JP2018525329A - 蛍光コンジュゲート - Google Patents
蛍光コンジュゲート Download PDFInfo
- Publication number
- JP2018525329A JP2018525329A JP2017563110A JP2017563110A JP2018525329A JP 2018525329 A JP2018525329 A JP 2018525329A JP 2017563110 A JP2017563110 A JP 2017563110A JP 2017563110 A JP2017563110 A JP 2017563110A JP 2018525329 A JP2018525329 A JP 2018525329A
- Authority
- JP
- Japan
- Prior art keywords
- tumor
- conjugate
- fluorescent
- composition
- 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.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 197
- 239000007850 fluorescent dye Substances 0.000 claims abstract description 74
- 230000008685 targeting Effects 0.000 claims abstract description 65
- 238000002271 resection Methods 0.000 claims abstract description 35
- 239000000439 tumor marker Substances 0.000 claims abstract description 35
- 238000001356 surgical procedure Methods 0.000 claims abstract description 28
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims abstract description 13
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 63
- 210000001519 tissue Anatomy 0.000 claims description 62
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 claims description 58
- 239000000427 antigen Substances 0.000 claims description 34
- 102000036639 antigens Human genes 0.000 claims description 34
- 108091007433 antigens Proteins 0.000 claims description 34
- 201000011510 cancer Diseases 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 18
- 230000021615 conjugation Effects 0.000 claims description 15
- 210000004185 liver Anatomy 0.000 claims description 11
- 210000000496 pancreas Anatomy 0.000 claims description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 102000037865 fusion proteins Human genes 0.000 claims description 10
- 108020001507 fusion proteins Proteins 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 9
- 208000035346 Margins of Excision Diseases 0.000 claims description 9
- 150000001768 cations Chemical class 0.000 claims description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
- 210000000481 breast Anatomy 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- -1 succinimidyl Chemical group 0.000 claims description 8
- 230000018732 detection of tumor cell Effects 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 210000001672 ovary Anatomy 0.000 claims description 7
- 210000002784 stomach Anatomy 0.000 claims description 7
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 6
- 210000003238 esophagus Anatomy 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 229930064664 L-arginine Natural products 0.000 claims description 5
- 235000014852 L-arginine Nutrition 0.000 claims description 5
- 210000000013 bile duct Anatomy 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 230000002496 gastric effect Effects 0.000 claims description 4
- 238000007912 intraperitoneal administration Methods 0.000 claims description 4
- 239000007928 intraperitoneal injection Substances 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 230000010412 perfusion Effects 0.000 claims description 4
- 210000002307 prostate Anatomy 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 239000012062 aqueous buffer Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 230000001678 irradiating effect Effects 0.000 claims description 3
- 230000036210 malignancy Effects 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 239000000032 diagnostic agent Substances 0.000 claims description 2
- 229940039227 diagnostic agent Drugs 0.000 claims description 2
- 238000010255 intramuscular injection Methods 0.000 claims description 2
- 239000007927 intramuscular injection Substances 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 102000012406 Carcinoembryonic Antigen Human genes 0.000 claims 5
- 206010004593 Bile duct cancer Diseases 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 208000026900 bile duct neoplasm Diseases 0.000 claims 1
- 208000006990 cholangiocarcinoma Diseases 0.000 claims 1
- 201000004101 esophageal cancer Diseases 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 238000002405 diagnostic procedure Methods 0.000 abstract description 4
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 53
- 210000004027 cell Anatomy 0.000 description 40
- 210000004881 tumor cell Anatomy 0.000 description 26
- 239000000872 buffer Substances 0.000 description 17
- 238000001514 detection method Methods 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 230000027455 binding Effects 0.000 description 11
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine group Chemical group N1=CCC2=CC=CC=C12 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 206010027476 Metastases Diseases 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 238000012800 visualization Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 201000002528 pancreatic cancer Diseases 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000002494 anti-cea effect Effects 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 230000003902 lesion Effects 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 239000013598 vector Substances 0.000 description 8
- 230000005284 excitation Effects 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 230000009401 metastasis Effects 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 239000001488 sodium phosphate Substances 0.000 description 7
- 229910000162 sodium phosphate Inorganic materials 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000006862 quantum yield reaction Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 6
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- 229930182816 L-glutamine Natural products 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- 206010061269 Malignant peritoneal neoplasm Diseases 0.000 description 4
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 4
- 206010067482 No adverse event Diseases 0.000 description 4
- 238000002679 ablation Methods 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000002559 palpation Methods 0.000 description 4
- 201000002524 peritoneal carcinoma Diseases 0.000 description 4
- 238000004393 prognosis Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 210000000664 rectum Anatomy 0.000 description 4
- 150000003839 salts Chemical group 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000002798 spectrophotometry method Methods 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 210000000232 gallbladder Anatomy 0.000 description 3
- 230000000762 glandular Effects 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 201000002628 peritoneum cancer Diseases 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 239000012465 retentate Substances 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 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
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 239000012099 Alexa Fluor family Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 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 2
- 108020004414 DNA Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- 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 2
- 206010020843 Hyperthermia Diseases 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
- 229930195725 Mannitol Natural products 0.000 description 2
- 238000011786 NMRI nude mouse Methods 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229960001413 acetanilide Drugs 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 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
- 238000001574 biopsy Methods 0.000 description 2
- 208000035269 cancer or benign tumor Diseases 0.000 description 2
- 238000005277 cation exchange chromatography Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 210000003679 cervix uteri Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000011026 diafiltration Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical group O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 239000006167 equilibration buffer Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012537 formulation buffer Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 230000036031 hyperthermia Effects 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- MHYFEEDKONKGEB-UHFFFAOYSA-N oxathiane 2,2-dioxide Chemical compound O=S1(=O)CCCCO1 MHYFEEDKONKGEB-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009258 tissue cross reactivity Effects 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 238000011179 visual inspection Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 description 1
- SSSROGPPPVTHLX-FXQIFTODSA-N Ala-Arg-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSROGPPPVTHLX-FXQIFTODSA-N 0.000 description 1
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 1
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 1
- QDGMZAOSMNGBLP-MRFFXTKBSA-N Ala-Trp-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N QDGMZAOSMNGBLP-MRFFXTKBSA-N 0.000 description 1
- GCTANJIJJROSLH-GVARAGBVSA-N Ala-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C)N GCTANJIJJROSLH-GVARAGBVSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- IZSMEUDYADKZTJ-KJEVXHAQSA-N Arg-Tyr-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IZSMEUDYADKZTJ-KJEVXHAQSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 1
- PPCORQFLAZWUNO-QWRGUYRKSA-N Asn-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N PPCORQFLAZWUNO-QWRGUYRKSA-N 0.000 description 1
- XLDMSQYOYXINSZ-QXEWZRGKSA-N Asn-Val-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N XLDMSQYOYXINSZ-QXEWZRGKSA-N 0.000 description 1
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 1
- UGIBTKGQVWFTGX-BIIVOSGPSA-N Asp-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N)C(=O)O UGIBTKGQVWFTGX-BIIVOSGPSA-N 0.000 description 1
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 1
- MFDPBZAFCRKYEY-LAEOZQHASA-N Asp-Val-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MFDPBZAFCRKYEY-LAEOZQHASA-N 0.000 description 1
- GYNUXDMCDILYIQ-QRTARXTBSA-N Asp-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)O)N GYNUXDMCDILYIQ-QRTARXTBSA-N 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 206010060999 Benign neoplasm Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical class CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ROHVCXBMIAAASL-HJGDQZAQSA-N Gln-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)N)N)O ROHVCXBMIAAASL-HJGDQZAQSA-N 0.000 description 1
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 1
- RWQCWSGOOOEGPB-FXQIFTODSA-N Gln-Ser-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O RWQCWSGOOOEGPB-FXQIFTODSA-N 0.000 description 1
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 1
- MIWJDJAMMKHUAR-ZVZYQTTQSA-N Glu-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N MIWJDJAMMKHUAR-ZVZYQTTQSA-N 0.000 description 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 1
- IWAXHBCACVWNHT-BQBZGAKWSA-N Gly-Asp-Arg Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IWAXHBCACVWNHT-BQBZGAKWSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- YOBGUCWZPXJHTN-BQBZGAKWSA-N Gly-Ser-Arg Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YOBGUCWZPXJHTN-BQBZGAKWSA-N 0.000 description 1
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 1
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 1
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 1
- ASCFJMSGKUIRDU-ZPFDUUQYSA-N Ile-Arg-Gln Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O ASCFJMSGKUIRDU-ZPFDUUQYSA-N 0.000 description 1
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 1
- GVEODXUBBFDBPW-MGHWNKPDSA-N Ile-Tyr-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 GVEODXUBBFDBPW-MGHWNKPDSA-N 0.000 description 1
- DZMWFIRHFFVBHS-ZEWNOJEFSA-N Ile-Tyr-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N DZMWFIRHFFVBHS-ZEWNOJEFSA-N 0.000 description 1
- 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 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- ZRLUISBDKUWAIZ-CIUDSAMLSA-N Leu-Ala-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O ZRLUISBDKUWAIZ-CIUDSAMLSA-N 0.000 description 1
- BOFAFKVZQUMTID-AVGNSLFASA-N Leu-Gln-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N BOFAFKVZQUMTID-AVGNSLFASA-N 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- LVTJJOJKDCVZGP-QWRGUYRKSA-N Leu-Lys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LVTJJOJKDCVZGP-QWRGUYRKSA-N 0.000 description 1
- DRWMRVFCKKXHCH-BZSNNMDCSA-N Leu-Phe-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=CC=C1 DRWMRVFCKKXHCH-BZSNNMDCSA-N 0.000 description 1
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 1
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 1
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 1
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- ABHVWYPPHDYFNY-WDSOQIARSA-N Met-His-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CN=CN1 ABHVWYPPHDYFNY-WDSOQIARSA-N 0.000 description 1
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 1
- 206010027457 Metastases to liver Diseases 0.000 description 1
- 206010051676 Metastases to peritoneum Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 1
- FQUUYTNBMIBOHS-IHRRRGAJSA-N Phe-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FQUUYTNBMIBOHS-IHRRRGAJSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 1
- TYYBJUYSTWJHGO-ZKWXMUAHSA-N Ser-Asn-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TYYBJUYSTWJHGO-ZKWXMUAHSA-N 0.000 description 1
- VMVNCJDKFOQOHM-GUBZILKMSA-N Ser-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N VMVNCJDKFOQOHM-GUBZILKMSA-N 0.000 description 1
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 1
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 0.000 description 1
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 1
- YAAPRMFURSENOZ-KATARQTJSA-N Thr-Cys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N)O YAAPRMFURSENOZ-KATARQTJSA-N 0.000 description 1
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 1
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 1
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 1
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 1
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 1
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 1
- KZTLJLFVOIMRAQ-IHPCNDPISA-N Trp-Asn-Tyr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZTLJLFVOIMRAQ-IHPCNDPISA-N 0.000 description 1
- UIRVSEPRMWDVEW-RNXOBYDBSA-N Trp-Tyr-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CNC4=CC=CC=C43)N UIRVSEPRMWDVEW-RNXOBYDBSA-N 0.000 description 1
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 1
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 1
- KRXFXDCNKLANCP-CXTHYWKRSA-N Tyr-Tyr-Ile Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 KRXFXDCNKLANCP-CXTHYWKRSA-N 0.000 description 1
- LABUITCFCAABSV-UHFFFAOYSA-N Val-Ala-Tyr Natural products CC(C)C(N)C(=O)NC(C)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LABUITCFCAABSV-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 108010081404 acein-2 Proteins 0.000 description 1
- 150000008061 acetanilides Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 230000002528 anti-freeze Effects 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229960003589 arginine hydrochloride Drugs 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 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
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000000298 carbocyanine Substances 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000000701 chemical imaging Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 210000001728 clone cell Anatomy 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000011498 curative surgery Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 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 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011462 intraperitoneal chemotherapy Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 239000003014 ion exchange membrane Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 108010038320 lysylphenylalanine Proteins 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 208000029565 malignant colon neoplasm Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 108010024607 phenylalanylalanine Proteins 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 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
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 210000004896 polypeptide structure Anatomy 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical class [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 150000008053 sultones Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical class [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
-
- 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
- A61K39/39516—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum from serum, plasma
- A61K39/39525—Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0058—Antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- 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
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3007—Carcino-embryonic Antigens
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Pathology (AREA)
- Mycology (AREA)
- Optics & Photonics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biodiversity & Conservation Biology (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Hospice & Palliative Care (AREA)
- General Physics & Mathematics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Surgery (AREA)
- Medical Informatics (AREA)
Abstract
Description
がんは、現在、世界中の全死亡数のおよそ13%を占めている。数十年にわたるさかんな研究にもかかわらず、がんは依然として先進国における死因の第2位であり、死亡数のおよそ25%を占めている。多くの型のがんでは、手術(多くの場合、化学療法、放射線処置または温熱療法との併用で)が治療の主流である。
簡単には、本発明により、標的化部分Tにカップリングされた蛍光色素部分Fを含む蛍光コンジュゲートであって、該部分Fは、本明細書において以下に規定する式(I)(式中、Yは各存在の場合で、独立して、SO3H、SO3 −およびSO3Mから選択され;Mは一価のカチオンであり;x、zおよびyは独立して、1〜8の整数から選択される)を有するものであり;該部分Tは腫瘍マーカーに対する親和性を有するものである、蛍光コンジュゲートを提供する。一実施形態では、蛍光色素部分Fは、以下に規定する式(II)を有するものであり得る。
第1の態様において、本発明により、標的化部分Tにカップリングされた蛍光色素部分Fを含む蛍光コンジュゲートであって、該部分Fは、式(I):
を有するものであり;該部分Tは腫瘍マーカーに対する親和性を有するものである、蛍光コンジュゲートを提供する。
の蛍光色素部分Fを含むものである。
(A)重鎖(配列番号:1):
GGTACCGCCGCCACCATGGACTCCAGACTGAACCTGGTGTTCCTGGTGCTGATCCTGAAG GGCGTGCAGTGCGACGTGCAGCTGGTGGAATCTGGCGGAGGACTGGTGCAGCCTGGCGGC TCCAGAAAGCTGTCTTGTGCCGCCTCCGGCTTCACCTTCTCCAACTTCGGCATGCACTGG ATCCGGCAGGCCCCTGAGAAGGGCCTGGAATGGGTGGCCTATATCTCCGGCGGCTCCTCC ACCATCTACTTCGCCGACACCCTGAAGGGACGGTTCACCATCTCCCGGGACAACCCCAAG AACACCCTGTTTCTGCAGATGACCTCCCTGCGGAGCGAGGACACCGCCATCTACTACTGC GCCAGAGACTACTACATCAACAACTACTGGTACTTCGACGTGTGGGGCGCTGGCACCACC GTGACAGTGTCATCTGCTAGC
(B)軽鎖(配列番号:2):
GTCGACGCCGCCACCATGGAATTTCAGACCCAGGTGTTCGTGTTCGTGCTGCTGTGGCTG TCTGGCGTGGACGGCGACATCGTGATGACCCAGTCCCAGAAATTCATGTCCACCTCCGTG GGCGACCGGGTGTCCATCACATGCAAGGCCTCTCAGAACGTGCGGAGCGCCGTGGCCTGG TATCAGCAGACACCTGGCCAGAGCCCCAAGGCCCTGATCTACCTGGCCTCCAACAGATAC ACCGGCGTGCCCGATCGGTTCACCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATC TCCAACGTGCAGTCCGAGGACCTGGCCGACTACTTCTGTCTGCAACACTGGAACTACCCC CTGACCTTCGGCGGAGGCACCAAGCTGGAACTGAAGCGTACG
(A)重鎖(配列番号:3):
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe Gly Met His Trp
Ile Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val Ala Tyr Ile Ser Gly Gly Ser Ser
Thr Ile Tyr Phe Ala Asp Thr Leu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys
Asn Thr Leu Phe Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
Ala Arg Asp Tyr Tyr Ile Asn Asn Tyr Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr
Val Thr Val Ser Ser
(B)軽鎖(配列番号:4):
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val
Gly Asp Arg Val Ser lie Thr Cys Lys Ala Ser Gln Asn Val Arg Ser Ala Val Ala Trp
Tyr Gln Gin Thr Pro Gly Gln Ser Pro Lys Ala Leu Ile Tyr Leu Ala Ser Asn Arg Tyr
Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He
Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys Leu Gln His Trp Asn Tyr Pro
Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
(a)式(III):
を有する蛍光色素を準備する工程;(b)腫瘍マーカーに対する親和性を有する標的化薬剤を準備する工程;ならびに(c)該蛍光色素を該標的化薬剤とカップリングさせる工程を含む、蛍光コンジュゲートの調製方法を提供する。
(a)該コンジュゲートまたは組成物を腫瘍ができている患者に投与する工程;
(b)前記患者に対して腫瘍切除手術を開始する工程;
(c)切除手術を受けている該患者の切除部位の組織に約660〜700nmの波長を有する光を照射する工程
を含むものであり、
工程(b)が、工程(a)後、約96時間または72時間以下の時間内に行なわれる。
実施例1−キメラ型の抗CEAモノクローナル抗体の調製
遺伝子の設計および合成
それぞれ天然のマウスVHおよびVL可変ドメインをコードしている以下のヌクレオチド配列(A)および(B)をマウス抗CEA抗体ハイブリドーマから得て、デノボ合成し、宿主pVVS Tandem発現ベクター内にクローニングする。これらの配列には、最適なクローニングおよびCHO細胞内での最適な発現を確実にするためのいくつかのヌクレオチド修飾(天然のタンパク質の配列を変化させない)が組み込まれている。KpnI制限部位およびNheI制限部位が、それぞれ、VHドメインをコードしている配列の5’末端および3’末端に挿入されている。同様に、2つの制限部位の配列SalIおよびBSiWIを、それぞれ、VLドメインをコードしている配列の5’末端および3’末端に挿入した。
(A)重鎖(配列番号:1):
GGTACCGCCGCCACCATGGACTCCAGACTGAACCTGGTGTTCCTGGTGCTGATCCTGAAGG GCGTGCAGTGCGACGTGCAGCTGGTGGAATCTGGCGGAGGACTGGTGCAGCCTGGCGGCTC CAGAAAGCTGTCTTGTGCCGCCTCCGGCTTCACCTTCTCCAACTTCGGCATGCACTGGATCC GGCAGGCCCCTGAGAAGGGCCTGGAATGGGTGGCCTATATCTCCGGCGGCTCCTCC ACCATCTACTTCGCCGACACCCTGAAGGGACGGTTCACCATCTCCCGGGACAACCCCAAG
AACACCCTGTTTCTGCAGATGACCTCCCTGCGGAGCGAGGACACCGCCATCTACTACTGC GCCAGAGACTACTACATCAACAACTACTGGTACTTCGACGTGTGGGGCGCTGGCACCACC GTGACAGTGTCATCTGCTAGC
(B)軽鎖(配列番号:2):
GTCGACGCCGCCACCATGGAATTTCAGACCCAGGTGTTCGTGTTCGTGCTGCTGTGGCTG TCTGGCGTGGACGGCGACATCGTGATGACCCAGTCCCAGAAATTCATGTCCACCTCCGTG GGCGACCGGGTGTCCATCACATGCAAGGCCTCTCAGAACGTGCGGAGCGCCGTGGCCTGG TATCAGCAGACACCTGGCCAGAGCCCCAAGGCCCTGATCTACCTGGCCTCCAACAGATAC ACCGGCGTGCCCGATCGGTTCACCGGCTCTGGCTCTGGCACCGACTTCACCCTGACCATC TCCAACGTGCAGTCCGAGGACCTGGCCGACTACTTCTGTCTGCAACACTGGAACTACCCC CTGACCTTCGGCGGAGGCACCAAGCTGGAACTGAAGCGTACG
VHおよびVLの遺伝子の宿主ベクターとして使用するために選択したpVVS Tandemベクターを、Sall/BsiWIおよびKpnI/NheIを用いた逐次二重消化によって調製した。この発現ベクターは、重鎖はヒトIgG1アロタイプG1m3の定常ドメインおよびヒトIgG1アロタイプKm3の配列をコードしている。このベクターに、さらに、以下の機能性エレメント:pCMVプロモーター(重鎖と軽鎖の両方)、このプロモーターと翻訳のための開始コドンの間にキメラ型イントロン、pUC複製起点、BGHポリアデニル化部位、HS4 TKポリAインシュレータ(insulator)、SV40プロモーターならびにベクターの増幅中およびトランスフェクション後の細胞の選択のためのカナマイシン/ネオマイシン耐性遺伝子を含める。消化後、得られたベクターの主鎖断片を、ゲル精製を用いて回収した。
上記のベクターによってトランスフェクトしたCHO細胞は、European Collection of Cell Cultures(ECACC)から入手したCHO(タンパク質フリー)細胞株(整理番号00102307,ロット02K/008)に由来するものである。この細胞株(最初にECACCが1985年に取得)は、ハムスター卵巣組織に由来し、Puck et al.(1958)によって最初に確立された親CHO細胞株のサブクローンである。
リードクローンの細胞を解凍し、リバイタライゼーション培地(EX−CELL(登録商標)ACF CHO培地,4mMのL−グルタミン)に移す。バイアブル細胞の密度を測定し、遠心分離後、細胞ペレットを培地中に2×106細胞/mLの密度で、75cm2フラスコへの播種後に再懸濁させる。細胞を37℃±1℃、8%±2%CO2にてオービタルシェーカー内で増殖させる。2日目から、培養を、容量を上げた振盪フラスコ内にてスケールアップする(EX−CELL(登録商標)ACF CHO培地,4mMのL−グルタミン,37℃±1℃、8%±2% CO2でオービタルシェーカー内)。細胞バイアビリティ、密度および増殖を各継代時に評価し、夾雑物が無いことを顕微鏡検査によって確認する。17日目、7回の継代後、振盪フラスコ内の内容物をプールする。細胞をカウントし、2つの15L容バイオリアクターに0.5×106バイアブル細胞/mLの密度で7Lの容量にて播種するために使用する。細胞を、フェドバッチ培養にてEX−CELL(登録商標)ACF CHO培地,5mMのL−グルタミン,0.2%のプルロニック中、37℃で、pHと酸素の調節下にて20日間、増殖させる。BalanCD(商標) CHO Feed 3、グルコースおよびL−グルタミンを必要に応じて添加する。細胞密度、バイアビリティ、pHを毎日評価し;また、試料を6日目から毎日採取してグルコース濃度を測定し、10日目から抗体濃度を評価する(プロテインA HPLC)。
アセトアニリド中間体(B):
中間体Dは、ウィリアムソン縮合によりインドレニン前駆物質Cのカルボキシアルキルオキシ誘導体を形成した後、1,4−ブタンスルトンで4級化することによって調製される。インドレニンCは、アミノ化芳香族前駆物質のジアゾ化/還元の後、スルホネート形成、ヒドロキシル化およびケトンを用いたフィッシャー環化によって得られる。
精製した実施例1の抗体を15〜25℃でおよそ24時間解凍する。バッファー交換(0.1Mナトリウムリン酸塩/炭酸塩,pH9.3)を行なうための限外濾過/ダイアフィルトレーション(30kDaカットオフ膜を使用)。蛍光色素(実施例2の式(IV))をDMFに2.25mg/mLの濃度で、15〜25℃での一晩の撹拌によって溶解させる。DMFを抗体溶液(0.1Mナトリウムリン酸塩/炭酸塩バッファー,pH9.3を用いて終濃度1mg/mLに希釈)に添加し、終濃度を10%v/vにする。次いで、この蛍光色素溶液を抗体溶液に、20mL/分の流速にて4.5のモル過剰で添加する。得られた反応混合物をオービタルシェーカー内で周囲温度にておよそ45分間インキュベートする。
実施例3に従って調製した蛍光コンジュゲートのフォーミュレーションに使用されるバッファーは、必要に応じて、本発明の範囲内の使用および方法のために適合させてもよい。例えば、該蛍光コンジュゲートは、好ましくは、10mM KH2PO4(VWR Prolabo)10mMクエン酸Na3/クエン酸(Fluka),300mMアルギニンHCl(Sigma),0.02%(w/v)Tween 20(Merck)を含むバッファー(このときpHは6.0に調整する)でフォーミュレーションが行なわれ得る。
蛍光試験
式(IV)の蛍光色素および実施例3に従って調製した蛍光コンジュゲートの消光、光退色および蛍光量子収率を、臨床使用に関連する波長である680nmの励起波長(光学デバイスFluobeam700を用いて供給)で測定した。
ビオチン標識コンジュゲートを用いて実施例3の場合のようにして調製した蛍光コンジュゲートの組織の交差反応性試験を、無関連の3例の個体に由来する42例のヒト凍結組織および血液塗抹のパネルにおいて、標準的な免疫組織化学的手法を用いて行なった。抗体コンジュゲートの特異的染色は、CEAを発現していると文献で報告されていた消化管およびいくつかの他の組織の上皮成分(主に、頂端細胞の境界部または腔側)に限定されていることがわかり、オンターゲットのみの抗体結合が確認された。
また、実施例3で調製した蛍光コンジュゲートの標的癌胎児性抗原に対する親和性を、表面プラズモン共鳴(SPR)を用いてBIACORE 3000デバイスで測定した。癌胎児性抗原をCM5チップに、チオール基によってカップリングさせた(Surface Thiol Coupling GE healthcare;使用説明22−0618−10AB)。会合速度と解離速度を、フロー中で6つの異なる濃度(50nM〜1.5nM)の実施例1のキメラ型モノクローナル抗体、モノクローナル抗体m511(実施例1のキメラ型モノクローナル抗体の可変領域のベースの元のマウス抗体)および蛍光コンジュゲートを用いて測定した。データ収集およびパラメータ計算は、BiaソフトウェアおよびBia評価プログラムを用いて行なった。実施例1のキメラ型モノクローナル抗体のCEA(3.27×10〜11nM)に対する親和性は、親マウス511抗体のもの(3.82×10〜11nM)に非常に近い状態が維持され、近赤外蛍光色素での標識後、変更されなかった(実施例3の蛍光コンジュゲートのKDは3.21×10〜11nMと測定された)。
実施例3の蛍光コンジュゲートの有効性を、ヒトCEAを発現している4つの異なるマウスモデルにおいてインビボで評価した。
(a)腹膜癌症−実施例3のコンジュゲートの安全性と機能性を、消化器起源の腹膜癌症(転移性腫瘍)を有する15名のヒト患者において評価するための臨床試験.
5〜15mgの範囲の用量の実施例3の蛍光コンジュゲートを静脈内注射によって投与した。予備調査結果は、これらのいずれの用量でも有害反応は観察されないことを示す。
5mg用量の蛍光コンジュゲート(手術の48時間前に静脈内注射)を用いた試験を実施した。試験した患者において、これまでのところ、投与中または投与直後の有害効果は報告されなかった。一般に、ベースライン値からのバイタルサインの臨床的に有意な変化は観察されなかった。
Claims (23)
- 標的化部分Tにカップリングされた蛍光色素部分Fを含む蛍光コンジュゲートであって、前記部分Fは、式(I):
Yは独立して、各存在の場合でSO3H、SO3 −およびSO3Mから選択され、ここで、Mは一価のカチオンであり;
x、zおよびyは独立して、1〜8の整数から選択される)
を有するものであり;
前記部分Tは腫瘍マーカーに対する親和性を有するものである、
蛍光コンジュゲート。 - Yが、SO3 −およびSO3Naから選択される、請求項1に記載のコンジュゲート。
- 部分Fが、式(II):
- 前記腫瘍マーカーが腫瘍抗原である、請求項1〜3のいずれか1項に記載のコンジュゲート。
- 前記腫瘍抗原が癌胎児性抗原(CEA)である、請求項4に記載のコンジュゲート。
- 部分Tが、抗体、抗体断片、および抗体の少なくとも1つの可変領域を含む融合タンパク質から選択され;前記抗体が任意選択で、キメラ型モノクローナル抗体(mAb)である、請求項1〜5のいずれか1項に記載のコンジュゲート。
- 前記部分Tが、前記CEA抗原の1つ以上のエピトープに結合するキメラ型モノクローナル抗体である、請求項1〜6のいずれか1項に記載のコンジュゲート。
- 部分Fが式(II)を有するものであり、前記キメラ型モノクローナル抗体がCEAのGOLD−2エピトープに対して指向され、G1m3アロタイプの重鎖とkm3アロタイプの軽鎖を含むものであり、各重鎖および各軽鎖が少なくとも1つのマウスIgG1可変ドメインと少なくとも1つのヒト定常ドメインを含むものである、請求項7に記載のコンジュゲート。
- 前記キメラ型モノクローナル抗体が配列番号:4の軽鎖の可変領域と配列番号:3の重鎖の可変部を含むものである、請求項8に記載のコンジュゲート。
- 前記部分Tが非ペプチドリガンドである、請求項1〜5のいずれか1項に記載のコンジュゲート。
- n個の部分Fが1個の部分Tにカップリングされており、nが1〜4から選択される整数である、請求項1〜10のいずれか1項に記載のコンジュゲート。
- 請求項1〜11のいずれか1項に記載のコンジュゲートを含む組成物であって、任意選択で、
(a)滅菌されており、水性バッファーとL−アルギニンを含むものである、および/または
(b)部分Fにカップリングされていない部分Tを含む化合物を含むものである、
組成物。 - 前記組成物中のコンジュゲートの平均コンジュゲーション度が約0.5〜3である、請求項12に記載の組成物。
- (a)式(III):
x、zおよびyは独立して、1〜8の整数から選択され、
Zは、対イオン、水素、スクシンイミジル、スルホスクシンイミジルおよびニトロフェニルから選択される)
を有する蛍光色素を準備する工程、
(b)腫瘍マーカーに対する親和性を有する標的化薬剤を準備する工程;ならびに
(c)前記蛍光色素を前記標的化薬剤とカップリングさせる工程
を含む、蛍光コンジュゲートの調製方法。 - Yが、SO3 −およびSO3Naから選択される、請求項14に記載の方法。
- 標的化薬剤が、CEAに対する親和性を有するキメラ型モノクローナル抗体である、および/または前記蛍光色素が、式(IV):
- 試料中の腫瘍細胞の検出のため、あるいは腫瘍の診断および/またはモニタリングのための請求項1〜11のいずれか1項に記載のコンジュゲートまたは請求項12〜13のいずれか1項に記載の組成物のインビトロ使用。
- 医薬または診断用薬剤としての使用のための請求項1〜11のいずれか1項に記載のコンジュゲートまたは請求項12〜13のいずれか1項に記載の組成物。
- (a)腫瘍マーカーを発現している腫瘍巣の検出における使用のため、もしくは前記腫瘍マーカーを発現している腫瘍の位置を患者において調べるため、および/または
(b)前記腫瘍マーカーを発現している腫瘍の切除手術を受けている、もしくは受けたばかりの患者の切除マージンにおける腫瘍細胞もしくは腫瘍組織の検出における使用のための
請求項1〜11のいずれか1項に記載のコンジュゲートまたは請求項12〜13のいずれか1項に記載の組成物。 - 前記使用が
(a)前記コンジュゲートまたは組成物を腫瘍ができている患者に投与する工程;
(b)前記患者に対して腫瘍切除手術を開始する工程;
(c)前記切除手術を受けている前記患者の切除部位の組織に約660〜700nmの波長を有する光を照射する工程
を含むものであり、
工程(b)が、工程(a)後、約96時間以下の時間内に行なわれる、
請求項18または19に記載の使用のためのコンジュゲートまたは組成物。 - 前記腫瘍が、結腸直腸、胃、胆管、膵臓、食道、卵巣、乳房、前立腺、肝臓または肺のがんである、請求項18〜20のいずれか1項に記載の使用のためのコンジュゲートまたは組成物。
- 前記腫瘍が胃腸の悪性腫瘍であり、前記コンジュゲートが請求項8または9に記載のコンジュゲートである、請求項21に記載の使用のためのコンジュゲートまたは組成物。
- 前記コンジュゲートまたは組成物が吸入によって、または静脈内、腹腔内、皮下もしくは筋肉内への注射もしくは灌流によって局所投与される、請求項18〜22のいずれか1項に記載の使用のためのコンジュゲートまたは組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15170617.3 | 2015-06-03 | ||
EP15170617 | 2015-06-03 | ||
PCT/EP2016/062557 WO2016193396A1 (en) | 2015-06-03 | 2016-06-02 | Fluorescent conjugates |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018525329A true JP2018525329A (ja) | 2018-09-06 |
JP6912389B2 JP6912389B2 (ja) | 2021-08-04 |
Family
ID=53365860
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017563110A Active JP6912389B2 (ja) | 2015-06-03 | 2016-06-02 | 蛍光コンジュゲート |
Country Status (23)
Country | Link |
---|---|
US (2) | US9821079B2 (ja) |
EP (1) | EP3166606B1 (ja) |
JP (1) | JP6912389B2 (ja) |
KR (1) | KR20180014027A (ja) |
CN (1) | CN107949385B (ja) |
AR (1) | AR104895A1 (ja) |
AU (1) | AU2016271853B2 (ja) |
CA (1) | CA2986078C (ja) |
CL (1) | CL2017003000A1 (ja) |
DK (1) | DK3166606T3 (ja) |
ES (1) | ES2683554T3 (ja) |
HR (1) | HRP20181164T1 (ja) |
HU (1) | HUE038696T2 (ja) |
IL (1) | IL255633B (ja) |
MX (1) | MX2017015036A (ja) |
NZ (1) | NZ737353A (ja) |
PL (1) | PL3166606T3 (ja) |
PT (1) | PT3166606T (ja) |
RU (1) | RU2720976C2 (ja) |
TR (1) | TR201810532T4 (ja) |
TW (1) | TWI702259B (ja) |
WO (1) | WO2016193396A1 (ja) |
ZA (1) | ZA201707817B (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2986078C (en) * | 2015-06-03 | 2023-09-12 | Surgimab S.A.S. | Fluorescent conjugates |
ES2911273T3 (es) * | 2019-03-19 | 2022-05-18 | Miltenyi Biotec Bv & Co Kg | Método para proporcionar células personalizadas con receptores de antígeno quimérico (CAR) |
CN112851809A (zh) * | 2021-01-20 | 2021-05-28 | 上海交通大学 | 一种抗终末糖基化蛋白受体的抗体及其应用 |
WO2023114248A1 (en) * | 2021-12-16 | 2023-06-22 | Curadel Surgical Innovations, Inc. | Near-infrared fluorescent contrast bioimaging agents for imaging of sentinel lymph nodes |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000095758A (ja) * | 1998-09-18 | 2000-04-04 | Schering Ag | 近赤外蛍光造影剤および蛍光造影方法 |
BR9917587A (pt) * | 1999-12-15 | 2002-08-06 | Schering Ag | Agente de contraste fluorescente próximo ao infravermelho e formação de imagem por fluorescência |
EP1796733A2 (en) * | 2004-09-29 | 2007-06-20 | GE Healthcare AS | Urokinase plasminogen activator receptor targeted contrast agents |
FR2889700B1 (fr) * | 2005-08-11 | 2012-11-23 | Synthinnove Lab | Marqueurs, leur procede de fabrication et leurs applications |
MX2010009530A (es) * | 2008-02-27 | 2010-11-30 | Yeda Res & Dev | Conjugados de rgd-(bacterio) clorofila para terapia fotodinámica y formación de imágenes de tumores necróticos. |
WO2012027618A2 (en) * | 2010-08-25 | 2012-03-01 | Pacific Biosciences Of California, Inc. | Functionalized cyanine dyes |
WO2012054784A1 (en) * | 2010-10-20 | 2012-04-26 | Li-Cor, Inc. | Fluorescent imaging with substituted cyanine dyes |
US9751868B2 (en) * | 2012-02-28 | 2017-09-05 | Pierce Biotechnology, Inc. | Benzocyanine compounds |
CA2986078C (en) * | 2015-06-03 | 2023-09-12 | Surgimab S.A.S. | Fluorescent conjugates |
-
2016
- 2016-06-02 CA CA2986078A patent/CA2986078C/en active Active
- 2016-06-02 PL PL16728275T patent/PL3166606T3/pl unknown
- 2016-06-02 CN CN201680032722.2A patent/CN107949385B/zh active Active
- 2016-06-02 EP EP16728275.5A patent/EP3166606B1/en active Active
- 2016-06-02 AU AU2016271853A patent/AU2016271853B2/en active Active
- 2016-06-02 NZ NZ737353A patent/NZ737353A/en unknown
- 2016-06-02 KR KR1020177037365A patent/KR20180014027A/ko not_active Application Discontinuation
- 2016-06-02 ES ES16728275.5T patent/ES2683554T3/es active Active
- 2016-06-02 HU HUE16728275A patent/HUE038696T2/hu unknown
- 2016-06-02 PT PT16728275T patent/PT3166606T/pt unknown
- 2016-06-02 MX MX2017015036A patent/MX2017015036A/es active IP Right Grant
- 2016-06-02 WO PCT/EP2016/062557 patent/WO2016193396A1/en active Application Filing
- 2016-06-02 DK DK16728275.5T patent/DK3166606T3/en active
- 2016-06-02 JP JP2017563110A patent/JP6912389B2/ja active Active
- 2016-06-02 TW TW105117475A patent/TWI702259B/zh active
- 2016-06-02 TR TR2018/10532T patent/TR201810532T4/tr unknown
- 2016-06-02 RU RU2017141422A patent/RU2720976C2/ru active
- 2016-06-03 AR ARP160101650A patent/AR104895A1/es unknown
- 2016-10-19 US US15/297,975 patent/US9821079B2/en active Active
-
2017
- 2017-10-20 US US15/789,851 patent/US10159757B2/en active Active
- 2017-11-13 IL IL255633A patent/IL255633B/en active IP Right Grant
- 2017-11-17 ZA ZA201707817A patent/ZA201707817B/en unknown
- 2017-11-27 CL CL2017003000A patent/CL2017003000A1/es unknown
-
2018
- 2018-07-24 HR HRP20181164TT patent/HRP20181164T1/hr unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Deken et al. | Nanobody-targeted photodynamic therapy induces significant tumor regression of trastuzumab-resistant HER2-positive breast cancer, after a single treatment session | |
US10746741B2 (en) | CA IX—NIR dyes and their uses | |
US10159757B2 (en) | Fluorescent conjugates | |
US10507251B2 (en) | Anti-human MUC1 antibody fab fragment | |
Gao et al. | A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer | |
US20190125903A1 (en) | Upar targeting peptide for use in peroperative optical imaging of invasive cancer | |
Nagaya et al. | Near infrared photoimmunotherapy using a fiber optic diffuser for treating peritoneal gastric cancer dissemination | |
US20220242853A1 (en) | Modified cyanine dyes and conjugates thereof | |
Muselaers et al. | Radionuclide and fluorescence imaging of clear cell renal cell carcinoma using dual labeled anti-carbonic anhydrase IX antibody G250 | |
Gong et al. | A 3E8. scFv. Cys-IR800 conjugate targeting TAG-72 in an orthotopic colorectal cancer model | |
BR112017025935B1 (pt) | Conjugados fluorescentes | |
WO2023057508A1 (en) | Fluorescently labeled immunoglobulin single variable domai ns | |
Fung | Leveraging Antibodies for Positron Emission Tomography and Near-Infrared Fluorescence Imaging of Cancer | |
EA044968B1 (ru) | Гуманизированное антитело и способ его применения | |
Chopra | Cy5. 5-Conjugated anti-epidermal growth factor receptor monoclonal antibody C225 C225-Cy5. 5 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190508 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200721 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210121 |
|
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: 20210622 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210708 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6912389 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |