JP2014524243A - ヒト化ユニバーサル軽鎖マウス - Google Patents
ヒト化ユニバーサル軽鎖マウス Download PDFInfo
- Publication number
- JP2014524243A JP2014524243A JP2014524126A JP2014524126A JP2014524243A JP 2014524243 A JP2014524243 A JP 2014524243A JP 2014524126 A JP2014524126 A JP 2014524126A JP 2014524126 A JP2014524126 A JP 2014524126A JP 2014524243 A JP2014524243 A JP 2014524243A
- Authority
- JP
- Japan
- Prior art keywords
- mouse
- human
- light chain
- gene
- heavy chain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 241000699666 Mus <mouse, genus> Species 0.000 claims abstract description 895
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 598
- 241000699670 Mus sp. Species 0.000 claims abstract description 328
- 108060003951 Immunoglobulin Proteins 0.000 claims abstract description 152
- 102000018358 immunoglobulin Human genes 0.000 claims abstract description 152
- 239000012634 fragment Substances 0.000 claims abstract description 98
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 68
- 210000004027 cell Anatomy 0.000 claims description 186
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 138
- 150000007523 nucleic acids Chemical group 0.000 claims description 107
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 100
- 210000004602 germ cell Anatomy 0.000 claims description 98
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims description 78
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims description 74
- 230000006870 function Effects 0.000 claims description 43
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 claims description 31
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 claims description 31
- 101150117115 V gene Proteins 0.000 claims description 29
- 101150008942 J gene Proteins 0.000 claims description 24
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 claims description 22
- 108700031127 mouse Adam6a Proteins 0.000 claims description 15
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 claims description 14
- 101100060131 Mus musculus Cdk5rap2 gene Proteins 0.000 claims description 6
- 238000000034 method Methods 0.000 abstract description 53
- 102000014914 Carrier Proteins Human genes 0.000 abstract description 37
- 108091008324 binding proteins Proteins 0.000 abstract description 37
- 239000000203 mixture Substances 0.000 abstract description 19
- 239000000427 antigen Substances 0.000 description 145
- 108091007433 antigens Proteins 0.000 description 129
- 102000036639 antigens Human genes 0.000 description 129
- 238000011577 humanized mouse model Methods 0.000 description 79
- 230000014509 gene expression Effects 0.000 description 74
- 239000000523 sample Substances 0.000 description 65
- 238000006467 substitution reaction Methods 0.000 description 65
- 230000027455 binding Effects 0.000 description 63
- 235000018102 proteins Nutrition 0.000 description 61
- 230000008685 targeting Effects 0.000 description 55
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 54
- 239000002773 nucleotide Substances 0.000 description 50
- 125000003729 nucleotide group Chemical group 0.000 description 50
- 101001094887 Ambrosia artemisiifolia Pectate lyase 1 Proteins 0.000 description 43
- 101001123576 Ambrosia artemisiifolia Pectate lyase 2 Proteins 0.000 description 43
- 101001123572 Ambrosia artemisiifolia Pectate lyase 3 Proteins 0.000 description 43
- 101000573177 Ambrosia artemisiifolia Pectate lyase 5 Proteins 0.000 description 43
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 39
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 39
- 230000004048 modification Effects 0.000 description 39
- 238000012986 modification Methods 0.000 description 39
- 108700028369 Alleles Proteins 0.000 description 36
- 238000012217 deletion Methods 0.000 description 35
- 230000037430 deletion Effects 0.000 description 35
- 239000013598 vector Substances 0.000 description 35
- 210000003101 oviduct Anatomy 0.000 description 31
- 230000006798 recombination Effects 0.000 description 29
- 238000005215 recombination Methods 0.000 description 29
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 28
- 108020004414 DNA Proteins 0.000 description 28
- 239000011324 bead Substances 0.000 description 28
- 230000002441 reversible effect Effects 0.000 description 27
- 238000011144 upstream manufacturing Methods 0.000 description 27
- 108700019146 Transgenes Proteins 0.000 description 26
- 238000003780 insertion Methods 0.000 description 25
- 230000037431 insertion Effects 0.000 description 25
- 238000003752 polymerase chain reaction Methods 0.000 description 25
- 210000002966 serum Anatomy 0.000 description 24
- 206010069754 Acquired gene mutation Diseases 0.000 description 23
- 230000035558 fertility Effects 0.000 description 23
- 230000037439 somatic mutation Effects 0.000 description 23
- 229930193140 Neomycin Natural products 0.000 description 22
- 239000003446 ligand Substances 0.000 description 22
- 229960004927 neomycin Drugs 0.000 description 22
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 21
- 238000003556 assay Methods 0.000 description 21
- 230000000392 somatic effect Effects 0.000 description 21
- 238000004519 manufacturing process Methods 0.000 description 20
- 239000006228 supernatant Substances 0.000 description 20
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 19
- 101710189008 Immunoglobulin kappa light chain Proteins 0.000 description 19
- 239000003623 enhancer Substances 0.000 description 19
- 102100029567 Immunoglobulin kappa light chain Human genes 0.000 description 18
- 210000000349 chromosome Anatomy 0.000 description 18
- 230000008569 process Effects 0.000 description 18
- 125000003275 alpha amino acid group Chemical group 0.000 description 17
- 210000004408 hybridoma Anatomy 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 210000000952 spleen Anatomy 0.000 description 17
- 238000013518 transcription Methods 0.000 description 17
- 230000035897 transcription Effects 0.000 description 17
- 108091022885 ADAM Proteins 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 210000004291 uterus Anatomy 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 15
- 210000001185 bone marrow Anatomy 0.000 description 14
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 13
- 102100039564 Leukosialin Human genes 0.000 description 13
- 101100370002 Mus musculus Tnfsf14 gene Proteins 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- 230000011712 cell development Effects 0.000 description 13
- 210000004698 lymphocyte Anatomy 0.000 description 13
- 230000013011 mating Effects 0.000 description 13
- 108091008146 restriction endonucleases Proteins 0.000 description 13
- 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 12
- 102000025171 antigen binding proteins Human genes 0.000 description 12
- 108091000831 antigen binding proteins Proteins 0.000 description 12
- 230000007547 defect Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 102000029791 ADAM Human genes 0.000 description 10
- 101150097493 D gene Proteins 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 238000011161 development Methods 0.000 description 10
- 230000018109 developmental process Effects 0.000 description 10
- 238000000684 flow cytometry Methods 0.000 description 10
- 230000003053 immunization Effects 0.000 description 10
- 229940072221 immunoglobulins Drugs 0.000 description 10
- 238000003753 real-time PCR Methods 0.000 description 10
- 230000008707 rearrangement Effects 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 108700026244 Open Reading Frames Proteins 0.000 description 9
- 238000010494 dissociation reaction Methods 0.000 description 9
- 230000005593 dissociations Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000002068 genetic effect Effects 0.000 description 9
- 238000002649 immunization Methods 0.000 description 9
- CRQPDNIUPWXPNK-UHFFFAOYSA-N madam-6 Chemical compound C1=C(C)C(CC(C)NC)=CC2=C1OCO2 CRQPDNIUPWXPNK-UHFFFAOYSA-N 0.000 description 9
- 210000003519 mature b lymphocyte Anatomy 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 108010069446 Fertilins Proteins 0.000 description 8
- 102000001133 Fertilins Human genes 0.000 description 8
- 241001529936 Murinae Species 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 8
- 238000010353 genetic engineering Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 8
- 239000013642 negative control Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 210000004988 splenocyte Anatomy 0.000 description 8
- 230000009261 transgenic effect Effects 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 241000282412 Homo Species 0.000 description 7
- 101100322565 Mus musculus Adam3 gene Proteins 0.000 description 7
- 238000010240 RT-PCR analysis Methods 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 102000005936 beta-Galactosidase Human genes 0.000 description 7
- 108010005774 beta-Galactosidase Proteins 0.000 description 7
- 238000009395 breeding Methods 0.000 description 7
- 230000001488 breeding effect Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 230000024245 cell differentiation Effects 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 210000001550 testis Anatomy 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 108010087819 Fc receptors Proteins 0.000 description 6
- 102000009109 Fc receptors Human genes 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 description 6
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 description 6
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 description 6
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 description 6
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 description 6
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 6
- 108091029795 Intergenic region Proteins 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 210000004899 c-terminal region Anatomy 0.000 description 6
- 230000007812 deficiency Effects 0.000 description 6
- 201000010063 epididymitis Diseases 0.000 description 6
- 230000004720 fertilization Effects 0.000 description 6
- 238000002744 homologous recombination Methods 0.000 description 6
- 230000006801 homologous recombination Effects 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 210000000987 immune system Anatomy 0.000 description 6
- 230000002163 immunogen Effects 0.000 description 6
- 210000001161 mammalian embryo Anatomy 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 6
- 201000000050 myeloid neoplasm Diseases 0.000 description 6
- 210000005259 peripheral blood Anatomy 0.000 description 6
- 239000011886 peripheral blood Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 230000019100 sperm motility Effects 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 238000010561 standard procedure Methods 0.000 description 6
- 230000007704 transition Effects 0.000 description 6
- 102000000844 Cell Surface Receptors Human genes 0.000 description 5
- 108010001857 Cell Surface Receptors Proteins 0.000 description 5
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 description 5
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 description 5
- 238000012286 ELISA Assay Methods 0.000 description 5
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 description 5
- 230000009824 affinity maturation Effects 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 238000010367 cloning Methods 0.000 description 5
- 238000010276 construction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 235000013601 eggs Nutrition 0.000 description 5
- 210000002257 embryonic structure Anatomy 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000012239 gene modification Methods 0.000 description 5
- 230000005017 genetic modification Effects 0.000 description 5
- 235000013617 genetically modified food Nutrition 0.000 description 5
- 230000008348 humoral response Effects 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000011830 transgenic mouse model Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 108010046276 FLP recombinase Proteins 0.000 description 4
- 102000006395 Globulins Human genes 0.000 description 4
- 108010044091 Globulins Proteins 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 101000599048 Homo sapiens Interleukin-6 receptor subunit alpha Proteins 0.000 description 4
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 210000000918 epididymis Anatomy 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 108020005243 folate receptor Proteins 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 102000054766 genetic haplotypes Human genes 0.000 description 4
- 102000052623 human IL6R Human genes 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 230000035800 maturation Effects 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 230000002381 testicular Effects 0.000 description 4
- 210000004340 zona pellucida Anatomy 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 3
- 101000746783 Homo sapiens Cytochrome b-c1 complex subunit 6, mitochondrial Proteins 0.000 description 3
- 101000914680 Homo sapiens Fanconi anemia group C protein Proteins 0.000 description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 102100022964 Immunoglobulin kappa variable 3-20 Human genes 0.000 description 3
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-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
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108010090804 Streptavidin Proteins 0.000 description 3
- 101100240365 Streptomyces fradiae neoK gene Proteins 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 230000007720 allelic exclusion Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 210000004102 animal cell Anatomy 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000001627 detrimental effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 102000048638 human UQCRH Human genes 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 208000000509 infertility Diseases 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 231100000535 infertility Toxicity 0.000 description 3
- 229940100601 interleukin-6 Drugs 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 210000005210 lymphoid organ Anatomy 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 230000005257 nucleotidylation Effects 0.000 description 3
- 102220117530 rs112626848 Human genes 0.000 description 3
- 102220238658 rs1468529365 Human genes 0.000 description 3
- 102220268018 rs201210997 Human genes 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 101150086149 39 gene Proteins 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 101710098119 Chaperonin GroEL 2 Proteins 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108060002716 Exonuclease 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
- 239000004471 Glycine Substances 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 101000854886 Homo sapiens Immunoglobulin iota chain Proteins 0.000 description 2
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 2
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 2
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 2
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 2
- 102100020744 Immunoglobulin iota chain Human genes 0.000 description 2
- 108010038501 Interleukin-6 Receptors Proteins 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
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 239000007987 MES buffer Substances 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 108020005067 RNA Splice Sites Proteins 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 108700005077 Viral Genes Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000003314 affinity selection Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000008350 antigen-specific antibody response Effects 0.000 description 2
- 230000007503 antigenic stimulation 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
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 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 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 210000002459 blastocyst Anatomy 0.000 description 2
- 102220349284 c.287A>T Human genes 0.000 description 2
- 238000010805 cDNA synthesis kit Methods 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 230000009849 deactivation Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 102000013165 exonuclease Human genes 0.000 description 2
- 231100000502 fertility decrease Toxicity 0.000 description 2
- 238000003205 genotyping method Methods 0.000 description 2
- 210000001280 germinal center Anatomy 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 239000000710 homodimer Substances 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 210000003297 immature b lymphocyte Anatomy 0.000 description 2
- 238000007901 in situ hybridization Methods 0.000 description 2
- 208000021267 infertility disease Diseases 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 210000003563 lymphoid tissue Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 208000024393 maple syrup urine disease Diseases 0.000 description 2
- 239000012092 media component Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000011325 microbead Substances 0.000 description 2
- 238000007857 nested PCR Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 210000004681 ovum Anatomy 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000003906 pulsed field gel electrophoresis Methods 0.000 description 2
- 238000001472 pulsed field gradient Methods 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 102200148758 rs116840795 Human genes 0.000 description 2
- 102220142694 rs192332456 Human genes 0.000 description 2
- 239000012146 running buffer Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000001082 somatic cell Anatomy 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 125000000134 2-(methylsulfanyl)ethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])[*] 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
- 125000000981 3-amino-3-oxopropyl group Chemical group [H]C([*])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- VGSKDSRZIZUQEB-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-N,N-dimethylaniline sulfuric acid Chemical compound CN(C1=CC=C(C2=CC=C(N(C)C)C=C2)C=C1)C.S(O)(O)(=O)=O VGSKDSRZIZUQEB-UHFFFAOYSA-N 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 1
- 101001073212 Arabidopsis thaliana Peroxidase 33 Proteins 0.000 description 1
- 241000239290 Araneae Species 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 1
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 102100027314 Beta-2-microglobulin Human genes 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- 102000016897 CCCTC-Binding Factor Human genes 0.000 description 1
- 108010014064 CCCTC-Binding Factor Proteins 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 108010051219 Cre recombinase Proteins 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical class O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 1
- 101800001224 Disintegrin Proteins 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 1
- 101001128634 Homo sapiens NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial Proteins 0.000 description 1
- 101001123325 Homo sapiens Peroxisome proliferator-activated receptor gamma coactivator 1-beta Proteins 0.000 description 1
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 1
- 101000666382 Homo sapiens Transcription factor E2-alpha Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 102000012960 Immunoglobulin kappa-Chains Human genes 0.000 description 1
- 108010090227 Immunoglobulin kappa-Chains Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102100025305 Integrin alpha-2 Human genes 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 208000030426 Intermediate maple syrup urine disease Diseases 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 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 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 101100351020 Mus musculus Pax5 gene Proteins 0.000 description 1
- 101000894412 Mycolicibacterium paratuberculosis (strain ATCC BAA-968 / K-10) Bacterioferritin Proteins 0.000 description 1
- 102100032194 NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 241001452677 Ogataea methanolica Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 102100028961 Peroxisome proliferator-activated receptor gamma coactivator 1-beta Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010016231 Pre-B Cell Receptors Proteins 0.000 description 1
- 102000000434 Pre-B Cell Receptors Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100038081 Signal transducer CD24 Human genes 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 101000588258 Taenia solium Paramyosin Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102100027654 Transcription factor PU.1 Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 238000012452 Xenomouse strains Methods 0.000 description 1
- 101100351021 Xenopus laevis pax5 gene Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 238000012867 alanine scanning Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009833 antibody interaction Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 1
- 208000005980 beta thalassemia Diseases 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 239000002458 cell surface marker Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 230000031154 cholesterol homeostasis Effects 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 208000030432 classic maple syrup urine disease Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 210000001771 cumulus cell Anatomy 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 238000009585 enzyme analysis Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000000285 follicular dendritic cell Anatomy 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000012224 gene deletion Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 210000002980 germ line cell Anatomy 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000003917 human chromosome Anatomy 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 101150083745 preT gene Proteins 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 108010008929 proto-oncogene protein Spi-1 Proteins 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000005903 regulation of histone modification Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000012340 reverse transcriptase PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102220210869 rs1057524586 Human genes 0.000 description 1
- 102220220520 rs1060503090 Human genes 0.000 description 1
- 102220206698 rs142514490 Human genes 0.000 description 1
- 102220325921 rs1555376589 Human genes 0.000 description 1
- 102200164344 rs63751661 Human genes 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000005212 secondary lymphoid organ Anatomy 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000030847 signal maturation Effects 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 230000021595 spermatogenesis Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940124598 therapeutic candidate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000011816 wild-type C57Bl6 mouse Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229950009002 zanolimumab Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0278—Humanized animals, e.g. knockin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6489—Metalloendopeptidases (3.4.24)
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/15—Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/01—Animal expressing industrially exogenous proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- 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
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- 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
- C12N2800/00—Nucleic acids vectors
- C12N2800/20—Pseudochromosomes, minichrosomosomes
- C12N2800/204—Pseudochromosomes, minichrosomosomes of bacterial origin, e.g. BAC
-
- 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
- C12N2800/00—Nucleic acids vectors
- C12N2800/30—Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
Abstract
Description
ヒト免疫グロブリン重鎖可変ドメインをコードする配列および抗体(二重特異性抗体(ユニバーサル軽鎖(universal light chain)を含む二重特異性抗体が含まれる)が含まれる)の作製のための遺伝子改変されたマウス、細胞、胚、組織、および単離核酸。組成物および方法は、内因性マウス重鎖可変遺伝子座に生殖系列置換を有する遺伝子改変マウスであって、生殖系列置換が1つまたは2つ以下の異なる軽鎖V遺伝子セグメントに由来する軽鎖を発現する改変軽鎖遺伝子座を含み、マウスはこれらの改変を有する雄マウスが繁殖性を示すようにその生殖系列においてさらに遺伝子改変されている、遺伝子改変マウスを含む。ユニバーサル軽鎖およびヒト化重鎖可変ドメインを発現する遺伝子改変マウスであって、該マウスが雄マウスにおいて機能するADAM6活性を含む、遺伝子改変マウスを提供する。
ヒトへの治療薬(therapeutic)として用いるための抗体の開発には長く且つ複雑な歴史がある。1つの重要な進展は、免疫原性の可能性が軽減された有効なヒト治療薬のデザインで使用するための本質的に完全ヒト抗体配列を作製することができたことである。現在、その生殖系列において内因性マウス免疫グロブリン遺伝子座での導入遺伝子としてか置換物として、再構成されていない遺伝子セグメント(重鎖および軽鎖)に由来するヒト抗体配列が生成するように改変されたマウスが存在する。VELOCIMMUNE(登録商標)ヒト化マウスのようなマウス内の内因性遺伝子座でのマウス可変配列のヒト可変配列への置換により、マウス免疫系が本質的に正常に機能することが可能である。結果として、これらのマウスの最適な抗原への曝露により、最適な抗原に指向する完全ヒト抗体の作製において使用することができる高親和性体細胞変異ヒト可変ドメインを発現する非常に多様で豊富なクローン選択されたB細胞集団が生成される。
二重特異性結合性タンパク質(二重特異性抗体が含まれる)での使用に適切なヒト免疫グロブリン可変ドメインを発現するマウスであって、該マウスが内因性マウス重鎖可変遺伝子座のヒト化を含み、ヒト化を含む雄マウスが繁殖性を示し、マウスが1つ以下または2つ以下のλおよび/またはκV遺伝子セグメントに由来する免疫グロブリン軽鎖レパートリーを発現するマウスが得られる内因性免疫グロブリン軽鎖遺伝子座のヒト化をさらに含む、マウスを記載する。
本明細書で用いる用語「抗体」は、ジスルフィド結合によって相互接続する4つのポリペプチド鎖、2つの重(H)鎖および2つの軽(L)鎖を含む免疫グロブリン分子を含む。各重鎖は、重鎖可変(VH)領域および重鎖定常領域(CH)を含む。重鎖定常領域は、3つのドメイン、CH1、CH2およびCH3を含む。各軽鎖は、軽鎖可変(VL)領域および軽鎖定常領域(CL)を含む。VHおよびVL領域は、フレームワーク領域(FR)と呼ばれる保存されている領域の間に散在する、相補性決定領域(CDR)と呼ばれる超可変性の領域にさらに細分化することができる。各VHおよびVLは、アミノ末端からカルボキシ末端まで以下の順序で配置される3つのCDRおよび4つのFRを含む:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4(重鎖CDRは、HCDR1、HCDR2およびHCDR3と略すことができ;軽鎖CDRは、LCDR1、LCDR2およびLCDR3と略すことができる)。用語「高親和性」抗体は、その標的エピトープに関して約10−9M以下のKD(例えば、約1×10−9M、1×10−10M、1×10−11Mまたは約1×10−12M)を有する抗体を指す。一実施形態では、KDは表面プラズモン共鳴、例えばBIACORETMによって測定され、別の実施形態では、KDはELISAによって測定される。
遺伝モデルとしてのマウスは、トランスジェニックおよびノックアウト技術によって大きく向上され、これらの技術により特定の遺伝子の指向性過発現または欠失の効果の研究が可能になった。あらゆるその利点にもかかわらず、前記マウスは、マウスをヒト疾患についての不完全なモデルにならしめるおよびヒト治療薬を試験するまたはそれらを作製するための不完全なプラットホームにならしめる遺伝的障害をやはり提示する。第一に、ヒト遺伝子の約99%はマウスホモログを有する(Waterston,R.H.ら(2002)Initial sequencing and comparative analysis of the mouse genome、Nature.420,520−562)が、可能性のある治療薬は、多くの場合、所期のヒト標的のマウスオルソログと交叉反応することができない、または不適切に交叉反応する。この問題を未然に防ぐために、選択標的遺伝子を「ヒト化」することができる、すなわち、マウス遺伝子を消去して、対応するオルソロガスヒト遺伝子配列により置換することができる(例えば、米国特許第6,586,251号、同第6,596,541号および同第7,105,348号明細書;これらは参照により本明細書に援用されている)。最初、「ノックアウト・プラス・トランスジェニックヒト化(knockout−plus−transgenic humanization)」戦略によりマウス遺伝子をヒト化する努力は、前記内因性遺伝子の欠失(すなわち、ノックアウト)を保有するマウスとランダムに組み込まれたヒト導入遺伝子を保有するマウスとの交配を必要とした(例えば、Bril,W.S.ら(2006)Tolerance to factor VIII in a transgenic mouse expressing human factor VIII cDNA carrying an Arg(593) to Cys substitution、Thromb Haemost 95、341−347;Homanics,G.E.ら(2006)Production and characterization of murine models of classic and intermediate maple syrup urine disease.BMC Med Genet 7、33;Jamsai,D.ら(2006)A humanized BAC transgenic/knockout mouse model for HbE/beta−thalassemia.Genomics 88(3):309−15;Pan,Q.ら(2006)Different role for mouse and human CD3delta/epsilon heterodimer in preT cell receptor(preTCR)function:human CD3delta/epsilon heterodimer restores the defective preTCR function in CD3gamma− and CD3gammadelta−deficient mice.Mol Immunol 43、1741−1750参照)。しかし、これらの努力は、サイズ制限によって妨げられた;従来のノックアウト技術は、大きなマウス遺伝子を該遺伝子の大きなヒトゲノムカウンターパートで直接置換するのに十分なものではなかった。該マウス遺伝子の同じまさにその遺伝子の場所で(すなわち内因性マウス遺伝子座で)ヒトカウンターパート遺伝子により内因性マウス遺伝子を直接置換する直接相同置換の直接的なアプローチは、技術的な難しさのため、滅多に試みられない。今まで、直接置換に対する努力は手の込んだ厄介な手順を必要とし、それ故、取り扱うことができる遺伝子材料の長さおよび操作することができる精度が限定された。
いずれかの機能的ADAM6タンパク質を発現する能力が無い雄マウスは、交配して子孫をもたらす該マウスの能力の重大な欠陥を示す。これらのマウスには、すべてのまたは実質的にすべてのマウス免疫グロブリン可変領域遺伝子セグメントをヒト可変領域遺伝子セグメントで置換することによって機能的ADAM6タンパク質を発現する能力が無い。ADAM6遺伝子座が、DH遺伝子セグメントの上流にあるVH遺伝子セグメント遺伝子座の3’端の近位の、前記内因性マウス免疫グロブリン重鎖可変領域遺伝子遺伝子座の領域内にあるため、このADAM6機能の喪失が生ずる結果となる。すべてのまたは実質的にすべての内因性マウス重鎖可変遺伝子セグメントの、ヒト重鎖可変遺伝子セグメントでの置換に関してホモ接合性であるマウスを交配させるために、それぞれが該置換に関してホモ接合性であり、生産的交配を待つ雄と雌を供給することは、一般に厄介なアプローチである。好結果の同腹子は、比較的まれであり、同腹仔の平均サイズが非常に小さい。その代り、前記置換に関してヘテロ接合性の雄を用いて、前記置換に関してホモ接合性の雌と交配させて、前記置換に対してヘテロ接合性の後代をもたらし、その後、それらからホモ接合型マウスを繁殖させた。前記雄マウスの妊性の喪失についての可能性のある原因は、ホモ接合型雄マウスにおける機能的ADAM6タンパク質の不在であると本発明者らは決定した。
ヒト抗体を作るマウスは、ここしばらくの間に利用可能になった。これらのマウスは、ヒト治療用抗体の開発の重要な前進の代表であるが、その有用性を制限する多数の重大な異常を提示する。例えば、これらのマウスは、損なわれたB細胞発生を提示する。この損なわれた発生は、トランスジェニックマウスと野生型マウスの間の様々な相違に起因し得る。
有用な多重特異性エピトープ結合性タンパク質、例えば二重特異性抗体を作製するこれまでの努力は、共通のパラダイムをしばしば共有する様々な問題によって妨害された:ヘテロダイマー二重特異性ヒト免疫グロブリンを対合させるのに適するフォーマットを、合理的に操作するか、試行錯誤を通して遺伝子操作するための配列のin vitro選択または操作。残念ながら、in vitro操作手法の全てではないにしてもそのほとんどは、個々の分子に適する(あるとしても)主にその場しのぎの修正を提供する。他方、ヒト治療法へと導くことが可能である適当な対合を選択するために複雑な生物体を使用するためのin vivo方法は、実現されていない。
本明細書に記載される組成物および方法は、複数のエピトープに高親和性で結合する結合性タンパク質、例えば二重特異性抗体を作製するために用いることができる。本発明の利点には、その各々が単一の軽鎖と会合する好適に高い結合性の(例えば、親和性成熟した)重鎖免疫グロブリン鎖を選択する能力が含まれる。
4つの異なる抗原に対して形成された親和性成熟抗体からの様々なヒト可変領域は、それらの関連軽鎖、またはヒトVκ1−39Jκ5、ヒトVκ3−20Jκ1もしくはヒトVpreBJλ5から選択される少なくとも1つのヒト軽鎖と共に発現された(実施例10を参照)。抗原の各々に対する抗体について、異なる遺伝子ファミリーからの体細胞変異高親和性重鎖は、再構成されたヒト生殖系列Vκ1−39Jκ5およびVκ3−20Jκ1領域と上手く対合し、重鎖および軽鎖を発現する細胞から分泌された。Vκ1−39Jκ5およびVκ3−20Jκ1について、以下のヒトVH遺伝子ファミリーに由来するVHドメインが有利に発現した:1−2、1−8、1−24、2−5、3−7、3−9、3−11、3−13、3−15、3−20、3−23、3−30、3−33、3−48、4−31、4−39、4−59、5−51および6−1。したがって、Vκ1−39Jκ5およびVκ3−20Jκ1の片方または両方からヒトVLドメインの限られたレパートリーを発現するように遺伝子操作されているマウスは、ヒトVH遺伝子セグメントでマウスVH遺伝子セグメントを置換するように改変されたVH遺伝子座から、体細胞変異ヒトVHドメインの多様な集団を生成する。
マウス免疫グロブリン遺伝子のヒト化
複数のヒト化免疫グロブリン対立遺伝子の組み合わせによる完全ヒト化マウスの産生
ヒト化免疫グロブリン遺伝子を有するマウスにおけるリンパ球集団
ヒト化免疫グロブリンマウスにおける可変遺伝子レパートリー
リンパ系構造および血清アイソタイプの分析
ヒト化免疫グロブリンマウスにおける免疫および抗体産生
異なるバージョンのVELOCIMMUNE(登録商標)ヒト化マウスを抗原で免疫して、外来抗原攻撃に対する体液性応答を調査した。
マウスADAM6ターゲティングベクターの構築
VELOCIGENE(登録商標)遺伝子工学技術(上記)を用いて、マウスADAM6aおよびADAM6b遺伝子のヒト化重鎖遺伝子座への挿入のためのターゲティングベクターを構築して、Dr.Fred Alt(Havard University)から入手した細菌人工染色体(BAC)929d24を改変した。マウスADAM6aおよびADAM6b遺伝子を含有するゲノム断片と、ヒト化重鎖遺伝子座のヒトVH1−2遺伝子セグメントとヒトVH6−1遺伝子セグメントの間にあるヒトADAM6偽遺伝子(hADAM6Ψ)の標的欠失のためのハイグロマイシンカセットとを含有するように、929d24 BAC DNAを操作して作製した(図12)。
ADAM6レスキューマウスの特徴づけ
フローサイトメトリー。
ADAM6レスキューマウスにおけるヒト重鎖可変遺伝子使用法
選択されたヒト軽鎖可変領域と会合するヒト重鎖可変領域の同定
再構成されたヒト生殖系列軽鎖遺伝子座の生成
単一の再構成されたヒト軽鎖を発現するマウスの生成
単一の再構成されたヒト生殖系列軽鎖を発現するマウスの繁殖
ヒト重鎖および再構成されたヒト生殖系列軽鎖領域を発現するマウスからの抗体の生成
抗原特異的共通軽鎖抗体での重鎖遺伝子セグメントの使用
LuminexTMアッセイによる抗原特異的共通軽鎖抗体のブロック能力の判定
ビーズベースのアッセイで、抗原Eに対する98個のヒト共通軽鎖抗体を、抗原Eへの抗原Eの天然のリガンド(リガンドY)の結合をブロックするそれらの能力について試験した。
ELISAによる抗原特異的共通軽鎖抗体のブロック能力の判定
抗原特異的共通軽鎖抗体についてのBIACORETM親和性判定
LuminexTMアッセイによる抗原特異的共通軽鎖抗体の結合特異性の判定
選択された抗抗原E共通軽鎖抗体を、抗原EのECDおよび抗原E ECDバリアントに結合するそれらの能力について試験した(例えば、そのアミノ酸残基の約10%がヒトタンパク質と異なる、カニクイザルオルソログ(Mf抗原E);ECDのC末端から最後の10アミノ酸を欠く抗原Eの欠失変異体(抗原E−ΔCT);ならびにリガンドYとの相互作用が疑われる位置にアラニン置換を含む2つの変異体(抗原E−Ala1および抗原E−Ala2))。抗原Eタンパク質はCHO細胞で生成され、各々はmyc−myc−His C末端タグを含んでいた。
(項目1) マウスであって、該マウスの生殖系列において:
(a)重鎖定常領域遺伝子に作動可能に連結される少なくとも1つの再構成されていないヒトV、少なくとも1つの再構成されていないヒトD、および少なくとも1つの再構成されていないヒトJセグメントを含むヒト化免疫グロブリン重鎖可変遺伝子座;
(b)軽鎖定常領域遺伝子に作動可能に連結される1つ以下または2つ以下の再構成されたヒト軽鎖V/J配列を含むヒト化免疫グロブリン軽鎖可変遺伝子座;および
(c)マウスADAM6タンパク質をコードする異所性核酸配列またはそのオルソログもしくはホモログもしくは機能的断片
を含むマウス。
(項目2) 前記マウスADAM6タンパク質をコードする核酸配列またはそのオルソログもしくはホモログもしくは機能的断片が前記免疫グロブリン重鎖可変遺伝子座以外の遺伝子座に存在する、項目1に記載のマウス。
(項目3) 前記重鎖定常領域遺伝子がマウス遺伝子である、項目1に記載のマウス。
(項目4) 前記軽鎖定常領域遺伝子がマウス遺伝子である、項目1に記載のマウス。
(項目5) ヒト化重鎖免疫グロブリン可変遺伝子座およびヒト化軽鎖免疫グロブリン可変遺伝子座を含むマウスであって、該マウスが単一の軽鎖を発現し、該マウスが雄マウスにおいて機能するADAM6遺伝子をコードする異所性核酸配列を含む、マウス。
(項目6) 前記ヒト化重鎖免疫グロブリン遺伝子座が内因性マウス重鎖定常領域遺伝子に作動可能に連結されている、項目5に記載のマウス。
(項目7) 前記単一の軽鎖が、軽鎖定常遺伝子に作動可能に連結される1つ以下の軽鎖V遺伝子セグメントおよび軽鎖J遺伝子セグメントをコードする免疫グロブリン軽鎖可変遺伝子遺伝子座からコードされる、項目5に記載のマウス。
(項目8) 前記単一の軽鎖が、前記マウスの前記生殖系列における免疫グロブリン軽鎖可変遺伝子遺伝子座に由来し、該遺伝子座が軽鎖定常遺伝子に作動可能に連結される、該生殖系列中の1つ以下の再構成された軽鎖V/J遺伝子セグメントをコードする、項目5に記載のマウス。
(項目9) 前記異所性核酸配列が雄マウスにおいて機能するマウスADAM6タンパク質をコードするか、マウスADAM6タンパク質の断片をコードする、項目5に記載のマウス。
(項目10) 前記異所性核酸配列が内因性免疫グロブリン重鎖遺伝子座内ではない位置に存在する、項目5に記載のマウス。
(項目11) 遺伝子改変マウスであって、複数の異なるIgG重鎖を発現し、該複数の異なるIgG重鎖の各々がヒト可変ドメインを含み、前記複数の異なるIgG重鎖の各々が単一のヒト免疫グロブリンV遺伝子セグメントに由来するヒト免疫グロブリン軽鎖可変ドメインをコードする軽鎖配列と会合しており、該マウスが雄マウスにおいて機能するADAM6タンパク質をコードする異所性核酸配列を含む、遺伝子改変マウス。
(項目12) 前記マウスが、雄マウスにおいて機能するADAM6タンパク質またはその断片を発現し、該ADAM6タンパク質またはその断片が前記異所性核酸配列から発現される、項目11に記載のマウス。
(項目13) マウス細胞であって、以下:
重鎖定常遺伝子に作動可能に連結されるヒト化重鎖免疫グロブリン可変遺伝子遺伝子座;
軽鎖定常遺伝子に作動可能に連結される1つ以下または2つ以下の軽鎖V遺伝子セグメントを含むヒト化軽鎖免疫グロブリン遺伝子座;および
ADAM6タンパク質またはその断片をコードする異所性核酸配列であって、該ADAM6タンパク質またはその断片が雄マウスにおいて機能する、異所性核酸配列
を含む、マウス細胞。
(項目14) 前記異所性核酸配列がマウスADAM6タンパク質をコードする、項目13に記載のマウス細胞。
(項目15) 前記重鎖定常遺伝子が非ヒト重鎖定常遺伝子である、項目13に記載のマウス。
(項目16) 前記軽鎖定常遺伝子が非ヒト軽鎖定常遺伝子である、項目13に記載のマウス。
(項目17) 前記1つ以下または2つ以下(no more that two)の軽鎖V遺伝子セグメントが再構成されたV/J遺伝子セグメントに存在する、項目13に記載のマウス。
(項目18) ヒト重鎖V遺伝子セグメントに由来する免疫グロブリン重鎖可変ドメインを含むキメラ免疫グロブリン重鎖;ならびに
(a)再構成されたヒトVκ1−39/J配列、
(b)再構成されたヒトVκ3−20/J配列、または
(c)その組み合わせ;
に由来する軽鎖を発現するマウスB細胞であって、
該重鎖可変ドメインが定常領域と融合されており、該軽鎖可変ドメインが定常領域と融合されており、該B細胞が異所性ADAM6核酸配列を含む、マウスB細胞。
(項目19) 前記重鎖可変ドメインと融合される前記定常ドメインがマウス定常領域を含む、項目18に記載のマウスB細胞。
(項目20) 前記軽鎖可変ドメインと融合される前記定常領域がマウス定常領域およびヒト定常領域から選択される、項目18に記載のマウスB細胞。
Claims (20)
- マウスであって、該マウスの生殖系列において:
(a)重鎖定常領域遺伝子に作動可能に連結される少なくとも1つの再構成されていないヒトV、少なくとも1つの再構成されていないヒトD、および少なくとも1つの再構成されていないヒトJセグメントを含むヒト化免疫グロブリン重鎖可変遺伝子座;
(b)軽鎖定常領域遺伝子に作動可能に連結される1つ以下または2つ以下の再構成されたヒト軽鎖V/J配列を含むヒト化免疫グロブリン軽鎖可変遺伝子座;および
(c)雄マウスにおいて機能する、マウスADAM6タンパク質をコードする異所性核酸配列またはそのオルソログもしくはホモログもしくは機能的断片
を含むマウス。 - 前記雄マウスにおいて機能する、マウスADAM6タンパク質をコードする核酸配列またはそのオルソログもしくはホモログもしくは機能的断片が前記免疫グロブリン重鎖可変遺伝子座以外の遺伝子座に存在する、請求項1に記載のマウス。
- 前記重鎖定常領域遺伝子がマウス遺伝子である、請求項1に記載のマウス。
- 前記軽鎖定常領域遺伝子がマウス遺伝子である、請求項1に記載のマウス。
- ヒト化重鎖免疫グロブリン可変遺伝子座およびヒト化軽鎖免疫グロブリン可変遺伝子座を含むマウスであって、該マウスが単一の軽鎖を発現し、該マウスが雄マウスにおいて機能するADAM6遺伝子をコードする異所性核酸配列を含む、マウス。
- 前記ヒト化重鎖免疫グロブリン遺伝子座が内因性マウス重鎖定常領域遺伝子に作動可能に連結されている、請求項5に記載のマウス。
- 前記単一の軽鎖が、軽鎖定常遺伝子に作動可能に連結される1つ以下の軽鎖V遺伝子セグメントおよび軽鎖J遺伝子セグメントをコードする免疫グロブリン軽鎖可変遺伝子遺伝子座からコードされる、請求項5に記載のマウス。
- 前記単一の軽鎖が、前記マウスの前記生殖系列における免疫グロブリン軽鎖可変遺伝子遺伝子座に由来し、該遺伝子座が軽鎖定常遺伝子に作動可能に連結される、該生殖系列中の1つ以下の再構成された軽鎖V/J遺伝子セグメントをコードする、請求項5に記載のマウス。
- 前記異所性核酸配列が雄マウスにおいて機能するマウスADAM6タンパク質をコードするか、マウスADAM6タンパク質の断片をコードする、請求項5に記載のマウス。
- 前記異所性核酸配列が内因性免疫グロブリン重鎖遺伝子座内ではない位置に存在する、請求項5に記載のマウス。
- 遺伝子改変マウスであって、複数の異なるIgG重鎖を発現し、該複数の異なるIgG重鎖の各々がヒト可変ドメインを含み、前記複数の異なるIgG重鎖の各々が単一のヒト免疫グロブリンV遺伝子セグメントに由来するヒト免疫グロブリン軽鎖可変ドメインをコードする軽鎖配列と会合しており、該マウスが雄マウスにおいて機能するADAM6タンパク質をコードする異所性核酸配列を含む、遺伝子改変マウス。
- 前記マウスが、雄マウスにおいて機能するADAM6タンパク質またはその断片を発現し、該ADAM6タンパク質またはその断片が前記異所性核酸配列から発現される、請求項11に記載のマウス。
- マウス細胞であって、以下:
重鎖定常遺伝子に作動可能に連結されるヒト化重鎖免疫グロブリン可変遺伝子遺伝子座;
軽鎖定常遺伝子に作動可能に連結される1つ以下または2つ以下の軽鎖V遺伝子セグメントを含むヒト化軽鎖免疫グロブリン遺伝子座;および
ADAM6タンパク質またはその断片をコードする異所性核酸配列であって、該ADAM6タンパク質またはその断片が雄マウスにおいて機能する、異所性核酸配列
を含む、マウス細胞。 - 前記異所性核酸配列がマウスADAM6タンパク質をコードする、請求項13に記載のマウス細胞。
- 前記重鎖定常遺伝子が非ヒト重鎖定常遺伝子である、請求項13に記載のマウス。
- 前記軽鎖定常遺伝子が非ヒト軽鎖定常遺伝子である、請求項13に記載のマウス。
- 前記1つ以下または2つ以下(no more that two)の軽鎖V遺伝子セグメントが再構成されたV/J遺伝子セグメントに存在する、請求項13に記載のマウス。
- ヒト重鎖V遺伝子セグメントに由来する免疫グロブリン重鎖可変ドメインを含むキメラ免疫グロブリン重鎖;ならびに
(a)再構成されたヒトVκ1−39/J配列、
(b)再構成されたヒトVκ3−20/J配列、または
(c)その組み合わせ;
に由来する軽鎖を発現するマウスB細胞であって、
該重鎖可変ドメインが定常領域と融合されており、該軽鎖可変ドメインが定常領域と融合されており、該B細胞が異所性ADAM6核酸配列を含む、マウスB細胞。 - 前記重鎖可変ドメインと融合される前記定常ドメインがマウス定常領域を含む、請求項18に記載のマウスB細胞。
- 前記軽鎖可変ドメインと融合される前記定常領域がマウス定常領域およびヒト定常領域から選択される、請求項18に記載のマウスB細胞。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161515374P | 2011-08-05 | 2011-08-05 | |
US61/515,374 | 2011-08-05 | ||
PCT/US2012/049600 WO2013022782A1 (en) | 2011-08-05 | 2012-08-03 | Humanized universal light chain mice |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016201462A Division JP2017006146A (ja) | 2011-08-05 | 2016-10-13 | ヒト化ユニバーサル軽鎖マウス |
JP2018244118A Division JP6724126B2 (ja) | 2011-08-05 | 2018-12-27 | ヒト化ユニバーサル軽鎖マウス |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2014524243A true JP2014524243A (ja) | 2014-09-22 |
JP2014524243A5 JP2014524243A5 (ja) | 2016-05-19 |
JP6510234B2 JP6510234B2 (ja) | 2019-05-08 |
Family
ID=46650953
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014524126A Active JP6510234B2 (ja) | 2011-08-05 | 2012-08-03 | ヒト化ユニバーサル軽鎖マウス |
JP2016201462A Pending JP2017006146A (ja) | 2011-08-05 | 2016-10-13 | ヒト化ユニバーサル軽鎖マウス |
JP2018244118A Active JP6724126B2 (ja) | 2011-08-05 | 2018-12-27 | ヒト化ユニバーサル軽鎖マウス |
JP2019236290A Active JP6886002B2 (ja) | 2011-08-05 | 2019-12-26 | ヒト化ユニバーサル軽鎖マウス |
JP2021081543A Active JP7174805B2 (ja) | 2011-08-05 | 2021-05-13 | ヒト化ユニバーサル軽鎖マウス |
JP2022178043A Pending JP2023011882A (ja) | 2011-08-05 | 2022-11-07 | ヒト化ユニバーサル軽鎖マウス |
Family Applications After (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016201462A Pending JP2017006146A (ja) | 2011-08-05 | 2016-10-13 | ヒト化ユニバーサル軽鎖マウス |
JP2018244118A Active JP6724126B2 (ja) | 2011-08-05 | 2018-12-27 | ヒト化ユニバーサル軽鎖マウス |
JP2019236290A Active JP6886002B2 (ja) | 2011-08-05 | 2019-12-26 | ヒト化ユニバーサル軽鎖マウス |
JP2021081543A Active JP7174805B2 (ja) | 2011-08-05 | 2021-05-13 | ヒト化ユニバーサル軽鎖マウス |
JP2022178043A Pending JP2023011882A (ja) | 2011-08-05 | 2022-11-07 | ヒト化ユニバーサル軽鎖マウス |
Country Status (25)
Country | Link |
---|---|
US (3) | US10130081B2 (ja) |
EP (3) | EP2739740B1 (ja) |
JP (6) | JP6510234B2 (ja) |
CN (2) | CN103917650B (ja) |
AU (4) | AU2012294624B2 (ja) |
BR (1) | BR112014002713B1 (ja) |
CA (1) | CA2844070A1 (ja) |
CY (2) | CY1122435T1 (ja) |
DK (2) | DK2739740T3 (ja) |
ES (2) | ES2872081T3 (ja) |
HR (2) | HRP20192255T1 (ja) |
HU (2) | HUE047278T2 (ja) |
IL (4) | IL273982B2 (ja) |
LT (2) | LT3572517T (ja) |
MX (2) | MX357623B (ja) |
MY (1) | MY172718A (ja) |
NZ (3) | NZ727084A (ja) |
PL (2) | PL2739740T3 (ja) |
PT (2) | PT2739740T (ja) |
RS (2) | RS61946B1 (ja) |
RU (1) | RU2664232C2 (ja) |
SG (3) | SG2014007686A (ja) |
SI (2) | SI3572517T1 (ja) |
WO (1) | WO2013022782A1 (ja) |
ZA (1) | ZA201401006B (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016513957A (ja) * | 2013-02-20 | 2016-05-19 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 修飾された免疫グロブリン重鎖配列を有する非ヒト動物 |
JP2018508224A (ja) * | 2015-03-19 | 2018-03-29 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 抗原を結合する軽鎖可変領域を選択する非ヒト動物 |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9445581B2 (en) | 2012-03-28 | 2016-09-20 | Kymab Limited | Animal models and therapeutic molecules |
DK2564695T3 (en) | 2009-07-08 | 2015-05-26 | Kymab Ltd | Animal models and therapeutic molecules |
US20120204278A1 (en) | 2009-07-08 | 2012-08-09 | Kymab Limited | Animal models and therapeutic molecules |
US9796788B2 (en) | 2010-02-08 | 2017-10-24 | Regeneron Pharmaceuticals, Inc. | Mice expressing a limited immunoglobulin light chain repertoire |
WO2011097603A1 (en) | 2010-02-08 | 2011-08-11 | Regeneron Pharmaceuticals, Inc. | Common light chain mouse |
US20130045492A1 (en) | 2010-02-08 | 2013-02-21 | Regeneron Pharmaceuticals, Inc. | Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain |
US10662256B2 (en) | 2010-07-26 | 2020-05-26 | Trianni, Inc. | Transgenic mammals and methods of use thereof |
EP2597945B1 (en) | 2010-07-26 | 2020-07-22 | Trianni, Inc. | Transgenic animals and methods of use |
US10793829B2 (en) | 2010-07-26 | 2020-10-06 | Trianni, Inc. | Transgenic mammals and methods of use thereof |
SG10201912639SA (en) | 2010-08-02 | 2020-02-27 | Regeneron Pharma | Mice that make binding proteins comprising vl domains |
ME02106B (me) | 2011-02-25 | 2015-10-20 | Regeneron Pharma | Miševi sa adam6 |
IL273982B2 (en) | 2011-08-05 | 2023-03-01 | Regeneron Pharma | Humanized mice possess a universal light chain |
CN107056936B (zh) | 2011-09-19 | 2021-09-03 | 科马布有限公司 | 免疫球蛋白基因多样性的操纵及多抗体治疗剂 |
WO2013045916A1 (en) | 2011-09-26 | 2013-04-04 | Kymab Limited | Chimaeric surrogate light chains (slc) comprising human vpreb |
PT3216871T (pt) * | 2011-10-17 | 2022-03-15 | Regeneron Pharma | Ratos com cadeia pesada de imunoglobulina restrita |
US20180295821A1 (en) * | 2011-12-02 | 2018-10-18 | Kymab Limited | Transgenic Animals |
US9253965B2 (en) | 2012-03-28 | 2016-02-09 | Kymab Limited | Animal models and therapeutic molecules |
GB201122047D0 (en) * | 2011-12-21 | 2012-02-01 | Kymab Ltd | Transgenic animals |
SG10201913164YA (en) | 2011-12-20 | 2020-03-30 | Regeneron Pharma | Humanized light chain mice |
NZ627977A (en) * | 2012-02-01 | 2016-06-24 | Regeneron Pharma | Humanized rodents that express heavy chains containing vl domains |
LT2825037T (lt) | 2012-03-16 | 2019-08-12 | Regeneron Pharmaceuticals, Inc. | Graužikai, ekspresuojantys ph jautrias imunoglobulino sekas |
RU2014141536A (ru) | 2012-03-16 | 2016-05-10 | Регенерон Фармасьютикалз, Инк. | Мыши, которые продуцируют антигенсвязывающие белки с зависимыми от величины ph характеристиками связывания |
RS57118B1 (sr) | 2012-03-16 | 2018-06-29 | Regeneron Pharma | Antitela sa lakim lancem konstruisanim sa histidinom i genetički modifikovani glodari za generisanje istih |
US20140013456A1 (en) | 2012-03-16 | 2014-01-09 | Regeneron Pharmaceuticals, Inc. | Histidine Engineered Light Chain Antibodies and Genetically Modified Non-Human Animals for Generating the Same |
GB2502127A (en) | 2012-05-17 | 2013-11-20 | Kymab Ltd | Multivalent antibodies and in vivo methods for their production |
US10251377B2 (en) | 2012-03-28 | 2019-04-09 | Kymab Limited | Transgenic non-human vertebrate for the expression of class-switched, fully human, antibodies |
RU2014153674A (ru) * | 2012-06-05 | 2016-07-27 | Регенерон Фармасьютикалз, Инк. | Способ получения полностью человеческих биспецифических антител с применением общей легкой цепи |
CA2876172C (en) | 2012-06-12 | 2021-01-19 | Regeneron Pharmaceuticals, Inc. | Humanized non-human animals with restricted immunoglobulin heavy chain loci |
EP4218409A3 (en) * | 2013-03-13 | 2023-08-30 | Regeneron Pharmaceuticals, Inc. | Mice expressing a limited immunoglobulin light chain repertoire |
US9788534B2 (en) | 2013-03-18 | 2017-10-17 | Kymab Limited | Animal models and therapeutic molecules |
US20150033372A1 (en) * | 2013-05-01 | 2015-01-29 | Kymab Limited | Human VpreB & Chimaeric Surrogate Light Chains in Transgenic Non-Human Vertebrates |
US9783618B2 (en) | 2013-05-01 | 2017-10-10 | Kymab Limited | Manipulation of immunoglobulin gene diversity and multi-antibody therapeutics |
US11707056B2 (en) | 2013-05-02 | 2023-07-25 | Kymab Limited | Animals, repertoires and methods |
US9783593B2 (en) | 2013-05-02 | 2017-10-10 | Kymab Limited | Antibodies, variable domains and chains tailored for human use |
EP3051942B1 (en) | 2013-10-01 | 2020-09-02 | Kymab Limited | Animal models and therapeutic molecules |
US10034463B2 (en) | 2014-01-24 | 2018-07-31 | Children's Medical Center Corporation | High-throughput mouse model for optimizing antibody affinities |
RU2016141307A (ru) * | 2014-03-21 | 2018-04-24 | Регенерон Фармасьютикалз, Инк. | Отличные от человека животные, которые вырабатывают однодоменные связывающие белки |
JP2017510273A (ja) | 2014-03-21 | 2017-04-13 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 異なる結合特性を示すvl抗原結合タンパク質 |
IL257411B1 (en) * | 2015-08-24 | 2024-01-01 | Trianni Inc | Improved production of immunoglobulins |
TWI756187B (zh) | 2015-10-09 | 2022-03-01 | 美商再生元醫藥公司 | 抗lag3抗體及其用途 |
CN105274116B (zh) * | 2015-10-21 | 2020-09-29 | 重庆金迈博生物科技有限公司 | 一种制备人源化抗体的核酸分子及其应用 |
WO2017095939A1 (en) | 2015-12-03 | 2017-06-08 | Trianni, Inc. | Enhanced immunoglobulin diversity |
IL260743B2 (en) | 2016-02-04 | 2024-03-01 | Trianni Inc | Advanced production of antibodies |
BR112018071285A2 (pt) | 2016-04-20 | 2019-02-12 | Regeneron Pharma | célula, conjunto de vetores, vetor, sistema, e, método |
EP3457840B1 (en) | 2016-05-20 | 2024-04-10 | Regeneron Pharmaceuticals, Inc. | Methods for breaking immunological tolerance using multiple guide rnas |
DK3462853T3 (da) | 2016-06-03 | 2023-04-03 | Regeneron Pharma | Gnavere, der udtrykker exogen, terminal deoxynukleotidyltransferase |
CN110650974B (zh) | 2017-02-10 | 2024-04-19 | 瑞泽恩制药公司 | 用于免疫-pet成像的放射性标记的抗-lag3抗体 |
AU2019242551A1 (en) | 2018-03-24 | 2020-10-22 | Regeneron Pharmaceuticals, Inc. | Genetically modified non-human animals for generating therapeutic antibodies against peptide-MHC complexes, methods of making and uses thereof |
KR20210133234A (ko) | 2019-02-18 | 2021-11-05 | 바이오사이토젠 파마슈티컬스 (베이징) 컴퍼니 리미티드 | 인간화 면역글로불린 유전자좌를 갖는 유전적으로 변형된 비-인간 동물 |
JP2022535418A (ja) | 2019-06-05 | 2022-08-08 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | カッパ遺伝子座から発現される限られたラムダ軽鎖レパートリーを有する非ヒト動物及びその使用 |
JP2023504172A (ja) | 2019-12-02 | 2023-02-01 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | ペプチド-mhc iiタンパク質構築物およびそれらの使用 |
KR20210095781A (ko) | 2020-01-24 | 2021-08-03 | 주식회사 에이프릴바이오 | 항원결합 단편 및 생리활성 이펙터 모이어티로 구성된 융합 컨스트럭트를 포함하는 다중결합항체 및 이를 포함하는 약학조성물 |
US10994021B1 (en) * | 2020-04-11 | 2021-05-04 | Bliss Biopharmaceutical (Hangzhou) Co., Ltd. | Tetravalent antibody-drug conjugates and use thereof |
JP2023541216A (ja) * | 2020-06-25 | 2023-09-29 | ヒューマブ カンパニー リミテッド | ヘテロ接合型トランスジェニック動物 |
CA3187680A1 (en) | 2020-09-11 | 2022-03-17 | Yashu Liu | Identification and production of antigen-specific antibodies |
CN116848254A (zh) | 2020-12-16 | 2023-10-03 | 瑞泽恩制药公司 | 表达人源化Fcα受体的小鼠 |
AU2022261074A1 (en) | 2021-04-20 | 2023-09-28 | Regeneron Pharmaceuticals, Inc. | Human antibodies to artemin and methods of use thereof |
WO2024015816A1 (en) | 2022-07-12 | 2024-01-18 | Regeneron Pharmaceuticals, Inc. | Antibodies to ciliary neurotrophic factor receptor (cntfr) and methods of use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060015957A1 (en) * | 1991-08-28 | 2006-01-19 | Genpharm International, Inc. | Transgenic non-human animals for producing chimeric antibodies |
WO2009157771A2 (en) * | 2008-06-27 | 2009-12-30 | Merus B.V. | Antibody producing non-human mammals |
Family Cites Families (188)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8626412D0 (en) | 1986-11-05 | 1986-12-03 | Clark M R | Antibodies |
GB8626413D0 (en) | 1986-11-05 | 1986-12-03 | Gilliland L K | Antibodies |
ATE190355T1 (de) | 1988-09-06 | 2000-03-15 | Xoma Corp | Genexpressions-elemente und herstellung von chimären maus-mensch-antikörpern |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
WO1991000906A1 (en) | 1989-07-12 | 1991-01-24 | Genetics Institute, Inc. | Chimeric and transgenic animals capable of producing human antibodies |
US5574205A (en) | 1989-07-25 | 1996-11-12 | Cell Genesys | Homologous recombination for universal donor cells and chimeric mammalian hosts |
US5959177A (en) | 1989-10-27 | 1999-09-28 | The Scripps Research Institute | Transgenic plants expressing assembled secretory antibodies |
DE69027683T2 (de) | 1989-12-01 | 1997-02-13 | Pharming Bv | Herstellung rekombinanter polypeptide durch rinder und transgene methoden |
US6673986B1 (en) | 1990-01-12 | 2004-01-06 | Abgenix, Inc. | Generation of xenogeneic antibodies |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6657103B1 (en) | 1990-01-12 | 2003-12-02 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6713610B1 (en) | 1990-01-12 | 2004-03-30 | Raju Kucherlapati | Human antibodies derived from immunized xenomice |
JP3068180B2 (ja) | 1990-01-12 | 2000-07-24 | アブジェニックス インコーポレイテッド | 異種抗体の生成 |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
ATE158021T1 (de) | 1990-08-29 | 1997-09-15 | Genpharm Int | Produktion und nützung nicht-menschliche transgentiere zur produktion heterologe antikörper |
US6255458B1 (en) | 1990-08-29 | 2001-07-03 | Genpharm International | High affinity human antibodies and human antibodies against digoxin |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US7084260B1 (en) | 1996-10-10 | 2006-08-01 | Genpharm International, Inc. | High affinity human antibodies and human antibodies against human antigens |
US7067284B1 (en) | 1992-01-27 | 2006-06-27 | The Scripps Research Institute | Methods for producing antibody libraries using universal or randomized immunoglobulin light chains |
US5667988A (en) | 1992-01-27 | 1997-09-16 | The Scripps Research Institute | Methods for producing antibody libraries using universal or randomized immunoglobulin light chains |
ES2301158T3 (es) | 1992-07-24 | 2008-06-16 | Amgen Fremont Inc. | Produccion de anticuerpos xenogenicos. |
CA2140280A1 (en) | 1992-08-17 | 1994-03-03 | Avi J. Ashkenazi | Bispecific immunoadhesins |
WO1994012215A1 (en) | 1992-12-01 | 1994-06-09 | Protein Design Labs, Inc. | Humanized antibodies reactive with l-selectin |
GB9308271D0 (en) | 1993-04-21 | 1993-06-02 | Univ Edinburgh | Method of isolating and/or enriching and/or selectively propagating pluripotential animal cells and animals for use in said method |
US5877396A (en) | 1993-04-23 | 1999-03-02 | Sloan Kettering Institute For Cancer Research | Mice mutant for functional Fc receptors and method of treating autoimmune diseases |
AU6819494A (en) | 1993-04-26 | 1994-11-21 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5693506A (en) | 1993-11-16 | 1997-12-02 | The Regents Of The University Of California | Process for protein production in plants |
US5827690A (en) | 1993-12-20 | 1998-10-27 | Genzyme Transgenics Corporatiion | Transgenic production of antibodies in milk |
ATE213771T1 (de) | 1993-12-23 | 2002-03-15 | Infigen Inc | Embryonale stammzellen von huftieren als kerndonatoren und kerntransfertechniken zur herstellung chimärer und transgener tiere |
GB9401380D0 (en) | 1994-01-25 | 1994-03-23 | Pharmaceutical Proteins Ltd | Embryonic cell isolation |
ATE300610T1 (de) | 1994-01-31 | 2005-08-15 | Univ Boston | Bibliotheken aus polyklonalen antikörpern |
US7119248B1 (en) | 1994-04-12 | 2006-10-10 | Miltenyi Biotec Gmbh | Antibodies against epitopes with homology to self antigens, methods of preparation and applications thereof |
US6080560A (en) | 1994-07-25 | 2000-06-27 | Monsanto Company | Method for producing antibodies in plant cells |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
CA2246333A1 (en) | 1996-03-05 | 1997-09-12 | The Scripps Research Institute | Recombinant constructs encoding t cell receptors specific for human hla-restricted tumor antigens |
ATE218143T1 (de) | 1996-09-03 | 2002-06-15 | Gsf Forschungszentrum Umwelt | Verwendung bi-und trispezifischer antikörper zur induktion einer tumorimmunität |
KR20080059467A (ko) | 1996-12-03 | 2008-06-27 | 아브게닉스, 인크. | 복수의 vh 및 vk 부위를 함유하는 사람 면역글로불린유전자좌를 갖는 형질전환된 포유류 및 이로부터 생성된항체 |
WO1998039416A1 (en) | 1997-03-06 | 1998-09-11 | Infigen, Inc. | Method of cloning animals |
CN1203922A (zh) | 1997-03-21 | 1999-01-06 | 三共株式会社 | 人源化抗人fas抗体 |
US7227002B1 (en) | 1997-04-14 | 2007-06-05 | Micromet Ag | Human antibodies that bind human 17-A1/EpCAM tumor antigen |
US20020062010A1 (en) * | 1997-05-02 | 2002-05-23 | Genentech, Inc. | Method for making multispecific antibodies having heteromultimeric and common components |
JP4213224B2 (ja) | 1997-05-02 | 2009-01-21 | ジェネンテック,インコーポレーテッド | ヘテロマルチマー及び共通成分を有する多重特異性抗体の製造方法 |
US6774279B2 (en) | 1997-05-30 | 2004-08-10 | Carnegie Institution Of Washington | Use of FLP recombinase in mice |
RU2221809C2 (ru) | 1997-10-03 | 2004-01-20 | Тугаи Сейяку Кабусики Кайся | Способ получения природного гуманизированного антитела |
PT1034262E (pt) | 1997-11-18 | 2005-10-31 | Pioneer Hi Bred Int | Composicoes e metodos para a modificacao genetica de plantas |
GB9823930D0 (en) | 1998-11-03 | 1998-12-30 | Babraham Inst | Murine expression of human ig\ locus |
US6914128B1 (en) | 1999-03-25 | 2005-07-05 | Abbott Gmbh & Co. Kg | Human antibodies that bind human IL-12 and methods for producing |
RU10506U1 (ru) | 1999-04-08 | 1999-08-16 | Кривулин Виталий Николаевич | Ручной культиватор |
SI1161548T2 (sl) | 1999-04-15 | 2010-02-26 | Crucell Holland Bv | Priprava rekombinantnega proteina v humani celici z uporabo sekvenc, ki kodirajo adenovirusni E1 protein |
WO2000073323A2 (en) | 1999-05-27 | 2000-12-07 | Human Genome Sciences, Inc. | Adam polynucleotides and polypeptides |
GB0001448D0 (en) | 2000-01-21 | 2000-03-08 | Novartis Ag | Organic compounds |
AU2001245358A1 (en) | 2000-02-29 | 2001-09-12 | Auburn University | Production of antibodies in transgenic plastids |
RU2262511C2 (ru) | 2000-05-18 | 2005-10-20 | Джапан Тобакко, Инк. | Человеческое моноклональное антитело против ailim, костимулирующей молекулы передачи сигнала, и его фармацевтическое применение |
JP2004511430A (ja) | 2000-05-24 | 2004-04-15 | イムクローン システムズ インコーポレイティド | 二重特異性免疫グロブリン様抗原結合蛋白および製造方法 |
EP1309709A2 (en) | 2000-07-21 | 2003-05-14 | The United States of America, represented by The Secretary of Agriculture | Methods for the replacement, translocation and stacking of dna in eukaryotic genomes |
AU2001284703B2 (en) | 2000-08-03 | 2007-03-22 | Therapeutic Human Polyclonals Inc. | Production of humanized antibodies in transgenic animals |
EP1184458A1 (en) | 2000-08-28 | 2002-03-06 | U-BISys B.V. | Differentially expressed CD46 epitopes, proteinaceous molecules capable of binding thereto, and uses thereof |
US20020119148A1 (en) | 2000-09-01 | 2002-08-29 | Gerritsen Mary E. | ErbB4 antagonists |
US6596541B2 (en) * | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US7105348B2 (en) | 2000-10-31 | 2006-09-12 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US6586251B2 (en) | 2000-10-31 | 2003-07-01 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
WO2002040685A2 (en) | 2000-11-16 | 2002-05-23 | Cornell Research Foundation, Inc. | Vectors for conditional gene inactivation |
TWI255272B (en) | 2000-12-06 | 2006-05-21 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
DE10064750A1 (de) | 2000-12-22 | 2002-06-27 | Bayer Ag | Verfahren zur Herstellung von 1,6-Hexandiolen |
ME00502B (me) | 2001-01-05 | 2011-10-10 | Amgen Fremont Inc | Antitjela za insulinu sličan receptor faktora i rasta |
US6961875B2 (en) | 2001-03-22 | 2005-11-01 | International Business Machines Corporation | Method and apparatus for capturing event traces for debug and analysis |
GB0110029D0 (en) | 2001-04-24 | 2001-06-13 | Grosveld Frank | Transgenic animal |
US7034134B2 (en) | 2001-04-26 | 2006-04-25 | Bristol-Myers Squibb Company | Polynucleotide encoding a novel metalloprotease highly expressed in the testis, MMP-29 |
US7074611B2 (en) | 2001-04-27 | 2006-07-11 | Gie-Cerbn, Centre Europeen De Recherche En Biologie Et En Medecine (Gie) | Method for the stable inversion of DNA sequence by site-specific recombination and DNA vectors and transgenic cells thereof |
AU2002309063B8 (en) | 2001-05-11 | 2008-04-24 | Kyowa Kirin Co., Ltd. | Artificial human chromosome containing human antibody lambda light chain gene |
ATE477280T1 (de) | 2001-06-28 | 2010-08-15 | Domantis Ltd | Doppelspezifischer ligand und dessen verwendung |
CN1671416B (zh) | 2001-07-12 | 2013-01-02 | 杰斐逊·富特 | 超人源化抗体 |
US20030138440A1 (en) | 2001-07-19 | 2003-07-24 | Fang Fang | Multimeric proteins and methods of making and using same |
EP1652920B1 (de) | 2001-10-01 | 2010-08-04 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Verfahren zur Herstellung von Protein-Bibliotheken und zur Selektion von Proteinen daraus |
US20030108925A1 (en) | 2001-10-05 | 2003-06-12 | U.S. Epa | Genetic testing for male factor infertility |
US20060199204A1 (en) | 2001-10-05 | 2006-09-07 | U.S. Epa | Genetic testing for male factor infertility |
CA2847885C (en) | 2001-11-30 | 2022-03-22 | Amgen Fremont Inc. | Transgenic animals bearing human ig.lambda. light chain genes |
GB0130267D0 (en) | 2001-12-19 | 2002-02-06 | Neutec Pharma Plc | Focussed antibody technology |
US20050095712A1 (en) | 2002-01-17 | 2005-05-05 | Alberto Martin | Mutations caused by activation-induced cytidine deaminase |
US20040052773A1 (en) | 2002-01-18 | 2004-03-18 | Inovio As | Production of multi-chain protein from muscle |
JP4518941B2 (ja) | 2002-04-26 | 2010-08-04 | 中外製薬株式会社 | アゴニスト抗体のスクリーニング方法 |
AU2003243190A1 (en) | 2002-05-03 | 2003-11-17 | Regeneron Pharmaceuticals, Inc. | Methods of inducing formation of functional and organized lymphatic vessels |
EP2301968A3 (en) | 2002-06-14 | 2011-06-29 | Immunomedics, Inc. | Humanized monoclonal antibody HPAM4 |
CN101962408A (zh) | 2002-07-12 | 2011-02-02 | 杰斐逊·富特 | 超人源化抗体 |
SI1523496T1 (sl) * | 2002-07-18 | 2011-11-30 | Merus B V | Rekombinantno proizvajanje zmesi protiteles |
AR042145A1 (es) | 2002-11-27 | 2005-06-08 | Dow Agrociences Llc | Produccion de inmunoglobulinas en plantas con una fucocilacion reducida |
GB0228210D0 (en) | 2002-12-03 | 2003-01-08 | Babraham Inst | Single chain antibodies |
GB0230201D0 (en) | 2002-12-27 | 2003-02-05 | Domantis Ltd | Retargeting |
GB0230203D0 (en) | 2002-12-27 | 2003-02-05 | Domantis Ltd | Fc fusion |
EP1439234A1 (en) | 2003-01-08 | 2004-07-21 | ARTEMIS Pharmaceuticals GmbH | Targeted transgenesis using the rosa26 locus |
WO2004065611A1 (ja) | 2003-01-21 | 2004-08-05 | Chugai Seiyaku Kabushiki Kaisha | 抗体の軽鎖スクリーニング方法 |
EP2559759A1 (en) | 2003-01-28 | 2013-02-20 | Cellectis | Custom-made meganuclease and use thereof |
JP2006520610A (ja) | 2003-03-04 | 2006-09-14 | アレクシオン ファーマシューティカルズ, インコーポレイテッド | ハイブリッド不変領域を産生するのに用いるベクター |
WO2004106375A1 (en) | 2003-05-30 | 2004-12-09 | Merus Biopharmaceuticals B.V. I.O. | Fab library for the preparation of anti vegf and anti rabies virus fabs |
US20100069614A1 (en) * | 2008-06-27 | 2010-03-18 | Merus B.V. | Antibody producing non-human mammals |
US7205148B2 (en) | 2003-06-11 | 2007-04-17 | Regeneron Pharmaceuticals, Inc. | Genome mutation by intron insertion into an embryonic stem cell genome |
ES2473596T3 (es) | 2003-07-15 | 2014-07-07 | Therapeutic Human Polyclonals, Inc. | Loci de inmunoglobulina humanizada |
US20050153392A1 (en) | 2003-08-11 | 2005-07-14 | Roland Buelow | Transgenesis with humanized immunoglobulin loci |
RU2251699C1 (ru) | 2003-09-25 | 2005-05-10 | Киселев Всеволод Иванович | Способ ранней и доклинической диагностики цервикального рака |
WO2005038001A2 (en) | 2003-10-14 | 2005-04-28 | Therapeutic Human Polyclonals, Inc. | Improved transgenesis by sperm-mediated gene transfer |
AU2005206536B2 (en) | 2004-01-16 | 2010-09-02 | Regeneron Pharmaceuticals, Inc. | Fusion polypeptides capable of activating receptors |
JP4890269B2 (ja) | 2004-02-12 | 2012-03-07 | ウォルター アンド エリザ ホール インスティテュート オブ メディカル リサーチ | Blimp1およびレポーター分子を共発現する改変細胞およびその使用方法 |
CN1560081A (zh) | 2004-02-17 | 2005-01-05 | 大连帝恩生物工程有限公司 | 用能产生人IgGl重链-κ轻链小鼠作为制备人源化单克隆抗体和应用 |
US7625549B2 (en) | 2004-03-19 | 2009-12-01 | Amgen Fremont Inc. | Determining the risk of human anti-human antibodies in transgenic mice |
AU2005295269B2 (en) | 2004-10-19 | 2010-05-13 | Regeneron Pharmaceuticals, Inc. | Method for generating an animal homozygous for a genetic modification |
US20060117398A1 (en) | 2004-10-22 | 2006-06-01 | Roland Buelow | Suppression of endogenous immunoglobulin expression |
JP2008520552A (ja) * | 2004-10-22 | 2008-06-19 | メディミューン,インコーポレーテッド | Hmgb1に対する高親和性の抗体およびその使用法 |
EP1815001B8 (en) | 2004-11-26 | 2011-03-23 | Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | Gene trap cassettes for random and targeted conditional gene inactivation |
EP1662005A1 (en) | 2004-11-26 | 2006-05-31 | FrankGen Biotechnologie AG | Enhancer-containing gene trap vectors for random and targeted gene trapping |
US20110041370A1 (en) | 2005-04-21 | 2011-02-24 | Saint Andre M | Face sheet, identification band, and related methods |
US20080196112A1 (en) | 2005-04-29 | 2008-08-14 | Innate Pharma, S.A. | Transgenic Animals and Methods of Making Recombinant Antibodies |
MX2007014139A (es) | 2005-05-14 | 2008-10-09 | Univ Fudan | Piggybac como una herramienta para manipulacion genetica y analisis en vertebrados. |
CA2609142C (en) | 2005-05-27 | 2016-02-09 | Fondazione Centro San Raffaele Del Monte Tabor | Therapeutic gene vectors comprising mirna target sequences |
DE602005011421D1 (de) | 2005-06-30 | 2009-01-15 | Borealis Tech Oy | Überzug-Schicht für Energie- oder Kommunikationskabel |
FR2888850B1 (fr) | 2005-07-22 | 2013-01-11 | Pf Medicament | Nouveaux anticorps anti-igf-ir et leurs applications |
EP1966241A2 (en) | 2005-12-05 | 2008-09-10 | Symphogen A/S | Anti-orthopoxvirus recombinant polyclonal antibody |
AU2007219159B8 (en) | 2006-01-25 | 2012-06-28 | Roger Kingdon Craig | Generation of heavy-chain only antibodies in transgenic animals |
GB2434578A (en) | 2006-01-26 | 2007-08-01 | Univ Basel | Transgenic animals |
US7462759B2 (en) | 2006-02-03 | 2008-12-09 | Pioneer Hi-Bred International, Inc. | Brittle stalk 2 gene family and related methods and uses |
GB0615327D0 (en) | 2006-03-30 | 2006-09-13 | Univ Edinburgh | Culture medium containing kinase inhibitors and uses thereof |
EP2003960B1 (en) | 2006-03-31 | 2015-06-10 | E. R. Squibb & Sons, L.L.C. | Transgenic animals expressing chimeric antibodies for use in preparing human antibodies |
ATE537190T1 (de) | 2006-06-02 | 2011-12-15 | Regeneron Pharma | Hochaffine antikörper gegen den humanen il-6- rezeptor |
US20090217397A1 (en) | 2006-06-12 | 2009-08-27 | Patrick Stern | Cre-lox based gene knockdown constructs and methods of use thereof |
EP2061812A4 (en) | 2006-08-22 | 2010-06-09 | G2 Inflammation Pty Ltd | METHOD FOR THE PRODUCTION OF ANTIBODIES |
ES2378407T3 (es) | 2006-09-01 | 2012-04-12 | Therapeutic Human Polyclonals, Inc. | Aumento de la expresión de inmunoglobulina humana o humanizada en animales transgénicos no humanos |
RU2445318C2 (ru) | 2006-10-02 | 2012-03-20 | Ридженерон Фармасьютикалз, Инк. | Высокоаффинные антитела человека к рецептору il-4 человека |
US7608693B2 (en) | 2006-10-02 | 2009-10-27 | Regeneron Pharmaceuticals, Inc. | High affinity human antibodies to human IL-4 receptor |
NO347649B1 (no) | 2006-12-14 | 2024-02-12 | Regeneron Pharma | Humant antistoff eller antistoff fragment som spesifikt binder human deltaliknende ligand 4 (hDII4), nukleinsyremolekyl som koder for slike og vektor og vert-vektorsystemer, samt fremgangsmåte for fremstilling, sammensetning og anvendelse. |
GB0700194D0 (en) | 2007-01-05 | 2007-02-14 | Univ Edinburgh | Humanisation of animals |
EP2583551A1 (en) | 2007-03-13 | 2013-04-24 | National Jewish Health | Methods for generation of antibodies |
WO2008112226A2 (en) | 2007-03-13 | 2008-09-18 | Massachusetts Institute Of Technology | Cre-lox based gene knockdown constructs and methods of use thereof |
GB0706628D0 (en) | 2007-04-04 | 2007-05-16 | Univ Erasmus | Germ-line manipulation 1 |
DK2336329T3 (da) | 2007-06-01 | 2013-01-07 | Omt Inc | Sammensætninger og fremgangsmåder til hæmning af endogene immunglobulingener og til produktion af transgene, humane, idiotypiske antistoffer |
WO2009013620A2 (en) | 2007-06-11 | 2009-01-29 | Erasmus University Medical Center Rotterdam | Homologous recombination |
ITMI20071522A1 (it) | 2007-07-27 | 2009-01-28 | Areta Internat S R L | Vaccino idiotipico |
US9693539B2 (en) | 2007-08-10 | 2017-07-04 | E. R. Squibb & Sons, L.L.C. | HCO32 and HCO27 and related examples |
EP2185701A4 (en) | 2007-08-15 | 2011-03-02 | Amunix Operating Inc | COMPOSITIONS AND METHODS FOR ENHANCING THE PRODUCTION OF RECOMBINANT POLYPEPTIDES |
WO2009026660A1 (en) | 2007-08-30 | 2009-03-05 | Walter And Eliza Hall Institute Of Medical Research | Dendritic cell marker and uses thereof |
MX344415B (es) | 2007-09-14 | 2016-12-15 | Adimab Inc | Bancos de anticuerpos sinteticos, designados racionalmente y usos para los mismos. |
EP2050764A1 (en) | 2007-10-15 | 2009-04-22 | sanofi-aventis | Novel polyvalent bispecific antibody format and uses thereof |
WO2009051974A1 (en) | 2007-10-17 | 2009-04-23 | Nuvelo, Inc. | Antibodes to cll-1 |
US7659842B2 (en) | 2007-10-24 | 2010-02-09 | Infineon Technologies Ag | Quantization error reduction in PWM full-MASH converters |
CN110698561A (zh) | 2007-12-14 | 2020-01-17 | 诺沃—诺迪斯克有限公司 | 抗人nkg2d抗体及其用途 |
ES2774337T3 (es) | 2008-01-07 | 2020-07-20 | Amgen Inc | Método para fabricación de moléculas heterodímeras Fc de anticuerpos utilizando efectos de conducción electrostática |
ES2665068T3 (es) | 2008-03-07 | 2018-04-24 | Regeneron Pharmaceuticals, Inc. | Ratones derivados de células ES a partir de inyección de un embrión hospedador diploide |
CA2721231C (en) | 2008-04-14 | 2015-10-06 | Innovative Targeting Solutions Inc. | Sequence diversity generation in immunoglobulins |
US20110123527A1 (en) | 2008-05-23 | 2011-05-26 | Hiroaki Shizuya | Method of generating single vl domain antibodies in transgenic animals |
KR101826224B1 (ko) | 2008-09-30 | 2018-02-06 | 아블렉시스, 엘엘씨 | 키메라 항체의 제조를 위한 인간 이외의 포유동물 |
US9403904B2 (en) | 2008-11-07 | 2016-08-02 | Fabrus, Inc. | Anti-DLL4 antibodies and uses thereof |
US8497325B2 (en) | 2008-12-15 | 2013-07-30 | Exxonmobil Chemical Patents Inc. | Thermoplastic polyolefin blends and films therefrom |
CA2747534C (en) | 2008-12-18 | 2020-08-18 | Erasmus University Medical Center Rotterdam | Non-human transgenic animals expressing humanised antibodies and use therof |
US20110305692A1 (en) | 2009-02-24 | 2011-12-15 | Glaxo Group Limited | Antigen-binding contructs |
GB0905023D0 (en) | 2009-03-24 | 2009-05-06 | Univ Erasmus Medical Ct | Binding molecules |
RU2011149353A (ru) | 2009-05-07 | 2013-06-20 | Вольво Констракшн Эквипмент Аб | Рабочая машина и способ управления ее работой |
MX2011012696A (es) | 2009-05-29 | 2012-03-29 | Morphosys Ag | Una coleccion y metodos para su uso. |
CN102471378B (zh) | 2009-06-26 | 2014-04-02 | 瑞泽恩制药公司 | 容易地分离的具有天然免疫球蛋白形式的双特异性抗体 |
DK2564695T3 (en) | 2009-07-08 | 2015-05-26 | Kymab Ltd | Animal models and therapeutic molecules |
US20120204278A1 (en) | 2009-07-08 | 2012-08-09 | Kymab Limited | Animal models and therapeutic molecules |
RU2425880C2 (ru) * | 2009-07-30 | 2011-08-10 | Учреждение Российской академии наук Институт общей генетики им. Н.И. Вавилова РАН | Способ получения трансгенных мышей |
CA2781159A1 (en) | 2009-11-17 | 2011-05-26 | Kyowa Hakko Kirin Co., Ltd. | Human artificial chromosome vector |
MY172472A (en) | 2009-12-10 | 2019-11-26 | Regeneron Pharma | Mice that make heavy chain antibodies |
US20120021409A1 (en) | 2010-02-08 | 2012-01-26 | Regeneron Pharmaceuticals, Inc. | Common Light Chain Mouse |
US20130045492A1 (en) | 2010-02-08 | 2013-02-21 | Regeneron Pharmaceuticals, Inc. | Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain |
US20130185821A1 (en) | 2010-02-08 | 2013-07-18 | Regeneron Pharmaceuticals, Inc. | Common Light Chain Mouse |
WO2011097603A1 (en) * | 2010-02-08 | 2011-08-11 | Regeneron Pharmaceuticals, Inc. | Common light chain mouse |
US9796788B2 (en) | 2010-02-08 | 2017-10-24 | Regeneron Pharmaceuticals, Inc. | Mice expressing a limited immunoglobulin light chain repertoire |
WO2011143545A1 (en) | 2010-05-14 | 2011-11-17 | Rinat Neuroscience Corporation | Heterodimeric proteins and methods for producing and purifying them |
AU2011266843C9 (en) | 2010-06-17 | 2018-03-01 | Kymab Limited | Animal models and therapeutic molecules |
CN104404050B (zh) | 2010-06-22 | 2018-06-08 | 瑞泽恩制药公司 | 杂交轻链小鼠 |
SG10201912639SA (en) | 2010-08-02 | 2020-02-27 | Regeneron Pharma | Mice that make binding proteins comprising vl domains |
EP2638155A1 (en) | 2010-11-08 | 2013-09-18 | Kymab Limited | Cells & vertebrates for enhanced somatic hypermutation and class switch recombination |
ME02106B (me) | 2011-02-25 | 2015-10-20 | Regeneron Pharma | Miševi sa adam6 |
IL273982B2 (en) | 2011-08-05 | 2023-03-01 | Regeneron Pharma | Humanized mice possess a universal light chain |
US20130044257A1 (en) | 2011-08-18 | 2013-02-21 | Lattice Energy Technology Corporation | Mobile device with side-mounted camera module |
CN107056936B (zh) | 2011-09-19 | 2021-09-03 | 科马布有限公司 | 免疫球蛋白基因多样性的操纵及多抗体治疗剂 |
WO2013041845A2 (en) | 2011-09-19 | 2013-03-28 | Kymab Limited | Animals, repertoires & methods |
WO2013045916A1 (en) | 2011-09-26 | 2013-04-04 | Kymab Limited | Chimaeric surrogate light chains (slc) comprising human vpreb |
CA2791109C (en) | 2011-09-26 | 2021-02-16 | Merus B.V. | Generation of binding molecules |
PT3216871T (pt) | 2011-10-17 | 2022-03-15 | Regeneron Pharma | Ratos com cadeia pesada de imunoglobulina restrita |
GB2496375A (en) | 2011-10-28 | 2013-05-15 | Kymab Ltd | A non-human assay vertebrate comprising human antibody loci and human epitope knock-in, and uses thereof |
US9253965B2 (en) | 2012-03-28 | 2016-02-09 | Kymab Limited | Animal models and therapeutic molecules |
GB201122047D0 (en) | 2011-12-21 | 2012-02-01 | Kymab Ltd | Transgenic animals |
SG10201913164YA (en) | 2011-12-20 | 2020-03-30 | Regeneron Pharma | Humanized light chain mice |
NZ627977A (en) | 2012-02-01 | 2016-06-24 | Regeneron Pharma | Humanized rodents that express heavy chains containing vl domains |
EA035344B1 (ru) | 2012-04-20 | 2020-05-29 | Мерюс Н.В. | Способ получения двух антител из одной клетки-хозяина |
CA2876172C (en) | 2012-06-12 | 2021-01-19 | Regeneron Pharmaceuticals, Inc. | Humanized non-human animals with restricted immunoglobulin heavy chain loci |
EP4218409A3 (en) | 2013-03-13 | 2023-08-30 | Regeneron Pharmaceuticals, Inc. | Mice expressing a limited immunoglobulin light chain repertoire |
JP2016519568A (ja) | 2013-03-13 | 2016-07-07 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 共通軽鎖のマウス |
-
2012
- 2012-08-03 IL IL273982A patent/IL273982B2/en unknown
- 2012-08-03 DK DK12746246T patent/DK2739740T3/da active
- 2012-08-03 SI SI201231920T patent/SI3572517T1/sl unknown
- 2012-08-03 MX MX2014001454A patent/MX357623B/es active IP Right Grant
- 2012-08-03 ES ES19184217T patent/ES2872081T3/es active Active
- 2012-08-03 LT LTEP19184217.8T patent/LT3572517T/lt unknown
- 2012-08-03 CN CN201280049374.1A patent/CN103917650B/zh active Active
- 2012-08-03 AU AU2012294624A patent/AU2012294624B2/en active Active
- 2012-08-03 NZ NZ727084A patent/NZ727084A/en unknown
- 2012-08-03 EP EP12746246.3A patent/EP2739740B1/en active Active
- 2012-08-03 WO PCT/US2012/049600 patent/WO2013022782A1/en active Application Filing
- 2012-08-03 CN CN201710786672.3A patent/CN107602696B/zh active Active
- 2012-08-03 PL PL12746246T patent/PL2739740T3/pl unknown
- 2012-08-03 IL IL297371A patent/IL297371A/en unknown
- 2012-08-03 PT PT127462463T patent/PT2739740T/pt unknown
- 2012-08-03 US US13/566,765 patent/US10130081B2/en active Active
- 2012-08-03 RS RS20210708A patent/RS61946B1/sr unknown
- 2012-08-03 MY MYPI2014000309A patent/MY172718A/en unknown
- 2012-08-03 SG SG2014007686A patent/SG2014007686A/en unknown
- 2012-08-03 EP EP19184217.8A patent/EP3572517B1/en active Active
- 2012-08-03 BR BR112014002713-7A patent/BR112014002713B1/pt active IP Right Grant
- 2012-08-03 SI SI201231688T patent/SI2739740T1/sl unknown
- 2012-08-03 RU RU2014108208A patent/RU2664232C2/ru active
- 2012-08-03 JP JP2014524126A patent/JP6510234B2/ja active Active
- 2012-08-03 HU HUE12746246A patent/HUE047278T2/hu unknown
- 2012-08-03 PT PT191842178T patent/PT3572517T/pt unknown
- 2012-08-03 EP EP21157152.6A patent/EP3865581A1/en active Pending
- 2012-08-03 ES ES12746246T patent/ES2758051T3/es active Active
- 2012-08-03 HU HUE19184217A patent/HUE055276T2/hu unknown
- 2012-08-03 PL PL19184217T patent/PL3572517T3/pl unknown
- 2012-08-03 DK DK19184217.8T patent/DK3572517T3/da active
- 2012-08-03 SG SG10201914002RA patent/SG10201914002RA/en unknown
- 2012-08-03 SG SG10201606158TA patent/SG10201606158TA/en unknown
- 2012-08-03 NZ NZ743520A patent/NZ743520A/en unknown
- 2012-08-03 RS RS20191651A patent/RS59728B1/sr unknown
- 2012-08-03 NZ NZ781020A patent/NZ781020A/en unknown
- 2012-08-03 LT LT12746246T patent/LT2739740T/lt unknown
- 2012-08-03 CA CA2844070A patent/CA2844070A1/en active Pending
-
2014
- 2014-02-02 IL IL23076614A patent/IL230766B/en active IP Right Grant
- 2014-02-05 MX MX2021001074A patent/MX2021001074A/es unknown
- 2014-02-10 ZA ZA2014/01006A patent/ZA201401006B/en unknown
-
2015
- 2015-11-13 AU AU2015255276A patent/AU2015255276B2/en active Active
-
2016
- 2016-10-13 JP JP2016201462A patent/JP2017006146A/ja active Pending
-
2018
- 2018-05-22 AU AU2018203592A patent/AU2018203592B2/en active Active
- 2018-10-02 US US16/149,838 patent/US11357217B2/en active Active
- 2018-12-27 JP JP2018244118A patent/JP6724126B2/ja active Active
-
2019
- 2019-08-01 IL IL268413A patent/IL268413B/en active IP Right Grant
- 2019-12-16 HR HRP20192255TT patent/HRP20192255T1/hr unknown
- 2019-12-20 CY CY20191101345T patent/CY1122435T1/el unknown
- 2019-12-26 JP JP2019236290A patent/JP6886002B2/ja active Active
-
2020
- 2020-11-23 AU AU2020277108A patent/AU2020277108A1/en active Pending
-
2021
- 2021-05-13 JP JP2021081543A patent/JP7174805B2/ja active Active
- 2021-06-09 HR HRP20210916TT patent/HRP20210916T1/hr unknown
- 2021-06-14 CY CY20211100521T patent/CY1124341T1/el unknown
-
2022
- 2022-05-02 US US17/734,392 patent/US20220394959A1/en active Pending
- 2022-11-07 JP JP2022178043A patent/JP2023011882A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060015957A1 (en) * | 1991-08-28 | 2006-01-19 | Genpharm International, Inc. | Transgenic non-human animals for producing chimeric antibodies |
WO2009157771A2 (en) * | 2008-06-27 | 2009-12-30 | Merus B.V. | Antibody producing non-human mammals |
Non-Patent Citations (3)
Title |
---|
"Comprehensive analysis of reproductive ADAMs: relationship of ADAM4 and ADAM6 with an ADAM complex r", BIOLOGY OF REPRODUCTION, vol. 80(5), JPN6016024920, 2009, pages 1001 - 1008, ISSN: 0003714307 * |
"The mouse immunoglobulin heavy chain V-D intergenic sequence contais insulators that may regulate or", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 285(13), JPN6016024919, 2010, pages 9327 - 9338, ISSN: 0003714306 * |
MURPHY D., "BAC-BASED MODIFICATIONS OF THE MOUSE GENOME: THE BIG AND THE BACKWARD", WELLCOME TRUST A, JPN7016002559, 3 November 2009 (2009-11-03), ISSN: 0003866551 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016513957A (ja) * | 2013-02-20 | 2016-05-19 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 修飾された免疫グロブリン重鎖配列を有する非ヒト動物 |
JP2016127840A (ja) * | 2013-02-20 | 2016-07-14 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 修飾された免疫グロブリン重鎖配列を有する非ヒト動物 |
JP2018508224A (ja) * | 2015-03-19 | 2018-03-29 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | 抗原を結合する軽鎖可変領域を選択する非ヒト動物 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7174805B2 (ja) | ヒト化ユニバーサル軽鎖マウス | |
US10905109B2 (en) | ADAM6 mice | |
JP6327750B2 (ja) | ヒト化軽鎖マウス | |
RU2787781C2 (ru) | Мыши с гуманизированной универсальной легкой цепью | |
NZ620586B2 (en) | Humanized universal light chain mice | |
NZ710301B2 (en) | Humanized universal light chain mice |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150730 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150730 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160323 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20160526 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160701 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20161003 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161013 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170306 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20170602 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170807 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20170807 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180105 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180323 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180605 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20180827 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181227 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20190110 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190308 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190404 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6510234 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |