JP2017506513A - キメラ抗原受容体及びその製造方法 - Google Patents
キメラ抗原受容体及びその製造方法 Download PDFInfo
- Publication number
- JP2017506513A JP2017506513A JP2016551764A JP2016551764A JP2017506513A JP 2017506513 A JP2017506513 A JP 2017506513A JP 2016551764 A JP2016551764 A JP 2016551764A JP 2016551764 A JP2016551764 A JP 2016551764A JP 2017506513 A JP2017506513 A JP 2017506513A
- Authority
- JP
- Japan
- Prior art keywords
- vector
- cell
- cells
- car
- cd3ζ
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 title claims abstract description 345
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 239000013598 vector Substances 0.000 claims abstract description 253
- 239000000427 antigen Substances 0.000 claims abstract description 142
- 108091007433 antigens Proteins 0.000 claims abstract description 142
- 102000036639 antigens Human genes 0.000 claims abstract description 142
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 201
- 210000004027 cell Anatomy 0.000 claims description 188
- 238000000034 method Methods 0.000 claims description 117
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 78
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 78
- 206010028980 Neoplasm Diseases 0.000 claims description 63
- 238000002744 homologous recombination Methods 0.000 claims description 58
- 230000006801 homologous recombination Effects 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 52
- 230000014509 gene expression Effects 0.000 claims description 50
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 46
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 46
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 46
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 46
- 240000007019 Oxalis corniculata Species 0.000 claims description 42
- 102100027207 CD27 antigen Human genes 0.000 claims description 41
- 102100025278 Coxsackievirus and adenovirus receptor Human genes 0.000 claims description 41
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 41
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 claims description 37
- 201000011510 cancer Diseases 0.000 claims description 36
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 claims description 32
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 29
- 102000008579 Transposases Human genes 0.000 claims description 25
- 108010020764 Transposases Proteins 0.000 claims description 25
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 21
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims description 21
- 238000005215 recombination Methods 0.000 claims description 21
- 230000006798 recombination Effects 0.000 claims description 20
- 102000004127 Cytokines Human genes 0.000 claims description 18
- 108090000695 Cytokines Proteins 0.000 claims description 18
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- 210000000822 natural killer cell Anatomy 0.000 claims description 15
- 108020004707 nucleic acids Proteins 0.000 claims description 15
- 102000039446 nucleic acids Human genes 0.000 claims description 15
- 150000007523 nucleic acids Chemical class 0.000 claims description 15
- 230000035755 proliferation Effects 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 14
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 14
- -1 CD3e Proteins 0.000 claims description 13
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 241000233866 Fungi Species 0.000 claims description 12
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 12
- 230000034994 death Effects 0.000 claims description 12
- 210000000130 stem cell Anatomy 0.000 claims description 12
- 244000052769 pathogen Species 0.000 claims description 11
- 229920001184 polypeptide Polymers 0.000 claims description 11
- 150000001720 carbohydrates Chemical class 0.000 claims description 9
- 238000012360 testing method Methods 0.000 claims description 9
- 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 claims description 8
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 claims description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 8
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 8
- 101000641826 Mycobacterium phage L5 Gene 75 protein Proteins 0.000 claims description 8
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 8
- 230000001717 pathogenic effect Effects 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 7
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 7
- 230000004927 fusion Effects 0.000 claims description 7
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 6
- 241000228212 Aspergillus Species 0.000 claims description 6
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 claims description 6
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 claims description 6
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 claims description 6
- 241000192019 Human endogenous retrovirus K Species 0.000 claims description 6
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 claims description 6
- 210000004263 induced pluripotent stem cell Anatomy 0.000 claims description 6
- 210000000581 natural killer T-cell Anatomy 0.000 claims description 6
- 230000028327 secretion Effects 0.000 claims description 6
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 5
- 108010058905 CD44v6 antigen Proteins 0.000 claims description 5
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 5
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 claims description 5
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 5
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 5
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 5
- 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 5
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 4
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 4
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 4
- 102100024217 CAMPATH-1 antigen Human genes 0.000 claims description 4
- 108010065524 CD52 Antigen Proteins 0.000 claims description 4
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 claims description 4
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 4
- 101100239628 Danio rerio myca gene Proteins 0.000 claims description 4
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 4
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 claims description 4
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 4
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 4
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 4
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain 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
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims description 4
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 claims description 4
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 4
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 108090000015 Mesothelin Proteins 0.000 claims description 4
- 102000003735 Mesothelin Human genes 0.000 claims description 4
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 4
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 4
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims description 4
- 241000277331 Salmonidae Species 0.000 claims description 4
- 102100035721 Syndecan-1 Human genes 0.000 claims description 4
- 230000006052 T cell proliferation Effects 0.000 claims description 4
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 4
- 229960002685 biotin Drugs 0.000 claims description 4
- 235000020958 biotin Nutrition 0.000 claims description 4
- 239000011616 biotin Substances 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 230000016396 cytokine production Effects 0.000 claims description 4
- 238000003384 imaging method Methods 0.000 claims description 4
- 230000036210 malignancy Effects 0.000 claims description 4
- 108010054624 red fluorescent protein Proteins 0.000 claims description 4
- 230000004936 stimulating effect Effects 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 230000004069 differentiation Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 208000025321 B-lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 102000019034 Chemokines Human genes 0.000 claims description 2
- 108010012236 Chemokines Proteins 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 230000006786 activation induced cell death Effects 0.000 claims description 2
- 230000007348 cell dedifferentiation Effects 0.000 claims description 2
- 230000012292 cell migration Effects 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 210000000987 immune system Anatomy 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 238000005259 measurement Methods 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 claims 2
- 241000545067 Venus Species 0.000 claims 2
- 208000011654 childhood malignant neoplasm Diseases 0.000 claims 1
- 230000005012 migration Effects 0.000 claims 1
- 238000013508 migration Methods 0.000 claims 1
- 238000012216 screening Methods 0.000 abstract description 2
- 239000013612 plasmid Substances 0.000 description 29
- 108020004414 DNA Proteins 0.000 description 27
- 230000011664 signaling Effects 0.000 description 23
- 231100000135 cytotoxicity Toxicity 0.000 description 19
- 230000003013 cytotoxicity Effects 0.000 description 19
- 230000001225 therapeutic effect Effects 0.000 description 15
- 230000006870 function Effects 0.000 description 14
- 230000003834 intracellular effect Effects 0.000 description 14
- 239000011651 chromium Substances 0.000 description 13
- 239000012636 effector Substances 0.000 description 13
- 230000012010 growth Effects 0.000 description 13
- 102100037850 Interferon gamma Human genes 0.000 description 12
- 108010074328 Interferon-gamma Proteins 0.000 description 12
- 230000004913 activation Effects 0.000 description 12
- 238000000684 flow cytometry Methods 0.000 description 12
- 230000004068 intracellular signaling Effects 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 11
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 10
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 10
- 238000000338 in vitro Methods 0.000 description 10
- 238000003556 assay Methods 0.000 description 9
- 238000013461 design Methods 0.000 description 9
- 238000004520 electroporation Methods 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 238000012546 transfer Methods 0.000 description 9
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 8
- 229910052804 chromium Inorganic materials 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 7
- 241000701022 Cytomegalovirus Species 0.000 description 6
- 108060003951 Immunoglobulin Proteins 0.000 description 6
- 108091008874 T cell receptors Proteins 0.000 description 6
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 6
- 150000001413 amino acids Chemical group 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 235000014633 carbohydrates Nutrition 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 102000018358 immunoglobulin Human genes 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 102000006306 Antigen Receptors Human genes 0.000 description 5
- 108010083359 Antigen Receptors Proteins 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 230000003302 anti-idiotype Effects 0.000 description 5
- 238000003501 co-culture Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000003827 upregulation Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 4
- 102100040840 C-type lectin domain family 7 member A Human genes 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102100029360 Hematopoietic cell signal transducer Human genes 0.000 description 4
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 4
- 101000990188 Homo sapiens Hematopoietic cell signal transducer Proteins 0.000 description 4
- 102000008100 Human Serum Albumin Human genes 0.000 description 4
- 108091006905 Human Serum Albumin Proteins 0.000 description 4
- 108091061960 Naked DNA Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 230000000139 costimulatory effect Effects 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 108010025838 dectin 1 Proteins 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 102000001398 Granzyme Human genes 0.000 description 3
- 108060005986 Granzyme Proteins 0.000 description 3
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 3
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 3
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 3
- 102100033467 L-selectin Human genes 0.000 description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 3
- 102000043129 MHC class I family Human genes 0.000 description 3
- 108091054437 MHC class I family Proteins 0.000 description 3
- 108700019146 Transgenes Proteins 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 230000003044 adaptive effect Effects 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000030741 antigen processing and presentation Effects 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 210000002421 cell wall Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 108700010039 chimeric receptor Proteins 0.000 description 3
- 230000009089 cytolysis Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 2
- 102100021260 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Human genes 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 102100022132 High affinity immunoglobulin epsilon receptor subunit gamma Human genes 0.000 description 2
- 108091010847 High affinity immunoglobulin epsilon receptor subunit gamma Proteins 0.000 description 2
- 101000894906 Homo sapiens Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Proteins 0.000 description 2
- 101000971533 Homo sapiens Killer cell lectin-like receptor subfamily G member 1 Proteins 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- 108010073807 IgG Receptors Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 102100021457 Killer cell lectin-like receptor subfamily G member 1 Human genes 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- 241000713666 Lentivirus Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 2
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102100029198 SLAM family member 7 Human genes 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000007503 antigenic stimulation Effects 0.000 description 2
- 208000007654 attenuated familial adenomatous polyposis Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 108091008034 costimulatory receptors Proteins 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 102000027596 immune receptors Human genes 0.000 description 2
- 108091008915 immune receptors Proteins 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000009126 molecular therapy Methods 0.000 description 2
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000006384 oligomerization reaction Methods 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000000644 propagated effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000000476 thermogenic effect Effects 0.000 description 2
- 238000003211 trypan blue cell staining Methods 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 1
- 241000701242 Adenoviridae Species 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- 241000588807 Bordetella Species 0.000 description 1
- 108010084313 CD58 Antigens Proteins 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 108010032795 CD8 receptor Proteins 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 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
- 241000283707 Capra Species 0.000 description 1
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 1
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 102100026234 Cytokine receptor common subunit gamma Human genes 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 1
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 1
- 102100027723 Endogenous retrovirus group K member 6 Rec protein Human genes 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 108010075944 Erythropoietin Receptors Proteins 0.000 description 1
- 102100036509 Erythropoietin receptor Human genes 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 102100027377 HBS1-like protein Human genes 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000700739 Hepadnaviridae Species 0.000 description 1
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 101000858031 Homo sapiens Coxsackievirus and adenovirus receptor Proteins 0.000 description 1
- 101001055227 Homo sapiens Cytokine receptor common subunit gamma Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 1
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 1
- 101001009070 Homo sapiens HBS1-like protein Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101001047640 Homo sapiens Linker for activation of T-cells family member 1 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101001090688 Homo sapiens Lymphocyte cytosolic protein 2 Proteins 0.000 description 1
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 1
- 101000702132 Homo sapiens Protein spinster homolog 1 Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000635799 Homo sapiens Run domain Beclin-1-interacting and cysteine-rich domain-containing protein Proteins 0.000 description 1
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 101000809875 Homo sapiens TYRO protein tyrosine kinase-binding protein Proteins 0.000 description 1
- 241000829111 Human polyomavirus 1 Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000009438 IgE Receptors Human genes 0.000 description 1
- 108010073816 IgE Receptors Proteins 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 241000701460 JC polyomavirus Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical group OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- 101150030213 Lag3 gene Proteins 0.000 description 1
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 description 1
- 102100024032 Linker for activation of T-cells family member 1 Human genes 0.000 description 1
- 102100034709 Lymphocyte cytosolic protein 2 Human genes 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 108010008707 Mucin-1 Proteins 0.000 description 1
- 102100023123 Mucin-16 Human genes 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 102100026450 POU domain, class 3, transcription factor 4 Human genes 0.000 description 1
- 101710133389 POU domain, class 3, transcription factor 4 Proteins 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 102000002508 Peptide Elongation Factors Human genes 0.000 description 1
- 108010068204 Peptide Elongation Factors Proteins 0.000 description 1
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 241000711931 Rhabdoviridae Species 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 102100030852 Run domain Beclin-1-interacting and cysteine-rich domain-containing protein Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Chemical group OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 108010047827 Sialic Acid Binding Immunoglobulin-like Lectins Proteins 0.000 description 1
- 102000007073 Sialic Acid Binding Immunoglobulin-like Lectins Human genes 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 108700042075 T-Cell Receptor Genes Proteins 0.000 description 1
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 1
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102100038717 TYRO protein tyrosine kinase-binding protein Human genes 0.000 description 1
- 241000710924 Togaviridae Species 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108091023045 Untranslated Region Proteins 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 101001038499 Yarrowia lipolytica (strain CLIB 122 / E 150) Lysine acetyltransferase Proteins 0.000 description 1
- 108010046882 ZAP-70 Protein-Tyrosine Kinase Proteins 0.000 description 1
- 102000007624 ZAP-70 Protein-Tyrosine Kinase Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 229940022720 acetadote Drugs 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 108700010877 adenoviridae proteins Proteins 0.000 description 1
- 238000011467 adoptive cell therapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 235000021028 berry Nutrition 0.000 description 1
- 238000013406 biomanufacturing process Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 101150047356 dec-1 gene Proteins 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010291 electrical method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000012595 freezing medium Substances 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 108091008582 intracellular receptors Proteins 0.000 description 1
- 102000027411 intracellular receptors Human genes 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 108010025001 leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 229950010203 nimotuzumab Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 108010089193 pattern recognition receptors Proteins 0.000 description 1
- 102000007863 pattern recognition receptors Human genes 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 108010038196 saccharide-binding proteins Proteins 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 230000035945 sensitivity Effects 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
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
- A61K39/464411—Immunoglobulin superfamily
- A61K39/464412—CD19 or B4
-
- 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
- A61K39/464416—Receptors for cytokines
- A61K39/464417—Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4746—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used p53
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
-
- 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
-
- 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
- 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
- C07K14/70517—CD8
-
- 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
- C07K14/70521—CD28, CD152
-
- 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
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/1034—Isolating an individual clone by screening libraries
- C12N15/1082—Preparation or screening gene libraries by chromosomal integration of polynucleotide sequences, HR-, site-specific-recombination, transposons, viral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N9/1241—Nucleotidyltransferases (2.7.7)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/07—Nucleotidyltransferases (2.7.7)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Virology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Bioinformatics & Computational Biology (AREA)
Abstract
Description
本発明は通常分子生物学及び医薬の分野に関する。特に本発明はキメラ抗原受容体(CAR)を製造する方法に関する。
養子T細胞移入に関連した一つの問題は、例えば特定の癌を治療する目的で、どのCARが所定の患者集団においてより効果的に作用するかについて可変性が大きいことである。生成可能であり癌に対する治療活性を発揮しうる見込みのある異なるCARが多数存在することによって、現在臨床医にとってどのCARが所定の癌または癌のサブタイプに対する治療活性を提示できるのか予測することを非常に難しくなっている。養子T細胞移入の大きな治療可能性によって、新たなCARを特定及び生成する方法の向上に対する明らかなニーズが存在する。
表2:CARの生成に使用するライブラリーの例
I.ライブラリー生成
II.キメラ抗原受容体
IV.人工的な抗原提示細胞
IV
実施例1:
材料及び方法
前述のSBトランスポゾンであるCoOpCD19RCD28ζ/pSBSOは、伸長因子1a(EF−1a [Kimら、1990])及び前述のヒトT細胞白血病ウイルス(HTLV)の59非翻訳領域[Singhら、2011、Daviesら、2010]含むEF−1/HTLVハイブリッド複合プロモーター(InvivoGen)下で前述のヒトコドン最適化(CoOp)第二世代CoOpCD19RCD28ζ CARを発現する。このDNAプラスミドの起源を図S1に示す。 前述のSBトランスポーゼースであるSB11は、前述のサイトメガロウイルス(CMV)プロモーター下においてシス型の前述のDNA プラスミド pCMV−SB11に発現される(Singhら、2011、Singhら、2008)。 いずれのプラスミドも全体を配列決定し、Waisman Clinical Biomanufacturing Facility(ウィスコンシン州マディソン)においてE.Coli細菌株DH5a選択用カナマイシンを用いて製造した。
上記CAR(CoOpCD19RCD28z/pSBSO)由来のDNA配列を用いて、CD3ζシグナリングドメインに抱合されるCD19 ScFv部分、ヒンジIgG4 Fc部分及びドメインCD28膜貫通部分及び細胞質部分をλ組換え部位に隣接させ、PCR産物としてGeneart(Life Technologies)により合成した。これら3つの部分を、BPクロナーゼ酵素(Invitrogen)によりそれぞれpDonors221プラスミド(Invitrogen)に挿入した。scFv−B−スキャフォールド−C−シグナリングドメイン型のEZ−Build CD19CD28ζ CARを生成するLR PLUSクロナーゼ酵素(Invitrogen)によって三重部位特異的組換えSleeping Beautyプラスミドを用いて前述の3つのプラスミドを組み替えた(図1)。
トリパンブルー色素排除試験法を用いて生細胞と死細胞を識別し、細胞数をCellometer(Nexecelom Bioscience)(Singhら、2011)を用いてカウントした。
二人の健康な男性ボランティアドナー由来の白血球除去輸血製品をKey Biologics LLC(テネシー州メンフィス)から購入した。末梢血単核細胞細胞(PBMC)を、cGMP準拠のBiosafe Sepax(エザン、スイス)の本発明に適応したシステムにより単離した。簡潔には、CS−900キットの全てのクランプを閉めた後、100mLのFicoll(GE Healthcare)を無菌的にLuerロックコネクター付き密度勾配培地バッグ(「ficollバッグ」)へ60mLシリンジを使って移し、チューブをハンドヘルドシーラー(Sebra、Model#2380)で加熱密封した。前述のキットを、20mLの25%ヒト血清アルブミン(HSA)(Baxter)(2%v/v、洗浄バッファー)を含むCliniMACSバッファー(PBS/EDTA、Miltenyi、Cat#70026)を入れた洗浄用1,000mLバッグ、最終製品バッグ[Coupler(Baxter/Fenwal 4R2014)付き300mLトランスファーパック]、及び試薬/血液バッグにスパイクで接続した。密度勾配系分離プロトコル(v126)を用いて、シリンジピストンをSepax aAPC(クローン#4)の遠心室及びカバーに装着しCAR+T細胞を選択的に増殖した。c照射aAPCを用いて前述の遺伝子改変T細胞を数的に増殖した。WCB由来の融解aAPCをVueLife細胞培養バッグを用いてCM中で60日間増殖し、Biosafe Sepax II集菌手順に従って集菌した。簡潔には、CS−490.1キットを、Luerロック接続により300mLアウトプットバッグ(トランスファーパック)に接続した。前述のピットに分離室を設置し、前述のチューブを光学センサへ挿入し活栓をT位置にあわせた。圧力センサラインを接続後、前述の製品バッグ及び上清/血漿バッグをホルダーに吊るした。Sepaxメニューから改変プロトコルPBSCv302を選択し、インプット製品の処理容量(最初の量)を#840mLに設定した。バリデーション及びキット試験後、前述の手順を開始した。終了後、前述のバッグを取り外し、クランプを閉め、前述のキットを取り外した。前述の最終製品バッグから前述の細胞を無菌的に除去し、洗浄培地(10% HSA含有Plasmalyte)で二回洗浄後、細胞数をカウントした。CIS BIO Internationalラジエーター(IBL−437C#09433)を用いてaAPCを照射し(100Gy)、後で用いるため速度制御フリーザー(Planer Kryo 750)で凍結保存培地に凍結保存した。抗CD3(OKT3)負荷K562由来aAPCクローン#4を用いて、遺伝子改変していないコントロール(CARneg)の自己コントロールT細胞を増殖した。培養で得た前述のaAPCを、ローディング培地(LM)と称する0.2%アセチルシステイン(Acetadote、Cumberland Pharmaceuticals)を含有する無血清X−Vivo 15(カタログ番号04−744Q、Lonza)で一晩培養した。翌日、細胞を洗浄し、Gamma Cell 1000 Elite Cs−137ラジエーター(MDS Nordion)で照射し(100Gy)、106個の細胞/mL濃度で1mg/106個の細胞の機能性グレード精製抗ヒトCD3(クローン−OKT3、16−0037−85、eBioscience)とともにLMに再懸濁し、3−Dローテーター(Lab−Line)で静かに攪拌しながら4℃で30分間培養した。LMで三回洗浄後、前述の細胞を実験に使用または後で用いるために蒸気層の液体窒素中のアリコート中で凍結した。
融解したPBMCを、(i)ヒトT細胞キット(カタログ番号VPA−1002、Lonza、一つのキュベット中100μL中2×107個の細胞)に再懸濁した。(i)は、(ii)CD19RCD28CARトランスポゾンコード化DNAプラスミド(CoOpCD19RCD28/pSBSO)(キュベット中2×107個のPBMCに対し15μgの超らせんDNA)及び(iii)SB11トランスポーゼースコード化DNAプラスミド(pCMVSB11)(キュベット中2×107個のPBMCに対し5μgの超らせんDNA)をそれぞれ含む。混合物をただちにキュベット(Lonza)へ移し、Nucleofector II(Program U−14、Amaxa/Lonza)を用いて電気穿孔し(培養0日目とする)、10%RPMI完全培地中で2〜3時間休ませ、培地の半量を交換後、5%CO2中37℃で一晩培養した。翌日、細胞を集菌し、カウントし、フローサイトメトリーで表現型を決定し、c照射aAPCと1:2の比率で(CAR+T細胞:aAPC)共培養した。この日を培養1日目とし7日間の刺激サイクルを開始した。月・水・金のスケジュールで1日目及び7日目以降にそれぞれIL−21(カタログ番号AF−200−21、PeproTech)及びIL−2(カタログ番号NDC65483−116−07、Novartis)を添加した。NK細胞は、特に組織培養プロセス初期に異常増殖が起こる場合、CAR+T細胞の数的増殖を抑制できる。よって、25%HSA(80mL/107個の細胞)含有CliniMACSバッファー中を入れたCD56ビーズ(カタログ番号70206、Miltenyi Biotech、20mLビーズ/107個の細胞)を充填したLSカラム(カタログ番号130−042−401、Miltenyi Biotech)を用いてCD3negCD56+細胞が$10%の場合、CD56欠乏とした。
コントロールとして、5×106個のモックトランスフェクトしたPBMCを照射済み抗CD3(OKT3)負荷K562由来aAPCクローン#4と1:1の比率で7日間刺激サイクルで共培養した。全ての培養物にIL−21(30ng/mL)を培養1日目以降添加し、培養開始後7日目からIL−2(50U/mL)を添加した。全てのサイトカインを1日おきに添加した。
100mLのFACSバッファー(2%FBS、0.1%アジ化ナトリウム)中で細胞を抗体を用いて4℃で30分間染色した。免疫表現型の獲得はFACSCalibur(BD Bioscience)を用いて実施し、FCS Express 3.00.0612を用いて分析した。
51Cr標識標的細胞を用いた標準4時間クロミウムリリースアッセイで、T細胞の細胞毒性を評価した。T細胞を底面プレート(Costar)にトリプリケートに播種した(1×105、0.5×105、0.25×105、0.125×105)。培養後、50μLの上清をLumaPlate(Perkin Elmer)上に回収し、TopCount NXT(Perkin Elmer)で読み出し、パーセント特異的な溶解を下記のとおり計算した。
実験的 51 Cr放出−自発的 51 Cr放出×100
最大51Cr放出−自発的51Cr放出
実施例2:
実施例1に記載の方法(「EZ」法と称する)を用いてCD19+CARを生成した。得られたCD19+CAR(CD19CAR)を前述の方法で生成したクリニカルグレート(「CG」)のCD19CARと比較した。
実施例3:
試験した種々のCARは同様の増殖、細胞毒性、及びTh1細胞毒性を示した。CD19−BB−zはTh2 サイトカインの産生低下を示し、インビボでマウスの疾患コントロールに効果的であった(Molecular Therapy 17(8):1453−1464、2009)。しかしながら、インビトロでは抗原性刺激なしに細胞が維持された事実に対する懸念がある。
表2:臨床におけるCAR
実施例4
CD3ζ含有CARを本実施例で提供する。CARデザインの一般的なダイアグラムを図24に示す。図24にCARデザイン(図24、右)と抗体分子(図24、左)との比較を示す。
実施例5
本発明者らは、クリニカルグレードのCD19RCD28mζ CAR+T細胞(CG CAR)と共にEZ CARプラットフォームを用いてキメラCD28/CD3−ζを介して活性化されるCD19特異的CARを生成した。クリニカルグレードCD28/CD3−ζ及びEZ CAR CD19RCD28mζ CAR配列の両方をSleeping Beautyトランスポゾンベクターへ挿入し、T細胞に電気穿孔した。電気穿孔後、前述のT細胞を、T細胞の抗原特異的増殖ためのCD19+人工抗原提示細胞(活性化及び増殖性細胞と称する、またはAaPC)の存在下で培養した。T細胞表面のCARの発現をフローサイトメトリー(Fc+発現)で毎週測定した結果、クリニカルグレードCD19 CART細胞及びEZ CD19 CART細胞における同様のCAR発現が示された。またクロミウムリリースアッセイ(CRA)を実施し、EZ CARプラットフォームにより生成したCD19CAR+T細胞の腫瘍細胞に対する死滅機能を評価した。培養4時間後、特異的な細胞溶解の割合はEZ CART細胞では52%、CG CART細胞では49%であった。
* * *
参考文献
以下に記載の文献は、本明細書の記載における補完的かつ例示的手順またはその他補足的な詳細を提供する範囲において、参照により本明細書に組み入れる。
米国特許公開第2009/0017000号
米国特許公開第2009/0004142号
米国特許第6,225,042号
米国特許第6,355,479号
米国特許第6,362,001号
米国特許第6,410,319号
米国特許第6,790,662号
米国特許第7,109,304号
WO2007/103009
Ahmed and Cheung, FEBS Lett. 2014 Jan 21;588(2):288−97.
Altenschmidtら,Adoptive transfer of in vitro−targeted, activated T lymphocytes results in total tumor regression, J Immunol. 1997 Dec 1;159(11):5509−15.
Audetら,Sci Rep. 2014 Nov 6;4:6881.
Berryら Adoptive immunotherapy for cancer: the next generation of gene−engineered immune cells. Tissue Antigens. 2009 Oct;74(4):277−89.
Brockerら,Adv. Immunol., 68:257, 1998.
Curtinら,MAbs. 2015 Jan 2;7(1):265−75.
Czerwinskiら,Drug Metab Dispos. 2015 Jan;43(1):42−52.
Davies JK, Singh H, Huls H, Yuk D, Lee DA,ら(2010)Combining CD19 redirection and alloanergization to generate tumor−specific human T cells for allogeneic cell therapy of B−cell malignancies. Cancer Res 70: 3915−3924.
de Weersら,J Immunol. 2011 Feb 1;186(3):1840−8.
Duongら,(2013)Engineering T Cell Function Using Chimeric Antigen Receptors Identified Using a DNA Library Approach. PLOS ONE 8(5):e63037.
Eshharら,Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody−binding domains and the gamma or zeta subunits of the immunoglobulin and T−cell receptors. Proc Natl Acad Sci U S A.;90(2):720−4, 1993.
Eshhar, Tumor−specific T−bodies: towards clinical application. Cancer Immunol Immunother. 1997 Nov−Dec;45(3−4):131−6. 1997
Fitzer−Attasら,Harnessing Syk family tyrosine kinases as signaling domains for chimeric single chain of the variable domain receptors: optimal design for T cell activation. J Immunol. 1998 Jan 1;160(1):145−54. 1998
Funakoshiら,Cancer Treat Rev. 2014 Dec;40(10):1221−9.
Gerberら,Clin Cancer Res. 2011 Nov 1;17(21):6888−96.
Goldbergら,J Clin Oncol. 2014 May 10;32(14):1445−52.
Grossら,Expression of immunoglobulin−T−cell receptor chimeric molecules as functional receptors with antibody−type specificity. Proc. Natl. Acad. Sci. USA, 86:10024−10028, 1989.
Grossら(1992)Endowing T cells with antibody specificity using chimeric T cell receptors. FASEB J. 1992 Dec;6(15):3370−8.
Hackettら,A transposon and transposase system for human application, Mol Ther. 2010 Apr;18(4):674−83).
Hekeleら Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44v6−specific scFv:zeta−chimera. Int J Cancer. 1996 Oct 9;68(2):232−8, 1996.
Hulsら,Clinical Application of Sleeping Beauty and Artificial Antigen Presenting Cells to Genetically Modify T Cells from Peripheral and Umbilical Cord Blood. J. Vis. Exp., doi:10.3791/50070, 2013.
Hulsら “Clinical application of Sleeping Beauty and artificial antigen presenting cells to genetically modify T cells from peripheral and umbilical cord blood” J Vis Exp. 2013 Feb 1;(72):e50070.
Humblet−Baron and Baron, Immunol Cell Biol. 2015 Feb 10. doi: 10.1038/icb.2014.120.
Hwuら(1995)In vivo antitumor activity of T cells redirected with chimeric antibody/T−cell receptor genes. Cancer Res. 1995 Aug 1;55(15):3369−73.
Ikedaら,Clin Cancer Res. 2009 Jun 15;15(12):4028−37.
Jabbourら,Am J Hematol. 2014 Nov 18.
Kaufmannら,Hum Pathol. 1997 Dec;28(12):1373−8.
Kaufmanら,Br J Haematol. 2013 Nov;163(4):478−86.
Kim DW, Uetsuki T, Kaziro Y, Yamaguchi N, Sugano S(1990)Use of the human elongation factor 1 alpha promoter as a versatile and efficient expression system. Gene 91: 217−223.
Kimら,2004, Nature, Vol. 22(4), pp. 403−410.
Kimら,Immunology. 2010 Aug;130(4):545−55.
Kongら,Leuk Res. 2014 Nov;38(11):1320−6.
Krebsら,T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology. 2013 Aug;145(2):456−65.
Le Garff−Tavernierら,Haematologica. 2014 Dec 31.
Lennard S., Standard protocols for the construction of scFv libraries. Methods Mol Biol. 2002;178:59−71.
Leung, Molecular Imaging and Contrast Agent Database(MICAD), Bethesda(MD): National Center for Biotechnology Information(US); 2004−2013. 2010 Mar 25
Leung 2011, IRDye800CW−anti−CD105 TRC105 chimeric monoclonal antibody. Molecular Imaging and Contrast Agent Database(MICAD). Bethesda(MD): National Center for Biotechnology Information(US); 2004−2013. 2011 Dec 01
Maitiら,Sleeping beauty system to redirect T−cell specificity for human applications. J Immunother. 36(2):112−23, 2013.
Maneroら,Haematologica. 2013 Feb;98(2):217−21.
Molecular Therapy 17(8): 1453−1464, 2009.
Moritzら(1994)Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2−expressing tumor cells. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4318−22.
Patelら,Anticancer Res. 2008 Sep−Oct;28(5A):2679−86.
Qiuら,PLoS Negl Trop Dis. 2012;6(3):e1575.
Remington's Pharmaceutical Sciences, 16th Ed., Mack, ed.(1980)
Rushworthら,(2014)“Universal Artificial Antigen Presenting Cells to Selectively Propagate T Cells Expressing Chimeric Antigen Receptor Independent of Specificity” J Immunother. May;37(4):204−13.
Sarupら,Mol Cancer Ther. 2008 Oct;7(10):3223−36.
Schneider, J. Embryol. Exp. Morph. 1972 Vol 27, pp. 353−365
Schultz−Thaterら,Br J Cancer. 2000 Jul;83(2):204−8.
Shinら, Immune Netw. 2011 Apr;11(2):114−22.
Singhら,Redirecting specificity of T−cell populations for CD19 using the Sleeping Beauty system. Cancer Res., 68:2961−2971, 2008.
Singh H, Figliola MJ, Dawson MJ, Huls H, Olivares S,ら(2011)Reprogramming CD19−specific T cells with IL−21 signaling can improve adoptive immunotherapy of B−lineage malignancies. Cancer Res 71: 3516−3527.
Singhら “A new approach to gene therapy using Sleeping Beauty to genetically modify clinical−grade T cells to target CD19.” Immunol Rev. 2014 Jan;257(1):181−90.
Singhら,“Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19−specific chimeric antigen receptor.” Cancer Gene Ther. 2015 Jan 16.
Stancovskiら(1993)
Stynenら,Fungal Cell Wall and Immune Response, NATO ASI Series Volume 53, 1991, pp 181−193.
Sunら,Cell Mol Immunol. 2007 Jun;4(3):209−14.
Turtleら,“Artificial antigen−presenting cells for use in adoptive immunotherapy” Cancer J. 2010 Jul−Aug;16(4):374−81.
Verel, Int J Cancer. 2002 May 20;99(3):396−402.
Vincent and Samuel, Journal of Immunological Methods, Volume 165, Issue 2, 15 October 1993, Pages 177−182.
Wangら,Immunology. 2015 Feb;144(2):254−62.
Weijtensら(1996)Single chain Ig/gamma gene−redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity. J Immunol. 1996 Jul 15;157(2):836−43.
Wieczorekら,Genetically Modified T Cells for the Treatment of Malignant Disease. Transfus Med Hemother. 2013 Dec;40(6):388−402.
Winiarskaら,MAbs. 2014;6(5):1300−13.
Zhuangら,Cancer Cell Int. 2014 Nov 30;14(1):109.
Zhangら,Angiogenesis. 2002;5(1−2):35−44.
Claims (88)
- (a)1つまたは複数の特徴的な抗原結合ドメインをコード化する複数の第一のベクター、
(b)1つまたは複数の特徴的なヒンジドメインをコード化する複数の第二のベクター、及び
(c)1つまたは複数の特徴的なエンドドメインをコード化する複数の第三のベクターを含む組成物であって、
少なくとも2つの第一、第二、及び第三のベクターが複数の2つ以上の特徴的な抗原結合ドメイン、ヒンジドメイン、及び/またはエンドドメインをコード化するベクターをそれぞれ含み、さらに前記ベクターが、キメラ抗原受容体(CAR)をコード化する第四のベクターの生成を可能にする相同組換え部位を含む、前記組成物。 - 前記複数の第一のベクターが複数の特徴的な抗原結合ドメインをコード化し、前記複数の第二のベクターが一つのヒンジドメインをコード化し、及び前記複数の第三のベクターが複数の特徴的なエンドドメインをコード化する、請求項1に記載の組成物。
- 前記複数の第一のベクターが複数の特徴的な抗原結合ドメインをコード化し、前記複数の第二のベクターが、複数の特徴的なヒンジドメインをコード化し、及び前記複数の第三のベクターが複数の特徴的なエンドドメインをコード化する、請求項1に記載の組成物。
- 前記複数の第一のベクターが複数の特徴的な抗原結合ドメインをコード化し、前記複数の第二のベクターが複数の特徴的なヒンジドメインをコード化し、及び前記複数の第三のベクターが一つのエンドドメインをコード化する、請求項1に記載の組成物。
- 前記複数の第一のベクターが一つの抗原結合ドメインをコード化し、前記複数の第二のベクターが複数の特徴的なヒンジドメインをコード化し、及び前記複数の第三のベクターが複数の特徴的なエンドドメインをコード化する、請求項1に記載の組成物。
- 前記抗原結合ドメインがscFvを含むまたはからなる、請求項1〜5に記載の前記組成物。
- 前記第三のベクターが膜貫通ドメインをコード化する、請求項1〜5に記載の前記組成物。
- 前記第二のベクターが膜貫通ドメインをコード化する、請求項1〜5に記載の前記組成物。
- 前記組成物がさらに1つまたは複数の膜貫通ドメインをコード化する複数の第五のベクター含み、前記第一のベクター、前記第二のベクター、前記第三のベクター、及び前記第五のベクターは、キメラ抗原受容体(CAR)をコード化する第四のベクターを生成するための相同組換え部位を含む、請求項1〜8に記載の前記組成物。
- 前記第一のベクターが第一の相同組換え配列及び第二の相同組換え部位を含む、請求項1〜9に記載の前記組成物。
- 前記第二のベクターが前記第二の相同組換え配列及び第三の相同組換え配列を含む、請求項1〜10に記載の前記組成物。
- 前記第三のベクターが前記第三の相同組換え配列及び第四の相同組換え配列を含む、請求項1〜11に記載の前記組成物。
- 前記第三のベクターが前記第三の相同組換え配列及び第四の相同組換え配列を含む、請求項1〜12に記載の前記組成物。
- 前記第四のベクターは、前記第一の相同組換え配列及び前記第四の相同組換え配列を含む、請求項1〜13に記載の前記組成物。
- 前記第一のベクター、前記第二のベクター、及び/または前記第三のベクターがトランスポーゼースをコード化する、請求項1〜14に記載の前記組成物。
- 前記トランスポーゼースはサケ科型Tc1様トランスポーゼース(SB)である、請求項1〜15に記載の前記組成物。
- 前記第一のベクター、前記第二のベクター、前記第三のベクター、及び/または前記第五のベクターのうち1、2、3、4、5個がSleeping Beauty(SB)またはpiggyBacトランスポゾンベクターである、請求項1〜16に記載の前記組成物。
- 前記特徴的な抗原結合ドメインが異なる抗原に選択的に結合する、請求項1〜17に記載の前記組成物。
- 前記特徴的な抗原結合ドメインが同一の抗原に選択的に結合する、請求項1〜18に記載の前記組成物。
- 前記抗原結合ドメインが、CD19、汎用抗原(マウス)、HER−3、GD2、Gp75、CS1 タンパク質、メソテリン、ホスファチジルセリン、cMyc、CD22、CD4、CD44v6、CD45、CD28、CD3、CD3e、CD123、CD138、CD52、CD56、CD74、CD30、Gp75、CD38、CD33、CD20、Her1/HER3融合物、GD2、炭水化物、Aspergillus、ROR1、c−MET、EGFR、デクチン、エボラ、真菌、GP、HERV−K(HERVK)、NY−ESO−1、VEGF−R2、TGF−b2R、IgG4、ビオチン、またはO−AcGD2に選択的に結合する、請求項1〜19に記載の前記組成物。
- 前記特徴的な抗原結合ドメインがscFvを含むまたはからなる、請求項1〜20に記載の前記組成物。
- 前記ヒンジ領域が、12AAペプチド(GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCT、配列番号1)、t−20AAペプチド、IgG4 Fc Δ EQ、IgG4 Fc Δ Q、(t−12AA+t−20AA)、mKate、phiLov、dsRed、Venus、eGFP、CH3 HA、(CD8 α+t−20AA)、Double t−20 AA、(t−20AA+CD8α)、(CD8α+Leucine Zipper Basep1)、(CD8α+Leucine Zipper Acid1)、2D3、CD8α、またはIgG4Fcをコード化する、請求項1〜21に記載の前記組成物。
- 少なくとも1つの前記エンドドメインがCD3ζを含む、請求項1〜22に記載の前記方法。
- 少なくとも1つの前記エンドドメインが1つまたは複数のITAMドメインを含む、請求項1〜23に記載の前記方法。
- 少なくとも1つの前記エンドドメインが、(CD28+CD3ζ)、(CD28+CD27+CD3ζ)、(CD28+OX40+CD3ζ)、(CD28+4−1BB+CD3ζ)、(CD28+CD27+OX40+CD3ζ)、(CD28+4−1BB+CD27+CD3ζ)、(CD28+4−1BB+OX40+CD3ζ)、(4−1BB+CD3ζ)、(4−1BB+OX40+CD3ζ)、(4−1BB+CD27+CD3ζ)、(CD27+CD3ζ)、(CD27+OX 40+CD3ζ)、(CD28Δ+CD3ζ)、(CD28Δ+CD27+CD3ζ)、(CD28Δ+OX40+CD3ζ)、(CD28Δ+4−1BB+CD3ζ)、(CD28Δ+4−1BB+OX40+CD3ζ)、(CD28Δ+CD27+OX40+CD3ζ)、(CD28Δ+4−1BB+CD27+CD3ζ)、(4−1BB+ICOS+CD3ζ)、(CD28+ICOS+CD3ζ)、(ICOS+CD3ζ)、またはCD3ζ若しくはCD28のみを含む、請求項1〜24に記載の前記方法。
- 複数の特徴的な抗原結合ドメイン、ヒンジドメイン、及びエンドドメインをコード化するキメラ抗原受容体をコード化するベクターのコレクションを含む組成物であって、該コレクションにおける前記ベクターを前記ドメインに対してランダム化した前記組成物。
- それぞれキメラ抗原受容体(CAR)をコード化する複数のベクターを製造する方法であって、(i)請求項1〜25のいずれか1項に記載の前記組成物を得ること、及び(ii)前記組成物を、前記ベクターにコード化される前記特徴的な抗原結合ドメイン、ヒンジドメイン及び/またはエンドドメインを相同組換えにより組み替え可能とする条件に供することにより、複数の第四のベクターを製造することを含み、該第四のベクターがそれぞれCARをコード化する前記方法。
- 前記CARを細胞中で発現することをさらに含む、請求項27に記載の前記方法。
- 前記CARの活性を試験することをさらに含む、請求項27〜28に記載の前記方法。
- 1つまたは複数の前記第一のベクターがscFv領域をコード化する、請求項27〜29に記載の前記方法。
- 1つまたは複数の前記第三のベクターが膜貫通ドメインをコード化する、請求項27〜30に記載の前記方法。
- 1つまたは複数の前記第二のベクターが膜貫通ドメインをコード化する、請求項27〜30に記載の前記方法。
- 膜貫通ドメインをコード化する第五のベクターを前記第一のベクター、第二のベクター、及び第三のベクターに組換えによりランダムに組み込んで前記第四のベクターを形成することをさらに含む、請求項27〜32に記載の前記方法。
- 前記第一のベクター及び前記第二のベクターは、複数の特徴的なscFv領域及び複数の特徴的なヒンジ領域をコード化する複数のベクターからランダムに結合される、請求項27〜33に記載の前記方法。
- 前記第一のベクター及び前記第三のベクターは、複数の特徴的なscFv領域及び複数の特徴的なエンドドメインをコード化する複数のベクターからランダムに結合される、請求項27〜34に記載の前記方法。
- 前記第二のベクター及び前記第三のベクターは、複数の特徴的なヒンジ領域及び複数の特徴的なエンドドメインをコード化する複数のベクターからランダムに結合される、請求項27〜35に記載の前記方法。
- 前記第一のベクター、前記第二のベクター、及び前記第三のベクターは、複数の特徴的なscFv領域、複数の特徴的なヒンジ領域、及び複数の特徴的なエンドドメインをコード化する複数のベクターからランダムに結合される、請求項27〜36に記載の前記方法。
- 複数のscFv領域をコード化するベクターの第一のライブラリーからの前記第一のベクターのランダムな結合、複数のscFv領域をコード化するベクターの第二のライブラリーからの前記第二のベクターのランダムな結合、及び複数のエンドドメインをコード化するベクターの第三のライブラリーからの前記第三のベクターのランダムな結合により前記第四のベクターを生成することによって、前記CARをコード化する前記第四のベクターを形成することさらに含む、請求項27〜36に記載の前記方法。
- 前記第一のベクターは、第一の相同組換え配列及び第二の相同組換え部位を含む、請求項27〜38に記載の前記方法。
- 前記第二のベクターが前記第二の相同組換え配列及び第三の相同組換え配列を含む、請求項27〜39に記載の前記方法。
- 前記第三のベクターが前記第三の相同組換え配列及び第四の相同組換え配列を含む、請求項27〜40に記載の前記方法。
- 前記第三のベクターが前記第三の相同組換え配列及び第四の相同組換え配列を含む、請求項27〜41に記載の前記方法。
- 前記第四のベクターが前記第一の相同組換え配列及び前記第四の相同組換え配列を含む、請求項27〜42に記載の前記方法。
- 前記第一のベクター、前記第二のベクター、及び/または前記第三のベクターがトランスポーゼースをコード化する、請求項27〜43に記載の前記方法。
- 第六のベクターがトランスポーゼースをコード化し、1つまたは複数の前記第四のベクター及び前記第六のベクターを細胞に導入する、電気穿孔する、またはトランスフェクトすることを含む、請求項27〜44に記載の前記方法。
- 前記トランスポーゼースがサケ科型Tc1様トランスポーゼース(SB)である、請求項45に記載の前記方法。
- 前記CAR発現T細胞の増殖を刺激可能な人工抗原提示細胞(aAPC)の存在下で前記CARをトランスフェクトした細胞を培養または提供することをさらに含む、請求項27〜46に記載の前記方法。
- 前記scFv領域、前記ヒンジ領域、及び前記エンドドメインをそれぞれSleeping Beauty (SB)またはpiggyBacトランスポゾンベクターでコード化する、請求項27〜47に記載の前記方法。
- 前記組換えにより、前記第一のベクター、前記第二のベクター、及び/または前記第三のベクターそれぞれが、複数の特徴的なscFv領域、前記ヒンジ領域、及びエンドドメインをコード化する複数のベクターからランダムに結合される、請求項27〜48に記載の前記方法。
- 前記第一のベクター、前記第二のベクター、及び前記第三のベクターはそれぞれトランスポゾンを含有し、前記相同組換えによる結合が部位特異的組換えを含む、請求項27〜49に記載の前記方法。
- 前記第一のベクター及び前記第二のベクターがそれぞれ第一の相同組換え部位を有し、前記第二のベクター及び前記第三のベクターがそれぞれ第二の相同組換え部位を有する、請求項50に記載の前記方法。
- 前記第一のベクターが第三の組換え部位を有し、前記第四のベクターが第四の組換え部位を有し、前記第三の組換え部位及び第四の組換え部位が細胞における相同組換えを可能とする、請求項50〜51に記載の前記方法。
- 前記細胞がT細胞である、請求項28〜52に記載の前記方法。
- 前記T細胞がαβT細胞、γδT細胞、NK細胞、またはNKT細胞である、請求項53に記載の前記方法。
- 前記細胞が多能性細胞である、請求項53に記載の前記方法。
- 前記多能性細胞が幹細胞または人工多能性幹細胞である、請求項55に記載の前記方法。
- 前記細胞が幹細胞、人工多能性幹細胞、または幹細胞に由来する、請求項53に記載の前記方法。
- 前記細胞が人工多能性幹細胞由来のT細胞またはNK細胞である、請求項56〜57に記載の前記方法。
- 前記特徴的な抗原結合ドメインが、異なる抗原を選択的に認識する少なくとも2、3、4、5、6、7、8、9個またはそれ以上のscFvを含む、請求項27〜58に記載の前記方法。
- 前記特徴的な抗原結合ドメインが、同一抗原を選択的に認識する少なくとも2、3、4、5、6、7、8、9個またはそれ以上のscFvを含む、請求項27〜59に記載の前記方法。
- 前記抗原結合ドメインが、CD19、汎用抗原(マウス)、HER−3、GD2、Gp75、CS1タンパク質、メソテリン、ホスファチジルセリン、cMyc、CD22、CD4、CD44v6、CD45、CD28、CD3、CD3e、CD123、CD138、CD52、CD56、CD74、CD30、Gp75、CD38、CD33、CD20、Her1/HER3融合物、GD2、炭水化物、Aspergillus、ROR1、c−MET、EGFR、デクチン、エボラ、真菌、GP、HERV−K(HERVK)、NY−ESO−1、VEGF−R2、TGF−b2R、IgG4、ビオチン、またはO−AcGD2に選択的に結合する、請求項27〜60に記載の前記方法。
- 前記抗原結合ドメインがscFvを含むまたはからなる、請求項27〜61に記載の前記方法。
- 前記ヒンジ領域が12AAペプチド(GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCT、配列番号1)、t−20 AAペプチド、IgG4 Fc Δ EQ、IgG4 Fc Δ Q、(t−12AA+t−20AA)、mKate、phiLov、dsRed、Venus、eGFP、CH3 HA、(CD8 α+t−20AA)、Double t−20 AA、(t−20AA+CD8α)、(CD8α+Leucine Zipper Basep1)、(CD8α+Leucine Zipper Acid1)、2D3、CD8α、またはIgG4 Fcをコード化する、請求項27〜62に記載の前記方法。
- 前記エンドドメインがCD3ζをコード化する、請求項27〜63に記載の前記方法。
- 前記エンドドメインが1つまたは複数のITAMドメインをコード化する、請求項27〜64に記載の前記方法。
- 前記エンドドメインが、(CD28+CD3ζ)、(CD28+CD27+CD3ζ)、(CD28+OX40+CD3ζ)、(CD28+4−1BB+CD3ζ)、(CD28+CD27+OX40+CD3ζ)、(CD28+4−1BB+CD27+CD3ζ)、(CD28+4−1BB+OX40+CD3ζ)、(4−1BB+CD3ζ)、(4−1BB+OX40+CD3ζ)、(4−1BB+CD27+CD3ζ)、(CD27+CD3ζ)、(CD27+OX40+CD3ζ)、(CD28Δ+CD3ζ)、(CD28Δ+CD27+CD3ζ)、(CD28Δ+OX40+CD3ζ)、(CD28Δ+4−1BB+CD3ζ)、(CD28Δ+4−1BB+OX40+CD3ζ)、(CD28Δ+CD27+OX40+CD3ζ)、(CD28Δ+4−1BB+CD27+CD3ζ)、(4−1BB+ICOS+CD3ζ)、(CD28+ICOS+CD3ζ)、(ICOS+CD3ζ)、またはCD3ζ若しくはCD28のみをコード化する、請求項27〜65に記載の前記方法。
- 前記活性が、前記CARが癌細胞選択的に結合する、病原体に選択的に結合する、自己免疫疾患に関与する細胞に選択的に結合するまたはT細胞の活性化、T細胞の破壊、T細胞の分化、T細胞の増殖、T細胞の脱分化、T細胞の移動、T細胞によるサイトカイン産生、またはT細胞による死滅を促進する能力を備える、請求項29〜66に記載の前記方法。
- 前記癌細胞が、卵巣癌、リンパ腫、腎細胞癌、B細胞悪性腫瘍、CLL、B−ALL、ALL、白血病、B細胞悪性腫瘍またはリンパ腫、マントル細胞リンパ腫、無痛性B細胞リンパ腫、ホジキンリンパ腫、AML、子宮頸癌、乳癌、結腸直腸癌、卵巣癌、神経芽細胞腫、皮膚癌、メラノーマ、肺癌、骨肉腫、神経膠腫、上皮由来腫瘍、前立腺癌、または小児癌である、請求項67に記載の前記方法。
- 前記病原体がウイルス、真菌、または細菌である、請求項67に記載の前記方法。
- 前記試験が、単一細胞イメージング、単一細胞遺伝学、単一T細胞またはT細胞集団のアセスメント、特異的な死滅または連続的死滅の測定、遺伝子発現、タンパク質発現、標的に近づくまたは標的から遠のく移動、増殖、活性化誘発細胞死、サイトカイン分泌、またはケモカイン分泌を含む、請求項29〜69に記載の前記方法。
- 単一のCARを該単一のCARの特性に基づいて前記複数のベクターから選択することをさらに含む、請求項27〜70に記載の前記方法。
- 前記単一のCARを被験体に治療上投与することをさらに含む、請求項71に記載の前記方法。
- 前記被験体が哺乳類である、請求項72に記載の前記方法。
- 前記哺乳類がヒトである、請求項73に記載の前記方法。
- CAR217(配列番号2)、CAR194(配列番号3)、CAR212(配列番号4)、CAR213(配列番号5)、CAR265(配列番号6)、CAR214(配列番号56)、CAR215(配列番号57)、CAR216(配列番号58)、CAR218(配列番号59)、CAR193(配列番号55)、またはCAR268(配列番号7)を含むまたはからなるポリペプチド。
- 請求項75に記載の前記ポリペプチドを発現する形質転換T細胞。
- 前記細胞が不死化細胞である、請求項76に記載の前記形質転換細胞。
- 前記T細胞がαβT細胞、γδT細胞、NK細胞、NKT細胞、幹細胞、または前記免疫システムの細胞を含む幹細胞由来の細胞である、請求項76に記載の前記T細胞。
- 請求項76−78のいずれか1項に記載の前記形質転換T細胞を含む医薬品。
- CAR217(配列番号2)、CAR194(配列番号3)、CAR212(配列番号4)、CAR213(配列番号5)、CAR265(配列番号6)、CAR214(配列番号56)、CAR215(配列番号57)、CAR216(配列番号58)、CAR218(配列番号59)、CAR193(配列番号55)、またはCAR268(配列番号7)を含むまたはからなるキメラ抗原受容体をコード化する核酸。
- 前記核酸がT細胞に含まれる、請求項80に記載の前記核酸。
- 前記T細胞がαβT細胞、γδT細胞、NK細胞、NKT細胞、幹細胞、または多能性細胞由来のT細胞である、請求項81に記載の前記核酸。
- 前記T細胞が医薬的に許容される担体または賦形剤に含まれる、請求項81に記載の前記核酸。
- 異なるCARをコード化するベクターのライブラリーを含む組成物であって、該ライブラリーの前記ベクターを特徴的な抗原結合ドメイン、ヒンジドメイン及び/またはエンドドメインについてランダム化した、前記組成物。
- 前記ライブラリーは、特徴的な抗原結合ドメイン、ヒンジドメイン、及びエンドドメインについてランダム化したものである、請求項84に記載の前記組成物。
- 前記ライブラリーは、特徴的な抗原結合ドメイン及びエンドドメインについてランダム化したものである、請求項84に記載の前記組成物。
- 前記ライブラリーは、特徴的な抗原結合ドメイン及びヒンジドメインについてランダム化したものである、請求項84に記載の前記組成物。
- 前記ライブラリーは、特徴的な抗原ヒンジドメイン及びエンドドメインについてランダム化したものである、請求項84に記載の前記組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461940339P | 2014-02-14 | 2014-02-14 | |
US61/940,339 | 2014-02-14 | ||
PCT/US2015/016057 WO2015123642A1 (en) | 2014-02-14 | 2015-02-16 | Chimeric antigen receptors and methods of making |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019235725A Division JP2020058380A (ja) | 2014-02-14 | 2019-12-26 | キメラ抗原受容体及びその製造方法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017506513A true JP2017506513A (ja) | 2017-03-09 |
JP2017506513A5 JP2017506513A5 (ja) | 2018-03-08 |
JP6640726B2 JP6640726B2 (ja) | 2020-02-05 |
Family
ID=53800695
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016551764A Active JP6640726B2 (ja) | 2014-02-14 | 2015-02-16 | キメラ抗原受容体及びその製造方法 |
JP2019235725A Withdrawn JP2020058380A (ja) | 2014-02-14 | 2019-12-26 | キメラ抗原受容体及びその製造方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019235725A Withdrawn JP2020058380A (ja) | 2014-02-14 | 2019-12-26 | キメラ抗原受容体及びその製造方法 |
Country Status (15)
Country | Link |
---|---|
US (3) | US10125193B2 (ja) |
EP (2) | EP3105335B1 (ja) |
JP (2) | JP6640726B2 (ja) |
KR (1) | KR102375998B1 (ja) |
CN (2) | CN113234757A (ja) |
AU (2) | AU2015218239B2 (ja) |
CA (2) | CA3190002A1 (ja) |
DK (1) | DK3105335T3 (ja) |
ES (1) | ES2764471T3 (ja) |
IL (3) | IL247208B (ja) |
MX (2) | MX369513B (ja) |
RU (2) | RU2753965C2 (ja) |
SG (2) | SG11201606664UA (ja) |
WO (1) | WO2015123642A1 (ja) |
ZA (1) | ZA201605655B (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021500882A (ja) * | 2017-10-18 | 2021-01-14 | プレシゲン,インコーポレイテッド | スペーサーを含むポリペプチド組成物 |
JP2021502070A (ja) * | 2017-11-03 | 2021-01-28 | レンティジェン・テクノロジー・インコーポレイテッドLentigen Technology, Inc. | 抗ror1免疫療法によってがんを処置するための組成物および方法 |
JP2021509290A (ja) * | 2017-12-28 | 2021-03-25 | 上海細胞治療集団有限公司Shanghai Cell Therapy Group Co., Ltd. | 双方向活性化共刺激分子受容体及びその用途 |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9511092B2 (en) | 2013-01-28 | 2016-12-06 | St. Jude Children's Research Hospital, Inc. | Chimeric receptor with NKG2D specificity for use in cell therapy against cancer and infectious disease |
EP3783098A1 (en) | 2013-05-14 | 2021-02-24 | Board Of Regents, The University Of Texas System | Human application of engineered chimeric antigen receptor (car) t-cells |
WO2014190273A1 (en) | 2013-05-24 | 2014-11-27 | Board Of Regents, The University Of Texas System | Chimeric antigen receptor-targeting monoclonal antibodies |
KR102375998B1 (ko) * | 2014-02-14 | 2022-03-21 | 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 | 키메라 항원 수용체 및 제조방법 |
SG11201609118RA (en) | 2014-05-15 | 2016-11-29 | Univ Singapore | Modified natural killer cells and uses thereof |
GB201506423D0 (en) | 2015-04-15 | 2015-05-27 | Tc Biopharm Ltd | Gamma delta T cells and uses thereof |
JP2017535284A (ja) | 2014-11-05 | 2017-11-30 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 免疫エフェクター細胞の拡大のための遺伝子改変免疫エフェクター細胞及び遺伝子操作細胞 |
EP3215534B1 (en) | 2014-11-05 | 2020-04-15 | Board of Regents, The University of Texas System | Chimeric antigen receptors (car) to selectively target protein complexes |
MX2017010721A (es) | 2015-02-24 | 2018-08-28 | Univ California | Interruptores transcripcionales activados mediante unión y métodos para su uso. |
CN107667169B (zh) | 2015-02-24 | 2021-10-29 | 得克萨斯州大学系统董事会 | 遗传修饰的t细胞的选择方法 |
AU2016229094B2 (en) | 2015-03-11 | 2020-02-06 | Board Of Regents, The University Of Texas System | Transposase polypeptides and uses thereof |
US9777064B2 (en) | 2015-03-17 | 2017-10-03 | Chimera Bioengineering, Inc. | Smart CAR devices, DE CAR polypeptides, side CARs and uses thereof |
KR20180021683A (ko) * | 2015-04-23 | 2018-03-05 | 베일러 칼리지 오브 메디신 | 생체내 지속성 및 치료학적 활성 및 이의 증식을 위한 nkt-세포 서브세트 |
GB201507368D0 (en) * | 2015-04-30 | 2015-06-17 | Ucl Business Plc | Cell |
FI3298033T4 (fi) | 2015-05-18 | 2023-09-22 | Tcr2 Therapeutics Inc | Koostumuksia ja lääkinnällisiä käyttöjä fuusioproteiineja käyttävälle tcr:n uudelleenohjelmoinnille |
WO2017011316A1 (en) * | 2015-07-10 | 2017-01-19 | The Trustees Of The University Of Pennsylvania | Treatment of a canine cd20 positive disease or condition using a canine cd20-specific chimeric antigen receptor |
WO2017027291A1 (en) | 2015-08-07 | 2017-02-16 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Bispecific car t-cells for solid tumor targeting |
IL293963A (en) * | 2015-09-01 | 2022-08-01 | Univ California | Modular polypeptide libraries and methods for their preparation and use |
IL258009B2 (en) | 2015-09-15 | 2024-03-01 | Univ Texas | Antibodies that bind receptors on T cells (TCR) and their use |
WO2017075147A1 (en) | 2015-10-27 | 2017-05-04 | Board Of Regents, The University Of Texas System | Chimeric antigen receptor molecules and uses thereof |
US11052111B2 (en) | 2015-12-08 | 2021-07-06 | Chimera Bioengineering, Inc. | Smart CAR devices and DE CAR polypeptides for treating disease and methods for enhancing immune responses |
US11400116B2 (en) | 2016-05-06 | 2022-08-02 | The Regents Of The University Of California | Systems and methods for targeting cancer cells |
US10222369B2 (en) | 2016-05-17 | 2019-03-05 | Chimera Bioengineering, Inc. | Methods for making novel antigen binding domains |
AU2017279548A1 (en) | 2016-06-08 | 2018-12-13 | Precigen, Inc. | Cd33 specific chimeric antigen receptors |
CN106167527A (zh) * | 2016-06-13 | 2016-11-30 | 长沙郝怡雅医药科技有限公司 | 一种融合蛋白 |
EP3263595A1 (en) * | 2016-06-30 | 2018-01-03 | Medizinische Hochschule Hannover | Fusion protein for use in the treatment of hvg disease |
AU2017306432A1 (en) | 2016-08-02 | 2019-03-21 | TCR2 Therapeutics Inc. | Compositions and methods for TCR reprogramming using fusion proteins |
EP3504245A4 (en) | 2016-08-23 | 2020-04-22 | The Regents of The University of California | PROTEOLYTICALLY CLAVABLE CHIMERIC POLYPEPTIDES AND METHODS OF USE |
WO2018045177A1 (en) | 2016-09-01 | 2018-03-08 | Chimera Bioengineering, Inc. | Gold optimized car t-cells |
RU2019112860A (ru) * | 2016-09-27 | 2020-10-30 | Серо Терапьютикс, Инк. | Молекулы химерных интернализационных рецепторов |
US20190119636A1 (en) * | 2017-10-23 | 2019-04-25 | Poseida Therapeutics, Inc. | Modified stem cell memory t cells, methods of making and methods of using same |
AU2017341048A1 (en) | 2016-10-07 | 2019-05-23 | TCR2 Therapeutics Inc. | Compositions and methods for T-cell receptors reprogramming using fusion proteins |
US11851491B2 (en) | 2016-11-22 | 2023-12-26 | TCR2 Therapeutics Inc. | Compositions and methods for TCR reprogramming using fusion proteins |
WO2018182511A1 (en) | 2017-03-27 | 2018-10-04 | National University Of Singapore | Stimulatory cell lines for ex vivo expansion and activation of natural killer cells |
EP3600356A4 (en) | 2017-03-27 | 2020-12-23 | National University of Singapore | ABBREVIATED NKG2D CHIMERIC RECEPTORS AND USES THEREOF IN IMMUNOTHERAPY WITH NATURAL KILLER CELLS |
CN107177632B (zh) * | 2017-05-27 | 2020-02-07 | 上海优卡迪生物医药科技有限公司 | 一种基于octs技术的髓系白血病car-t治疗载体及其构建方法和应用 |
CN109337872B (zh) * | 2017-07-27 | 2023-06-23 | 上海细胞治疗研究院 | 高效扩增car-t细胞的人工抗原递呈细胞及其用途 |
CN107529550A (zh) * | 2017-08-28 | 2018-01-02 | 马晓冬 | 一种基于PiggyBac载体的CD‑19‑CAR‑T系统构建方法 |
CN111727256A (zh) * | 2017-09-08 | 2020-09-29 | 波赛达治疗公司 | 用于嵌合配体受体(clr)-介导的条件性基因表达的组合物和方法 |
AU2018331517A1 (en) * | 2017-09-15 | 2020-04-30 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-CD19 immunotherapy |
CA3073421A1 (en) | 2017-09-26 | 2019-04-04 | Daniel Mark COREY | Chimeric engulfment receptor molecules and methods of use |
AU2018342246A1 (en) | 2017-09-29 | 2020-04-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | T cell receptors recognizing mutated p53 |
US10329543B2 (en) * | 2017-10-23 | 2019-06-25 | Poseida Therapeutics, Inc. | Modified stem cell memory T cells, methods of making and methods of using same |
CN111886015B (zh) * | 2017-10-31 | 2024-04-26 | 艾洛基治疗公司 | 用于同种异体嵌合抗原受体t细胞的给药的方法和组合物 |
EP3728563A4 (en) | 2017-12-22 | 2021-11-10 | Fate Therapeutics, Inc. | ENHANCED IMMUNE EFFECTIVE CELLS AND THEIR USE |
JP2021518747A (ja) | 2018-02-13 | 2021-08-05 | キメラ・バイオエンジニアリング,インコーポレーテッド | Rna不安定化エレメントを使用した遺伝子発現の調整 |
EP3774906A1 (en) * | 2018-03-28 | 2021-02-17 | Cero Therapeutics, Inc. | Chimeric tim4 receptors and uses thereof |
MX2020010241A (es) * | 2018-03-28 | 2020-10-16 | Cero Therapeutics Inc | Composiciones de inmunoterapia celular y usos de las mismas. |
US20210024959A1 (en) | 2018-03-29 | 2021-01-28 | Fate Therapeutics, Inc. | Engineered immune effector cells and use thereof |
CN110577605A (zh) * | 2018-06-11 | 2019-12-17 | 浙江启新生物技术有限公司 | 一种靶向多发性骨髓瘤多种抗原的嵌合抗原受体t(car-t)细胞的构建方法及其应用 |
CN110850068B (zh) * | 2018-08-21 | 2023-08-15 | 上海恒润达生生物科技股份有限公司 | 一种嵌合抗原受体亲和力检测方法 |
CN111253487B (zh) * | 2018-12-03 | 2024-02-02 | 广东东阳光药业股份有限公司 | Cd19抗体及其应用 |
CN113412117A (zh) | 2018-12-12 | 2021-09-17 | 凯德药业股份有限公司 | 嵌合抗原和t细胞受体及使用的方法 |
CN109777784B (zh) * | 2019-02-22 | 2021-12-31 | 上海尚泰生物技术有限公司 | 一种增强向肿瘤部位迁移的嵌合抗原受体载体构建方法与应用 |
MX2021010670A (es) | 2019-03-05 | 2021-11-12 | Nkarta Inc | Receptores de antigeno quimerico dirigidos a cd19 y usos de los mismos en inmunoterapia. |
WO2020209934A1 (en) * | 2019-04-11 | 2020-10-15 | Massachusetts Institute Of Technology | Novel chimeric antigen receptors and libraries |
EP4013431A4 (en) | 2019-08-18 | 2024-05-01 | Chimera Bioengineering Inc | COMBINATION THERAPY WITH GOLD-CONTROLLED TRANSGENES |
MX2022002613A (es) | 2019-09-03 | 2022-06-02 | Myeloid Therapeutics Inc | Metodos y composiciones para la integracion del genoma. |
US20220332780A1 (en) | 2019-09-10 | 2022-10-20 | Obsidian Therapeutics, Inc. | Ca2-il15 fusion proteins for tunable regulation |
CN111304244A (zh) * | 2019-11-13 | 2020-06-19 | 沣潮医药科技(上海)有限公司 | 携带基因元件组合的载体组件、受体细胞文库、制备和筛选方法及用途 |
CN110964750A (zh) * | 2019-11-13 | 2020-04-07 | 沣潮医药科技(上海)有限公司 | 携带基因元件组合的嵌合抗原受体细胞文库、制备和筛选方法及用途 |
IL294715A (en) | 2020-01-23 | 2022-09-01 | Childrens Medical Ct Corp | Inducible t-cell differentiation from human pluripotent stem cells |
JP2023522933A (ja) | 2020-04-23 | 2023-06-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 遺伝子操作された食細胞、並びに関連する組成物、ベクター、方法、及びシステム |
WO2021240240A1 (en) | 2020-05-27 | 2021-12-02 | Antion Biosciences Sa | Adapter molecules to re-direct car t cells to an antigen of interest |
GB202008688D0 (en) * | 2020-06-09 | 2020-07-22 | Cancer Research Tech Ltd | Chimeric antigen receptor cell |
CN113913458A (zh) * | 2020-07-09 | 2022-01-11 | 杭州优凯瑞医药科技有限公司 | 非病毒方法制备稳定高表达嵌合受体的nk细胞 |
CN112062859B (zh) * | 2020-07-24 | 2022-08-09 | 沣潮医药科技(上海)有限公司 | 用于病原体清除的嵌合抗原受体及其应用 |
US20240067955A1 (en) | 2021-01-20 | 2024-02-29 | Coding Bio Limited | Methods for high throughput screening of chimeric antigen receptors |
CA3215938A1 (en) * | 2021-04-23 | 2022-10-27 | Henry Hongjun Ji | Dimeric antigen receptors (dars) that bind gd2 |
WO2023150672A1 (en) * | 2022-02-04 | 2023-08-10 | Duke University | Compositions for and methods of treating hematological cancers |
WO2023150674A2 (en) * | 2022-02-04 | 2023-08-10 | Duke University | Compositions for and methods of effecting tumor cell death |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004529636A (ja) * | 2000-11-07 | 2004-09-30 | シティ・オブ・ホープ | Cd19特異的再指向免疫細胞 |
WO2013063419A2 (en) * | 2011-10-28 | 2013-05-02 | The Trustees Of The University Of Pennsylvania | A fully human, anti-mesothelin specific chimeric immune receptor for redirected mesothelin-expressing cell targeting |
JP2013116891A (ja) * | 2011-11-01 | 2013-06-13 | Nagoya Univ | 髄膜腫治療用医薬組成物 |
US20130266551A1 (en) * | 2003-11-05 | 2013-10-10 | St. Jude Children's Research Hospital, Inc. | Chimeric receptors with 4-1bb stimulatory signaling domain |
Family Cites Families (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL104570A0 (en) | 1992-03-18 | 1993-05-13 | Yeda Res & Dev | Chimeric genes and cells transformed therewith |
US8211422B2 (en) | 1992-03-18 | 2012-07-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric receptor genes and cells transformed therewith |
CA2214649C (en) | 1995-03-08 | 2007-06-12 | Zeling Cai | Antigen presenting system and methods for activation of t-cells |
IL126843A (en) | 1996-05-23 | 2007-06-17 | Scripps Research Inst | Mhc class ii antigen-presenting systems and methods for activating cd4+t cells in vitro |
WO2000023573A2 (en) | 1998-10-20 | 2000-04-27 | City Of Hope | Cd20-specific redirected t cells and their use in cellular immunotherapy of cd20+ malignancies |
US6790662B1 (en) | 1999-03-12 | 2004-09-14 | Ortho-Mcneil Pharmaceutical, Inc. | Method of isolating CD8+ cells, and related hybridoma cells antibodies and polypeptides |
US20040071671A1 (en) | 2001-02-20 | 2004-04-15 | Leturcq Didier J. | Cell therapy method for the treatment of tumors |
US20030157561A1 (en) * | 2001-11-19 | 2003-08-21 | Kolkman Joost A. | Combinatorial libraries of monomer domains |
CA2445746C (en) | 2001-04-30 | 2012-09-18 | City Of Hope | Chimeric immunoreceptor useful in treating human cancers |
US7446190B2 (en) | 2002-05-28 | 2008-11-04 | Sloan-Kettering Institute For Cancer Research | Nucleic acids encoding chimeric T cell receptors |
EP1648512A4 (en) | 2003-07-31 | 2009-01-21 | Immunomedics Inc | ANTI-CD19 ANTIBODIES |
US20050113564A1 (en) | 2003-11-05 | 2005-05-26 | St. Jude Children's Research Hospital | Chimeric receptors with 4-1BB stimulatory signaling domain |
US7435596B2 (en) | 2004-11-04 | 2008-10-14 | St. Jude Children's Research Hospital, Inc. | Modified cell line and method for expansion of NK cell |
BRPI0708446A2 (pt) | 2006-03-01 | 2011-06-07 | Janssen Pharmaceutica Nv | tratamento de cáncer combinando agente de linfodepleção com ctls e citocinas |
MX2009003764A (es) | 2006-10-04 | 2009-04-22 | Janssen Pharmaceutica Nv | Preparaciones de celulas presentadoras de antigeno artificiales y su uso en terapias celulares. |
ZA200902346B (en) * | 2006-10-12 | 2010-07-28 | Genentech Inc | Antibodies to lymphotoxin-alpha |
EP2141997B1 (en) | 2007-03-30 | 2012-10-31 | Memorial Sloan-Kettering Cancer Center | Constitutive expression of costimulatory ligands on adoptively transferred t lymphocytes |
WO2009091826A2 (en) | 2008-01-14 | 2009-07-23 | The Board Of Regents Of The University Of Texas System | Compositions and methods related to a human cd19-specific chimeric antigen receptor (h-car) |
WO2011041093A1 (en) | 2009-10-01 | 2011-04-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-vascular endothelial growth factor receptor-2 chimeric antigen receptors and use of same for the treatment of cancer |
US9242014B2 (en) | 2010-06-15 | 2016-01-26 | The Regents Of The University Of California | Receptor tyrosine kinase-like orphan receptor 1 (ROR1) single chain Fv antibody fragment conjugates and methods of use thereof |
EP3305798A1 (en) * | 2010-12-09 | 2018-04-11 | The Trustees of The University of Pennsylvania | Use of chimeric antigen receptor-modified t cells to treat cancer |
CA2824997C (en) * | 2011-01-18 | 2023-01-17 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating cancer |
US10391126B2 (en) | 2011-11-18 | 2019-08-27 | Board Of Regents, The University Of Texas System | CAR+ T cells genetically modified to eliminate expression of T-cell receptor and/or HLA |
AU2013222288A1 (en) * | 2012-02-22 | 2014-08-14 | The Trustees Of The University Of Pennsylvania | Use of ICOS-based CARs to enhance antitumor activity and CAR persistence |
SG11201406414WA (en) | 2012-04-11 | 2014-11-27 | Us Health | Chimeric antigen receptors targeting b-cell maturation antigen |
US20130280220A1 (en) * | 2012-04-20 | 2013-10-24 | Nabil Ahmed | Chimeric antigen receptor for bispecific activation and targeting of t lymphocytes |
ES2962571T3 (es) * | 2012-05-25 | 2024-03-19 | Cellectis | Métodos para modificar células T alogénicas y resistentes a la inmunosupresión para inmunoterapia |
EP3783098A1 (en) * | 2013-05-14 | 2021-02-24 | Board Of Regents, The University Of Texas System | Human application of engineered chimeric antigen receptor (car) t-cells |
WO2014190273A1 (en) | 2013-05-24 | 2014-11-27 | Board Of Regents, The University Of Texas System | Chimeric antigen receptor-targeting monoclonal antibodies |
KR20160068960A (ko) | 2013-10-25 | 2016-06-15 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 면역요법을 위한 다클론성 감마 델타 t 세포 |
KR102375998B1 (ko) * | 2014-02-14 | 2022-03-21 | 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 | 키메라 항원 수용체 및 제조방법 |
CA2945388A1 (en) | 2014-04-23 | 2015-10-29 | Board Of Regents, The University Of Texas System | Chimeric antigen receptors (car) for use in therapy and methods for making the same |
KR20160145186A (ko) | 2014-04-24 | 2016-12-19 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 입양 세포 요법 생성물을 생성하기 위한 유도 만능 줄기 세포의 응용 |
JP2017535284A (ja) | 2014-11-05 | 2017-11-30 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 免疫エフェクター細胞の拡大のための遺伝子改変免疫エフェクター細胞及び遺伝子操作細胞 |
EP3215534B1 (en) | 2014-11-05 | 2020-04-15 | Board of Regents, The University of Texas System | Chimeric antigen receptors (car) to selectively target protein complexes |
CN107667169B (zh) | 2015-02-24 | 2021-10-29 | 得克萨斯州大学系统董事会 | 遗传修饰的t细胞的选择方法 |
AU2016229094B2 (en) | 2015-03-11 | 2020-02-06 | Board Of Regents, The University Of Texas System | Transposase polypeptides and uses thereof |
IL258009B2 (en) | 2015-09-15 | 2024-03-01 | Univ Texas | Antibodies that bind receptors on T cells (TCR) and their use |
WO2017075147A1 (en) | 2015-10-27 | 2017-05-04 | Board Of Regents, The University Of Texas System | Chimeric antigen receptor molecules and uses thereof |
JP7288401B2 (ja) * | 2017-01-10 | 2023-06-07 | プレシゲン,インコーポレイテッド | 新規の遺伝子スイッチ発現系を介したポリペプチドの発現のモジュレーション |
-
2015
- 2015-02-16 KR KR1020167024697A patent/KR102375998B1/ko active IP Right Grant
- 2015-02-16 WO PCT/US2015/016057 patent/WO2015123642A1/en active Application Filing
- 2015-02-16 US US15/118,245 patent/US10125193B2/en active Active
- 2015-02-16 SG SG11201606664UA patent/SG11201606664UA/en unknown
- 2015-02-16 EP EP15749056.6A patent/EP3105335B1/en active Active
- 2015-02-16 DK DK15749056.6T patent/DK3105335T3/da active
- 2015-02-16 RU RU2016136370A patent/RU2753965C2/ru active
- 2015-02-16 AU AU2015218239A patent/AU2015218239B2/en active Active
- 2015-02-16 EP EP19200716.9A patent/EP3656864A1/en active Pending
- 2015-02-16 MX MX2016010566A patent/MX369513B/es active IP Right Grant
- 2015-02-16 CA CA3190002A patent/CA3190002A1/en active Pending
- 2015-02-16 CA CA2938887A patent/CA2938887C/en active Active
- 2015-02-16 RU RU2021123419A patent/RU2021123419A/ru unknown
- 2015-02-16 JP JP2016551764A patent/JP6640726B2/ja active Active
- 2015-02-16 ES ES15749056T patent/ES2764471T3/es active Active
- 2015-02-16 CN CN202110505479.4A patent/CN113234757A/zh active Pending
- 2015-02-16 CN CN201580017207.2A patent/CN106414748B/zh active Active
- 2015-02-16 SG SG10201811816RA patent/SG10201811816RA/en unknown
-
2016
- 2016-08-10 IL IL247208A patent/IL247208B/en active IP Right Grant
- 2016-08-12 MX MX2019009295A patent/MX2019009295A/es unknown
- 2016-08-16 ZA ZA2016/05655A patent/ZA201605655B/en unknown
-
2018
- 2018-09-28 US US16/145,790 patent/US20190085079A1/en not_active Abandoned
-
2019
- 2019-04-10 AU AU2019202514A patent/AU2019202514B2/en active Active
- 2019-12-26 JP JP2019235725A patent/JP2020058380A/ja not_active Withdrawn
-
2020
- 2020-01-26 IL IL272264A patent/IL272264B/en active IP Right Grant
-
2021
- 2021-02-26 US US17/187,074 patent/US20210324071A1/en active Pending
- 2021-03-25 IL IL281819A patent/IL281819B2/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004529636A (ja) * | 2000-11-07 | 2004-09-30 | シティ・オブ・ホープ | Cd19特異的再指向免疫細胞 |
US20130266551A1 (en) * | 2003-11-05 | 2013-10-10 | St. Jude Children's Research Hospital, Inc. | Chimeric receptors with 4-1bb stimulatory signaling domain |
WO2013063419A2 (en) * | 2011-10-28 | 2013-05-02 | The Trustees Of The University Of Pennsylvania | A fully human, anti-mesothelin specific chimeric immune receptor for redirected mesothelin-expressing cell targeting |
JP2013116891A (ja) * | 2011-11-01 | 2013-06-13 | Nagoya Univ | 髄膜腫治療用医薬組成物 |
Non-Patent Citations (3)
Title |
---|
MILONE ET AL., MOLECULAR THERAPY, vol. 17, no. 8, JPN6019001209, 2009, pages 1453 - 1464, ISSN: 0003959504 * |
SINGH ET AL., PLOS ONE, vol. 8, no. 5, JPN6019001207, 2013, pages 64138 - 1, ISSN: 0003959503 * |
中川ら, DRUG DELIVERY SYSTEM, vol. 28, no. 1, JPN6019001212, 2013, pages 35 - 44, ISSN: 0003959505 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021500882A (ja) * | 2017-10-18 | 2021-01-14 | プレシゲン,インコーポレイテッド | スペーサーを含むポリペプチド組成物 |
JP2021502070A (ja) * | 2017-11-03 | 2021-01-28 | レンティジェン・テクノロジー・インコーポレイテッドLentigen Technology, Inc. | 抗ror1免疫療法によってがんを処置するための組成物および方法 |
JP7448903B2 (ja) | 2017-11-03 | 2024-03-13 | レンティジェン・テクノロジー・インコーポレイテッド | 抗ror1免疫療法によってがんを処置するための組成物および方法 |
JP2021509290A (ja) * | 2017-12-28 | 2021-03-25 | 上海細胞治療集団有限公司Shanghai Cell Therapy Group Co., Ltd. | 双方向活性化共刺激分子受容体及びその用途 |
JP7386177B2 (ja) | 2017-12-28 | 2023-11-24 | 上海細胞治療集団有限公司 | 双方向活性化共刺激分子受容体及びその用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210324071A1 (en) | Chimeric antigen receptors and methods of making | |
US20220160765A1 (en) | Engineered gamma delta t-cells | |
AU2018202976B2 (en) | Polyclonal gamma delta t cells for immunotherapy | |
US20220025001A1 (en) | Nucleic acid constructs for co-expression of chimeric antigen receptor and transcription factor, cells containing and therapeutic use thereof | |
KR20230007559A (ko) | 태그된 키메라 이펙터 분자 및 그의 리셉터 | |
US20220064255A1 (en) | Anti-tcr antibody molecules and uses thereof | |
US20230048244A1 (en) | Anti-tcr antibody molecules and uses thereof | |
TW201837175A (zh) | 用於黑色素瘤之嵌合抗原受體及其用途 | |
KR20220110199A (ko) | 태반-유래 동종이계 car-t 세포 및 이의 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180124 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180124 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190121 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190422 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190621 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20191127 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20191226 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6640726 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |