JP7286267B2 - 修飾t細胞に対する条件的活性型キメラ抗原受容体 - Google Patents
修飾t細胞に対する条件的活性型キメラ抗原受容体 Download PDFInfo
- Publication number
- JP7286267B2 JP7286267B2 JP2017511696A JP2017511696A JP7286267B2 JP 7286267 B2 JP7286267 B2 JP 7286267B2 JP 2017511696 A JP2017511696 A JP 2017511696A JP 2017511696 A JP2017511696 A JP 2017511696A JP 7286267 B2 JP7286267 B2 JP 7286267B2
- Authority
- JP
- Japan
- Prior art keywords
- cells
- antigen
- cell
- protein
- cancer
- 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.)
- Active
Links
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 title claims description 156
- 210000001744 T-lymphocyte Anatomy 0.000 title claims description 64
- 108090000623 proteins and genes Proteins 0.000 claims description 331
- 210000004027 cell Anatomy 0.000 claims description 309
- 102000004169 proteins and genes Human genes 0.000 claims description 271
- 239000000427 antigen Substances 0.000 claims description 242
- 108091007433 antigens Proteins 0.000 claims description 241
- 102000036639 antigens Human genes 0.000 claims description 241
- 206010028980 Neoplasm Diseases 0.000 claims description 171
- 238000000034 method Methods 0.000 claims description 165
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 118
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 102
- 229920001184 polypeptide Polymers 0.000 claims description 100
- 230000027455 binding Effects 0.000 claims description 98
- 230000000694 effects Effects 0.000 claims description 86
- 102000040430 polynucleotide Human genes 0.000 claims description 85
- 108091033319 polynucleotide Proteins 0.000 claims description 85
- 239000002157 polynucleotide Substances 0.000 claims description 85
- 201000011510 cancer Diseases 0.000 claims description 58
- 239000013598 vector Substances 0.000 claims description 57
- 230000002159 abnormal effect Effects 0.000 claims description 54
- 230000014509 gene expression Effects 0.000 claims description 47
- 108020004414 DNA Proteins 0.000 claims description 45
- 239000013604 expression vector Substances 0.000 claims description 44
- 210000004556 brain Anatomy 0.000 claims description 40
- 238000002703 mutagenesis Methods 0.000 claims description 39
- 231100000350 mutagenesis Toxicity 0.000 claims description 39
- 231100000433 cytotoxic Toxicity 0.000 claims description 37
- 230000001472 cytotoxic effect Effects 0.000 claims description 37
- 230000001965 increasing effect Effects 0.000 claims description 34
- 238000003556 assay Methods 0.000 claims description 32
- 230000002829 reductive effect Effects 0.000 claims description 30
- 230000004068 intracellular signaling Effects 0.000 claims description 27
- 238000004519 manufacturing process Methods 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 25
- 241000700605 Viruses Species 0.000 claims description 20
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 17
- 210000000822 natural killer cell Anatomy 0.000 claims description 16
- 230000008685 targeting Effects 0.000 claims description 16
- 238000001727 in vivo Methods 0.000 claims description 14
- 230000001225 therapeutic effect Effects 0.000 claims description 14
- 230000001404 mediated effect Effects 0.000 claims description 13
- 239000013603 viral vector Substances 0.000 claims description 12
- 238000000338 in vitro Methods 0.000 claims description 11
- 210000002540 macrophage Anatomy 0.000 claims description 9
- 239000012636 effector Substances 0.000 claims description 8
- 210000003071 memory t lymphocyte Anatomy 0.000 claims description 8
- 230000001177 retroviral effect Effects 0.000 claims description 8
- 206010027476 Metastases Diseases 0.000 claims description 7
- 238000004458 analytical method Methods 0.000 claims description 7
- 238000002741 site-directed mutagenesis Methods 0.000 claims description 7
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 102000009465 Growth Factor Receptors Human genes 0.000 claims description 5
- 108010009202 Growth Factor Receptors Proteins 0.000 claims description 5
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 5
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 5
- 238000012219 cassette mutagenesis Methods 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000017604 Hodgkin disease Diseases 0.000 claims description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 210000003651 basophil Anatomy 0.000 claims description 4
- 210000003979 eosinophil Anatomy 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 210000000440 neutrophil Anatomy 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 201000000053 blastoma Diseases 0.000 claims description 3
- 201000008184 embryoma Diseases 0.000 claims description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 3
- 238000007834 ligase chain reaction Methods 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 2
- 241000175212 Herpesvirales Species 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000009956 adenocarcinoma Diseases 0.000 claims description 2
- 238000007845 assembly PCR Methods 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 230000036210 malignancy Effects 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 230000001568 sexual effect Effects 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 2
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims 2
- 206010003571 Astrocytoma Diseases 0.000 claims 1
- 206010004146 Basal cell carcinoma Diseases 0.000 claims 1
- 208000005243 Chondrosarcoma Diseases 0.000 claims 1
- 208000006332 Choriocarcinoma Diseases 0.000 claims 1
- 206010014967 Ependymoma Diseases 0.000 claims 1
- 208000006168 Ewing Sarcoma Diseases 0.000 claims 1
- 201000008808 Fibrosarcoma Diseases 0.000 claims 1
- 208000000527 Germinoma Diseases 0.000 claims 1
- 208000032612 Glial tumor Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 208000018142 Leiomyosarcoma Diseases 0.000 claims 1
- 208000007054 Medullary Carcinoma Diseases 0.000 claims 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 claims 1
- 208000000172 Medulloblastoma Diseases 0.000 claims 1
- 206010027406 Mesothelioma Diseases 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 claims 1
- 206010029260 Neuroblastoma Diseases 0.000 claims 1
- 201000010133 Oligodendroglioma Diseases 0.000 claims 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims 1
- 208000007641 Pinealoma Diseases 0.000 claims 1
- 208000006265 Renal cell carcinoma Diseases 0.000 claims 1
- 201000000582 Retinoblastoma Diseases 0.000 claims 1
- 201000010208 Seminoma Diseases 0.000 claims 1
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 1
- 208000014070 Vestibular schwannoma Diseases 0.000 claims 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims 1
- 208000008383 Wilms tumor Diseases 0.000 claims 1
- 208000004064 acoustic neuroma Diseases 0.000 claims 1
- 208000017733 acquired polycythemia vera Diseases 0.000 claims 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims 1
- 208000006990 cholangiocarcinoma Diseases 0.000 claims 1
- 238000009109 curative therapy Methods 0.000 claims 1
- 230000002518 glial effect Effects 0.000 claims 1
- 201000009277 hairy cell leukemia Diseases 0.000 claims 1
- 208000025750 heavy chain disease Diseases 0.000 claims 1
- 201000002222 hemangioblastoma Diseases 0.000 claims 1
- 201000005787 hematologic cancer Diseases 0.000 claims 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims 1
- 206010024627 liposarcoma Diseases 0.000 claims 1
- 210000003810 lymphokine-activated killer cell Anatomy 0.000 claims 1
- 208000001611 myxosarcoma Diseases 0.000 claims 1
- 208000025189 neoplasm of testis Diseases 0.000 claims 1
- 201000008026 nephroblastoma Diseases 0.000 claims 1
- 208000007538 neurilemmoma Diseases 0.000 claims 1
- 238000002515 oligonucleotide synthesis Methods 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 claims 1
- 201000010198 papillary carcinoma Diseases 0.000 claims 1
- 208000028591 pheochromocytoma Diseases 0.000 claims 1
- 208000024724 pineal body neoplasm Diseases 0.000 claims 1
- 201000004123 pineal gland cancer Diseases 0.000 claims 1
- 208000037244 polycythemia vera Diseases 0.000 claims 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims 1
- 206010039667 schwannoma Diseases 0.000 claims 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 claims 1
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 1
- 201000010965 sweat gland carcinoma Diseases 0.000 claims 1
- 201000008753 synovium neoplasm Diseases 0.000 claims 1
- 201000003120 testicular cancer Diseases 0.000 claims 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 claims 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims 1
- 235000018102 proteins Nutrition 0.000 description 247
- 230000004962 physiological condition Effects 0.000 description 64
- 150000007523 nucleic acids Chemical class 0.000 description 63
- 102000039446 nucleic acids Human genes 0.000 description 53
- 108020004707 nucleic acids Proteins 0.000 description 53
- 241000282414 Homo sapiens Species 0.000 description 52
- 239000003446 ligand Substances 0.000 description 45
- 210000001519 tissue Anatomy 0.000 description 43
- 108090000790 Enzymes Proteins 0.000 description 40
- 102000004190 Enzymes Human genes 0.000 description 39
- 229940088598 enzyme Drugs 0.000 description 39
- 210000000130 stem cell Anatomy 0.000 description 39
- 239000012634 fragment Substances 0.000 description 37
- 210000001179 synovial fluid Anatomy 0.000 description 37
- 125000005647 linker group Chemical group 0.000 description 35
- 235000001014 amino acid Nutrition 0.000 description 34
- 102000005962 receptors Human genes 0.000 description 34
- 108020003175 receptors Proteins 0.000 description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 32
- 230000008499 blood brain barrier function Effects 0.000 description 31
- 210000001218 blood-brain barrier Anatomy 0.000 description 31
- 230000035772 mutation Effects 0.000 description 31
- 238000012216 screening Methods 0.000 description 30
- 201000010099 disease Diseases 0.000 description 28
- 239000002245 particle Substances 0.000 description 28
- 150000001413 amino acids Chemical class 0.000 description 27
- 229940024606 amino acid Drugs 0.000 description 26
- -1 ICOS Proteins 0.000 description 25
- 238000012360 testing method Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 210000000603 stem cell niche Anatomy 0.000 description 24
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 23
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 23
- 210000003722 extracellular fluid Anatomy 0.000 description 20
- 230000003612 virological effect Effects 0.000 description 20
- 102000004127 Cytokines Human genes 0.000 description 19
- 108090000695 Cytokines Proteins 0.000 description 19
- 108091028043 Nucleic acid sequence Proteins 0.000 description 19
- 125000006850 spacer group Chemical group 0.000 description 19
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 18
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 18
- 230000003834 intracellular effect Effects 0.000 description 18
- 239000002773 nucleotide Substances 0.000 description 18
- 125000003729 nucleotide group Chemical group 0.000 description 18
- 210000004369 blood Anatomy 0.000 description 17
- 239000008280 blood Substances 0.000 description 17
- 230000002255 enzymatic effect Effects 0.000 description 16
- 230000018109 developmental process Effects 0.000 description 15
- 210000002966 serum Anatomy 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- 238000013518 transcription Methods 0.000 description 15
- 230000035897 transcription Effects 0.000 description 15
- 210000004881 tumor cell Anatomy 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 230000006870 function Effects 0.000 description 14
- 230000011664 signaling Effects 0.000 description 14
- 108020004705 Codon Proteins 0.000 description 13
- 102000001301 EGF receptor Human genes 0.000 description 13
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 13
- 238000003491 array Methods 0.000 description 13
- 238000011161 development Methods 0.000 description 13
- 239000003792 electrolyte Substances 0.000 description 13
- 230000028993 immune response Effects 0.000 description 13
- 230000008569 process Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 12
- 108060006698 EGF receptor Proteins 0.000 description 12
- 230000004069 differentiation Effects 0.000 description 12
- 239000013612 plasmid Substances 0.000 description 12
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 11
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 11
- 229940045513 CTLA4 antagonist Drugs 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000003623 enhancer Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 102100026882 Alpha-synuclein Human genes 0.000 description 10
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 241000894007 species Species 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 9
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 9
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 9
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 9
- 206010021143 Hypoxia Diseases 0.000 description 9
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 9
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 125000003275 alpha amino acid group Chemical group 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 230000002068 genetic effect Effects 0.000 description 9
- 210000000987 immune system Anatomy 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 210000004962 mammalian cell Anatomy 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 8
- 108091026890 Coding region Proteins 0.000 description 8
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 8
- 208000012659 Joint disease Diseases 0.000 description 8
- 241000713666 Lentivirus Species 0.000 description 8
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 8
- 108091008874 T cell receptors Proteins 0.000 description 8
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 8
- 108010033576 Transferrin Receptors Proteins 0.000 description 8
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 8
- 210000003169 central nervous system Anatomy 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 239000003102 growth factor Substances 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 230000006798 recombination Effects 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 230000032258 transport Effects 0.000 description 8
- 241000701161 unidentified adenovirus Species 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- 102000004264 Osteopontin Human genes 0.000 description 7
- 108010081689 Osteopontin Proteins 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 101150058049 car gene Proteins 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000035790 physiological processes and functions Effects 0.000 description 7
- 238000012552 review Methods 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- 210000005253 yeast cell Anatomy 0.000 description 7
- 108091033409 CRISPR Proteins 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 6
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 6
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000000890 antigenic effect Effects 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 238000010367 cloning Methods 0.000 description 6
- 238000004520 electroporation Methods 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 210000004408 hybridoma Anatomy 0.000 description 6
- 210000002865 immune cell Anatomy 0.000 description 6
- 230000036039 immunity Effects 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 229920002521 macromolecule Polymers 0.000 description 6
- 238000011275 oncology therapy Methods 0.000 description 6
- 230000003204 osmotic effect Effects 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 230000004936 stimulating effect Effects 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 5
- 101150013553 CD40 gene Proteins 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 102000003886 Glycoproteins Human genes 0.000 description 5
- 108090000288 Glycoproteins Proteins 0.000 description 5
- 108020005004 Guide RNA Proteins 0.000 description 5
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 5
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 206010061598 Immunodeficiency Diseases 0.000 description 5
- 208000029462 Immunodeficiency disease Diseases 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 5
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 5
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 5
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 210000000612 antigen-presenting cell Anatomy 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 239000012472 biological sample Substances 0.000 description 5
- 210000001124 body fluid Anatomy 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000000139 costimulatory effect Effects 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 238000010362 genome editing Methods 0.000 description 5
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 5
- 230000001146 hypoxic effect Effects 0.000 description 5
- 230000007813 immunodeficiency Effects 0.000 description 5
- 102000006495 integrins Human genes 0.000 description 5
- 108010044426 integrins Proteins 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 210000001503 joint Anatomy 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 235000001055 magnesium Nutrition 0.000 description 5
- 229940091250 magnesium supplement Drugs 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000010369 molecular cloning Methods 0.000 description 5
- 230000036542 oxidative stress Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 238000005215 recombination Methods 0.000 description 5
- 108091008146 restriction endonucleases Proteins 0.000 description 5
- 150000003384 small molecules Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 235000015424 sodium Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 description 5
- 241001430294 unidentified retrovirus Species 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 108010083359 Antigen Receptors Proteins 0.000 description 4
- 102000006306 Antigen Receptors Human genes 0.000 description 4
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 4
- 102100038078 CD276 antigen Human genes 0.000 description 4
- 101710185679 CD276 antigen Proteins 0.000 description 4
- 238000010354 CRISPR gene editing Methods 0.000 description 4
- 238000000018 DNA microarray Methods 0.000 description 4
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 4
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 4
- 238000012286 ELISA Assay Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 4
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 4
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 description 4
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 4
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 4
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 4
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 4
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 230000006052 T cell proliferation Effects 0.000 description 4
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 4
- 102000007000 Tenascin Human genes 0.000 description 4
- 108010008125 Tenascin Proteins 0.000 description 4
- 241001648840 Thosea asigna virus Species 0.000 description 4
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 4
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 4
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 4
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 description 4
- 235000011010 calcium phosphates Nutrition 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 230000024245 cell differentiation Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 210000001671 embryonic stem cell Anatomy 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 210000003527 eukaryotic cell Anatomy 0.000 description 4
- 210000002744 extracellular matrix Anatomy 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000009396 hybridization Methods 0.000 description 4
- 230000002163 immunogen Effects 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 208000027866 inflammatory disease Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 210000000581 natural killer T-cell Anatomy 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 238000009168 stem cell therapy Methods 0.000 description 4
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- XQUPVDVFXZDTLT-UHFFFAOYSA-N 1-[4-[[4-(2,5-dioxopyrrol-1-yl)phenyl]methyl]phenyl]pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C(C=C1)=CC=C1CC1=CC=C(N2C(C=CC2=O)=O)C=C1 XQUPVDVFXZDTLT-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 3
- 102100021257 Beta-secretase 1 Human genes 0.000 description 3
- 101710150192 Beta-secretase 1 Proteins 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 3
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 3
- 239000004971 Cross linker Substances 0.000 description 3
- 102100032218 Cytokine-inducible SH2-containing protein Human genes 0.000 description 3
- 101710132484 Cytokine-inducible SH2-containing protein Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 241000702421 Dependoparvovirus Species 0.000 description 3
- 102100027723 Endogenous retrovirus group K member 6 Rec protein Human genes 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 102100037907 High mobility group protein B1 Human genes 0.000 description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 3
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 3
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 3
- 101001025337 Homo sapiens High mobility group protein B1 Proteins 0.000 description 3
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 3
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 3
- 102100025390 Integrin beta-2 Human genes 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- 108010021466 Mutant Proteins Proteins 0.000 description 3
- 102000008300 Mutant Proteins Human genes 0.000 description 3
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 3
- 229930193140 Neomycin Natural products 0.000 description 3
- 108010038807 Oligopeptides Proteins 0.000 description 3
- 102000015636 Oligopeptides Human genes 0.000 description 3
- 102000057297 Pepsin A Human genes 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 3
- 108020005067 RNA Splice Sites Proteins 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- 241000713311 Simian immunodeficiency virus Species 0.000 description 3
- 241000700584 Simplexvirus Species 0.000 description 3
- 230000006044 T cell activation Effects 0.000 description 3
- 102100027208 T-cell antigen CD7 Human genes 0.000 description 3
- 108020004440 Thymidine kinase Proteins 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 3
- 102100024568 Tumor necrosis factor ligand superfamily member 11 Human genes 0.000 description 3
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000002659 cell therapy Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 239000013599 cloning vector Substances 0.000 description 3
- 230000002860 competitive effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 239000003596 drug target Substances 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 230000006862 enzymatic digestion Effects 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000001638 lipofection Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 229960004927 neomycin Drugs 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 229920003192 poly(bis maleimide) Polymers 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000006337 proteolytic cleavage Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 238000009580 stem-cell therapy Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 239000013607 AAV vector Substances 0.000 description 2
- 102100034452 Alternative prion protein Human genes 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 108020005544 Antisense RNA Proteins 0.000 description 2
- 108010060159 Apolipoprotein E4 Proteins 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 description 2
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 108700012439 CA9 Proteins 0.000 description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- 108010065524 CD52 Antigen Proteins 0.000 description 2
- 102100035793 CD83 antigen Human genes 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 101710091045 Envelope protein Proteins 0.000 description 2
- 102100023688 Eotaxin Human genes 0.000 description 2
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 2
- 241000206602 Eukaryota Species 0.000 description 2
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 102100028072 Fibroblast growth factor 4 Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229930186217 Glycolipid Natural products 0.000 description 2
- 108060003393 Granulin Proteins 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 2
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 2
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 2
- 101001060274 Homo sapiens Fibroblast growth factor 4 Proteins 0.000 description 2
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 2
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 2
- 101000941879 Homo sapiens Leucine-rich repeat serine/threonine-protein kinase 2 Proteins 0.000 description 2
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 2
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein Proteins 0.000 description 2
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 2
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 2
- 101000809875 Homo sapiens TYRO protein tyrosine kinase-binding protein Proteins 0.000 description 2
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 2
- 108050009527 Hypoxia-inducible factor-1 alpha Proteins 0.000 description 2
- 108010073816 IgE Receptors Proteins 0.000 description 2
- 102000009438 IgE Receptors Human genes 0.000 description 2
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 description 2
- 108010042918 Integrin alpha5beta1 Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- 108050003558 Interleukin-17 Proteins 0.000 description 2
- 102000013691 Interleukin-17 Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 108091092195 Intron Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 102000002698 KIR Receptors Human genes 0.000 description 2
- 108010043610 KIR Receptors Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 102100033467 L-selectin Human genes 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 101150028321 Lck gene Proteins 0.000 description 2
- 102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 description 2
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 2
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 2
- 102000015728 Mucins Human genes 0.000 description 2
- 108010063954 Mucins Proteins 0.000 description 2
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 description 2
- 108010004222 Natural Cytotoxicity Triggering Receptor 3 Proteins 0.000 description 2
- 102100032852 Natural cytotoxicity triggering receptor 3 Human genes 0.000 description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 2
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 2
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- 201000011152 Pemphigus Diseases 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 description 2
- 108091000054 Prion Proteins 0.000 description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
- 101710188315 Protein X Proteins 0.000 description 2
- 108010025832 RANK Ligand Proteins 0.000 description 2
- 102000001218 Rec A Recombinases Human genes 0.000 description 2
- 108010055016 Rec A Recombinases Proteins 0.000 description 2
- 102100034201 Sclerostin Human genes 0.000 description 2
- 108010029389 Simplexvirus glycoprotein B Proteins 0.000 description 2
- 241000710960 Sindbis virus Species 0.000 description 2
- 108010017622 Somatomedin Receptors Proteins 0.000 description 2
- 102000004584 Somatomedin Receptors Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 2
- 102100038717 TYRO protein tyrosine kinase-binding protein Human genes 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 102000006601 Thymidine Kinase Human genes 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 2
- 102100040247 Tumor necrosis factor Human genes 0.000 description 2
- 102100022205 Tumor necrosis factor receptor superfamily member 21 Human genes 0.000 description 2
- 101710187751 Tumor necrosis factor receptor superfamily member 21 Proteins 0.000 description 2
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 238000004026 adhesive bonding Methods 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 2
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 2
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000005098 blood-cerebrospinal fluid barrier Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000007969 cellular immunity Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 230000002759 chromosomal effect Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000000368 destabilizing effect Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001976 enzyme digestion Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000001476 gene delivery Methods 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- 230000006801 homologous recombination Effects 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000016784 immunoglobulin production Effects 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 238000005304 joining Methods 0.000 description 2
- 229940001447 lactate Drugs 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000001365 lymphatic vessel Anatomy 0.000 description 2
- 230000002934 lysing effect Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 238000002493 microarray Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 230000033607 mismatch repair Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000001823 molecular biology technique Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000003499 nucleic acid array Methods 0.000 description 2
- 235000021232 nutrient availability Nutrition 0.000 description 2
- 230000000771 oncological effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 201000001976 pemphigus vulgaris Diseases 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000004952 protein activity Effects 0.000 description 2
- 108020001580 protein domains Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000002708 random mutagenesis Methods 0.000 description 2
- 239000012070 reactive reagent Substances 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 230000002483 superagonistic effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001258 synovial membrane Anatomy 0.000 description 2
- 210000002437 synoviocyte Anatomy 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 101150047061 tag-72 gene Proteins 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 241001515965 unidentified phage Species 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- FLCQLSRLQIPNLM-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate Chemical compound CC(=O)SCC(=O)ON1C(=O)CCC1=O FLCQLSRLQIPNLM-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BEJKOYIMCGMNRB-GRHHLOCNSA-N (2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BEJKOYIMCGMNRB-GRHHLOCNSA-N 0.000 description 1
- 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 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical class NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- WTLKTXIHIHFSGU-UHFFFAOYSA-N 2-nitrosoguanidine Chemical compound NC(N)=NN=O WTLKTXIHIHFSGU-UHFFFAOYSA-N 0.000 description 1
- 108020005065 3' Flanking Region Proteins 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- KKAJSJJFBSOMGS-UHFFFAOYSA-N 3,6-diamino-10-methylacridinium chloride Chemical compound [Cl-].C1=C(N)C=C2[N+](C)=C(C=C(N)C=C3)C3=CC2=C1 KKAJSJJFBSOMGS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 102000002627 4-1BB Ligand Human genes 0.000 description 1
- 108010082808 4-1BB Ligand Proteins 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 102000007471 Adenosine A2A receptor Human genes 0.000 description 1
- 108010085277 Adenosine A2A receptor Proteins 0.000 description 1
- 101150051188 Adora2a gene Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102100036601 Aggrecan core protein Human genes 0.000 description 1
- 108010067219 Aggrecans Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 239000000592 Artificial Cell Substances 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000037914 B-cell disorder Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 102100032412 Basigin Human genes 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 108010008629 CA-125 Antigen Proteins 0.000 description 1
- 102000007269 CA-125 Antigen Human genes 0.000 description 1
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 102100037904 CD9 antigen Human genes 0.000 description 1
- 101150018129 CSF2 gene Proteins 0.000 description 1
- 101150069031 CSN2 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102100025466 Carcinoembryonic antigen-related cell adhesion molecule 3 Human genes 0.000 description 1
- 102000013602 Cardiac Myosins Human genes 0.000 description 1
- 108010051609 Cardiac Myosins Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
- 102000004018 Caspase 6 Human genes 0.000 description 1
- 108090000425 Caspase 6 Proteins 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108010082548 Chemokine CCL11 Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101710198480 Clumping factor A Proteins 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 101150074775 Csf1 gene Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 101710096438 DNA-binding protein Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 101100044298 Drosophila melanogaster fand gene Proteins 0.000 description 1
- 208000010975 Dystrophic epidermolysis bullosa Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 101710121417 Envelope glycoprotein Proteins 0.000 description 1
- 102000050554 Eph Family Receptors Human genes 0.000 description 1
- 108091008815 Eph receptors Proteins 0.000 description 1
- 241001379910 Ephemera danica Species 0.000 description 1
- 206010066919 Epidemic polyarthritis Diseases 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 1
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 1
- 102000044591 ErbB-4 Receptor Human genes 0.000 description 1
- 101000943592 Escherichia coli (strain K12) Sodium-potassium/proton antiporter ChaA Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 101150064015 FAS gene Proteins 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 1
- 108010021470 Fc gamma receptor IIC Proteins 0.000 description 1
- 102100031507 Fc receptor-like protein 5 Human genes 0.000 description 1
- 101710120217 Fc receptor-like protein 5 Proteins 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000713800 Feline immunodeficiency virus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 102000010451 Folate receptor alpha Human genes 0.000 description 1
- 108050001931 Folate receptor alpha Proteins 0.000 description 1
- 101150074355 GS gene Proteins 0.000 description 1
- 102100031351 Galectin-9 Human genes 0.000 description 1
- 101100229077 Gallus gallus GAL9 gene Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 108010054017 Granulocyte Colony-Stimulating Factor Receptors Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102100039622 Granulocyte colony-stimulating factor receptor Human genes 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 108010039334 HIV Envelope Protein gp120 Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 102100028967 HLA class I histocompatibility antigen, alpha chain G Human genes 0.000 description 1
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 description 1
- 108010024164 HLA-G Antigens Proteins 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 102100029360 Hematopoietic cell signal transducer Human genes 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000773083 Homo sapiens 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein 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
- 101000738354 Homo sapiens CD9 antigen Proteins 0.000 description 1
- 101000914337 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 3 Proteins 0.000 description 1
- 101000722264 Homo sapiens DENN domain-containing protein 2B Proteins 0.000 description 1
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 1
- 101000978392 Homo sapiens Eotaxin Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101100334515 Homo sapiens FCGR3A gene Proteins 0.000 description 1
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 101000990188 Homo sapiens Hematopoietic cell signal transducer Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 1
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 1
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 description 1
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101001078143 Homo sapiens Integrin alpha-IIb Proteins 0.000 description 1
- 101001046677 Homo sapiens Integrin alpha-V Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 1
- 101000984189 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 2 Proteins 0.000 description 1
- 101000984186 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 4 Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000984626 Homo sapiens Low-density lipoprotein receptor-related protein 12 Proteins 0.000 description 1
- 101000991061 Homo sapiens MHC class I polypeptide-related sequence B Proteins 0.000 description 1
- 101001106413 Homo sapiens Macrophage-stimulating protein receptor Proteins 0.000 description 1
- 101000694615 Homo sapiens Membrane primary amine oxidase Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 1
- 101000589305 Homo sapiens Natural cytotoxicity triggering receptor 2 Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 description 1
- 101001098352 Homo sapiens OX-2 membrane glycoprotein Proteins 0.000 description 1
- 101000769159 Homo sapiens Protein yippee-like 3 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 1
- 101000711796 Homo sapiens Sclerostin Proteins 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 101000661807 Homo sapiens Suppressor of tumorigenicity 14 protein Proteins 0.000 description 1
- 101000701411 Homo sapiens Suppressor of tumorigenicity 7 protein Proteins 0.000 description 1
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 1
- 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 description 1
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 1
- 101100207070 Homo sapiens TNFSF8 gene Proteins 0.000 description 1
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 description 1
- 101000830603 Homo sapiens Tumor necrosis factor ligand superfamily member 11 Proteins 0.000 description 1
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 1
- 101000597785 Homo sapiens Tumor necrosis factor receptor superfamily member 6B Proteins 0.000 description 1
- 101000818543 Homo sapiens Tyrosine-protein kinase ZAP-70 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101150003028 Hprt1 gene Proteins 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 241000430519 Human rhinovirus sp. Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000003352 Hyper-IgM Immunodeficiency Syndrome Diseases 0.000 description 1
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102100034980 ICOS ligand Human genes 0.000 description 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 1
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 1
- 208000007924 IgA Deficiency Diseases 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 1
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102100036721 Insulin receptor Human genes 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102000012330 Integrases Human genes 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 108010047852 Integrin alphaVbeta3 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
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102100039897 Interleukin-5 Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108020003285 Isocitrate lyase Proteins 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 241001138401 Kluyveromyces lactis Species 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 102100020870 La-related protein 6 Human genes 0.000 description 1
- 108050008265 La-related protein 6 Proteins 0.000 description 1
- 241000186606 Lactobacillus gasseri Species 0.000 description 1
- 241000194034 Lactococcus lactis subsp. cremoris Species 0.000 description 1
- 241000282842 Lama glama Species 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 1
- 102100025583 Leukocyte immunoglobulin-like receptor subfamily B member 2 Human genes 0.000 description 1
- 102100025578 Leukocyte immunoglobulin-like receptor subfamily B member 4 Human genes 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 108010015340 Low Density Lipoprotein Receptor-Related Protein-1 Proteins 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029206 Low affinity immunoglobulin gamma Fc region receptor II-c Human genes 0.000 description 1
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- 102100040705 Low-density lipoprotein receptor-related protein 8 Human genes 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 1
- 102000018170 Lymphotoxin beta Receptor Human genes 0.000 description 1
- 108010091221 Lymphotoxin beta Receptor Proteins 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101001018085 Lysobacter enzymogenes Lysyl endopeptidase Proteins 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 102100030301 MHC class I polypeptide-related sequence A Human genes 0.000 description 1
- 102100030300 MHC class I polypeptide-related sequence B Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 102100021435 Macrophage-stimulating protein receptor Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 1
- 101710127721 Membrane protein Proteins 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100219625 Mus musculus Casd1 gene Proteins 0.000 description 1
- 101000969137 Mus musculus Metallothionein-1 Proteins 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 101100207071 Mus musculus Tnfsf8 gene Proteins 0.000 description 1
- 101000835089 Mus musculus Transferrin receptor protein 1 Proteins 0.000 description 1
- 108010056852 Myostatin Proteins 0.000 description 1
- 101001055320 Myxine glutinosa Insulin-like growth factor Proteins 0.000 description 1
- 206010028665 Myxoedema Diseases 0.000 description 1
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical group CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 1
- SUHQNCLNRUAGOO-UHFFFAOYSA-N N-glycoloyl-neuraminic acid Natural products OCC(O)C(O)C(O)C(NC(=O)CO)C(O)CC(=O)C(O)=O SUHQNCLNRUAGOO-UHFFFAOYSA-N 0.000 description 1
- FDJKUWYYUZCUJX-UHFFFAOYSA-N N-glycolyl-beta-neuraminic acid Natural products OCC(O)C(O)C1OC(O)(C(O)=O)CC(O)C1NC(=O)CO FDJKUWYYUZCUJX-UHFFFAOYSA-N 0.000 description 1
- FDJKUWYYUZCUJX-KVNVFURPSA-N N-glycolylneuraminic acid Chemical compound OC[C@H](O)[C@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-KVNVFURPSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 108010004217 Natural Cytotoxicity Triggering Receptor 1 Proteins 0.000 description 1
- 102100032870 Natural cytotoxicity triggering receptor 1 Human genes 0.000 description 1
- 102100032851 Natural cytotoxicity triggering receptor 2 Human genes 0.000 description 1
- 102100029527 Natural cytotoxicity triggering receptor 3 ligand 1 Human genes 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 101100385413 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) csm-3 gene Proteins 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 208000035823 Non-specific autoimmune cerebellar ataxia without characteristic antibodies Diseases 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 101710149086 Nuclease S1 Proteins 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 102100037589 OX-2 membrane glycoprotein Human genes 0.000 description 1
- 102000004473 OX40 Ligand Human genes 0.000 description 1
- 108010042215 OX40 Ligand Proteins 0.000 description 1
- 241000238413 Octopus Species 0.000 description 1
- 241000320412 Ogataea angusta Species 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 240000007019 Oxalis corniculata Species 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108010090127 Periplasmic Proteins Proteins 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 101100335198 Pneumocystis carinii fol1 gene Proteins 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108010036933 Presenilin-1 Proteins 0.000 description 1
- 102000012412 Presenilin-1 Human genes 0.000 description 1
- 108010036908 Presenilin-2 Proteins 0.000 description 1
- 102000012419 Presenilin-2 Human genes 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- WDVSHHCDHLJJJR-UHFFFAOYSA-N Proflavine Chemical compound C1=CC(N)=CC2=NC3=CC(N)=CC=C3C=C21 WDVSHHCDHLJJJR-UHFFFAOYSA-N 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102100021923 Prolow-density lipoprotein receptor-related protein 1 Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102100028368 Protein yippee-like 3 Human genes 0.000 description 1
- 102100028965 Proteoglycan 4 Human genes 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000589540 Pseudomonas fluorescens Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 101900083372 Rabies virus Glycoprotein Proteins 0.000 description 1
- 101001039269 Rattus norvegicus Glycine N-methyltransferase Proteins 0.000 description 1
- 101100047461 Rattus norvegicus Trpm8 gene Proteins 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241001068295 Replication defective viruses Species 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 108050002653 Retinoblastoma protein Proteins 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000710942 Ross River virus Species 0.000 description 1
- 102100029198 SLAM family member 7 Human genes 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 108050006698 Sclerostin Proteins 0.000 description 1
- 206010039915 Selective IgA immunodeficiency Diseases 0.000 description 1
- 206010057863 Selective IgG subclass deficiency Diseases 0.000 description 1
- 241000710961 Semliki Forest virus Species 0.000 description 1
- 102000007365 Sialoglycoproteins Human genes 0.000 description 1
- 108010032838 Sialoglycoproteins Proteins 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 101800001707 Spacer peptide Proteins 0.000 description 1
- 241000256248 Spodoptera Species 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 235000014962 Streptococcus cremoris Nutrition 0.000 description 1
- 244000057717 Streptococcus lactis Species 0.000 description 1
- 235000014897 Streptococcus lactis Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102100035721 Syndecan-1 Human genes 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 108091007178 TNFRSF10A Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108700009124 Transcription Initiation Site Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 1
- 101710181056 Tumor necrosis factor ligand superfamily member 13B Proteins 0.000 description 1
- 102100032100 Tumor necrosis factor ligand superfamily member 8 Human genes 0.000 description 1
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 1
- 101710187743 Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 1
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 1
- 101710187830 Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 1
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 1
- 102100035284 Tumor necrosis factor receptor superfamily member 6B Human genes 0.000 description 1
- 108091005906 Type I transmembrane proteins Proteins 0.000 description 1
- 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 1
- 108010065472 Vimentin Proteins 0.000 description 1
- 102100035071 Vimentin Human genes 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 108070000030 Viral receptors Proteins 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 241000282485 Vulpes vulpes Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 230000005856 abnormality Effects 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
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940023020 acriflavine Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000004504 adult stem cell Anatomy 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 230000004103 aerobic respiration Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000007801 affinity label Substances 0.000 description 1
- 230000009824 affinity maturation Effects 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 108010003059 aggrecanase Proteins 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229950001537 amatuximab Drugs 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009925 apoptotic mechanism Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 1
- 210000004507 artificial chromosome Anatomy 0.000 description 1
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 230000008267 autocrine signaling Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004781 brain capillary Anatomy 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 239000003710 calcium ionophore Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 230000004858 capillary barrier Effects 0.000 description 1
- 210000001043 capillary endothelial cell Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 101150055766 cat gene Proteins 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000002962 chemical mutagen Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000002987 choroid plexus Anatomy 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 101150055601 cops2 gene Proteins 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000004940 costimulation Effects 0.000 description 1
- 108091008034 costimulatory receptors Proteins 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 108091007930 cytoplasmic receptors Proteins 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940057307 dihydrate calcium sulfate Drugs 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229950010640 ensituximab Drugs 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 208000004298 epidermolysis bullosa dystrophica Diseases 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Natural products O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 1
- 210000001368 germline stem cell Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000010005 growth-factor like effect Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 238000012872 hydroxylapatite chromatography Methods 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 206010066130 hyper-IgM syndrome Diseases 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000035874 hyperreactivity Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 210000001822 immobilized cell Anatomy 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 201000007156 immunoglobulin alpha deficiency Diseases 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 238000000530 impalefection Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 108010043603 integrin alpha4beta7 Proteins 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 108010052754 interleukin-14 receptor Proteins 0.000 description 1
- 108010074109 interleukin-22 Proteins 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 210000004966 intestinal stem cell Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 101150066555 lacZ gene Proteins 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 108010031117 low density lipoprotein receptor-related protein 8 Proteins 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 108010009030 lubricin Proteins 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 230000005741 malignant process Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 229960000901 mepacrine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002406 microsurgery Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 1
- 238000012806 monitoring device Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 101150049514 mutL gene Proteins 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 208000003786 myxedema Diseases 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000005155 neural progenitor cell Anatomy 0.000 description 1
- 210000001178 neural stem cell Anatomy 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 230000020520 nucleotide-excision repair Effects 0.000 description 1
- 235000021048 nutrient requirements Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000008789 oxidative DNA damage Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 102000045222 parkin Human genes 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 210000004896 polypeptide structure Anatomy 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229960000286 proflavine Drugs 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 230000030788 protein refolding Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 208000009305 pseudorabies Diseases 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 101150056906 recJ gene Proteins 0.000 description 1
- 108091006084 receptor activators Proteins 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 108020004418 ribosomal RNA Proteins 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 101150072534 sbcB gene Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 208000029138 selective IgA deficiency disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 108091005475 signaling receptors Proteins 0.000 description 1
- 102000035025 signaling receptors Human genes 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229940124598 therapeutic candidate Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 201000002389 transient hypogammaglobulinemia Diseases 0.000 description 1
- 208000016367 transient hypogammaglobulinemia of infancy Diseases 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 101150115617 umuC gene Proteins 0.000 description 1
- 101150046028 umuD gene Proteins 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 102100035070 von Hippel-Lindau disease tumor suppressor Human genes 0.000 description 1
- 101150100239 vsr gene Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- C07K14/70521—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
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
-
- 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
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
- C12N15/102—Mutagenizing nucleic acids
-
- 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
- C12N15/1058—Directional evolution of libraries, e.g. evolution of libraries is achieved by mutagenesis and screening or selection of mixed population of organisms
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5156—Animal cells expressing foreign proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
-
- 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
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- 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
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- 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
-
- 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
- C12N2510/00—Genetically modified cells
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Hematology (AREA)
- Bioinformatics & Computational Biology (AREA)
- Ecology (AREA)
- Endocrinology (AREA)
Description
本明細書に提供される実施例の理解を容易にするために、特定のしばしば登場する方法及び/又は用語は以下に記載される。
哺乳動物、特にヒトの免疫系は、罹患組織及び/又は病原体を標的化して破壊する細胞傷害性細胞を有する。これらの細胞傷害性細胞を使用して腫瘍などの望ましくない組織(即ち標的組織)を除去することは、有望な治療手法である。除去の標的とし得る他の組織としては、腺(例えば前立腺)過形成、疣贅、及び望ましくない脂肪組織が挙げられる。しかしながら、この比較的新しい治療手法は、これまでのところ限られた成功しか収めていない。例えば、T細胞を使用した腫瘍の標的化及び破壊は、癌細胞が表面抗原の発現を低下させて新しい療法に適応することによりこの療法の有効性が低下し得るため、長期的利益が比較的少ない。癌細胞は、腫瘍特異的T細胞に応答した検出を逃れるため脱分化することさえある。Maher,“Immunotherapy of Malignant Disease Using Chimeric Antigen Receptor Engrafted T Cells,”ISRN Oncology,vol.2012,article ID 278093,2012。
CARは、上記で考察した種々のドメインを全て共に融合して融合タンパク質を形成することによって生成されるキメラタンパク質である。CARは、典型的には、CARの種々のドメインをコードするポリヌクレオチド配列を含む発現ベクターによって生成される。標的細胞上の抗原を認識してそれと結合する働きをする本発明のASTRは、条件的活性型である。具体的には、ASTRは、対応する野生型タンパク質のASTRと比較して、標的抗原との結合に関して正常生理条件では低活性又は不活性であり、異常条件では活性である。本発明は、野生型タンパク質又はその結合ドメイン(野生型ASTR)から条件的活性型ASTRを生成する方法を提供する。
野生型タンパク質、又はその結合ドメイン(野生型ASTR)が突然変異誘発のプロセスを受けると変異ポリペプチドの集団が産生され、次にそれをスクリーニングすることにより、野生型ASTRとの比較において異常条件では標的抗原に対する結合親和性が増強した、且つ任意選択で、正常生理条件では標的抗原に対する結合親和性が実質的に同じか、又は低い変異ASTRを同定することができる。
発達工程から生成された変異ポリヌクレオチドは、変異ポリペプチドの産生(発現)のため、既発表のプロトコルに従いアガロースゲルでサイズ分画され、発現ベクターに挿入され、及び適切な宿主細胞にトランスフェクトされても、又はされなくてもよい。発現は、ルーチンの分子生物学的技術を用い得る。従って、発現工程は様々な公知の方法を用いることができる。
望ましい分子の同定は、許容型の条件及び野生型の条件におけるタンパク質活性を測定することによって、非常に直接的に達成される。最も高い活性の比(許容型/野生型)を示す変異体を、次いで選択し、標準的な方法を用いて個々の変異を組み合わせることで、点変異の並べ替え(permutation)を生成することが出来る。次いで、この組み合わせた並べ替えタンパク質ライブラリーから、許容型と野生型の活性に最も大きい差を示すタンパク質をスクリーニングする。
本開示は、本開示の酵素に特異的に結合する、単離された抗体又は組換え抗体を提供する。これらの抗体を用いて、本開示の酵素、又は関連するポリペプチドの酵素を、単離、同定、又は定量化することが出来る。これらの抗体を用いて、本開示の範囲内の他のポリペプチド、又は他の関連する酵素を単離することが出来る。抗体は、酵素の活性部位に結合するように設計することが出来る。従って、本開示は、本開示の抗体を用いて、酵素を抑制する方法を提供する。
Struct.26:27-45.を参照のこと。
本開示の方法の実施においては、様々な装置及び方法を本開示のポリペプチド及び核酸と併せて使用することが出来る。その装置及び方法には、例えば、酵素活性によるペプチドのスクリーニングするためのもの、酵素活性に対してアクチベーター又はインヒビターなどの潜在モジュレーターとなる化合物のスクリーニングするためのもの、本開示のポリペプチドに結合する抗体のためのもの、本開示の核酸にハイブリダイズする核酸のためのもの、本開示のポリペプチドを発現する細胞をスクリーニングするためのものなどが挙げられる。
本開示の核酸又はポリペプチドは、アレイに固定化又は適用することが出来る。アレイを用いることで、組成物(例えば、小分子、抗体、核酸など)のライブラリーに対して、本開示の核酸又はポリペプチドに結合する能力、又はそれらの活性を調整する能力によって、スクリーニング又はモニターすることが出来る。例えば、本開示の一態様においては、モニターされるパラメーターは酵素遺伝子の転写発現である。ある細胞の転写産物の、1つ又は複数、或いは全てを、その細胞の転写産物或いは細胞の転写産物の代表的又は相補的な核酸を有するサンプルを、アレイ又は「バイオチップ」に固定化した核酸にハイブリダイズすることで、測定することが可能である。マイクロチップ上の核酸の「アレイ」を用いることで、転写産物の一部又は全部を同時に定量化する事が出来る。或いは、ゲノム核酸を有するアレイを用いることで、本開示の方法によって作られた、新たに設計された株の遺伝子型を決定することも出来る。ポリペプチド「アレイ」を用いることで、同時に複数のタンパク質を定量化することも出来る。本開示は、任意の既知の「アレイ」とともに実施することが可能であって、この「アレイ」は、「マイクロアレイ」又は「核酸アレイ」又は「ポリペプチドアレイ」又は「抗体アレイ」又は「バイオチップ」又はそれらの変型とも見なされる。アレイは一般的に、複数の「スポット」又は「標的要素」であって、それぞれの標的要素は、規定の量の1つ又は複数の生体分子、例えば、オリゴヌクレオチドを有するものであり、サンプル分子、例えばmRNA転写産物に特異的に結合する基質表面の規定の領域に、固定化されているものである。
GIGAMATRIX(商標)(Diversa Corporation、San Diego,Calif.)などのキャピラリーアレイを、本開示の方法において用いることが出来る。本開示の核酸又はポリペプチドを、キャピラリーアレイを含むアレイに対して固定化又は適用することが出来る。アレイを用いることで、組成物(例えば、小分子、抗体、核酸など)のライブラリーに対して、本開示の核酸又はポリペプチドに結合する能力、又はそれらの活性を調整する能力によって、スクリーニング又はモニターすることが出来る。キャピラリーアレイは、サンプルを保持且つスクリーニングするためのもう一つのシステムを提供する。例えば、サンプルスクリーニング装置は、隣接したキャピラリーアレイとして形成される複数のキャピラリーを含むことが出来、ここで各キャピラリーは少なくとも1つの、サンプルを保持する管腔を形成する壁を有するものである。装置は、さらに、アレイ中の隣接したキャピラリーの間に配置される間質材を含み得るものであって、その間質剤の中に、1つまた複数の参照指標が形成されているものである。サンプルをスクリーニングするためのキャピラリーは、キャピラリーアレイに結合するように適合されたものであって、サンプルを保持するための管腔を形作る第一の壁と、サンプルを励起するために管腔に与えられる励起エネルギーをフィルターするフィルター材から形成される第二の壁を含み得るものである。ポリペプチド又は核酸、例えばリガンドを、キャピラリーアレイの少なくとも一部のキャピラリーの第一成分に、導入することが出来る。キャピラリーアレイの各キャピラリーは、少なくとも1つの、第一成分を保持する管腔を形作る壁を有することが出来る。キャピラリー中の第一成分の後ろに、気泡を導入することが出来る。第二成分をキャピラリーに導入することが可能であり、ここでこの第二成分は気泡によって第一成分と分離される。対象サンプルは、検出可能粒子で標識された第一液として、キャピラリーアレイ中の一つのキャピラリーに導入され、このキャピラリーアレイ中の各キャピラリーは、第一液と検出可能粒子とを保持するための管腔を形作る少なくとも1つの壁を有するものであって、少なくとも一つの壁は、検出可能粒子を結合させるための結合材料で被覆されている。本方法は、さらに、結合した検出可能粒子が保持されているキャピラリーチューブから第一液を除去する工程と、そのキャピラリーに第二液を導入する工程とを含むものである。キャピラリーアレイは、管腔を形作る少なくとも一つの外壁を有する、複数の個々のキャピラリーを含むものである。外壁は、互いに融合した1つ又は複数の壁であってもよい。同様に、壁は、その壁が液体又はサンプルを保持する管腔を形成する限り、円筒形、四角形、六角形、又はその他の幾何学的形態の管腔を形作ることができる。キャピラリーアレイ中のキャピラリーは、平面構造を形成するように近接して互いに支え合うことが出来る。キャピラリーは、隣同士を融合(例えば、ここではキャピラリーはガラス製)、接着、粘結、又は固定することによって、互いに結合することが出来る。キャピラリーアレイは、任意の数、例えば100~4,000,000の、個々のキャピラリーから形成することが可能である。キャピラリーアレイは、約100,000又はそれより多くの、互いに結合した個々のキャピラリーを持つ、マイクロタイタープレートを形成することが出来る。
条件的活性型抗体は、多重特異性条件的活性型抗体を生成するように操作し得る。多重特異性抗体は、国際公開第2013/170168号パンフレット(全体として参照により本明細書に援用される)に記載されるとおりの、多エピトープ特異性を有する抗体であり得る。多重特異性抗体には、限定はされないが、VHVL単位が多エピトープ特異性を有する重鎖可変ドメイン(VH)及び軽鎖可変ドメイン(VL)を含む抗体、各VHVL単位が異なるエピトープに結合する2つ以上のVL及びVHドメインを有する抗体、各単一可変ドメインが異なるエピトープに結合する2つ以上の単一可変ドメインを有する抗体、及び1つ又はそれ以上の抗体フラグメントを含む抗体並びに共有結合的又は非共有結合的に連結されている抗体フラグメントを含む抗体が含まれる。
関節疾患は、工業先進国における身体障害及び早期退職の主な原因である。関節疾患は多くの場合に関節の損傷をもたらし、これは修復が困難である。滑液は、ヒト又は動物の体の関節(例えば、膝、股関節部、肩)の滑膜腔において向かい合う関節表面の軟骨と滑膜との間に見られる体液である。滑液は軟骨に栄養を供給し、また関節の潤滑剤としても働く。軟骨及び滑膜の細胞は、関節表面間の潤滑剤として働く体液を分泌する。ヒト滑液は約85%の水を含む。これは血漿の透析液に由来し、この透析液それ自体は、水、溶解したタンパク質、グルコース、凝固因子、無機イオン、ホルモン等から成る。アルブミン及びグロブリンなどのタンパク質が滑液中に存在し、関節領域の潤滑において重要な役割を果たすと考えられる。ヒト滑液中には、α-1-酸性糖タンパク質(AGP)、α-1-アンチトリプシン(A1AT)及びルブリシンなどの糖タンパク質を含め、いくつかの他のタンパク質もまた見られる。
固形腫瘍の癌細胞は、その周囲に腫瘍微小環境を形成して癌細胞の成長及び転移を支援する能力を有する。腫瘍微小環境は、周囲血管、免疫細胞、線維芽細胞、他の細胞、可溶性因子、シグナル伝達分子、細胞外マトリックス、並びに新生物形質転換を促進し、腫瘍成長及び浸潤を支援し、腫瘍を宿主免疫から保護し、治療抵抗性を助長し、及び潜伏転移が発育するためのニッチを提供することのできる機械的キューを含めた、腫瘍が存在する細胞環境である。腫瘍及びその周囲微小環境は密接に関係し、常に相互作用している。腫瘍は、細胞外シグナルを放出し、腫瘍血管新生を促進し、及び末梢性免疫寛容を誘導することによってその微小環境に影響を与え得る一方、微小環境における免疫細胞が癌性細胞の成長及び発達に影響を及ぼし得る。Swarts et al.“Tumor Microenvironment Complexity:Emerging Roles in Cancer Therapy,”Cancer Res,vol.,72,pages 2473-2480,2012を参照のこと。
幹細胞は体の幹細胞ニッチと呼ばれる環境に存在し、幹細胞ニッチは組織生理学の基本的な単位を成し、生物の要求に対する幹細胞の応答を媒介するシグナルを統合する。しかしニッチは、幹細胞又は他の標的に異常機能を課すことによって病理もまた誘導し得る。幹細胞とそれらのニッチとの間の相互作用により、組織の持続及び幹細胞療法の最終設計に必要な動的システムが作り出される(Scadden,“The stem-cell niche as an entity of action,”Nature,vol.441,pages 1075-1079,2006)。脊椎動物における一般的な幹細胞ニッチには、生殖細胞系列幹細胞ニッチ、造血幹細胞ニッチ、毛包幹細胞ニッチ、腸幹細胞ニッチ、及び心血管幹細胞ニッチが含まれる。
ウイルス粒子は、長年、タンパク質、核酸分子、化学的化合物又は放射性同位元素を標的細胞又は組織に輸送するための送達媒体として使用されている。送達媒体として一般的に用いられているウイルス粒子としては、レトロウイルス(retrovirus)、アデノウイルス、レンチウイルス、ヘルペスウイルス、及びアデノ随伴ウイルスが挙げられる。ウイルス粒子は、多くの場合にリガンド-受容体結合系において、標的細胞の標的タンパク質として働く細胞タンパク質との特異的結合のための認識タンパク質として働く表面タンパク質を介してその標的細胞を認識する(Lentz,“The recognition event between virus and host cell receptor:a target for antiviral agents,”J.of Gen.Virol.,vol.71,pages 751-765,1990(参照により本明細書に援用される))。例えば、ウイルス認識タンパク質は、標的細胞上の受容体に対するリガンドであり得る。リガンドと受容体との間の特異性により、ウイルス粒子が標的細胞を特異的に認識して、そこにその内容物を送達することが可能となる。
新規ゲノム操作ツールの一形態としてDNA/RNA修飾タンパク質、特にCRISPRと呼ばれるものが発見されており、これらによれば、研究者は遺伝子にマイクロサージェリーを施して、染色体上の正確な位置にあるDNA配列を精密且つ容易に変化させることが可能になる(ゲノム編集、Mali et al.,“Cas9 as a versatile tool for engineering biology,”Nature Methods,vol.10,pages 957-963,2013)。例えば、鎌状赤血球貧血は単一塩基突然変異によって引き起こされ、これはDNA/RNA修飾タンパク質を使用して修正し得る可能性がある。この技術は、染色体の小片を、一塩基対の変更による場合であっても、精密に欠失させ、又は編集し得る(Makarova et al.,“Evolution and classification of the CRISPR-Cas systems,”Nature Reviews Microbiology,vol.9,pages 467-477,2011)。
スクリーニング工程によって条件的活性型ASTRが同定されると、個々のドメインをコードするポリヌクレオチド配列をライゲートして単一のポリヌクレオチド配列(CAR遺伝子、これは条件的活性型CARをコードする)を形成することにより、キメラ抗原受容体をアセンブルし得る。個々のドメインには、条件的活性型ASTR、TM、及びISDが含まれる。一部の実施形態において、ESD及びCSDを含めた他のドメインもまたCARに導入され得る(図1)。条件的活性型CARが二重特異性CARである場合、CAR遺伝子は、例えば、N末端からC末端の向きに以下の構成:N末端シグナル配列-ASTR1-リンカー-ASTR2-細胞外スペーサードメイン-膜貫通ドメイン-共刺激ドメイン-細胞内シグナル伝達ドメインであってもよい。一実施形態において、かかるCAR遺伝子は2つ以上の共刺激ドメインを含み得る。
マルチウォールプレートの各ウェルに蛍光基質を加え、野生型の温度と、新規の型で低い反応温度の両方(例えば、上述の通り37℃又は25℃のいずれか)に適切な時間おく。蛍光プレートリーダーによって、適切な励起及び発光スペクトル(例えば、320nmの励起スペクトル、405nmの発光スペクトル)において、蛍光を測定することによって、蛍光を検出する。相対蛍光ユニット(Relative fluorescence unit:RFU)を決定する。野生型分子からの上清及びプラスミド/ベクターで形質転換された細胞を、ポジティブコントロール及びネガティブコントロールとして用いる。各サンプル、反応温度、ポジティブコントロール及びネガティブコントロールにおいて、複製反応を行う。
温度感受性一次ヒットとして同定された変異体を、14mLの培養チューブで発現させ、それらの酵素活性を野生型の温度(例えば、37℃)とより低い温度(例えば、25℃)とにおいて測定する。タンパク質を発現させ、上述の通りにマルチウォール形式で用いるために精製するが、マルチウォール(96ウェルプレート)でない異なる形式(14mlチューブ)における発現も別に行う。
必要な場合、新規のコンビナトリアル変異体ライブラリーを、上述において同定した変異体ヒットの全て又は選択したものから作成する。この新規のライブラリーを、選択した変異体それぞれについて、可能な全てのアミノ酸変異体を含むようにデザインし、新しいヒットについての記載の通り再度スクリーニングをすることが出来る。
温度感受性の発達させた変異体に対してさらにアッセイを行い、低い温度(例えば、25℃)における酵素活性が可逆的か非可逆的か、当該変異体を高い温度に曝し、続けて低い温度(例えば、25℃)に戻すことによって、確認することが出来る。この温度感受性変異体を、所望の形式、例えば、概述のような14mL培養チューブにおいて発現させる。この変異体を、野生型の温度(例えば、37℃)及びその他の温度を含んだ幾つかの条件下においてテストし、続いて、必要な低い温度(例えば、25℃)に再度曝す。低い温度において活性のある変異体であって、より高い温度又は野生型の温度まで上昇させたとき、活性の低下を示し(つまり、低い温度における活性の高い温度に対する活性の比が、1、1.5、2、又はそれより高い値以上である)、再度低い温度まで下げられたときにベースラインの活性を示す、変異体を、「可逆性ヒット」と判定する。低い温度において活性のある変異体であって、より高い温度又は野生型の温度まで上昇させたとき、活性の低下を示し(つまり、低い温度における活性の高い温度に対する活性の比が、1、1.5、2、又はそれより高い値以上である)、再度低い温度まで下げられたときに少なくとも低下した活性と同じ程度の活性を示す、変異体を、「非可逆性ヒット」と判定する。
ヒトのプラスミノーゲン由来の、野生型アンジオスタチンのクリングル1~3は、Calbiochem(Darmstadt,Germany)から入手可能であり、無菌PBS中で再構成することが出来る。過去に記載されているように、ATP合成酵素の触媒的βサブユニットに対するポリクローナル抗体は作製可能であり、ウシのATP合成酵素F1サブユニットは精製可能である((Moser et al.,"Angiostatin binds ATP synthase on the surface of human endothelial cells",Proc Natl Acad Sci USA 1999;96:2811-6;Moser et al."Endothelial cell surface Fl-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin",Proc Natl Acad Sci USA;2001;98:6656-61)。カリポリドは、無菌の水に可溶化し、無菌にフィルターすることが出来る。
A549(肺がん組織由来のヒト上皮細胞株)又は他のがん細胞株(DU145、LNCaP、又はPC-3細胞)は、例えばATCCから入手可能である。ヒト臍帯静脈内皮細胞(HUVEC)は、文献に記載されているようにヒト臍帯静脈から単離可能である(Grant et al.,"Matrigel induces thymosin h 4 gene in differentiating endothelial cells",J Cell Sci 1995;108:3685-94.)。HUVEC細胞は、ATP合成酵素を細胞表面に発現する細胞株で、ポジティブコントロールとして使用することが出来る。細胞は、1%ペニシリンストレプトマイシン及び10%血清置換培地3(Sigma、St.Louis,MO)を入れたDMEM(Life Technologies、Carlsbad,CA)で培養し、プラスミミノーゲンの存在を最小限にすることが出来る。低いpH(6.7)の培地は、重炭酸塩を5%CO2条件下で10mmol/Lまで減少させ、浸透圧を維持するために34mmol/LのNaClを追加するか、又は22mmol/Lの重炭酸塩培地を17%CO2条件下でインキュベートすることで調製することが出来る。pHを低下させる方法は、実験的制約及びアッセイによって変化してもよい。
ATP合成酵素が腫瘍細胞株の細胞表面において機能的であることを確認するために、フローサイトメトリー実験を行うことが出来る。例えば、A549細胞株を、低酸素状態(0.5%O2、5%CO2、N2平衡)対酸素正常状態(21%O2、5%CO2)で、異なるpHの培地(10、22、及び44mmol/Lの重炭酸塩DMEM)において、0、12、24、48、お及び72時間培養することが出来る。生細胞をブロックし、抗βサブユニット抗体とともにインキュベートし、洗浄し、ブロックし、二次抗体のヤギ抗ウサギ抗体FITC(Southern Biotech、Birmingham,AL)とともにインキュベートし、再度洗浄することが出来る(全ての工程は4℃で行われる)。ヨウ化プロピジウム(BD Biosciences、San Jose,CA)を、細胞膜を損傷した細胞を識別するために全てのサンプルに含めることが出来る。10,000細胞中のFITCの平均蛍光強度を、FACSCaliburフローサイトメーター(Becton Dickinson、Franklin Lakes,NJ)によって定量化し、CELLQuestソフトウェア(BD Biosciences)上で、ヨウ化プロピジウムを取り込んだ細胞を取り除くことで、ミトコンドリアATP合成酵素の検出を除去することが出来る。
96ウェルプレート中のA549又は1-LN細胞(ウェル毎に60,000個)を、培地で満たし、アンジオスタチン、アンジオスタチン変異体、抗βサブユニット抗体、ウシ血清アルブミンに対して作成されたウサギIgG(Organon Teknika、West Chester,PA)、ピセタノール(既知のATP合成酵素F1の阻害剤でポジティブコントロールとして用いられる、Sigma)、又は培地のみによって、37℃、5%CO2で30分間処理することが出来る。次いで、細胞を0.05mmol/LのADPで20秒間インキュベートすることが出来る。上清を除去し、記載(23)の通り、にCellTiterGloルミネセンスアッセイ(Promega、Madison,WI)によって、ATP産生を分析することが出来る。細胞溶解物を同様に分析し、ATPの細胞内プールが全ての条件において変わらないことを確認することが出来る。記録を、Luminoskan Ascent(Thermo Labsystems、Helsinki,Finland)上でとることが出来る。データは、それぞれの独立した実験において決定された基準に基づいて、細胞毎のATPのモル数によって表される。
アンジオスタチンのがん細胞株への効果を、無血清培地に置いて、3-(4,5-ジメチルチアゾール-2-イル)-5-(3-カルボキシフェニル)-2-(4-スルホフェニル)-2H-テトラゾリウム、分子内塩(MTS)増殖アッセイによって評価することが出来る。アンジオスタチンの存在下又は非存在下において、37℃、5%CO2で20時間インキュベートした後、96ウェルマイクロプレートの各ウェルにおける相対的な細胞数を、AQueous One細胞増殖アッセイ(Promega)を用いて製品のプロトコルに従って、決定することが出来る。培地のpHを、5%CO2において重炭酸塩濃度によって調節することが出来る。
細胞死及び細胞溶解を定量化するために、サイトゾルから上清に放出された乳酸デヒドロゲナーゼ(lactate cehydrogenase:LDH)の活性を、Cytotoxicity Detectionキット(Roche、Indianapolis,IN)によって計測することが出来る。アンジオスタチン、アンジオスタチン変異体、抗βサブユニット抗体、ウサギIgG、カリポリド、及びトリトンX(細胞を透過処理する界面活性剤でポジティブコントロールとして用いる)によって処理したがん細胞(例えば、A549細胞)(ウェル毎に5,000個)を、5%CO2又は17%CO2(それぞれ、中性及び低pH条件)で、37℃、15時間インキュベートすることが出来る。細胞毒性の指標は、同じpHの培地に対応させて、4組の処理したサンプルの平均吸光度を、4組の未処理サンプルの平均吸光度によって除算することで計算することが出来る。細胞のネクローシス及びアポトーシスの評価アンジオスタチンの細胞死を引き起こす作用を決定するために、ヒストン-DNA ELISAを行うことが出来る。A549細胞(ウェル毎に5,000個)に対するアンジオスタチン、アンジオスタチン変異体、抗βサブユニット抗体、ウサギIgG、カリポリドの効果を、核外のヒストン-DNA断片の検出に基づいた、ELISAアポトーシス及びネクローシスアッセイ(Roche)を用いることで、決定することが出来る。試薬の存在下又は非存在下で、37℃15時間インキュベートした後、4組のサンプルの細胞溶解物又は上清から、それぞれアポトーシス又はネクローシスを決定することが出来る。アポトーシス又はネクローシスは、同じpHの培地に対応させて、4組の処理したサンプルの平均吸光度を、4組の未処理サンプルの平均吸光度によって除算することで計算することが出来る。培地のpHを、5%CO2又は17%CO2においてインキュベートすることで調節することが出来る。
pHiは、カバーガラス付きの35mmマイクロウェルディッシュ(MatTek、Ashland,MA)にプレーティングした細胞の蛍光によって計測することができる。細胞を成長因子低減フェノールレッド不含Matrigel(BD Biosciences)にプレーティングすることができる。一晩成長させた後、培地を交換することができ、細胞にpH感受性蛍光色素cSNARF(Molecular Probes、Eugene,OR)を15分間ロードし、続いて新鮮培地中で20分間回復させることができる。次に細胞を顕微鏡ステージに37℃、5%CO2でマウントし、1時間にわたる発光スペクトル収集から、各7~15細胞を含む視野からのpHiを記載のとおり計算することができる(Wahl ML,Grant DS.“Effects of microenvironmental extracellular pH and extracellular matrix proteins on angiostatin’s activity and on intracellular pH,”Gen Pharmacol 2002;35:277-85)。スペクトル収集の開始時に、ディッシュから培地を取り除くことができ、pH阻害薬アンジオスタチン、抗β-サブユニット、ウサギIgG、又はナトリウム-プロトン交換阻害薬カリポリドの存在下又は非存在下で細胞を1mLの新鮮培地によってチャレンジすることができる。培地pHは、%CO2を一定として、上記に記載したとおり重炭酸塩濃度によって調節することができる。
薬物標的Xに対する2つの条件的活性型抗体(CAB-scFv-63.9-4及びCAB-scFv-63.9-6)を野生型ヒトIgG1 Fcとのホモ二量体として発現させ(図2~図3の二価抗体CAB-scFv-63.9-4-01及びCAB-scFv-63.9-6-01が得られた)、並びにノブ・イン・ホールシステムのヘテロ二量体として発現させて一価scFvを得た(図2~図3の一価抗体scFv CAB-scFv-63.9-4-02及びCAB-scFv-63.9-6-02が得られた)。
本発明の一実施形態において、選択性及び親和性、並びにpH6.0及びpH7.4の両方での発現レベルに関して同時にスクリーニングすることにより、薬物標的Xに対する条件的活性型抗体を生成した。血清中にはスクリーニングに関して偽陽性を生じ得るヒト抗体があったため、スクリーニングは血清中でFLAGタグを使用して行った。スクリーニング緩衝液はカーボネート緩衝液(リンゲル標準緩衝液を含むがPBSとは異なるクレブス緩衝液)であった。生成された条件的活性型抗体は、両方ともに野生型抗体との比較において、pH6.0で薬物標的Xに対してより高い親和性を有するが、同じ薬物標的Xに対してpH7.4では親和性がより低いことが分かった。さらに、これらの条件的活性型抗体は全て、以下の表2に示すとおり(列「クローン」は抗体を示し、及び発現レベル「mg/ml」が2番目の列に示される)、高い発現レベルを有する。
Claims (17)
- 少なくとも1つの抗原特異的標的領域と膜貫通ドメインと細胞内シグナル伝達ドメインとを含むキメラ抗原受容体の作製方法であって、
癌細胞の表面上に位置する標的抗原に特異的に結合する親タンパク質又はそのドメインから、
i.前記親タンパク質又はそのドメインをコードするDNAを1つ以上の発達的技術を用いて発達させる工程であって、それにより変異DNAを作成することと、
ii.前記変異DNAを発現させて変異ポリペプチドを得ることと、
iii.前記変異ポリペプチドを正常生理pH下での分析及び異常pH下での分析に供することと、
iv.工程(iii)において発現した前記変異ポリペプチドから、異常pH下での分析における癌細胞の表面上に位置する標的抗原への結合における活性と比較して、正常生理pHでの分析における癌細胞の表面上に位置する標的抗原への結合における同活性の低下を呈する条件的活性型抗原特異的標的領域を選択することと
によって癌細胞の表面上に位置する標的抗原に結合する前記少なくとも1つの抗原特異的標的領域を生成する工程、および
少なくとも1つの抗原特異的標的領域、膜貫通ドメインおよび細胞内シグナル伝達ドメインを連結して、キメラ抗原受容体を作製する工程、および
前記キメラ抗原受容体を、キメラ抗原受容体を含むタンパク質が、親タンパク質またはそのドメインと比較して発現レベルが増加するように構成する工程
を含み、
前記標的抗原が癌細胞の表面上に過剰発現するチロシンキナーゼ成長因子受容体である、方法。 - 前記抗原特異的標的領域が、正常生理pHでの前記分析において前記親タンパク質又はそのドメインの抗原特異的標的領域と比較して前記標的抗原に対する結合親和性の低下もまた有する、請求項1に記載の方法。
- 前記抗原特異的標的領域が、異常pH下での前記分析において前記親タンパク質又はそのドメインの抗原特異的標的領域と比較して活性の増加を有する、請求項1に記載の方法。
- 前記抗原特異的標的領域が、異常pH下での前記分析において前記親タンパク質又はそのドメインの抗原特異的標的領域と比較して選択性の増加を有する、請求項1に記載の方法。
- 前記正常生理pHが7.4であり、前記異常pHが腫瘍微小環境のpHである、請求項1~4のいずれか一項に記載の方法。
- 前記条件的活性型生物学的タンパク質が、前記正常生理pHでは実質的に不活性であり、且つ前記正常生理pH未満の異常pHでは活性である、請求項1~4のいずれか一項に記載の方法。
- 前記発達させる工程が、PCR、エラープローンPCR、シャッフリング、オリゴヌクレオチド特異的突然変異誘発、アセンブリPCR、セクシャルPCR突然変異誘発、インビボ突然変異誘発、カセット突然変異誘発、再帰的アンサンブル突然変異誘発、指数関数的アンサンブル突然変異誘発、部位特異的突然変異誘発、遺伝子リアセンブリ、遺伝子部位飽和突然変異誘発、インビトロ突然変異誘発、リガーゼ連鎖反応、オリゴヌクレオチド合成及びこれらの組み合わせから選択される技術を含む、請求項1~4のいずれか一項に記載の方法。
- 遺伝子工学的に改変された細胞傷害性細胞の、対象の癌の治癒的及び/又は予防的治療用医薬の製造のための使用であって、遺伝子工学的に改変された細胞傷害性細胞は、癌細胞の表面上に位置する標的抗原に結合するキメラ抗原受容体をコードするポリヌクレオチド配列を含む発現ベクターを前記対象から得られた細胞傷害性細胞に導入することにより作製され、前記キメラ抗原受容体が
i.癌細胞の表面上に位置する標的抗原に結合する少なくとも1つの抗原特異的標的領域であって、前記抗原特異的標的領域は癌細胞の表面上に位置する標的抗原に結合する親タンパク質又はそのドメインから発達させたものであり、且つ異常pH下での分析における標的抗原への結合における活性と比較して、正常生理pHでの分析における標的抗原への結合における同活性の低下を有する少なくとも1つの抗原特異的標的領域と、
ii.膜貫通ドメインと、
iii.細胞内シグナル伝達ドメインと
を含み、
前記標的抗原が癌細胞の表面上に過剰発現するチロシンキナーゼ成長因子受容体であり、
前記キメラ抗原受容体は、キメラ抗原受容体を含むタンパク質が、親タンパク質またはそのドメインと比較して発現レベルが増加するように構成される、使用。 - 前記抗原特異的標的領域が、正常生理pHにおける標的抗原への結合活性に対する異常pH下における結合親和性の比率、少なくとも1.6、又は少なくとも1.8、又は少なくとも2、又は少なくとも2.5、又は少なくとも3、又は少なくとも5、又は少なくとも7、又は少なくとも8、又は少なくとも9、又は少なくとも10、又は少なくとも15、又は少なくとも20を有する、請求項8に記載の使用。
- 前記発現ベクターが、レンチウイルスベクター、γレトロウイルスベクター、フォーミーウイルスベクター、アデノ随伴ウイルスベクター、アデノウイルスベクター、ポックスウイルスベクター、ヘルペスウイルスベクター、遺伝子操作されたハイブリッドウイルス、及びトランスポゾン媒介性ベクターから選択される、請求項8に記載の使用。
- 前記細胞傷害性細胞がT細胞である、請求項8に記載の使用。
- 前記T細胞が、ナイーブT細胞、セントラルメモリーT細胞、及びエフェクターメモリーT細胞から選択される、請求項11に記載の使用。
- 前記細胞傷害性細胞が、ナチュラルキラー細胞、活性化NK細胞、好中球、好酸球、好塩基球、B細胞、マクロファージ及びリンホカイン活性化キラー細胞から選択される、請求項8に記載の使用。
- 前記ポリヌクレオチド配列が前記細胞傷害性細胞のゲノムに組み込まれる、請求項8に記載の使用。
- 前記細胞傷害性細胞が、治療用途に十分な量の前記キメラ抗原受容体を産生する、請求項8に記載の使用
- 前記癌が、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫、及び他の肉腫、滑膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、結腸癌、リンパ性悪性病変、膵癌、乳癌、肺癌、卵巣癌、前立腺癌、肝細胞癌、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、甲状腺髄様癌、甲状腺乳頭癌、褐色細胞腫、皮脂腺癌、乳頭癌、乳頭腺癌、髄様癌、気管支原性癌、腎細胞癌、肝細胞癌、胆管癌、絨毛癌、ウィルムス腫瘍、子宮頸癌、精巣腫瘍、セミノーマ、膀胱癌、メラノーマ、神経膠腫、膠芽腫、星状細胞腫、CNSリンパ腫、胚細胞腫、髄芽腫、シュワン腫、頭蓋咽頭腫(craniopharyogioma)、上衣腫、松果体腫、血管芽細胞腫、聴神経腫、乏突起膠腫、髄膜腫(menangioma)、神経芽細胞腫、網膜芽細胞腫及び脳転移から選択される固形腫瘍である、請求項8に記載の使用。
- 前記癌が、白血病、真性赤血球増加症、リンパ腫、ホジキン病、非ホジキンリンパ腫、多発性骨髄腫、ワルデンシュトレームマクログロブリン血症、重鎖病、骨髄異形成症候群、ヘアリー細胞白血病及び骨髄形成異常から選択される血液腫瘍である、請求項8に記載の使用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021082062A JP7405444B2 (ja) | 2014-08-28 | 2021-05-14 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462043067P | 2014-08-28 | 2014-08-28 | |
US62/043,067 | 2014-08-28 | ||
PCT/US2015/047197 WO2016033331A1 (en) | 2014-08-28 | 2015-08-27 | Conditionally active chimeric antigen receptors for modified t-cells |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021082062A Division JP7405444B2 (ja) | 2014-08-28 | 2021-05-14 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017532014A JP2017532014A (ja) | 2017-11-02 |
JP2017532014A5 JP2017532014A5 (ja) | 2018-09-20 |
JP7286267B2 true JP7286267B2 (ja) | 2023-06-05 |
Family
ID=55400578
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017511696A Active JP7286267B2 (ja) | 2014-08-28 | 2015-08-27 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
JP2018530483A Active JP7048494B2 (ja) | 2014-08-28 | 2016-02-24 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
JP2021082062A Active JP7405444B2 (ja) | 2014-08-28 | 2021-05-14 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018530483A Active JP7048494B2 (ja) | 2014-08-28 | 2016-02-24 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
JP2021082062A Active JP7405444B2 (ja) | 2014-08-28 | 2021-05-14 | 修飾t細胞に対する条件的活性型キメラ抗原受容体 |
Country Status (14)
Country | Link |
---|---|
US (5) | US20170260261A1 (ja) |
EP (3) | EP4074735A1 (ja) |
JP (3) | JP7286267B2 (ja) |
KR (4) | KR20230172625A (ja) |
CN (2) | CN107074975A (ja) |
AU (3) | AU2015308818B2 (ja) |
BR (1) | BR112018003535A2 (ja) |
CA (2) | CA2959141A1 (ja) |
DK (1) | DK3186284T3 (ja) |
ES (1) | ES2913865T3 (ja) |
HK (1) | HK1246803A1 (ja) |
MX (4) | MX2017002605A (ja) |
RU (2) | RU2764074C2 (ja) |
WO (2) | WO2016033331A1 (ja) |
Families Citing this family (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014117121A1 (en) | 2013-01-28 | 2014-07-31 | St. Jude Children's Research Hospital, Inc. | A chimeric receptor with nkg2d specificity for use in cell therapy against cancer and infectious disease |
CN112175911B (zh) | 2014-05-15 | 2023-10-13 | 新加坡国立大学 | 经修饰的自然杀伤细胞及其用途 |
US11111288B2 (en) * | 2014-08-28 | 2021-09-07 | Bioatla, Inc. | Conditionally active chimeric antigen receptors for modified t-cells |
ES2913865T3 (es) | 2014-08-28 | 2022-06-06 | Bioatla Inc | Receptores de antígeno quimérico condicionalmente activos para células T modificadas |
US20170151281A1 (en) | 2015-02-19 | 2017-06-01 | Batu Biologics, Inc. | Chimeric antigen receptor dendritic cell (car-dc) for treatment of cancer |
US10590182B2 (en) | 2015-02-24 | 2020-03-17 | The Regents Of The University Of California | Binding-triggered transcriptional switches and methods of use thereof |
CN114634943A (zh) | 2015-05-18 | 2022-06-17 | T细胞受体治疗公司 | 使用融合蛋白对tcr重编程的组合物和方法 |
US10434153B1 (en) | 2015-05-20 | 2019-10-08 | Kim Leslie O'Neill | Use of car and bite technology coupled with an scFv from an antibody against human thymidine kinase 1 to specifically target tumors |
TWI833684B (zh) | 2015-06-25 | 2024-03-01 | 美商生物細胞基因治療有限公司 | 嵌合抗原受體(car)、組合物及其使用方法 |
US11173179B2 (en) | 2015-06-25 | 2021-11-16 | Icell Gene Therapeutics Llc | Chimeric antigen receptor (CAR) targeting multiple antigens, compositions and methods of use thereof |
WO2017222593A1 (en) | 2016-06-24 | 2017-12-28 | Icell Gene Therapeutics Llc | Chimeric antigen receptors (cars), compositions and methods thereof |
BR112018001858B1 (pt) | 2015-07-28 | 2022-02-08 | The Trustees Of The University Of Pennsylvania | Composições compreendendo células modificadas que compreendem um receptor de antígeno quimérico (car), seus usos terapêuticos e método para modificar uma célula |
US11352439B2 (en) * | 2015-08-13 | 2022-06-07 | Kim Leslie O'Neill | Macrophage CAR (MOTO-CAR) in immunotherapy |
BR112018069075A2 (pt) * | 2016-03-19 | 2019-01-29 | F1 Oncology Inc | métodos e composições para transduzir linfócitos e expansão regulada dos mesmos |
US11325948B2 (en) | 2016-03-19 | 2022-05-10 | Exuma Biotech Corp. | Methods and compositions for genetically modifying lymphocytes to express polypeptides comprising the intracellular domain of MPL |
WO2020047527A2 (en) | 2018-09-02 | 2020-03-05 | F1 Bioventures, Llc | Methods and compositions for genetically modifying lymphocytes in blood or in enriched pbmcs |
WO2022047417A1 (en) * | 2020-08-31 | 2022-03-03 | Exuma Biotech Corp. | Anti-idiotype compositions and methods of use thereof |
US11111505B2 (en) | 2016-03-19 | 2021-09-07 | Exuma Biotech, Corp. | Methods and compositions for transducing lymphocytes and regulating the activity thereof |
EP3443001A4 (en) | 2016-04-11 | 2020-04-29 | Obsidian Therapeutics, Inc. | REGULATED BIOCIRCUIT SYSTEMS |
KR102459684B1 (ko) * | 2016-04-15 | 2022-10-26 | 바이오아트라, 인코퍼레이티드 | 항 Axl항체 및 이의 면역접합체와 이것들의 용도 |
WO2017192536A1 (en) | 2016-05-02 | 2017-11-09 | University Of Kansas | Eliminating mhc restriction from the t cell receptor as a strategy for immunotherapy |
WO2017193059A1 (en) * | 2016-05-06 | 2017-11-09 | The Regents Of The University Of California | Systems and methods for targeting cancer cells |
HRP20221298T1 (hr) | 2016-05-13 | 2022-12-23 | Bioatla, Inc. | Anti-ror2 protutijela, fragmenti protutijela, njihovi imunokonjugati i njihove uporabe |
CN109563507B (zh) | 2016-07-08 | 2024-03-05 | 埃克苏马生物技术公司 | 用于转导淋巴细胞及调节其活性的方法及组合物 |
KR102223822B1 (ko) * | 2016-07-12 | 2021-03-11 | 카이트 파마 인코포레이티드 | 항원 결합 분자 및 그의 사용 방법 |
EP3494138A1 (en) | 2016-08-02 | 2019-06-12 | 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 |
CN106279438B (zh) * | 2016-08-24 | 2019-10-22 | 北京领柯生物科技有限公司 | 新型嵌合抗原受体及其用途 |
CN110121506A (zh) | 2016-08-31 | 2019-08-13 | 生物蛋白有限公司 | 条件活性多肽及产生它们的方法 |
WO2018063985A1 (en) | 2016-09-28 | 2018-04-05 | Atossa Genetics Inc. | Methods of adoptive cell therapy |
WO2018067993A1 (en) | 2016-10-07 | 2018-04-12 | TCR2 Therapeutics Inc. | Compositions and methods for t-cell receptors reprogramming using fusion proteins |
EP3315511A1 (en) * | 2016-10-29 | 2018-05-02 | Miltenyi Biotec GmbH | Adapter chimeric antigen receptor expressing cells for targeting of multiple antigens |
JP7291396B2 (ja) | 2016-11-22 | 2023-06-15 | ティーシーアール2 セラピューティクス インク. | 融合タンパク質を用いたtcrの再プログラミングのための組成物及び方法 |
WO2018102547A1 (en) * | 2016-12-02 | 2018-06-07 | H. Lee Moffitt Cancer Center And Research Institute Inc. | Tag-72-binding chimeric antigen receptors |
WO2018129007A1 (en) * | 2017-01-03 | 2018-07-12 | Bioatla Llc | Protein therapeutics for treatment of senescent cells |
MX2019008503A (es) * | 2017-01-18 | 2019-09-13 | F1 Oncology Inc | Receptores de antigenos quimericos contra axl o ror2 y metodos de uso de los mismos. |
CA3054064A1 (en) | 2017-03-03 | 2018-09-07 | F1 Oncology, Inc. | Methods and compositions for transducing and expanding lymphocytes and regulating the activity thereof |
SG11201908337VA (en) | 2017-03-27 | 2019-10-30 | Nat Univ Singapore | Stimulatory cell lines for ex vivo expansion and activation of natural killer cells |
AU2018246235B2 (en) | 2017-03-27 | 2023-12-21 | National University Of Singapore | Truncated NKG2D chimeric receptors and uses thereof in natural killer cell immunotherapy |
JP2020517259A (ja) * | 2017-04-19 | 2020-06-18 | 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 | 操作された抗原受容体を発現する免疫細胞 |
WO2018201088A1 (en) * | 2017-04-27 | 2018-11-01 | Washington University | Activation of natural cytotoxicity receptor 2 (ncr2) |
US10415017B2 (en) | 2017-05-17 | 2019-09-17 | Thunder Biotech, Inc. | Transgenic macrophages, chimeric antigen receptors, and associated methods |
EP3638262A4 (en) * | 2017-06-16 | 2021-03-24 | Mayo Foundation for Medical Education and Research | MATERIALS AND METHODS FOR INCREASING IMMUNE REACTION |
CN111108104A (zh) | 2017-07-07 | 2020-05-05 | 拜康有限公司 | 达沙替尼的多晶形式 |
IL272103B1 (en) | 2017-07-20 | 2024-06-01 | Aptevo Res & Development Llc | Antigen-binding proteins that bind to 5T4 and 4-1BB, as well as compositions and methods for treating cancer related to them |
KR20200047687A (ko) | 2017-09-08 | 2020-05-07 | 매버릭 테라퓨틱스, 인크. | 제약된 조건적으로 활성화된 결합 단백질 |
CN111479921B (zh) * | 2017-09-18 | 2024-08-02 | 埃克苏马生物技术公司 | 用于以基因方式修饰且扩增淋巴细胞以及调节其活性的方法及组合物 |
CN109776671B (zh) * | 2017-11-14 | 2022-05-27 | 杭州康万达医药科技有限公司 | 分离的t细胞受体、其修饰的细胞、编码核酸、表达载体、制备方法、药物组合物和应用 |
CN109796532B (zh) * | 2017-11-17 | 2024-09-10 | 恺兴生命科技(上海)有限公司 | 靶向成纤维激活蛋白α的结合单元及其应用 |
CN109957019A (zh) * | 2017-12-25 | 2019-07-02 | 深圳宾德生物技术有限公司 | 一种靶向dr5的单链抗体、嵌合抗原受体t细胞及其制备方法和应用 |
CN109957025A (zh) * | 2017-12-25 | 2019-07-02 | 深圳宾德生物技术有限公司 | 一种靶向dr5的单链抗体、嵌合抗原受体t细胞及其制备方法和应用 |
WO2019127215A1 (en) * | 2017-12-28 | 2019-07-04 | Nanjing Legend Biotech Co., Ltd. | Multispecific chimeric receptors comprising an nkg2d domain and methods of use thereof |
CA3089991A1 (en) * | 2018-02-02 | 2019-08-08 | The Trustees Of The University Of Pennsylvania | Modified monocytes/macrophages/dendritic cells expressing chimeric antigen receptors and uses in diseases and disorders associated with protein aggregates |
GB201801831D0 (en) * | 2018-02-05 | 2018-03-21 | Autolus Ltd | Chimeric receptor |
CN108314739B (zh) * | 2018-02-05 | 2020-07-14 | 深圳市默赛尔生物医学科技发展有限公司 | 多信号嵌合抗原受体及其表达基因、其修饰的nk细胞及应用 |
CN111954684B (zh) * | 2018-02-11 | 2024-05-07 | 加利福尼亚大学董事会 | Car-t细胞与自身免疫性疾病 |
US11945878B2 (en) | 2018-04-18 | 2024-04-02 | Abclon Inc. | Switch molecule and switchable chimeric antigen receptor |
EP3806888B1 (en) | 2018-06-12 | 2024-01-31 | Obsidian Therapeutics, Inc. | Pde5 derived regulatory constructs and methods of use in immunotherapy |
CN117866095A (zh) * | 2018-07-09 | 2024-04-12 | 普众发现医药科技(上海)有限公司 | 叶酸受体α特异性抗体 |
US20210275589A1 (en) * | 2018-07-13 | 2021-09-09 | Nanjing Legend Biotech Co. Ltd. | Co-receptor systems for treating infectious diseases |
CA3107421A1 (en) * | 2018-08-10 | 2020-02-13 | Kyoto University | Method for producing cd3-positive cell |
CN112823166A (zh) * | 2018-09-07 | 2021-05-18 | 生物蛋白有限公司 | 用于修饰的t细胞的条件活性嵌合抗原受体 |
CN109266618B (zh) * | 2018-10-18 | 2021-04-23 | 赛元生物科技(杭州)有限公司 | 能够靶向肿瘤细胞的巨噬细胞及其制备方法 |
EP3870600A1 (en) | 2018-10-24 | 2021-09-01 | Obsidian Therapeutics, Inc. | Er tunable protein regulation |
EP3894011A1 (en) | 2018-12-11 | 2021-10-20 | Obsidian Therapeutics, Inc. | Membrane bound il12 compositions and methods for tunable regulation |
WO2020146267A1 (en) * | 2019-01-11 | 2020-07-16 | Promab Biotechnologies, Inc. | Cd37-antibody and cd37-car-t cells |
SG11202107973PA (en) * | 2019-02-14 | 2021-08-30 | Res Inst Nationwide Childrens Hospital | Use of plasma membrane particles, liposomes, and exosomes to assay immune cell potency |
WO2020181140A1 (en) | 2019-03-05 | 2020-09-10 | Maverick Therapeutics, Inc. | Constrained conditionally activated binding proteins |
KR20210137085A (ko) | 2019-03-05 | 2021-11-17 | 엔카르타, 인크. | Cd19 유도된 키메라 항원 수용체 및 면역 요법에서 이의 용도 |
CN111825769B (zh) * | 2019-04-16 | 2022-03-25 | 上海科技大学 | 一种泛素化缺失的嵌合抗原受体及其用途 |
US20220143094A1 (en) * | 2019-04-19 | 2022-05-12 | Chugai Seiyaku Kabushiki Kaisha | Chimeric receptor that recognizes engineered site in antibody |
US11026973B2 (en) | 2019-04-30 | 2021-06-08 | Myeloid Therapeutics, Inc. | Engineered phagocytic receptor compositions and methods of use thereof |
US20240124889A1 (en) | 2019-05-07 | 2024-04-18 | Voyager Therapeutics, Inc. | Compositions and methods for the vectored augmentation of protein destruction, expression and/or regulation |
CA3140172A1 (en) * | 2019-05-16 | 2020-11-19 | University Of Washington | Ultraspecific cell targeting using de novo designed co-localization dependent protein switches |
CN114173822A (zh) * | 2019-06-03 | 2022-03-11 | 芝加哥大学 | 用胶原结合药物载体治疗癌症的方法和组合物 |
WO2020252095A1 (en) | 2019-06-11 | 2020-12-17 | Bioatla, Inc. | Conditionally active anti-epcam antibodies, antibody fragments, their immunoconjugates and uses thereof |
WO2021030257A1 (en) * | 2019-08-14 | 2021-02-18 | The Regents Of The University Of California | Car-t cells specific for modified proteins in extracellular spaces |
MX2022002613A (es) | 2019-09-03 | 2022-06-02 | Myeloid Therapeutics Inc | Metodos y composiciones para la integracion del genoma. |
WO2021046451A1 (en) | 2019-09-06 | 2021-03-11 | Obsidian Therapeutics, Inc. | Compositions and methods for dhfr tunable protein regulation |
AR120430A1 (es) * | 2019-11-08 | 2022-02-16 | Humanigen Inc | Células car-t dirigidas a epha3 para el tratamiento de tumores |
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 |
EP4106802A1 (en) * | 2020-02-17 | 2022-12-28 | Miltenyi Biotec B.V. & Co. KG | Method for providing personalized cells with chimeric antigen receptors (car) against tumor microenvironment cells |
CN115867294A (zh) | 2020-06-04 | 2023-03-28 | 凯瑞斯马治疗公司 | 嵌合抗原受体的新型构建体 |
CN111848797B (zh) * | 2020-07-20 | 2021-02-09 | 北京鼎成肽源生物技术有限公司 | 一种靶向c-Met的单链抗体、嵌合抗原受体、重组载体、CAR-T细胞及应用 |
WO2022036495A1 (en) | 2020-08-17 | 2022-02-24 | Utc Therapeutics Inc. | Lymphocytes-antigen presenting cells co-stimulators and uses thereof |
AU2021376354A1 (en) | 2020-11-04 | 2023-06-22 | Myeloid Therapeutics, Inc. | Engineered chimeric fusion protein compositions and methods of use thereof |
KR20230107615A (ko) * | 2020-11-12 | 2023-07-17 | 바이오아트라, 인코퍼레이티드 | 항-axl 항체, 항체 단편 및 이들의 면역접합체로 axl 발현 암을 치료하는 방법 |
CN118146395A (zh) * | 2021-02-08 | 2024-06-07 | 浙江大学 | 一种以内源性蛋白质分子替代单结构域抗体的嵌合抗原受体 |
WO2022187289A1 (en) | 2021-03-01 | 2022-09-09 | Exuma Biotech Corp. | Methods and compositions for the delivery of retroviral particles |
WO2022197949A2 (en) | 2021-03-17 | 2022-09-22 | Myeloid Therapeutics, Inc. | Engineered chimeric fusion protein compositions and methods of use thereof |
WO2022203227A1 (ko) * | 2021-03-23 | 2022-09-29 | 주식회사 이뮤노로지컬디자이닝랩 | 키메릭 항원 수용체(car)를 포함하는 형질전환된 항원 특이적 전문적 항원표출세포 및 이의 용도 |
MX2024001206A (es) | 2021-07-29 | 2024-03-19 | Sonoma Biotherapeutics Inc | Receptor de antigeno quimerico especifico de la matriz extracelular sinovial para dirigir las celulas t reguladoras para tratar enfermedades autoinmunes. |
WO2023044483A2 (en) | 2021-09-20 | 2023-03-23 | Voyager Therapeutics, Inc. | Compositions and methods for the treatment of her2 positive cancer |
WO2023092004A1 (en) | 2021-11-17 | 2023-05-25 | Voyager Therapeutics, Inc. | Compositions and methods for the treatment of tau-related disorders |
WO2023168305A1 (en) | 2022-03-01 | 2023-09-07 | Exuma Biotech Corp. | Viral particles with membrane-bound hyaluronidase |
WO2023220695A2 (en) | 2022-05-13 | 2023-11-16 | Voyager Therapeutics, Inc. | Compositions and methods for the treatment of her2 positive cancer |
WO2024030976A2 (en) | 2022-08-03 | 2024-02-08 | Voyager Therapeutics, Inc. | Compositions and methods for crossing the blood brain barrier |
WO2024128219A1 (ja) * | 2022-12-13 | 2024-06-20 | 愛知県 | キメラ抗原受容体 |
WO2024182645A1 (en) * | 2023-03-02 | 2024-09-06 | Bioatla, Inc. | Conditionally active anti-epcam antibodies, antibody fragments and constructs incorporating same |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012519499A (ja) | 2009-03-09 | 2012-08-30 | バイオアトラ、エルエルシー | Miracタンパク質 |
JP2012533307A (ja) | 2009-07-17 | 2012-12-27 | バイオアトラ、エルエルシー | 産生宿主における抗体/タンパク質パフォーマンス及び発現の同時で統合された選択及び進化 |
WO2013123061A1 (en) | 2012-02-13 | 2013-08-22 | Seattle Children's Hospital D/B/A Seattle Children's Research Institute | Bispecific chimeric antigen receptors and therapeutic uses thereof |
WO2013126729A1 (en) | 2012-02-22 | 2013-08-29 | The Trustees Of The University Of Pennsylvania | Use of the cd2 signaling domain in second-generation chimeric antigen receptors |
JP2013541940A (ja) | 2010-09-08 | 2013-11-21 | ハロザイム インコーポレイテッド | 条件的活性治療用タンパク質を評価および同定する、または発展させる方法 |
WO2014039523A1 (en) | 2012-09-04 | 2014-03-13 | Cellectis | Multi-chain chimeric antigen receptor and uses thereof |
WO2014127261A1 (en) | 2013-02-15 | 2014-08-21 | The Regents Of The University Of California | Chimeric antigen receptor and methods of use thereof |
Family Cites Families (239)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4683A (en) | 1846-08-08 | waring and richard e | ||
US195A (en) | 1837-05-15 | Machine fob cutting and dressing stone | ||
US3896111A (en) | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4265814A (en) | 1978-03-24 | 1981-05-05 | Takeda Chemical Industries | Matansinol 3-n-hexadecanoate |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
JPS5562090A (en) | 1978-10-27 | 1980-05-10 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55164687A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS55164685A (en) | 1979-06-08 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164686A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4309428A (en) | 1979-07-30 | 1982-01-05 | Takeda Chemical Industries, Ltd. | Maytansinoids |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
WO1981001145A1 (en) | 1979-10-18 | 1981-04-30 | Univ Illinois | Hydrolytic enzyme-activatible pro-drugs |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4797368A (en) | 1985-03-15 | 1989-01-10 | The United States Of America As Represented By The Department Of Health And Human Services | Adeno-associated virus as eukaryotic expression vector |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4737456A (en) | 1985-05-09 | 1988-04-12 | Syntex (U.S.A.) Inc. | Reducing interference in ligand-receptor binding assays |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US4777127A (en) | 1985-09-30 | 1988-10-11 | Labsystems Oy | Human retrovirus-related products and methods of diagnosing and treating conditions associated with said retrovirus |
US5139941A (en) | 1985-10-31 | 1992-08-18 | University Of Florida Research Foundation, Inc. | AAV transduction vectors |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
GB8702816D0 (en) | 1987-02-07 | 1987-03-11 | Al Sumidaie A M K | Obtaining retrovirus-containing fraction |
US5219740A (en) | 1987-02-13 | 1993-06-15 | Fred Hutchinson Cancer Research Center | Retroviral gene transfer into diploid fibroblasts for gene therapy |
DE3883899T3 (de) | 1987-03-18 | 1999-04-22 | Sb2, Inc., Danville, Calif. | Geänderte antikörper. |
US5606040A (en) | 1987-10-30 | 1997-02-25 | American Cyanamid Company | Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group |
US5770701A (en) | 1987-10-30 | 1998-06-23 | American Cyanamid Company | Process for preparing targeted forms of methyltrithio antitumor agents |
US6054270A (en) | 1988-05-03 | 2000-04-25 | Oxford Gene Technology Limited | Analying polynucleotide sequences |
US5700637A (en) | 1988-05-03 | 1997-12-23 | Isis Innovation Limited | Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays |
AP129A (en) | 1988-06-03 | 1991-04-17 | Smithkline Biologicals S A | Expression of retrovirus gag protein eukaryotic cells |
WO1990005144A1 (en) | 1988-11-11 | 1990-05-17 | Medical Research Council | Single domain ligands, receptors comprising said ligands, methods for their production, and use of said ligands and receptors |
US5858358A (en) | 1992-04-07 | 1999-01-12 | The United States Of America As Represented By The Secretary Of The Navy | Methods for selectively stimulating proliferation of T cells |
US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
US6905680B2 (en) | 1988-11-23 | 2005-06-14 | Genetics Institute, Inc. | Methods of treating HIV infected subjects |
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
JP2752788B2 (ja) | 1989-01-23 | 1998-05-18 | カイロン コーポレイション | 感染および過剰増殖障害の為の組換え療法 |
US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5527681A (en) | 1989-06-07 | 1996-06-18 | Affymax Technologies N.V. | Immobilized molecular synthesis of systematically substituted compounds |
US5800992A (en) | 1989-06-07 | 1998-09-01 | Fodor; Stephen P.A. | Method of detecting nucleic acids |
US5744101A (en) | 1989-06-07 | 1998-04-28 | Affymax Technologies N.V. | Photolabile nucleoside protecting groups |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
EP0845537A1 (en) | 1989-08-18 | 1998-06-03 | Chiron Corporation | Recombinant retroviruses delivering vector constructs to target cells |
US5585362A (en) | 1989-08-22 | 1996-12-17 | The Regents Of The University Of Michigan | Adenovirus vectors for gene therapy |
CA2026147C (en) | 1989-10-25 | 2006-02-07 | Ravi J. Chari | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
AU675916B2 (en) | 1991-06-14 | 1997-02-27 | Genentech Inc. | Method for making humanized antibodies |
GB9114948D0 (en) | 1991-07-11 | 1991-08-28 | Pfizer Ltd | Process for preparing sertraline intermediates |
ATE237694T1 (de) | 1991-08-20 | 2003-05-15 | Us Gov Health & Human Serv | Adenovirus vermittelter gentransfer in den gastrointestinaltrakt |
US5362852A (en) | 1991-09-27 | 1994-11-08 | Pfizer Inc. | Modified peptide derivatives conjugated at 2-hydroxyethylamine moieties |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
US5632957A (en) | 1993-11-01 | 1997-05-27 | Nanogen | Molecular biological diagnostic systems including electrodes |
WO1993010218A1 (en) | 1991-11-14 | 1993-05-27 | The United States Government As Represented By The Secretary Of The Department Of Health And Human Services | Vectors including foreign genes and negative selective markers |
GB9125623D0 (en) | 1991-12-02 | 1992-01-29 | Dynal As | Cell modification |
DE69333807T2 (de) | 1992-02-06 | 2006-02-02 | Chiron Corp., Emeryville | Marker für krebs und biosynthetisches bindeprotein dafür |
JPH05236997A (ja) | 1992-02-28 | 1993-09-17 | Hitachi Ltd | ポリヌクレオチド捕捉用チップ |
FR2688514A1 (fr) | 1992-03-16 | 1993-09-17 | Centre Nat Rech Scient | Adenovirus recombinants defectifs exprimant des cytokines et medicaments antitumoraux les contenant. |
ZA932522B (en) | 1992-04-10 | 1993-12-20 | Res Dev Foundation | Immunotoxins directed against c-erbB-2(HER/neu) related surface antigens |
US5427954A (en) | 1992-04-29 | 1995-06-27 | Shriner's Hospitals For Crippled Children | Compositions and methods for detection and treatment of human osteoarthritis |
EP0650370A4 (en) | 1992-06-08 | 1995-11-22 | Univ California | METHODS AND COMPOSITIONS TARGETED ON SPECIFIC TISSUES. |
EP0644946A4 (en) | 1992-06-10 | 1997-03-12 | Us Health | VECTOR PARTICLES RESISTANT TO HUMAN SERUM INACTIVATION. |
GB2269175A (en) | 1992-07-31 | 1994-02-02 | Imperial College | Retroviral vectors |
NZ258392A (en) | 1992-11-13 | 1997-09-22 | Idec Pharma Corp | Chimeric and radiolabelled antibodies to the b lymphocyte cellsurface antigen bp35 (cd-20) and their use in the treatment of b cell lymphona |
EP0905253A3 (en) | 1992-12-03 | 2000-11-02 | Genzyme Corporation | Adenoviral vector deleted of all E4-ORF except ORF6 |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
WO1994029351A2 (en) | 1993-06-16 | 1994-12-22 | Celltech Limited | Antibodies |
JP3532566B2 (ja) | 1993-06-24 | 2004-05-31 | エル. グラハム,フランク | 遺伝子治療のためのアデノウイルスベクター |
AU689131B2 (en) | 1993-10-01 | 1998-03-26 | Teikoku Hormone Mfg. Co., Ltd. | Novel peptide derivative |
ATE314482T1 (de) | 1993-10-25 | 2006-01-15 | Canji Inc | Rekombinante adenoviren-vektor und verfahren zur verwendung |
US6045996A (en) | 1993-10-26 | 2000-04-04 | Affymetrix, Inc. | Hybridization assays on oligonucleotide arrays |
US5965452A (en) | 1996-07-09 | 1999-10-12 | Nanogen, Inc. | Multiplexed active biologic array |
US6468742B2 (en) | 1993-11-01 | 2002-10-22 | Nanogen, Inc. | Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US7175843B2 (en) | 1994-06-03 | 2007-02-13 | Genetics Institute, Llc | Methods for selectively stimulating proliferation of T cells |
US5807522A (en) | 1994-06-17 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for fabricating microarrays of biological samples |
US5556752A (en) | 1994-10-24 | 1996-09-17 | Affymetrix, Inc. | Surface-bound, unimolecular, double-stranded DNA |
US5830645A (en) | 1994-12-09 | 1998-11-03 | The Regents Of The University Of California | Comparative fluorescence hybridization to nucleic acid arrays |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US5959098A (en) | 1996-04-17 | 1999-09-28 | Affymetrix, Inc. | Substrate preparation process |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US7067318B2 (en) | 1995-06-07 | 2006-06-27 | The Regents Of The University Of Michigan | Methods for transfecting T cells |
US6692964B1 (en) | 1995-05-04 | 2004-02-17 | The United States Of America As Represented By The Secretary Of The Navy | Methods for transfecting T cells |
US5714586A (en) | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
US5712374A (en) | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
US5856174A (en) | 1995-06-29 | 1999-01-05 | Affymetrix, Inc. | Integrated nucleic acid diagnostic device |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6013516A (en) | 1995-10-06 | 2000-01-11 | The Salk Institute For Biological Studies | Vector and method of use for nucleic acid delivery to non-dividing cells |
US6022963A (en) | 1995-12-15 | 2000-02-08 | Affymetrix, Inc. | Synthesis of oligonucleotide arrays using photocleavable protecting groups |
SG83659A1 (en) | 1996-01-10 | 2001-10-16 | Kibun Shokuhin Kk | Cylindrical food consisting of plurality of concentric cylindrical layers of food material and method and apparatus for making the same |
GB9603256D0 (en) | 1996-02-16 | 1996-04-17 | Wellcome Found | Antibodies |
US6013440A (en) | 1996-03-11 | 2000-01-11 | Affymetrix, Inc. | Nucleic acid affinity columns |
US6300065B1 (en) * | 1996-05-31 | 2001-10-09 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
US6057100A (en) | 1996-06-07 | 2000-05-02 | Eos Biotechnology, Inc. | Oligonucleotide arrays |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
CA2293829C (en) | 1997-06-24 | 2011-06-14 | Genentech, Inc. | Methods and compositions for galactosylated glycoproteins |
US6826296B2 (en) | 1997-07-25 | 2004-11-30 | Affymetrix, Inc. | Method and system for providing a probe array chip design database |
AU8908198A (en) | 1997-08-15 | 1999-03-08 | Hyseq, Inc. | Methods and compositions for detection or quantification of nucleic acid species |
PT1012564E (pt) | 1997-09-11 | 2003-08-29 | Bioventures Inc | Metodo de producao de arranjos de alta densidade |
US6465178B2 (en) | 1997-09-30 | 2002-10-15 | Surmodics, Inc. | Target molecule attachment to surfaces |
EP1028751B1 (en) | 1997-10-31 | 2008-12-31 | Genentech, Inc. | Methods and compositions comprising glycoprotein glycoforms |
EP1034298B1 (en) | 1997-12-05 | 2011-11-02 | The Scripps Research Institute | Humanization of murine antibody |
US5994136A (en) | 1997-12-12 | 1999-11-30 | Cell Genesys, Inc. | Method and means for producing high titer, safe, recombinant lentivirus vectors |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
JP2002510481A (ja) | 1998-04-02 | 2002-04-09 | ジェネンテック・インコーポレーテッド | 抗体変異体及びその断片 |
JP2002510505A (ja) | 1998-04-03 | 2002-04-09 | フィロス インク. | 位置特定可能な蛋白質アレイ |
ES2340112T3 (es) | 1998-04-20 | 2010-05-28 | Glycart Biotechnology Ag | Ingenieria de glicosilacion de anticuerpos para la mejora de la citotoxicidad celular dependiente de anticuerpos. |
US6048695A (en) | 1998-05-04 | 2000-04-11 | Baylor College Of Medicine | Chemically modified nucleic acids and methods for coupling nucleic acids to solid support |
DE69925133T2 (de) | 1998-08-27 | 2006-01-19 | Spirogen Ltd., Ryde | Pyrrolobenzodiazepine |
US6277628B1 (en) | 1998-10-02 | 2001-08-21 | Incyte Genomics, Inc. | Linear microarrays |
US6277489B1 (en) | 1998-12-04 | 2001-08-21 | The Regents Of The University Of California | Support for high performance affinity chromatography and other uses |
PL209786B1 (pl) | 1999-01-15 | 2011-10-31 | Genentech Inc | Przeciwciało zawierające wariant regionu Fc ludzkiej IgG1, przeciwciało wiążące czynnik wzrostu śródbłonka naczyń oraz immunoadhezyna |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
US20090130718A1 (en) | 1999-02-04 | 2009-05-21 | Diversa Corporation | Gene site saturation mutagenesis |
CA2704600C (en) | 1999-04-09 | 2016-10-25 | Kyowa Hakko Kirin Co., Ltd. | A method for producing antibodies with increased adcc activity |
US6221653B1 (en) | 1999-04-27 | 2001-04-24 | Agilent Technologies, Inc. | Method of performing array-based hybridization assays using thermal inkjet deposition of sample fluids |
US6653151B2 (en) | 1999-07-30 | 2003-11-25 | Large Scale Proteomics Corporation | Dry deposition of materials for microarrays using matrix displacement |
JP4668498B2 (ja) | 1999-10-19 | 2011-04-13 | 協和発酵キリン株式会社 | ポリペプチドの製造方法 |
US20010008765A1 (en) | 1999-12-06 | 2001-07-19 | Fuji Photo Film Co., Ltd. | DNA chip and reactive solid carrier |
PT1242438E (pt) | 1999-12-29 | 2007-02-28 | Immunogen Inc | Agentes citotóxicos compreendendo dixorrubicinas e daunorrubicinas modificadas e seu uso terapêutico |
IL151287A0 (en) | 2000-02-24 | 2003-04-10 | Xcyte Therapies Inc | A method for stimulation and concentrating cells |
US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
US6797514B2 (en) | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
KR20020093029A (ko) | 2000-04-11 | 2002-12-12 | 제넨테크, 인크. | 다가 항체 및 그의 용도 |
JP3924113B2 (ja) | 2000-05-15 | 2007-06-06 | 株式会社日立グローバルストレージテクノロジーズ | 複数のヘッドサスペンションアッセンブリを有するヘッドキャリッジアッセンブリ及びこれを用いた磁気ディスク装置 |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
EP1331266B1 (en) | 2000-10-06 | 2017-01-04 | Kyowa Hakko Kirin Co., Ltd. | Cells producing antibody compositions |
US7064191B2 (en) | 2000-10-06 | 2006-06-20 | Kyowa Hakko Kogyo Co., Ltd. | Process for purifying antibody |
US6946292B2 (en) | 2000-10-06 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Cells producing antibody compositions with increased antibody dependent cytotoxic activity |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
NZ592087A (en) | 2001-08-03 | 2012-11-30 | Roche Glycart Ag | Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity |
WO2003026577A2 (en) | 2001-09-24 | 2003-04-03 | Seattle Genetics, Inc. | P-amidobenzylethers in drug delivery agents |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
MXPA04003798A (es) | 2001-10-25 | 2004-07-30 | Genentech Inc | Composiciones de glicoproteina. |
JP2005511627A (ja) | 2001-11-20 | 2005-04-28 | シアトル ジェネティクス,インコーポレーテッド | 抗cd30抗体を使用する免疫学的疾患の治療 |
US20040093621A1 (en) | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
ATE503829T1 (de) | 2002-04-09 | 2011-04-15 | Kyowa Hakko Kirin Co Ltd | Zelle mit erniedrigter oder deletierter aktivität eines am gdp-fucosetransport beteiligten proteins |
JPWO2003084569A1 (ja) | 2002-04-09 | 2005-08-11 | 協和醗酵工業株式会社 | 抗体組成物含有医薬 |
JP4832719B2 (ja) | 2002-04-09 | 2011-12-07 | 協和発酵キリン株式会社 | FcγRIIIa多型患者に適応する抗体組成物含有医薬 |
CN102911987B (zh) | 2002-04-09 | 2015-09-30 | 协和发酵麒麟株式会社 | 基因组被修饰的细胞 |
AU2003236015A1 (en) | 2002-04-09 | 2003-10-20 | Kyowa Hakko Kirin Co., Ltd. | Process for producing antibody composition |
US20040259150A1 (en) | 2002-04-09 | 2004-12-23 | Kyowa Hakko Kogyo Co., Ltd. | Method of enhancing of binding activity of antibody composition to Fcgamma receptor IIIa |
EP1382969A1 (en) | 2002-07-17 | 2004-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Diagnosis and prevention of cancer cell invasion |
US20050180972A1 (en) | 2002-07-31 | 2005-08-18 | Wahl Alan F. | Anti-CD20 antibody-drug conjugates for the treatment of cancer and immune disorders |
HUE027549T2 (hu) | 2002-07-31 | 2016-10-28 | Seattle Genetics Inc | Hatóanyagot tartalmazó konjugátumok és alkalmazásuk rák, autoimmun betegség vagy fertõzéses betegség kezelésére |
AU2003259163B2 (en) | 2002-08-16 | 2008-07-03 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
US7361740B2 (en) | 2002-10-15 | 2008-04-22 | Pdl Biopharma, Inc. | Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis |
BRPI0316779B1 (pt) | 2002-12-16 | 2020-04-28 | Genentech Inc | anticorpo humanizado que liga cd20 humano, composição, artigo manufaturado, método de indução da apoptose, método de tratamento de câncer cd20 positivo, métodos de tratamento de doenças autoimunes, ácidos nucléicos isolados, vetores de expressão, células hospedeiras, método para a produção de um anticorpo 2h7 humanizado, polipeptídeo isolado, formulação líquida, método de tratamento de artrite reumatóide (ra) e anticorpos de ligação de cd20 humanizados |
JP4148883B2 (ja) | 2002-12-18 | 2008-09-10 | 株式会社パイオラックス | グローブボックス用リッドロック装置 |
US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
CA2520898C (en) | 2003-03-31 | 2009-10-20 | Council Of Scientific And Industrial Research | Non-cross-linking pyrrolo(2,1-c)(1,4)benzodiazepines as potential antitumour agents and process thereof |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
US20080241884A1 (en) | 2003-10-08 | 2008-10-02 | Kenya Shitara | Fused Protein Composition |
CA2542125A1 (en) | 2003-10-09 | 2005-04-21 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing antibody composition by using rna inhibiting the function of .alpha.1,6-fucosyltransferase |
WO2005040170A2 (en) | 2003-10-22 | 2005-05-06 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
SI2380911T1 (en) | 2003-11-05 | 2018-07-31 | Roche Glycart Ag | ANTIGEN-RELATED PATIENTS WITH INCREASED ATTENTION ON THE RECEPTOR FC AND EFFECTORAL FUNCTION |
DK2489364T3 (en) | 2003-11-06 | 2015-03-02 | Seattle Genetics Inc | Monomethylvaline compounds conjugated to antibodies |
WO2005053742A1 (ja) | 2003-12-04 | 2005-06-16 | Kyowa Hakko Kogyo Co., Ltd. | 抗体組成物を含有する医薬 |
US7375078B2 (en) | 2004-02-23 | 2008-05-20 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
US7528126B2 (en) | 2004-03-09 | 2009-05-05 | Spirogen Limited | Pyrrolobenzodiazepines |
US20050260711A1 (en) | 2004-03-30 | 2005-11-24 | Deepshikha Datta | Modulating pH-sensitive binding using non-natural amino acids |
RU2386638C2 (ru) | 2004-03-31 | 2010-04-20 | Дженентек, Инк. | Гуманизированные анти-тфр-бета-антитела |
RU2368622C2 (ru) | 2004-04-13 | 2009-09-27 | Ф.Хоффманн-Ля Рош Аг | Антитела к р-селектину |
AU2005249490B2 (en) | 2004-06-01 | 2010-07-29 | Genentech, Inc. | Antibody drug conjugates and methods |
JP5015779B2 (ja) * | 2004-08-23 | 2012-08-29 | エモリー・ユニバーシテイ | インビボ治療のためのpH依存性化合物の改良選択法 |
TWI309240B (en) | 2004-09-17 | 2009-05-01 | Hoffmann La Roche | Anti-ox40l antibodies |
AU2005286607B2 (en) | 2004-09-23 | 2011-01-27 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
US20100111856A1 (en) | 2004-09-23 | 2010-05-06 | Herman Gill | Zirconium-radiolabeled, cysteine engineered antibody conjugates |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
US8871720B2 (en) | 2005-07-07 | 2014-10-28 | Seattle Genetics, Inc. | Monomethylvaline compounds having phenylalanine carboxy modifications at the C-terminus |
AU2006269422B2 (en) | 2005-07-07 | 2012-12-06 | Seagen Inc. | Monomethylvaline compounds having phenylalanine side-chain modifications at the C-terminus |
KR20080073293A (ko) | 2005-10-14 | 2008-08-08 | 메디뮨 엘엘씨 | 항체 라이브러리의 세포 디스플레이 |
RS52060B (en) | 2006-01-25 | 2012-04-30 | Sanofi | CYTOTOXIC AGENTS CONTAINING NEW TOMAIMYCIN DERIVATIVES |
ES2673822T3 (es) | 2006-07-18 | 2018-06-25 | Sanofi | Anticuerpo antagonista contra EphA2 para el tratamiento de cáncer |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
US20080226635A1 (en) | 2006-12-22 | 2008-09-18 | Hans Koll | Antibodies against insulin-like growth factor I receptor and uses thereof |
EP2137535B1 (en) | 2007-04-13 | 2015-06-03 | Dana-Farber Cancer Institute, Inc. | Receptor tyrosine kinase profiling |
PT2019104E (pt) | 2007-07-19 | 2013-12-03 | Sanofi Sa | Agentes citotóxicos compreendendo novos derivados de tomaimicina e sua utilização terapêutica |
US7947495B2 (en) | 2007-11-01 | 2011-05-24 | Abbott Biotherapeutics Corp. | Immunoglobulin display vectors |
DK2220121T3 (en) | 2007-11-12 | 2015-12-07 | U3 Pharma Gmbh | AXL antibodies |
SG188134A1 (en) | 2007-11-15 | 2013-03-28 | Chugai Pharmaceutical Co Ltd | Monoclonal antibody capable of binding to anexelekto, and use thereof |
EP2235064B1 (en) | 2008-01-07 | 2015-11-25 | Amgen Inc. | Method for making antibody fc-heterodimeric molecules using electrostatic steering effects |
ES2547552T3 (es) | 2008-02-01 | 2015-10-07 | Genentech, Inc. | Metabolito de nemorrubicina y reactivos análogos, conjugados anticuerpo-fármaco y métodos |
RU2523419C2 (ru) | 2008-07-15 | 2014-07-20 | Дженетек, Инк. | Конъюгаты производного антрациклина, способы их получения и их применение в качестве противоопухолевых соединений |
WO2010025177A1 (en) * | 2008-08-26 | 2010-03-04 | City Of Hope | Method and compositions for enhanced anti-tumor effector functioning of t cells |
CN114835812A (zh) | 2008-12-09 | 2022-08-02 | 霍夫曼-拉罗奇有限公司 | 抗-pd-l1抗体及它们用于增强t细胞功能的用途 |
AU2010270163B2 (en) * | 2009-07-10 | 2016-05-05 | Innate Pharma, S.A. | TLR3 binding agents |
FR2948364B1 (fr) | 2009-07-21 | 2011-07-15 | Rhodia Operations | Procede de preparation d'un fluorure d'halogenoacetyle et de ses derives |
AR077595A1 (es) | 2009-07-27 | 2011-09-07 | Genentech Inc | Tratamientos de combinacion |
TWI518325B (zh) * | 2010-02-04 | 2016-01-21 | 自治醫科大學 | 對alk抑制劑具有先抗性或後抗性癌症的識別、判斷和治療 |
WO2011109726A2 (en) | 2010-03-05 | 2011-09-09 | Bioatla Llc | Homologous multi-specific antibodies |
EP2528625B1 (en) | 2010-04-15 | 2013-07-10 | Spirogen Sàrl | Pyrrolobenzodiazepines and conjugates thereof |
CA2794731C (en) | 2010-06-18 | 2019-03-19 | Genentech, Inc. | Anti-axl antibodies and methods of use |
FI20105715A0 (fi) | 2010-06-18 | 2010-06-18 | Helsingin Yliopisto | Asetyloituun HMGB1:een sitoutuva polyklonaalinen vasta-aine |
ES2602743T3 (es) * | 2010-09-08 | 2017-02-22 | Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus | Receptores de antígenos quiméricos con una región bisagra optimizada |
WO2012044831A1 (en) | 2010-09-30 | 2012-04-05 | Board Of Trustees Of Northern Illinois University | Library-based methods and compositions for introducing molecular switch functionality into protein affinity reagents |
CA2818173C (en) | 2010-11-30 | 2022-05-03 | Genentech, Inc. | Low affinity blood brain barrier receptor antibodies and uses therefor |
US9402865B2 (en) * | 2011-01-18 | 2016-08-02 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating cancer |
GB201108236D0 (en) * | 2011-05-17 | 2011-06-29 | Ucl Business Plc | Method |
WO2013040371A2 (en) * | 2011-09-16 | 2013-03-21 | Baylor College Of Medicine | Targeting the tumor microenvironment using manipulated nkt cells |
WO2013046722A1 (ja) * | 2011-09-30 | 2013-04-04 | 中外製薬株式会社 | イオン濃度依存性結合分子ライブラリ |
US20140322234A1 (en) | 2012-01-03 | 2014-10-30 | The Board Of Trustees Of The Leland Stanford Junior University | Analysis and Targeting of ROR2 in Cancer |
WO2013126733A1 (en) * | 2012-02-22 | 2013-08-29 | The Trustees Of University Of Pennsylvania | Use of icos-based cars to enhance antitumor activity and car persistence |
MX2014010750A (es) | 2012-03-08 | 2015-02-05 | Halozyme Inc | Anticuerpos receptores del factor de crecimiento anti-epidermico condicionalmente activos y metodos de uso de los mismos. |
US9511152B2 (en) | 2012-04-05 | 2016-12-06 | The Board Of Regents Of The University Of Texas System | Multicolored pH-activatable fluorescence nanoplatform |
US20130280220A1 (en) | 2012-04-20 | 2013-10-24 | Nabil Ahmed | Chimeric antigen receptor for bispecific activation and targeting of t lymphocytes |
CN104583239B (zh) | 2012-05-10 | 2018-09-18 | 生物蛋白有限公司 | 多特异单克隆抗体 |
EP2872617A4 (en) * | 2012-07-13 | 2015-12-09 | Univ Pennsylvania | EXTENSION OF EPITOPES IN RELATION TO T CAR LYMPHOCYTES |
US9758591B2 (en) | 2012-08-24 | 2017-09-12 | The Regents Of The University Of California | Antibodies and vaccines for use in treating ROR1 cancers and inhibiting metastasis |
PL2958943T3 (pl) | 2013-02-20 | 2020-04-30 | The Trustees Of The University Of Pennsylvania | Leczenie nowotworu złośliwego za pomocą humanizowanego chimerycznego receptora antygenowego anty-egfrviii |
EP3995512A1 (en) * | 2013-08-26 | 2022-05-11 | Hinrich Abken | Anti cd30 chimeric antigen receptor and its use |
CA2922562A1 (en) | 2013-09-12 | 2015-03-19 | Halozyme, Inc. | Modified anti-epidermal growth factor receptor antibodies and methods of use thereof |
GB201402631D0 (en) | 2014-02-14 | 2014-04-02 | Alligator Bioscience Ab | Library |
US11111288B2 (en) | 2014-08-28 | 2021-09-07 | Bioatla, Inc. | Conditionally active chimeric antigen receptors for modified t-cells |
ES2913865T3 (es) | 2014-08-28 | 2022-06-06 | Bioatla Inc | Receptores de antígeno quimérico condicionalmente activos para células T modificadas |
EP3189152A4 (en) | 2014-09-03 | 2018-04-04 | BioAtla LLC | Discovering and producing conditionally active biologic proteins in the same eukaryotic cell production hosts |
WO2016138071A1 (en) | 2015-02-24 | 2016-09-01 | Short Jay M | Conditionally active biological proteins |
MX2019008503A (es) | 2017-01-18 | 2019-09-13 | F1 Oncology Inc | Receptores de antigenos quimericos contra axl o ror2 y metodos de uso de los mismos. |
-
2015
- 2015-08-27 ES ES15836397T patent/ES2913865T3/es active Active
- 2015-08-27 US US15/504,470 patent/US20170260261A1/en not_active Abandoned
- 2015-08-27 RU RU2017109966A patent/RU2764074C2/ru active
- 2015-08-27 KR KR1020237043017A patent/KR20230172625A/ko not_active Application Discontinuation
- 2015-08-27 MX MX2017002605A patent/MX2017002605A/es unknown
- 2015-08-27 DK DK15836397.8T patent/DK3186284T3/da active
- 2015-08-27 EP EP22164162.4A patent/EP4074735A1/en active Pending
- 2015-08-27 WO PCT/US2015/047197 patent/WO2016033331A1/en active Application Filing
- 2015-08-27 CA CA2959141A patent/CA2959141A1/en active Pending
- 2015-08-27 KR KR1020177006675A patent/KR102615681B1/ko active IP Right Grant
- 2015-08-27 JP JP2017511696A patent/JP7286267B2/ja active Active
- 2015-08-27 CN CN201580057728.0A patent/CN107074975A/zh active Pending
- 2015-08-27 AU AU2015308818A patent/AU2015308818B2/en active Active
- 2015-08-27 EP EP15836397.8A patent/EP3186284B1/en active Active
-
2016
- 2016-02-24 US US15/052,487 patent/US20160207989A1/en not_active Abandoned
- 2016-02-24 CA CA2996514A patent/CA2996514A1/en active Pending
- 2016-02-24 KR KR1020247007173A patent/KR20240034265A/ko active Application Filing
- 2016-02-24 JP JP2018530483A patent/JP7048494B2/ja active Active
- 2016-02-24 BR BR112018003535A patent/BR112018003535A2/pt active Search and Examination
- 2016-02-24 EP EP16839728.9A patent/EP3341406A4/en active Pending
- 2016-02-24 RU RU2018110553A patent/RU2759957C2/ru active
- 2016-02-24 US US15/753,872 patent/US20190010219A1/en not_active Abandoned
- 2016-02-24 KR KR1020187006771A patent/KR102646445B1/ko active IP Right Grant
- 2016-02-24 AU AU2016313107A patent/AU2016313107A1/en not_active Abandoned
- 2016-02-24 CN CN201680049877.7A patent/CN107922473A/zh active Pending
- 2016-02-24 WO PCT/US2016/019255 patent/WO2017034615A1/en active Application Filing
- 2016-02-24 MX MX2018002400A patent/MX2018002400A/es unknown
-
2017
- 2017-02-27 MX MX2022007894A patent/MX2022007894A/es unknown
-
2018
- 2018-02-26 MX MX2022009625A patent/MX2022009625A/es unknown
- 2018-05-10 HK HK18106062.0A patent/HK1246803A1/zh unknown
- 2018-08-02 US US16/053,166 patent/US11584927B2/en active Active
-
2021
- 2021-05-14 JP JP2021082062A patent/JP7405444B2/ja active Active
- 2021-06-16 AU AU2021203997A patent/AU2021203997B2/en active Active
-
2022
- 2022-12-02 US US18/061,197 patent/US20230183679A1/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012519499A (ja) | 2009-03-09 | 2012-08-30 | バイオアトラ、エルエルシー | Miracタンパク質 |
JP2012533307A (ja) | 2009-07-17 | 2012-12-27 | バイオアトラ、エルエルシー | 産生宿主における抗体/タンパク質パフォーマンス及び発現の同時で統合された選択及び進化 |
JP2013541940A (ja) | 2010-09-08 | 2013-11-21 | ハロザイム インコーポレイテッド | 条件的活性治療用タンパク質を評価および同定する、または発展させる方法 |
WO2013123061A1 (en) | 2012-02-13 | 2013-08-22 | Seattle Children's Hospital D/B/A Seattle Children's Research Institute | Bispecific chimeric antigen receptors and therapeutic uses thereof |
WO2013126729A1 (en) | 2012-02-22 | 2013-08-29 | The Trustees Of The University Of Pennsylvania | Use of the cd2 signaling domain in second-generation chimeric antigen receptors |
WO2014039523A1 (en) | 2012-09-04 | 2014-03-13 | Cellectis | Multi-chain chimeric antigen receptor and uses thereof |
WO2014127261A1 (en) | 2013-02-15 | 2014-08-21 | The Regents Of The University Of California | Chimeric antigen receptor and methods of use thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7405444B2 (ja) | 修飾t細胞に対する条件的活性型キメラ抗原受容体 | |
JP2021137013A5 (ja) | ||
US11111288B2 (en) | Conditionally active chimeric antigen receptors for modified t-cells | |
JP7432250B2 (ja) | 修飾t細胞に対する条件的活性型キメラ抗原受容体 | |
BR112017003835B1 (pt) | Método para produção de um receptor de antígeno quimérico | |
SHORT et al. | Patent 2996514 Summary |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170512 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180809 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180809 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190628 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190709 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190925 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191205 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200602 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200901 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20210119 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210514 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20210514 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210519 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20210629 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20210706 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20210903 |
|
C211 | Notice of termination of reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C211 Effective date: 20210907 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20220208 |
|
C13 | Notice of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: C13 Effective date: 20220705 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20220809 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20221005 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20230404 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230524 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7286267 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |