JP5855381B2 - 結合分子 - Google Patents
結合分子 Download PDFInfo
- Publication number
- JP5855381B2 JP5855381B2 JP2011166561A JP2011166561A JP5855381B2 JP 5855381 B2 JP5855381 B2 JP 5855381B2 JP 2011166561 A JP2011166561 A JP 2011166561A JP 2011166561 A JP2011166561 A JP 2011166561A JP 5855381 B2 JP5855381 B2 JP 5855381B2
- Authority
- JP
- Japan
- Prior art keywords
- heavy chain
- domain
- antibody
- binding
- effector
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000027455 binding Effects 0.000 title claims description 174
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 178
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 169
- 229920001184 polypeptide Polymers 0.000 claims description 168
- 210000004027 cell Anatomy 0.000 claims description 102
- 241000282414 Homo sapiens Species 0.000 claims description 100
- 238000004519 manufacturing process Methods 0.000 claims description 28
- 241000251539 Vertebrata <Metazoa> Species 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 23
- 238000010367 cloning Methods 0.000 claims description 21
- 239000013604 expression vector Substances 0.000 claims description 21
- 238000006471 dimerization reaction Methods 0.000 claims description 19
- 108091033319 polynucleotide Proteins 0.000 claims description 15
- 102000040430 polynucleotide Human genes 0.000 claims description 15
- 239000002157 polynucleotide Substances 0.000 claims description 15
- 210000004899 c-terminal region Anatomy 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 3
- 239000000710 homodimer Substances 0.000 claims description 3
- 108700029228 Immunoglobulin Heavy Chain Genes Proteins 0.000 claims 1
- 239000013599 cloning vector Substances 0.000 claims 1
- 239000012636 effector Substances 0.000 description 154
- 238000000034 method Methods 0.000 description 108
- 239000000427 antigen Substances 0.000 description 92
- 108091007433 antigens Proteins 0.000 description 90
- 102000036639 antigens Human genes 0.000 description 90
- 108090000623 proteins and genes Proteins 0.000 description 83
- 230000009261 transgenic effect Effects 0.000 description 48
- 230000006870 function Effects 0.000 description 46
- 241000282836 Camelus dromedarius Species 0.000 description 41
- 101150008942 J gene Proteins 0.000 description 38
- 239000012634 fragment Substances 0.000 description 36
- 101150117115 V gene Proteins 0.000 description 35
- 241000124008 Mammalia Species 0.000 description 34
- 101150097493 D gene Proteins 0.000 description 32
- 230000000295 complement effect Effects 0.000 description 29
- 210000003719 b-lymphocyte Anatomy 0.000 description 26
- 239000013598 vector Substances 0.000 description 26
- 102000004169 proteins and genes Human genes 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 23
- 238000011830 transgenic mouse model Methods 0.000 description 23
- 241000283707 Capra Species 0.000 description 20
- 210000004408 hybridoma Anatomy 0.000 description 20
- 238000001727 in vivo Methods 0.000 description 20
- 239000000539 dimer Substances 0.000 description 19
- 239000013612 plasmid Substances 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 16
- 244000052769 pathogen Species 0.000 description 16
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 15
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 15
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 15
- 241000699660 Mus musculus Species 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 238000010561 standard procedure Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 210000002966 serum Anatomy 0.000 description 14
- 108700024394 Exon Proteins 0.000 description 13
- 206010069754 Acquired gene mutation Diseases 0.000 description 12
- 241000238631 Hexapoda Species 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 230000006798 recombination Effects 0.000 description 12
- 238000005215 recombination Methods 0.000 description 12
- 230000037439 somatic mutation Effects 0.000 description 12
- 244000303258 Annona diversifolia Species 0.000 description 11
- 235000002198 Annona diversifolia Nutrition 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 11
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 108020001507 fusion proteins Proteins 0.000 description 11
- 102000037865 fusion proteins Human genes 0.000 description 11
- 108020004999 messenger RNA Proteins 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 238000002965 ELISA Methods 0.000 description 10
- 101000840258 Homo sapiens Immunoglobulin J chain Proteins 0.000 description 10
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 10
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 10
- 102100029571 Immunoglobulin J chain Human genes 0.000 description 10
- 230000001580 bacterial effect Effects 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 208000024191 minimally invasive lung adenocarcinoma Diseases 0.000 description 10
- 241000282832 Camelidae Species 0.000 description 9
- 230000009824 affinity maturation Effects 0.000 description 9
- 150000001413 amino acids Chemical group 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 241000588724 Escherichia coli Species 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 230000011748 cell maturation Effects 0.000 description 8
- 239000000032 diagnostic agent Substances 0.000 description 8
- 229940039227 diagnostic agent Drugs 0.000 description 8
- 210000004962 mammalian cell Anatomy 0.000 description 8
- 239000000178 monomer Substances 0.000 description 8
- 230000001717 pathogenic effect Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 108060003951 Immunoglobulin Proteins 0.000 description 7
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 7
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 7
- 108020004511 Recombinant DNA Proteins 0.000 description 7
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 7
- 239000002872 contrast media Substances 0.000 description 7
- 102000018358 immunoglobulin Human genes 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- 102000014914 Carrier Proteins Human genes 0.000 description 6
- 108020004705 Codon Proteins 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 6
- 101710120463 Prostate stem cell antigen Proteins 0.000 description 6
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 6
- 238000001042 affinity chromatography Methods 0.000 description 6
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 6
- 108091008324 binding proteins Proteins 0.000 description 6
- 229940098773 bovine serum albumin Drugs 0.000 description 6
- 239000002299 complementary DNA Substances 0.000 description 6
- 238000009295 crossflow filtration Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000010353 genetic engineering Methods 0.000 description 6
- 210000004602 germ cell Anatomy 0.000 description 6
- 230000003053 immunization Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- 238000001823 molecular biology technique Methods 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 210000004989 spleen cell Anatomy 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 235000018417 cysteine Nutrition 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000013613 expression plasmid Substances 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 238000003757 reverse transcription PCR Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 239000003053 toxin Substances 0.000 description 5
- 231100000765 toxin Toxicity 0.000 description 5
- 108700012359 toxins Proteins 0.000 description 5
- 210000005253 yeast cell Anatomy 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 101710177291 Gag polyprotein Proteins 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 4
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000013330 chicken meat Nutrition 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 229940072221 immunoglobulins Drugs 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 238000002823 phage display Methods 0.000 description 4
- 230000035790 physiological processes and functions Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical group OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 241000251730 Chondrichthyes Species 0.000 description 3
- 101100125027 Dictyostelium discoideum mhsp70 gene Proteins 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 101150031823 HSP70 gene Proteins 0.000 description 3
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 description 3
- 108091081024 Start codon Proteins 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000009395 breeding Methods 0.000 description 3
- 230000001488 breeding effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 230000000093 cytochemical effect Effects 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 101150052825 dnaK gene Proteins 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 239000000833 heterodimer Substances 0.000 description 3
- 238000002744 homologous recombination Methods 0.000 description 3
- 230000006801 homologous recombination Effects 0.000 description 3
- 102000057041 human TNF Human genes 0.000 description 3
- 238000012744 immunostaining Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 230000035800 maturation Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- 230000008707 rearrangement Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VFTRKSBEFQDZKX-UHFFFAOYSA-N 3,3'-diindolylmethane Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4NC=3)=CNC2=C1 VFTRKSBEFQDZKX-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000010755 BS 2869 Class G Substances 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 101100203200 Danio rerio shha gene Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 2
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 2
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 210000000628 antibody-producing cell Anatomy 0.000 description 2
- 238000003491 array Methods 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 230000024203 complement activation Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 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 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000003205 genotyping method Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000025750 heavy chain disease Diseases 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000008611 intercellular interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 230000013011 mating Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 102000013415 peroxidase activity proteins Human genes 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 210000002826 placenta Anatomy 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 231100000654 protein toxin Toxicity 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WKMPTBDYDNUJLF-UHFFFAOYSA-N 2-fluoroadenine Chemical compound NC1=NC(F)=NC2=C1N=CN2 WKMPTBDYDNUJLF-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108010032595 Antibody Binding Sites Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 101710098119 Chaperonin GroEL 2 Proteins 0.000 description 1
- 102000004405 Collectins Human genes 0.000 description 1
- 108090000909 Collectins Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 208000012239 Developmental disease Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 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 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010046276 FLP recombinase Proteins 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 102000018932 HSP70 Heat-Shock Proteins Human genes 0.000 description 1
- 108010027992 HSP70 Heat-Shock Proteins Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 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
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000012741 Laemmli sample buffer Substances 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 102000014171 Milk Proteins Human genes 0.000 description 1
- 108010011756 Milk Proteins Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- -1 OCT compound Chemical class 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 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
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000011230 antibody-based therapy Methods 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000000981 bystander Effects 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000010370 cell cloning Methods 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000002458 cell surface marker Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000012411 cloning technique Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000005210 lymphoid organ Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 235000021239 milk protein Nutrition 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000012514 monoclonal antibody product Substances 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000008010 parenteral excipient Substances 0.000 description 1
- 210000001986 peyer's patch Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000003168 reconstitution method Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 230000035938 sexual maturation Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 238000012409 standard PCR amplification Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/241—Tumor Necrosis Factors
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
- C07K16/1054—Lentiviridae, e.g. HIV, FIV, SIV gag-pol, e.g. p17, p24
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
- C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
- C07K16/1228—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K16/1232—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia from Escherichia (G)
-
- 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
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
Description
(a)抗原を、本明細書に記載したようなトランスジェニック哺乳類に注射するステップと、
(b)目的とする抗原特異的の重鎖のみ抗体を発現する細胞又は組織を単離するステップと、
(c)ステップ(b)の細胞又は組織からハイブリドーマを産生するステップと、
(d)前記ハイブリドーマ由来の重鎖のみ抗体mRNAを、次に哺乳類、植物、昆虫、微生物、真菌又は代替の系などの異種発現系中に産生させるため、任意選択的にクローン化するステップと
を含む重鎖のみ抗体を産生させて選択する方法を提供する。
(a)抗原を本明細書に記載のトランスジェニック哺乳類に注射するステップと、
(b)目的とする抗原特異的重鎖のみ抗体を発現する細胞又は組織を単離するステップと、
(c)上記単離された細胞又は組織から得られたmRNAからVH遺伝子座をクローン化するステップと、
(d)ファージ又は類似のライブラリーを使ってコード化されたタンパク質をディスプレイするステップと、
(e)一種又は複数種の抗原特異的VHドメインを同定するステップと、
(f)上記一種もしくは複数種のVH結合ドメインだけを、又は融合タンパク質として細菌、酵母又は代替の発現系に発現させるステップと
によって製造することもできる。
本発明の文脈において、用語「異種」は、本明細書に記載されているように、ヌクレオチド配列又は遺伝子座が、それを配置された哺乳類にとって内在性ではないことを意味する。
操作的に、重鎖定常領域は、天然又はB細胞内でV遺伝子セグメント、D遺伝子セグメント及びJ遺伝子セグメントで組換えできる遺伝子工学的に処理された遺伝子セグメントによってコードされている。好ましくは、その重鎖定常領域は、免疫グロブリンの遺伝子座由来である。
本発明の方法に使うトランスジェニック哺乳類はヒトではない。トランスジェニック哺乳類としては、ウサギ、モルモット、ラット又はマウスなどのげっ歯類が好ましい。マウスが特に好ましい。ヤギ、ヒツジ、ネコ、イヌ又は他の動物などの代替動物も利用できる。
もう一つの態様で、本発明は、本発明の方法で得ることができる重鎖のみ抗体及びその機能性フラグメントと誘導体を提供する。VH結合ドメインを含むフラグメントは、本発明の重鎖のみ抗体すなわち軽鎖を欠いている抗体を、酵素又は臭化シアンで開裂することによって誘導できる(Jaton et al.,(1968)Biochemistry,7,4185−4195)。
(a)目的とする抗原特異的重鎖のみ抗体(好ましくは、対象の可溶性の抗原特異的重鎖のみ抗体)を発現する細胞又は組織を単離するステップと、
(b)前記単離した細胞又は組織から誘導したmRNAからVH結合ドメインをコードする配列をクローン化するステップと、
(c)そのコードされたタンパク質を、ファージ又は類似のライブラリーを使ってディスプレイするステップと、
(d)抗原特異的VH結合ドメインを同定するステップと、
(e)そのVH結合ドメインを、単独で又は融合タンパク質として、細菌、酵母、哺乳類又は代替の発現系で発現させるステップと
を含むVH結合ドメインの製造方法を提供する。
本発明者らは、抗体重鎖の少なくとも一部分を、単独で又は相補的会合ドメインを含みかつ追加のエフェクター活性を有する別のエフェクター(軽)鎖と組み合わせて含む二価又は多価のポリペプチド複合体を産生できることを明らかにした。本発明のポリペプチド複合体は、エフェクター鎖に付随する追加エフェクター部分の機能と組み合わせた重鎖定常領域によって付与された生理学的機能を保持している(図3)。
その一対の重鎖は互いに会合し、
一方のエフェクター鎖は一方の重鎖と会合し、他方のエフェクター鎖は他方の重鎖と会合し、
各重鎖は、結合ドメイン、好ましくは少なくともCH2、CH3及び任意選択的にCH4の定常領域ドメインを含む二量体化ドメイン並びにエフェクター鎖の相補的会合ドメインに結合できるエフェクター部分を含み、
そのエフェクター鎖は、エフェクター部分に連結された相補的会合ドメインを含み、そして
前記会合ドメインと相補的会合ドメインは非共有相互作用によって互いに会合している。
エフェクター鎖は、相補結合ドメインとエフェクター部分を含み、重鎖のエフェクター部分を通じて重鎖と結びついて、会合されたポリペプチド結合複合体を形成する。そのエフェクター鎖の相補的会合ドメインは、エフェクター部分の不可欠な成分であってもよいし、又はエフェクター部分に融合もしくは化学的に結合されたタンパク質もしくは別のリガンドでもよい。前記会合されたポリペプチド結合複合体の重鎖は、標的に結合してエフェクター(軽)鎖部分を標的の直近まで運んで標的に生物学的効果を発揮できる。
用語「エフェクター部分」は、本明細書で使用するときは、細胞に対して望ましい生物学的効果を仲介する任意の部分を含む。そのエフェクタードメインは、細胞例えばT細胞、ペプチド、ポリペプチドもしくはタンパク質でもよく、又は非ペプチド構造体でもよい。例えば、エフェクタードメインは、酵素、医薬、プロドラッグ、毒素特にタンパク質毒素、キレート化構造体の放射性核種又は結合ドメインでもよい。相補的会合ドメインと会合しているエフェクター部分は、所望の効果によって、自然状態で、細胞の、たんぱく質の、有機又は無機の部分でよい。
重鎖がエフェクター鎖と会合しているとき、用語「エフェクター部分」と「相補的会合ドメイン」は、本明細書で使う場合、少なくとも一つの非共有結合を、互いに形成できる部分を含む。例えば、そのエフェクター部分と相補的会合ドメインは、免疫グロブリン重鎖のCH1ドメイン−免疫グロブリン軽鎖の定常領域間、ロイシンジッパー間、VCAM−VLA−4間、インテグリン−細胞外マトリックスタンパク質間、インテグリン−CD54もしくはCD102などの細胞表面分子間、ALCAM−SRCRドメイン間、scFv−抗原間又はVH結合ドメイン−抗原間などにみられるようなタンパク質−タンパク質相互作用を形成できるタンパク質、ペプチドフラグメント又は共通配列でもよい。
重鎖の二量体化ドメインが免疫グロブリン重鎖の定常領域を含むときは、その定常領域(CHエキソン)は、さらなる生理的機能をポリペプチド結合複合体に付与してもよい。特に、その免疫グロブリン重鎖の定常ドメインは、その抗体定常ドメインのクラス又はサブクラスに依存して、特に補体の結合、マクロファージの活性化及びFc受容体への結合を提供してもよい。
各ポリペプチド重鎖が、結合ドメイン並びに任意選択的に少なくともCH2、CH3及び任意選択的にCH4の抗体定常領域のドメイン及び任意選択的にエフェクター部分を含む二量体化ドメインを含み、
好ましくは第一ポリペプチド重鎖の結合ドメインは、第二ポリペプチド重鎖の結合ドメインと同じ特異性を有し、そして
これら二つのポリペプチド重鎖の定常領域(二量体化ドメイン)は同一である
ポリペプチド複合体が提供される。
複数のポリペプチド重鎖二量体がJ鎖によって会合され、
各ポリペプチド重鎖が、結合ドメイン並びに同一のμ、ε、α又はγのCH2、CH3及び任意選択的にCH4のドメインを含み、そして
そのポリペプチド複合体中に、異なる特異性を有する少なくとも二つの結合ドメインが存在している
ポリペプチド複合体を提供する(図4と5参照)。
本発明のポリペプチド複合体のモジュールドメインの構成は、その複合体を、多種類の可能な順列で構築することを可能にする。ポリペプチド複合体のドメインの構造及びアミノ酸の配列におけるこのような変更は、配列をコードする対応DNAの適切な領域を適切に変異させるか又は部分的に合成し及び置換することによって達成されてもよい。置換ドメイン又は付加ドメインは、互換性がある組換えDNA配列から得られてもよい。例えば、重鎖は、結合ドメインとCH2ドメインのアミノ末端との間及びエフェクタードメインと重鎖のC末端(CH3又はCH4)との間の両方に、天然ヒンジ又は遺伝子工学的に処理された可撓性ポリペプチドドメインを含んでもよい。
本発明はまた、本発明のポリペプチド複合体のいずれか一つの重鎖をコードするポリヌクレオチド配列、上記ポリヌクテオチド配列を一つ以上含むベクター及び本発明のポリペプチド複合体の重鎖をコードするベクターで形質転換された宿主細胞を提供する。そのポリヌクレオチドは、好ましくは、発現された重鎖をホモ二量体として、宿主細胞が増殖している培地中に分泌させる配列を含む。その宿主細胞は、細菌及び酵母の細胞を含む任意の起源の細胞でもよいが、脊椎動物の宿主細胞が好ましく、哺乳類の宿主細胞が一層好ましい。
本発明の重鎖のみ抗体及びポリペプチド結合複合体には、多数の用途がある。
本明細書で使用されている技術用語と科学用語は、特に定義しない限り、当業者(例えば細胞培養、分子遺伝学、核酸化学、ハイブリッド形成技術及び生化学の当業者)が共通して理解しているのと同じ意味を持っている。分子、遺伝子及び生化学の方法(一般に、Sambrook et al.,Molecular Cloning:A Laboratory Manual,2nd Ed.(1989)Cold Spring Harbor Laboratory Press,Cold Spring Harbor N.Y.及びAusubel et al.,Short Protocols in Molecular Biology(1999)4th Ed.,John Wiley & Sons,Inc.参照)並びに化学的方法の標準方法が使用される。さらに、標準の免疫学的方法として、Harlow & Lane,A Laboratory ManualCold Spring Harbor N.Y.がある。
用語:本発明の「ポリペプチド複合体」、「単一重鎖抗体」及び「異種重鎖遺伝子座」は、例えば、類縁の細胞ホモログ、他の種由来のホモログ及びその変異体もしくは誘導体などの任意の供給源から得られる同族のポリペプチド及び核酸配列を含むことは当然明らかであろう。
さらなる態様で、本発明は、抗原を、本発明のトランスジェニック生物に投与することを含む本発明の抗体の製造方法を提供する。
本発明のポリペプチド複合体及び抗体とそのフラグメントは、インビボでの治療と予防の用途、インビトロとインビボで診断する際の用途、インビトロでの検定と試薬の用途などに利用されてもよい。
この問題を克服するため、標準の方法を使って、ゲノムコスミドライブラリーをVH遺伝子を含有するクローンについてスクリーニングした。一つ(又は二つ以上)の異なる生殖細胞系VHを、その配列に基づいて無作為に選んだ(ヒトVHの場合は五つの属クラス)。親水性アミノ酸のコドンを、IMGTナンバリング法(Lefranc et al.(1999)によって、42、49、50及び52の位置に導入した。これらのVH遺伝子は、カスタムメイドのリンカーを使う直接クローン化法又は相同的組換え法などの標準法によってBACベクター中に組み入れられた。
IgM構造体を得るため(図11)、ヒトのDとJの重鎖セグメント及びCμが続く一つ以上のVH遺伝子(好ましくは、可溶性を提供するため遺伝子工学的に処理されたヒトVH遺伝子又はラクダVHH遺伝子)をBAC中にクローン化した(本方法については上記を参照のこと)。この場合、Cμ領域だけが、最終のBAC中にクローン化された。
IgMプラスIgG構造体を得るため(図12)、ヒトのDとJの重鎖セグメント、Cμ(CH1エキソンは含有しないがCH4エキソンは含有する)、(任意選択的なCδ)及び修飾されたヒトCγ2とCγ3遺伝子と3’LCRが続く一つ以上のVH遺伝子(好ましくは、可溶性を提供するため遺伝子工学的に処理されたヒトVHセグメント又はラクダVHH遺伝子)をBAC中にクローン化した。IgGのみ遺伝子座を生成させるために、loxP部位を、標準クローン化ステップ(上記)によって導入し次いでそのBACを294 Cre大腸菌株中で成長させ(Buscholz et al.)、次いでcreにより仲介される組換え法によってIgGのみ遺伝子座を産生する細菌を得た。さらなる構築の詳細については先の説明を参照のこと。
IgMプラスIgG構造体を得るため(図13)、ヒトのDとJの重鎖セグメント、Cμ(CH1とCH4を含有する)、(任意選択的なCδ)及び修飾されたヒトCγ2とCγ3遺伝子と3’LCRが続く一つ以上のVH遺伝子(好ましくは、可溶性を提供するため遺伝子工学的に処理されたヒトVH遺伝子又はラクダVHH遺伝子)をBAC中にクローン化した。IgGのみ遺伝子座を生成させるために、loxP部位を、標準クローン化ステップ(上記)によって導入し次いでそのBACを294 Cre大腸菌株中で成長させ(Buscholz et al.)、次いでcreにより仲介される組換え法によってIgGのみ遺伝子座を産生する細菌を得た。
受精卵に対する標準マイクロインジェクション法又は胚幹細胞トランスフェクション法によって、前記最終BACを、トランスジェニックマウスに導入した。
脾臓をOCT化合物中に包埋した。クライオスタットによる5μmの凍結切片をアセトン中で固定し、すでに述べられているようにして(Leenen et al.1998)単一又は二重の標識を行った。モノクローナル抗体抗B220/RA3−6B2、モノクローナル抗体抗CD11c/N418(Steinman et al.1997)にはハイブリドーマ培養上澄み液が用いられた。ペルオキシダーゼを連結したヤギ抗ヒトIgG及びヤギ抗ヒトIgMをSigmaから入手した。第二ステップの試薬は、ペルオキシダーゼの標識をつけた、ヤギ抗ラットIg(DAKO,Glostrup,Denmark)もしくはヤギ抗ハムスターIg(Jackson ImmunoResearch Laboratories,West Grove,AL,USA)及びヤギ抗ラットIgアルカリホスファターゼ(Southern Biotechnology,Birmingam,AL,USA)であった。
単一細胞の懸濁液を、(Slieker et al.1993)、PBS中のリンパ系器官から調製した。約1×106個の細胞を抗体とともに、96ウェルプレート中のPBS/0.5%ウシ血清アルブミン(BSA)内で4℃にて30分間インキュベートした。細胞をPBS/0.5%BSA中で2回洗浄した。各試料について、FACScan analyzer(Becton Dickinson,Sunnyvale,CA)を使って、3×104個の細胞を計測した。FACSのデータは、CellQuest version 1.0 computer softwareを使って分析した。四色分析を、Becton Dickinson FACS Caliburで実施した。以下のmAb:FITC複合抗B220−RA3−6B2及びPE複合抗CD19をBD Pharmingen(San Diego,CA)から入手した。抗CD19及び抗B220で染色した脾臓細胞のFACSスキャンデータを図15の下部のパネルに示した。
二つのラマVHHドメイン、ヒトのDとJの領域及びIgG2とIgG3の定常領域(CH1ドメインは含まない)からなる重鎖のみ抗体の遺伝子座を含有するトランスジェニックマウスを作製した。
15〜25週齢のマウスから血液を、EDTAをコートしたチューブに集めて、室温(RT)で15分間遠心し、次いでその上澄み液をPBSで1:5の比率で希釈した。96ウェルプレートを、5mg/ml濃度のヤギ抗ヒトIgG(YES Biotechnology)又はヤギ抗ヒトIgM(Sigma)で2時間コートし、PBSで洗浄し、ブロッキング溶液(1.5%BSA/1.5%粉乳/0.1%tween20/PBS)でRTにて1時間ブロックし、次にPBSで3回洗浄した。血清試料と標準液(ヒトIgG2又はヒトIgM(Sigma,Zwijndrecht,NL))の希釈シリーズを負荷して2〜4時間インキュベートし次いでプレートをPBSで6回洗浄した後、第二抗体(HRPに連結したヤギ抗ヒトIgG又はヤギ抗ヒトIgMを1:2000の比率で希釈したもの(Sigma,Zwijndrecht,NL))を添加した。希釈は全てブロッキング溶液で実施した。RTで1〜2時間インキュベートしてPBSで洗浄した後、POD基質(Roche)を添加した。
Ultraspec RNA isolation system(Biotex Laboratories,Houston,Texas,USA)を使って、DKTPで免疫した単一コピーIgGのみマウスの脾臓から全RNAを単離した(図12 cre処理をした後)。oligo dTを使ってcDNAを作製した。vhl back SfiIプライマー(Dekker et al 2003)をhIgG2hingrevプライマー(5’−AATCTGGGCAGCGGCCGCCTCGACACAACATTTGCGCTC−3’)と組み合わせた特異的プライマーを使用してPCRによって、VHHのDJフラグメントをコードするDNAフラグメントを増幅した。その増幅されたVHHのDJフラグメント(約400 bp)を、Sfi I/Not Iで消化し、ゲルで精製し次いでSfi I/NotIで消化したファージミドベクターpHEN−1中にクローン化した。
HLL−MD遺伝子座が、多様な抗体レパートリーを産生する際に正常な遺伝子座として機能するかどうかを、パイエル板由来のcDNAに対してIgG2とIgG3の特異的プライマーを使って得たRT−PCR産物の配列を決定することによって試験した。図17は、免疫されていないマウス(左パネル)と免疫されたマウス(右パネル)由来のクローンの体細胞変異のいくつかの例を示す。これらのマウスは、IgGのみ遺伝子座、大腸菌hsp70、百日咳菌溶解物、破傷風トキソイドで免疫されたものであった。灰色の影付きの部分はERKCCVで始まるIgG2ヒンジ領域である。
図18は、A5抗体(Dekker et al.2003)を含有する応答プラスミドで追加的にトランスフェクトされたTet−on細胞系の一つを免疫染色した結果を示す。上のパネルは、ドキシサイクリンによって細胞質中に誘発され産生したA5抗体(赤色)及びDAPIによる細胞核の染色(青色)を示す。下のパネルは、核の中にrtTAを発現する細胞が、誘発(上のパネル)によってA5を産生する細胞であることを示す。下記配列を有するrtTAに対するヒトHCAbのうちの一種で染色を実施した(緑色)。FITC複合ヤギ抗ヒトIgGを第二ステップとして使用した。Dekker et al.2003にすでに記載されているようにして、A5を検出した。rTTA抗体は下記配列を有するIgG3であった。
図19は、IgMプラスIgG遺伝子座(図10)を含有する異なるトランスジェニックマウス系の血清の、cre処理を行った後(すなわち、IgMが欠失しIgGのみ残留)のウエスタンブロットを示す。血清は、prot Gで精製し次いで還元条件下(図19の右のパネル)及び非還元条件下(図19の左のパネル)でゲル分画を行なった。対照は、バックグランドのKOマウス及び正常なヒトの血清の試料である。ヒト重鎖のみIgGが二量体であることを示す二つのゲルのサイズ間の差に留意されたい。
IgMプラスIgGマウス(図13)由来の血清を、対照のヒト血清の試料と混合した後、非還元条件下でゲル濾過することによって分画した。結果を図20に示す。カラムの複合体の分子量は、各レーンについて(各画分を示す)左から右に進むにつれて減少する。これら画分(各レーン)を、還元条件下にてゲル電気泳動法で分析した。
抗gag:ウサギポリクローナル(1:2000)2時間RT
抗ダイアボディ体:ヤギαヒトIgG−HRP(1:2500)2時間RT
抗HSP70:モノクローナルG20−380培地(1:2)2時間RT
二次抗体は、ヤギ抗ウサギーAP(1:2000)2時間RT及びHSP70モノクローナルに対するヤギ抗ヒトIgG−HRP(1:2500)2時間RTであった。
二重特異性IgAの生成は、IgGについて先に述べたのとほぼ同じであるが、Vhsol、D及びJに加えて、IgAを生成する定常領域Cαを使用する(図25)。
PSCA(前立腺幹細胞抗原)に結合する結合ドメイン及びVCAMと抗体ヒンジからなる会合ドメイン、CH2ドメイン及びCH3ドメインを含む重鎖;並びにリシンA毒素に融合したVLA−4からなる相補的会合ドメインを含む軽鎖を含むポリペプチド複合体をコードする発現ベクターを、Sambrook et alに記載されている分子生物学の技術を使って構築する。
Claims (10)
- 第一の重鎖及び第二の重鎖のホモ二量体からなる結合ポリペプチド複合体であって、
各重鎖は、二量体化ドメインにより連結された2つのVH結合ドメインからなり、前記第一の重鎖及び第二の重鎖のアミノ末端に位置するVH結合ドメインは同一であり、前記第一の重鎖及び第二の重鎖のカルボキシ末端に位置するVH結合ドメインは同一であり、かつ、
各二量体化ドメインは同一であり、免疫グロブリンの重鎖遺伝子のいずれかのクラスから誘導される少なくともCH2、CH3及び任意選択的にCH4の抗体定常ドメインを含み、かつ、
CH1ドメインを含まない、
結合ポリペプチド複合体。 - 前記VH結合ドメインは、ラクダVHH結合ドメインを含む天然のVH結合ドメインまたは任意の脊椎動物由来の修飾されたVH結合ドメイン由来であってもよい、請求項1に記載の結合ポリペプチド複合体。
- 前記VHドメインはヒトVHドメインである請求項1又は2に記載の結合ポリペプチド複合体。
- 請求項1〜3のいずれか1項に記載の結合ポリペプチド複合体の両重鎖をコードする、単離されたポリヌクレオチド。
- 前記第一の重鎖及び第二の重鎖をコードする請求項4に記載の単離されたポリヌクレオチドを含むクローニングベクター又は発現ベクター。
- 請求項5に記載の発現ベクターをトランスフェクトした宿主細胞。
- 請求項6に記載の宿主細胞を培養するステップと、ポリペプチド複合体を単離するステップを含む、請求項1〜3のいずれか1項に記載の結合ポリペプチド複合体を産生する方法。
- 請求項1〜3のいずれか1項に記載の結合ポリペプチド複合体と、薬理学的に適切な担体とを含む組成物。
- 治療に使用するための、請求項1〜3のいずれか1項に記載の結合ポリペプチド複合体又は請求項8に記載の組成物。
- 疾患の診断に使用するための、請求項1〜3のいずれか1項に記載の結合ポリペプチド複合体。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0416392.9 | 2004-07-22 | ||
GB0416392A GB2416768A (en) | 2004-07-22 | 2004-07-22 | Heavy chain immunoglobulin complexes |
GB0511881.5 | 2005-06-10 | ||
GB0511881A GB0511881D0 (en) | 2005-06-10 | 2005-06-10 | Binding molecules |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007522034A Division JP2008512987A (ja) | 2004-07-22 | 2005-07-22 | 結合分子 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2012005491A JP2012005491A (ja) | 2012-01-12 |
JP5855381B2 true JP5855381B2 (ja) | 2016-02-09 |
Family
ID=35431831
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007522034A Pending JP2008512987A (ja) | 2004-07-22 | 2005-07-22 | 結合分子 |
JP2011166562A Expired - Fee Related JP5888893B2 (ja) | 2004-07-22 | 2011-07-29 | 結合分子 |
JP2011166561A Active JP5855381B2 (ja) | 2004-07-22 | 2011-07-29 | 結合分子 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007522034A Pending JP2008512987A (ja) | 2004-07-22 | 2005-07-22 | 結合分子 |
JP2011166562A Expired - Fee Related JP5888893B2 (ja) | 2004-07-22 | 2011-07-29 | 結合分子 |
Country Status (21)
Country | Link |
---|---|
US (7) | US20090285805A1 (ja) |
EP (6) | EP3272770B1 (ja) |
JP (3) | JP2008512987A (ja) |
KR (4) | KR101457753B1 (ja) |
CN (2) | CN102659940B (ja) |
AU (2) | AU2005263994B2 (ja) |
BR (1) | BRPI0513577A (ja) |
CA (1) | CA2580336C (ja) |
CY (2) | CY1115762T1 (ja) |
DK (3) | DK1864998T4 (ja) |
ES (3) | ES2635497T3 (ja) |
HU (1) | HUE034335T2 (ja) |
LT (1) | LT2311874T (ja) |
MX (2) | MX2007000921A (ja) |
PL (2) | PL1776383T3 (ja) |
PT (2) | PT1776383E (ja) |
RU (1) | RU2398882C2 (ja) |
SG (1) | SG188080A1 (ja) |
SI (2) | SI2311874T1 (ja) |
WO (1) | WO2006008548A2 (ja) |
ZA (3) | ZA200701186B (ja) |
Families Citing this family (121)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
SI2311874T1 (sl) * | 2004-07-22 | 2017-12-29 | Erasmus University Medical Center Rotterdam Department of Cell Biology and Genetics | Vezavne molekule |
SI1912675T1 (sl) | 2005-07-25 | 2014-07-31 | Emergent Product Development Seattle, Llc | zmanjšanje števila celic B z uporabo molekul, ki se specifično vežejo na CD37 in CD20 |
GB0601513D0 (en) * | 2006-01-25 | 2006-03-08 | Univ Erasmus Medical Ct | Binding molecules 3 |
GB0618345D0 (en) * | 2006-09-18 | 2006-10-25 | Univ Erasmus | Binding molecules |
WO2007096779A2 (en) | 2006-01-25 | 2007-08-30 | Erasmus University Medical Center Rotterdam | Generation of heavy-chain only antibodies in transgenic animals |
MX363905B (es) * | 2006-06-12 | 2019-04-08 | Aptevo Res & Development Llc | Proteinas de union multivalentes monocatenarias con funcion efectora. |
WO2008074840A2 (en) | 2006-12-19 | 2008-06-26 | Ablynx N.V. | Amino acid sequences directed against a metalloproteinase from the adam family and polypeptides comprising the same for the treatment of adam-related diseases and disorders |
EP2557090A3 (en) | 2006-12-19 | 2013-05-29 | Ablynx N.V. | Amino acid sequences directed against GPCRs and polypeptides comprising the same for the treatment of GPCR-related diseases and disorders |
GB0706628D0 (en) * | 2007-04-04 | 2007-05-16 | Univ Erasmus | Germ-line manipulation 1 |
KR101886610B1 (ko) | 2007-06-01 | 2018-08-09 | 오픈 모노클로날 테크놀로지, 인코포레이티드 | 내생적 면역글로불린 유전자를 억제하고 트랜스제닉 인간 이디오타입 항체를 생산하기 위한 방법 및 조성물 |
WO2009013620A2 (en) * | 2007-06-11 | 2009-01-29 | Erasmus University Medical Center Rotterdam | Homologous recombination |
CA2691940C (en) * | 2007-07-03 | 2018-03-06 | Joost Alexander Kolkman | Methods for providing improved immunoglobulin sequences |
WO2009068630A1 (en) | 2007-11-27 | 2009-06-04 | Ablynx N.V. | Immunoglobulin constructs |
CA2710483C (en) | 2007-12-26 | 2018-05-08 | Biotest Ag | Methods and agents for improving targeting of cd138 expressing tumor cells |
DK2242772T3 (en) | 2007-12-26 | 2015-01-05 | Biotest Ag | Immunoconjugates that targets CD138, and uses thereof |
CN101952315B (zh) | 2007-12-26 | 2015-04-01 | 生物测试股份公司 | 靶向cd138的试剂及其应用 |
WO2009124931A2 (en) | 2008-04-07 | 2009-10-15 | Ablynx Nv | Amino acid sequences directed against the notch pathways and uses thereof |
EP2132228B1 (en) | 2008-04-11 | 2011-06-22 | Emergent Product Development Seattle, LLC | Cd37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
US9212226B2 (en) | 2008-05-16 | 2015-12-15 | Ablynx N.V. | Amino acid sequences directed against CXCR4 and other GPCRs and compounds comprising the same |
ES2436044T3 (es) | 2008-05-23 | 2013-12-26 | Ablexis, Llc | Procedimiento de generación de anticuerpos de dominio VL individual en animales transgénicos |
DK2285408T3 (en) | 2008-06-05 | 2019-02-04 | Ablynx Nv | AMINO ACID SEQUENCES AGAINST COATING PROTEINS IN A VIRUS AND POLYPEPTIDES INCLUDING THESE FOR TREATMENT OF VIRUSAL DISEASES |
US20100136584A1 (en) * | 2008-09-22 | 2010-06-03 | Icb International, Inc. | Methods for using antibodies and analogs thereof |
SG172176A1 (en) | 2008-12-18 | 2011-07-28 | Univ Erasmus Medical Ct | Non-human transgenic animals expressing humanised antibodies and use therof |
US9260508B2 (en) | 2008-12-19 | 2016-02-16 | Ablynx N.V. | Method for generation of immunoglobulin sequences |
WO2010079149A1 (de) | 2009-01-09 | 2010-07-15 | Ipk Gatersleben | Fusionsantikörper |
GB0905023D0 (en) * | 2009-03-24 | 2009-05-06 | Univ Erasmus Medical Ct | Binding molecules |
US9445581B2 (en) | 2012-03-28 | 2016-09-20 | Kymab Limited | Animal models and therapeutic molecules |
US20120204278A1 (en) | 2009-07-08 | 2012-08-09 | Kymab Limited | Animal models and therapeutic molecules |
ES2965212T3 (es) | 2009-07-08 | 2024-04-11 | Kymab Ltd | Modelos de animales y moléculas terapéuticas |
LT2954779T (lt) * | 2009-12-10 | 2019-05-27 | Regeneron Pharmaceuticals, Inc. | Pelės, gaminančios sunkiosios grandinės antikūnus |
EP2513145B1 (en) | 2009-12-14 | 2018-01-24 | Ablynx N.V. | Single variable domain antibodies against ox40l, constructs and therapeutic use |
US9120855B2 (en) | 2010-02-10 | 2015-09-01 | Novartis Ag | Biologic compounds directed against death receptor 5 |
RU2624027C2 (ru) * | 2010-04-23 | 2017-06-30 | Дженентек, Инк. | Получение гетеромультимерных белков |
NZ707327A (en) | 2010-08-02 | 2017-01-27 | Regeneron Pharma | Mice that make binding proteins comprising vl domains |
EP2638068B1 (en) | 2010-11-08 | 2018-12-26 | Novartis AG | Cxcr2 binding polypeptides |
WO2012122512A1 (en) * | 2011-03-10 | 2012-09-13 | Hco Antibody, Inc. | Recombinant production of mixtures of single chain antibodies |
UA117218C2 (uk) | 2011-05-05 | 2018-07-10 | Мерк Патент Гмбх | Поліпептид, спрямований проти il-17a, il-17f та/або il17-a/f |
WO2012156981A1 (en) | 2011-05-13 | 2012-11-22 | Cadila Healthcare Limited | Pharmaceutical compositions of lurasidone |
CA2846322A1 (en) | 2011-09-19 | 2013-03-28 | Kymab Limited | Manipulation of immunoglobulin gene diversity and multi-antibody therapeutics |
WO2013045916A1 (en) | 2011-09-26 | 2013-04-04 | Kymab Limited | Chimaeric surrogate light chains (slc) comprising human vpreb |
US9253965B2 (en) | 2012-03-28 | 2016-02-09 | Kymab Limited | Animal models and therapeutic molecules |
US9409899B2 (en) | 2012-02-13 | 2016-08-09 | Cadila Healthcare Limited | Process for preparing benzisothiazol-3-yl-piperazin-1-yl-methyl-cyclo hexylmethanisoindol-1,3-dione and its intermediates |
US9815909B2 (en) * | 2012-03-13 | 2017-11-14 | Novimmune S.A. | Readily isolated bispecific antibodies with native immunoglobulin format |
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 |
US9765342B2 (en) | 2012-04-11 | 2017-09-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric antigen receptors targeting B-cell maturation antigen |
US9328174B2 (en) | 2012-05-09 | 2016-05-03 | Novartis Ag | Chemokine receptor binding polypeptides |
LT2931030T (lt) | 2012-12-14 | 2020-11-10 | Open Monoclonal Technology, Inc. | Polinukleotidai, koduojantys graužikų antikūnus su žmogaus idiotipais, ir juos apimantys gyvūnai |
WO2014141189A1 (en) | 2013-03-14 | 2014-09-18 | Erasmus University Medical Center | Transgenic non-human mammal for antibody production |
US10993420B2 (en) | 2013-03-15 | 2021-05-04 | Erasmus University Medical Center | Production of heavy chain only antibodies in transgenic mammals |
US9788534B2 (en) | 2013-03-18 | 2017-10-17 | Kymab Limited | Animal models and therapeutic molecules |
US9783593B2 (en) | 2013-05-02 | 2017-10-10 | Kymab Limited | Antibodies, variable domains and chains tailored for human use |
US11707056B2 (en) | 2013-05-02 | 2023-07-25 | Kymab Limited | Animals, repertoires and methods |
CN105722855B (zh) * | 2013-09-05 | 2021-04-23 | Igm生物科学股份有限公司 | 恒定链经修饰的双特异性五价和六价Ig-M抗体 |
JP7133902B2 (ja) | 2013-10-01 | 2022-09-09 | カイマブ・リミテッド | 動物モデル及び治療用分子 |
CN105992772A (zh) * | 2014-02-10 | 2016-10-05 | Igm生命科学股份有限公司 | IgA多特异性结合分子 |
KR20210088756A (ko) | 2014-03-21 | 2021-07-14 | 리제너론 파마슈티칼스 인코포레이티드 | 단일 도메인 결합 단백질을 생산하는 비-인간 동물 |
AU2015231155B2 (en) | 2014-03-21 | 2020-11-12 | X-Body, Inc. | Bi-specific antigen-binding polypeptides |
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 |
CN106659765B (zh) | 2014-04-04 | 2021-08-13 | 德玛医药 | 二脱水半乳糖醇及其类似物或衍生物用于治疗非小细胞肺癌和卵巢癌的用途 |
ES2701061T5 (es) | 2014-10-22 | 2022-05-09 | Crescendo Biologics Ltd | Ratones transgénicos |
AU2016232715A1 (en) | 2015-03-19 | 2017-09-28 | Regeneron Pharmaceuticals, Inc. | Non-human animals that select for light chain variable regions that bind antigen |
WO2017020001A2 (en) | 2015-07-29 | 2017-02-02 | Allergan, Inc. | Heavy chain only antibodies to ang-2 |
CN105384825B (zh) | 2015-08-11 | 2018-06-01 | 南京传奇生物科技有限公司 | 一种基于单域抗体的双特异性嵌合抗原受体及其应用 |
AU2016307943A1 (en) | 2015-08-14 | 2018-02-15 | Allergan, Inc. | Heavy chain only antibodies to PDGF |
WO2017053469A2 (en) | 2015-09-21 | 2017-03-30 | Aptevo Research And Development Llc | Cd3 binding polypeptides |
CA2997444A1 (en) | 2015-09-29 | 2017-04-06 | Amgen Inc. | Asgr inhibitors for reducing cholesterol levels |
WO2018014260A1 (en) | 2016-07-20 | 2018-01-25 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
BR112019003547A2 (pt) * | 2016-08-24 | 2019-05-28 | Teneobio Inc | animais transgênicos não humanos que produzem anticorpos modificados somente de cadeia pesada |
WO2018052503A1 (en) | 2016-09-14 | 2018-03-22 | Teneobio, Inc. | Cd3 binding antibodies |
WO2018068201A1 (en) | 2016-10-11 | 2018-04-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against ctla-4 |
EP3332637A1 (en) * | 2016-12-09 | 2018-06-13 | Universitätsklinikum Hamburg-Eppendorf | Vhh-containing heavy chain antibody and production thereof |
JP7254699B2 (ja) | 2016-12-21 | 2023-04-10 | テネオバイオ, インコーポレイテッド | 抗bcma重鎖のみ抗体 |
KR20190104400A (ko) | 2017-01-19 | 2019-09-09 | 오픈 모노클로날 테크놀로지, 인코포레이티드 | 다중 중쇄 면역글로불린 유전자좌를 갖는 트랜스제닉 설치류 기원의 인간 항체 |
CN117838729A (zh) | 2017-04-13 | 2024-04-09 | 森迪生物科学公司 | 组合癌症免疫疗法 |
CN117567624A (zh) | 2017-06-20 | 2024-02-20 | 特纳奥尼股份有限公司 | 仅有重链的抗bcma抗体 |
KR20200018498A (ko) | 2017-06-20 | 2020-02-19 | 테네오바이오, 인코포레이티드 | 항-bcma 중쇄-단독 항체 |
US20200207867A1 (en) | 2017-09-13 | 2020-07-02 | Teneobio, Inc. | Heavy chain antibodies binding to ectoenzymes |
WO2019120232A1 (en) | 2017-12-20 | 2019-06-27 | Harbour Biomed (Shanghai) Co., Ltd | Antibodies binding ctla-4 and uses thereof |
US11873336B2 (en) | 2017-12-22 | 2024-01-16 | Teneobio, Inc. | Heavy chain antibodies binding to CD22 |
CA3082280A1 (en) | 2017-12-28 | 2019-07-04 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against tigit |
EP3740507A4 (en) | 2018-01-15 | 2022-08-24 | Nanjing Legend Biotech Co., Ltd. | SINGLE DOMAIN ANTIBODIES AND VARIANTS THEREOF AGAINST PD-1 |
WO2019185040A1 (en) | 2018-03-30 | 2019-10-03 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies against lag-3 and uses thereof |
KR102115300B1 (ko) * | 2018-06-01 | 2020-05-26 | 재단법인 목암생명과학연구소 | 항체 라이브러리 및 이를 이용한 항체 스크리닝 방법 |
JP2021526828A (ja) * | 2018-06-13 | 2021-10-11 | クリスタル バイオサイエンス インコーポレイテッドCrystal Bioscience Inc. | 遺伝子変換による自律型重鎖可変ドメインの改変による抗体の産生 |
JP7439046B2 (ja) | 2018-07-20 | 2024-02-27 | テネオツー・インコーポレイテッド | Cd19に結合する重鎖抗体 |
GB2576914A (en) | 2018-09-06 | 2020-03-11 | Kymab Ltd | Antigen-binding molecules comprising unpaired variable domains produced in mammals |
US11419898B2 (en) | 2018-10-17 | 2022-08-23 | Senti Biosciences, Inc. | Combinatorial cancer immunotherapy |
KR20210086651A (ko) | 2018-10-26 | 2021-07-08 | 테네오바이오, 인코포레이티드 | Cd38에 결합하는 중쇄 항체 |
WO2020169755A2 (en) | 2019-02-20 | 2020-08-27 | Harbour Antibodies Bv | Antibodies |
KR20210149076A (ko) | 2019-04-05 | 2021-12-08 | 테네오바이오, 인코포레이티드 | Psma에 결합하는 중쇄 항체 |
JP2022535060A (ja) | 2019-06-07 | 2022-08-04 | アムジエン・インコーポレーテツド | 選択的に切断可能なリンカーを有する二重特異性結合構築物 |
AR119746A1 (es) | 2019-06-14 | 2022-01-05 | Teneobio Inc | Anticuerpos multiespecíficos de cadena pesada que se unen a cd22 y cd3 |
JP2022545541A (ja) * | 2019-08-28 | 2022-10-27 | センティ バイオサイエンシズ インコーポレイテッド | 組み合わせがん免疫療法 |
CN115023441A (zh) | 2019-12-18 | 2022-09-06 | 特诺福尔股份有限公司 | 与cd38结合的重链抗体 |
GB202003632D0 (en) | 2020-03-12 | 2020-04-29 | Harbour Antibodies Bv | SARS-Cov-2 (SARS2, COVID-19) antibodies |
UY39191A (es) | 2020-04-29 | 2021-11-30 | Teneobio Inc | Anticuerpos de cadena pesada multiespecíficos con regiones constantes de cadena pesada modificadas |
CN115803057A (zh) | 2020-04-29 | 2023-03-14 | 特纳奥尼公司 | 治疗多发性骨髓瘤的方法 |
CN115894703A (zh) | 2020-04-29 | 2023-04-04 | 特尼奥生物股份有限公司 | 具有经修饰重链恒定区的多特异性重链抗体 |
CA3184351A1 (en) | 2020-06-04 | 2021-12-09 | Amgen Inc. | Bispecific binding constructs |
CN116472049A (zh) | 2020-06-30 | 2023-07-21 | 特尼奥生物股份有限公司 | 与bcma结合的多特异性抗体 |
US20220090060A1 (en) | 2020-09-11 | 2022-03-24 | Regeneron Pharmaceuticals, Inc. | Identification and production of antigen-specific antibodies |
GB202017555D0 (en) | 2020-11-06 | 2020-12-23 | Harbour Antibodies Bv | Antibody-conjugated nanoparticles |
TW202233684A (zh) | 2020-11-18 | 2022-09-01 | 美商泰尼歐生物公司 | 結合於葉酸受體α之重鏈抗體 |
EP4255931A1 (en) | 2020-12-03 | 2023-10-11 | Amgen Inc. | Immunoglobuline constructs with multiple binding domains |
KR20230150779A (ko) | 2020-12-09 | 2023-10-31 | 트리아니, 인코포레이티드 | 중쇄-단독 항체 |
EP4262373A1 (en) | 2020-12-16 | 2023-10-25 | Regeneron Pharmaceuticals, Inc. | Mice expressing humanized fc alpha receptors |
IL305301A (en) | 2021-02-19 | 2023-10-01 | Us Health | Single domain antibodies neutralizing SARS CoV-2 |
CA3211138A1 (en) | 2021-02-25 | 2022-09-01 | Teneobio, Inc. | Anti-psma antibodies and car-t structures |
CA3211142A1 (en) | 2021-02-26 | 2022-09-01 | Teneobio, Inc. | Anti-muc1-c antibodies and car-t structures |
TW202304994A (zh) | 2021-04-02 | 2023-02-01 | 美商泰尼歐生物公司 | 促效性抗il-2r抗體及使用方法 |
CA3214283A1 (en) | 2021-04-06 | 2022-10-13 | Teneobio, Inc. | Anti-cd19 antibodies and car-t structures |
KR20230171952A (ko) | 2021-04-16 | 2023-12-21 | 테네오바이오, 인코포레이티드 | 항-cd20 항체 및 car-t 구조 |
WO2022235988A1 (en) * | 2021-05-05 | 2022-11-10 | Leveragen, Inc. | Engineered non-human animals for producing antibodies |
WO2022271987A1 (en) | 2021-06-23 | 2022-12-29 | TeneoFour, Inc. | Anti-cd38 antibodies and epitopes of same |
WO2023004197A1 (en) | 2021-07-23 | 2023-01-26 | Teneoten, Inc. | Heavy chain antibodies binding to hepatitis b surface antigen |
GB202112935D0 (en) | 2021-09-10 | 2021-10-27 | Harbour Antibodies Bv | Sars-cov-2 (sars2, covid-19) heavy chain only antibodies |
WO2023036982A1 (en) | 2021-09-10 | 2023-03-16 | Harbour Antibodies Bv | Anti-sars2-s antibodies |
WO2024077044A1 (en) | 2022-10-05 | 2024-04-11 | Amgen Inc. | Combination therapies comprising t-cell redirecting therapies and agonistic anti-il-2r antibodies or fragments thereof |
WO2024083843A1 (en) | 2022-10-18 | 2024-04-25 | Confo Therapeutics N.V. | Amino acid sequences directed against the melanocortin 4 receptor and polypeptides comprising the same for the treatment of mc4r-related diseases and disorders |
Family Cites Families (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0144488A3 (en) | 1980-08-11 | 1985-07-10 | BAUSCH & LOMB INCORPORATED | Apparatus for supporting and positioning the halves of a refractor |
JPH02500329A (ja) | 1987-05-21 | 1990-02-08 | クリエイテイブ・バイオマリキユールズ・インコーポレーテツド | ターゲット化多機能蛋白質 |
JP3771253B2 (ja) | 1988-09-02 | 2006-04-26 | ダイアックス コープ. | 新規な結合タンパク質の生成と選択 |
AU634186B2 (en) | 1988-11-11 | 1993-02-18 | Medical Research Council | Single domain ligands, receptors comprising said ligands, methods for their production, and use of said ligands and receptors |
US5175384A (en) | 1988-12-05 | 1992-12-29 | Genpharm International | Transgenic mice depleted in mature t-cells and methods for making transgenic mice |
US6673986B1 (en) | 1990-01-12 | 2004-01-06 | Abgenix, Inc. | Generation of xenogeneic antibodies |
US6150584A (en) * | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
WO1991010741A1 (en) | 1990-01-12 | 1991-07-25 | Cell Genesys, Inc. | Generation of xenogeneic antibodies |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US7041871B1 (en) | 1995-10-10 | 2006-05-09 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5843440A (en) | 1990-10-03 | 1998-12-01 | Redcell Canada, Inc. | Cellular and serum protein anchors for modulating pharmacokinetics |
WO1992005801A1 (en) | 1990-10-04 | 1992-04-16 | University Of Virginia Alumni Patents Foundation | Primate erythrocyte bound monoclonal antibody heteropolymers |
DK1087013T3 (da) * | 1992-08-21 | 2009-05-11 | Univ Bruxelles | Immunoglobuliner uden lette kæder |
EP0739981A1 (en) | 1995-04-25 | 1996-10-30 | Vrije Universiteit Brussel | Variable fragments of immunoglobulins - use for therapeutic or veterinary purposes |
WO1998021355A1 (en) * | 1996-11-15 | 1998-05-22 | Life Technologies, Inc. | Mutants of green fluorescent protein |
EP1500329B1 (en) | 1996-12-03 | 2012-03-21 | Amgen Fremont Inc. | Human antibodies that specifically bind human TNF alpha |
EP0954978B1 (en) * | 1998-03-12 | 2011-11-30 | VHsquared Limited | New products comprising inactivated yeasts or moulds provided with active antibodies |
US7083950B2 (en) † | 1998-09-25 | 2006-08-01 | Regeneron Pharmaceuticals, Inc. | High affinity fusion proteins and therapeutic and diagnostic methods for use |
CA2634294A1 (en) * | 2000-08-03 | 2002-02-14 | Therapeutic Human Polyclonals, Inc. | Production of humanized antibodies in transgenic animals |
AU2001278154A1 (en) | 2000-08-04 | 2002-02-18 | Incyte Genomics, Inc. | Drug metabolizing enzymes |
US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US6992174B2 (en) * | 2001-03-30 | 2006-01-31 | Emd Lexigen Research Center Corp. | Reducing the immunogenicity of fusion proteins |
US20030022240A1 (en) | 2001-04-17 | 2003-01-30 | Peizhi Luo | Generation and affinity maturation of antibody library in silico |
GB0110029D0 (en) * | 2001-04-24 | 2001-06-13 | Grosveld Frank | Transgenic animal |
CN100497389C (zh) | 2001-06-13 | 2009-06-10 | 根马布股份公司 | 表皮生长因子受体(egfr)的人单克隆抗体 |
GB0115256D0 (en) | 2001-06-21 | 2001-08-15 | Babraham Inst | Mouse light chain locus |
WO2004003019A2 (en) | 2002-06-28 | 2004-01-08 | Domantis Limited | Immunoglobin single variant antigen-binding domains and dual-specific constructs |
EP1399484B1 (en) * | 2001-06-28 | 2010-08-11 | Domantis Limited | Dual-specific ligand and its use |
US6880232B2 (en) | 2001-09-26 | 2005-04-19 | Intel Corporation | Method of making an electrical inductor using a sacrificial electrode |
JP2005289809A (ja) * | 2001-10-24 | 2005-10-20 | Vlaams Interuniversitair Inst Voor Biotechnologie Vzw (Vib Vzw) | 突然変異重鎖抗体 |
US6755339B2 (en) † | 2002-06-21 | 2004-06-29 | Delphi Technologies, Inc. | Fluxing apparatus for applying powdered flux |
GB0218030D0 (en) | 2002-08-02 | 2002-09-11 | Minos Biosystems | Multi-submit protein production system |
GB0228210D0 (en) * | 2002-12-03 | 2003-01-08 | Babraham Inst | Single chain antibodies |
GB0230203D0 (en) | 2002-12-27 | 2003-02-05 | Domantis Ltd | Fc fusion |
AU2004215125B2 (en) | 2003-02-26 | 2011-01-06 | Institute For Research In Biomedicine | Monoclonal antibody production by EBV transformation of B cells |
DE602005027309D1 (de) † | 2004-01-16 | 2011-05-19 | Regeneron Pharma | Zur aktivierung von rezeptoren fähige fusionspolypeptide |
US7785903B2 (en) | 2004-04-09 | 2010-08-31 | Genentech, Inc. | Variable domain library and uses |
SI2311874T1 (sl) * | 2004-07-22 | 2017-12-29 | Erasmus University Medical Center Rotterdam Department of Cell Biology and Genetics | Vezavne molekule |
US20080184380A1 (en) | 2004-10-22 | 2008-07-31 | Therapeutic Human Polyclonals Inc. | Suppression of Endogenous Immunoglobulin Expression in Non-Human Transgenic Animals |
AU2005325801A1 (en) | 2005-01-31 | 2006-08-03 | Ablynx N.V. | Method for generating variable domain sequences of heavy chain antibodies |
PL3415535T3 (pl) | 2005-05-20 | 2021-06-14 | Ablynx N.V. | Ulepszone Nanociała TM do leczenia zaburzeń, w których pośredniczy agregacja |
GB0618345D0 (en) * | 2006-09-18 | 2006-10-25 | Univ Erasmus | Binding molecules |
WO2007096779A2 (en) * | 2006-01-25 | 2007-08-30 | Erasmus University Medical Center Rotterdam | Generation of heavy-chain only antibodies in transgenic animals |
AU2007249408A1 (en) | 2006-05-09 | 2007-11-22 | Genentech, Inc. | Binding polypeptides with optimized scaffolds |
US7731969B1 (en) | 2006-12-06 | 2010-06-08 | Neoclone Biotechnology International, Llc | Methods for developing and producing antigen-specific antibody-producing cells |
KR101886610B1 (ko) | 2007-06-01 | 2018-08-09 | 오픈 모노클로날 테크놀로지, 인코포레이티드 | 내생적 면역글로불린 유전자를 억제하고 트랜스제닉 인간 이디오타입 항체를 생산하기 위한 방법 및 조성물 |
WO2009013620A2 (en) | 2007-06-11 | 2009-01-29 | Erasmus University Medical Center Rotterdam | Homologous recombination |
GB0905023D0 (en) | 2009-03-24 | 2009-05-06 | Univ Erasmus Medical Ct | Binding molecules |
LT2954779T (lt) | 2009-12-10 | 2019-05-27 | Regeneron Pharmaceuticals, Inc. | Pelės, gaminančios sunkiosios grandinės antikūnus |
DK2550363T3 (en) | 2011-02-25 | 2015-03-23 | Regeneron Pharma | ADAM6 mice |
WO2012122512A1 (en) | 2011-03-10 | 2012-09-13 | Hco Antibody, Inc. | Recombinant production of mixtures of single chain antibodies |
GB2502127A (en) | 2012-05-17 | 2013-11-20 | Kymab Ltd | Multivalent antibodies and in vivo methods for their production |
LT2931030T (lt) | 2012-12-14 | 2020-11-10 | Open Monoclonal Technology, Inc. | Polinukleotidai, koduojantys graužikų antikūnus su žmogaus idiotipais, ir juos apimantys gyvūnai |
US10993420B2 (en) | 2013-03-15 | 2021-05-04 | Erasmus University Medical Center | Production of heavy chain only antibodies in transgenic mammals |
-
2005
- 2005-07-22 SI SI200532162T patent/SI2311874T1/sl unknown
- 2005-07-22 US US11/658,361 patent/US20090285805A1/en not_active Abandoned
- 2005-07-22 EP EP17173113.6A patent/EP3272770B1/en active Active
- 2005-07-22 MX MX2007000921A patent/MX2007000921A/es active IP Right Grant
- 2005-07-22 KR KR1020117019563A patent/KR101457753B1/ko active IP Right Review Request
- 2005-07-22 CN CN201210057668.0A patent/CN102659940B/zh active Active
- 2005-07-22 ES ES10179784.3T patent/ES2635497T3/es active Active
- 2005-07-22 BR BRPI0513577-0A patent/BRPI0513577A/pt active Search and Examination
- 2005-07-22 EP EP05766644.8A patent/EP1776383B1/en not_active Revoked
- 2005-07-22 LT LTEP10179784.3T patent/LT2311874T/lt unknown
- 2005-07-22 AU AU2005263994A patent/AU2005263994B2/en active Active
- 2005-07-22 RU RU2007106728/13A patent/RU2398882C2/ru active
- 2005-07-22 CN CN201210057684.XA patent/CN102659941B/zh active Active
- 2005-07-22 WO PCT/GB2005/002892 patent/WO2006008548A2/en active Application Filing
- 2005-07-22 EP EP07075586.3A patent/EP1864998B2/en active Active
- 2005-07-22 KR KR1020107026625A patent/KR101151957B1/ko active IP Right Grant
- 2005-07-22 HU HUE10179784A patent/HUE034335T2/en unknown
- 2005-07-22 PT PT57666448T patent/PT1776383E/pt unknown
- 2005-07-22 EP EP08075481A patent/EP1978032A3/en not_active Withdrawn
- 2005-07-22 DK DK07075586.3T patent/DK1864998T4/da active
- 2005-07-22 EP EP23218163.6A patent/EP4353819A2/en active Pending
- 2005-07-22 ES ES07075586T patent/ES2440990T5/es active Active
- 2005-07-22 CA CA2580336A patent/CA2580336C/en active Active
- 2005-07-22 PL PL05766644T patent/PL1776383T3/pl unknown
- 2005-07-22 SI SI200531906T patent/SI1776383T1/sl unknown
- 2005-07-22 KR KR1020127016031A patent/KR101443473B1/ko active IP Right Grant
- 2005-07-22 PL PL10179784T patent/PL2311874T3/pl unknown
- 2005-07-22 SG SG2013004643A patent/SG188080A1/en unknown
- 2005-07-22 ES ES05766644.8T patent/ES2523661T3/es active Active
- 2005-07-22 PT PT101797843T patent/PT2311874T/pt unknown
- 2005-07-22 JP JP2007522034A patent/JP2008512987A/ja active Pending
- 2005-07-22 EP EP10179784.3A patent/EP2311874B1/en active Active
- 2005-07-22 DK DK10179784.3T patent/DK2311874T3/en active
- 2005-07-22 KR KR1020077004055A patent/KR101422286B1/ko active IP Right Grant
- 2005-07-22 DK DK05766644.8T patent/DK1776383T3/da active
-
2007
- 2007-01-22 MX MX2012000436A patent/MX338603B/es unknown
- 2007-02-09 ZA ZA2007/01186A patent/ZA200701186B/en unknown
-
2008
- 2008-02-26 ZA ZA2008/01820A patent/ZA200801820B/en unknown
-
2009
- 2009-12-23 US US12/645,684 patent/US8921524B2/en active Active
- 2009-12-23 US US12/645,653 patent/US8921522B2/en active Active
-
2010
- 2010-08-24 AU AU2010212518A patent/AU2010212518B2/en active Active
-
2011
- 2011-01-25 US US13/013,156 patent/US20110118444A1/en active Pending
- 2011-07-29 JP JP2011166562A patent/JP5888893B2/ja not_active Expired - Fee Related
- 2011-07-29 JP JP2011166561A patent/JP5855381B2/ja active Active
-
2013
- 2013-02-25 ZA ZA2013/01416A patent/ZA201301416B/en unknown
- 2013-03-15 US US13/837,402 patent/US9353179B2/en active Active
- 2013-03-15 US US13/837,520 patent/US9346877B2/en active Active
-
2014
- 2014-11-17 CY CY20141100953T patent/CY1115762T1/el unknown
-
2017
- 2017-08-11 CY CY20171100869T patent/CY1119561T1/el unknown
-
2018
- 2018-04-16 US US15/953,622 patent/US10906970B2/en active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5855381B2 (ja) | 結合分子 | |
AU2011203061B2 (en) | Binding molecules |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130208 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130508 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130513 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130605 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130610 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20130709 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20130802 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131202 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20140204 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20140228 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20150706 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151013 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20151209 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5855381 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 |
|
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 |