JP7250766B2 - FCγRII結合フィブロネクチンIII型ドメイン、それらのコンジュゲート、及びそれらを含む多重特異性分子 - Google Patents
FCγRII結合フィブロネクチンIII型ドメイン、それらのコンジュゲート、及びそれらを含む多重特異性分子 Download PDFInfo
- Publication number
- JP7250766B2 JP7250766B2 JP2020510561A JP2020510561A JP7250766B2 JP 7250766 B2 JP7250766 B2 JP 7250766B2 JP 2020510561 A JP2020510561 A JP 2020510561A JP 2020510561 A JP2020510561 A JP 2020510561A JP 7250766 B2 JP7250766 B2 JP 7250766B2
- Authority
- JP
- Japan
- Prior art keywords
- seq
- domain
- binding
- fcγrii
- antibody
- 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
- 102000002090 Fibronectin type III Human genes 0.000 title claims description 7
- 108050009401 Fibronectin type III Proteins 0.000 title claims description 7
- 230000027455 binding Effects 0.000 claims description 215
- 238000000034 method Methods 0.000 claims description 64
- 230000000694 effects Effects 0.000 claims description 63
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 claims description 35
- 239000013598 vector Substances 0.000 claims description 24
- 230000001268 conjugating effect Effects 0.000 claims description 10
- 230000002708 enhancing effect Effects 0.000 claims description 8
- 238000010367 cloning Methods 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 229940127121 immunoconjugate Drugs 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 110
- 108091033319 polynucleotide Proteins 0.000 description 85
- 239000002157 polynucleotide Substances 0.000 description 85
- 102000040430 polynucleotide Human genes 0.000 description 85
- 108090000765 processed proteins & peptides Proteins 0.000 description 66
- 102000004196 processed proteins & peptides Human genes 0.000 description 63
- 229920001184 polypeptide Polymers 0.000 description 62
- 239000012634 fragment Substances 0.000 description 54
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 44
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 description 44
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 43
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 43
- 108090000623 proteins and genes Proteins 0.000 description 42
- 102000005962 receptors Human genes 0.000 description 41
- 108020003175 receptors Proteins 0.000 description 41
- 102000004169 proteins and genes Human genes 0.000 description 39
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 36
- 206010028980 Neoplasm Diseases 0.000 description 35
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 34
- 125000003275 alpha amino acid group Chemical group 0.000 description 34
- 206010054094 Tumour necrosis Diseases 0.000 description 33
- 230000000259 anti-tumor effect Effects 0.000 description 33
- 235000018102 proteins Nutrition 0.000 description 33
- 239000000556 agonist Substances 0.000 description 31
- 229940024606 amino acid Drugs 0.000 description 30
- 235000001014 amino acid Nutrition 0.000 description 30
- 150000001413 amino acids Chemical class 0.000 description 28
- 239000000427 antigen Substances 0.000 description 27
- 108091007433 antigens Proteins 0.000 description 27
- 102000036639 antigens Human genes 0.000 description 27
- 229940034880 tencon Drugs 0.000 description 26
- 201000011510 cancer Diseases 0.000 description 25
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 24
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 24
- 238000003556 assay Methods 0.000 description 23
- -1 methionine oxidation Chemical class 0.000 description 22
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 21
- 230000014509 gene expression Effects 0.000 description 20
- 238000004132 cross linking Methods 0.000 description 18
- 239000012636 effector Substances 0.000 description 17
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 15
- 239000002299 complementary DNA Chemical group 0.000 description 15
- 108060003951 Immunoglobulin Proteins 0.000 description 14
- 229940127089 cytotoxic agent Drugs 0.000 description 14
- 102000018358 immunoglobulin Human genes 0.000 description 14
- 239000008194 pharmaceutical composition Substances 0.000 description 14
- 239000002254 cytotoxic agent Substances 0.000 description 13
- 229910052751 metal Inorganic materials 0.000 description 13
- 239000002184 metal Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 12
- 231100000599 cytotoxic agent Toxicity 0.000 description 12
- 230000008484 agonism Effects 0.000 description 11
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 210000003719 b-lymphocyte Anatomy 0.000 description 9
- 230000000903 blocking effect Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 8
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 8
- 206010060862 Prostate cancer Diseases 0.000 description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 description 8
- 239000013604 expression vector Substances 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 206010017758 gastric cancer Diseases 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 201000011549 stomach cancer Diseases 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 8
- 108010088751 Albumins Proteins 0.000 description 7
- 102000009027 Albumins Human genes 0.000 description 7
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 230000006044 T cell activation Effects 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000000684 flow cytometry Methods 0.000 description 7
- 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 6
- 102100027207 CD27 antigen Human genes 0.000 description 6
- 101150013553 CD40 gene Proteins 0.000 description 6
- 108020004705 Codon Proteins 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 108010067306 Fibronectins Proteins 0.000 description 6
- 102000016359 Fibronectins Human genes 0.000 description 6
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 6
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 6
- 108010042215 OX40 Ligand Proteins 0.000 description 6
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 description 6
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 6
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000001270 agonistic effect Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 210000002540 macrophage Anatomy 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000004091 panning Methods 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 108010087819 Fc receptors Proteins 0.000 description 5
- 102000009109 Fc receptors Human genes 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 210000004602 germ cell Anatomy 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 229960004452 methionine Drugs 0.000 description 5
- 210000001616 monocyte Anatomy 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000003174 Brain Neoplasms Diseases 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 201000009273 Endometriosis Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 4
- 201000001342 Fallopian tube cancer Diseases 0.000 description 4
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 4
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 4
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010073807 IgG Receptors Proteins 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- 241000282577 Pan troglodytes Species 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 4
- 108010090804 Streptavidin Proteins 0.000 description 4
- 239000006180 TBST buffer Substances 0.000 description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 description 4
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 108010044540 auristatin Proteins 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 210000004443 dendritic cell Anatomy 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical group CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 4
- 229960002885 histidine Drugs 0.000 description 4
- 230000002998 immunogenetic effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 201000008443 lung non-squamous non-small cell carcinoma Diseases 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 230000001394 metastastic effect Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 235000006109 methionine Nutrition 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 201000002510 thyroid cancer Diseases 0.000 description 4
- 230000006433 tumor necrosis factor production Effects 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 208000037964 urogenital cancer Diseases 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 239000012129 DRAQ7 reagent Substances 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 238000012286 ELISA Assay Methods 0.000 description 3
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 102000009490 IgG Receptors Human genes 0.000 description 3
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 3
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 3
- 102100022338 Integrin alpha-M Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- 241000282567 Macaca fascicularis Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 3
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010057249 Phagocytosis Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101710090029 Replication-associated protein A Proteins 0.000 description 3
- 102000007000 Tenascin Human genes 0.000 description 3
- 108010008125 Tenascin Proteins 0.000 description 3
- 101710120037 Toxin CcdB Proteins 0.000 description 3
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 3
- 208000006593 Urologic Neoplasms Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 238000001042 affinity chromatography Methods 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical group [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229930188854 dolastatin Natural products 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 230000008782 phagocytosis Effects 0.000 description 3
- 230000007112 pro inflammatory response Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- DIHXSRXTECMMJY-MURFETPASA-N 2-[dimethyl-[(9z,12z)-octadeca-9,12-dienyl]azaniumyl]acetate Chemical group CCCCC\C=C/C\C=C/CCCCCCCC[N+](C)(C)CC([O-])=O DIHXSRXTECMMJY-MURFETPASA-N 0.000 description 2
- VPFUWHKTPYPNGT-UHFFFAOYSA-N 3-(3,4-dihydroxyphenyl)-1-(5-hydroxy-2,2-dimethylchromen-6-yl)propan-1-one Chemical compound OC1=C2C=CC(C)(C)OC2=CC=C1C(=O)CCC1=CC=C(O)C(O)=C1 VPFUWHKTPYPNGT-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 102100035793 CD83 antigen Human genes 0.000 description 2
- 241000288950 Callithrix jacchus Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 description 2
- 102000016607 Diphtheria Toxin Human genes 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 102000006354 HLA-DR Antigens Human genes 0.000 description 2
- 108010058597 HLA-DR Antigens Proteins 0.000 description 2
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 2
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- 101000666340 Homo sapiens Tenascin Proteins 0.000 description 2
- 101000610602 Homo sapiens Tumor necrosis factor receptor superfamily member 10C Proteins 0.000 description 2
- 101000610609 Homo sapiens Tumor necrosis factor receptor superfamily member 10D Proteins 0.000 description 2
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 2
- 101000597785 Homo sapiens Tumor necrosis factor receptor superfamily member 6B Proteins 0.000 description 2
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 2
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical class OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 108010039491 Ricin Proteins 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 102100040115 Tumor necrosis factor receptor superfamily member 10C Human genes 0.000 description 2
- 102100040110 Tumor necrosis factor receptor superfamily member 10D Human genes 0.000 description 2
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 description 2
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 2
- 102100033725 Tumor necrosis factor receptor superfamily member 16 Human genes 0.000 description 2
- 101710187743 Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 2
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 2
- 102100022205 Tumor necrosis factor receptor superfamily member 21 Human genes 0.000 description 2
- 102100022202 Tumor necrosis factor receptor superfamily member 27 Human genes 0.000 description 2
- 102100035284 Tumor necrosis factor receptor superfamily member 6B Human genes 0.000 description 2
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 229960002433 cysteine Drugs 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 238000007822 cytometric assay Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- DGXRZJSPDXZJFG-UHFFFAOYSA-N docosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O DGXRZJSPDXZJFG-UHFFFAOYSA-N 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical group [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 102000057345 human TNC Human genes 0.000 description 2
- 102000050320 human TNFRSF4 Human genes 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 230000005865 ionizing radiation Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- BNJOQKFENDDGSC-UHFFFAOYSA-N octadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCC(O)=O BNJOQKFENDDGSC-UHFFFAOYSA-N 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical group [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 2
- HQHCYKULIHKCEB-UHFFFAOYSA-N tetradecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCC(O)=O HQHCYKULIHKCEB-UHFFFAOYSA-N 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 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 1
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- 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
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- IEUUDEWWMRQUDS-UHFFFAOYSA-N (6-azaniumylidene-1,6-dimethoxyhexylidene)azanium;dichloride Chemical compound Cl.Cl.COC(=N)CCCCC(=N)OC IEUUDEWWMRQUDS-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 description 1
- VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CNWINRVXAYPOMW-FCNJXWMTSA-N 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 4,5-biphosphate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)O[C@H](COC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)O[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O CNWINRVXAYPOMW-FCNJXWMTSA-N 0.000 description 1
- YBBNVCVOACOHIG-UHFFFAOYSA-N 2,2-diamino-1,4-bis(4-azidophenyl)-3-butylbutane-1,4-dione Chemical compound C=1C=C(N=[N+]=[N-])C=CC=1C(=O)C(N)(N)C(CCCC)C(=O)C1=CC=C(N=[N+]=[N-])C=C1 YBBNVCVOACOHIG-UHFFFAOYSA-N 0.000 description 1
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical class OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- KKMIHKCGXQMFEU-UHFFFAOYSA-N 2-[dimethyl(tetradecyl)azaniumyl]acetate Chemical group CCCCCCCCCCCCCC[N+](C)(C)CC([O-])=O KKMIHKCGXQMFEU-UHFFFAOYSA-N 0.000 description 1
- LMVGXBRDRZOPHA-UHFFFAOYSA-N 2-[dimethyl-[3-(16-methylheptadecanoylamino)propyl]azaniumyl]acetate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O LMVGXBRDRZOPHA-UHFFFAOYSA-N 0.000 description 1
- TYIOVYZMKITKRO-UHFFFAOYSA-N 2-[hexadecyl(dimethyl)azaniumyl]acetate Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)CC([O-])=O TYIOVYZMKITKRO-UHFFFAOYSA-N 0.000 description 1
- SNQVCAOGQHOSEN-UHFFFAOYSA-N 2-[methyl(octadecyl)amino]acetic acid Chemical compound CCCCCCCCCCCCCCCCCCN(C)CC(O)=O SNQVCAOGQHOSEN-UHFFFAOYSA-N 0.000 description 1
- FBUTXZSKZCQABC-UHFFFAOYSA-N 2-amino-1-methyl-7h-purine-6-thione Chemical compound S=C1N(C)C(N)=NC2=C1NC=N2 FBUTXZSKZCQABC-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical group [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- DIROHOMJLWMERM-UHFFFAOYSA-N 3-[dimethyl(octadecyl)azaniumyl]propane-1-sulfonate Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCS([O-])(=O)=O DIROHOMJLWMERM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- PVXPPJIGRGXGCY-TZLCEDOOSA-N 6-O-alpha-D-glucopyranosyl-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)C(O)(CO)O1 PVXPPJIGRGXGCY-TZLCEDOOSA-N 0.000 description 1
- BZTDTCNHAFUJOG-UHFFFAOYSA-N 6-carboxyfluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(C(=O)O)C=C21 BZTDTCNHAFUJOG-UHFFFAOYSA-N 0.000 description 1
- 101710187798 60S ribosomal protein L23 Proteins 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- IGAZHQIYONOHQN-UHFFFAOYSA-N Alexa Fluor 555 Chemical compound C=12C=CC(=N)C(S(O)(=O)=O)=C2OC2=C(S(O)(=O)=O)C(N)=CC=C2C=1C1=CC=C(C(O)=O)C=C1C(O)=O IGAZHQIYONOHQN-UHFFFAOYSA-N 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229910052695 Americium Inorganic materials 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 101000669426 Aspergillus restrictus Ribonuclease mitogillin Proteins 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 108010046304 B-Cell Activation Factor Receptor Proteins 0.000 description 1
- 102000007536 B-Cell Activation Factor Receptor Human genes 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229910052686 Californium Inorganic materials 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101710158575 Cap-specific mRNA (nucleoside-2'-O-)-methyltransferase Proteins 0.000 description 1
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 241000218645 Cedrus Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 108700032819 Croton tiglium crotin II Proteins 0.000 description 1
- 229910052685 Curium Inorganic materials 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000010831 Cytoskeletal Proteins Human genes 0.000 description 1
- 108010037414 Cytoskeletal Proteins Proteins 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
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 1
- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 229910052690 Einsteinium Inorganic materials 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 101710082714 Exotoxin A Proteins 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000724791 Filamentous phage Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical group [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 206010056740 Genital discharge Diseases 0.000 description 1
- 108700002054 Glucocorticoid-Induced TNFR-Related Proteins 0.000 description 1
- 102000050627 Glucocorticoid-Induced TNFR-Related Human genes 0.000 description 1
- 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 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- GIZQLVPDAOBAFN-UHFFFAOYSA-N HEPPSO Chemical compound OCCN1CCN(CC(O)CS(O)(=O)=O)CC1 GIZQLVPDAOBAFN-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 229910052689 Holmium Inorganic materials 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 description 1
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 description 1
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 1
- 101000801228 Homo sapiens Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 1
- 101000801232 Homo sapiens Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 1
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 1
- 101000679907 Homo sapiens Tumor necrosis factor receptor superfamily member 27 Proteins 0.000 description 1
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 102220475874 Keratin, type I cytoskeletal 10_L17A_mutation Human genes 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 229930195722 L-methionine Natural products 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910052766 Lawrencium Inorganic materials 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- DNDWZFHLZVYOGF-KKUMJFAQSA-N Leu-Leu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O DNDWZFHLZVYOGF-KKUMJFAQSA-N 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 229910052765 Lutetium Inorganic materials 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- NBGXQZRRLOGAJF-UHFFFAOYSA-N Maltulose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)(CO)OCC1O NBGXQZRRLOGAJF-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 108010060408 Member 25 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 102000008166 Member 25 Tumor Necrosis Factor Receptors Human genes 0.000 description 1
- 229910052764 Mendelevium Inorganic materials 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical group [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 244000302512 Momordica charantia Species 0.000 description 1
- 235000009811 Momordica charantia Nutrition 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000574441 Mus musculus Alkaline phosphatase, germ cell type Proteins 0.000 description 1
- 101000597780 Mus musculus Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910052779 Neodymium Inorganic materials 0.000 description 1
- 229910052781 Neptunium Inorganic materials 0.000 description 1
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
- 102220609775 Nuclear protein MDM1_E11R_mutation Human genes 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- 108010035042 Osteoprotegerin Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 101100413173 Phytolacca americana PAP2 gene Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000010995 Pleckstrin homology domains Human genes 0.000 description 1
- 108050001185 Pleckstrin homology domains Proteins 0.000 description 1
- 229910052778 Plutonium Inorganic materials 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052777 Praseodymium Inorganic materials 0.000 description 1
- 101710130420 Probable capsid assembly scaffolding protein Proteins 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 229910052773 Promethium Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- 101710204410 Scaffold protein Proteins 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 1
- 108091007178 TNFRSF10A Proteins 0.000 description 1
- 108010014401 TWEAK Receptor Proteins 0.000 description 1
- 102000016946 TWEAK Receptor Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229910052771 Terbium Inorganic materials 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229910052775 Thulium Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical group [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 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 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100035283 Tumor necrosis factor ligand superfamily member 18 Human genes 0.000 description 1
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 description 1
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 1
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 description 1
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 1
- 101710187830 Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 1
- 101710187751 Tumor necrosis factor receptor superfamily member 21 Proteins 0.000 description 1
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 1
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 150000001224 Uranium Chemical group 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 240000001866 Vernicia fordii Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 108010054754 Xedar Receptor Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical group [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 108010076089 accutase Proteins 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical class C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
- 229910052768 actinide Inorganic materials 0.000 description 1
- 150000001255 actinides Chemical class 0.000 description 1
- 229910052767 actinium Inorganic materials 0.000 description 1
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical group [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 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 1
- LHAOFBCHXGZGOR-NAVBLJQLSA-N alpha-D-Manp-(1->3)-alpha-D-Manp-(1->2)-alpha-D-Manp Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1 LHAOFBCHXGZGOR-NAVBLJQLSA-N 0.000 description 1
- 108010001818 alpha-sarcin Proteins 0.000 description 1
- LXQXZNRPTYVCNG-UHFFFAOYSA-N americium atom Chemical group [Am] LXQXZNRPTYVCNG-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical group [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical group [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical group [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000010953 base metal Substances 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 229940116224 behenate Drugs 0.000 description 1
- UKMSUNONTOPOIO-UHFFFAOYSA-M behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC([O-])=O UKMSUNONTOPOIO-UHFFFAOYSA-M 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 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 1
- DLRVVLDZNNYCBX-ZZFZYMBESA-N beta-melibiose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-ZZFZYMBESA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- TVBISCWBJBKUDP-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-] TVBISCWBJBKUDP-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical group [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical group [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- HGLDOAKPQXAFKI-UHFFFAOYSA-N californium atom Chemical group [Cf] HGLDOAKPQXAFKI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 239000000298 carbocyanine Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000004671 cell-free system Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical group [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000003508 chemical denaturation Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- NIWWFAAXEMMFMS-UHFFFAOYSA-N curium atom Chemical group [Cm] NIWWFAAXEMMFMS-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 125000005442 diisocyanate group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- ZWIBGKZDAWNIFC-UHFFFAOYSA-N disuccinimidyl suberate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O ZWIBGKZDAWNIFC-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical group [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- CKBRQZNRCSJHFT-UHFFFAOYSA-N einsteinium atom Chemical group [Es] CKBRQZNRCSJHFT-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 108010028531 enomycin Proteins 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical group [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical group [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 108010052621 fas Receptor Proteins 0.000 description 1
- 102000018823 fas Receptor Human genes 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- MIORUQGGZCBUGO-UHFFFAOYSA-N fermium Chemical group [Fm] MIORUQGGZCBUGO-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229910052730 francium Inorganic materials 0.000 description 1
- KLMCZVJOEAUDNE-UHFFFAOYSA-N francium atom Chemical group [Fr] KLMCZVJOEAUDNE-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940075613 gadolinium oxide Drugs 0.000 description 1
- 229910001938 gadolinium oxide Inorganic materials 0.000 description 1
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 1
- 229910052733 gallium Inorganic materials 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical group [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000001279 glycosylating effect Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- ZJYYHGLJYGJLLN-UHFFFAOYSA-N guanidinium thiocyanate Chemical compound SC#N.NC(N)=N ZJYYHGLJYGJLLN-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical group [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical group [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 description 1
- 102000046699 human CD14 Human genes 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical group [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 108091008042 inhibitory receptors Proteins 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical group [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical group [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical group [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- CNQCVBJFEGMYDW-UHFFFAOYSA-N lawrencium atom Chemical group [Lr] CNQCVBJFEGMYDW-UHFFFAOYSA-N 0.000 description 1
- 229910052745 lead Inorganic materials 0.000 description 1
- WABPQHHGFIMREM-UHFFFAOYSA-N lead(0) Chemical group [Pb] WABPQHHGFIMREM-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 108010049589 leucyl-leucyl-leucine Proteins 0.000 description 1
- 238000002898 library design Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical group [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- JCQLYHFGKNRPGE-HFZVAGMNSA-N maltulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-HFZVAGMNSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- FYGDTMLNYKFZSV-UHFFFAOYSA-N mannotriose Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(O)C(O)C2O)CO)C(O)C1O FYGDTMLNYKFZSV-UHFFFAOYSA-N 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- MQVSLOYRCXQRPM-UHFFFAOYSA-N mendelevium atom Chemical group [Md] MQVSLOYRCXQRPM-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical group [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 108010010621 modeccin Proteins 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- NZXVYLJKFYSEPO-UHFFFAOYSA-N n-[3-(dimethylamino)propyl]-16-methylheptadecanamide Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)NCCCN(C)C NZXVYLJKFYSEPO-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical group [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- LFNLGNPSGWYGGD-UHFFFAOYSA-N neptunium atom Chemical group [Np] LFNLGNPSGWYGGD-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical group [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 1
- ORQBXQOJMQIAOY-UHFFFAOYSA-N nobelium Chemical group [No] ORQBXQOJMQIAOY-UHFFFAOYSA-N 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical group [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 108010076042 phenomycin Proteins 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- QWYZFXLSWMXLDM-UHFFFAOYSA-M pinacyanol iodide Chemical compound [I-].C1=CC2=CC=CC=C2N(CC)C1=CC=CC1=CC=C(C=CC=C2)C2=[N+]1CC QWYZFXLSWMXLDM-UHFFFAOYSA-M 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 210000003281 pleural cavity Anatomy 0.000 description 1
- OYEHPCDNVJXUIW-UHFFFAOYSA-N plutonium atom Chemical group [Pu] OYEHPCDNVJXUIW-UHFFFAOYSA-N 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 108010094020 polyglycine Proteins 0.000 description 1
- 229920000232 polyglycine polymer Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 125000004424 polypyridyl Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical group [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 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
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- VQMWBBYLQSCNPO-UHFFFAOYSA-N promethium atom Chemical group [Pm] VQMWBBYLQSCNPO-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XLROVYAPLOFLNU-UHFFFAOYSA-N protactinium atom Chemical group [Pa] XLROVYAPLOFLNU-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000004223 radioprotective effect Effects 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical group [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 239000013643 reference control Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical group [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical group [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical group [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical group [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical group [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 210000004911 serous fluid Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 150000003378 silver Chemical group 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 239000012128 staining reagent Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical group [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940104261 taurate Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical group [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical group [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical group [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical group [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical compound N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- FRNOGLGSGLTDKL-UHFFFAOYSA-N thulium atom Chemical group [Tm] FRNOGLGSGLTDKL-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- RUELTTOHQODFPA-UHFFFAOYSA-N toluene 2,6-diisocyanate Chemical compound CC1=C(N=C=O)C=CC=C1N=C=O RUELTTOHQODFPA-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 150000003327 trichothecene derivatives Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical group [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical group [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical group [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical group [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical group [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
-
- 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
- C07K16/2875—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 NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
-
- 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
- C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- 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
-
- 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
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- 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
- C07K2317/75—Agonist effect on antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2318/00—Antibody mimetics or scaffolds
- C07K2318/20—Antigen-binding scaffold molecules wherein the scaffold is not an immunoglobulin variable region or antibody mimetics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/70—Vectors or expression systems specially adapted for E. coli
Description
本願は、EFS-Webを介して提出された配列表を含み、その内容全体は参照により本明細書に援用される。2018年7月25日に作成されたASCIIテキストファイルは、ファイル名がJBI5136WOPC11SEQLIST.txtであり、サイズは119キロバイトである。
本発明は、FcγRII結合FN3ドメイン、それらのコンジュゲート及びそれらを含む多重特異性分子、その分子をコードする単離されたヌクレオチド、ベクター、宿主細胞、並びにそれらの作製及び使用方法に関する。
MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDPPATQPQETQGPPARPITVQPTEAWPRTSQGPSTRPVEVPGGRAVAAILGLGLVLGLLGPLAILLALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI
MTMETQMSQNVCPRNLWLLQPLTVLLLLASADSQAAPPKAVLKLEPPWINVLQEDSVTLTCQGARSPESDSIQWFHNGNLIPTHTQPSYRFKANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIMLRCHSWKDKPLVKVTFFQNGKSQKFSHLDPTFSIPQANHSHSGDYHCTGNIGYTLFSSKPVTITVQVPSMGSSSPMGIIVAVVIATAVAAIVAAVVALIYCRKKRISANSTDPVKAAQFEPPGRQMIAIRKRQLEETNNDYETADGGYMTLNPRAPTDDDKNIYLTLPPNDHVNSNN
MGILSFLPVLATESDWADCKSPQPWGHMLLWTAVLFLAPVAGTPAAPPKAVLKLEPQWINVLQEDSVTLTCRGTHSPESDSIQWFHNGNLIPTHTQPSYRFKANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIVLRCHSWKDKPLVKVTFFQNGKSKKFSRSDPNFSIPQANHSHSGDYHCTGNIGYTLYSSKPVTITVQAPSSSPMGIIVAVVTGIAVAAIVAAVVALIYCRKKRISALPGYPECREMGETLPEKPANPTNPDEADKVGAENTITYSLLMHPDALEEPDDQNRI
LPAPKNLVVSEVTEDSLRLSWTAPDAAFDSFLIQYQESEKVGEAINLTVPGSERSYDLTGLKPGTEYTVSIYGVKGGHRSNPLSAEFTT
LPAPKNLVVSRVTEDSARLSWTAPDAAFDSFLIQYQESEKVGEAIVLTVPGSERSYDLTGLKPGTEYTVSIYGVKGGHRSNPLSAIFTT
本発明は、FcγRII結合FN3ドメイン及びそれらの融合タンパク質を提供する。FN3ドメインは、例えば、造影剤及び/又は治療薬として有用である。
Tencon(配列番号4)は、ヒトテネイシン-Cからの15個のFN3ドメインのコンセンサス配列から設計された天然に存在しないフィブロネクチンIII型(FN3)ドメインである(米国特許公開第2010/0216708号)。Tenconの結晶構造は、FN3ドメインの特徴である7個のβ鎖をつなぐ6回表面露出ループを示し、β鎖は、A、B、C、D、E、F、及びGと呼ばれ、ループは、AB、BC、CD、DE、EF、及びFGループと呼ばれる(Bork and Doolittle(1992)Proc Natl Acad Sci USA 89:8990-8994)。これらのループ又は各ループ内の選択された残基を、フィブロネクチンIII型(FN3)ドメインのライブラリを構築するためにランダム化することができ、これらを用いてFcγRIIに結合する新規分子を選択することができる。表2は、Tencon(配列番号4)の各ループ及びβ鎖の位置及び配列を示す。これにより、Tencon配列に基づいて設計されたライブラリは、無作為化FGループ、又は無作為化BC及びFGループを有し得る。Tencon BCループは、長さがアミノ酸7個であり、このため、1、2、3、4、5、6、又は7個のアミノ酸を、BCループで多様化させてTencon配列に基づいて設計したライブラリにおいて無作為化してもよい。Tencon FGループは、長さがアミノ酸7個であり、このため、1、2、3、4、5、6、又は7個のアミノ酸を、FGループで多様化させてTencon配列に基づいて設計したライブラリにおいて無作為化してもよい。Tenconライブラリにおけるループでの更なる多様性は、ループでの残基の挿入及び/又は欠失によって達成され得る。例えば、FG及び/又はBCループを、アミノ酸1~22個伸長させてもよく、又はアミノ酸1~3個減少させてもよい。TenconにおけるFGループは、長さがアミノ酸7個であり、抗体重鎖における対応するループは、残基4~28個の範囲である。最大の多様性を提供するために、FGループを、残基4~28個の抗体CDR3の長さの範囲に対応するように、配列並びに長さを多様化させてもよい。例えば、追加の1、2、3、4、又は5個のアミノ酸によってループを伸長させることにより、FGループの長さを更に多様化させることができる。Tencon配列に基づいて設計されたライブラリはまた、FN3ドメインの側面を形成するランダム化された代替表面を有してもよく、それらは2本以上のβ鎖と少なくとも1つのループを含んでもよい。そのような1つの代替表面は、C及びFのβ鎖、並びにCD及びFGループのアミノ酸によって形成される(C-CD-F-FG表面)。Tenconの代替的なC-CD-F-FG表面に基づいたライブラリの設計については、米国特許出願公開第2013/0226834号に記載されている。Tencon配列に基づいて設計されたライブラリはまた、11、14、17、37、46、73、又は86番目の位置(残基の番号付けは配列番号4に対応する)の残基で置換を有し、改善された熱安定性を示すTencon変異体などのTencon変種に基づいて設計されたライブラリを含む。例示的なTencon変異体が米国特許出願公開第2011/0274623号に記載されており、配列番号4のTenconと比較したとき、E11R、L17A、N46V、E86Iの置換を有するTencon27(配列番号5)が含まれる。
本発明は、単離されたFcγRII結合FN3ドメインを提供する。いくつかの実施形態では、単離されたFN3ドメインは、配列番号4のTenconアミノ酸配列又は配列番号5のTencon27配列に基づき、配列番号4又は配列番号5は、残基位置11、14、17、37、46、73、及び/又は86において置換を場合により有する。
本発明は、異種分子にコンジュゲートしたFcγRII結合FN3ドメインも提供する。いくつかの実施形態では、FcγRII結合FN3ドメインは、ポリペプチドにコンジュゲートされる。いくつかの実施形態では、FcγRII結合FN3ドメインは、抗体にコンジュゲートされる。いくつかの実施形態では、FcγRII結合FN3ドメインは、半減期延長部分にコンジュゲートされる。いくつかの実施形態では、FcγRII結合FN3ドメインは、検出可能な標識にコンジュゲートされる。いくつかの実施形態では、FcγRII結合FN3ドメインは、細胞毒性薬物にコンジュゲートされる。コンジュゲートは、FN3ドメインとのペプチド結合を介してもよく、標準的なクローニング及び発現技術によって生成され得る。代替的に、周知の化学カップリング方法を用いて、組み換え技術によって産生された本発明のFN3ドメインにその部分を結合させることができる。異種分子にコンジュゲートした本発明のFcγRII結合FN3ドメインは、いくつかの周知のアッセイによって機能性に関して比較され得る。例えば、Fcドメイン及び/又はFcドメイン変異体を組み込むことにより変化した特性を、FcγRI、FcγRII、FcγRIII、又はFcRn受容体などの可溶性型受容体を用いるFc受容体結合アッセイにおいてアッセイしてもよく、又は例えばADCC若しくはCDCを測定する周知の細胞系アッセイを用いて、又はインビボモデルにおける本発明の分子の薬物動態特性を評価してアッセイしてもよい。
例示的な半減期延長部分としては、アルブミン、アルブミン変異体、アルブミン結合タンパク質及び/又はドメイン、トランスフェリン、並びにそのフラグメント及び類似体、並びにFc領域がある。例示的なアルブミン変異体の1つに、配列番号15に示されるものがある。ヒトFc領域のアミノ酸配列は周知のものであり、IgG1、IgG2、IgG3、IgG4、IgM、IgA及びIgE Fc領域を含んでいる。
DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL
検出可能な標識にコンジュゲートされた本発明のFcγRII結合FN3ドメインは、例えば、対象からの試料などの組織又は細胞試料上のFcγRIIの発現を評価するために、又は対象のリンパ球などのFcγRII発現細胞を検出するためのインビボ撮像に使用されてもよい。
配列番号16、17、18、19、20、21又は22のアミノ酸配列を含むFcγRII結合FN3ドメインを検出可能な標識にコンジュゲートしてコンジュゲートを形成することと、
このコンジュゲートを対象に投与することと、
コンジュゲートが結合しているFcγRII発現細胞を可視化することとを含む。
試料を得ることと、
試料を、配列番号16、17、18、19、20、21又は22のアミノ酸配列を含むFcγRII結合FN3ドメイ接触させることと、
FcγRII結合FN3ドメインの結合を検出することとを含む。
細胞毒性剤にコンジュゲートされたFcγRII結合FN3ドメインは、例えば、これらの細胞毒性剤の全身投与が正常細胞に許容されないレベルの毒性を生じうる場合に、細胞毒性剤のFcγRII発現細胞、及びその細胞内蓄積部への標的化送達に使用することができる。
FcγRII結合FN3ドメインを任意のポリペプチドにコンジュゲートさせて、FcγRII結合特性をポリペプチドに提供してもよい。例えば、改変されたエフェクタサイレントFcを有する抗体は、ADCP活性を選択的にレスキューするために、本発明のFcγRII結合FN3ドメインにコンジュゲートさせることができる。腫瘍抗原に結合するポリペプチドは、ADCPを介して腫瘍細胞を排除するために、本発明のFcγRII結合FN3ドメインにコンジュゲートさせることができる。
本発明は、重鎖若しくはその断片及び軽鎖若しくはその断片と、FcγRII結合FN3ドメインとを含む抗腫瘍壊死因子受容体(TNFR)スーパーファミリーメンバー抗体を含む多重特異性分子も提供する。抗TNFRスーパーファミリーメンバー抗体へのFcγRII結合FN3ドメインのコンジュゲーションは、抗体のアゴニスト活性を増強し、エフェクタFc抗体においてADCP活性を提供する。
本発明は、本発明のFcγRII結合FN3ドメイン又は多重特異性分子をコードする核酸を、インビトロ転写/翻訳のために使用される直鎖DNA配列、その組成物の真核生物、原核生物、又はフィラメントファージでの発現、分泌、及び/又は提示と適合するベクター、又はその標的化突然変異源を含む、単離されたポリヌクレオチドとして、又は発現ベクターの一部として、又は直鎖DNA配列の一部として、提供する。ある特定の例示的なポリヌクレオチドが本明細書に開示されているが、遺伝コードの縮重又は所与の発現系におけるコドンの選択性を考慮すると、本発明のFN3ドメイン又は多重特異性分子をコードする他のポリヌクレオチドも本発明の範囲内に含まれる。
本発明は、本発明のFcγRII結合FN3ドメインに結合する抗イディオタイプ抗体も提供する。
本発明は、本発明のFcγRII結合FN3ドメインを含むキットも提供する。
FcγRII結合FN3ドメインは、NK細胞及びT細胞を除いて、エンドサイトーシス及び貪食作用に関与する活性化された免疫細胞、並びに白血球をモニタするために有用である。
本発明は、本発明のFcγRII結合FN3ドメイン又は多重特異性分子と、医薬的に許容される担体とを含む医薬組成物も提供する。治療用途では、本発明のFcγRII結合FN3ドメイン又は多重特異性分子は、医薬的に許容される担体中に活性成分として、有効量の抗体又はFcドメイン含有分子を含有する医薬組成物として調製することができる。例示的な医薬的に許容される担体は、生理学的に適合性の溶剤、分散媒体、コーティング剤、抗菌及び抗真菌剤、等張及び吸収遅延剤などであり、例えば、塩、緩衝液、抗酸化剤、糖類、植物油又はピーナッツオイルなどの水性若しくは非水性担体、防腐剤、湿潤剤、界面活性剤若しくは乳化剤、又はそれらの組み合わせである。
FcγRII結合FN3ドメインを、安定化されたTencon27(配列番号5)に基づいてライブラリから選択した。
mAbtyrinを生成するために、選択FcγRII FN3ドメインを、IgG2σアイソタイプ(野生型IgG2と比較したとき、置換V234A、G237A、P238S、H268A、V309L、A330S及びP331Sを有するエフェクタFc)としてクローン化した抗OX40抗体OX40SF2IgG2sigma(HC配列番号30、LC配列番号31)の重鎖のC末端で操作した。FcγRIIへの結合、NF-κBレポータアッセイにおけるアゴニズム、及び候補mAbtyrinのADCC/ADCPエフェクタ活性を評価した。親抗体OX40SF2IgG2sigmaを、実験における対照として使用した。表6は、生成されたmAbtyrinを示す。
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYINYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFLIQYQESEKVGEAIVLTVPGSERSYDLTGLKPGTEYTVSIYGVQYAAWYLPRHHEASNPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFWIYYLEYWRGGEAIVLTVPGSERSYDLTGLKPGTEYFVQIHGVKGGQYSYPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFLIAYAEYWEGGEAVVLTVPGSERSYDLTGLKPGTEYFVQINGVKGGFWSIPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFPIAYIEYWTGGEAIVLTVPGSERSYDLTGLKPGTEYFVWIHGVKGGAWSSPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFPIYYWEYRVGGEAIVLTVPGSERSYDLTGLKPGTEYFVYINGVKGGEESRPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFLIQYQESEKVGEAIVLTVPGSERSYDLTGLKPGTEYTVSIYGVSHGPWYNYGEWRSNPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFSIAYWEYRKGGEAIVLTVPGSERSYDLTGLKPGTEYFVLIYGVKGGWQSKPLSAIFTT
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
GACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCTAGCGTGGGCGACAGAGTGACCATCACCTGCAAGGCCAGCCAGGATGTGGGAGCCGCCGTGGCCTGGTATCAGCAGAAGCCCGGAAAGGCCCCCAAGCTGCTGATCTACTGGGCCAGCACCAGACACACCGGCGTGCCTAGCAGGTTTAGCGGCAGCGGCAGCGGCACCGACTTTACCCTGACCATCAGCAGCCTGCAGCCCGAGGATTTCGCCACCTACTACTGCCAGCAGTACATCAACTACCCCCTGACCTTCGGCGGCGGCACCAAAGTGGAGATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCGGCGCCGAAAAACCTGGTTGTTTCTCGTGTTACCGAAGACTCTGCGCGTCTGTCTTGGACCGCGCCGGACGCGGCGTTCGACTCTTTCCTGATCCAGTACCAGGAATCTGAAAAAGTTGGTGAAGCGATCGTGCTGACCGTTCCGGGTTCTGAACGTTCTTACGACCTGACCGGTCTGAAACCGGGTACCGAATACACCGTTTCTATCTACGGTGTTCAATATGCGGCGTGGTATCTGCCGCGTCACCACGAGGCGAGCAACCCGCTGTCTGCGATCTTCACCACC
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCGGCGCCGAAAAACCTGGTTGTTTCTCGTGTTACCGAAGACTCTGCGCGTCTGTCTTGGACCGCGCCGGACGCGGCGTTCGACTCTTTCTGGATTTATTACCTGGAGTATTGGCGTGGCGGTGAAGCGATCGTTCTGACCGTTCCGGGTTCTGAACGTTCTTACGACCTGACCGGTCTGAAACCGGGTACCGAATATTTCGTTCAAATTCACGGCGTTAAGGGCGGTCAATATAGTTATCCACTGTCTGCGATCTTCACCACC
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCGGCGCCGAAAAACCTGGTTGTTTCTCGTGTTACCGAAGACTCTGCGCGTCTGTCTTGGACCGCGCCGGACGCGGCGTTCGACTCTTTTCTGATCGCGTATGCGGAATATTGGGAGGGCGGTGAAGCGGTCGTTCTGACCGTTCCGGGTTCTGAACGTTCTTACGACCTGACCGGTCTGAAACCGGGTACCGAATATTTCGTTCAAATCAATGGCGTTAAGGGTGGTTTCTGGAGTATCCCACTGTCTGCGATCTTCACCACC
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCGGCGCCGAAAAACCTGGTTGTTTCTCGTGTTACCGAAGACTCTGCGCGTCTGTCTTGGACCGCGCCGGACGCGGCGTTCGACTCTTTTCCGATCGCGTATATCGAGTATTGGACTGGCGGTGAAGCGATCGTTCTGACCGTTCCGGGTTCTGAACGTTCTTACGACCTGACCGGTCTGAAACCGGGTACCGAATATTTCGTTTGGATTCACGGCGTTAAGGGTGGTGCGTGGTCCAGCCCGCTGTCTGCGATCTTCACCACC
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCCGCCCCCAAGAACCTGGTGGTGAGCAGGGTGACCGAGGACAGCGCCAGGCTGAGCTGGACAGCTCCTGACGCCGCCTTCGACAGCTTCCCCATCTATTACTGGGAGTACAGGGTGGGCGGAGAGGCCATCGTGCTGACAGTGCCCGGCAGCGAGAGGAGCTACGACCTGACCGGCCTGAAGCCTGGCACCGAGTACTTCGTGTACATCAACGGCGTGAAGGGCGGCGAGGAATCCAGACCCCTGAGCGCCATCTTCACCACC
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCGGCGCCGAAAAACCTGGTTGTTTCTCGTGTTACCGAAGACTCTGCGCGTCTGTCTTGGACCGCGCCGGACGCGGCGTTCGACTCTTTCCTGATCCAGTACCAGGAATCTGAAAAAGTTGGTGAAGCGATCGTGCTGACCGTTCCGGGTTCTGAACGTTCTTACGACCTGACCGGTCTGAAACCGGGTACCGAATACACCGTTTCTATCTACGGTGTGAGCCACGGCCCGTGGTATAATTATGGCGAGTGGCGTTCTAACCCGCTGTCTGCGATCTTCACCACC
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCGGCGCCGAAAAACCTGGTTGTTTCTCGTGTTACCGAAGACTCTGCGCGTCTGTCTTGGACCGCGCCGGACGCGGCGTTCGACTCTTTTAGCATTGCGTACTGGGAGTATCGTAAAGGCGGTGAAGCGATCGTTCTGACCGTTCCGGGTTCTGAACGTTCTTACGACCTGACCGGTCTGAAACCGGGTACCGAATATTTCGTTCTGATCTATGGTGTCAAGGGCGGTTGGCAATCCAAACCACTGTCTGCGATCTTCACCACC
生成されたmAbtyrinを、それらのFcγRへの結合及びアゴニスト活性について特性化した。親OX40抗体OX40SF2IgG2sigmaを、アッセイをとおしてコンパレータとして使用した。
フローサイトメトリ染色
ヒトFcγRI(NM_000566)(配列番号:44)、FcγRIIA(NM_021642)(配列番号:2)、FcγRIIB(NM_004001)(配列番号:3)、及びFcγRIIIA(NM_000569)(配列番号:45)をコードするcDNAを発現するプラスミド(Origene)を、ExpiFectamine293トランスフェクションキット(Life Technologies)により、Expi293F細胞に一過的にトランスフェクションした。トランスフェクションの48時間後にフローサイトメトリアッセイを実施した。トランスフェクションしたFc受容体の発現を確認するために、特異的抗体:FcγRIについては10.1(BD Pharmingen)、FcγRIIAについてはIV.3(StemCell Technologies)、FcγRIIBについては(社内で調製)2B6(Veri et al.(2007)Immunology 121:392-404)、及びFcγRIIIAについては3G8(BD Pharmingen)を、陽性対照としてフローサイトメトリ染色に用いた。
MWFLTTLLLWVPVDGQVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFLNGTATQTSTPSYRITSASVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNVLYYRNGKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLNASVTSPLLEGNLVTLSCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDSGLYWCEAATEDGNVLKRSPELELQVLGLQLPTPVWFHVLFYLAVGIMFLVNTVLWVTIRKELKRKKKWDLEISLDSGHEKKVISSLQEDRHLEEELKCQEQKEEQLQEGVHRKEPQGAT
MAEGTLWQILCVSSDAQPQTFEGVKGADPPTLPPGSFLPGPVLWWGSLARLQTEKSDEVSRKGNWWVTEMGGGAGERLFTSSCLVGLVPLGLRISLVTCPLQCGIMWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQWFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKEEDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKNVSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDWKDHKFKWRKDPQDK
Raji細胞は、優勢にFcγRIIBを発現するB細胞に由来する細胞株である。Raji細胞上のmAbtyrinの結合を、FcγRに結合するmAbtyrinの試験について記載したフローサイトメトリアッセイによって検討した。ヒトIgG(γ)に対するPE標識ヤギF(ab’)2を使用して、mAbtyrinの結合をフローサイトメトリによって検出した。
細胞上に発現されたOX40に対するmAbtyrinの結合を、FcγRに結合するmAbtyrinの試験について記載したフローサイトメトリアッセイによって検討した。NF-κB誘導性プロモータ(IFN-β最小プロモータ)の制御下で分泌型胚アルカリホスファターゼ(SEAP)レポータ遺伝子を発現するように改変されたHEK-Blue(商標)Null1細胞に、OX40発現プラスミド(pUNO1-hOX40)をトランスフェクションし、ヒトOX40を発現する安定なHEK-Blueレポータ細胞株(HEK-Blue:OX40)を樹立した。mAbtyrinをHEK-Blue:OX40細胞と共にインキュベートし、ヒトIgG(γ)に対してPE標識ヤギF(ab’)2を使用して、フローサイトメトリによって結合を検出した。
mAbtyrinのアゴニスト活性を、HEK-BlueNF-κBレポータアッセイを用いて評価した。簡潔に言えば、200μL培地に再懸濁した、1×105個のHEK-Blue:OX40細胞を、96ウェルアッセイプレートの各ウェルに分け、OX40リガンド又はmAbtyrinを添加した。架橋効果を試験するために、1μLのプロテインG磁気ビーズ(Pierce)又は1×105個のRaji細胞のいずれかを、同じアッセイウェルに添加した。37℃で一晩インキュベーションした後、Quanti-Blue検出キット(Invivogen)を使用して、誘導により分泌されたアルカリホスファターゼ(SEAP)レポータ遺伝子発現を定量化することにより、mAbtyrinのアゴニスト活性を評価した。簡潔に言えば、40μLの細胞培養上清を160μLのQuanti-Blue試薬と混合し、適切な青色が生じるまで、37℃でインキュベーションした。SpectraMaxマイクロプレートリーダー(Molecular Devices,Sunnyvale,CA)を使用して、650nmにおけるODを測定した。mAbtyrinのアゴニスト活性を、1μg/mLのOX40リガンドにより誘導される活性に対する活性(%)として、正規化した。
生成されたmAbtyrinのADCC及びADCP活性を評価した。
ADCCアッセイ
製造元(Promega)により指示されるとおりに、ADCCレポータバイオアッセイにより、mAbtyrinのADCC活性を評価した。簡潔に言えば、96ウェルプレートにプレートしたウェル当たり25,000個のHEK-Blue:OX40細胞を、FcγRIIIA受容体の活性化がルシフェラーゼレポータの発現につながる操作されたエフェクタ細胞と一晩混合した。mAbtyrinをこの細胞に添加し、37℃で6時間インキュベートした。次いで、Bio-Gloルシフェラーゼ試薬を添加し、ルシフェラーゼシグナルをEnvisionにより定量化した。mAbtyrinのADCC活性を、試験抗体を添加しない活性化に対して、ルシフェラーゼシグナルの活性化が何倍であるかとして表した。
GFPを発現するOX40標的細胞株を、Turbo GFP形質導入粒子(Sigma Aldrich)をHEK-Blue:OX40細胞を感染させることにより樹立した。安定なGFP発現細胞を、ピューロマイシンを用いて選択した。CD16が枯渇(depletion)していない、陰性ヒト単球濃縮キット(StemCell technologies)を使用して、ヒトCD14+CD16+単球をPBMC(Biologics Specialty)から単離した。10%FBSを含有するX-VIVO-10培地(Lonza)に、単離した単球を蒔き、25ng/mLのマクロファージコロニー刺激因子(R&D Systems)を7日間添加することで、単球をマクロファージに分化させた。IFNγ(50ng/mL;R&D Systems)を、分化の最後の24時間の間添加した。ADCPアッセイのため、1×105個/ウェルの分化したマクロファージを、96ウェルU底プレートで、200μL培地(DMEM+10% FBS)中、0.25×105個/ウェルのGFP発現HEK-Blue:OX40細胞(4:1比)と混合した。試験mAbtyrinを添加し、37℃のインキュベータ内で24時間プレートをインキュベートした。次いで、Accutase(Sigma)を使用して細胞を剥離し、BSA染色バッファに再懸濁させた。Alexa Fluor 647(Invitrogen)を連結した抗CD11b及び抗CD14抗体(BD Biosciences)により、マクロファージを染色した。Miltenyi MACSQuantフローサイトメータ(Miltenyi Biotec,Auburn,USA)を使用するフローサイトメトリにより、GFP陽性HEK-Blue:OX40標的細胞及びAlexa647陽性マクロファージを識別した。FlowJoソフトウェア(Tree Star)を使用してデータを分析し、以下の式:殺傷された標的細胞の割合=((抗体濃度が最小の場合のGFP+、CD11b-、CD14-細胞の割合)-(抗体濃度が試験濃度の場合のGFP+、CD11b-、CD14-細胞の割合))/(抗体濃度が最小の場合のGFP+、CD11b-、CD14-細胞の割合)×100を使用して、GFP蛍光の減少を測定することにより、ADCPが介在する細胞殺傷を測定した。
mAbtyrinもOX40SF2IgG2sigmaも、エフェクタサイレントFcのために、ADCC活性を有しなかった。このデータは、同定されたFN3ドメインが、FcγRIIIAとの相互作用を有しなかったこと、及び親抗体のC末端へのFN3の添加が、ADCCに影響を及ぼさなかったことを示した(データは示さず)。全ての試験されたmAbtyrinは、OX40発現細胞の有意なADCPを媒介したが、一方OX40SF2IgG2sigmaはADCPを媒介しなかった。表13は、ADCPアッセイにおいて、1μg/mlの試験mAbtyrinによって殺傷されたOX40細胞の割合を示す。mAbtyrinのADCP活性は、おそらくは、mAbtyrinのマクロファージ上のFcγRIIAとの相互作用によって媒介された。
FcγRII FN3ドメインの配置がmAbtyrin特性に影響を及ぼすかどうかを評価するために、R2BS29 FN3ドメインを、抗OX40抗体への異なる位置で操作した。抗体重鎖のC末端にFN3ドメインを結合させる以外に、OX40抗体の軽鎖のC末端にFN3ドメインを有するmAbtyrin(LC-C構築物)、軽鎖のN末端にFN3ドメインを有するmAbtyrin(LC-N)構築物、又は重鎖のN末端にFN3ドメインを有するmAbtyrin(HC-N構築物)を生成した。mAbtyrinを、野生型IgG1又はエフェクタサイレントIgG2sigmaとしてクローン化した。mAbtyrinを、Expi293F細胞中に重鎖及び軽鎖構築物をトランスフェクトし、続いてプロテインA親和性クロマトグラフィによってmAbtyrin精製を行うことによって生成した。精製されたmAbtyrinのSDS-PAGE分析により、非還元(NR)条件下で、予想される170kDaのタンパク質バンドが明らかになった。
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
LPAPKNLVVSRVTEDSARLSWTAPDAAFDSFPIYYWEYRVGGEAIVLTVPGSERSYDLTGLKPGTEYFVYINGVKGGEESRPLSAIFTTGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
LPAPKNLVVSRVTEDSARLSWTAPDAAFDSFPIYYWEYRVGGEAIVLTVPGSERSYDLTGLKPGTEYFVYINGVKGGEESRPLSAIFTTGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVGAAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYINYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
DIQMTQSPSSLSASVGDRVTITCKASQDVGAAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYINYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGGGGSMLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFPIYYWEYRVGGEAIVLTVPGSERSYDLTGLKPGTEYFVYINGVKGGEESRPLSAIFTT
QVQLVQSGAEVKKPGSSVKVSCKASGYTFKDYTMHWVRQAPGQGLEWIGGIYPNNGGSTYNQNFKDRVTLTADKSTSTAYMELSSLRSEDTAVYYCARMGYHGPHLDFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGSGGGGSGGGGSGGGGSLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFPIYYWEYRVGGEAIVLTVPGSERSYDLTGLKPGTEYFVYINGVKGGEESRPLSAIFTT
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
CTGCCCGCCCCCAAGAACCTGGTCGTCAGCAGAGTGACCGAGGACTCCGCCAGACTGAGCTGGACAGCCCCTGACGCCGCCTTCGATTCCTTCCCCATCTACTACTGGGAGTACAGAGTGGGCGGAGAGGCCATCGTGCTGACCGTGCCTGGCTCCGAGAGGTCCTACGACCTGACCGGCCTGAAGCCTGGCACCGAGTACTTCGTGTACATCAACGGCGTGAAGGGCGGAGAGGAGTCCAGACCCCTGAGCGCCATTTTCACCACAGGCGGCGGCGGCTCCGGCGGAGGCGGCTCCGGCGGAGGAGGAAGCGGCGGCGGAGGGAGCCAAGTGCAGCTCGTGCAGTCCGGCGCTGAGGTGAAGAAACCTGGCTCCAGCGTCAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGGCAAGCCCCTGGCCAAGGCCTGGAGTGGATCGGAGGCATCTACCCCAACAACGGCGGCTCCACCTATAACCAGAATTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTATCACGGCCCCCACCTGGACTTTGACGTGTGGGGCCAGGGCACAACCGTCACCGTGTCCAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGCCGCAGCCAGCTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCGCCGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
CTGCCTGCCCCCAAGAACCTGGTGGTGAGCAGAGTGACCGAGGATAGCGCCAGACTGTCCTGGACAGCCCCCGATGCCGCCTTCGACTCCTTCCCCATCTATTACTGGGAGTACAGGGTGGGAGGCGAGGCCATCGTGCTGACCGTGCCTGGCTCCGAGAGGAGCTACGATCTGACCGGCCTGAAGCCCGGCACCGAGTACTTCGTGTACATCAACGGCGTCAAGGGAGGCGAGGAGAGCAGACCCCTGTCCGCCATCTTCACCACAGGAGGCGGCGGCAGCGGCGGCGGAGGCAGCGGCGGCGGAGGCTCCGGCGGCGGCGGCAGCGATATCCAGATGACCCAGAGCCCCAGCTCCCTGTCCGCTAGCGTGGGCGACAGAGTGACCATCACCTGCAAGGCTAGCCAGGACGTGGGCGCTGCTGTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTGGGCCTCCACAAGGCACACCGGAGTGCCCAGCAGATTTTCCGGCAGCGGCAGCGGCACCGATTTCACCCTGACCATCAGCTCCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACATCAATTACCCCCTGACCTTCGGCGGAGGCACCAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
GACATCCAGATGACCCAGAGCCCCAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACATGCAAGGCCAGCCAGGACGTGGGAGCCGCCGTGGCTTGGTATCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTACTGGGCCAGCACCAGACACACCGGCGTGCCCAGCAGATTTTCTGGCAGCGGCTCCGGCACCGACTTCACCCTGACAATCAGCTCCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACATCAACTACCCCCTGACCTTCGGCGGAGGCACCAAGGTGGAAATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGAGGAGGATCCATGCTGCCTGCCCCCAAGAACCTGGTGGTGAGCAGGGTGACCGAGGACAGCGCCAGACTGAGCTGGACAGCTCCCGACGCCGCCTTCGACTCCTTCCCCATCTACTACTGGGAGTACAGAGTGGGCGGCGAAGCCATTGTGCTGACCGTGCCCGGCAGCGAGAGGAGCTACGACCTGACCGGCCTGAAGCCCGGCACCGAGTACTTCGTGTACATCAACGGCGTGAAGGGCGGCGAAGAGAGCAGGCCTCTGAGCGCCATCTTCACCACA
CAGGTGCAGCTGGTCCAGAGCGGAGCCGAGGTGAAGAAGCCCGGCTCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCAAGGACTACACCATGCACTGGGTGAGACAGGCCCCTGGACAGGGCCTGGAATGGATCGGCGGCATCTACCCCAACAACGGCGGCTCCACCTACAACCAGAACTTCAAGGACAGGGTGACCCTGACCGCCGACAAGAGCACCAGCACCGCTTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGGATGGGCTACCACGGCCCTCACCTGGACTTCGACGTGTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGGAGGCGGAGGGAGTGGCGGGGGAGGCTCTGGCGGCGGAGGATCCGGCGGCGGAGGAAGCCTGCCCGCCCCCAAGAACCTGGTGGTGAGCAGGGTGACCGAGGACAGCGCCAGGCTGAGCTGGACAGCTCCTGACGCCGCCTTCGACAGCTTCCCCATCTATTACTGGGAGTACAGGGTGGGCGGAGAGGCCATCGTGCTGACAGTGCCCGGCAGCGAGAGGAGCTACGACCTGACCGGCCTGAAGCCTGGCACCGAGTACTTCGTGTACATCAACGGCGTGAAGGGCGGCGAGGAATCCAGACCCCTGAGCGCCATCTTCACCACC
Expi293F細胞上で一過的に発現されたFcγRIIA、FcγRIIB、FcγRI及びFcγRIIIAに対するOX40mAb×R2BS29センチリンの結合を、上記のフローサイトメトリによって検討した。R2BS29 FN3ドメインを有するmAbtyrinは、FN3ドメインの位置付けに無関係にFcγRIIA及びFcγRIIBに結合し、FcγRI及びFcγRIIIAへの結合は示さなかった。表15は、Expi293F細胞で発現された様々なFcγRに対するmAbtyrinの結合のEC50値を示す。
生成されたmAbtyrinは、FN3ドメインの位置付けに無関係にRaji細胞への結合を示したが、一方親エフェクタサイレントmAb OX40SF2IgG2sigmaは結合を示さなかった。全てのmAbtyrinは、FN3ドメインの位置に無関係に、HEKBlue:OX40細胞上に発現されたOX40への結合を実証した。表16は、結合のEC50値を示す。mAbtyrinについての結合の効力は、対応する天然抗体と同等であり、R2BS29 FN3ドメインの様々な位置での抗体上への結合が、それらの標的を認識する抗体に影響を及ぼさなかったことを示唆している。
全ての生成されたmAbtyrinは、HEK-Blue:OX40細胞に対する弱い架橋非依存性アゴニスト活性を実証した。プロテインGとの架橋は、mAbtyrinのアゴニスト活性を押し上げた。Raji細胞との架橋は、重鎖又は軽鎖のいずれかにおいてC末端結合FN3ドメインを有するmAbtyrinのアゴニスト活性を押し上げた。しかしながら、Raji細胞は、FN3ドメインが重鎖又は軽鎖のいずれかのN末端に位置付けられたmAbtyrinのアゴニスト活性を有意に押し上げなかった。アゴニズムは、野生型IgG1又はエフェクタサイレントIgG2sigmaとしてクローン化されたmAbtyrinで観察され、アイソタイプが、mAbtyrinを含有するFcγRII FN3ドメインのアゴニズムに影響を及ぼさないことを示した。表17は、アッセイで得られたEC50値を示す。
mAbtyrinのADCC、ADCP及びCDC活性を評価した。ADCC及びADCPを、上記のプロトコルを用いて評価した。
抗OX40抗体の補体依存性細胞傷害(CDC)活性を、補体が介在する細胞殺傷アッセイにより評価した。簡潔に言えば、ウサギ補体(Cedar Lane Labs)及び試験mAbtyrinと共に、100,000個のHEK-Blue:OX40細胞を96ウェルプレートで1時間、インキュベーションした。溶解させたHEK-Blue:OX40細胞の細胞質基質から上清中に放出された乳酸デヒドロゲナーゼ(lactate dehydrogenase、LDH)の活性を、細胞傷害性検出キット(Roche)により定量化した。補体が介在する細胞傷害を、Triton X-100により溶解されたものに対する細胞傷害性(%)として表した。
T細胞活性化に対するmAbtyrinの効果を評価した。簡潔に言えば、組み換えFcRIIB又はFcRIIAタンパク質をプレート上にコーティングして、架橋活性を提供した。γγT細胞活性化アッセイについては、DPBS中、30ng/mLの抗CD3抗体(OKT3)及び1μg/mLのFcγRIIB又はFcμRIIAタンパク質の100γLを、U底96ウェル組織培養プレートで一晩コーティングした。CD4陽性T細胞を、陰性選択によってPBMCから単離した。OX40発現を、単離されたT細胞を、1μg/mLのPHAの存在下で一晩培養することによって誘導した。アッセイ当日に、プレート中のコーティング溶液を吸引し、プレートをブロックするために、150μLのRPMI培地を添加した。培養したT細胞を、RPMI培養培地で3回洗浄し、25,000~50,000個のCD4陽性T細胞をアッセイプレート内の各ウェルに播種した。試験mAbtyrinをこの細胞に添加し、プレートを3日間インキュベートした。T細胞活性化を、ヒトIFNγ又はTNFαELISA検出キット(Biolegend)によって定量化されるIFNγ又はTNFα産生の誘導によって評価した。T細胞活性化アッセイの前に、mAbtyrinの固定化FcγRIIB又はFcγRIIAタンパク質に対する結合親和性を、ELISAアッセイによって評価した。このアッセイでは、1日前に、1γg/mLのFcγRIIB又はFcγRIIAタンパク質の100γLをMaxisorp96ウェルプレート上にコーティングした。mAbtyrinをアッセイウェルに添加し、2時間インキュベートした。mAbtyrinの固定化FcγRIIB又はFcμRIIAへの結合を、HRPコンジュゲート抗ヒトIgG(γ)二次抗体によって検出し、TMB基質を使用するELISAアッセイで定量化した。
以下に、本願の当初の特許請求の範囲に記載の発明を列挙する。
[発明1]
単離されたFcγRII結合フィブロネクチンII型(FN3)ドメイン。
[発明2]
場合により残基位置11、14、17、46、73、及び/又は86に置換を有する、Tencon27(配列番号5)又はTencon(配列番号4)に基づく、発明1に記載の単離されたFN3ドメイン。
[発明3]
配列番号16、17、18、19、20、21、又は22のアミノ酸配列を含む、発明1又は2に記載の単離されたFN3ドメイン。
[発明4]
前記FN3ドメインが、配列番号23、24、25、26、27、28、又は29のポリヌクレオチド配列によってコードされる、発明1~3のいずれか一つに記載の単離されたFN3ドメイン。
[発明5]
異種分子にコンジュゲートされている、発明1~4のいずれか一つに記載の単離されたFN3ドメイン。
[発明6]
前記異種分子が、ポリペプチド、抗体、半減期延長部分、検出可能な標識、又は細胞毒性剤である、発明5に記載の単離されたFN3ドメイン。
[発明7]
前記検出可能な標識が、アウリスタチン、モノメチルアウリスタチンフェニルアラニン、ドラスタチン(dolostatin)、化学療法剤、薬剤、増殖阻害剤、毒素、又は放射性同位体である、発明6に記載の単離されたFN3ドメイン。
[発明8]
前記半減期延長部分が、アルブミン結合分子、ポリエチレングリコール(PEG)、アルブミン、アルブミン変異体、又は免疫グロブリンのFc領域である、発明6に記載の単離されたFN3ドメイン。
[発明9]
前記抗体が、抗TNFRスーパーファミリーメンバー抗体である、発明6に記載の単離されたFN3ドメイン。
[発明10]
前記FN3ドメインのN末端にメチオニンを更に含む、発明1~9のいずれか一つに記載の単離されたFN3ドメイン。
[発明11]
a)配列番号23、24、25、26、27、28、若しくは29のポリヌクレオチド配列を含むか、又は
b)配列番号16、17、18、19、20、21、若しくは22のポリペプチドをコードする、
ポリヌクレオチド。
[発明12]
発明11に記載のポリヌクレオチドを含む、ベクター。
[発明13]
発現ベクターである、発明12に記載のベクター。
[発明14]
発明12又は13に記載のベクターを含む、宿主細胞。
[発明15]
発明1に記載の単離されたFN3ドメインを生成する方法であって、前記FN3ドメインが発現される条件下で、発明14に記載の宿主細胞を培養することと、前記FN3ドメインを精製することとを含む、前記方法。
[発明16]
発明1~10のいずれか一つに記載のFN3ドメインと、医薬的に許容される担体とを含む、医薬組成物。
[発明17]
発明3に記載のFN3ドメインに特異的に結合する、抗イディオタイプ抗体。
[発明18]
発明3に記載のFN3ドメインを含むキット。
[発明19]
ポリペプチドの抗体依存性細胞貪食作用(ADCP)活性を増強する方法であって、前記ポリペプチドにFcγRII結合FN3ドメインをコンジュゲートすることと、前記ポリペプチドの増強されたADCP活性を測定することとを含む、前記方法。
[発明20]
前記FN3ドメインが、配列番号16、17、18、19、20、21、又は22のポリペプチド配列を含む、発明19に記載の方法。
[発明21]
重鎖若しくはその断片及び軽鎖若しくはその断片と、FcγRII結合FN3ドメインとを含む、抗腫瘍壊死因子受容体(TNFR)スーパーファミリーメンバー抗体を含む、多重特異性分子。
[発明22]
前記抗TNFRスーパーファミリーメンバー抗体、及び前記FcγRII結合FN3ドメインが、ペプチド結合を介して共有結合している、発明21に記載の多重特異性分子。
[発明23]
前記FcγRII結合FN3ドメインが、前記重鎖若しくはその断片のC末端、前記重鎖若しくはその断片のN末端、前記軽鎖若しくはその断片のC末端、又は前記軽鎖若しくはその断片のN末端に結合されている、発明21又は22に記載の多重特異性分子。
[発明24]
前記抗TNFRスーパーファミリーメンバー抗体が、IgG1、IgG2、IgG3、又はIgG4アイソタイプである、発明21~23のいずれか一つに記載の多重特異性分子。
[発明25]
前記抗TNFRスーパーファミリーメンバー抗体が、エフェクタサイレントFcを含む、発明21~24のいずれか一つに記載の多重特異性分子。
[発明26]
前記抗TNFRスーパーファミリーメンバー抗体が、OX40、CD27、CD40、CD137、又はGITRに結合する、発明21~25のいずれか一つに記載の多重特異性分子。
[発明27]
前記FN3ドメインが、配列番号16、17、18、19、20、21、又は22のアミノ酸配列を含む、発明21~26のいずれか一つに記載の多重特異性分子。
[発明28]
前記FN3ドメインが、配列番号23、24、25、26、27、28、又は29のポリヌクレオチドによってコードされている、発明21~27のいずれか一つに記載の多重特異性分子。
[発明29]
a)配列番号30及び31、
b)配列番号32及び31、
c)配列番号33及び31、
d)配列番号34及び31、
e)配列番号35及び31、
f)配列番号36及び31、
g)配列番号37及び31、
h)配列番号38及び31、
i)配列番号39及び31、
j)配列番号40及び31、
k)配列番号30及び41、
l)配列番号30及び42、
m)配列番号43及び31又は
n)配列番号39及び42
のポリペプチド含む、発明21~28のいずれか一つに記載の多重特異性分子。
[発明30]
a)配列番号46及び47、
b)配列番号48及び47、
c)配列番号49及び47、
d)配列番号50及び47、
e)配列番号51及び47、
f)配列番号52及び47、
g)配列番号53及び47、
h)配列番号54及び47、
i)配列番号55及び47、
j)配列番号56及び47、
k)配列番号46及び57、
l)配列番号46及び58、
m)配列番号59及び47又は
n)配列番号55及び58
のポリヌクレオチドによってコードされるポリペプチドを含む、発明21~29のいずれか一つに記載の多重特異性分子。
[発明31]
a)配列番号46、47、48、49、50、51、52、53、54、55、56、57、58、若しくは59のポリヌクレオチド配列を含むか、又は
b)配列番号30、31、32、33、34、35、36、37、38、39、40、41、42、若しくは43のポリペプチドをコードする、
ポリヌクレオチド。
[発明32]
発明31に記載のポリヌクレオチドを含む、ベクター。
[発明33]
発現ベクターである、発明32に記載のベクター。
[発明34]
発明32又は33に記載のベクターを含む、宿主細胞。
[発明35]
抗TNFRスーパーファミリーメンバー抗体のアゴニスト活性を増強させる方法であって、
a)前記抗体を、FcγRIIB結合FN3ドメインにコンジュゲートして、操作された抗TNFRスーパーファミリーメンバー抗体を生成することと、
b)前記操作された抗TNFRスーパーファミリーメンバー抗体の前記増強したアゴニスト活性を測定することとを含む、
前記方法。
[発明36]
対象において癌を治療する方法であって、治療的有効量の、重鎖若しくはその断片及び軽鎖若しくはその断片と、FcγRII結合FN3ドメインとを含む、抗TNFRスーパーファミリーメンバー抗体を含む、単離された多重特異性分子を、前記対象に投与して、前記癌を治療することを含む、前記方法。
[発明37]
前記抗TNFRスーパーファミリーメンバー抗体、及び前記FcγRII結合FN3ドメインが、ペプチド結合を介して共有結合している、発明36に記載の方法。
[発明38]
前記FcγRII結合FN3ドメインが、前記重鎖若しくはその前記断片の前記C末端、前記重鎖若しくはその前記断片の前記N末端、前記軽鎖若しくはその前記断片の前記C末端、又は前記軽鎖若しくはその前記断片の前記N末端に結合されている、発明36又は37に記載の方法。
[発明39]
前記抗TNFRスーパーファミリーメンバー抗体が、IgG1、IgG2、IgG3、又はIgG4アイソタイプであり、場合によりエフェクタサイレントFcを含む、発明36~38のいずれか一つに記載の方法。
[発明40]
前記抗TNFRスーパーファミリーメンバー抗体が、OX40、CD27、CD40、CD137、又はGITRに結合する、発明36~39のいずれか一つに記載の方法。
[発明41]
前記FN3ドメインが、配列番号16、17、18、19、20、21、又は22のアミノ酸配列を含む、発明36~40のいずれか一つに記載の方法。
[発明42]
前記多重特異性分子が、
a)配列番号30及び31、
b)配列番号32及び31、
c)配列番号33及び31、
d)配列番号34及び31、
e)配列番号35及び31、
f)配列番号36及び31、
g)配列番号37及び31、
h)配列番号38及び31、
i)配列番号39及び31、
j)配列番号40及び31、
k)配列番号30及び41、
l)配列番号30及び42、
m)配列番号43及び31、又は
n)配列番号39及び42
のポリペプチドを含む、発明36~41のいずれか一つに記載の方法。
[発明43]
癌が、固形腫瘍である、発明36~42のいずれか一つに記載の方法。
[発明44]
前記固形腫瘍が、黒色腫、肺癌、扁平非小細胞肺癌(NSCLC)、非扁平NSCLC、結腸直腸癌、前立腺癌、去勢抵抗性前立腺癌、胃癌(stomach cancer)、卵巣癌、胃癌(gastric cancer)、肝癌、膵臓癌、甲状腺癌、頭頸部の扁平上皮細胞癌、食道又は胃腸管の癌、乳癌、卵管癌、脳腫瘍、尿道癌、泌尿生殖器癌、子宮内膜症、子宮頸癌、又は癌の転移性病変である、発明43に記載の方法。
[発明45]
癌の治療において使用するための、重鎖若しくはその断片及び軽鎖若しくはその断片と、FcγRII結合FN3ドメインとを含む、抗TNFRスーパーファミリーメンバー抗体を含む、単離された多重特異性分子。
[発明46]
前記癌が、黒色腫、肺癌、扁平非小細胞肺癌(NSCLC)、非扁平NSCLC、結腸直腸癌、前立腺癌、去勢抵抗性前立腺癌、胃癌(stomach cancer)、卵巣癌、胃癌(gastric cancer)、肝癌、膵臓癌、甲状腺癌、頭頸部の扁平上皮細胞癌、食道又は胃腸管の癌、乳癌、卵管癌、脳腫瘍、尿道癌、泌尿生殖器癌、子宮内膜症、子宮頸癌、又は前記癌の転移性病変である、癌の治療において使用するための、発明45に記載の多重特異性分子。
[発明47]
癌の治療のための薬剤の製造における、重鎖若しくはその断片及び軽鎖若しくはその断片と、FcγRII結合FN3ドメインとを含む、抗TNFRスーパーファミリーメンバー抗体を含む、単離された多重特異性分子の使用。
[発明48]
前記癌が、黒色腫、肺癌、扁平非小細胞肺癌(NSCLC)、非扁平NSCLC、結腸直腸癌、前立腺癌、去勢抵抗性前立腺癌、胃癌(stomach cancer)、卵巣癌、胃癌(gastric cancer)、肝癌、膵臓癌、甲状腺癌、頭頸部の扁平上皮細胞癌、食道又は胃腸管の癌、乳癌、卵管癌、脳腫瘍、尿道癌、泌尿生殖器癌、子宮内膜症、子宮頸癌、又は前記癌の転移性病変である、発明47に記載の使用。
Claims (12)
- 抗体の抗体依存性細胞貪食作用(ADCP)活性を増強する方法であって、配列番号16、17、18、19、20、21、又は22の配列を含むFcγRII結合フィブロネクチンIII型(FN3)ドメインを前記抗体にコンジュゲートすることによって、前記抗体のADCP活性を増強することを含む、前記方法。
- 前記FN3ドメインが配列番号16の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインが配列番号17の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインが配列番号18の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインが配列番号19の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインが配列番号20の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインが配列番号21の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインが配列番号22の配列を含む、請求項1に記載の方法。
- 前記FN3ドメインを前記抗体のN末端にコンジュゲートする、請求項1に記載の方法。
- 前記FN3ドメインを前記抗体のC末端にコンジュゲートする、請求項1に記載の方法。
- 前記コンジュゲートすることが、前記FN3ドメイン及び前記抗体をベクターにクローニングし、FN3-抗体コンジュゲートを発現させることを含む、請求項1に記載の方法。
- 前記コンジュゲートすることが、前記FN3ドメインと前記抗体とを化学カップリングすることを含む、請求項1に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762550152P | 2017-08-25 | 2017-08-25 | |
US62/550,152 | 2017-08-25 | ||
PCT/US2018/047843 WO2019040808A1 (en) | 2017-08-25 | 2018-08-24 | TYPE III FIBRONECTIN BINDER FCγRII DOMAINS, THEIR CONJUGATES AND MULTISPECIFIC MOLECULES COMPRISING THE SAME |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020537492A JP2020537492A (ja) | 2020-12-24 |
JP7250766B2 true JP7250766B2 (ja) | 2023-04-03 |
Family
ID=65437103
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020510561A Active JP7250766B2 (ja) | 2017-08-25 | 2018-08-24 | FCγRII結合フィブロネクチンIII型ドメイン、それらのコンジュゲート、及びそれらを含む多重特異性分子 |
Country Status (5)
Country | Link |
---|---|
US (1) | US11078263B2 (ja) |
EP (1) | EP3672611A4 (ja) |
JP (1) | JP7250766B2 (ja) |
CA (1) | CA3074317A1 (ja) |
WO (1) | WO2019040808A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023218051A1 (en) * | 2022-05-12 | 2023-11-16 | Genmab A/S | Binding agents capable of binding to cd27 in combination therapy |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130280249A1 (en) | 2008-10-23 | 2013-10-24 | Massachusetts Institute Of Technology | Directed Engagement Of Activating Fc Receptors |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3785186T2 (de) | 1986-09-02 | 1993-07-15 | Enzon Lab Inc | Bindungsmolekuele mit einzelpolypeptidkette. |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
AU5670194A (en) | 1992-11-20 | 1994-06-22 | Enzon, Inc. | Linker for linked fusion polypeptides |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
EP0672142B1 (en) | 1992-12-04 | 2001-02-28 | Medical Research Council | Multivalent and multispecific binding proteins, their manufacture and use |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
AUPO591797A0 (en) | 1997-03-27 | 1997-04-24 | Commonwealth Scientific And Industrial Research Organisation | High avidity polyvalent and polyspecific reagents |
US7115396B2 (en) * | 1998-12-10 | 2006-10-03 | Compound Therapeutics, Inc. | Protein scaffolds for antibody mimics and other binding proteins |
US20130226834A1 (en) | 2000-04-27 | 2013-08-29 | Networth Services, Inc. | Systems and methods for determining the financial status of bonds |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
DE60335000D1 (de) | 2002-09-06 | 2010-12-30 | Isogenica Ltd | In vitro peptid-expressionsbank |
WO2009085462A1 (en) | 2007-12-19 | 2009-07-09 | Centocor, Inc. | Design and generation of human de novo pix phage display libraries via fusion to pix or pvii, vectors, antibodies and methods |
CA3149920A1 (en) * | 2008-10-31 | 2010-05-06 | Janssen Biotech, Inc. | Fibronectin type iii domain based scaffold compositions, methods and uses |
PT3103478T (pt) * | 2010-04-30 | 2019-07-10 | Janssen Biotech Inc | Composições, métodos e utilizações de domínios de fibronectinas estabilizadas |
EP3431993A1 (en) * | 2010-12-20 | 2019-01-23 | The Rockefeller University | Modulating agonistic tnfr antibodies |
EP3144320B9 (en) * | 2011-04-13 | 2018-08-22 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
CN107903325B (zh) * | 2011-05-16 | 2021-10-29 | 埃泰美德(香港)有限公司 | 多特异性fab融合蛋白及其使用方法 |
WO2013049275A1 (en) * | 2011-09-27 | 2013-04-04 | Janssen Biotech, Inc. | Fibronectin type iii repeat based protein scaffolds with alternative binding surfaces |
BR112014018481A2 (pt) * | 2012-02-01 | 2017-07-04 | Compugen Ltd | anticorpo monoclonal ou policlonal ou um fragmento de ligação a antígeno do mesmo, polinucleotídeo, anticorpo monoclonal, vetor, hibridoma, anticorpo, hibridoma 5166-2 e/ou 5166-9, anticorpo ou fragmento de ligação a antígeno, composição farmacêutica, uso do anticorpo ou fragmento de ligação a anticorpo, método para tratar câncer, método para diagnosticar câncer em um indivíduo, anticorpo, método, composição ou uso |
HUE052548T2 (hu) * | 2012-11-21 | 2021-05-28 | Janssen Biotech Inc | Bispecifikus EGFR/C-MET-ellenanyagok |
EP3409690A1 (en) * | 2013-03-18 | 2018-12-05 | BiocerOX Products B.V. | Humanized anti-cd134 (ox40) antibodies and uses thereof |
CA2932819A1 (en) * | 2013-12-09 | 2015-06-18 | New York University | Compositions and methods for phagocyte delivery of anti-staphylococcal agents |
MA42060A (fr) | 2015-05-06 | 2018-03-14 | Janssen Biotech Inc | Domaines de type iii de fibronectines fixant l'antigène membranaire spécifique de la prostate |
US20180044430A1 (en) * | 2016-08-12 | 2018-02-15 | Janssen Biotech, Inc. | FC Engineered Anti-TNFR Superfamily Member Antibodies Having Enhanced Atonistic Activity and Methods of Using Them |
-
2018
- 2018-08-24 EP EP18848670.8A patent/EP3672611A4/en active Pending
- 2018-08-24 CA CA3074317A patent/CA3074317A1/en active Pending
- 2018-08-24 JP JP2020510561A patent/JP7250766B2/ja active Active
- 2018-08-24 WO PCT/US2018/047843 patent/WO2019040808A1/en unknown
- 2018-08-24 US US16/111,360 patent/US11078263B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130280249A1 (en) | 2008-10-23 | 2013-10-24 | Massachusetts Institute Of Technology | Directed Engagement Of Activating Fc Receptors |
Non-Patent Citations (3)
Title |
---|
Chen TF et al,Fibronectin domains engineered for specificity to individual murine Fc gamma receptors modulate tumoricidal activity of immune cells,Cancer Research,2013年,Vol 73 No 8 Suppl 1,Abstract Number 1250 |
MABS, 2018, Vol.10, No.3, pp.463-475 |
Zhang D et al,Fc engineering approaches to enhance the agonism and effector functions of an anti-OX40 antibody,Journal of Biological Chemistry,2016年,Vol 291 No 53,27134-27146 |
Also Published As
Publication number | Publication date |
---|---|
JP2020537492A (ja) | 2020-12-24 |
US20190062420A1 (en) | 2019-02-28 |
CA3074317A1 (en) | 2019-02-28 |
EP3672611A1 (en) | 2020-07-01 |
WO2019040808A1 (en) | 2019-02-28 |
EP3672611A4 (en) | 2021-07-14 |
US11078263B2 (en) | 2021-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10875921B2 (en) | Anti-4-1BB antibodies and their uses | |
TWI806873B (zh) | 特異性結合pd-1之抗體及使用方法 | |
JP7178342B2 (ja) | アゴニズム及びエフェクター機能が増強した改変抗体、及び他のFcドメイン含有分子 | |
CN110997013A (zh) | 抗cd8抗体和其用途 | |
RU2762704C2 (ru) | Новое psma-связывающее антитело и его применения | |
JP2019502698A (ja) | Hla−drに特異的に結合する抗体及びその使用 | |
JP2011523414A (ja) | 抗fn14抗体、およびその使用 | |
CN109476742B (zh) | Tl1a抗体及其用途 | |
TWI790370B (zh) | 抗trem-1抗體及其用途 | |
JP7285936B2 (ja) | Il-7rアルファサブユニットに対する抗体及びその使用 | |
KR20220104783A (ko) | Cd3 및 bcma에 대한 항체, 및 이로부터 제조된 이중특이적 결합 단백질 | |
AU2016335750A1 (en) | IL-7R-alpha specific antibodies for treating acute lymphoblastic leukemia | |
JP7250766B2 (ja) | FCγRII結合フィブロネクチンIII型ドメイン、それらのコンジュゲート、及びそれらを含む多重特異性分子 | |
JP2022540674A (ja) | 抗trem-1抗体およびその使用 | |
BR112021008486A2 (pt) | Anticorpo biespecífico e seu uso | |
EA046142B1 (ru) | Антитела к trem-1 и их применения | |
BR112021014106A2 (pt) | Anticorpos contra subunidade alfa de il-7r e usos dos mesmos |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210730 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220608 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220621 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220916 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20221118 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221221 |
|
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: 20230228 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230322 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7250766 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |