121A1 (fr) |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109265561A (zh) * | 2018-09-25 | 2019-01-25 | 山东兴瑞生物科技有限公司 | 抗EGFRvⅢ安全型嵌合抗原受体、其制备方法、利用其修饰的NK细胞及应用 |
US20190046659A1 (en) * | 2015-08-03 | 2019-02-14 | Carsgen Therapeutics Ltd | Antibody against glypican-3 and application thereof |
EP3327036A4 (fr) * | 2015-07-21 | 2019-03-13 | Carsgen Therapeutics Co., Ltd. | Anticorps anti-egfr spécifique d'une tumeur et application associée |
CN110055275A (zh) * | 2018-01-19 | 2019-07-26 | 科济生物医药(上海)有限公司 | 一种质粒载体对、其修饰的免疫细胞及其应用 |
WO2019149279A1 (fr) | 2018-02-02 | 2019-08-08 | 科济生物医药(上海)有限公司 | Association d'immunothérapie cellulaire |
WO2019179871A1 (fr) | 2018-03-19 | 2019-09-26 | Svar Life Science Ab | Système et procédé de quantification améliorée d'activité d'adcc et d'adcp |
WO2019219029A1 (fr) | 2018-05-15 | 2019-11-21 | 科济生物医药(上海)有限公司 | Cellule génétiquement modifiée et application de cette dernière |
WO2020114518A1 (fr) | 2018-12-07 | 2020-06-11 | 科济生物医药(上海)有限公司 | Polyimmunothérapie anti-tumorale |
CN111315402A (zh) * | 2017-08-15 | 2020-06-19 | 艾达普特免疫有限公司 | T细胞修饰 |
WO2020143631A1 (fr) | 2019-01-07 | 2020-07-16 | 科济生物医药(上海)有限公司 | Association pour immunothérapie cellulaire |
WO2020156554A1 (fr) | 2019-02-01 | 2020-08-06 | 科济生物医药(上海)有限公司 | Protéine de fusion tcr et cellule exprimant une protéine de fusion tcr |
CN111989344A (zh) * | 2018-03-09 | 2020-11-24 | 科济生物医药(上海)有限公司 | 用于治疗肿瘤的方法和组合物 |
EP3753566A1 (fr) * | 2019-06-21 | 2020-12-23 | Medizinische Hochschule Hannover | Vecteur viral tout-en-un pour molécules car et effectrices thérapeutiques |
CN112402596A (zh) * | 2019-08-22 | 2021-02-26 | 上海细胞治疗集团有限公司 | 多肽组合物及疫苗 |
CN112481304A (zh) * | 2020-09-27 | 2021-03-12 | 镇江维根生物科技有限公司 | 一种多功能病毒载体的构建和应用 |
WO2022028623A1 (fr) | 2020-08-07 | 2022-02-10 | 佧珐药业有限公司 | Cellules modifiées et procédé de modification de cellules |
US20220185880A1 (en) * | 2016-07-08 | 2022-06-16 | Cafa Therapeutics Limited | Antibody for anti-claudin 18a2 and use thereof |
WO2023278641A1 (fr) * | 2021-06-29 | 2023-01-05 | Flagship Pioneering Innovations V, Inc. | Cellules immunitaires modifiées pour favoriser la thanotransmission de phényléthanolamines et leurs utilisations |
WO2023274303A1 (fr) | 2021-06-29 | 2023-01-05 | 科济生物医药(上海)有限公司 | Polypeptide chimérique pour la régulation de l'activité physiologique cellulaire |
EP3952885A4 (fr) * | 2019-04-12 | 2023-01-18 | The Trustees of The University of Pennsylvania | Compositions et procédés comprenant un récepteur antigénique chimérique (car) de haute affinité possédant une réactivité croisée à des protéines mutées d'egfr présentant une pertinence clinique |
CN115925948A (zh) * | 2021-12-16 | 2023-04-07 | 华道(上海)生物医药有限公司 | 一种抗cd22纳米抗体及其应用 |
WO2023213280A1 (fr) * | 2022-05-06 | 2023-11-09 | 上海先博生物科技有限公司 | Récepteur de lymphocytes t antigéniques chimériques ciblant la cldn18.2 et son utilisation |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3907280A4 (fr) * | 2018-12-13 | 2022-06-22 | CRAGE medical Co., Limited | Cellules effectrices immunitaires ciblant gpc3 et leur utilisation |
WO2022214089A1 (fr) | 2021-04-08 | 2022-10-13 | 克莱格医学有限公司 | Utilisation d'immunothérapie cellulaire |
CN113604437A (zh) * | 2021-08-13 | 2021-11-05 | 青岛华赛伯曼医学细胞生物有限公司 | 过表达ccr2的免疫细胞及其应用 |
CN114214330A (zh) * | 2021-12-20 | 2022-03-22 | 杭州百凌生物科技有限公司 | 一种检测脊索瘤的质控品及其制备方法和应用 |
CN114317610A (zh) * | 2022-01-27 | 2022-04-12 | 上海本导基因技术有限公司 | 一种适用于帕金森疾病基因治疗的慢病毒载体 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014138348A1 (fr) * | 2013-03-06 | 2014-09-12 | The Trustees Of The University Of Pennsylvania | Inhibition d'ikaros pour augmenter le transfert adoptif de cellules t |
CN104159909A (zh) * | 2012-02-22 | 2014-11-19 | 宾夕法尼亚大学董事会 | 产生用于癌症治疗的t细胞持续性群体的组合物和方法 |
CN104789595A (zh) * | 2015-04-20 | 2015-07-22 | 范国煌 | 嵌合抗原受体双阴性t细胞的构建方法 |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7355024B2 (en) * | 2002-01-11 | 2008-04-08 | Gmp Endotherapeutics, Inc. | Regulatory sequences for modulation of INGAP expression and reporter constructs |
US7728118B2 (en) * | 2004-09-17 | 2010-06-01 | Promega Corporation | Synthetic nucleic acid molecule compositions and methods of preparation |
KR101243577B1 (ko) * | 2004-10-07 | 2013-03-20 | 아고스 쎄라퓨틱스, 인코포레이티드 | 성숙 수지상 세포 조성물 및 그의 배양 방법 |
CN101289653A (zh) * | 2007-04-16 | 2008-10-22 | 上海市肿瘤研究所 | 尼古丁处理后树突状细胞用于预防和治疗肿瘤 |
CN102010892A (zh) * | 2009-09-07 | 2011-04-13 | 上海市免疫学研究所 | β-干扰素免疫干预类风湿关节炎的体外评价方法 |
CN102008716A (zh) * | 2009-09-07 | 2011-04-13 | 上海市免疫学研究所 | β-干扰素在制药中的用途 |
NZ609967A (en) * | 2010-10-27 | 2015-04-24 | Baylor College Medicine | Chimeric cd27 receptors for redirecting t cells to cd70-positive malignancies |
NZ743310A (en) * | 2011-03-23 | 2022-11-25 | Fred Hutchinson Cancer Center | Method and compositions for cellular immunotherapy |
CN104087607B (zh) * | 2013-04-01 | 2017-06-20 | 科济生物医药(上海)有限公司 | 编码嵌合抗原受体蛋白的核酸及表达嵌合抗原受体蛋白的t淋巴细胞 |
CN107460201A (zh) * | 2013-05-08 | 2017-12-12 | 科济生物医药(上海)有限公司 | 编码gpc‑3嵌合抗原受体蛋白的核酸及表达gpc‑3嵌合抗原受体蛋白的t淋巴细胞 |
CN105030825A (zh) * | 2015-07-27 | 2015-11-11 | 深圳爱生再生医学科技有限公司 | mRNA-DC肺癌治疗性疫苗及其增强性制备方法和CTL细胞 |
CN105153315B (zh) * | 2015-10-09 | 2019-04-02 | 重庆精准生物技术有限公司 | 免疫抑制受体联合肿瘤抗原嵌合受体及其应用 |
CN105331585A (zh) * | 2015-11-13 | 2016-02-17 | 科济生物医药(上海)有限公司 | 携带pd-l1阻断剂的嵌合抗原受体修饰的免疫效应细胞 |
ES2937699T3 (es) * | 2016-04-22 | 2023-03-30 | Crage Medical Co Ltd | Composiciones y métodos de inmunoterapia celular |
EA201990930A1 (ru) * | 2016-10-24 | 2019-11-29 | Способы, композиции и режимы дозирования для лечения или профилактики связанных с интерфероном-гамма заболеваний | |
CN108866003A (zh) * | 2017-05-16 | 2018-11-23 | 科济生物医药(上海)有限公司 | 基因工程化的细胞及应用 |
CN109468279A (zh) * | 2017-09-08 | 2019-03-15 | 科济生物医药(上海)有限公司 | 靶向gpc3的免疫效应细胞及其应用 |
US20230071098A1 (en) * | 2018-07-17 | 2023-03-09 | Noile-Immune Biotech, Inc. | Anti-gpc3 single-chain antibody-containing car |
WO2021052496A1 (fr) * | 2019-09-20 | 2021-03-25 | 科济生物医药(上海)有限公司 | Cellule effectrice immunitaire dans laquelle l'expression est régulée par des cytokines |
-
2017
- 2017-04-26 CN CN201780021791.8A patent/CN108884459B/zh active Active
- 2017-04-26 WO PCT/CN2017/082024 patent/WO2017186121A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104159909A (zh) * | 2012-02-22 | 2014-11-19 | 宾夕法尼亚大学董事会 | 产生用于癌症治疗的t细胞持续性群体的组合物和方法 |
WO2014138348A1 (fr) * | 2013-03-06 | 2014-09-12 | The Trustees Of The University Of Pennsylvania | Inhibition d'ikaros pour augmenter le transfert adoptif de cellules t |
CN104789595A (zh) * | 2015-04-20 | 2015-07-22 | 范国煌 | 嵌合抗原受体双阴性t细胞的构建方法 |
Cited By (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3327036A4 (fr) * | 2015-07-21 | 2019-03-13 | Carsgen Therapeutics Co., Ltd. | Anticorps anti-egfr spécifique d'une tumeur et application associée |
US20190046659A1 (en) * | 2015-08-03 | 2019-02-14 | Carsgen Therapeutics Ltd | Antibody against glypican-3 and application thereof |
US20220185880A1 (en) * | 2016-07-08 | 2022-06-16 | Cafa Therapeutics Limited | Antibody for anti-claudin 18a2 and use thereof |
CN111315402B (zh) * | 2017-08-15 | 2024-05-07 | 艾达普特免疫有限公司 | T细胞修饰 |
CN111315402A (zh) * | 2017-08-15 | 2020-06-19 | 艾达普特免疫有限公司 | T细胞修饰 |
CN110055275A (zh) * | 2018-01-19 | 2019-07-26 | 科济生物医药(上海)有限公司 | 一种质粒载体对、其修饰的免疫细胞及其应用 |
WO2019149279A1 (fr) | 2018-02-02 | 2019-08-08 | 科济生物医药(上海)有限公司 | Association d'immunothérapie cellulaire |
CN110123837A (zh) * | 2018-02-02 | 2019-08-16 | 科济生物医药(上海)有限公司 | 细胞免疫治疗的组合 |
EP3747433A4 (fr) * | 2018-02-02 | 2021-12-22 | Cafa Therapeutics Limited | Association d'immunothérapie cellulaire |
EP3778649A4 (fr) * | 2018-03-09 | 2022-05-04 | CRAGE medical Co., Limited | Méthode et composition de traitement de tumeurs |
CN111989344A (zh) * | 2018-03-09 | 2020-11-24 | 科济生物医药(上海)有限公司 | 用于治疗肿瘤的方法和组合物 |
US20220110973A1 (en) * | 2018-03-09 | 2022-04-14 | Cafa Therapeutics Limited | Method and composition for treating tumors |
JP2021523090A (ja) * | 2018-03-09 | 2021-09-02 | 科済生物医薬(上海)有限公司Carsgen Therapeutics Co.,Ltd. | 腫瘍を治療するための方法および組成物 |
KR102593359B1 (ko) | 2018-03-19 | 2023-10-24 | 사바 라이프 사이언스 에이비 | Adcc 및 adcp 활성의 향상된 정량화를 위한 시스템 및 제품 |
WO2019179871A1 (fr) | 2018-03-19 | 2019-09-26 | Svar Life Science Ab | Système et procédé de quantification améliorée d'activité d'adcc et d'adcp |
JP2021518123A (ja) * | 2018-03-19 | 2021-08-02 | スワール ライフ サイエンス エービー | Adcc及びadcp活性の改善された定量化のためのシステム及び製品 |
KR20200131865A (ko) * | 2018-03-19 | 2020-11-24 | 사바 라이프 사이언스 에이비 | Adcc 및 adcp 활성의 향상된 정량화를 위한 시스템 및 제품 |
JP7059390B2 (ja) | 2018-03-19 | 2022-04-25 | スワール ライフ サイエンス エービー | Adcc及びadcp活性の改善された定量化のためのシステム及び製品 |
WO2019219029A1 (fr) | 2018-05-15 | 2019-11-21 | 科济生物医药(上海)有限公司 | Cellule génétiquement modifiée et application de cette dernière |
CN112154204A (zh) * | 2018-05-15 | 2020-12-29 | 科济生物医药(上海)有限公司 | 基因工程化的细胞及应用 |
CN109265561A (zh) * | 2018-09-25 | 2019-01-25 | 山东兴瑞生物科技有限公司 | 抗EGFRvⅢ安全型嵌合抗原受体、其制备方法、利用其修饰的NK细胞及应用 |
WO2020114518A1 (fr) | 2018-12-07 | 2020-06-11 | 科济生物医药(上海)有限公司 | Polyimmunothérapie anti-tumorale |
WO2020143631A1 (fr) | 2019-01-07 | 2020-07-16 | 科济生物医药(上海)有限公司 | Association pour immunothérapie cellulaire |
WO2020156554A1 (fr) | 2019-02-01 | 2020-08-06 | 科济生物医药(上海)有限公司 | Protéine de fusion tcr et cellule exprimant une protéine de fusion tcr |
EP3919517A4 (fr) * | 2019-02-01 | 2023-03-15 | CRAGE medical Co., Limited | Protéine de fusion tcr et cellule exprimant une protéine de fusion tcr |
EP3952885A4 (fr) * | 2019-04-12 | 2023-01-18 | The Trustees of The University of Pennsylvania | Compositions et procédés comprenant un récepteur antigénique chimérique (car) de haute affinité possédant une réactivité croisée à des protéines mutées d'egfr présentant une pertinence clinique |
WO2020254694A1 (fr) * | 2019-06-21 | 2020-12-24 | Medizinische Hochschule Hannover | Vecteur tout-en-un pour un car et molécule effectrice thérapeutique |
EP3753566A1 (fr) * | 2019-06-21 | 2020-12-23 | Medizinische Hochschule Hannover | Vecteur viral tout-en-un pour molécules car et effectrices thérapeutiques |
CN112402596A (zh) * | 2019-08-22 | 2021-02-26 | 上海细胞治疗集团有限公司 | 多肽组合物及疫苗 |
CN112402596B (zh) * | 2019-08-22 | 2023-12-08 | 上海细胞治疗集团有限公司 | 多肽组合物及疫苗 |
WO2022028623A1 (fr) | 2020-08-07 | 2022-02-10 | 佧珐药业有限公司 | Cellules modifiées et procédé de modification de cellules |
CN112481304A (zh) * | 2020-09-27 | 2021-03-12 | 镇江维根生物科技有限公司 | 一种多功能病毒载体的构建和应用 |
WO2023274303A1 (fr) | 2021-06-29 | 2023-01-05 | 科济生物医药(上海)有限公司 | Polypeptide chimérique pour la régulation de l'activité physiologique cellulaire |
WO2023278641A1 (fr) * | 2021-06-29 | 2023-01-05 | Flagship Pioneering Innovations V, Inc. | Cellules immunitaires modifiées pour favoriser la thanotransmission de phényléthanolamines et leurs utilisations |
CN115925948B (zh) * | 2021-12-16 | 2023-07-07 | 华道(上海)生物医药有限公司 | 一种抗cd22纳米抗体及其应用 |
CN115925948A (zh) * | 2021-12-16 | 2023-04-07 | 华道(上海)生物医药有限公司 | 一种抗cd22纳米抗体及其应用 |
WO2023213280A1 (fr) * | 2022-05-06 | 2023-11-09 | 上海先博生物科技有限公司 | Récepteur de lymphocytes t antigéniques chimériques ciblant la cldn18.2 et son utilisation |
Also Published As
Publication number | Publication date |
---|---|
CN108884459A (zh) | 2018-11-23 |
CN108884459B (zh) | 2024-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2017186121A1 (fr) | Procédé d'amélioration de la fonction d'une cellule de réponse immunitaire | |
US20220185880A1 (en) | Antibody for anti-claudin 18a2 and use thereof | |
US20230181643A1 (en) | Use of trans-signaling approach in chimeric antigen receptors | |
AU2017225161B2 (en) | Use of chimeric antigen receptor-modified t cells to treat cancer | |
JP7145761B2 (ja) | 細胞免疫療法の組成物および方法 | |
US20210032661A1 (en) | Methods And Compositions Comprising A Viral Vector For Expression Of A Transgene And An Effector | |
US9688740B2 (en) | Mutant CTLA4 gene transfected T cell and composition including same for anticancer immunotherapy | |
JP2019508027A (ja) | T細胞免疫療法のための方法および組成物 | |
US20200370013A1 (en) | Engineered Expression of Cell Surface and Secreted Sialidase by CAR T Cells for Increased Efficacy in Solid Tumors | |
BR112015027567B1 (pt) | Polipeptídeo, sequência de ácido nucleico isolada, vetor, método de obtenção de célula, uso de uma célula | |
JP2014509841A (ja) | 癌を治療するための組成物および方法 | |
CN118146379A (zh) | 一种改善免疫应答细胞功能的方法 | |
US20240165231A1 (en) | Car-t delivery of synthetic peptide therapeutics | |
RU2793445C2 (ru) | Антитело против клаудина 18а2 и его применение | |
WO2023086882A1 (fr) | Compositions et méthodes comprenant des lymphocytes t car présentant une inactivation de prdm1 et/ou nr4a3 | |
JP2023500671A (ja) | がんのt細胞治療のための細胞傷害性エフェクターメモリーt細胞の産生方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201780021791.8 Country of ref document: CN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17788773 Country of ref document: EP Kind code of ref document: A1 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 17788773 Country of ref document: EP Kind code of ref document: A1 |