JP7450743B2 - 抗ヒトcd19抗体 - Google Patents
抗ヒトcd19抗体 Download PDFInfo
- Publication number
- JP7450743B2 JP7450743B2 JP2022551767A JP2022551767A JP7450743B2 JP 7450743 B2 JP7450743 B2 JP 7450743B2 JP 2022551767 A JP2022551767 A JP 2022551767A JP 2022551767 A JP2022551767 A JP 2022551767A JP 7450743 B2 JP7450743 B2 JP 7450743B2
- Authority
- JP
- Japan
- Prior art keywords
- seq
- antibody
- human
- cell
- nucleic acid
- 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
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 title description 170
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 title description 168
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 110
- 150000007523 nucleic acids Chemical class 0.000 claims description 104
- 210000004027 cell Anatomy 0.000 claims description 98
- 239000013598 vector Substances 0.000 claims description 72
- 108020004707 nucleic acids Proteins 0.000 claims description 43
- 102000039446 nucleic acids Human genes 0.000 claims description 43
- 101100383038 Homo sapiens CD19 gene Proteins 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 13
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims description 10
- 201000006417 multiple sclerosis Diseases 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-UHFFFAOYSA-N 0.000 claims description 6
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 6
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 6
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 6
- 206010047115 Vasculitis Diseases 0.000 claims description 6
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 6
- 208000008795 neuromyelitis optica Diseases 0.000 claims description 6
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
- 201000011152 Pemphigus Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000001976 pemphigus vulgaris Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 3
- 230000000295 complement effect Effects 0.000 claims description 2
- 238000012258 culturing Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000001963 growth medium Substances 0.000 claims description 2
- 210000004962 mammalian cell Anatomy 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 208000003926 Myelitis Diseases 0.000 claims 2
- 206010003549 asthenia Diseases 0.000 claims 2
- 241000282414 Homo sapiens Species 0.000 description 93
- 108091028043 Nucleic acid sequence Proteins 0.000 description 59
- 241000699670 Mus sp. Species 0.000 description 37
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 35
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 35
- 210000004369 blood Anatomy 0.000 description 30
- 239000008280 blood Substances 0.000 description 30
- 230000027455 binding Effects 0.000 description 27
- 230000000779 depleting effect Effects 0.000 description 27
- 108020004414 DNA Proteins 0.000 description 20
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 15
- 239000012636 effector Substances 0.000 description 15
- 229940121470 obexelimab Drugs 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 13
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 13
- 239000002953 phosphate buffered saline Substances 0.000 description 13
- 208000009386 Experimental Arthritis Diseases 0.000 description 12
- 241001529936 Murinae Species 0.000 description 12
- 230000004069 differentiation Effects 0.000 description 12
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 241000282567 Macaca fascicularis Species 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- 239000000427 antigen Substances 0.000 description 10
- 102000036639 antigens Human genes 0.000 description 10
- 108091007433 antigens Proteins 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 10
- 238000000338 in vitro Methods 0.000 description 10
- 230000024704 B cell apoptotic process Effects 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 201000002491 encephalomyelitis Diseases 0.000 description 9
- 102000001708 Protein Isoforms Human genes 0.000 description 8
- 108010029485 Protein Isoforms Proteins 0.000 description 8
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000012091 fetal bovine serum Substances 0.000 description 8
- 210000003720 plasmablast Anatomy 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 8
- 230000004663 cell proliferation Effects 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 229940027941 immunoglobulin g Drugs 0.000 description 7
- 210000000440 neutrophil Anatomy 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000035899 viability Effects 0.000 description 7
- 239000004793 Polystyrene Substances 0.000 description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 210000001806 memory b lymphocyte Anatomy 0.000 description 6
- 229920002223 polystyrene Polymers 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 230000003442 weekly effect Effects 0.000 description 6
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 5
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 5
- 230000003844 B-cell-activation Effects 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 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 5
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 5
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000009871 nonspecific binding Effects 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 108091008875 B cell receptors Proteins 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- 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 4
- 241000282412 Homo Species 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 238000010162 Tukey test Methods 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 206010028417 myasthenia gravis Diseases 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000012146 running buffer Substances 0.000 description 4
- 229940054269 sodium pyruvate Drugs 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- 108090000672 Annexin A5 Proteins 0.000 description 3
- 102000004121 Annexin A5 Human genes 0.000 description 3
- 101100476210 Caenorhabditis elegans rnt-1 gene Proteins 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 238000012286 ELISA Assay Methods 0.000 description 3
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 3
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 3
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 3
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 238000003782 apoptosis assay Methods 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 239000005018 casein Substances 0.000 description 3
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 3
- 235000021240 caseins Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 235000013312 flour Nutrition 0.000 description 3
- 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 3
- 239000012634 fragment Substances 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000007837 negative regulation of B cell activation Effects 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 2
- 102100032768 Complement receptor type 2 Human genes 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 2
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 2
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 description 2
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 2
- 102100022964 Immunoglobulin kappa variable 3-20 Human genes 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 102100022338 Integrin alpha-M Human genes 0.000 description 2
- 101000974353 Mus musculus Nuclear receptor coactivator 5 Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 102220567143 Ornithine decarboxylase antizyme 1_F54Y_mutation Human genes 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 108010081690 Pertussis Toxin Proteins 0.000 description 2
- 101710138747 Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- 102220471540 Single-stranded DNA cytosine deaminase_Y31H_mutation Human genes 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 238000012754 cardiac puncture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000018937 joint inflammation Diseases 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 231100000219 mutagenic Toxicity 0.000 description 2
- 230000003505 mutagenic effect Effects 0.000 description 2
- 230000014089 negative regulation of B cell differentiation Effects 0.000 description 2
- 238000004091 panning Methods 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940121503 tafasitamab Drugs 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 101150011571 BSL2 gene Proteins 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 102100027221 CD81 antigen Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 229940046168 CpG oligodeoxynucleotide Drugs 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102220488661 Dimethylglycine dehydrogenase, mitochondrial_F29I_mutation Human genes 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108091006020 Fc-tagged proteins Proteins 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000914479 Homo sapiens CD81 antigen Proteins 0.000 description 1
- 101001037147 Homo sapiens Immunoglobulin heavy variable 1-69 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 102100040232 Immunoglobulin heavy variable 1-69 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 1
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108090000143 Mouse Proteins Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 102220592550 Neuroserpin_S52R_mutation Human genes 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 108010010974 Proteolipids Proteins 0.000 description 1
- 102000016202 Proteolipids Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102220493341 Sodium/calcium exchanger 3_H34A_mutation Human genes 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102220504159 Testis-specific XK-related protein, Y-linked 2_N93Q_mutation Human genes 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 description 1
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 1
- 102220469752 Voltage-dependent L-type calcium channel subunit beta-2_G50D_mutation Human genes 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- GGKQIOFASHYUJZ-UHFFFAOYSA-N ametoctradin Chemical compound NC1=C(CCCCCCCC)C(CC)=NC2=NC=NN21 GGKQIOFASHYUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000011948 assay development Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012512 bulk drug substance Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 238000013368 capillary electrophoresis sodium dodecyl sulfate analysis Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012468 concentrated sample Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003210 demyelinating effect Effects 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000002998 immunogenetic effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 229950005015 inebilizumab Drugs 0.000 description 1
- 229940050282 inebilizumab-cdon Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012004 kinetic exclusion assay Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 108010064578 myelin proteolipid protein (139-151) Proteins 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000021766 negative regulation of B cell proliferation Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 108010087904 neutravidin Proteins 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000012510 peptide mapping method Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 230000003234 polygenic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 230000029610 recognition of host Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 102220137600 rs112862820 Human genes 0.000 description 1
- 102200077165 rs118204021 Human genes 0.000 description 1
- 102220277465 rs1403203490 Human genes 0.000 description 1
- 102220125995 rs144185168 Human genes 0.000 description 1
- 102220286033 rs1553301271 Human genes 0.000 description 1
- 102200126997 rs17081389 Human genes 0.000 description 1
- 102200097265 rs199472846 Human genes 0.000 description 1
- 102200124819 rs28928899 Human genes 0.000 description 1
- 102220040213 rs587778234 Human genes 0.000 description 1
- 102220170950 rs769916550 Human genes 0.000 description 1
- 102220072337 rs794728990 Human genes 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000013389 whole blood assay Methods 0.000 description 1
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- 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
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
図1A~図1Bは、抗ヒトCD19親抗体C323(図1A)および最適化された抗ヒトCD19抗体CB3f(図1B)の表面疎水性プロファイルを示す。
図2は、ELISAアッセイにおける抗ヒトCD19抗体のヒトCD19への結合を示す。
図3は、抗ヒトCD19 mAb CB3f による初代B細胞増殖の阻害を示す。
図4は、抗ヒトCD19 mAb CB3fによる全血中のB細胞活性化の阻害を示す。
図5は、抗ヒトCD19 mAb CB3fによるB細胞の形質芽細胞への分化の阻害を示す。
図6A~図6Bは、抗ヒトCD19 mAb CB3fがCDC(図6A)およびADCC(図6B)活性を欠いていることを示す。
図7は、ヒト全血中の細胞に対する抗ヒトCD19 mAb CB3fおよびオベキセリマブの結合特異性を示す。
図8は、オベキシリマブと抗ヒトCD19 mAb CB3fによるB細胞アポトーシスの誘導における違いを示す。
図9A~図9Bは、抗ヒトCD19 mAb CB3fで処理したNSGマウスにおける処理後6日目(図9A)および10日目(図9B)のヒトIgMの減少を示す。
図10は、抗ヒトCD19 mAb CB3fで処理したNSGマウスのヒトB細胞におけるCD86発現の減少を示す。
図11は、抗ヒトCD19 mAb CB3fで処理したNSGマウスにおけるB細胞の頻度を示す。
図12は、初代ヒトB細胞における抗ヒトCD19 mAb1(CB3f)および抗ヒトCD19 mAb2(C323.C1)の内在化を示す。
図13A~13Bは、マウスコラーゲン誘発関節炎(CIA)モデルにおける非枯渇CD19代替Abと枯渇CD20代替Abの有効性の比較を示す。図13Aは、マウスCIAモデルにおいて、半確立モードでの非枯渇CD19代替Abによる処理が、枯渇CD20代替Abよりも臨床スコアを大きく低下させたことを示す。試験の21日目~42日目のマウスの臨床スコア(n=12/群、アイソタイプ対照で処理した非疾患対照群のn=5を除く)。記号は群の平均を表し、エラーバーは平均の標準誤差(SEM)を表す。動物は19日目から投与を開始した。図13Bは、マウスCIAモデルにおいて、非枯渇CD19代用Abによる処理が、枯渇CD20代用Abよりも臨床スコアAUC(24日目~42日目)を大きく低下させたことを示す。試験の24日目~42日目のマウスの臨床スコアAUC(n=12/群、アイソタイプ対照で処理した非疾患対照群のn=5を除く)。バーは群の平均を表し、エラーバーは平均の標準誤差(SEM)を表す。動物は19日目から投与を開始した。共通の文字を共有しないバーは、互いに有意に異なる(p<0.05、一元配置分散分析(ANOVA)、Tukeyの事後検定)。
図14は、1型糖尿病のNODモデルにおいて、半治療モードでの非枯渇CD19代替Abによる処理が、糖尿病の発生を枯渇CD20代替Abよりも大きく遅らせ、かつ低減させたことを示す。糖尿病の発生率(血糖値が240mg/dlを超えるマウスを糖尿病であるとみなした。>n=10/群、未処理群のn=9を除く)。動物は12週齢から投与を開始した。
図15は、マウスEAEモデルにおいて、半治療モードでの非枯渇CD19代替Abによる半処理が、枯渇CD20代替Abよりも臨床スコアを大きく低下させたことを示す。試験の6日目~42日目のマウスの臨床スコア(n=12/群)。記号は群の平均を表し、エラーバーは平均の標準誤差(SEM)を表す。動物は6日目から投与を開始した。*同日のアイソタイプ対照に対するp<0.05
抗ヒトCD19抗体C323は、ヒトCD19(配列番号56)およびその共受容体CD21でコトランスフェクトされたヒト胎児腎臓(HEK)細胞に対する細胞ベースのパニングを用いてファージディスプレイライブラリーから発見される。親HEK-293細胞に対するネガティブパニングを用いて非特異的な細胞結合剤を除去する。CD19特異的結合は、CD19細胞外ドメイン(ECD)タンパク質を使用してELISAにより確認する。IgGフォーマットへの変換および精製の後、ヒトバーキットリンパ腫細胞株Daudiおよび単離された初代ヒトB細胞を用いて、FACSにより細胞結合を確認する。
CD19に対する結合親和性
CHO細胞上で安定に発現した膜結合型ヒトCD19およびカニクイザルCD19への抗ヒトCD19 mAb CB3fの液相平衡結合親和性を、37℃のMSD溶液平衡滴定(MSD-SET)アッセイによって測定する。さらに、CD19に結合するCB3f Fab断片の一価親和性および動力学を、37℃で表面プラズモン共鳴(SPR)によって測定する。
CB3fの安定性を、賦形剤を含む5mMヒスチジン緩衝液(pH6.0)中で高濃度(約100mg/mL)で評価する。濃縮サンプルを5℃および35℃で4週間の期間にわたってインキュベートする。インキュベーション後、サンプルを、サイズ排除クロマトグラフィー(SEC)により高分子量の割合(%HMW)について、キャピラリー電気泳動により断片化(CE-SDS)について、およびLC-MSペプチドマッピングにより化学修飾(例えば、脱アミド化、異性化、または酸化)について分析する。35℃で4週間後、CB3fは、0.5%のΔ%HMW、0.6%のΔ%断片を示すが、0.2%を超えるCDRの化学修飾は示さない。
溶解度は、100mgのCB3fを30kDaの分子量カットオフ遠心フィルター(例えば、Amicon UCフィルター、Millipore、カタログ番号UFC903024)で約0.5mLの体積に濃縮することによって評価する。Solo VPE分光光度計(C Technologies,Inc)を使用して、280nmでのUV吸光度によってサンプルの最終濃度を測定する。
CB3fの粘度を、異なる賦形剤を含むpH6.0の5mMヒスチジン中約125mg/mLの濃度で、15℃で分析する。粘度測定は、VROC Initium(RheoSense)で行われる。CB3fは、pH6の5mMヒスチジン+280mMマンニトール中131mg/mLで14.2cP、pH6.0の5mMヒスチジン+150mM塩化ナトリウム中で9.5cP、および5mMヒスチジンpH6.0+280mMアルギニン中で6.1cPの粘度を示した。これらの結果は、CB3fが低粘度を示し、高濃度投与が可能であることを示唆している。
CB3fのPK特性を、0.03、0.3、1および10mg/kgのCB3fの単回皮下投与、または1mg/kgのCB3fの単回静脈内ボーラス投与後に、カニクイザルにおいて調べる。CB3fは、調べた皮下投与量範囲にわたって線形のPKを示し、終末半減期(T1/2)が182時間~301時間の範囲である。1mg/kgのCB3fの単回静脈内ボーラス投与後のT1/2は324時間である。
抗ヒトCD19 mAb CB3fによるB細胞増殖のインビトロ阻害。
全血中の初代ヒトB細胞の活性化を阻害する抗ヒトCD19 mAb CB3fの能力を、インビトロ全血活性化アッセイで試験する。
メモリーB細胞単離キット(Miltenyi Biotec)を使用して、健康なドナーのPBMCからヒトメモリーB細胞を単離する。ヒト初代メモリーB細胞を1×106細胞/mLで再懸濁し、完全培地(10%ウシ胎児血清を含むRPMI-1640、1×MEM-非必須アミノ酸、1mMピルビン酸ナトリウム、1×ペニシリン-ストレプトマイシン溶液(すべてCorning)および1×GlutaMAX(Gibco)、0.1%β-メルカプトエタノール(LifeTechnologies)で、ポリスチレン96ウェルU底プレート中、37℃で培養する。細胞を抗ヒトCD19 mAb CB3fで1時間前処理し、50ng/mL抗CD40、200ng/mLBAFF、1ng/mLIL-2、100ng/mLIL-21(すべてR&D)で5日間刺激する。細胞を洗浄し、適切な組み合わせの蛍光色素結合抗体で4℃で30分間染色して、メモリーB細胞の形質芽細胞への分化を同定する:CD38 PE、CD3 FITC(カタログ番号300306)、CD19 APC(カタログ番号363006)(すべてBioLegend)、BD PharminogenのCD20 PerCP-Cy5.5(カタログ番号560736)、および固定可能な生存性色素eFluor(商標)780(eBioscience)。各サンプルについて、生細胞でゲートをかけた少なくとも25,000~50,000の事象を分析する。BD Fortessa X-20でサンプルを取得し、FlowJoソフトウェアを使用して結果を分析する{1]。形質芽細胞のパーセントは、CD38bright/CD20low B細胞の%として定義される。
抗ヒトCD19 mAb CB3fは、B細胞阻害抗体であり、B細胞の枯渇を引き起こすことなくB細胞の機能を阻害するように設計される。インビトロアッセイを行って、CB3fが補体依存性細胞傷害(CDC)および抗体依存性細胞傷害(ADCC)活性を欠くことを確認するが、それはCB3fが枯渇機能を有しないことを意味する。
抗ヒトCD19 mAb CB3fはB細胞阻害抗体であり、B細胞機能を抑制することによって作用する。オベキセリマブは、CD19とFcγRIIbの両方に結合する抗体である。しかしながら、FcγRIIbに対するオベキセリマブの高親和性結合は、CD19に依存しない様式で他の細胞型への結合をもたらす可能性がある。したがって、オベキセリマブと抗ヒトCD19 mAb CB3fの結合特異性を、ヒト全血結合アッセイを使用して比較する。
前述のように、オベキシリマブは臨床試験中にヒト患者の B 細胞数を減少させることが示された(Jaraczewska-Baumann,et al.,EULAR 2015 Annual Meeting Poster:A Phase 1b/2a Study of the Safety,Tolerability,Pharmacokinetics and Pharmacodynamics of XmAb(登録商標)5871 in Patients with Rheumatoid Arthritis,June 12,2015)。
雌NSGマウス(NOD.Cg-Prkdcscid Il2rgtm1Wjl / SzJ、JAX Labs、ストック#05557)は、72℃、12時間の明:暗サイクル下でケージあたり3匹収容され、飼料および水を自由に摂取できる(n=33)。ヒト末梢血単核細胞(PBMC)は、製造業者の指示(StemCell Technologies、Vancouver、BC)に従ってSepMate 50 Ficol調製チューブを使用して、San Diego Blood Bank(San Diego CA)から得られたLRSチューブから単離する。新たに単離したPBMCを1.2e8細胞/mLでPBSに懸濁し、0日目にマウスに100μLのPBMC懸濁液を静脈内移植する(1.2e7/マウス、n=29)。4匹のマウスには、非移植対照としてPBMCを投与しない。1日目に、体重が一致するようにマウスを3つの群に分け、ヒトIgG4アイソタイプ対照またはCB3fを0.01または1.0mg/kgで皮下投与する(200μL/マウス、それぞれn=10、10、および9)。投与を、実験の残りの間、週に1回続ける。健康診断および体重測定を定期的に行う。6日目および10日目に、テールスニップにより、ヘパリンでコーティングされたキャピラリーチューブに血液を採取する。15日目に、血液を、イソフルラン麻酔下で心臓穿刺によってFACS分析のためにEDTAチューブに収集し、血漿分析のために遠心分離によって清澄化する。脾臓を回収し、FACS分析のために単一細胞懸濁液に処理する。
標準的な密度勾配遠心分離法を用いて、健康なボランティアのLRS-WBCから末梢血単核細胞(PBMC)を収集する。B細胞単離キットを用いたネガティブ選択により、健康なドナーのPBMCからヒト初代B細胞を単離する。内在化試験のために、B細胞を4×106細胞/mLで再懸濁し、50μLを96ウェルプレートの各ウェルに加える。ヒトIg Fcγ断片を標的とする標識されたF(ab’)2(F(ab’)2-TAMRA-QSY7)を、内在化を追跡するためのプローブとして使用する。試験抗体をプローブとともに4℃で30分間インキュベートして複合体を形成し、50μLを各ウェルのB細胞に加える。試験抗体の最終濃度は2μg/mLである。細胞をCO2インキュベーターで、37℃で24時間インキュベートする。次いで、細胞を2%FBS PBSで2回洗浄し、生存性色素(SYTOX Green、Invitrogen)を含む2%FBS PBSに再懸濁する。BD Fortessa X-20でデータを収集し、FlowJoで分析する。
マウスCIAモデルにおける非枯渇CD19代替抗体およびB細胞枯渇CD20代替抗体のインビボ有効性
この試験では、非枯渇抗マウスCD19代替抗体(CD19代替Ab)およびB細胞枯渇抗マウスCD20代替抗体(CD20代替Ab)を、アイソタイプ対照抗体とともに、半確立疾患モードのマウスコラーゲン誘発関節炎(CIA)モデルで試験した(すなわち、疾患の誘発後、動物が検出可能な臨床スコアを示し始める前に抗体が導入された)。
NOD/ShiLtJマウス系統(一般に非肥満糖尿病と呼ばれる)は、自己免疫1型糖尿病(T1D)の多遺伝子モデルである。NODマウスの糖尿病は、高血糖、および膵島の白血球浸潤である膵島炎によって特徴付けられる。疾患の有病率は、雌のマウスにおいて最も高い。
マウス実験的自己免疫性脳脊髄炎(EAE)は、多発性硬化症(MS)等の炎症性神経変性および脱髄性疾患のモデルとして広く使用されている。
配列表
C323
配列番号1 C323 HCDR1(North)
KASGGTFSSYAIS
配列番号2 C323 HCDR2(North)
GIIPIFGTAN
配列番号3 C323 HCDR3(North)
AREDFGYNYGMDV
配列番号4 C323 LCDR1(North)
RASQGVNSYYLA
配列番号5 C323 LCDR2(North)
YATSTRAT
配列番号6 C323 LCDR3(North)
QHYGNSLFT
配列番号7 C323 HC IgG4-S228P
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREDFGYNYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
配列番号8 C323 HC IgG4-S228P DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGACTTCGGCTACAATTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTTCTACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTTCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGT
配列番号9 C323HC可変領域(VH)
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSPDYSPYYYYGMDVWGQGTTVTVSS
配列番号10 C323 HC VH DNA
CAGGTTCAGCTGGTGCAGTCTGGTGCTGAGGTGAAGAAGCCTGGTGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCGACTACTACATGCACTGGGTGCGTCAGGCCCCTGGTCAAGGTCTTGAGTGGATGGGTCGTGTTAATCCTAACCGGAGGGGTACTACCTACAACCAGAAATTCGAGGGCCGTGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGCGTAGCCTGCGTTCTGACGACACGGCCGTGTATTACTGTGCGCGTGCGAACTGGCTTGACTACTGGGGCCAGGGCACCACCGTCACCGTCTCC
配列番号11 C323 LCEIVLTQSPGTLSLSPGERATLSCRASSSVPYIHWYQQKPGQAPRLLIYATSALASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWLSNPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号12 C323 LC DNA
GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGGGTGTTAACAGCTACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATGTATGCTACATCCACCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTATGGTAACTCACTATTCACTTTCGGCCCTGGGACCAAGGTGGAGATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC
配列番号13 C323 LC可変領域(VL)
EIVLTQSPGTLSLSPGERATLSCRASQGVNSYYLAWYQQKPGQAPRLLMYATSTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGNSLFTFGPGTKVEIK
配列番号14 C323 LC VL DNA
GCCCTGACTCAGCCGTCCTCGGTGTCAGCAAACCTGGGAGGAACAGTCAAGATCACCTGCTCCGGGGGTAGTGGCAGCTATGGCTGGTTCCGGCAGAAGTCTCCTGGCAGTGCCCCTGTCACTGTGATCTATTACAACGACAAGAGACCCTCGGACATCCCTTCACGATTCTCCGGTTCCAAATCCGGCTCCACAGCCACATTAACCATCACTGGGGTCCGAGCCGAGGACGAGGCTGTCTATTTCTGTGGGAGTGCAGGCAACAGTGGTGCATTTGGGGCCGGGACAACCCTGACCGTCCTT
C323.C1
配列番号15 C323.C1 HCDR1(North)
KASGGTISSYAYS
配列番号16 C323.C1 HCDR2(North)
GIIPIFDTAN
配列番号17 C323.C1 HCDR3(North)
AREDFGYNYAMDV
配列番号18 C323.C1 LCDR1(North)
RASQKVNSYYLH
配列番号19 C323.C1 LCDR2(North)
YATRTRPT
配列番号20 C323.C1 LCDR3(North)
QHYGQSLFT
配列番号21 C323.C1 HC IgG4-S228P
QVQLVQSGAEVKKPGSSVKVSCKASGGTISSYAYSWVRQAPGQGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREDFGYNYAMDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
配列番号22 C323.C1 HC IgG4-S228P DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCATTAGCAGCTATGCTTACAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGACACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGACTTCGGCTACAATTACGCGATGGACGTCTGGGGCCAAGGGACCCTTGTCACCGTCTCCTCAGCTTCTACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTTCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGT
配列番号23 C323.C1 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDGGDYGDMGYWGQGTLVTVSS
配列番号24 C323.C1 VH DNA
CAGGTTCAGCTGGTGCAGTCTGGTGCTGAGGTGAAGAAGCCTGGTGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCGACTACTACATGCACTGGGTGCGTCAGGCCCCTGGTCAAGGTCTTGAGTGGATGGGTCGTGTTAATCCTAACCGGAGGGGTACTACCTACAACCAGAAATTCGAGGGCCGTGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGCGTAGCCTGCGTTCTGACGACACGGCCGTGTATTACTGTGCGCGTGCGAACTGGCTTGACTACTGGGGCCAGGGCACCACCGTCACCGTCTCC
配列番号25 C323.C1 LC
EIVLTQSPGTLSLSPGERATLSCRASSSVPYIHWYQQKPGQAPRLLIYATSALASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWLSNPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号26 C323.C1 LC DNA
GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAAAGTTAACAGCTACTACTTACATTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTACAAGAACCAGGCCAACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTATGGTCAGTCACTATTCACTTTCGGCCAGGGGACCAAGGTGGAGATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC
配列番号27 C323.C1 VL
EIVLTQSPGTLSLSPGERATLSCRASRSVPYIHWYQQKPGQAPRLLIYATSALASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWLSNPPTFGQGTKLEIK
配列番号28 C323.C1 VL DNA
GCCCTGACTCAGCCGTCCTCGGTGTCAGCAAACCTGGGAGGAACCGTCAAGATCACCTGCTCCGGGGGTTACAGCAGCTATGGCTGGTATCAGCAGAAGTCTCCTGGCAGTGCTCCTGTCACTCTGATCTATTACAACGCCAAGAGACCCTCGAACATCCCTTCACGATTCTCCGGTTCCAAATCCGGCTCCACAGCCACATTAACCATCACTGGGGTCCAAGCCGAGGACGAGGCTGTCTATTTCTGTGGGACTGCAGACAGGAGCAGTACTGCTTTATTTGGGGCCGGGACAACCCTGACCGTCCTT
CB3f
配列番号29 CB3f/CB3 HCDR1(North)
KASGHTISSYAYS
配列番号30 CB3f/CB3 HCDR2(North)
DIIPAYGSPN
配列番号31 CB3f/CB3 HCDR3(North)
AREDFGKNYAMDV
配列番号32 CB3f LCDR1(North)
RASQHVSSHYLA
配列番号33 CB3f LCDR2(North)
GASSRAT
配列番号34 CB3f LCDR3(North)
QHYGQSQFT
配列番号35 CB3f/CB3 HC IgG4-S228P
QVQLVQSGAEVKKPGSSVKVSCKASGHTISSYAYSWVRQAPGQGLEWMGDIIPAYGSPNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREDFGKNYAMDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
配列番号36 CB3f/CB3 HC IgG4-S228P DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGACATACCATTAGCAGCTATGCTTACAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGACATCATCCCTGCCTATGGCTCACCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGACTTCGGCAAGAATTACGCGATGGACGTCTGGGGCCAAGGGACCCTTGTCACCGTCTCCTCAGCTTCTACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTTCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGT
配列番号37 CB3f/CB3 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDGGDYGDMGYWGQGTLVTVSS
配列番号38 CB3f/CB3 VH DNA
ACGAATTCGGCCGTGACGTTGGACGAGTCTGGGGGCGGCCTCCAGACGCCCGGAGGAGGGCTCAGCCTCGTCTGCAAGGCCTCCGGGTTCTCCTTCAGCAGTTATGGCATGGGCTGGGTGCGACAGGCGCCCGGCAAGGGGCTGGAATTCATCGCGGGTATTAGAAGCAGTGGTAGTAGCACATACTACGGGGCGGCGGTGAAGGGCCGTGCCACCATCACGAGGGACAACGGGCAGAGCACAGTGAGGCTGCAGCTGAACAACCTCAGGGCTGAGGACACCGCCACCTACTACTGCGCCAAAGCTGGTTGTAGTGATTGTTGGCGTAGTACTCCTGGTAGGATCGACGCATGGGGCCACGGGACCGAAGTCATCGTCTCCTCG
配列番号39 CB3f LC
EIVLTQSPGTLSLSPGERATLSCRASQSVRSNYFAWYQQKPGQAPRLLIYGVSRRAFGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGASLITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号40 CB3f LC DNA
GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGCATGTTAGCAGCCACTACTTAGCTTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTATGGTCAGTCACAGTTCACTTTCGGCCAGGGGACCAAGGTGGAGATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC
配列番号41 CB3f VL
EIVLTQSPGTLSLSPGERATLSCRASQSVRSNYFAWYQQKPGQAPRLLIYGVSRRAFGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGASLITFGQGTRLEIK
配列番号42 CB3f VL DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCCGGCGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
CB3(LCのみ、HCはCB3fと同一)
配列番号43 CB3 LCDR1(North)
RASQHVNSHYLA
配列番号44 CB3 LCDR2(North)
YATRTRPT
配列番号45 CB3 LCDR3(North)
QHYGQSQFT
配列番号46 CB3 LC
EIVLTQSPGTLSLSPGERATLSCRASSSVPYIHWYQQKPGQAPRLLIYATSALASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWLSNPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号47 CB3 LC DNA
GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGCATGTTAACAGCCACTACTTAGCTTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTACAAGAACCAGGCCAACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTATGGTCAGTCACAGTTCACTTTCGGCCAGGGGACCAAGGTGGAGATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC
配列番号48 CB3 VL
EIVLTQSPGTLSLSPGERATLSCRASRSVPYIHWYQQKPGQAPRLLIYATSALASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWLSNPPTFGQGTKLEIK
配列番号49 CB3 VL DNA
GCCCTGACTCAGCCGTCCTCGGTGTCAGCAAACCTGGGAGGAACAGTCAAGATCACCTGCTCCGGGGGTAGTGGCAGCTATGGCTGGTTCCGGCAGAAGTCTCCTGGCAGTGCCCCTGTCACTGTGATCTATTACAACGACAAGAGACCCTCGGACATCCCTTCACGATTCTCCGGTTCCAAATCCGGCTCCACAGCCACATTAACCATCACTGGGGTCCGAGCCGAGGACGAGGCTGTCTATTTCTGTGGGAGTGCAGGCAACAGTGGTGCATTTGGGGCCGGGACAACCCTGACCGTCCTT
CB3f/CB3-IgG1
配列番号50 CB3f/CB3 IgG1 HC
QVQLVQSGAEVKKPGSSVKVSCKASGHTISSYAYSWVRQAPGQGLEWMGDIIPAYGSPNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREDFGKNYAMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
配列番号51 CB3f/CB3 IgG1 HC DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGACATACCATTAGCAGCTATGCTTACAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGACATCATCCCTGCCTATGGCTCACCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGACTTCGGCAAGAATTACGCGATGGACGTCTGGGGCCAAGGGACCCTTGTCACCGTCTCCTCAGCTTCTACCAAGGGCCCATCGGTCTTCCCGCTAGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGACGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCCCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGT
CB3f/CB3-IgG1エフェクターヌル
配列番号52 CB3f/CB3 IgG1エフェクターヌルHC(LCはCB3f/CB3と同一)(下線部はIgG1 WTからの変化)
CAGGTGCAACTTGTCCAAAGCGGAGCTGAGGTTAAGAAACCAGGTTCATCTGTGAAGGTGTCATGTAAGGCAAGCGGCCACACCATTTCATCTTACGCATACTCCTGGGTTCGACAAGCTCCAGGCCAGGGATTGGAATGGATGGGAGACATAATCCCAGCATACGGATCACCTAACTACGCACAGAAGTTTCAGGGGAGAGTGACAATTACAGCCGACGAGTCTACTAGCACTGCTTACATGGAGTTGTCTTCACTTCGGTCAGAGGATACAGCAGTTTACTATTGTGCCAGGGAGGATTTCGGGAAAAATTATGCTATGGATGTATGGGGTCAGGGCACCCTGGTTACTGTATCATCTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAA
C323.C1-IgG1エフェクターヌル
配列番号54 C323.C1 IgG1エフェクターヌルHC(LCはCB3.C1と同一)(下線部はIgG1 WTからの変化)
CAGGTTCAGCTCGTGCAAAGTGGAGCTGAGGTGAAAAAACCTGGTTCTAGCGTCAAGGTCTCTTGTAAGGCCTCTGGGGGCACTATAAGCTCTTATGCTTATAGTTGGGTGCGCCAGGCCCCAGGACAGGGCTTGGAATGGATGGGCGGCATAATACCCATATTCGACACAGCCAACTACGCTCAAAAATTTCAGGGGAGAGTGACTATAACTGCAGACGAGAGCACTAGCACCGCTTACATGGAGTTGAGTAGTCTCCGCAGTGAAGACACAGCCGTCTATTATTGCGCTAGGGAGGACTTTGGTTACAACTACGCCATGGATGTCTGGGGCCAGGGTACTTTGGTCACCGTATCTAGTGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAA
配列番号56 ヒトCD19アイソフォーム1(NCBI参照配列:NP_001171569.1)
MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLAGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR
配列番号57 ヒトCD19アイソフォーム2(NCBI参照配列:NP_001761.3)
MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR
Claims (31)
- ヒトCD19に結合する抗体であって、前記抗体が、配列番号37を含む重鎖可変領域(VH)、および配列番号41を含む軽鎖可変領域(VL)を含み、前記VHが、重鎖相補性決定領域HCDR1、HCDR2、およびHCDR3を含み、前記VLが、軽鎖相補性決定領域LCDR1、LCDR2、およびLCDR3を含み、
前記HCDR1が、配列番号29を含み、
前記HCDR2が、配列番号30を含み、
前記HCDR3が、配列番号31を含み、
前記LCDR1が、配列番号32を含み、
前記LCDR2が、配列番号33を含み、ならびに
前記LCDR3が、配列番号34を含む、抗体。 - 前記抗体が、配列番号35を含む重鎖(HC)、および配列番号39を含む軽鎖(LC)を含む、請求項1に記載の抗体。
- 前記抗体が、配列番号52を含むHC、および配列番号39を含むLCを含む、請求項1に記載の抗体。
- ヒトCD19に結合する抗体であって、前記抗体が、配列番号37を含むVH、および配列番号48を含むVLを含み、前記VHが、HCDR1、HCDR2、およびHCDR3を含み、前記VLが、LCDR1、LCDR2、およびLCDR3を含み、
前記HCDR1が、配列番号29を含み、
前記HCDR2が、配列番号30を含み、
前記HCDR3が、配列番号31を含み、
前記LCDR1が、配列番号43を含み、
前記LCDR2が、配列番号44を含み、ならびに
前記LCDR3が、配列番号45を含む、抗体。 - 前記抗体が、配列番号35を含むHC、および配列番号46を含むLCを含む、請求項4に記載の抗体。
- 前記抗体が、配列番号52を含むHC、および配列番号46を含むLCを含む、請求項4に記載の抗体。
- ヒトCD19に結合する抗体であって、前記抗体が、配列番号23を含むVH、および配列番号27を含むVLを含み、前記VHが、HCDR1、HCDR2、およびHCDR3を含み、前記VLが、LCDR1、LCDR2、およびLCDR3を含み、
前記HCDR1が、配列番号15を含み、
前記HCDR2が、配列番号16を含み、
前記HCDR3が、配列番号17を含み、
前記LCDR1が、配列番号18を含み、
前記LCDR2が、配列番号19を含み、
前記LCDR3が、配列番号20を含む、抗体。 - 配列番号21を含むHC、および配列番号25を含むLCを含む、請求項7に記載の抗体。
- 配列番号54を含むHC、および配列番号25を含むLCを含む、請求項7に記載の抗体。
- 前記抗体が非枯渇抗体である、請求項1~9のいずれか一項に記載の抗体。
- 配列番号35または52、および39をコードする配列を含む、核酸であって、前記配列が、請求項1~3のいずれか一項に記載の抗体をコードする、核酸。
- 配列番号35または52、および46をコードする配列を含む、核酸であって、前記配列が、請求項4~6のいずれか一項に記載の抗体をコードする、核酸。
- 配列番号21または54、および25をコードする配列を含む、核酸であって、前記配列が、請求項7~9のいずれか一項に記載の抗体をコードする、核酸。
- 請求項11~13のいずれか一項に記載の核酸を含む、ベクター。
- 請求項11または12に記載の核酸を含む、請求項14に記載のベクター。
- 請求項13に記載の核酸を含む、請求項14に記載のベクター。
- 請求項11または12に記載の核酸を含むベクターを含む、組成物。
- 請求項13に記載の核酸を含むベクターを含む、組成物。
- 請求項15に記載のベクターを含む、細胞。
- 請求項16に記載のベクターを含む、細胞。
- 前記細胞が、哺乳動物細胞である、請求項19または20に記載の細胞。
- 抗体を生成するための方法であって、前記抗体が発現するような条件下で、請求項19~21のいずれか一項に記載の細胞を培養し、次いで発現した抗体を培養培地から回収することを含む、方法。
- 請求項22に記載の方法によって生成された、抗体。
- 請求項1~10および23のいずれか一項に記載の抗体、および薬学的に許容される賦形剤、希釈剤、または担体を含む、医薬組成物。
- 療法に使用するための、請求項1~10および23のいずれか一項に記載の抗体を含む、医薬組成物。
- B細胞関連疾患の治療における使用のための、請求項24に記載の医薬組成物。
- 前記B細胞関連疾患が、自己免疫疾患である、請求項26に記載の医薬組成物。
- 前記B細胞関連疾患が、全身性エリテマトーデス、多発性硬化症、関節リウマチ、シェーグレン症候群、特発性血小板減少性紫斑病、1型糖尿病、尋常性天疱瘡、視神経脊髄炎、ANCA血管炎、または重症筋無力症から選択される、請求項26に記載の医薬組成物。
- B細胞関連疾患の治療のための薬物の製造における、請求項1~10および23のいずれか一項に記載の抗体の使用。
- 前記B細胞関連疾患が、自己免疫疾患である、請求項29に記載の使用。
- 前記B細胞関連疾患が、全身性エリテマトーデス、多発性硬化症、関節リウマチ、シェーグレン症候群、特発性血小板減少性紫斑病、1型糖尿病、尋常性天疱瘡、視神経脊髄炎、ANCA血管炎、または重症筋無力症から選択される、請求項29に記載の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062983093P | 2020-02-28 | 2020-02-28 | |
US62/983,093 | 2020-02-28 | ||
PCT/US2021/018989 WO2021173471A1 (en) | 2020-02-28 | 2021-02-22 | Anti-human cd19 antibodies |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2023515219A JP2023515219A (ja) | 2023-04-12 |
JP7450743B2 true JP7450743B2 (ja) | 2024-03-15 |
Family
ID=74885029
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022551767A Active JP7450743B2 (ja) | 2020-02-28 | 2021-02-22 | 抗ヒトcd19抗体 |
Country Status (20)
Country | Link |
---|---|
US (1) | US11623956B2 (ja) |
EP (1) | EP4110815A1 (ja) |
JP (1) | JP7450743B2 (ja) |
KR (1) | KR20220132579A (ja) |
CN (1) | CN115151570A (ja) |
AR (1) | AR121370A1 (ja) |
AU (1) | AU2021225792A1 (ja) |
BR (1) | BR112022015902A2 (ja) |
CA (1) | CA3169155A1 (ja) |
CL (1) | CL2022002329A1 (ja) |
CO (1) | CO2022012212A2 (ja) |
CR (1) | CR20220421A (ja) |
DO (1) | DOP2022000173A (ja) |
EC (1) | ECSP22067275A (ja) |
IL (1) | IL295494A (ja) |
JO (1) | JOP20220204A1 (ja) |
MX (1) | MX2022010621A (ja) |
PE (1) | PE20221593A1 (ja) |
TW (1) | TWI790548B (ja) |
WO (1) | WO2021173471A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW202346576A (zh) | 2022-04-13 | 2023-12-01 | 新加坡商泰莎治療有限公司 | 治療性t細胞產品 |
US20230399375A1 (en) | 2022-04-15 | 2023-12-14 | Kyverna Therapeutics, Inc. | Methods and compositions for treating autoimmune disease |
WO2023240064A1 (en) | 2022-06-08 | 2023-12-14 | Kyverna Therapeutics, Inc. | Methods and compositions for treating autoimmune disease |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016014039A (ja) | 2005-12-30 | 2016-01-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | 低減された免疫原性を有する抗cd19抗体 |
JP2017521046A (ja) | 2014-05-08 | 2017-08-03 | ザ・ヘンリー・エム・ジャクソン・ファンデイション・フォー・ジ・アドヴァンスメント・オヴ・ミリタリー・メディシン、インコーポレイテッド | 有害な免疫応答を処置するための寛容原性タンパク質療法としてのB細胞標的化抗原IgG融合物の使用 |
JP2019525949A (ja) | 2016-06-08 | 2019-09-12 | ゼンコー,インコーポレイティド | CD32Bに交差結合した抗CD19抗体を用いたIgG4関連疾患の治療 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8323653B2 (en) * | 2006-09-08 | 2012-12-04 | Medimmune, Llc | Humanized anti-CD19 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
-
2021
- 2021-02-18 TW TW110105560A patent/TWI790548B/zh active
- 2021-02-18 AR ARP210100425A patent/AR121370A1/es unknown
- 2021-02-22 CR CR20220421A patent/CR20220421A/es unknown
- 2021-02-22 IL IL295494A patent/IL295494A/en unknown
- 2021-02-22 PE PE2022001851A patent/PE20221593A1/es unknown
- 2021-02-22 AU AU2021225792A patent/AU2021225792A1/en active Pending
- 2021-02-22 EP EP21712613.5A patent/EP4110815A1/en active Pending
- 2021-02-22 BR BR112022015902A patent/BR112022015902A2/pt unknown
- 2021-02-22 KR KR1020227029214A patent/KR20220132579A/ko active Search and Examination
- 2021-02-22 CA CA3169155A patent/CA3169155A1/en active Pending
- 2021-02-22 WO PCT/US2021/018989 patent/WO2021173471A1/en active Application Filing
- 2021-02-22 JO JOP/2022/0204A patent/JOP20220204A1/ar unknown
- 2021-02-22 CN CN202180016785.XA patent/CN115151570A/zh active Pending
- 2021-02-22 MX MX2022010621A patent/MX2022010621A/es unknown
- 2021-02-22 JP JP2022551767A patent/JP7450743B2/ja active Active
- 2021-02-22 US US17/181,184 patent/US11623956B2/en active Active
-
2022
- 2022-08-25 CL CL2022002329A patent/CL2022002329A1/es unknown
- 2022-08-26 CO CONC2022/0012212A patent/CO2022012212A2/es unknown
- 2022-08-26 EC ECSENADI202267275A patent/ECSP22067275A/es unknown
- 2022-08-26 DO DO2022000173A patent/DOP2022000173A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016014039A (ja) | 2005-12-30 | 2016-01-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | 低減された免疫原性を有する抗cd19抗体 |
JP2017521046A (ja) | 2014-05-08 | 2017-08-03 | ザ・ヘンリー・エム・ジャクソン・ファンデイション・フォー・ジ・アドヴァンスメント・オヴ・ミリタリー・メディシン、インコーポレイテッド | 有害な免疫応答を処置するための寛容原性タンパク質療法としてのB細胞標的化抗原IgG融合物の使用 |
JP2019525949A (ja) | 2016-06-08 | 2019-09-12 | ゼンコー,インコーポレイティド | CD32Bに交差結合した抗CD19抗体を用いたIgG4関連疾患の治療 |
Non-Patent Citations (4)
Title |
---|
Best Practice and Research Clinical Rheumatology,2016年,30(2),261-278 |
Blood,2008年,112(11),2621 |
Blood,2009年,113(16),3735-3743 |
International Journal of Molecular and Cellular Medicine,2015年,4(3),143-151 |
Also Published As
Publication number | Publication date |
---|---|
WO2021173471A1 (en) | 2021-09-02 |
CN115151570A (zh) | 2022-10-04 |
AU2021225792A1 (en) | 2022-09-15 |
TW202146451A (zh) | 2021-12-16 |
JOP20220204A1 (ar) | 2023-01-30 |
US20210269520A1 (en) | 2021-09-02 |
CR20220421A (es) | 2022-09-23 |
DOP2022000173A (es) | 2022-10-31 |
CO2022012212A2 (es) | 2022-09-09 |
AR121370A1 (es) | 2022-06-01 |
PE20221593A1 (es) | 2022-10-10 |
KR20220132579A (ko) | 2022-09-30 |
BR112022015902A2 (pt) | 2022-10-04 |
CL2022002329A1 (es) | 2023-04-10 |
JP2023515219A (ja) | 2023-04-12 |
TWI790548B (zh) | 2023-01-21 |
IL295494A (en) | 2022-10-01 |
US11623956B2 (en) | 2023-04-11 |
ECSP22067275A (es) | 2022-09-30 |
MX2022010621A (es) | 2022-11-30 |
CA3169155A1 (en) | 2021-09-02 |
EP4110815A1 (en) | 2023-01-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10493148B2 (en) | PD-1 agonist antibodies and uses thereof | |
CN108779179B (zh) | Cd47抗体、其抗原结合片段及其医药用途 | |
CN110366560B (zh) | 抗b7-h4抗体、其抗原结合片段及其医药用途 | |
JP7450743B2 (ja) | 抗ヒトcd19抗体 | |
US11525005B2 (en) | Anti-CD40 antibody, antigen binding fragment thereof and medical use thereof | |
KR20160113113A (ko) | Pd-1 항체, 이의 항원 결합 단편, 및 이의 의약 용도 | |
EP3712170A1 (en) | Cd96 antibody, antigen-binding fragment and pharmaceutical use thereof | |
US20210009706A1 (en) | Anti-CD27 Antibody, Antigen-binding Fragment Thereof, and Medical Use Thereof | |
RU2792748C2 (ru) | Антитело к b7-h4, его антигенсвязывающий фрагмент и его фармацевтическое применение | |
WO2021209066A1 (zh) | 特异性抗原结合分子,其制备方法及医药用途 | |
US20240166745A1 (en) | Lag-3 and pd-1/lag-3-antibodies | |
JP2024074278A (ja) | Lag-3およびpd-1/lag-3抗体 | |
CA3229503A1 (en) | Pharmaceutical composition containing fusion protein | |
CN115947855A (zh) | 抗cd24抗体的制备及其用途 | |
CN116133684A (zh) | 抗人nr1抗体衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221020 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20221020 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230929 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231010 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240109 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240206 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240305 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7450743 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |