JP2023508065A - 抗SIRPαモノクローナル抗体およびその使用 - Google Patents
抗SIRPαモノクローナル抗体およびその使用 Download PDFInfo
- Publication number
- JP2023508065A JP2023508065A JP2022538930A JP2022538930A JP2023508065A JP 2023508065 A JP2023508065 A JP 2023508065A JP 2022538930 A JP2022538930 A JP 2022538930A JP 2022538930 A JP2022538930 A JP 2022538930A JP 2023508065 A JP2023508065 A JP 2023508065A
- Authority
- JP
- Japan
- Prior art keywords
- amino acid
- seq
- acid sequence
- antibody
- fragment
- 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
- 101000863873 Homo sapiens Tyrosine-protein phosphatase non-receptor type substrate 1 Proteins 0.000 claims abstract description 102
- 239000012634 fragment Substances 0.000 claims abstract description 101
- 230000027455 binding Effects 0.000 claims abstract description 94
- 102100029948 Tyrosine-protein phosphatase non-receptor type substrate 1 Human genes 0.000 claims abstract description 80
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 49
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 48
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 371
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 86
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 65
- 206010028980 Neoplasm Diseases 0.000 claims description 49
- 239000000427 antigen Substances 0.000 claims description 48
- 108091007433 antigens Proteins 0.000 claims description 47
- 102000036639 antigens Human genes 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 28
- 201000011510 cancer Diseases 0.000 claims description 25
- 102000049963 human SIRPA Human genes 0.000 claims description 22
- -1 CSFR1 Proteins 0.000 claims description 8
- 206010025323 Lymphomas Diseases 0.000 claims description 8
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 230000014207 opsonization Effects 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 102100022464 5'-nucleotidase Human genes 0.000 claims description 3
- 102100026882 Alpha-synuclein Human genes 0.000 claims description 3
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 3
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 3
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 claims description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 claims description 3
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 claims description 3
- 101150013553 CD40 gene Proteins 0.000 claims description 3
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 3
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 102100032530 Glypican-3 Human genes 0.000 claims description 3
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 3
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 claims description 3
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims description 3
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 3
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 3
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 claims description 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 3
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims description 3
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 3
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 claims description 3
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 claims description 3
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 claims description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims description 3
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 3
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims description 3
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 claims description 3
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 claims description 3
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 claims description 3
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 claims description 3
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 102000017578 LAG3 Human genes 0.000 claims description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 claims description 3
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 102100038081 Signal transducer CD24 Human genes 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 101100215487 Sus scrofa ADRA2A gene Proteins 0.000 claims description 3
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 3
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 claims description 3
- 108091008605 VEGF receptors Proteins 0.000 claims description 3
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 3
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 3
- 230000003571 opsonizing effect Effects 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 102000002029 Claudin Human genes 0.000 claims description 2
- 108050009302 Claudin Proteins 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 206010046431 Urethral cancer Diseases 0.000 claims description 2
- 206010046458 Urethral neoplasms Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 abstract description 31
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 abstract description 31
- 210000002540 macrophage Anatomy 0.000 abstract description 20
- 206010057249 Phagocytosis Diseases 0.000 abstract description 17
- 230000008782 phagocytosis Effects 0.000 abstract description 17
- 210000004881 tumor cell Anatomy 0.000 abstract description 14
- 230000001404 mediated effect Effects 0.000 abstract description 12
- 230000003993 interaction Effects 0.000 abstract description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 70
- 238000006467 substitution reaction Methods 0.000 description 50
- 229920001184 polypeptide Polymers 0.000 description 48
- 238000012217 deletion Methods 0.000 description 44
- 230000037430 deletion Effects 0.000 description 44
- 238000007792 addition Methods 0.000 description 43
- 235000018102 proteins Nutrition 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 34
- 241000282414 Homo sapiens Species 0.000 description 28
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 27
- 150000001413 amino acids Chemical class 0.000 description 25
- 229940024606 amino acid Drugs 0.000 description 24
- 238000011282 treatment Methods 0.000 description 24
- 108060003951 Immunoglobulin Proteins 0.000 description 20
- 102000018358 immunoglobulin Human genes 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 14
- 108091033319 polynucleotide Proteins 0.000 description 14
- 102000040430 polynucleotide Human genes 0.000 description 14
- 239000002157 polynucleotide Substances 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 150000007523 nucleic acids Chemical group 0.000 description 11
- 201000010099 disease Diseases 0.000 description 10
- 102000039446 nucleic acids Human genes 0.000 description 10
- 108020004707 nucleic acids Proteins 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 125000000539 amino acid group Chemical group 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 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 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 210000004980 monocyte derived macrophage Anatomy 0.000 description 6
- 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 5
- 230000000295 complement effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 229960004641 rituximab Drugs 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 4
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000011275 oncology therapy Methods 0.000 description 4
- 210000001539 phagocyte Anatomy 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 150000003839 salts Chemical group 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 102000008096 B7-H1 Antigen Human genes 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 240000007594 Oryza sativa Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 3
- 101150036449 SIRPA gene Proteins 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 3
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 3
- 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 3
- 239000011230 binding agent Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000002405 diagnostic procedure 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
- 210000004408 hybridoma Anatomy 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 229920001469 poly(aryloxy)thionylphosphazene Polymers 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing 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
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000004475 Arginine Substances 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
- 241000283690 Bos taurus Species 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 101000617285 Homo sapiens Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 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 2
- 206010027476 Metastases Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical group OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 2
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 2
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical class C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 235000021186 dishes Nutrition 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 102000048776 human CD274 Human genes 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 210000000066 myeloid cell Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000006337 proteolytic cleavage Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000012146 running buffer Substances 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001519 tissue Anatomy 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
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 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
- VYEWZWBILJHHCU-OMQUDAQFSA-N (e)-n-[(2s,3r,4r,5r,6r)-2-[(2r,3r,4s,5s,6s)-3-acetamido-5-amino-4-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[2-[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl]-4,5-dihydroxyoxan-3-yl]-5-methylhex-2-enamide Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)C(O)C[C@@H]2[C@H](O)[C@H](O)[C@H]([C@@H](O2)O[C@@H]2[C@@H]([C@@H](O)[C@H](N)[C@@H](CO)O2)NC(C)=O)NC(=O)/C=C/CC(C)C)C=CC(=O)NC1=O VYEWZWBILJHHCU-OMQUDAQFSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- HUDPLKWXRLNSPC-UHFFFAOYSA-N 4-aminophthalhydrazide Chemical compound O=C1NNC(=O)C=2C1=CC(N)=CC=2 HUDPLKWXRLNSPC-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 102000002038 Claudin-18 Human genes 0.000 description 1
- 108050009324 Claudin-18 Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 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
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 102100035261 FYN-binding protein 1 Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 101001022163 Homo sapiens FYN-binding protein 1 Proteins 0.000 description 1
- 101000633708 Homo sapiens Src kinase-associated phosphoprotein 2 Proteins 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
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 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
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 102100029213 Src kinase-associated phosphoprotein 2 Human genes 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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- YJQCOFNZVFGCAF-UHFFFAOYSA-N Tunicamycin II Natural products O1C(CC(O)C2C(C(O)C(O2)N2C(NC(=O)C=C2)=O)O)C(O)C(O)C(NC(=O)C=CCCCCCCCCC(C)C)C1OC1OC(CO)C(O)C(O)C1NC(C)=O YJQCOFNZVFGCAF-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003095 anti-phagocytic effect Effects 0.000 description 1
- 238000011230 antibody-based therapy Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 125000003118 aryl group Chemical group 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
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000006334 disulfide bridging Effects 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 239000011521 glass Substances 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
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000011577 humanized mouse model Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 108091008042 inhibitory receptors Proteins 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 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
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000015286 negative regulation of phagocytosis Effects 0.000 description 1
- 208000025402 neoplasm of esophagus Diseases 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 206010035059 pineocytoma Diseases 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 230000001296 transplacental effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- MEYZYGMYMLNUHJ-UHFFFAOYSA-N tunicamycin Natural products CC(C)CCCCCCCCCC=CC(=O)NC1C(O)C(O)C(CC(O)C2OC(C(O)C2O)N3C=CC(=O)NC3=O)OC1OC4OC(CO)C(O)C(O)C4NC(=O)C MEYZYGMYMLNUHJ-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
- C07K16/28—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
-
- 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
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
-
- 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
- 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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
-
- 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
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/522—CH1 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/524—CH2 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/526—CH3 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- 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
- C07K2317/50—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
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
シグナル調節タンパク質アルファ(SIRPα)は、シグナル調節タンパク質(SIRP)ファミリーのメンバーであり、また、免疫グロブリンスーパーファミリーにも属している。SIRPファミリーメンバーは、受容体チロシンキナーゼ結合シグナル伝達プロセスの負の調節に関与することが知られている受容体型膜貫通糖タンパク質である。SIRPαは、チロシンキナーゼによってリン酸化され得る。このPTPのホスホチロシン残基は、SH2ドメインを含むチロシンホスファターゼ(PTP)をリクルートすることが示されており、かつ、PTPの基質として働く。SIRPαは、種々の成長因子受容体によって媒介されるシグナル伝達に関与することが見いだされた。CD47は、リガンドであることが実証されている。SIRPαは、SIRPファミリーのいくつかの他のメンバーと非常に高い類似性を共有している。SIRPαは、主に骨髄性細胞によって発現され、また、幹細胞またはニューロンによっても発現される。
バリアントv1とv2の両方に対して高い親和性を有する抗SIRPα抗体が、本明細書において見いだされ、SIRPαとCD47の間の相互作用を用量依存的かつ効率的にブロックすることができ、かつCD47を発現している細胞のマクロファージ媒介ファゴサイトーシスを効率的に誘導することができる。対照的に、既知の抗SIRPα抗体は、バリアント1を認識できるだけである。
定義
用語「a(1つの、ある)」または「an(1つの、ある)」実体は、1つまたはそれを超えるその実体を指す。例えば、「1つの抗体(an antibody)」は、1つまたはそれを超える抗体を表すものと理解すべきである。従って、用語「a」(または「an」)、「1つまたはそれを超える(one or more)」、および「少なくとも1つの(at least one)」は、本明細書において、互換的に使用され得る。
抗SIRPα抗体
表A.アミノ酸類似性マトリックス
二官能性分子および併用治療
抗体をコードするポリヌクレオチド、および抗体の調製方法
処置方法
診断方法
組成物
ヒトSIRPαタンパク質(human SIRPa protein)を、異なる系統のマウスを免役するために使用し、それによってハイブリドーマを生成させた。十分な数のハイブリドーマクローンを生成させるために、8つの融合体を作製した。SIRPα v1/v2陽性バインダー(SIRPa v1/v2 positive binders)を選択し、サブクローニングした。その後、約30の精製抗体を使用して、in vitro結合および機能的スクリーニングを行い、最も高い結合親和性および最も強い機能的能力を有するリード抗体を同定した。リード抗体は、ヒト化した。
実施例4.マクロファージ媒介ファゴサイトーシスの誘導
実施例5.マウスmAbのヒト化
ヒト化配列
A.248G3F6
表2A.248G3F6のヒト化-VH
表3A.300A6A6のヒト化-VH
表4A.102A10F2のヒト化-VH
表5A.62D2H6のヒト化-VH
表6A.211F8E11のヒト化-VH
表7A.217D11E5のヒト化-VH
表7E.ヒト化抗体
表8A.234B7D5のヒト化-VH
表9.ヒト化抗体の、SIRPαとCD47の相互作用をブロックする活性
実施例8.SIRPα v1とv2に対する結合親和性
本発明は、例えば、以下の項目を提供する。
(項目1)
野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで
(a)前記CDRH1が、配列番号15のアミノ酸配列を含み、前記CDRH2が、配列番号16、21、または22のアミノ酸配列を含み、前記CDRH3が、配列番号17のアミノ酸配列を含み、前記CDRL1が、配列番号18のアミノ酸配列を含み、前記CDRL2が、配列番号19のアミノ酸配列を含み、および前記CDRL3が、配列番号20のアミノ酸配列を含み;
(b)前記CDRH1が、配列番号30のアミノ酸配列を含み、前記CDRH2が、配列番号31、36、37、または38のアミノ酸配列を含み、前記CDRH3が、配列番号32のアミノ酸配列を含み、前記CDRL1が、配列番号33のアミノ酸配列を含み、前記CDRL2が、配列番号34のアミノ酸配列を含み、および前記CDRL3が、配列番号35のアミノ酸配列を含み;
(c)前記CDRH1が、配列番号47のアミノ酸配列を含み、前記CDRH2が、配列番号48、53、または54のアミノ酸配列を含み、前記CDRH3が、配列番号49のアミノ酸配列を含み、前記CDRL1が、配列番号50のアミノ酸配列を含み、前記CDRL2が、配列番号51のアミノ酸配列を含み、および前記CDRL3が、配列番号52のアミノ酸配列を含み;
(d)前記CDRH1が、配列番号63のアミノ酸配列を含み、前記CDRH2が、配列番号64のアミノ酸配列を含み、前記CDRH3が、配列番号65のアミノ酸配列を含み、前記CDRL1が、配列番号66のアミノ酸配列を含み、前記CDRL2が、配列番号67のアミノ酸配列を含み、および前記CDRL3が、配列番号68のアミノ酸配列を含み;
(e)前記CDRH1が、配列番号77のアミノ酸配列を含み、前記CDRH2が、配列番号78のアミノ酸配列を含み、前記CDRH3が、配列番号79のアミノ酸配列を含み、前記CDRL1が、配列番号80のアミノ酸配列を含み、前記CDRL2が、配列番号81のアミノ酸配列を含み、前記CDRL3が、配列番号82のアミノ酸配列を含み;
(f)前記CDRH1が、配列番号91のアミノ酸配列を含み、前記CDRH2が、配列番号92のアミノ酸配列を含み、前記CDRH3が、配列番号93のアミノ酸配列を含み、前記CDRL1が、配列番号94のアミノ酸配列を含み、前記CDRL2が、配列番号95のアミノ酸配列を含み、および前記CDRL3が、配列番号96のアミノ酸配列を含み;または
(g)前記CDRH1が、配列番号103のアミノ酸配列を含み、前記CDRH2が、配列番号104のアミノ酸配列を含み、前記CDRH3が、配列番号105のアミノ酸配列を含み、前記CDRL1が、配列番号106のアミノ酸配列を含み、前記CDRL2が、配列番号107のアミノ酸配列を含み、および前記CDRL3が、配列番号108のアミノ酸配列を含む、
抗体またはそのフラグメント。
(項目2)
野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで前記CDRH1が、配列番号15のアミノ酸配列を含み、前記CDRH2が、配列番号16、21、または22のアミノ酸配列を含み、前記CDRH3が、配列番号17のアミノ酸配列を含み、前記CDRL1が、配列番号18のアミノ酸配列を含み、前記CDRL2が、配列番号19のアミノ酸配列を含み、および前記CDRL3が、配列番号20のアミノ酸配列を含む、
抗体またはそのフラグメント。
(項目3)
前記重鎖可変領域が、配列番号1および23~27からなる群から選択されるアミノ酸配列、または配列番号1および23~27からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、項目2に記載の抗体またはそのフラグメント。
(項目4)
前記軽鎖可変領域が、配列番号2および28~29からなる群から選択されるアミノ酸配列、または配列番号2および28~29からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、項目2または3に記載の抗体またはそのフラグメント。
(項目5)
前記重鎖可変領域が、配列番号27のアミノ酸配列を含み、および前記軽鎖可変領域が、配列番号29のアミノ酸配列を含む、項目2に記載の抗体またはそのフラグメント。
(項目6)
野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで前記CDRH1が、配列番号30のアミノ酸配列を含み、前記CDRH2が、配列番号31、36、37、または38のアミノ酸配列を含み、前記CDRH3が、配列番号32のアミノ酸配列を含み、前記CDRL1が、配列番号33のアミノ酸配列を含み、前記CDRL2が、配列番号34のアミノ酸配列を含み、および前記CDRL3が、配列番号35のアミノ酸配列を含む、
抗体またはそのフラグメント。
(項目7)
前記重鎖可変領域が、配列番号3および39~44からなる群から選択されるアミノ酸配列、または配列番号3および39~44からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、項目6に記載の抗体またはそのフラグメント。
(項目8)
前記軽鎖可変領域が、配列番号4および45~46からなる群から選択されるアミノ酸配列、または配列番号4および45~46からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、項目6または7に記載の抗体またはそのフラグメント。
(項目9)
前記重鎖可変領域が、配列番号43のアミノ酸配列を含み、および前記軽鎖可変領域が、配列番号45のアミノ酸配列を含む、項目6に記載の抗体またはそのフラグメント。
(項目10)
野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで前記CDRH1が、配列番号47のアミノ酸配列を含み、前記CDRH2が、配列番号48、53、または54のアミノ酸配列を含み、前記CDRH3が、配列番号49のアミノ酸配列を含み、前記CDRL1が、配列番号50のアミノ酸配列を含み、前記CDRL2が、配列番号51のアミノ酸配列を含み、および前記CDRL3が、配列番号52のアミノ酸配列を含む、
抗体またはそのフラグメント。
(項目11)
前記重鎖可変領域が、配列番号5および55~60からなる群から選択されるアミノ酸配列、または配列番号5および55~60からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、項目10に記載の抗体またはそのフラグメント。
(項目12)
前記軽鎖可変領域が、配列番号6および61~62からなる群から選択されるアミノ酸配列、または配列番号6および61~62からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、項目10または11に記載の抗体またはそのフラグメント。
(項目13)
SIRPαバリアント1およびバリアント2に結合することができる、項目1~12のいずれか一項に記載の抗体またはそのフラグメント。
(項目14)
ヒト化されている、項目1~13のいずれか一項に記載の抗体またはそのフラグメント。
(項目15)
第2の標的タンパク質に対する結合特異性をさらに有する、項目1~24のいずれか一項に記載の抗体またはそのフラグメント。
(項目16)
項目1~15のいずれか一項に記載の抗体またはそのフラグメント、および医薬的に許容され得るキャリアを含む、組成物。
(項目17)
腫瘍抗原に対する特異性を有する二次抗体をさらに含む、項目16に記載の組成物。
(項目18)
前記二次抗体が、腫瘍オプソニン化抗体である、項目17に記載の組成物。
(項目19)
がんを処置することを必要とする患者においてがんを処置する方法であって、項目1~15のいずれか一項に記載の抗体またはそのフラグメントを前記患者に投与することを含む、方法。
(項目20)
前記がんが、膀胱がん、肝臓がん、結腸がん、直腸がん、子宮内膜がん、白血病、リンパ腫、膵臓がん、小細胞肺がん、非小細胞肺がん、乳がん、尿道がん、頭頸部がん、胃腸がん、胃がん、食道がん、卵巣がん、腎臓がん、メラノーマ、前立腺がん、および甲状腺がんからなる群から選択される、項目19に記載の方法。
(項目21)
腫瘍オプソニン化を誘発するタンパク質を標的とする二次抗体を前記患者に投与することをさらに含む、項目19に記載の方法。
(項目22)
前記タンパク質が、CD19、CD20、EGFR、HER2、CD3、CD16、PD1、PD-L1、LAG3、TIM3、CTLA4、VISTA、CSFR1、A2AR、CD73、CD39、CD40、CEA、HER2、VEGFR、TIGIT、クローディン18.2、CD24、GPC3、Il13RA2、4-1BB、CCR8、およびCMETからなる群から選択される、項目21に記載の方法。
Claims (22)
- 野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで
(a)前記CDRH1が、配列番号15のアミノ酸配列を含み、前記CDRH2が、配列番号16、21、または22のアミノ酸配列を含み、前記CDRH3が、配列番号17のアミノ酸配列を含み、前記CDRL1が、配列番号18のアミノ酸配列を含み、前記CDRL2が、配列番号19のアミノ酸配列を含み、および前記CDRL3が、配列番号20のアミノ酸配列を含み;
(b)前記CDRH1が、配列番号30のアミノ酸配列を含み、前記CDRH2が、配列番号31、36、37、または38のアミノ酸配列を含み、前記CDRH3が、配列番号32のアミノ酸配列を含み、前記CDRL1が、配列番号33のアミノ酸配列を含み、前記CDRL2が、配列番号34のアミノ酸配列を含み、および前記CDRL3が、配列番号35のアミノ酸配列を含み;
(c)前記CDRH1が、配列番号47のアミノ酸配列を含み、前記CDRH2が、配列番号48、53、または54のアミノ酸配列を含み、前記CDRH3が、配列番号49のアミノ酸配列を含み、前記CDRL1が、配列番号50のアミノ酸配列を含み、前記CDRL2が、配列番号51のアミノ酸配列を含み、および前記CDRL3が、配列番号52のアミノ酸配列を含み;
(d)前記CDRH1が、配列番号63のアミノ酸配列を含み、前記CDRH2が、配列番号64のアミノ酸配列を含み、前記CDRH3が、配列番号65のアミノ酸配列を含み、前記CDRL1が、配列番号66のアミノ酸配列を含み、前記CDRL2が、配列番号67のアミノ酸配列を含み、および前記CDRL3が、配列番号68のアミノ酸配列を含み;
(e)前記CDRH1が、配列番号77のアミノ酸配列を含み、前記CDRH2が、配列番号78のアミノ酸配列を含み、前記CDRH3が、配列番号79のアミノ酸配列を含み、前記CDRL1が、配列番号80のアミノ酸配列を含み、前記CDRL2が、配列番号81のアミノ酸配列を含み、前記CDRL3が、配列番号82のアミノ酸配列を含み;
(f)前記CDRH1が、配列番号91のアミノ酸配列を含み、前記CDRH2が、配列番号92のアミノ酸配列を含み、前記CDRH3が、配列番号93のアミノ酸配列を含み、前記CDRL1が、配列番号94のアミノ酸配列を含み、前記CDRL2が、配列番号95のアミノ酸配列を含み、および前記CDRL3が、配列番号96のアミノ酸配列を含み;または
(g)前記CDRH1が、配列番号103のアミノ酸配列を含み、前記CDRH2が、配列番号104のアミノ酸配列を含み、前記CDRH3が、配列番号105のアミノ酸配列を含み、前記CDRL1が、配列番号106のアミノ酸配列を含み、前記CDRL2が、配列番号107のアミノ酸配列を含み、および前記CDRL3が、配列番号108のアミノ酸配列を含む、
抗体またはそのフラグメント。 - 野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで前記CDRH1が、配列番号15のアミノ酸配列を含み、前記CDRH2が、配列番号16、21、または22のアミノ酸配列を含み、前記CDRH3が、配列番号17のアミノ酸配列を含み、前記CDRL1が、配列番号18のアミノ酸配列を含み、前記CDRL2が、配列番号19のアミノ酸配列を含み、および前記CDRL3が、配列番号20のアミノ酸配列を含む、
抗体またはそのフラグメント。 - 前記重鎖可変領域が、配列番号1および23~27からなる群から選択されるアミノ酸配列、または配列番号1および23~27からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、請求項2に記載の抗体またはそのフラグメント。
- 前記軽鎖可変領域が、配列番号2および28~29からなる群から選択されるアミノ酸配列、または配列番号2および28~29からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、請求項2または3に記載の抗体またはそのフラグメント。
- 前記重鎖可変領域が、配列番号27のアミノ酸配列を含み、および前記軽鎖可変領域が、配列番号29のアミノ酸配列を含む、請求項2に記載の抗体またはそのフラグメント。
- 野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで前記CDRH1が、配列番号30のアミノ酸配列を含み、前記CDRH2が、配列番号31、36、37、または38のアミノ酸配列を含み、前記CDRH3が、配列番号32のアミノ酸配列を含み、前記CDRL1が、配列番号33のアミノ酸配列を含み、前記CDRL2が、配列番号34のアミノ酸配列を含み、および前記CDRL3が、配列番号35のアミノ酸配列を含む、
抗体またはそのフラグメント。 - 前記重鎖可変領域が、配列番号3および39~44からなる群から選択されるアミノ酸配列、または配列番号3および39~44からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、請求項6に記載の抗体またはそのフラグメント。
- 前記軽鎖可変領域が、配列番号4および45~46からなる群から選択されるアミノ酸配列、または配列番号4および45~46からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、請求項6または7に記載の抗体またはそのフラグメント。
- 前記重鎖可変領域が、配列番号43のアミノ酸配列を含み、および前記軽鎖可変領域が、配列番号45のアミノ酸配列を含む、請求項6に記載の抗体またはそのフラグメント。
- 野生型ヒトシグナル調節タンパク質アルファ(SIRPα)タンパク質に対して結合特異性を有する抗体またはそのフラグメントであって、前記抗体またはそのフラグメントが、重鎖相補性決定領域CDRH1、CDRH2、およびCDRH3を含む重鎖可変領域、ならびに相補性決定領域CDRL1、CDRL2、およびCDRL3を含む軽鎖可変領域軽鎖を含み、ここで前記CDRH1が、配列番号47のアミノ酸配列を含み、前記CDRH2が、配列番号48、53、または54のアミノ酸配列を含み、前記CDRH3が、配列番号49のアミノ酸配列を含み、前記CDRL1が、配列番号50のアミノ酸配列を含み、前記CDRL2が、配列番号51のアミノ酸配列を含み、および前記CDRL3が、配列番号52のアミノ酸配列を含む、
抗体またはそのフラグメント。 - 前記重鎖可変領域が、配列番号5および55~60からなる群から選択されるアミノ酸配列、または配列番号5および55~60からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、請求項10に記載の抗体またはそのフラグメント。
- 前記軽鎖可変領域が、配列番号6および61~62からなる群から選択されるアミノ酸配列、または配列番号6および61~62からなる群から選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するペプチドを含む、請求項10または11に記載の抗体またはそのフラグメント。
- SIRPαバリアント1およびバリアント2に結合することができる、請求項1~12のいずれか一項に記載の抗体またはそのフラグメント。
- ヒト化されている、請求項1~13のいずれか一項に記載の抗体またはそのフラグメント。
- 第2の標的タンパク質に対する結合特異性をさらに有する、請求項1~24のいずれか一項に記載の抗体またはそのフラグメント。
- 請求項1~15のいずれか一項に記載の抗体またはそのフラグメント、および医薬的に許容され得るキャリアを含む、組成物。
- 腫瘍抗原に対する特異性を有する二次抗体をさらに含む、請求項16に記載の組成物。
- 前記二次抗体が、腫瘍オプソニン化抗体である、請求項17に記載の組成物。
- がんを処置することを必要とする患者においてがんを処置する方法であって、請求項1~15のいずれか一項に記載の抗体またはそのフラグメントを前記患者に投与することを含む、方法。
- 前記がんが、膀胱がん、肝臓がん、結腸がん、直腸がん、子宮内膜がん、白血病、リンパ腫、膵臓がん、小細胞肺がん、非小細胞肺がん、乳がん、尿道がん、頭頸部がん、胃腸がん、胃がん、食道がん、卵巣がん、腎臓がん、メラノーマ、前立腺がん、および甲状腺がんからなる群から選択される、請求項19に記載の方法。
- 腫瘍オプソニン化を誘発するタンパク質を標的とする二次抗体を前記患者に投与することをさらに含む、請求項19に記載の方法。
- 前記タンパク質が、CD19、CD20、EGFR、HER2、CD3、CD16、PD1、PD-L1、LAG3、TIM3、CTLA4、VISTA、CSFR1、A2AR、CD73、CD39、CD40、CEA、HER2、VEGFR、TIGIT、クローディン18.2、CD24、GPC3、Il13RA2、4-1BB、CCR8、およびCMETからなる群から選択される、請求項21に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2024015855A JP2024042083A (ja) | 2019-12-24 | 2024-02-05 | 抗SIRPαモノクローナル抗体およびその使用 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNPCT/CN2019/127915 | 2019-12-24 | ||
CN2019127915 | 2019-12-24 | ||
PCT/CN2020/138800 WO2021129697A1 (en) | 2019-12-24 | 2020-12-24 | ANTI-SIRPα MONOCLONAL ANTIBODIES AND USES THEREOF |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024015855A Division JP2024042083A (ja) | 2019-12-24 | 2024-02-05 | 抗SIRPαモノクローナル抗体およびその使用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2023508065A true JP2023508065A (ja) | 2023-02-28 |
JP7437815B2 JP7437815B2 (ja) | 2024-02-26 |
Family
ID=76574855
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022538930A Active JP7437815B2 (ja) | 2019-12-24 | 2020-12-24 | 抗SIRPαモノクローナル抗体およびその使用 |
JP2024015855A Pending JP2024042083A (ja) | 2019-12-24 | 2024-02-05 | 抗SIRPαモノクローナル抗体およびその使用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024015855A Pending JP2024042083A (ja) | 2019-12-24 | 2024-02-05 | 抗SIRPαモノクローナル抗体およびその使用 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20220169726A1 (ja) |
EP (1) | EP4081548A1 (ja) |
JP (2) | JP7437815B2 (ja) |
KR (1) | KR20220119473A (ja) |
CN (3) | CN116621981A (ja) |
AU (1) | AU2020412093A1 (ja) |
CA (1) | CA3165619A1 (ja) |
CO (1) | CO2022010337A2 (ja) |
WO (1) | WO2021129697A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023010100A1 (en) * | 2021-07-28 | 2023-02-02 | Elpiscience (Suzhou) Biopharma, Ltd. | Novel anti-sirpa antibodies |
CN117164719A (zh) * | 2022-05-28 | 2023-12-05 | 启愈生物技术(上海)有限公司 | 靶向SIRPα和PD-L1的双特异性抗体或其抗原结合片段及应用 |
WO2024105180A1 (en) | 2022-11-16 | 2024-05-23 | Boehringer Ingelheim International Gmbh | Predictive efficacy biomarkers for anti-sirpa antibodies |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019023347A1 (en) * | 2017-07-26 | 2019-01-31 | Forty Seven, Inc. | ANTI-SIRP-ALPHA ANTIBODIES AND ASSOCIATED METHODS |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101880324B (zh) * | 2010-05-25 | 2012-10-17 | 中国人民解放军第二军医大学 | 一种抗人SIRPα的单克隆抗体及其细胞株、制备方法和应用 |
SG11201607143UA (en) * | 2014-03-11 | 2016-09-29 | Univ Leland Stanford Junior | Anti sirp-alpha antibodies and bi-specific macrophage enhancing antibodies |
CN109862910A (zh) * | 2016-08-03 | 2019-06-07 | 小利兰·斯坦福大学托管委员会 | 破坏巨噬细胞上的Fc受体接合增强抗SIRPα抗体疗法的功效 |
AU2017371070A1 (en) * | 2016-12-09 | 2019-06-13 | Alector Llc | Anti-SIRP-alpha antibodies and methods of use thereof |
CN118267470A (zh) * | 2017-04-13 | 2024-07-02 | 赛罗帕私人有限公司 | 抗SIRPα抗体 |
KR20200005659A (ko) * | 2017-05-16 | 2020-01-15 | 신톤 바이오파머슈티칼즈 비.브이. | 항-SIRPα 항체 |
-
2020
- 2020-12-24 JP JP2022538930A patent/JP7437815B2/ja active Active
- 2020-12-24 CN CN202310383265.3A patent/CN116621981A/zh active Pending
- 2020-12-24 CN CN202080045429.6A patent/CN114040925B/zh active Active
- 2020-12-24 EP EP20905432.9A patent/EP4081548A1/en active Pending
- 2020-12-24 CN CN202310387804.0A patent/CN116769031A/zh active Pending
- 2020-12-24 KR KR1020227025569A patent/KR20220119473A/ko active Search and Examination
- 2020-12-24 WO PCT/CN2020/138800 patent/WO2021129697A1/en unknown
- 2020-12-24 CA CA3165619A patent/CA3165619A1/en active Pending
- 2020-12-24 AU AU2020412093A patent/AU2020412093A1/en active Pending
-
2021
- 2021-11-18 US US17/530,302 patent/US20220169726A1/en active Pending
-
2022
- 2022-07-22 CO CONC2022/0010337A patent/CO2022010337A2/es unknown
-
2024
- 2024-02-05 JP JP2024015855A patent/JP2024042083A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019023347A1 (en) * | 2017-07-26 | 2019-01-31 | Forty Seven, Inc. | ANTI-SIRP-ALPHA ANTIBODIES AND ASSOCIATED METHODS |
Also Published As
Publication number | Publication date |
---|---|
CN116769031A (zh) | 2023-09-19 |
JP2024042083A (ja) | 2024-03-27 |
CN114040925A (zh) | 2022-02-11 |
KR20220119473A (ko) | 2022-08-29 |
AU2020412093A1 (en) | 2022-07-28 |
US20220169726A1 (en) | 2022-06-02 |
CO2022010337A2 (es) | 2022-08-09 |
JP7437815B2 (ja) | 2024-02-26 |
CN114040925B (zh) | 2023-04-28 |
EP4081548A1 (en) | 2022-11-02 |
CN116621981A (zh) | 2023-08-22 |
CA3165619A1 (en) | 2021-07-01 |
WO2021129697A1 (en) | 2021-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7156607B2 (ja) | Igおよびitimドメインを持つt細胞免疫受容体(tigit)に対する抗体およびその使用 | |
US20210206850A1 (en) | Blocking antibodies against cd47 and methods of use thereof | |
JP7410141B2 (ja) | 抗クローディン-18.2と抗4-1bbとの二重特異性抗体およびその使用 | |
KR20180095086A (ko) | 인간화된, 마우스 또는 키메라 항-cd47 단클론 항체 | |
JP7437815B2 (ja) | 抗SIRPαモノクローナル抗体およびその使用 | |
JP7098854B2 (ja) | 自己免疫疾患およびがんを治療するための抗cxcl13抗体 | |
CN112243443B (zh) | 抗trop-2抗体、其抗原结合片段及其医药用途 | |
JP2023547530A (ja) | 抗tigit抗体およびその使用 | |
JP7317148B2 (ja) | 抗cd47抗体およびその使用 | |
AU2022201736B2 (en) | Anti-GPRC5D monoclonal antibodies and uses thereof | |
WO2022148370A1 (en) | Anti-gprc5d monoclonal antibodies and uses thereof | |
JP2023551113A (ja) | 二重特異性抗体及びその応用 | |
WO2022127901A1 (en) | BISPECIFIC ANTIBODIES TARGETING SIRPα AND PD-L1 | |
WO2023246879A1 (en) | Anti-slc34a2 monoclonal antibodies and uses thereof | |
EA045759B1 (ru) | МОНОКЛОНАЛЬНЫЕ АНТИТЕЛА К SIRPα И ИХ ПРИМЕНЕНИЯ | |
WO2022206961A1 (en) | Anti-cd24 monoclonal antibodies and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220928 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220928 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230728 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231027 |
|
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: 20240105 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240205 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7437815 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |