TW202206454A - 抗pd-l1抗體及其於增進t細胞功能之用途 - Google Patents
抗pd-l1抗體及其於增進t細胞功能之用途 Download PDFInfo
- Publication number
- TW202206454A TW202206454A TW110115088A TW110115088A TW202206454A TW 202206454 A TW202206454 A TW 202206454A TW 110115088 A TW110115088 A TW 110115088A TW 110115088 A TW110115088 A TW 110115088A TW 202206454 A TW202206454 A TW 202206454A
- Authority
- TW
- Taiwan
- Prior art keywords
- antibody
- seq
- hvr
- sequence
- cells
- Prior art date
Links
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 157
- 239000000203 mixture Substances 0.000 claims abstract description 61
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 54
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 46
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 45
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 45
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 44
- 230000036039 immunity Effects 0.000 claims abstract description 38
- 208000015181 infectious disease Diseases 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 230000001684 chronic effect Effects 0.000 claims abstract description 4
- 210000004027 cell Anatomy 0.000 claims description 160
- 239000000427 antigen Substances 0.000 claims description 121
- 108091007433 antigens Proteins 0.000 claims description 118
- 102000036639 antigens Human genes 0.000 claims description 118
- 230000027455 binding Effects 0.000 claims description 94
- 238000000034 method Methods 0.000 claims description 86
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 81
- 241000282414 Homo sapiens Species 0.000 claims description 79
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 71
- 229920001184 polypeptide Polymers 0.000 claims description 65
- 239000012636 effector Substances 0.000 claims description 63
- 230000006870 function Effects 0.000 claims description 51
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 45
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 45
- 238000004519 manufacturing process Methods 0.000 claims description 41
- 239000013598 vector Substances 0.000 claims description 35
- 230000000139 costimulatory effect Effects 0.000 claims description 34
- 239000012634 fragment Substances 0.000 claims description 32
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 claims description 28
- 208000035475 disorder Diseases 0.000 claims description 28
- 230000002829 reductive effect Effects 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 24
- 241000700605 Viruses Species 0.000 claims description 22
- 244000052769 pathogen Species 0.000 claims description 22
- 229960005486 vaccine Drugs 0.000 claims description 21
- 230000001717 pathogenic effect Effects 0.000 claims description 20
- 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 claims description 19
- 241000894006 Bacteria Species 0.000 claims description 19
- 241000588724 Escherichia coli Species 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 230000035772 mutation Effects 0.000 claims description 18
- 208000037581 Persistent Infection Diseases 0.000 claims description 16
- 241001529936 Murinae Species 0.000 claims description 15
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 15
- 239000000556 agonist Substances 0.000 claims description 15
- 238000000338 in vitro Methods 0.000 claims description 15
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 14
- 239000003443 antiviral agent Substances 0.000 claims description 13
- 230000004064 dysfunction Effects 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000003242 anti bacterial agent Substances 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 11
- 230000005764 inhibitory process Effects 0.000 claims description 11
- 239000005557 antagonist Substances 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 10
- 230000002708 enhancing effect Effects 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 241000233866 Fungi Species 0.000 claims description 9
- 230000003115 biocidal effect Effects 0.000 claims description 9
- 229910052720 vanadium Inorganic materials 0.000 claims description 9
- 230000003915 cell function Effects 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 8
- 210000001236 prokaryotic cell Anatomy 0.000 claims description 7
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 229940121375 antifungal agent Drugs 0.000 claims description 6
- 239000003904 antiprotozoal agent Substances 0.000 claims description 6
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 5
- 229960005277 gemcitabine Drugs 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000009169 immunotherapy Methods 0.000 claims description 5
- 210000004962 mammalian cell Anatomy 0.000 claims description 5
- 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 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 239000003429 antifungal agent Substances 0.000 claims description 4
- 238000002512 chemotherapy Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 210000003527 eukaryotic cell Anatomy 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 230000002085 persistent effect Effects 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 238000012258 culturing Methods 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 210000001672 ovary Anatomy 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 241000699802 Cricetulus griseus Species 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 2
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 2
- 208000000728 Thymus Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 230000033115 angiogenesis Effects 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 238000001794 hormone therapy Methods 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 238000002638 palliative care Methods 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 238000002626 targeted therapy Methods 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 238000011269 treatment regimen Methods 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 108091035707 Consensus sequence Proteins 0.000 claims 2
- 208000032612 Glial tumor Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 210000005036 nerve Anatomy 0.000 claims 1
- 230000001154 acute effect Effects 0.000 abstract description 12
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 230000021633 leukocyte mediated immunity Effects 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 description 90
- 102000004169 proteins and genes Human genes 0.000 description 65
- 235000018102 proteins Nutrition 0.000 description 55
- 210000003719 b-lymphocyte Anatomy 0.000 description 47
- 230000011664 signaling Effects 0.000 description 44
- 230000014509 gene expression Effects 0.000 description 42
- 230000004044 response Effects 0.000 description 42
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 36
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 36
- 230000004913 activation Effects 0.000 description 35
- 125000003275 alpha amino acid group Chemical group 0.000 description 35
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 34
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 34
- 108060003951 Immunoglobulin Proteins 0.000 description 31
- 102000018358 immunoglobulin Human genes 0.000 description 31
- 230000000694 effects Effects 0.000 description 30
- 230000028993 immune response Effects 0.000 description 30
- 210000000612 antigen-presenting cell Anatomy 0.000 description 29
- 238000009472 formulation Methods 0.000 description 29
- -1 B7-H3 Proteins 0.000 description 28
- 102000005962 receptors Human genes 0.000 description 28
- 108020003175 receptors Proteins 0.000 description 28
- 108091034117 Oligonucleotide Proteins 0.000 description 27
- 210000004698 lymphocyte Anatomy 0.000 description 27
- 102000004127 Cytokines Human genes 0.000 description 24
- 108090000695 Cytokines Proteins 0.000 description 24
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 24
- 108091008874 T cell receptors Proteins 0.000 description 23
- 239000003112 inhibitor Substances 0.000 description 23
- 108020004414 DNA Proteins 0.000 description 22
- 230000001965 increasing effect Effects 0.000 description 22
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 21
- 108010087819 Fc receptors Proteins 0.000 description 21
- 102000009109 Fc receptors Human genes 0.000 description 21
- 235000001014 amino acid Nutrition 0.000 description 21
- 125000003729 nucleotide group Chemical group 0.000 description 21
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 20
- 229940045513 CTLA4 antagonist Drugs 0.000 description 20
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 20
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 20
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 19
- 229940024606 amino acid Drugs 0.000 description 19
- 239000002773 nucleotide Substances 0.000 description 19
- 108020004705 Codon Proteins 0.000 description 18
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 description 18
- 150000001413 amino acids Chemical class 0.000 description 18
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 230000001404 mediated effect Effects 0.000 description 17
- 108010002350 Interleukin-2 Proteins 0.000 description 16
- 102000000588 Interleukin-2 Human genes 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 16
- 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 16
- 239000003446 ligand Substances 0.000 description 16
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 15
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 15
- 102100027207 CD27 antigen Human genes 0.000 description 14
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 14
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 14
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 14
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 14
- 230000004927 fusion Effects 0.000 description 14
- 230000003993 interaction Effects 0.000 description 14
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 13
- 108010076504 Protein Sorting Signals Proteins 0.000 description 13
- 238000001727 in vivo Methods 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 230000006044 T cell activation Effects 0.000 description 12
- 125000000539 amino acid group Chemical group 0.000 description 12
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 12
- 230000002163 immunogen Effects 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 210000002540 macrophage Anatomy 0.000 description 12
- 230000035755 proliferation Effects 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- 108010038807 Oligopeptides Proteins 0.000 description 11
- 102000015636 Oligopeptides Human genes 0.000 description 11
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 11
- 230000009368 gene silencing by RNA Effects 0.000 description 11
- 229940088597 hormone Drugs 0.000 description 11
- 239000005556 hormone Substances 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 230000001105 regulatory effect Effects 0.000 description 11
- 150000003384 small molecules Chemical class 0.000 description 11
- 102100025221 CD70 antigen Human genes 0.000 description 10
- 102100034980 ICOS ligand Human genes 0.000 description 10
- 108010074328 Interferon-gamma Proteins 0.000 description 10
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 description 10
- 108091030071 RNAI Proteins 0.000 description 10
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 description 10
- 102100032100 Tumor necrosis factor ligand superfamily member 8 Human genes 0.000 description 10
- 230000001363 autoimmune Effects 0.000 description 10
- 210000001185 bone marrow Anatomy 0.000 description 10
- 230000000295 complement effect Effects 0.000 description 10
- 230000016396 cytokine production Effects 0.000 description 10
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 10
- 201000002491 encephalomyelitis Diseases 0.000 description 10
- 210000002443 helper t lymphocyte Anatomy 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 230000028327 secretion Effects 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 9
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 9
- 230000006052 T cell proliferation Effects 0.000 description 9
- 230000005867 T cell response Effects 0.000 description 9
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 230000000903 blocking effect Effects 0.000 description 9
- 230000001472 cytotoxic effect Effects 0.000 description 9
- 230000001419 dependent effect Effects 0.000 description 9
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 9
- 230000001939 inductive effect Effects 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 241000894007 species Species 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- 102100037850 Interferon gamma Human genes 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 108010042215 OX40 Ligand Proteins 0.000 description 8
- 230000001270 agonistic effect Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 210000004443 dendritic cell Anatomy 0.000 description 8
- 238000010494 dissociation reaction Methods 0.000 description 8
- 230000005593 dissociations Effects 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 239000003623 enhancer Substances 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 229940072221 immunoglobulins Drugs 0.000 description 8
- 238000003780 insertion Methods 0.000 description 8
- 230000037431 insertion Effects 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 238000003752 polymerase chain reaction Methods 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- 235000000346 sugar Nutrition 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 7
- 101100207070 Homo sapiens TNFSF8 gene Proteins 0.000 description 7
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 7
- 101100207071 Mus musculus Tnfsf8 gene Proteins 0.000 description 7
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 7
- 240000001717 Vaccinium macrocarpon Species 0.000 description 7
- 230000000840 anti-viral effect Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- PTOJXIKSKSASRB-UHFFFAOYSA-O candicine Chemical compound C[N+](C)(C)CCC1=CC=C(O)C=C1 PTOJXIKSKSASRB-UHFFFAOYSA-O 0.000 description 7
- 239000002679 microRNA Substances 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- 108010082808 4-1BB Ligand Proteins 0.000 description 6
- 102000002627 4-1BB Ligand Human genes 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 108010046080 CD27 Ligand Proteins 0.000 description 6
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 6
- 102000053602 DNA Human genes 0.000 description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 108090000174 Interleukin-10 Proteins 0.000 description 6
- 102000003814 Interleukin-10 Human genes 0.000 description 6
- 102000018697 Membrane Proteins Human genes 0.000 description 6
- 108010052285 Membrane Proteins Proteins 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 6
- 108020004459 Small interfering RNA Proteins 0.000 description 6
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 6
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 6
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 230000030741 antigen processing and presentation Effects 0.000 description 6
- 230000000890 antigenic effect Effects 0.000 description 6
- 230000002238 attenuated effect Effects 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 235000004634 cranberry Nutrition 0.000 description 6
- 231100000433 cytotoxic Toxicity 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 229940076144 interleukin-10 Drugs 0.000 description 6
- 210000003071 memory t lymphocyte Anatomy 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- 229960001592 paclitaxel Drugs 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 210000002706 plastid Anatomy 0.000 description 6
- 230000000284 resting effect Effects 0.000 description 6
- 239000004055 small Interfering RNA Substances 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 150000005846 sugar alcohols Chemical class 0.000 description 6
- 150000008163 sugars Chemical class 0.000 description 6
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 6
- 210000001541 thymus gland Anatomy 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 6
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 5
- 108091026890 Coding region Proteins 0.000 description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 5
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 5
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 102000004388 Interleukin-4 Human genes 0.000 description 5
- 108090000978 Interleukin-4 Proteins 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 108700011259 MicroRNAs Proteins 0.000 description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 5
- 108091027967 Small hairpin RNA Proteins 0.000 description 5
- 210000000447 Th1 cell Anatomy 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 230000007503 antigenic stimulation Effects 0.000 description 5
- 230000005784 autoimmunity Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 5
- 230000001086 cytosolic effect Effects 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 230000004073 interleukin-2 production Effects 0.000 description 5
- 125000005647 linker group Chemical group 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 238000002703 mutagenesis Methods 0.000 description 5
- 231100000350 mutagenesis Toxicity 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 102000040430 polynucleotide Human genes 0.000 description 5
- 108091033319 polynucleotide Proteins 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000000750 progressive effect Effects 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 238000010188 recombinant method Methods 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 230000004936 stimulating effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000014616 translation Effects 0.000 description 5
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 5
- 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 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 229930186147 Cephalosporin Natural products 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 4
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 4
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 4
- 108010047761 Interferon-alpha Proteins 0.000 description 4
- 102000006992 Interferon-alpha Human genes 0.000 description 4
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 4
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- 229940123237 Taxane Drugs 0.000 description 4
- 210000004241 Th2 cell Anatomy 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000013566 allergen Substances 0.000 description 4
- 229960000723 ampicillin Drugs 0.000 description 4
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 4
- 229930195731 calicheamicin Natural products 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000011712 cell development Effects 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 230000004940 costimulation Effects 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 4
- 210000003162 effector t lymphocyte Anatomy 0.000 description 4
- 229940031098 ethanolamine Drugs 0.000 description 4
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 230000035800 maturation Effects 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- 230000003076 paracrine Effects 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- 238000002823 phage display Methods 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 230000003248 secreting effect Effects 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 239000013589 supplement Substances 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 4
- 229960004528 vincristine Drugs 0.000 description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 4
- SCVHJVCATBPIHN-SJCJKPOMSA-N (3s)-3-[[(2s)-2-[[2-(2-tert-butylanilino)-2-oxoacetyl]amino]propanoyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid Chemical compound N([C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)COC=1C(=C(F)C=C(F)C=1F)F)C(=O)C(=O)NC1=CC=CC=C1C(C)(C)C SCVHJVCATBPIHN-SJCJKPOMSA-N 0.000 description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 230000003844 B-cell-activation Effects 0.000 description 3
- 235000014469 Bacillus subtilis Nutrition 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 208000014644 Brain disease Diseases 0.000 description 3
- 108010029697 CD40 Ligand Proteins 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 206010011968 Decreased immune responsiveness Diseases 0.000 description 3
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 3
- 208000032274 Encephalopathy Diseases 0.000 description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 102100029966 HLA class II histocompatibility antigen, DP alpha 1 chain Human genes 0.000 description 3
- 108091027305 Heteroduplex Proteins 0.000 description 3
- 101000864089 Homo sapiens HLA class II histocompatibility antigen, DP alpha 1 chain Proteins 0.000 description 3
- 101000930802 Homo sapiens HLA class II histocompatibility antigen, DQ alpha 1 chain Proteins 0.000 description 3
- 101000968032 Homo sapiens HLA class II histocompatibility antigen, DR beta 3 chain Proteins 0.000 description 3
- 101000764263 Homo sapiens Tumor necrosis factor ligand superfamily member 4 Proteins 0.000 description 3
- 101000638255 Homo sapiens Tumor necrosis factor ligand superfamily member 8 Proteins 0.000 description 3
- 101000648507 Homo sapiens Tumor necrosis factor receptor superfamily member 14 Proteins 0.000 description 3
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 3
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 3
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 3
- 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 3
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 3
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 3
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 3
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 102000003816 Interleukin-13 Human genes 0.000 description 3
- 108090000176 Interleukin-13 Proteins 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 102000015696 Interleukins Human genes 0.000 description 3
- 108010063738 Interleukins Proteins 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 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 3
- 239000004472 Lysine Substances 0.000 description 3
- 108010083674 Myelin Proteins Proteins 0.000 description 3
- 102000006386 Myelin Proteins Human genes 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 108091000054 Prion Proteins 0.000 description 3
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- 230000018199 S phase Effects 0.000 description 3
- 241000700584 Simplexvirus Species 0.000 description 3
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 3
- 230000024932 T cell mediated immunity Effects 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102100024586 Tumor necrosis factor ligand superfamily member 14 Human genes 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 3
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- ZVTDLPBHTSMEJZ-JSZLBQEHSA-N danoprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCC[C@@H](C(N1C[C@@H](C[C@H]1C(=O)N2)OC(=O)N1CC2=C(F)C=CC=C2C1)=O)NC(=O)OC(C)(C)C)NS(=O)(=O)C1CC1 ZVTDLPBHTSMEJZ-JSZLBQEHSA-N 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 229960003804 efavirenz Drugs 0.000 description 3
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 3
- 229950000234 emricasan Drugs 0.000 description 3
- 229960001904 epirubicin Drugs 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 229960002258 fulvestrant Drugs 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 239000003966 growth inhibitor Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000036737 immune function Effects 0.000 description 3
- 230000006058 immune tolerance Effects 0.000 description 3
- 239000012678 infectious agent Substances 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000007775 late Effects 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 3
- 210000005210 lymphoid organ Anatomy 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 210000005012 myelin Anatomy 0.000 description 3
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000007918 pathogenicity Effects 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 230000001124 posttranscriptional effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000009696 proliferative response Effects 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 208000035408 type 1 diabetes mellitus 1 Diseases 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
- 238000011144 upstream manufacturing Methods 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 3
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 2
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 2
- RCFNNLSZHVHCEK-IMHLAKCZSA-N (7s,9s)-7-(4-amino-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)C1CC([NH3+])CC(C)O1 RCFNNLSZHVHCEK-IMHLAKCZSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 description 2
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-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
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 2
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 2
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 2
- WRYLYDPHFGVWKC-UHFFFAOYSA-N 4-terpineol Chemical compound CC(C)C1(O)CCC(C)=CC1 WRYLYDPHFGVWKC-UHFFFAOYSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- 208000026872 Addison Disease Diseases 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 2
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 2
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 241000589968 Borrelia Species 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 102100038078 CD276 antigen Human genes 0.000 description 2
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 2
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- 241001478240 Coccus Species 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 2
- 206010010144 Completed suicide Diseases 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 102000004594 DNA Polymerase I Human genes 0.000 description 2
- 108010017826 DNA Polymerase I Proteins 0.000 description 2
- 108010041986 DNA Vaccines Proteins 0.000 description 2
- 229940021995 DNA vaccine Drugs 0.000 description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 101000867232 Escherichia coli Heat-stable enterotoxin II Proteins 0.000 description 2
- 241001524679 Escherichia virus M13 Species 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 101710195101 Flagellar filament outer layer protein Proteins 0.000 description 2
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- CATMPQFFVNKDEY-YPMHNXCESA-N Golotimod Chemical compound C1=CC=C2C(C[C@H](NC(=O)CC[C@@H](N)C(O)=O)C(O)=O)=CNC2=C1 CATMPQFFVNKDEY-YPMHNXCESA-N 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 2
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 2
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 2
- 101000840258 Homo sapiens Immunoglobulin J chain Proteins 0.000 description 2
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- 102100029571 Immunoglobulin J chain Human genes 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- 241000588748 Klebsiella Species 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 208000032420 Latent Infection Diseases 0.000 description 2
- 241000222722 Leishmania <genus> Species 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 241000186781 Listeria Species 0.000 description 2
- 239000006137 Luria-Bertani broth Substances 0.000 description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- 208000016604 Lyme disease Diseases 0.000 description 2
- 230000027311 M phase Effects 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- NBGXQZRRLOGAJF-UHFFFAOYSA-N Maltulose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)(CO)OCC1O NBGXQZRRLOGAJF-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 101000956000 Mus musculus V-set domain containing T-cell activation inhibitor 1 Proteins 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 241000282943 Odocoileus Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241001057811 Paracoccus <mealybug> Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 208000031845 Pernicious anaemia Diseases 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- 241000276498 Pollachius virens Species 0.000 description 2
- 102000029797 Prion Human genes 0.000 description 2
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 2
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- 241000242678 Schistosoma Species 0.000 description 2
- 241000607720 Serratia Species 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 241000607768 Shigella Species 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000037453 T cell priming Effects 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- 241000244155 Taenia Species 0.000 description 2
- 102000011923 Thyrotropin Human genes 0.000 description 2
- 108010061174 Thyrotropin Proteins 0.000 description 2
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 2
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 2
- 241000223996 Toxoplasma Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 241000223104 Trypanosoma Species 0.000 description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- HTJGLYIJVSDQAE-VWNXEWBOSA-N [(1s,6s,7s,8r,8ar)-1,7,8-trihydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl] butanoate Chemical compound O[C@H]1[C@H](O)[C@@H](OC(=O)CCC)CN2CC[C@H](O)[C@@H]21 HTJGLYIJVSDQAE-VWNXEWBOSA-N 0.000 description 2
- XZSRRNFBEIOBDA-CFNBKWCHSA-N [2-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 2,2-diethoxyacetate Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)C(OCC)OCC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 XZSRRNFBEIOBDA-CFNBKWCHSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- 229960003204 amorolfine Drugs 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 230000000842 anti-protozoal effect Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 229940046844 aromatase inhibitors Drugs 0.000 description 2
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 2
- 229960002521 artenimol Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 229960002118 asunaprevir Drugs 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- 230000003305 autocrine Effects 0.000 description 2
- 230000008003 autocrine effect Effects 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 239000008228 bacteriostatic water for injection Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- QZPQTZZNNJUOLS-UHFFFAOYSA-N beta-lapachone Chemical compound C12=CC=CC=C2C(=O)C(=O)C2=C1OC(C)(C)CC2 QZPQTZZNNJUOLS-UHFFFAOYSA-N 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
- 229960003237 betaine Drugs 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 229960000517 boceprevir Drugs 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 108700002839 cactinomycin Proteins 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229960003261 carmofur Drugs 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 108010047060 carzinophilin Proteins 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 229960001139 cefazolin Drugs 0.000 description 2
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 2
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 2
- 229960004069 cefditoren Drugs 0.000 description 2
- 229960004755 ceftriaxone Drugs 0.000 description 2
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000006369 cell cycle progression Effects 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 2
- 208000017580 chronic wasting disease Diseases 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229960002227 clindamycin Drugs 0.000 description 2
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 2
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 2
- 229940047766 co-trimoxazole Drugs 0.000 description 2
- 230000024203 complement activation Effects 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- COFJBSXICYYSKG-OAUVCNBTSA-N cph2u7dndy Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 COFJBSXICYYSKG-OAUVCNBTSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960005449 daclatasvir Drugs 0.000 description 2
- FKRSSPOQAMALKA-CUPIEXAXSA-N daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229940099385 daraprim Drugs 0.000 description 2
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 229950003913 detorubicin Drugs 0.000 description 2
- 229960002656 didanosine Drugs 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 229960002759 eflornithine Drugs 0.000 description 2
- 229960000366 emtricitabine Drugs 0.000 description 2
- QDGZDCVAUDNJFG-FXQIFTODSA-N entecavir (anhydrous) Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)C1=C QDGZDCVAUDNJFG-FXQIFTODSA-N 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- SLVAPEZTBDBAPI-GDLZYMKVSA-N filibuvir Chemical compound CCC1=NC(CC)=CC(CC[C@]2(OC(=O)C(CC3=NN4C(C)=CC(C)=NC4=N3)=C(O)C2)C2CCCC2)=C1 SLVAPEZTBDBAPI-GDLZYMKVSA-N 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 238000010230 functional analysis Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 229960001625 furazolidone Drugs 0.000 description 2
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- 230000012178 germinal center formation Effects 0.000 description 2
- 230000002518 glial effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 229960004275 glycolic acid Drugs 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 108010049353 golotimod Proteins 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 230000004727 humoral immunity Effects 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 230000016784 immunoglobulin production Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 108091008042 inhibitory receptors Proteins 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940124524 integrase inhibitor Drugs 0.000 description 2
- 239000002850 integrase inhibitor Substances 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 230000031261 interleukin-10 production Effects 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 description 2
- 229960000788 isavuconazole Drugs 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 206010023497 kuru Diseases 0.000 description 2
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 2
- 229960000511 lactulose Drugs 0.000 description 2
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- CIEYTVIYYGTCCI-UHFFFAOYSA-N lapachol Chemical compound C1=CC=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1 CIEYTVIYYGTCCI-UHFFFAOYSA-N 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 229960000681 leflunomide Drugs 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 229940040129 luteinizing hormone Drugs 0.000 description 2
- 210000003563 lymphoid tissue Anatomy 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- JCQLYHFGKNRPGE-HFZVAGMNSA-N maltulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-HFZVAGMNSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- 229960001962 mefloquine Drugs 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 2
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 2
- 229960004313 naftifine Drugs 0.000 description 2
- RICZEKWVNZFTNZ-LFGITCQGSA-N narlaprevir Chemical compound N([C@H](C(=O)N1C[C@H]2[C@H](C2(C)C)[C@H]1C(=O)N[C@@H](CCCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C(=O)NC1(CS(=O)(=O)C(C)(C)C)CCCCC1 RICZEKWVNZFTNZ-LFGITCQGSA-N 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- 108010068617 neonatal Fc receptor Proteins 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 210000004967 non-hematopoietic stem cell Anatomy 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 210000004789 organ system Anatomy 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 208000014837 parasitic helminthiasis infectious disease Diseases 0.000 description 2
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 2
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 229960001539 poliomyelitis vaccine Drugs 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 210000004986 primary T-cell Anatomy 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 229960000611 pyrimethamine Drugs 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000003289 regulatory T cell Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 2
- FGHMGRXAHIXTBM-TWFJNEQDSA-N s-[2-[[(2r,3r,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-(benzylamino)phosphoryl]oxyethyl] 3-hydroxy-2,2-dimethylpropanethioate Chemical compound C([C@@H]1[C@H]([C@@](C)(O)[C@H](N2C3=C(C(NC(N)=N3)=O)N=C2)O1)O)OP(=O)(OCCSC(=O)C(C)(CO)C)NCC1=CC=CC=C1 FGHMGRXAHIXTBM-TWFJNEQDSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 2
- 208000008864 scrapie Diseases 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 229960002091 simeprevir Drugs 0.000 description 2
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- SSERCMQZZYTNBY-UHFFFAOYSA-M sodium;3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylate Chemical compound [Na+].C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C([O-])=O)C1CCC(O)CC1 SSERCMQZZYTNBY-UHFFFAOYSA-M 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 2
- 229950006081 taribavirin Drugs 0.000 description 2
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 2
- 229940063683 taxotere Drugs 0.000 description 2
- 239000010677 tea tree oil Substances 0.000 description 2
- 229940111630 tea tree oil Drugs 0.000 description 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 2
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 206010043778 thyroiditis Diseases 0.000 description 2
- 229960005053 tinidazole Drugs 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 208000037956 transmissible mink encephalopathy Diseases 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 2
- 229950009268 zinostatin Drugs 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- UBWXUGDQUBIEIZ-UHFFFAOYSA-N (13-methyl-3-oxo-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl) 3-phenylpropanoate Chemical compound CC12CCC(C3CCC(=O)C=C3CC3)C3C1CCC2OC(=O)CCC1=CC=CC=C1 UBWXUGDQUBIEIZ-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- RNEACARJKXYVND-KQGZCTBQSA-N (2r)-2-[[(5z)-5-[(5-ethylfuran-2-yl)methylidene]-4-oxo-1,3-thiazol-2-yl]amino]-2-(4-fluorophenyl)acetic acid Chemical compound O1C(CC)=CC=C1\C=C/1C(=O)N=C(N[C@@H](C(O)=O)C=2C=CC(F)=CC=2)S\1 RNEACARJKXYVND-KQGZCTBQSA-N 0.000 description 1
- IRZRJANZDIOOIF-GAJNKVMBSA-N (2r,3r,4r,5r)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methyloxolane-3,4-diol Chemical compound C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(N)=C2C=C1 IRZRJANZDIOOIF-GAJNKVMBSA-N 0.000 description 1
- CIDUJQMULVCIBT-MQDUPKMGSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4-amino-3-[[(2s,3r)-3-amino-6-(aminomethyl)-3,4-dihydro-2h-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1OC(CN)=CC[C@H]1N CIDUJQMULVCIBT-MQDUPKMGSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- HLQXYDHLDZTWDW-KAWPREARSA-N (2r,4s,5r)-1-(4-tert-butyl-3-methoxybenzoyl)-4-(methoxymethyl)-2-(pyrazol-1-ylmethyl)-5-(1,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid Chemical compound C([C@]1(C[C@@H]([C@@H](N1C(=O)C=1C=C(OC)C(=CC=1)C(C)(C)C)C=1SC=CN=1)COC)C(O)=O)N1C=CC=N1 HLQXYDHLDZTWDW-KAWPREARSA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- HLQXYDHLDZTWDW-JCWFFFCVSA-N (2s,4r,5s)-1-(4-tert-butyl-3-methoxybenzoyl)-4-(methoxymethyl)-2-(pyrazol-1-ylmethyl)-5-(1,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid Chemical compound C([C@@]1(C[C@H]([C@H](N1C(=O)C=1C=C(OC)C(=CC=1)C(C)(C)C)C=1SC=CN=1)COC)C(O)=O)N1C=CC=N1 HLQXYDHLDZTWDW-JCWFFFCVSA-N 0.000 description 1
- KWMLJOLKUYYJFJ-GASJEMHNSA-N (2xi)-D-gluco-heptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C(O)=O KWMLJOLKUYYJFJ-GASJEMHNSA-N 0.000 description 1
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 1
- XUHRVZXFBWDCFB-QRTDKPMLSA-N (3R)-4-[[(3S,6S,9S,12R,15S,18R,21R,24R,27R,28R)-12-(3-amino-3-oxopropyl)-6-[(2S)-butan-2-yl]-3-(2-carboxyethyl)-18-(hydroxymethyl)-28-methyl-9,15,21,24-tetrakis(2-methylpropyl)-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octazacyclooctacos-27-yl]amino]-3-[[(2R)-2-[[(3S)-3-hydroxydecanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoic acid Chemical compound CCCCCCC[C@H](O)CC(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H]1[C@@H](C)OC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CO)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC1=O)[C@@H](C)CC XUHRVZXFBWDCFB-QRTDKPMLSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 1
- GPYKKBAAPVOCIW-HSASPSRMSA-N (6r,7s)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 GPYKKBAAPVOCIW-HSASPSRMSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- AESVUZLWRXEGEX-DKCAWCKPSA-N (7S,9R)-7-[(2S,4R,5R,6R)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione iron(3+) Chemical compound [Fe+3].COc1cccc2C(=O)c3c(O)c4C[C@@](O)(C[C@H](O[C@@H]5C[C@@H](N)[C@@H](O)[C@@H](C)O5)c4c(O)c3C(=O)c12)C(=O)CO AESVUZLWRXEGEX-DKCAWCKPSA-N 0.000 description 1
- YQUCBFIQSJVCOR-JOCHJYFZSA-N (7r)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)amino}-7,8-dihydro-6h-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid Chemical compound C([C@@H](CN1C2=CC(=CC=C22)C(O)=O)N(C)CCN(C)C)OC3=CC=CC=C3C1=C2C1CCCCC1 YQUCBFIQSJVCOR-JOCHJYFZSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- JBSNALXXNTWUEC-SFQUDFHCSA-N (e)-3-[4-[[1-[(3-cyclopentyl-1-methyl-2-pyridin-2-ylindole-6-carbonyl)amino]cyclobutanecarbonyl]amino]phenyl]prop-2-enoic acid Chemical compound C12=CC=C(C(=O)NC3(CCC3)C(=O)NC=3C=CC(\C=C\C(O)=O)=CC=3)C=C2N(C)C(C=2N=CC=CC=2)=C1C1CCCC1 JBSNALXXNTWUEC-SFQUDFHCSA-N 0.000 description 1
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- KPQZUUQMTUIKBP-UHFFFAOYSA-N 1-(2-methyl-5-nitro-1-imidazolyl)-2-propanol Chemical compound CC(O)CN1C(C)=NC=C1[N+]([O-])=O KPQZUUQMTUIKBP-UHFFFAOYSA-N 0.000 description 1
- XXFQZUDIYOPKJR-UHFFFAOYSA-N 1-(3,3-dibromopropyl)piperazine Chemical compound BrC(CCN1CCNCC1)Br XXFQZUDIYOPKJR-UHFFFAOYSA-N 0.000 description 1
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 1
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 1
- PXZDLINBBKAIPK-UHFFFAOYSA-N 1-ethyl-6-fluoro-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 PXZDLINBBKAIPK-UHFFFAOYSA-N 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- OIIMUKXVVLRCAF-UHFFFAOYSA-N 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl-triphenylphosphanium Chemical compound O=C1C(OC)=C(OC)C(=O)C(CCCCCCCCCC[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1C OIIMUKXVVLRCAF-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- YFXGICNMLCGLHJ-RSKRLRQZSA-N 2,2-dimethylpropyl (2s)-2-[[[(2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate Chemical compound C1=CC=C2C(OP(=O)(N[C@@H](C)C(=O)OCC(C)(C)C)OC[C@H]3O[C@H]([C@]([C@@H]3O)(C)O)N3C=4N=C(N)N=C(C=4N=C3)OC)=CC=CC2=C1 YFXGICNMLCGLHJ-RSKRLRQZSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- XMTQQYYKAHVGBJ-UHFFFAOYSA-N 3-(3,4-DICHLOROPHENYL)-1,1-DIMETHYLUREA Chemical compound CN(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XMTQQYYKAHVGBJ-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 1
- CKVYPTIWERNFSU-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CCC(O)CC1 CKVYPTIWERNFSU-UHFFFAOYSA-N 0.000 description 1
- OJDZHBWEGLIKRW-UHFFFAOYSA-N 3-[(4-hydroxyphenyl)methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CC=2C=CC(O)=CC=2)=C1 OJDZHBWEGLIKRW-UHFFFAOYSA-N 0.000 description 1
- RZXQBIKGWSLVEK-UHFFFAOYSA-N 3-[(4-methylcyclohexanecarbonyl)-propan-2-ylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1CCC(C)CC1 RZXQBIKGWSLVEK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- WRYLYDPHFGVWKC-SNVBAGLBSA-N 4-Terpineol Natural products CC(C)[C@]1(O)CCC(C)=CC1 WRYLYDPHFGVWKC-SNVBAGLBSA-N 0.000 description 1
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- ROSNVSQTEGHUKU-UHFFFAOYSA-N 4-[4-(4-chloro-phenoxy)-benzenesulfonylmethyl]-tetrahydro-pyran-4-carboxylic acid hydroxyamide Chemical compound C=1C=C(OC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)CC1(C(=O)NO)CCOCC1 ROSNVSQTEGHUKU-UHFFFAOYSA-N 0.000 description 1
- YLDCUKJMEKGGFI-QCSRICIXSA-N 4-acetamidobenzoic acid;9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one;1-(dimethylamino)propan-2-ol Chemical compound CC(O)CN(C)C.CC(O)CN(C)C.CC(O)CN(C)C.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.CC(=O)NC1=CC=C(C(O)=O)C=C1.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC=NC2=O)=C2N=C1 YLDCUKJMEKGGFI-QCSRICIXSA-N 0.000 description 1
- LHCOVOKZWQYODM-CPEOKENHSA-N 4-amino-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;1-[(2r,4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1.O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 LHCOVOKZWQYODM-CPEOKENHSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- WPMJNLCLKAKMLA-UHFFFAOYSA-N 5-(3,3-dimethylbut-1-ynyl)-3-[(4-hydroxycyclohexyl)-[(4-methylcyclohexyl)-oxomethyl]amino]-2-thiophenecarboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C#CC(C)(C)C)C(O)=O)C1CCC(O)CC1 WPMJNLCLKAKMLA-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- TZYVRXZQAWPIAB-FCLHUMLKSA-N 5-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4h-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound O=C1SC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O TZYVRXZQAWPIAB-FCLHUMLKSA-N 0.000 description 1
- GJOHLWZHWQUKAU-UHFFFAOYSA-N 5-azaniumylpentan-2-yl-(6-methoxyquinolin-8-yl)azanium;dihydrogen phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 GJOHLWZHWQUKAU-UHFFFAOYSA-N 0.000 description 1
- WTDWVLJJJOTABN-UHFFFAOYSA-N 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-n-methyl-1-benzofuran-3-carboxamide Chemical compound C1=C2C(C(=O)NC)=C(C=3C=CC(F)=CC=3)OC2=CC(N(CCO)S(C)(=O)=O)=C1C1CC1 WTDWVLJJJOTABN-UHFFFAOYSA-N 0.000 description 1
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- UPPWMBQIDFTBEQ-UHFFFAOYSA-N 6-(3,4-dimethoxyphenyl)-n-[4-(1,2,4-triazol-1-yl)phenyl]quinazolin-4-amine Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(=CC=3)N3N=CN=C3)C2=C1 UPPWMBQIDFTBEQ-UHFFFAOYSA-N 0.000 description 1
- PVXPPJIGRGXGCY-TZLCEDOOSA-N 6-O-alpha-D-glucopyranosyl-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)C(O)(CO)O1 PVXPPJIGRGXGCY-TZLCEDOOSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010059616 Activins Proteins 0.000 description 1
- 102000005606 Activins Human genes 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 230000007730 Akt signaling Effects 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000282979 Alces alces Species 0.000 description 1
- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 1
- 102100034452 Alternative prion protein Human genes 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 108010064760 Anidulafungin Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 241000203069 Archaea Species 0.000 description 1
- 208000002109 Argyria Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 102000005738 B7 Antigens Human genes 0.000 description 1
- 108010045634 B7 Antigens Proteins 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 108010062877 Bacteriocins Proteins 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- GWZYPXHJIZCRAJ-UHFFFAOYSA-N Biliverdin Natural products CC1=C(C=C)C(=C/C2=NC(=Cc3[nH]c(C=C/4NC(=O)C(=C4C)C=C)c(C)c3CCC(=O)O)C(=C2C)CCC(=O)O)NC1=O GWZYPXHJIZCRAJ-UHFFFAOYSA-N 0.000 description 1
- RCNSAJSGRJSBKK-NSQVQWHSSA-N Biliverdin IX Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(\C=C/2C(=C(C)C(=C/C=3C(=C(C=C)C(=O)N=3)C)/N\2)CCC(O)=O)N1 RCNSAJSGRJSBKK-NSQVQWHSSA-N 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010005098 Blastomycosis Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108700031361 Brachyury Proteins 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 102100026008 Breakpoint cluster region protein Human genes 0.000 description 1
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- PYMDEDHDQYLBRT-DRIHCAFSSA-N Buserelin acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 PYMDEDHDQYLBRT-DRIHCAFSSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010020326 Caspofungin Proteins 0.000 description 1
- JDVVGAQPNNXQDW-WCMLQCRESA-N Castanospermine Natural products O[C@H]1[C@@H](O)[C@H]2[C@@H](O)CCN2C[C@H]1O JDVVGAQPNNXQDW-WCMLQCRESA-N 0.000 description 1
- JDVVGAQPNNXQDW-TVNFTVLESA-N Castinospermine Chemical compound C1[C@H](O)[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21 JDVVGAQPNNXQDW-TVNFTVLESA-N 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 description 1
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 108091028075 Circular RNA Proteins 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- 241000223205 Coccidioides immitis Species 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 108020004394 Complementary RNA Proteins 0.000 description 1
- 108010060123 Conjugate Vaccines Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 108010091326 Cryoglobulins Proteins 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010072220 Cyclophilin A Proteins 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical class CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 240000004784 Cymbopogon citratus Species 0.000 description 1
- 235000017897 Cymbopogon citratus Nutrition 0.000 description 1
- 201000003808 Cystic echinococcosis Diseases 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
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 108010049047 Echinocandins Proteins 0.000 description 1
- 208000009366 Echinococcosis Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- MBYXEBXZARTUSS-QLWBXOBMSA-N Emetamine Natural products O(C)c1c(OC)cc2c(c(C[C@@H]3[C@H](CC)CN4[C@H](c5c(cc(OC)c(OC)c5)CC4)C3)ncc2)c1 MBYXEBXZARTUSS-QLWBXOBMSA-N 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- AFMYMMXSQGUCBK-UHFFFAOYSA-N Endynamicin A Natural products C1#CC=CC#CC2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3C34OC32C(C)C(C(O)=O)=C(OC)C41 AFMYMMXSQGUCBK-UHFFFAOYSA-N 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241001522878 Escherichia coli B Species 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 206010051841 Exposure to allergen Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000006353 Filariasis Diseases 0.000 description 1
- 229930183931 Filipin Natural products 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- 230000035519 G0 Phase Effects 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 230000037057 G1 phase arrest Effects 0.000 description 1
- 229940124897 Gardasil Drugs 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- LLEUXCDZPQOJMY-AAEUAGOBSA-N Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(O)=O)=CNC2=C1 LLEUXCDZPQOJMY-AAEUAGOBSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 229940124683 HCV polymerase inhibitor Drugs 0.000 description 1
- 229940122604 HCV protease inhibitor Drugs 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 108010051539 HLA-DR2 Antigen Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 101100508941 Halobacterium salinarum (strain ATCC 700922 / JCM 11081 / NRC-1) ppa gene Proteins 0.000 description 1
- FOHHNHSLJDZUGQ-VWLOTQADSA-N Halofantrine Chemical compound FC(F)(F)C1=CC=C2C([C@@H](O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-VWLOTQADSA-N 0.000 description 1
- CTETYYAZBPJBHE-UHFFFAOYSA-N Haloprogin Chemical compound ClC1=CC(Cl)=C(OCC#CI)C=C1Cl CTETYYAZBPJBHE-UHFFFAOYSA-N 0.000 description 1
- 208000016621 Hearing disease Diseases 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 208000006968 Helminthiasis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- 241000228404 Histoplasma capsulatum Species 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101100046560 Homo sapiens TNFRSF14 gene Proteins 0.000 description 1
- 101100370001 Homo sapiens TNFSF14 gene Proteins 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 101710093458 ICOS ligand Proteins 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000027601 Inner ear disease Diseases 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 108010041012 Integrin alpha4 Proteins 0.000 description 1
- 102100025304 Integrin beta-1 Human genes 0.000 description 1
- 108010005714 Interferon beta-1b Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102100039897 Interleukin-5 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 102100021592 Interleukin-7 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 102000000585 Interleukin-9 Human genes 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- 241000274177 Juniperus sabina Species 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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 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 1
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- JLERVPBPJHKRBJ-UHFFFAOYSA-N LY 117018 Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2S1 JLERVPBPJHKRBJ-UHFFFAOYSA-N 0.000 description 1
- 208000017119 Labyrinth disease Diseases 0.000 description 1
- 235000019687 Lamb Nutrition 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- MEPSBMMZQBMKHM-UHFFFAOYSA-N Lomatiol Natural products CC(=C/CC1=C(O)C(=O)c2ccccc2C1=O)CO MEPSBMMZQBMKHM-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000018170 Lymphotoxin beta Receptor Human genes 0.000 description 1
- 108010091221 Lymphotoxin beta Receptor Proteins 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 description 1
- TYMRLRRVMHJFTF-UHFFFAOYSA-N Mafenide Chemical compound NCC1=CC=C(S(N)(=O)=O)C=C1 TYMRLRRVMHJFTF-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- JCYZMTMYPZHVBF-UHFFFAOYSA-N Melarsoprol Chemical compound NC1=NC(N)=NC(NC=2C=CC(=CC=2)[As]2SC(CO)CS2)=N1 JCYZMTMYPZHVBF-UHFFFAOYSA-N 0.000 description 1
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 108010021062 Micafungin Proteins 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 241000243190 Microsporidia Species 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100515942 Mus musculus Nbl1 gene Proteins 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 1
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 1
- 240000005125 Myrtus communis Species 0.000 description 1
- 235000013418 Myrtus communis Nutrition 0.000 description 1
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 150000008522 N-ethylpiperidines Chemical class 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- OLUNPKFOFGZHRT-YGCVIUNWSA-N Naftifine hydrochloride Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OLUNPKFOFGZHRT-YGCVIUNWSA-N 0.000 description 1
- 241001481166 Nautilus Species 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 101100407828 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) ptr-3 gene Proteins 0.000 description 1
- ARFHIAQFJWUCFH-IZZDOVSWSA-N Nifurtimox Chemical compound CC1CS(=O)(=O)CCN1\N=C\C1=CC=C([N+]([O-])=O)O1 ARFHIAQFJWUCFH-IZZDOVSWSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 241000192656 Nostoc Species 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- QGXUNAZXHWLKFM-SJIDISLESA-N OC(=O)\C=C\C(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O Chemical compound OC(=O)\C=C\C(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O QGXUNAZXHWLKFM-SJIDISLESA-N 0.000 description 1
- 108010079246 OMPA outer membrane proteins Proteins 0.000 description 1
- 102000004473 OX40 Ligand Human genes 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 208000005225 Opsoclonus-Myoclonus Syndrome Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 241000609499 Palicourea Species 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 208000005155 Picornaviridae Infections Diseases 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 108010003044 Placental Lactogen Proteins 0.000 description 1
- 239000000381 Placental Lactogen Substances 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 241000233872 Pneumocystis carinii Species 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000677647 Proba Species 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 101710109947 Protein kinase C alpha type Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 229940122277 RNA polymerase inhibitor Drugs 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108090000103 Relaxin Proteins 0.000 description 1
- 102000003743 Relaxin Human genes 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 241000589180 Rhizobium Species 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- AWGBZRVEGDNLDZ-UHFFFAOYSA-N Rimocidin Natural products C1C(C(C(O)C2)C(O)=O)OC2(O)CC(O)CCCC(=O)CC(O)C(CC)C(=O)OC(CCC)CC=CC=CC=CC=CC1OC1OC(C)C(O)C(N)C1O AWGBZRVEGDNLDZ-UHFFFAOYSA-N 0.000 description 1
- AWGBZRVEGDNLDZ-JCUCCFEFSA-N Rimocidine Chemical compound O([C@H]1/C=C/C=C/C=C/C=C/C[C@H](OC(=O)[C@@H](CC)[C@H](O)CC(=O)CCC[C@H](O)C[C@@]2(O)O[C@H]([C@@H]([C@@H](O)C2)C(O)=O)C1)CCC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O AWGBZRVEGDNLDZ-JCUCCFEFSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- NSFWWJIQIKBZMJ-YKNYLIOZSA-N Roridin A Chemical compound C([C@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-YKNYLIOZSA-N 0.000 description 1
- AUVVAXYIELKVAI-UHFFFAOYSA-N SJ000285215 Natural products N1CCC2=CC(OC)=C(OC)C=C2C1CC1CC2C3=CC(OC)=C(OC)C=C3CCN2CC1CC AUVVAXYIELKVAI-UHFFFAOYSA-N 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 108091060271 Small temporal RNA Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- MHFMTUBUVQZIRE-WINRQGAFSA-N Sovaprevir Chemical compound C([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C=C2N=C(C=1)C=1C=CC=CC=1)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(=O)NS(=O)(=O)C1CC1)C(C)(C)C)C(=O)N1CCCCC1 MHFMTUBUVQZIRE-WINRQGAFSA-N 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010042254 Strongyloidiasis Diseases 0.000 description 1
- 241000272534 Struthio camelus Species 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
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 1
- 230000020385 T cell costimulation Effects 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 108010092262 T-Cell Antigen Receptors Proteins 0.000 description 1
- 208000037913 T-cell disorder Diseases 0.000 description 1
- 102000003714 TNF receptor-associated factor 6 Human genes 0.000 description 1
- 108090000009 TNF receptor-associated factor 6 Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 108010053950 Teicoplanin Proteins 0.000 description 1
- 102100024547 Tensin-1 Human genes 0.000 description 1
- 108010088950 Tensins Proteins 0.000 description 1
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 238000012338 Therapeutic targeting Methods 0.000 description 1
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 1
- 201000007023 Thrombotic Thrombocytopenic Purpura Diseases 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 208000027515 Tracheal disease Diseases 0.000 description 1
- 241000933173 Tragelaphus angasii Species 0.000 description 1
- 241000283904 Tragelaphus strepsiceros Species 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 208000003441 Transfusion reaction Diseases 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 241000242541 Trematoda Species 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 206010044608 Trichiniasis Diseases 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108010065158 Tumor Necrosis Factor Ligand Superfamily Member 14 Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 241000863000 Vitreoscilla Species 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 238000012452 Xenomouse strains Methods 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 1
- ZWELIJXAKMASLK-UGKPPGOTSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(=O)C)[C@@H](CO)O[C@H]1N1C(=O)SC2=CN=C(N)N=C21 ZWELIJXAKMASLK-UGKPPGOTSA-N 0.000 description 1
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- WWXBHTZSYYGCSG-UHFFFAOYSA-N [4-(carbamoylamino)phenyl]arsonic acid Chemical compound NC(=O)NC1=CC=C([As](O)(O)=O)C=C1 WWXBHTZSYYGCSG-UHFFFAOYSA-N 0.000 description 1
- CGZHFISPYUSNJI-QLERUFQFSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1.[C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1 Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1.[C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1 CGZHFISPYUSNJI-QLERUFQFSA-N 0.000 description 1
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Chemical compound CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000488 activin Substances 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000009824 affinity maturation Effects 0.000 description 1
- 229940026131 aftate Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 108010080374 albuferon Proteins 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 108010058359 alisporivir Proteins 0.000 description 1
- 125000006177 alkyl benzyl group Chemical group 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000000961 alloantigen Effects 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- LHAOFBCHXGZGOR-NAVBLJQLSA-N alpha-D-Manp-(1->3)-alpha-D-Manp-(1->2)-alpha-D-Manp Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1 LHAOFBCHXGZGOR-NAVBLJQLSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 229960003348 anidulafungin Drugs 0.000 description 1
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000708 anti-progestin effect Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 229940030139 aptivus Drugs 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 229960000981 artemether Drugs 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 description 1
- 229960002970 artemotil Drugs 0.000 description 1
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 1
- 229960004991 artesunate Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 201000009361 ascariasis Diseases 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
- 229960003277 atazanavir Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229940068561 atripla Drugs 0.000 description 1
- 201000005000 autoimmune gastritis Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 229940002637 baraclude Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- ZTTKEBYSXUCBSE-QDFUAKMASA-N beclabuvir Chemical compound C1([C@@H]2C[C@@]2(CN2C3=CC(=CC=C33)C(=O)NS(=O)(=O)N(C)C)C(=O)N4[C@@H]5CC[C@H]4CN(C)C5)=CC(OC)=CC=C1C2=C3C1CCCCC1 ZTTKEBYSXUCBSE-QDFUAKMASA-N 0.000 description 1
- 229950010541 beclabuvir Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 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
- 229940021459 betaseron Drugs 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- YJEJKUQEXFSVCJ-WRFMNRASSA-N bevirimat Chemical compound C1C[C@H](OC(=O)CC(C)(C)C(O)=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C YJEJKUQEXFSVCJ-WRFMNRASSA-N 0.000 description 1
- 229950002892 bevirimat Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- QBUVFDKTZJNUPP-UHFFFAOYSA-N biliverdin-IXalpha Natural products N1C(=O)C(C)=C(C=C)C1=CC1=C(C)C(CCC(O)=O)=C(C=C2C(=C(C)C(C=C3C(=C(C=C)C(=O)N3)C)=N2)CCC(O)=O)N1 QBUVFDKTZJNUPP-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 229960001169 brivudine Drugs 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 229950008349 buparvaquone Drugs 0.000 description 1
- 229960005064 buserelin acetate Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229960002962 butenafine Drugs 0.000 description 1
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 description 1
- LJBSAUIFGPSHCN-UHFFFAOYSA-N butenafine hydrochloride Chemical compound [Cl-].C=1C=CC2=CC=CC=C2C=1C[NH+](C)CC1=CC=C(C(C)(C)C)C=C1 LJBSAUIFGPSHCN-UHFFFAOYSA-N 0.000 description 1
- 229960005074 butoconazole Drugs 0.000 description 1
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 1
- PPKJUHVNTMYXOD-PZGPJMECSA-N c49ws9n75l Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1.N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O PPKJUHVNTMYXOD-PZGPJMECSA-N 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229950000776 carbarsone Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 229960003034 caspofungin Drugs 0.000 description 1
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-O cefepime(1+) Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-O 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- 229960002580 cefprozil Drugs 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 description 1
- 229960004086 ceftibuten Drugs 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- VOAZJEPQLGBXGO-SDAWRPRTSA-N ceftobiprole Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(\C=C/4C(N([C@H]5CNCC5)CC\4)=O)CS[C@@H]32)C(O)=O)=O)=N1 VOAZJEPQLGBXGO-SDAWRPRTSA-N 0.000 description 1
- 229950004259 ceftobiprole Drugs 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229950003414 celgosivir Drugs 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 230000008614 cellular interaction 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
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 1
- KLLIVCPQDTYMLC-HDJSIYSDSA-N chembl292009 Chemical compound C1C[C@@H](C(C)(C)C)CC[C@@H]1CC1=C(O)C(=O)C2=CC=CC=C2C1=O KLLIVCPQDTYMLC-HDJSIYSDSA-N 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229950008249 chlornaphazine Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- RMXVHZFHSKRNJN-UHFFFAOYSA-N chlorourea Chemical compound NC(=O)NCl RMXVHZFHSKRNJN-UHFFFAOYSA-N 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- PJZPDFUUXKKDNB-KNINVFKUSA-N ciluprevir Chemical compound N([C@@H]1C(=O)N2[C@H](C(N[C@@]3(C[C@H]3\C=C/CCCCC1)C(O)=O)=O)C[C@H](C2)OC=1C2=CC=C(C=C2N=C(C=1)C=1N=C(NC(C)C)SC=1)OC)C(=O)OC1CCCC1 PJZPDFUUXKKDNB-KNINVFKUSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000010632 citronella oil Substances 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 1
- 238000013377 clone selection method Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940014461 combivir Drugs 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 229940031670 conjugate vaccine Drugs 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 235000021019 cranberries Nutrition 0.000 description 1
- 229940088900 crixivan Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ZXJXZNDDNMQXFV-UHFFFAOYSA-M crystal violet Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1[C+](C=1C=CC(=CC=1)N(C)C)C1=CC=C(N(C)C)C=C1 ZXJXZNDDNMQXFV-UHFFFAOYSA-M 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000001939 cymbopogon martini roxb. stapf. oil Substances 0.000 description 1
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 1
- 229940099500 cystamine Drugs 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229940087451 cytovene Drugs 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- SUYVUBYJARFZHO-UHFFFAOYSA-N dATP Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-UHFFFAOYSA-N 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- 229960001418 dasabuvir Drugs 0.000 description 1
- NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- BMAIGAHXAJEULY-UKTHLTGXSA-N deleobuvir Chemical compound C12=CC=C(C(=O)NC3(CCC3)C=3N(C4=CC(\C=C\C(O)=O)=CC=C4N=3)C)C=C2N(C)C(C=2N=CC(Br)=CN=2)=C1C1CCCC1 BMAIGAHXAJEULY-UKTHLTGXSA-N 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 229940075968 desenex Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- 229930016266 dihydroartemisinin Natural products 0.000 description 1
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 229940042397 direct acting antivirals cyclic amines Drugs 0.000 description 1
- WLOHNSSYAXHWNR-DWIOZXRMSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-DWIOZXRMSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- VHJLVAABSRFDPM-ZXZARUISSA-N dithioerythritol Chemical compound SC[C@H](O)[C@H](O)CS VHJLVAABSRFDPM-ZXZARUISSA-N 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- AFMYMMXSQGUCBK-AKMKHHNQSA-N dynemicin a Chemical compound C1#C\C=C/C#C[C@@H]2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3[C@@]34O[C@]32[C@@H](C)C(C(O)=O)=C(OC)[C@H]41 AFMYMMXSQGUCBK-AKMKHHNQSA-N 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229960002030 edoxudine Drugs 0.000 description 1
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- AUVVAXYIELKVAI-CKBKHPSWSA-N emetine Chemical compound N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC AUVVAXYIELKVAI-CKBKHPSWSA-N 0.000 description 1
- 229960002694 emetine Drugs 0.000 description 1
- AUVVAXYIELKVAI-UWBTVBNJSA-N emetine Natural products N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@H]1CC AUVVAXYIELKVAI-UWBTVBNJSA-N 0.000 description 1
- 229940001018 emtriva Drugs 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 229960002062 enfuvirtide Drugs 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010213 eniluracil Drugs 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 229940072253 epivir Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229940041693 ertaczo Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
- 235000020774 essential nutrients Nutrition 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- QCYAXXZCQKMTMO-QFIPXVFZSA-N ethyl (2s)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]propanoate Chemical compound N([C@@H](CC=1C=CC(NC=2C3=CN=CC=C3C=CN=2)=CC=1)C(=O)OCC)C1=C(Br)C(=O)C11CCCCC1 QCYAXXZCQKMTMO-QFIPXVFZSA-N 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960002049 etravirine Drugs 0.000 description 1
- 229940085363 evista Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 108010052305 exodeoxyribonuclease III Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- LLGDPTDZOVKFDU-XUHJSTDZSA-N faldaprevir Chemical compound N([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1N=C(NC(=O)C(C)C)SC=1)Br)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(O)=O)C(C)(C)C)C(=O)OC1CCCC1 LLGDPTDZOVKFDU-XUHJSTDZSA-N 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 201000006061 fatal familial insomnia Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 208000037957 feline spongiform encephalopathy Diseases 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 229960001274 fenticonazole Drugs 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 description 1
- 229950000152 filipin Drugs 0.000 description 1
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 description 1
- 229940063190 flagyl Drugs 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- DLKYYJFLRUUGHJ-SSJCJZGYSA-A fomivirsen sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([S-])(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DLKYYJFLRUUGHJ-SSJCJZGYSA-A 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 229940112424 fosfonet Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 229940125777 fusion inhibitor Drugs 0.000 description 1
- 150000008195 galaktosides Chemical class 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229960001235 gentian violet Drugs 0.000 description 1
- 239000010648 geranium oil Substances 0.000 description 1
- 235000019717 geranium oil Nutrition 0.000 description 1
- 210000001280 germinal center Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003635 glucocorticoid antagonist Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000003563 glycoside group Chemical group 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 210000005256 gram-negative cell Anatomy 0.000 description 1
- 235000015201 grapefruit juice Nutrition 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229960003242 halofantrine Drugs 0.000 description 1
- 229960001906 haloprogin Drugs 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 108060003552 hemocyanin Proteins 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229940097709 hepsera Drugs 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 230000007236 host immunity Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- KNOSIOWNDGUGFJ-UHFFFAOYSA-N hydroxysesamone Natural products C1=CC(O)=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1O KNOSIOWNDGUGFJ-UHFFFAOYSA-N 0.000 description 1
- 229960000374 ibacitabine Drugs 0.000 description 1
- WEVJJMPVVFNAHZ-RRKCRQDMSA-N ibacitabine Chemical compound C1=C(I)C(N)=NC(=O)N1[C@@H]1O[C@H](CO)[C@@H](O)C1 WEVJJMPVVFNAHZ-RRKCRQDMSA-N 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- CFUQBFQTFMOZBK-QUCCMNQESA-N ibazocine Chemical compound C12=CC(O)=CC=C2C[C@H]2N(CC=C(C)C)CC[C@]1(C)C2(C)C CFUQBFQTFMOZBK-QUCCMNQESA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 208000014136 immunodeficiency 16 Diseases 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 201000006747 infectious mononucleosis Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 108700043043 inosine glycyl-cysteinyl-glutamate disodium Proteins 0.000 description 1
- 239000002919 insect venom Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940125798 integrin inhibitor Drugs 0.000 description 1
- 229940115474 intelence Drugs 0.000 description 1
- 108010045648 interferon omega 1 Proteins 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229940088976 invirase Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229950003954 isatoribine Drugs 0.000 description 1
- 229940111682 isentress Drugs 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 229960004849 isoconazole Drugs 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229940112586 kaletra Drugs 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
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 229940089474 lamisil Drugs 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- SIUGQQMOYSVTAT-UHFFFAOYSA-N lapachol Natural products CC(=CCC1C(O)C(=O)c2ccccc2C1=O)C SIUGQQMOYSVTAT-UHFFFAOYSA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229940113354 lexiva Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- 229960001977 loracarbef Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- 229940063175 lotrimin Drugs 0.000 description 1
- 229940092413 lotrimin ultra Drugs 0.000 description 1
- CJPLEFFCVDQQFZ-UHFFFAOYSA-N loviride Chemical compound CC(=O)C1=CC=C(C)C=C1NC(C(N)=O)C1=C(Cl)C=CC=C1Cl CJPLEFFCVDQQFZ-UHFFFAOYSA-N 0.000 description 1
- 229950006243 loviride Drugs 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 108010078259 luprolide acetate gel depot Proteins 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000002535 lyotropic 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
- 230000002101 lytic effect Effects 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229960003640 mafenide Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- FYGDTMLNYKFZSV-UHFFFAOYSA-N mannotriose Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(O)C(O)C2O)CO)C(O)C1O FYGDTMLNYKFZSV-UHFFFAOYSA-N 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- 229940099262 marinol Drugs 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- XOGYVDXPYVPAAQ-SESJOKTNSA-M meglumine antimoniate Chemical compound O[Sb](=O)=O.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO XOGYVDXPYVPAAQ-SESJOKTNSA-M 0.000 description 1
- 229940005559 meglumine antimoniate Drugs 0.000 description 1
- 229960001728 melarsoprol Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229950009246 mepitiostane Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- QRMNENFZDDYDEF-GOSISDBHSA-N methyl (8s)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-1-carboxylate Chemical compound C1([C@H](CBr)CN(C1=C1)C(=O)C=2NC3=C(OC)C(OC)=C(OC)C=C3C=2)=C2C(C(=O)OC)=C(C)NC2=C1OC(=O)N1CCN(C)CC1 QRMNENFZDDYDEF-GOSISDBHSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 229960002159 micafungin Drugs 0.000 description 1
- KOOAFHGJVIVFMZ-WZPXRXMFSA-M micafungin sodium Chemical compound [Na+].C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS([O-])(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 KOOAFHGJVIVFMZ-WZPXRXMFSA-M 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 206010063344 microscopic polyangiitis Diseases 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 229960005389 moroxydine Drugs 0.000 description 1
- AHKJGIUKIBGOKH-UHFFFAOYSA-N morpholine;piperidine Chemical compound C1CCNCC1.C1COCCN1 AHKJGIUKIBGOKH-UHFFFAOYSA-N 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 229960003128 mupirocin Drugs 0.000 description 1
- 229930187697 mupirocin Natural products 0.000 description 1
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- XMZSTQYSBYEENY-RMKNXTFCSA-N n-[4-[(e)-2-[3-tert-butyl-5-(2,4-dioxopyrimidin-1-yl)-2-methoxyphenyl]ethenyl]phenyl]methanesulfonamide Chemical compound C1=C(N2C(NC(=O)C=C2)=O)C=C(C(C)(C)C)C(OC)=C1\C=C\C1=CC=C(NS(C)(=O)=O)C=C1 XMZSTQYSBYEENY-RMKNXTFCSA-N 0.000 description 1
- WJSGOXONRXFGRY-UHFFFAOYSA-N n-[[4-pentoxy-3-(trifluoromethyl)phenyl]carbamothioyl]pyridine-3-carboxamide Chemical compound C1=C(C(F)(F)F)C(OCCCCC)=CC=C1NC(=S)NC(=O)C1=CC=CN=C1 WJSGOXONRXFGRY-UHFFFAOYSA-N 0.000 description 1
- XGXNTJHZPBRBHJ-UHFFFAOYSA-N n-phenylpyrimidin-2-amine Chemical class N=1C=CC=NC=1NC1=CC=CC=C1 XGXNTJHZPBRBHJ-UHFFFAOYSA-N 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- 229940100527 naftin Drugs 0.000 description 1
- 210000004296 naive t lymphocyte Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229950003504 narlaprevir Drugs 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 239000002018 neem oil Substances 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 208000008795 neuromyelitis optica Diseases 0.000 description 1
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 1
- 229940101771 nexavir Drugs 0.000 description 1
- 229960002644 nifurtimox Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229960002480 nitazoxanide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 229960001730 nitrous oxide Drugs 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 229940072250 norvir Drugs 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229950001189 oglufanide Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 olivomycin Drugs 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229960002313 ornidazole Drugs 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 1
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960003483 oxiconazole Drugs 0.000 description 1
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- UAUIUKWPKRJZJV-MDJGTQRPSA-N paritaprevir Chemical compound C1=NC(C)=CN=C1C(=O)N[C@@H]1C(=O)N2C[C@H](OC=3C4=CC=CC=C4C4=CC=CC=C4N=3)C[C@H]2C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@@H]2\C=C/CCCCC1 UAUIUKWPKRJZJV-MDJGTQRPSA-N 0.000 description 1
- 229960002754 paritaprevir Drugs 0.000 description 1
- 229960005065 paromomycin sulfate Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940002988 pegasys Drugs 0.000 description 1
- 229940106366 pegintron Drugs 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- 229940072689 plaquenil Drugs 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- CSOMAHTTWTVBFL-OFBLZTNGSA-N platensimycin Chemical compound C([C@]1([C@@H]2[C@@H]3C[C@@H]4C[C@@]2(C=CC1=O)C[C@@]4(O3)C)C)CC(=O)NC1=C(O)C=CC(C(O)=O)=C1O CSOMAHTTWTVBFL-OFBLZTNGSA-N 0.000 description 1
- CSOMAHTTWTVBFL-UHFFFAOYSA-N platensimycin Natural products O1C2(C)CC3(C=CC4=O)CC2CC1C3C4(C)CCC(=O)NC1=C(O)C=CC(C(O)=O)=C1O CSOMAHTTWTVBFL-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229960000471 pleconaril Drugs 0.000 description 1
- KQOXLKOJHVFTRN-UHFFFAOYSA-N pleconaril Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C KQOXLKOJHVFTRN-UHFFFAOYSA-N 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 1
- 229960001589 posaconazole Drugs 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- RYXIBQLRUHDYEE-UHFFFAOYSA-M potassium;5-(cyclohexen-1-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound [K+].C1CC(OC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C([O-])=O)C(=O)C1CCC(C)CC1 RYXIBQLRUHDYEE-UHFFFAOYSA-M 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940068586 prezista Drugs 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 210000005211 primary lymphoid organ Anatomy 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 229960005385 proguanil Drugs 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- ABBQGOCHXSPKHJ-WUKNDPDISA-N prontosil Chemical compound NC1=CC(N)=CC=C1\N=N\C1=CC=C(S(N)(=O)=O)C=C1 ABBQGOCHXSPKHJ-WUKNDPDISA-N 0.000 description 1
- TTZHDVOVKQGIBA-IAAJYNJHSA-N propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)COP(=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IAAJYNJHSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 108010087851 prorelaxin Proteins 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 244000000040 protozoan parasite Species 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 229940052337 quinupristin/dalfopristin Drugs 0.000 description 1
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 229950004154 ravuconazole Drugs 0.000 description 1
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003267 reducing disaccharides Chemical class 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000024833 regulation of cytokine production Effects 0.000 description 1
- 229940061374 relenza Drugs 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 229940063627 rescriptor Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940107904 reyataz Drugs 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- IMUQLZLGWJSVMV-UOBFQKKOSA-N roridin A Natural products CC(O)C1OCCC(C)C(O)C(=O)OCC2CC(=CC3OC4CC(OC(=O)C=C/C=C/1)C(C)(C23)C45CO5)C IMUQLZLGWJSVMV-UOBFQKKOSA-N 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- HHJUWIANJFBDHT-ZVTSDNJWSA-N rsa8ko39wh Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 HHJUWIANJFBDHT-ZVTSDNJWSA-N 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229960004076 secnidazole Drugs 0.000 description 1
- 229960005429 sertaconazole Drugs 0.000 description 1
- DEKOYVOWOVJMPM-RLHIPHHXSA-N setrobuvir Chemical compound N1([C@H]2[C@@H]3CC[C@@H](C3)[C@H]2C(O)=C(C1=O)C=1NC2=CC=C(C=C2S(=O)(=O)N=1)NS(=O)(=O)C)CC1=CC=C(F)C=C1 DEKOYVOWOVJMPM-RLHIPHHXSA-N 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229940112726 skelid Drugs 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 210000004215 spore Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960002607 sulconazole Drugs 0.000 description 1
- 229960002673 sulfacetamide Drugs 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940054565 sustiva Drugs 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 229940061367 tamiflu Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- 229960000580 terconazole Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940071127 thioglycolate Drugs 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 229940035290 tinactin Drugs 0.000 description 1
- 229960004214 tioconazole Drugs 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- 101150065732 tir gene Proteins 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[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 NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000011426 transformation method Methods 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 208000003982 trichinellosis Diseases 0.000 description 1
- 201000007588 trichinosis Diseases 0.000 description 1
- LZAJKCZTKKKZNT-PMNGPLLRSA-N trichothecene Chemical compound C12([C@@]3(CC[C@H]2OC2C=C(CCC23C)C)C)CO1 LZAJKCZTKKKZNT-PMNGPLLRSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960005041 troleandomycin Drugs 0.000 description 1
- LQCLVBQBTUVCEQ-QTFUVMRISA-N troleandomycin Chemical compound O1[C@@H](C)[C@H](OC(C)=O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](OC(C)=O)[C@@H](C)C(=O)[C@@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C LQCLVBQBTUVCEQ-QTFUVMRISA-N 0.000 description 1
- UXQDWARBDDDTKG-UHFFFAOYSA-N tromantadine Chemical compound C1C(C2)CC3CC2CC1(NC(=O)COCCN(C)C)C3 UXQDWARBDDDTKG-UHFFFAOYSA-N 0.000 description 1
- 229960000832 tromantadine Drugs 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 1
- 229960000497 trovafloxacin Drugs 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 201000002311 trypanosomiasis Diseases 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229940023080 viracept Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- 229940053728 vitrasert Drugs 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- 229940087450 zerit Drugs 0.000 description 1
- 229940052255 ziagen Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- 229940107931 zovirax Drugs 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
- C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- 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
-
- 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
- C07K16/3046—Stomach, Intestines
-
- 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
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—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
-
- 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
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/74—Inducing 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本申請案係關於一種抗PD-L1抗體,編碼其之核酸,其治療性組合物,及其用於增進T細胞功能以調升細胞介導之免疫反應及治療T細胞功能障礙病症(包括感染,例如急性及慢性感染,及腫瘤免疫)之用途。
Description
本發明大體而言係關於免疫功能及增進T細胞功能,包括調升細胞介導之免疫反應及治療T細胞功能障礙病症。
[相關申請案]
本申請案根據35 USC 119(e)主張2008年12月9日申請之美國臨時申請案第61/121092號之優先權,其揭示內容以全文引用的方式併入本文中。
用兩種不同信號協同刺激T細胞或向T細胞提供兩種不同信號為普遍接受之由抗原呈現細胞(APC)使靜息T淋巴細胞活化之淋巴細胞活化模型。Lafferty等人,Aust. J. Exp. Biol. Med. Sci. 53
: 27-42 (1975)。此模型進一步提供區別自身與非自身之辨別力及免疫耐受性。Bretscher等人,Science 169
: 1042-1049 (1970);Bretscher, P.A.,P.N.A.S. USA 96
: 185-190 (1999);Jenkins等人,J. Exp. Med. 165
: 302-319 (1987)。在識別在主要組織相容性複合物(MHC)之情形下存在之外來抗原肽之後,第一信號或抗原特異性信號經由T細胞受體(TCR)轉導。第二信號或協同刺激信號經由表現於抗原呈現細胞(APC)上之協同刺激分子傳遞至T細胞,且誘導T細胞促進純系擴增、細胞激素分泌及效應功能。Lenschow等人,Ann. Rev. Immunol. 14
:233 (1996)。在無協同刺激存在下,T細胞會變得對抗原刺激無反應,不產生有效免疫反應且可能進一步導致外來抗原耗竭
或耐受
外來抗原。
簡單的雙信號模型可能過於簡化,此係因為TCR信號之強度實際上對T細胞活化及分化產生定量影響。Viola等人,Science 273
: 104-106 (1996);Sloan-Lancaster,Nature 363
: 156-159 (1993)。此外,若TCR信號強度較高,則即使在無協同刺激信號存在下,T細胞活化亦可發生。更重要地,T細胞接收正性與負性第二協同刺激信號。該等正性與負性信號之調控對最大化宿主之保護性免疫反應至關重要,同時維持免疫耐受性及防止產生自體免疫。
負性第二信號對誘導T細胞耐受性而言似乎必不可少,而正性信號促進T細胞活化。當簡單的雙信號模型仍能有效說明原初淋巴細胞時,宿主之免疫反應為動力學過程,且亦可向暴露於抗原中之T細胞提供協同刺激信號。
協同刺激之機制具有治療意義,此係因為協同刺激信號之處理已展示提供一種增進或終止基於細胞之免疫反應之方法。近來,已發現T細胞功能障礙或因應性缺失(anergy)與抑制受體(漸進式死亡多肽1(PD-1))之經誘導及維持表現同時出現。因此,對治療性靶向PD-1及經由與PD-1相互作用傳導信號之其他分子(諸如漸進式死亡配位體1(PD-L1)及漸進式死亡配位體2(PD-L2))極度關注。已提出抑制PD-L1信號傳導作為增進T細胞免疫以治療癌症(例如腫瘤免疫)及感染(包括急性與慢性(例如持續性)感染)之方法。然而,因為針對此路徑中之標靶之最佳治療法尚未商業化,所以存在明顯的未滿足之醫療需求。
本發明提供抗PD-L1抗體,包括編碼該等抗體之核酸及含有該等抗體之組合物;且提供該等抗體於增進T細胞功能以調升細胞介導之免疫反應及治療T細胞功能障礙病症之用途,該等T細胞功能障礙病症包括感染(例如急性及慢性感染)及腫瘤免疫。
在一實施例中,本發明提供一種經分離重鏈可變區多肽,其包含HVR-H1、HVR-H2及HVR-H3序列,其中:
(a) HVR-H1序列為GFTFSX1
SWIH (SEQ ID NO:1);
(b) HVR-H2序列為AWIX2
PYGGSX3
YYADSVKG (SEQ ID NO:2);
(c) HVR-H3序列為RHWPGGFDY (SEQ ID NO:3);
另外其中:X1
為D或G;X2
為S或L;X3
為T或S。
在一特定態樣中,X1
為D;X2
為S且X3
為T。在另一態樣中,多肽進一步包含根據下式並列於HVR之間的可變區重鏈構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,構架序列為VH III亞群共同構架。在另一態樣中,至少一個構架序列如下:
HC-FR1為EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4);
HC-FR2為WVRQAPGKGLEWV (SEQ ID NO:5);
HC-FR3為RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR
(SEQ ID NO:6);
HC-FR4為WGQGTLVTVSA (SEQ ID NO:7)。
在另一態樣中,重鏈多肽進一步與可變區輕鏈組合,該等可變區輕鏈包含HVR-L1、HVR-L2及HVR-L3,其中:
(a) HVR-L1序列為RASQX4
X5
X6
TX7
X8
A (SEQ ID NO:8);
(b) HVR-L2序列為SASX9
LX10
S (SEQ ID NO:9);
(c) HVR-L3序列為QQX11
X12
X13
X14
PX15
T (SEQ ID NO:10);
另外其中:X4
為D或V;X5
為V或I;X6
為S或N;X7
為A或F;X8
為V或L;X9
為F或T;X10
為Y或A;X11
為Y、G、F或S;X12
為L、Y、F或W;X13
為Y、N、A、T、G、F或I;X14
為H、V、P、T或I;X15
為A、W、R、P或T。
在另一態樣中,X4
為D;X5
為V;X6
為S;X7
為A;X8
為V;X9
為F;X10
為Y;X11
為Y;X12
為L;X13
為Y;X14
為H;X15
為A。在另一態樣中,輕鏈進一步包含根據下式並列於HVR之間的可變區輕鏈構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,構架序列為VL κ I共同構架。在另一態樣中,至少一個構架序列如下:
LC-FR1為DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11);
LC-FR2為WYQQKPGKAPKLLIY (SEQ ID NO:12);
LC-FR3為GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC
(SEQ ID NO:13);
LC-FR4為FGQGTKVEIKR (SEQ ID NO:14)。
在另一實施例中,本發明提供一種經分離抗PD-L1抗體或抗原結合片段,其包含重鏈及輕鏈可變區序列,其中:
(a)重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中:
(i)HVR-H1序列為GFTFSX1
SWIH (SEQ ID NO:1)
(ii)HVR-H2序列為AWIX2
PYGGSX3
YYADSVKG (SEQ ID NO:2)
(iii)HVR-H3序列為RHWPGGFDY,且 (SEQ ID NO:3)
(b)輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中:
(i)HVR-L1序列為RASQX4
X5
X6
TX7
X8
A (SEQ ID NO:8)
(ii)HVR-L2序列為SASX9
LX10
S;且 (SEQ ID NO:9)
(iii)HVR-L3序列為QQX11
X12
X13
X14
PX15
T (SEQ ID NO:10)
另外其中:X1
為D或G;X2
為S或L;X3
為T或S;X4
為D或V;X5
為V或I;X6
為S或N;X7
為A或F;X8
為V或L;X9
為F或T;X10
為Y或A;X11
為Y、G、F或S;X12
為L、Y、F或W;X13
為Y、N、A、T、G、F或I;X14
為H、V、P、T或I;X15
為A、W、R、P或T。
在一特定態樣中,X1
為D;X2
為S且X3
為T。在另一態樣中,X4
為D;X5
為V;X6
為S;X7
為A;X8
為V;X9
為F;X10
為Y;X11
為Y;X12
為L;X13
為Y;X14
為H;X15
為A。在另一態樣中,X1
為D;X2
為S且X3
為T,X4
為D;X5
為V;X6
為S;X7
為A;X8
為V;X9
為F;X10
為Y;X11
為Y;X12
為L;X13
為Y;X14
為H且X15
為A。
在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS
(SEQ ID NO:4);
HC-FR2 WVRQAPGKGLEWV
(SEQ ID NO:5);
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR
(SEQ ID NO:6);
HC-FR4 WGQGTLVTVSA (SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11);
LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO:12);
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC
(SEQ ID NO:13);
LC-FR4 FGQGTKVEIKR (SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由「無效應Fc突變(effector-less Fc mutation)」或非糖基化(aglycosylation)產生。在另一實施例中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一實施例中,本發明提供一種抗PD-L1抗體,其包含重鏈及輕鏈可變區序列,其中:
(a) 重鏈進一步包含分別與GFTFSDSWIH(SEQ ID NO:15)、AWISPYGGSTYYADSVKG(SEQ ID NO:16)及RHWPGGFDY(SEQ ID NO:3)具有至少85%之序列一致性的HVR-H1、HVR-H2及HVR-H3序列,或
(b) 輕鏈進一步包含分別與RASQDVSTAVA(SEQ ID NO:17)、SASFLYS(SEQ ID NO:18)及QQYLYHPAT(SEQ ID NO:19)具有至少85%之序列一致性的HVR-L1、HVR-L2及HVR-L3序列。
在一特定態樣中,序列一致性為86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4);
HC-FR2 WVRQAPGKGLEWV (SEQ ID NO:5);
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR
(SEQ ID NO:6);
HC-FR4 WGQGTLVTVSA (SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11);
LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO:12);
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC
(SEQ ID NO:13);
LC-FR4 FGQGTKVEIKR (SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由「無效應Fc突變」或非糖基化產生。在另一實施例中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一實施例中,本發明提供一種經分離抗PD-L1抗體,其包含重鏈及輕鏈可變區序列,其中:
(a) 該重鏈序列與以下重鏈序列具有至少85%之序列一致性:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWIS PYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(SEQ ID NO:20),或
(b) 該輕鏈序列與以下輕鏈序列具有至少85%之序列一致性:DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO:21)。
在一特定態樣中,序列一致性為86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列係如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4);
HC-FR2 WVRQAPGKGLEWV (SEQ ID NO:5);
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR
(SEQ ID NO:6);
HC-FR4 WGQGTLVTVSA (SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11);
LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO:12);
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC
(SEQ ID NO:13);
LC-FR4 FGQGTKVEIKR (SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由在原核細胞中產生而產生。在另一特定態樣中,最小效應功能由「無效應Fc突變」或非糖基化產生。在另一實施例中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一實施例中,本發明提供組合物,其包含任何上述抗PD-L1抗體以及至少一種醫藥學上可接受之載劑。
在另一實施例中,本發明提供編碼抗PD-L1抗體之輕鏈或重鏈可變區序列之經分離核酸,其中:
(a) 重鏈進一步包含分別與GFTFSDSWIH(SEQ ID NO:15)、AWISPYGGSTYYADSVKG(SEQ ID NO:16)及RHWPGGFDY(SEQ ID NO:3)具有至少85%之序列一致性的HVR-H1、HVR-H2及HVR-H3序列,且
(b) 輕鏈進一步包含分別與RASQDVSTAVA(SEQ ID NO:17)、SASFLYS(SEQ ID NO:18)及QQYLYHPAT(SEQ ID NO:19)具有至少85%之序列一致性的HVR-L1、HVR-L2及HVR-L3序列。
在一特定態樣中,序列一致性為86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在另一態樣中,重鏈可變區包含一或多個如下並列於HVR之間的構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且輕鏈可變區包含一或多個如下並列於HVR之間的構架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在另一態樣中,構架序列係衍生自人類共同構架序列。在另一態樣中,重鏈構架序列係衍生自Kabat I、II或III亞群序列。在另一態樣中,重鏈構架序列為VH III亞群共同構架。在另一態樣中,一或多個重鏈構架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4);
HC-FR2 WVRQAPGKGLEWV (SEQ ID NO:5);
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR
(SEQ ID NO:6);
HC-FR4 WGQGTLVTVSA (SEQ ID NO:7)。
在另一態樣中,輕鏈構架序列係衍生自Kabat κ I、II、III或IV亞群序列。在另一態樣中,輕鏈構架序列為VL κ I共同構架。在另一態樣中,一或多個輕鏈構架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11);
LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO:12);
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC
(SEQ ID NO:13);
LC-FR4 FGQGTKVEIKR (SEQ ID NO:14)。
在另一特定態樣中,抗體進一步包含人類或鼠類恆定區。在另一態樣中,人類恆定區係選自由IgG1、IgG2、IgG2、IgG3、IgG4組成之群。在另一特定態樣中,人類恆定區為IgG1。在另一態樣中,鼠類恆定區係選自由IgG1、IgG2A、IgG2B、IgG3組成之群。在另一態樣中,鼠類恆定區為IgG2A。在另一特定態樣中,抗體具有減小的或最小效應功能。在另一特定態樣中,最小效應功能由在原核細胞中產生而產生。在另一特定態樣中,最小效應功能由「無效應Fc突變」或非糖基化產生。在另一態樣中,無效應Fc突變為恆定區中之N297A或D265A/N297A取代。
在另一態樣中,核酸進一步包含適用於表現編碼任何前述抗PD-L1抗體之核酸之載體。在另一特定態樣中,載體進一步包含適用於表現核酸之宿主細胞。在另一特定態樣中,宿主細胞為真核細胞或原核細胞。在另一特定態樣中,真核細胞為哺乳動物細胞,諸如中國倉鼠卵巢細胞(Chinese Hamster Ovary,CHO)。
在另一實施例中,本發明提供一種製造抗PD-L1抗體或其抗原結合片段之方法,該方法包含在適於產生該抗體或片段之條件下培養含有編碼任何前述呈適於表現之形式的抗PD-L1抗體或抗原結合片段之核酸的宿主細胞,及回收該抗體或片段。
在另一實施例中,本發明提供一種組合物,其包含如本文所提供之抗PD-L1抗體或其抗原結合片段及至少一種醫藥學上可接受之載劑。
在另一實施例中,本發明提供一種製品,其包含密封治療有效量之本文所揭示之組合物的容器及指示治療T細胞功能障礙病症之使用的包裝插頁。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1組合物與至少一種BNCA分子組合。在一態樣中,BNCA分子為抗體、抗原結合抗體片段、BNCA寡肽、BNCA RNAi或BNCA小分子。在另一態樣中,B7負性協同刺激分子係選自由以下組成之群:CTLA-4、PD-1、PD-L1、PD-L2、B7.1、B7-H3及B7-H4。
在另一實施例中,該製品包含任何上述抗PD-L1組合物與化學治療劑組合。在一態樣中,該化學治療劑為吉西他濱(gemcitabine)。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1抗體與一或多種針對正性協同刺激分子之促效劑組合。在一態樣中,正性協同刺激分子為B7家族協同刺激分子。在另一態樣中,正性協同刺激分子係選自由以下組成之群:CD28、CD80、CD86、ICOS/ICOSL。在另一態樣中,正性協同刺激分子為TNFR家族協同刺激分子。在另一態樣中,TNFR協同刺激分子係選自由以下組成之群:OX40/OX40L、4-1BB/4-1BBL、CD27/CD27L、CD30/CD30L及HVEM/LIGHT及其可溶性片段、構築體及促效抗體(agonist antibody)。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1抗體與一或多種抗生素組合。在一態樣中,該抗生素係選自由以下組成之群:抗病毒劑、抗細菌劑、抗真菌劑、抗原蟲劑。
在另一態樣中,抗病毒劑係選自由以下組成之群:逆轉錄酶抑制劑、蛋白酶抑制劑、整合酶抑制劑、進入或融合抑制劑、成熟抑制劑、病毒釋放抑制劑、免疫反應增強劑、抗病毒協同增強劑、疫苗、肝臟促效劑及草本治療劑。在另一態樣中,該組合包含一或多類抗病毒劑。
在另一實施例中,本發明提供一種製品,其包含任何上述抗PD-L1抗體與一或多種疫苗組合。
在另一實施例中,本發明提供一種增進T細胞功能之方法,該方法包含投與有效量之任何上述抗PD-L1抗體或組合物。在一態樣中,該抗PD-L1抗體或組合物使功能障礙T細胞變得非功能障礙。
在另一實施例中,本發明提供一種治療T細胞功能障礙病症之方法,該方法包含投與治療有效量之任何上述抗PD-L1抗體或組合物。在一特定態樣中,T細胞功能障礙病症為感染或腫瘤免疫。在另一態樣中,感染為急性感染或慢性感染。在另一態樣中,慢性感染為持續性的、潛伏性的或緩慢的。在另一態樣中,慢性感染由選自由細菌、病毒、真菌及原蟲組成之群的病原體引起。在另一態樣中,宿主中之病原體含量降低。在另一態樣中,該方法進一步包含用疫苗治療。在另一態樣中,該方法進一步包含用抗生素治療。在另一態樣中,該病原體為細菌,且該方法進一步包含投與抗細菌劑。在另一態樣中,細菌係選自由以下組成之群:分枝桿菌屬(Mycobacterium spp.
)、沙門氏桿菌屬(Salmonella spp.
)、李氏菌屬(Listeria spp.
)、鏈球菌屬(Streptococcus spp.
)、嗜血桿菌屬(Haemophilus spp.
)、奈瑟菌屬(Neisseria spp.)、克雷伯氏菌屬(Klebsiella spp.)、疏螺旋體屬(Borrelia spp.
)、鬆脆桿菌(Bacterioides fragillis
)、密螺旋體屬(Treponema spp.
)及幽門螺旋桿菌(Helicobacter pylori
)。在另一態樣中,該病原體為病毒,且該方法進一步包含投與抗病毒劑。在另一態樣中,該病毒係選自由以下組成之群:B型肝炎、C型肝炎、I型單純性疱疹病毒、II型單純性疱疹病毒、I型人類免疫缺乏病毒、II型人類免疫缺乏病毒、細胞巨大病毒、艾伯斯坦-巴爾病毒(Eppstein Barr virus)、人類乳頭狀瘤病毒、I型人類T淋巴細胞病毒、II型人類T淋巴細胞病毒、水痘帶狀疱疹病毒。在另一態樣中,該病原體為真菌,且該方法進一步包含投與抗真菌劑。在另一態樣中,該病症係選自由以下組成之群:麯黴病、芽生菌病、白色念珠菌病、粗球黴菌、組織漿菌病、副球黴菌病、微孢子蟲病。在另一態樣中,該病原體為原蟲,且該方法進一步包含投與抗原蟲劑。在另一態樣中,該病症係選自由以下組成之群:利什曼體病(leishmaniasis)、瘧原蟲病(亦即瘧疾)、隱孢子蟲病、弓蟲病、錐蟲病及蠕蟲感染,包括由吸蟲(例如血吸蟲病)、絛蟲(例如包蟲病)及線蟲(例如旋毛蟲病、蛔蟲病、絲蟲病及糞類圓線蟲病)引起之蠕蟲感染。
在另一態樣中,T細胞功能障礙病症為腫瘤免疫。在另一態樣中,PD-L1抗體或組合物與治療方案組合,該治療方案進一步包含選自由以下組成之群的傳統療法:輻射療法、化學療法、靶向療法、免疫療法、激素療法、血管生成抑制及緩解性護理。在另一特定態樣中,化學療法治療係選自由以下組成之群:吉西他濱、環磷醯胺、小紅莓(doxorubicin)、紫杉醇(paclitaxel)、順鉑(cisplatin)。在另一特定態樣中,腫瘤免疫由選自由以下組成之群的癌症引起:乳癌、肺癌、結腸癌、卵巢癌、黑素瘤、膀胱癌、腎癌、肝癌、唾液腺癌、胃癌、神經膠質瘤、甲狀腺癌、胸腺癌、上皮癌、頭頸癌、胃癌及胰臟癌。
本文所提及之所有參考文獻特定地以全文引用的方式併入本文中。 通用技術
除非另外指出,否則本發明之實施將採用在此項技術範圍內之分子生物學(包括重組技術)、微生物學、細胞生物學、生物化學及免疫學之習知技術。該等技術透徹說明於以下文獻中:諸如Molecular Cloning: A Laboratory Manual
, 第2版(Sambrook等人,1989);Oligonucleotide Synthesis
(M.J. Gait編,1984);Animal Cell Culture
(R.I. Freshney編,1987);Methods in Enzymology
(Academic Press, Inc.);Current Protocols in Molecular Biology
(F.M. Ausubel等人編,1987且定期更新);PCR: The Polymerase Chain Reaction
, (Mullis等人編,1994);A Practical Guide to Molecular Cloning
(Perbal Bernard V., 1988);Phage Display: A Laboratory Manual
(Barbas等人,2001)。I. 宿主免疫
A.淋巴細胞發育及活化
人類之兩種主要類型之淋巴細胞為T淋巴細胞(胸腺衍生)及B淋巴細胞(骨髓衍生)。此等細胞係衍生自已投入淋巴發育路徑中之骨髓及胎兒肝臟之造血幹細胞。此等幹細胞之子代遵循不同路徑以成熟為B或T淋巴細胞。人類B淋巴細胞發育完全在骨髓內進行。另一方面,T細胞由離開骨髓且穿過血液流到達胸腺之未成熟前驅體發育而來,在胸腺中該等未成熟前驅體增殖且分化為成熟T淋巴細胞。
自胸腺或骨髓中出現之成熟淋巴細胞處於靜止或「休眠」狀態,亦即其無有絲分裂活性。當分散至血液流中時,此等「初始」或「原始」淋巴細胞行進至諸如脾、淋巴結或扁桃體之各種次級或周邊淋巴器官中。大部分原始淋巴細胞具有固有較短的壽命且在離開骨髓或胸腺後幾天內即死亡。然而,若該類細胞接收指示抗原存在之信號,則其可活化且經歷連續幾輪細胞分裂。接著一些所得子代細胞恢復到休眠狀態變成記憶淋巴細胞(memory lymphocyte
)B及T細胞,其基本上經預致敏以與刺激過敏原再次相遇。活化的原始淋巴細胞之其他子代為效應細胞,雖然其僅存活幾天,但進行特異性防禦活動。
淋巴細胞活化係指當休眠淋巴細胞受到刺激分裂且產生子代時所經由的一系列有序事件,子代中之一些變為效應細胞。完全反應包括誘導細胞增殖(致有絲分裂)與表現免疫功能。當特異性配位體結合淋巴細胞表面上之受體時,該等淋巴細胞經活化。雖然針對T細胞及B細胞之配位體不同,但所得細胞內生理機制類似。
一些外來抗原本身可誘導淋巴細胞活化,交聯B細胞上之表面免疫球蛋白或T細胞上之其他醣蛋白之大聚合抗原尤其如此。然而,大部分抗原不為聚合的,且即使與大量B細胞直接結合,亦未能引起活化。當由鄰近經活化輔助T淋巴細胞協同刺激此等更常見抗原時,此等更常見抗原使B細胞活化。該刺激可自T細胞分泌之淋巴介質發生,但藉由使B細胞與T細胞表面蛋白質直接接觸最有效傳遞,該等T細胞表面蛋白質與某些B細胞表面受體相互作用產生第二信號。
B.T 細胞
T淋巴細胞不表現免疫球蛋白,相反,經由稱為T細胞受體(TCR)之表面蛋白質偵測外來物質之存在。此等受體藉由直接接觸其他免疫細胞或經由影響其他免疫細胞之活性來識別抗原。T細胞以及巨噬細胞為涉及細胞介導之免疫的初級細胞類型。
不同於B細胞,T細胞僅在特定情形下可偵測外來物質。詳言之,僅當外來蛋白質首先裂解為小肽,接著顯示於稱為抗原呈現細胞(APC)之第二宿主細胞之表面上時,T淋巴細胞才會識別該外來蛋白質。許多類型之宿主細胞可在一些條件下呈現抗原,但某些類型(包括巨噬細胞及其他B細胞)更特定地適於此目的且在控制T細胞活性方面尤其重要。抗原呈現部分視呈現細胞表面上之稱為主要組織相容性複合物(MHC)蛋白之特定蛋白質而定。因此,為刺激細胞介導之免疫,外來肽必須呈現給T細胞與MHC肽之組合,且此組合必須由T細胞受體識別。
存在兩個重要的T細胞子集:細胞毒性T淋巴細胞(Tc
細胞或CTL)及輔助T細胞(TH
),其可大致基於標記物CD8及CD4之細胞表面表現來鑑別。Tc
細胞在病毒防禦方面很重要,且可直接藉由識別表現病毒肽之某些細胞表面來殺死病毒。TH
細胞促進其他細胞類型之增殖、成熟及免疫功能,例如促進淋巴介質分泌以控制B細胞、巨噬細胞及細胞毒性T細胞之活性。原始與記憶T淋巴細胞通常保持處於休眠狀態,且在此狀態下,其不展現明顯的輔助或細胞毒活性。當活化時,此等細胞經歷若干輪有絲分裂產生子細胞。雖然一些此等子細胞回到休眠狀態成為記憶細胞,但其他變為積極表現輔助或細胞毒活性之效應細胞。此等子細胞類似其母體:CD4+細胞僅可產生CD4+子代,而CD8+細胞僅產生CD8+子代時。效應T細胞表現不表現於休眠T細胞上之細胞表面標記物,諸如CD25、CD28、CD29、CD40L、運鐵蛋白受體及II類MHC蛋白。當取出活化刺激物時,經若干天時間細胞毒性或輔助活性逐漸衰減,因為效應細胞已死亡或回到休眠狀態。
類似於B細胞活化,T淋巴細胞對大部分抗原之反應亦需要兩種類型之同步刺激物。首先為抗原,若該抗原由MHC蛋白適當顯示於抗原呈現細胞上,則其可由T細胞受體識別及結合。當此抗原-MHC複合物向細胞內部發送信號時,通常不足以引起T細胞活化。完全活化(諸如由輔助T細胞發生)需要用表現於抗原呈現細胞之表面上的稱為協同刺激劑之其他特異性配位體協同刺激。另一方面,活化細胞毒性T細胞一般需要IL-2,即由經活化輔助T細胞分泌之細胞激素。
C.免疫反應
使得哺乳動物免疫系統區別於其他身體防禦之三種主要功能性質包括:(1)特異性,個別地識別及應答或不應答許多標靶分子之一的能力,(2)辨別力,自非自身的中判定為自身的以便與所有數不清的蛋白質及其他有機物質和平共存,但仍強烈應答引入身體之外來物質之能力,及(3)記憶力,由經驗形成以致後續與特定外來病原體相遇將引發比最初相遇使所發生之反應快速且強烈之反應的能力。當一或多個此等功能無效時,病理病狀產生。
原始淋巴細胞不斷自初級淋巴器官中釋放至周邊中,各帶有能夠抗原結合之表面受體。B細胞中之抗原結合係由表面結合之免疫球蛋白介導,而在T細胞中,由T細胞受體介導。當原始淋巴細胞活化時,其增殖,從而產生子細胞,該等子細胞接著可再經歷活化及增殖週期。對既定抗原之反應的速度及強度主要由純系選擇決定:對特定抗原具有特異性之子細胞或純系之數目越大,可識別且參與免疫反應之細胞的數目越大。每一免疫反應均是一系列複雜且雜亂調控之涉及若干細胞類型之事件。當免疫原進入身體且遇到稱為抗原呈現細胞(APC)之特定類細胞時,觸發免疫反應。此等APC捕捉極少量之免疫原,且將其顯示為可由抗原特異性輔助T淋巴細胞識別之形式。接著輔助T細胞經活化,且此又促進諸如B細胞或細胞毒性T細胞之其他類淋巴細胞活化。接著經活化淋巴細胞增殖且執行其特異性效應功能。在此方法之各階段,淋巴細胞及APC經由直接接觸或藉由分泌調控細胞激素彼此連通。
由APC捕捉之外源抗原經歷一系列稱為抗原加工(antigen processing
)之變化。該加工(尤其蛋白質免疫原之該加工)包括變性及部分蛋白水解消化,以便使免疫原裂解為短肽。接著有限量之所得肽與II類MHC蛋白非共價締合且傳輸至APC表面,此為稱為抗原呈現(antigen presentation
)之過程。雖然與APC直接接觸之CD4+輔助T淋巴細胞可經活化,但僅當該細胞表現可識別且結合由APC呈現之特定肽-MHCT複合物之T細胞受體蛋白時才會活化。
輔助T(TH
)細胞為免疫反應之主要指揮者(orchestrators),因為其為兩種其他淋巴效應細胞(細胞毒性T(Tc)細胞及抗體分泌漿細胞)活化所需。TH
活化在免疫反應早期發生且需要至少兩個信號。一個信號係由T細胞抗原受體與APC表面上之抗原肽-MHC複合物結合提供,經由CD3蛋白複合物傳遞;而經由APC之第二協同刺激信號被認為由T細胞表面上之另一信號傳遞蛋白與APC上之特異性配位體結合產生。一種已知的該類相互作用為T細胞蛋白CD28與稱為B7之APC表面蛋白家族。其他表面蛋白對亦可介導協同刺激。協同刺激之過程更詳細地描述於下文中。相信本發明抗PD-L1抗體係經由PD-L1傳導信號所提供之負協同刺激信號的拮抗作用增進協同刺激。
兩個信號一起誘導輔助T細胞開始分泌細胞激素介白素-2(IL-2)以及開始表現特異性高親和力IL-2受體於其表面上。IL-2為T淋巴細胞之高度有效之有絲分裂因子且為活化T細胞之增殖反應所必需。IL-2對所分泌細胞的作用稱為自分泌作用(autocrine effect
)之現象。已進一步顯示即使T細胞接收到兩個信號,若其自身表面IL-2受體經阻斷,則其亦不會增殖。IL-2亦可對緊鄰之細胞作用,即所謂的旁泌性作用(paracrine effect
)。此作用對活化Tc細胞尤其重要,Tc細胞一般不產生足夠IL-2以刺激其自身之增殖。除IL-2以外,活化之TH
細胞亦分泌其他細胞激素且促進B細胞、巨噬細胞及其他細胞類型之生長、分化及功能。
APC與抗原特異性TH
細胞之間的接觸亦影響APC,一種最重要之影響為釋放IL-1。相信此細胞激素以自分泌方式作用來增加II類MHC蛋白及各種黏著性分子之表面表現,藉此強化TH
細胞之結合且增進抗原呈現。同時,IL-1以旁泌性方式對TH
細胞作用來促進IL-2分泌及IL-2受體表現。
在以前述方式活化TH
細胞期間,一些B細胞亦可經由其抗原受體接合免疫原,該等抗原受體為薄膜結合形式之抗體,隨後將分泌。不同於T細胞,B細胞識別呈游離、未加工形式之免疫原。特異性抗原結合提供一類可引起B細胞活化之信號。第二類係由活化之TH
細胞提供,該等活化之TH
細胞表現之蛋白質藉由與B細胞表面上之非免疫球蛋白受體結合來幫助活化B細胞。可不考慮B細胞抗原特異性對任何B細胞起作用的此等TH
衍生信號稱為輔助因子。此等輔助因子包括IL-2,IL-4及IL-6。然而,輔助經由允許T細胞表面上之蛋白質與B細胞上之蛋白質直接接觸之細胞-細胞接觸實現更有效。當僅在TH
細胞活化後表現於TH
細胞上之稱為CD40配位體(CD40L)之蛋白質與B細胞上之稱為CD40之蛋白質結合時,發生最有效形式之接觸介導之輔助。在稱為鄰近活化(by-stander activation
)之過程中,與經活化B細胞接觸甚至可足以活化休眠B細胞,即使B細胞之表面免疫球蛋白未與抗原接合。
Tc
淋巴細胞之功能在於消除表現外來抗原於其表面上之細胞,諸如經病毒感染宿主細胞。大部分Tc
細胞表現CD8而非CD4,且因此識別與I類而非II類MHC蛋白締合之抗原。當體細胞受病毒感染時,一些免疫原性病毒蛋白可在細胞內經受加工,且接著所得肽可作為與I類MHC分子之表面複合物出現。接著此等肽-MHC複合物可由抗原特異性純系之T細胞受體識別,從而提供Tc
細胞活化所必需之兩個信號中之一個。此第一信號單獨在Tc
細胞上誘導高親和力IL-2受體。第二信號由鄰近活化之TH
淋巴細胞分泌之IL-2提供。在接收到該兩個信號後,經活化Tc
細胞獲得細胞毒性活性,從而使其能夠殺死與其結合之細胞以及帶有相同肽-MHC I類複合物之任何其他細胞。在一些情況下,因為Tc
釋放特異性毒素於標靶細胞上而發生殺死;在其他情況下,Tc
誘導標靶細胞經細胞凋亡而自殺。經活化Tc
細胞亦增殖,從而再產生具有相同抗原特異性之Tc
細胞。
D.由免疫球蛋白超家族協同刺激:
1.B7.1/B7.2-CD28/CTLA-4
或許最明確之T細胞協同刺激路徑為經由B7.1(CD80)/B7.2(CD86) - CD28/CTLA-4(CD152)傳導信號之路徑。此信號傳導路徑對T細胞活化及耐受性而言至關重要。Karandikar等人,J. Neuroimmunol. 89
: 10-18 (1998);Oosterwegal等人,Curr. Opin. Immunol. 11
: 294-300 (1999);Salomon等人,Annu. Rev. Immunol. 19
: 225-252 (2001);Sansom, D.M.,Immunol
.101
: 169-177 (2000);Chambers等人,Annu. Rev. Immunol. 19
: 565-592 (2001)。
B7.1[Freeman等人,J. Exp. Med. 174
: 625-631 (1991);Freedman等人,J. Immunol. 137
: 3260-3267 (1987);Yokochi等人,J. Immunol. 128
: 823-827 (1982)]及B7.2[Freeman等人,Science 262
: 909-911 (1993);Freeman等人,J. Exp. Med. 178
: 2185-2192 (1993);Azuma等人,Nature 366
: 76-79 (1993)]具有針對兩種刺激受體CD-28及CTLA-4之雙特異性。Aruffo等人,Proc. Natl. Acad. Sci. USA 84
: 8573-8577 (1987);Gross等人,J. Immunol. 144
: 3201-3210 (1990)。CD28組成性表現於T細胞之表面上[Gross等人,J. Immunol. 149
: 380-388 (1992)],而較高親和力受體CTLA-4具有在T細胞活化後快速調升之表現。Peach等人,J. Exp. Med. 180
: 2049-2058 (1994);Linsley等人,J. Exp. Med. 176
: 1595-1604 (1992);Kinsley等人,Immunity 1
: 793-801 (1994);Linsley等人,Immunity 4
: 535-543 (1996)。大部分APC群體以低含量組成性表現B7.2,此表現可快速調升,而B7.1在活化後稍後誘導性表現。Freeman等人,Science 262
: 909-911 (1993);Hathcock等人,J. Exp. Med. 180
: 631-640 (1994)。B7.2之先前表現及小鼠基因剔除資料表明對引發免疫反應而言,B7.2為更重要之協同刺激分子,但另一方面,兩種分子之功能大部分重疊。McAdam等人,Immuno. Rev. 165
: 631-640 (1994)。
CD28與B7.1及B7.2相互反應以傳遞與TCR信號系統協同促進T細胞活化之信號。Lenschow等人,Annu. Rev. Immunol. 165
: 233-258 (1996);Lanzavecchia等人,Cell 96
: 1-4 (1999)。在無TCR信號存在下,CD28信號傳導不具有生理學重要性。CD28信號傳導調控T細胞活化之臨限值且顯著降低T細胞活化所需之TCR接合的數目。Viola等人,Science 273
: 104-106 (1996)。CD28活化藉由促進T細胞存活來維持T細胞反應,藉此使得細胞激素能夠引發T細胞純系擴充及分化。Thompson等人,Proc. Natl. Acad. Sci. USA 86
: 1333-1337 (1989);Lucas等人,J. Immunol. 154
: 5757-5768 (1995);Shahinian等人,Science 261
: 609-612 (1993);Sperling等人,J. Immunol. 157
: 3909-3917 (1996);Boise等人,Immunity 3
: 87-98 (1995)。CD28亦最優化先前活化之T細胞的反應,從而促進介白素2(IL-2)產生及T細胞存活。雖然一些反應與CD28無關,但尚不清楚此為由強抗原刺激物引起之獨立的協同刺激抑或為依賴於其他未知的協同刺激路徑之結果。
CTLA-4活化引起負性信號,其抑制TCR及CD-28介導之信號轉導。CTLA-4接合使得IL-2合成及經由細胞週期進展受到抑制且T細胞反應終止。Walunas等人,Immunity 1
: 405-413 (1994);Walunas等人,J. Exp. Med. 183
: 2541-2550 (1996);Krummel等人,J. Exp. Med. 182
: 459-466 (1995);Brunner等人,J. Immunol. 162
: 5813-5820 (1999);Greenwald等人,Immunity 14
: 145-155 (2001)。CTLA-4在調控包括周邊T細胞耐受性之T細胞反應中發揮重要作用。雖然尚不清楚信號傳導如何經由CTLA-4及CD28協調,但一些可能性包括藉由誘導免疫抑制細胞激素、CD28信號傳導及/或TCR介導之信號傳導之直接拮抗作用競爭過CD28以與B7結合。
因此,CTLA-4(例如拮抗劑抗CTLA抗體)之拮抗作用及/或促效B7.1/B7.2/CD28可適用於增強感染(例如急性及慢性感染)及腫瘤免疫治療中之免疫反應。
2.ICOS/ICOSL 信號傳導:
APC與T細胞之間的相互作用之另一路徑經由ICOS(CD278)及ICOSL(B7-H2,CD275)發生。雖然ICOS/ICOSL信號傳導促進T輔助細胞分化及效應功能且對介白素-10(IL-10)產生而言尤其重要,但在調控T細胞擴充及IL-2產生(包括調控性T細胞、T細胞耐受性及自體免疫)中發揮的作用較適中。
與CD28形成對比,雖然ICOS不組成性表現於初始T細胞上,但在TCR接合之後在T細胞上快速經誘導。Hutloff等人,Nature 397
: 263-266 (1999);Yoshinaga等人,Nature 402
: 827-832 (1999);Beier等人,Eur. J. Immunol. 30
: 3707-3717 (2000);Coyle等人,Immunity 13
: 95-105 (2000);Mages等人,Eur. J. Immunol. 30
: 1040-1047 (2000);McAdam等人,J. Immunol. 165
: 5035-5040 (2000)。此表明ICOS向經活化T細胞提供協同刺激信號。雖然由CD28協同刺激增強ICOS表現且在無B7.1及B7.2存在下ICOS表現降低,但ICOS不會完全依賴於CD28信號。McAdam等人,J. Immunol. 165
: 5035-5040 (2000);Aicher等人,J. Immunol. 164
: 4689-4696 (2000);Kopf等人,J. Exp. Med. 192
: 53-61 (2000)。在最初分化階段期間,在1型及2型T輔助(TH
1及TH
2)細胞上ICOS調升,但在TH
2細胞上含量仍較高且在TH
1細胞上含量降低。ICOS在T細胞生發中心(germinal center)之表現模式(Beier等人,Eur. J. Immunol. 30
: 3707-3717 (2000);Mages等人,Eur. J. Immunol. 30
: 1040-1047 (2000))指示T細胞中之ICOS輔助B細胞之作用。功能研究已證實此作用,且甚至已對大鼠B細胞證實ICOS之表現,但未對其他物種證實)。Tezuka等人,Biochem. Biophys. Res. Commun. 276
: 335-345 (2000);McAdam等人,Nature 409
: 102-105 (2001);Dong等人,Nature 409
: 97-101 (2001);Dong等人,J. Immunol. 166
: 3659-3662 (2001);Tafuri等人,Nature 409
: 105-109 (2001)。
ICOS/ICOSL信號傳導之一個作用似乎用於由最近經活化之T細胞以及效應T細胞調控細胞激素(例如IL-4、IL-13)產生。Hutloff等人,Nature 397
: 263-266 (1999);Coyle等人,Immunity 13
: 95-105 (2000);Dong等人,Nature 409
: 97-101 (2001)。在過敏性氣管疾病之研究中,ICOS阻斷提供TH
2效應功能而非TH
2分化。Tesciuba等人,J. Immunol. 167
: 1996-2003 (2001)。指示ICOS亦可調控TH
1效應功能,TH
1與TH
2細胞激素之產生可由ICOS-Ig融合蛋白在活體外再活化後抑制。Kopf等人,J. Exp. Med. 192
: 53-61 (2000)。
ICOS之另一潛在作用與維持TH
1反應相關。在多發性硬化症之自體免疫性腦脊髓炎之實驗模型(EAE)中,由髓鞘特異性CD4+
T細胞介導之TH
1疾病展示當依序在T細胞預致敏期間及EAE之效應階段期間阻斷協同刺激時,ICOS阻斷之結果可能不同。Dong等人,Nature 409
: 97-101 (2001);Rottman等人,Nature Immunol. 2
: 605-611 (2001);Sporici等人,Clin. Immunol. 100
: 277-288 (2001)。在ICOS-/-
基因剔除小鼠中,由髓鞘少樹突神經膠細胞醣蛋白(MOG)誘發之EAE極度惡化,同時與野生型相比IFN-γ之產生增加。類似地,EAE誘發期間,ICOS阻斷使疾病惡化,同時導致IFN-γ產生增加。因此,預致敏期間,ICOS阻斷導致反應向TH
1極化。有趣的是,與活體內觀測到之ICOS-Ig阻斷之結果形成鮮明對比,在ICOS-Ig存在下活體外使髓鞘特異性TCR轉殖基因T細胞預致敏抑制其誘發EAE之能力。Sporici等人,同上。雖然造成活體外及活體內之相反結果之差異尚不清楚,但可反映在活體內ICOS阻斷期間,ICOS對產生IL-10之調控性T細胞以及效應T細胞之作用。經由IL-10協同刺激對增進IL-10產生極有效,且比經由CD28協同刺激有效。Hutloff等人,同上。IL-10、IL-12調控性環在調控EAE中至關重要,此係因為IL-10-/-而非IL4-/-小鼠發展惡化的EAE。Segal等人,J. Exp. Med. 187
: 537-546 (1998)。
ICOS之另一潛在作用為增進T細胞依賴性B細胞體液反應。ICOS-/-
及ICOSL-/-
小鼠已展示ICOS為T細胞依賴性B細胞反應所需。Hutloff等人,Nature 397
:263-66 (1999);Chapoval等人,Nat. Immunol. 2
:269-74 (2001);Coyle等人,Immunity 13
: 95-105 (2000);McAdam等人,Nature 409
: 102-5 (2001);Tafuri等人,Nature 409
: 105-9 (2001);Suh等人,Nat. Immunol. 4
:899-906 (2003)。ICOS-/-
小鼠亦展示應答初級免疫生發中心減小,應答二次攻擊生發中心形成存在嚴重缺陷,及IgG種類轉換中存在缺陷。ICOS在T:B細胞相互作用中之作用由在患有成人發作型普通變異型免疫缺陷病之患者之T細胞中鑑別到ICOS的同種接合子損失得到進一步驗證。Grimbacher等人,Nat. Immunol. 4
: 261-68 (2003)。
因此,ICOS/ICOSL(例如促效劑抗ICOS抗體、可溶性ICOS/ICOSL配位體)之促效作用可適用於增強感染(例如急性及慢性感染)及/或腫瘤免疫治療中之免疫反應。
3.PD-1 路徑
:
調控T細胞活化之重要負性協同刺激信號由漸進式死亡-1受體(PD-1)(CD279)及其配位體結合搭配物PD-L1(B7-H1、CD274)及PD-L2(B7-DC、CD273)提供。PD-1之負性調控作用由易具有自體免疫之PD-1基因剔除物種(Pdcd1-/-
)揭示。Nishimura等人,Immunity 11
: 141-51 (1999);Nishimura等人,Science 291
: 319-22 (2001)。雖然PD-1與CD28及CTLA-4有關,但缺乏允許均二聚之近膜半胱胺酸。PD-1之細胞質域含有基於免疫受體酪胺酸之抑制基元(ITIM,V/IxYxxL/V)。PD-1僅與PD-L1及PD-L2結合。Freeman等人,J. Exp. Med. 192
: 1-9 (2000);Dong等人,Nature Med. 5
: 1365-1369 (1999);Latchman等人,Nature Immunol. 2
: 261-268 (2001);Tseng等人,J. Exp. Med. 193
: 839-846 (2001)。
PD-1可表現於T細胞、B細胞、天然殺傷T細胞、經活化單核細胞及樹突狀細胞(DC)上。PD-1由經活化人類CD4+
及CD8+
T細胞、B細胞及骨髓細胞表現,但不由未刺激之該等細胞表現。此與CD28及CTLA-4之更受限制之表現形成對比。Nishimura等人,Int. Immunol. 8
: 773-80 (1996);Boettler等人,J. Virol. 80
: 3532-40 (2006)。存在至少4種自經活化人類T細胞選殖之PD-1變異體,包括缺乏(i)外顯子2、(ii)外顯子3、(iii)外顯子2及3或(iv)外顯子2至4之轉錄物。Nielsen等人,Cell. Immunol. 235
: 109-16 (2005)。除PD-1Δex3以外,所有變異體均以類似於全長PD-1之含量表現於休眠周邊血液單核細胞(PBMC)中。所有變異體之表現在人類T細胞經抗CD3及抗CD28活化後均顯著誘導。PD-1Δex3變異體缺乏跨膜域且類似於在自體免疫中發揮重要作用之可溶性CTLA-4。Ueda等人,Nature 423
: 506-11 (2003)。此變異體富集於患類風濕性關節炎之患者的滑液及血清中。Wan等人,J. Immunol. 177
: 8844-50 (2006)。兩種PD-1配位體在其表現模式上有差異。PD-L1組成性表現於小鼠T及B細胞、CD、巨噬細胞、間葉幹細胞及骨髓衍生肥大細胞上。Yamazaki等人,J. Immunol. 169
: 5538-45 (2002)。PD-L1表現於各種非造血細胞(例如角膜、肺、血管上皮細胞、肝臟非實質細胞、間葉幹細胞、胰島、胎盤合體滋養層細胞、角質細胞等)上[Keir等人,Annu. Rev. Immunol.
26: 677-704 (2008)],且在許多細胞類型上經活化後調升。I型與II型干擾素(IFN)調升PD-L1。Eppihimer等人,Microcirculation 9
: 133-45 (2002);Schreiner等人,J. Neuroimmunol. 155
: 172-82 (2004)。當MyD88、TRAF6及MEK受到抑制時,細胞株中PD-L1之表現降低。Liu等人,Blood 110
: 296-304 (2007)。JAK2亦涉及PD-L1誘導。Lee等人,FEBS Lett. 580
: 755-62 (2006);Liu等人,Blood 110
: 296-304 (2007)。磷酸酶及張力蛋白同系物(PTEN)、修飾磷脂醯肌醇3-激酶(PI3K)之細胞磷酸酶及Akt信號傳導之損失或抑制增加癌症中轉錄後PD-L1之表現。Parsa等人,Nat. Med. 13
: 84-88 (2007)。
與PD-L1相比,PD-L2表現更受限制。PD-L2誘導性表現於DC、巨噬細胞及骨髓衍生肥大細胞上。PD-L2亦表現於約二分之一至三分之二之休眠腹膜B1細胞上,但不表現於習知B2 B細胞上。Zhong等人,Eur.J. Immunol. 37
: 2405-10 (2007)。PD-L2+B1細胞結合磷脂醯膽鹼,且對針對細菌性抗原之先天免疫反應而言可能很重要。由IFN-γ誘導PD-L2部分依賴於NF-κB。Liang等人,Eur. J. Immunol. 33
: 2706-16 (2003)。PD-L2亦可在單核細胞及巨噬細胞上由GM-CF、IL-4及IFN-γ誘導。Yamazaki等人,J. Immunol. 169
: 5538-45 (2002);Loke等人,PNAS 100
:5336-41 (2003)。
PD-1信號傳導對細胞激素產生之作用通常大於對細胞增殖之作用,且對IFN-γ、TNF-α及IL-2產生具有明顯作用。PD-1介導之抑制性信號傳導亦視TCR信號傳導之強度而定,在低含量TCR刺激下傳遞較大的抑制作用。該降低可藉由經由CD28協同刺激[Freeman等人,J. Exp. Med. 192
: 1027-34 (2000)]或存在IL-2[Carter等人,Eur. J. Immunol. 32
: 634-43 (2002)]來克服。
有證據證明經由PD-L1及PD-L2之信號傳導可為雙向的。亦即除改變TCR或BCR信號傳導以外,信號傳導亦可經傳遞回到表現PD-L1及PD-L2之細胞。雖然用自患有瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia)之患者分離之天然人類抗PD-L2抗體處理樹突狀細胞未發現調升MHC II或B7協同刺激分子,但該等細胞產生較大量之促炎細胞激素,尤其TNF-α及IL-6,且刺激T細胞增殖。Nguyen等人,J. Exp. Med. 196
: 1393-98 (2002)。用此抗體處理小鼠亦(1)增進針對移殖之b16黑素瘤之抗性且快速誘導腫瘤特異性CTL,Radhakrishnan等人,J. Immunol. 170
: 1830-38 (2003);Radhakrishnan等人,Cancer Res. 64
: 4965-72 (2004);Heckman等人,Eur. J. Immunol. 37
: 1827-35 (2007);(2)阻斷過敏性哮喘小鼠模型中氣管炎性疾病的發展,Radhakrishnan等人,J. Immunol. 173
: 1360-65 (2004);Radhakrishnan等人,J. Allergy Clin. Immunol. 116
: 668-74 (2005)。
反向信號傳導至樹突狀細胞(「DC」)之另一證據由關於與可溶性PD-1(與Ig恆定區融合之PD-1 EC域,「s-PD-1」)培養之骨髓衍生DC之研究得出。Kuipers等人,Eur. J. Immunol. 36
: 2472-82 (2006)。此sPD-1經由投與抗PD-1以可逆方式抑制DC活化且增加IL-10產生。
另外,若干研究展示與PD-1無關之PD-L1或PD-L2之受體。B7.1已鑑別為PD-L1之結合搭配物。Butte等人,Immunity 27
: 111-22 (2007)。化學交聯研究表明PD-L1與B7.1可經由其IgV樣域相互作用。B7.1:PD-L1相互作用可誘導向T細胞傳導抑制性信號。由B7.1連接CD4+ T細胞上之PD-L1或由PD-L1連接CD4+ T細胞上之B7.1傳遞抑制性信號。缺乏CD28及CTLA-4之T細胞當受抗CD3加B7.1塗布之珠粒刺激時,展示增殖及細胞激素產生降低。在缺乏B7.1之所有受體(亦即CD28、CTLA-4及PD-L1)之T細胞中,T細胞增殖及細胞激素產生不再受抗CD3加B7.1塗布之珠粒抑制。此指示在無CD28及CTLA-4存在下,B7.1經由PD-L1特異性對T細胞起作用。類似地,當在抗CD3加PD-L1塗布之珠粒存在下受刺激時,缺乏PD-1之T細胞展示增殖及細胞激素產生降低,從而說明PD-L1連接對T細胞上之B7.1的抑制作用。當T細胞缺乏PD-L1之所有已知受體(亦即無PD-1及B7.1)時,T細胞增殖不再經抗CD3加PD-L1塗布之珠粒減弱。因此,PD-L1可經由B7.1或PD-1發揮對T細胞之抑制性作用。
B7.1與PD-L1之間的直接相互作用表明目前對協同刺激之理解不完全,且強調此等分子於T細胞上表現之重要性。PD-L1-/-
T細胞之研究指示T細胞上之PD-L1可調降T細胞細胞激素產生。Latchman等人,Proc. Natl. Acad. Sci. USA 101
: 10691-96 (2004)。因為PD-L1與B7.1均表現於T細胞、B細胞、DC及巨噬細胞上,所以此等細胞類型上之B7.1與PD-L1之間可能存在定向的相互作用。另外,非造血細胞上之PD-L1可與T細胞上之B7.1以及PD-1相互作用,從而產生PD-L1是否涉及其調控的問題。B7.1:PD-1相互作用之抑制性作用之一種可能的解釋為T細胞PD-L1可攔截或隔斷APC B7.1與CD28之相互作用。
因此,經由PD-L1之信號傳導之拮抗作用(包括阻斷PD-L1與PD-1、B7.1或兩者之相互作用,藉此阻止PD-L1向T細胞及其他抗原呈現細胞發送負性協同刺激信號)很可能增強應答感染(例如急性及慢性感染)及腫瘤免疫之免疫。此外,本發明抗PD-L1抗體可與PD-1:PD-L1信號傳導之其他組分之拮抗劑(例如拮抗劑抗PD-1及抗PD-L2抗體)組合。
4.B7-H3
協同刺激信號亦經由廣泛表現於淋巴及非淋巴組織中之B7-H3(B7RP-2、CD276、PRO352)提供。Chapoval等人,Nat. Immunol. 2
: 269-74 (2001)。在人類中,B7-H3具有4Ig與2Ig變異體,其中4Ig形式佔優勢,而在小鼠中2Ig變異體佔優勢。Sun等人,J. Immunol. 168
: 6294-97 (2002);Steinberger等人,J. Immunol. 172
: 2352-59 (2004);Ling等人, Genomics 82
: 365-77 (2003)。
最近研究展示B7-H3為T細胞反應之刺激劑與抑制劑。刺激性活化之證據由以下提供:(1)與抗CD3組合,B7-H3/Ig融合體協同刺激CD4+及CD8+ T細胞增殖,且刺激IFN-γ及CD8溶解活性,Chapoval等人,Nat. Immunol. 2
: 269-74 (2001);及(2)將B7-H3表現質體注射至EL-4淋巴瘤模型之腫瘤中引起50%之腫瘤完全退化,此舉依賴於CD8+ T細胞及NK細胞。然而,若干最近研究已展示此分子之抑制性作用。B7-H3-/-
APC基因剔除物種展示在MLR反應中同種異體反應性T細胞增殖增加兩倍。在經任一形式之B7-H3轉染之HLA-DR2中,由抗CD3及抗CD28活化CD4 T細胞受到抑制。Ling等人,Genomics 82
: 365-77 (2003)。結果,IFN-γ、TNF-α、IL-10及GM-CSF之增殖及產生均降低。類似於CD28及CTLA-4如何經由B7.1及B7.2調控信號傳導,此等研究之一致之處在於存在兩種具有相反功能之B7-H3受體。
因此,當與本發明抗PD-L1抗體組合時,阻斷B7-H3信號傳導可有助於增強對感染及腫瘤免疫之免疫反應。
5.B7-H4
最近添加至B7家族中的是B7-H4(B7x、B7-S1、B7-H.5、VTCN1、PRO1291),其為T細胞反應之負性調控劑。Zang等人,Proc. Natl. Acad. Sci. U.S.A.100
(18), 10388-10392 (2003);Watanabe等人,Nat. Immunol. 4
(7), 670-679 (2003;Prasad等人,Immunity 18
(6), 863-873 (2003);Sica等人,Immunity 18
(6), 849-861 (2003)。人類與小鼠B7-H4廣泛表現於淋巴器官(脾臟及胸腺)及非淋巴器官(包括肺、肝臟、睾丸、卵巢、胎盤、骨骼肌、胰腺及小腸)中。在正常人組織中B7-H4不會藉由IHC或轉譯含量之B7-H4之調節偵測到。IHC展示B7-H4高度表現於肺及卵巢腫瘤中,且即時聚合酶鏈反應(PCR)分析指示小鼠B7-H4亦高度表現於前列腺、肺及結腸癌瘤細胞株中。B7-H4結合經活化而非初始之T細胞上之尚未知的受體,該受體不同於CTLA-4、ICOS、PD-1及B7-H3之受體。儘管最初報導BTLA為B7-H4之配位體,但所報導之B7-H4/Ig融合體與野生型而非BTLA-/-
細胞之結合得出如下結論:HVEM而非BTLA為B7-H4之獨特配位體。Sedy等人,Nat. Immunol. 6
: 90-98 (2004)。
關於B7-H4轉染物及固定之B7-H4/Ig融合體之研究說明B7-H4傳遞抑制TCR介導之CD4+
及CD8+
T細胞增殖、G0/G1期中之細胞週期進展及IL-2產生之信號。Sica等人,Immunity 18
: 849-61 (2003);Zang等人,PNAS 100
: 10388-92 (2003);Prasad等人,Immunity 18
: 863-73 (2003)。B7.1協同刺激不能克服B7-H4/Ig誘導之抑制。阻斷抗B7-H4抗體活體外增加T細胞增殖及IL-2產生。與投與於傅氏完全佐劑(complete Freund's adjuvant,CFA)中之匙孔螺血氰蛋白(KLH)相稱活體內投與抗B7-H4抗體在活體外經KLH再刺激後引起抗KLH抗體IgM產生適度增加及T細胞增殖及IL-2產生增加兩至三倍,從而表明在抗B7-H4存在下活體內T細胞預致敏較大。在抗B7-H4處理之自體免疫小鼠模型之腦中,抗B7-H4阻斷抗體顯著加速EAE之發作及嚴重性且CD4+
及CD8+
T細胞及CD11b+
巨噬細胞增加。關於B7-H4獲得之組合實驗資料表明其可調降周邊組織中之免疫反應且在調控T細胞耐受性中發揮作用。B7-H4之表現亦可在逃避腫瘤免疫之宿主免疫反應中發揮作用。Choi等人,J. Immunol. 171
: 4650-54 (2003)。因此,當與本發明抗PD-L1抗體組合時,B7-H4之拮抗作用可適用於增強對感染及腫瘤免疫之免疫反應。
6.BTLA
:
B7家族成員BTLA(CD272,BTLA-1)在功能上類似於PD-1及CTLA。最初鑑別為Th1細胞之選擇性標記物之BTLA僅表現於淋巴細胞上。類似於CTLA-4、ICOS及PD-1,在活化期間在T細胞上誘導BTLA。然而,與在Th2細胞上仍較高但在Th1細胞中調降之ICOS形成對比,BTLA仍表現於Th1細胞上,但不表現於Th2細胞上。類似於PD-1,BTLA亦表現於B細胞上。Gavrieli等人,Biochem. Biophys. Res. Commun. 312
: 1236-43 (2003)。然而,BTLA表現於休眠與經活化B細胞上,而在經活化B細胞上,調升PD-1。BTLA具有兩個ITIM基元。
BTLA對B與T淋巴細胞均具有抑制性作用。Watanabe等人,Nat. Immunol. 4
: 670-79 (2003)。BLTA-/-
B細胞活體外展示對抗IgM之反應適度,但對抗CD3之反應增加。經極化BTLA-/-
Th1細胞活體外展示應答抗原暴露之增殖增加約兩倍。BTLA-/-
小鼠活體內展示半抗原特異性抗體反應增加三倍且EAE感染性增加。BTLA-/-
小鼠之表型類似於PD-1-/-
小鼠之表型,展現自體免疫敏感性增加,但為比CTLA-4-/-
小鼠更精細的表型。然而,倘若BTLA之作用為負性調控劑,則當與本發明抗PD-L1抗體組合時,BTLA之阻斷可證明適用於增強感染及抗腫瘤免疫中之免疫反應。
有趣的是,最近已展示Ig超家族成員BTLA亦與TNFR家族成員HVEM相互作用。Sedy等人,Nat. Immunol. 6
: 90-98 (2005);Gonzalez等人,Proc. Natl. Acad. Sci. USA 102
: 1116-1121 (2005)。HVEM綜述於下文TNFR家族協同刺激劑中。
E.TNFR 家族協同刺激劑 1. OX40/OX40L(CD134)
缺乏OX40(CD134,TXPG1L,TNFRSF4)及OX40L(CD134L,CD252,GP34,TNFSF4,TXGP1)之小鼠對病毒及常見蛋白質抗原與在接觸敏感性反應中之初級CD4+ T細胞反應降低。Chen等人,Immunity 11
: 689-698 (1999);Kopf等人,Immunity 11
: 699-708 (1999);Murata等人,J. Exp. Med. 191
: 365-374 (2000);Gramaglia等人,J. Immunol. 165
: 3043-3050 (2000)。初級反應後期抗原特異性效應T細胞之出現率較低,且較少記憶T細胞發育。Gramaglia等人,同上。與缺乏CD27之T細胞形成對比,在缺乏OX40之初始CD4+ T細胞群體中早期增殖未減弱。然而,活化之後4-5天,增殖降低且細胞凋亡式細胞死亡顯著,結果是幾乎無T細胞長期存活。Rogers等人,Immunity 15
: 445-455 (2001)。對於缺乏OX40之CD8+ T細胞而言,雖然初始細胞分裂不受影響,但與抗原相遇之後3-6天,初級效應細胞之積聚顯著減少。Croft等人,Nat. Immunol. 3
: 609-620 (2003)。
由樹突狀細胞或T細胞轉殖基因表現OX40L增加抗原應答CD4+ T細胞的數目且產生與異常T細胞活化相關之自體免疫樣症狀。Brocker等人,Eur.J. Immunol. 29
:1610-1616 (1999);Murata等人,J. Immunol. 169
: 4628-4636 (2002)。免疫之後,注射促效抗OX40抗體引起更大量之抗原反應性CD4+ T細胞在初級反應峰值時積聚,且引起所產生之記憶T細胞的數目相伴增加。Gramaglia等人,同上;Bansai-Pakala等人,Nature Med. 7
: 907-912 (2001);Maxwell等人,J. Immunol. 164
: 107-112 (2000);Weatherill等人,Cell. Immunol. 209
: 63-75 (2001)。當用對OX40具有特異性之促效抗體處理經抗原預致敏之小鼠時,初級效應CTL之積聚增加。De Smedt等人,J. Immunol. 168
: 661-670 (2002)。
咸信OX40提供允許新近產生之效應細胞在初級免疫反應峰值時存活之後期作用信號。亦存在有力的證據證明除由CD28信號介導之OX40的表現增加以外,OX40在CD28之下游起作用,CD28缺乏對OX40缺乏之功能分析已展示在無CD28信號存在下早期初級T細胞反應顯著減弱,但在無OX40信號存在下僅後期反應減弱。Rogers等人,Immunity 15
: 445-455 (2001);Bertram等人,J. Immunol. 168
: 3777-3785 (2002)。
因此,當與本發明抗PD-L1抗體組合時,活化OX40/OX40L(諸如經由施用促效抗體)很可能可適用於治療T細胞功能障礙病症。2. 4-1BB (CD137)/4-1BBL
類似於OX40/OX40L,當4-1BBL不存在且較少記憶T細胞發育時,缺乏4-1BB(CD137,TNFRSF9)及4-1BBL(TNFSF9)之T細胞展示在初級反應中抗原反應性CD8+ T細胞積聚較少。DeBenedette等人,J. Immunol. 163
: 4833-4841 (1999);Tan等人,J. Immunol. 163
: 4859-4868 (1999);Tan等人,J. Immunol. 164
: 2320-2325 (2000)。此外,阻斷4-1BBL不會改變CD8+ T細胞之最初增殖反應,但會在3-6天之後抑制初級反應峰值時效應CTL之積聚,此係由於已分裂若干次之細胞凋亡。Cooper等人,Eur. J. Immunol. 32
: 521-529 (2002)。促效抗4-1BB抗體及抗4-1BBL轉染之APC亦已產生類似的結果:活體內CTL及CD4+ T細胞反應明顯增加。Melero等人,Nature Med. 3
: 682-685 (1997);Melero等人,Eur. J. Immunol. 28
: 1116-1121 (1998);Takahashi等人,J. Immunol
.162
: 5037-5040 (1999);Guinn等人,J. Immunol. 162
: 5003-5010 (1999);Halstead等人,Nature Immunol. 3
: 536-541 (2002);Takahashi等人,Immunol. Lett. 76
: 183-191 (2001);Bansal-Pakala等人,J. Immunol. 169
: 5005-5009 (2002)。4-1BB特異性抗體不會改變最初增殖反應,從而支持由4-1BBL阻斷實驗得出之結論且指出4-1BB在提供細胞存活信號中之後期活性。
如同OX40,咸信4-1BB提供允許新近產生之效應細胞在初級免疫反應峰值時存活之後期作用信號。亦存在有力的證據證明除由CD28信號介導之OX40及4-1BB的表現增加以外,4-1BB在CD28之後起作用,CD28缺乏對4-1BB缺乏之功能分析已展示在無CD28信號存在下早期初級T細胞反應顯著減弱,但在無OX40信號存在下僅後期反應減弱。Rogers等人,Immunity 15
: 445-455 (2001);Bertram等人,J. Immunol. 168
: 3777-3785 (2002)。
在CD8+ CTL起重要作用之癌症中促效抗CD137抗體可誘導腫瘤退化。Melero等人,Nat. Med. 3
: 682-5 (1997);Hirano等人,Cancer Res. 65
(3): 1089-96 (2005)。PD-L1之組成性及誘導性表現使該等腫瘤具有抗性,此表現當PD-L1阻斷後可逆。Hirano等人。
因此,活化4-1BB/4-BBL(諸如經由施用促效抗體,尤其與PD-L1拮抗劑(例如抗PD-L1抗體)組合)很可能可適用於治療T細胞功能障礙病症。3. CD27/CD27L(CD70)
在CD27/CD70相互作用已破壞之活體外阻斷研究中已說明T細胞反應之最初階段中CD27(TNFRSF7,S152)及CD27L(CD70,TNFSF7)信號傳導之重要性。Oshima等人,Int. Immunol. 10
: 517-526 (1998);Agematsu等人,J. Immunol. 153
: 1421-1429 (1994);Hintzen等人,J. Immunol. 154
: 2612-2623 (1995)。雖然缺乏CD27之T細胞最初正常分裂,但接著在活化之後3天或3天以上不佳地增殖。Hendriks等人,Nature Immunol. 1
: 433-440 (2000)。此指示CD27藉由早期抑制T細胞死亡或藉由在活化之後2-3天對細胞週期起作用以允許持續分裂來參與促進初始T細胞群體之最初擴充。此進一步得到缺乏CD27之小鼠的活體內研究支持,在該研究中經3週或3週以上出現較少數目之抗原特異性反應(第4-8天)且較少記憶T細胞發育。Hendriks等人,同上。在T細胞活化之後早期調升CD27之表現,表明其主要傳遞在效應反應峰值之前維持早期增殖之信號。
因此,活化CD27/CD27L(包括經由施用促效抗體,尤其與本文所述之抗PD-L1抗體組合)很可能可適用於治療T細胞功能障礙病症。4. CD30/CD30L(CD153)
CD30(TNFRSF8,Ki-1)及CD30L(CD153,TNFSF8)信號傳導活體外協同刺激若干T細胞功能。Del Prete等人,J. Exp. Med. 182
: 1655-1661 (1995);Bowen等人,J. Immunol. 156
: 442-449 (1995)。CD30L之阻斷試劑活體外抑制Th2細胞發育且增進Th1細胞發育。此活性與展示CD30由Th2細胞及2型細胞毒性Tc2細胞優先表現之資料一致。Del Prete等人,同上;Nakamura等人,J. Immunol. 158
: 2090-2098 (1996)。在未極化初級反應中活化初始T細胞之後3-4天表現CD30。Nakamura等人,同上指示其作用不限於2型細胞激素支配之反應。
雖然CD30/CD30L信號傳導之確切機制尚不清楚,但已表明可能類似於OX40及4-1BB。當將過繼轉移之抗原特異性CD8+ T細胞轉移至缺乏CD30L之小鼠中時,其不會在初級反應峰值時大量積聚,且較少記憶T細胞發育。因此,CD30亦可提供增殖及/或存活信號以允許在初級反應峰值時產生大量抗原特異性T細胞。
因此,活化CD27/CD27L(包括經由施用促效抗體,尤其與本文所述之抗PD-L1抗體組合)很可能可適用於治療T細胞功能障礙病症。5. HVEM/LIGHT
HVEM(HVEA,ATAR,LIGHTR,TNFRSF14,PRO509)及LIGHT(CD258,HVEML,TR2,TNFSF14,PRO726)對T細胞協同刺激之作用因以下而變得複雜:1)LIGHT亦能夠結合淋巴毒素-β受體(LTβR),及2)HVEM結合可溶性LTα3。因此,關於HVEM/LIGHT之作用的任何研究亦應考慮此信號傳導系統之其他結合搭配物的作用。阻斷LIGHT可早期抑制同種異體混合淋巴細胞反應(MLR)中之T細胞增殖及細胞激素分泌。Tamada等人,J. Immunol. 164
: 4105-4110 (2000);Kwon等人,J. Biol. Chem. 272
: 14272-14276 (1997);Harrop等人,J. Immunol. 161
: 1786-1794 (1998);Tamada等人,Nature Med. 6
: 283-289 (2000)。當阻斷MHC錯配心臟同種異體移植物中之LIGHT時,促炎性細胞激素之產生受到抑制。Ye等人,J. Exp. Med. 195
: 795-800 (2002)。此外,在缺乏LIGHT與CD28之接受者中,同種異體皮膚移植物因延遲之動力學而被排斥。Scheu等人, J. Exp. Med. 195
: 1613-1624 (2002)。有證據表明延遲之移植物排斥可能指示T細胞純系擴充或細胞激素產生早期受到抑制。此結論由以下來支持:(i)活體外研究展示應答同種異體抗原之缺乏LIGHT之脾細胞的TH1與TH2細胞激素之產生降低且產生弱細胞毒性T淋巴細胞活性(CTL活性)[Sheu等人,同上]及(ii)活體內研究展示阻斷LIGHT降低同種異體反應性CTL之產生的。Tamada等人,Nature Med. 6
: 283-289 (2000)。
因此,HVEM/LIGHT(諸如經由施用促效抗體,尤其與本文所述之抗PD-L1抗體組合)可適用於治療T細胞功能障礙病症。II. 定義
「過敏原」或「免疫原」為可觸發免疫反應之任何分子。如本文所用之術語涵蓋抗原分子本身或其來源,諸如花粉粒、動物皮屑、昆蟲毒液或食品。此與術語抗原形成對比,抗原係指可由免疫球蛋白或T細胞受體特異性識別之分子。能夠誘導免疫反應之任何外來物質均為潛在過敏原。已知許多天然與合成起源之不同化學物質具過敏原性。複合天然有機化學物質、尤其蛋白質很可能引起抗體介導之過敏反應,而簡單有機化合物、無機化學物質及金屬更優先引起T細胞介導之過敏反應。在一些情況下,同一過敏原可負責一種以上類型之過敏反應。可經由吸入、注射、注射或皮膚接觸暴露於過敏原。
「功能障礙」在免疫功能障礙情形下係指對抗原刺激之免疫應答降低之狀態。該術語包括可能發生抗原識別但後續免疫反應對控制感染或腫瘤生長無效之耗竭及/或無反應之共同要素。
「耐受性」或「免疫耐受性」係指免疫系統未能對特定抗原產生防禦性免疫反應。耐受性可為天然的或自身的,其中身體不攻擊其自身蛋白質及抗原,或其可因免疫系統經操縱而誘導。中樞耐受性在淋巴細胞發育期間出現且作用於胸腺及骨髓中。在此過程中,識別自身抗原之T及B淋巴細胞在其發育成全免疫活性細胞之前被除去。雖然此過程在胎兒發育期間最活躍,但持續整個生命過程,因為有未成熟淋巴細胞產生。周邊T細胞耐受性係指功能上不應答周邊組織中存在之自身抗原,且在T及B細胞成熟且進入周邊之後出現。此等過程包括由「調控性」T細胞抑制自身反應性細胞且在無伴隨發炎之協同刺激信號存在下遇到抗原的淋巴細胞中產生低應答(無反應)。「獲得」或「誘導耐受性」係指免疫系統對以淋巴組織對既定抗原之特異性無反應為特徵的外部抗原的適應,該既定抗原在其他情況下很可能將誘導細胞介導或體液免疫。在成人中,耐受性可藉由重複投與極大劑量之抗原或低於刺激免疫反應所需之臨限值的小劑量之可溶性抗原(諸如經由靜脈內或舌下投與)臨床誘導。免疫抑制亦有助於誘導耐受性。破環自身耐受性可產生自體免疫。
「增進T細胞功能」意謂誘導、引起或刺激T細胞具有持續或擴增之生物功能,或更新或再活化已耗竭或失活T細胞。增進T細胞功能之實例包括:相對於介入之前的程度,增加自CD8+
T細胞之γ-干擾素分泌、增加增殖、增加抗原應答(例如病毒或病原體清除)。在一實施例中,增進之程度為至少50%、或者60%、70%、80%、90%、100%、120%、150%、200%。一般熟習此項技術者已知量測此增進之方法。
「T細胞功能障礙病症」為以對抗原刺激之應答降低為特徵之T細胞病症或病狀。在一特定實施例中,T細胞功能障礙病症為與經由PD-1之信號傳導不當增加特定相關之病症。在另一實施例中,T細胞功能障礙病症為T細胞無反應性或分泌細胞激素、增殖或實行細胞溶解活性之能力降低的病症。在一特定態樣中,應答降低導致對表現免疫原之病原體或腫瘤之控制無效。以T細胞功能障礙為特徵之T細胞功能障礙病症之實例包括未消除之急性感染、慢性感染及腫瘤免疫。
「慢性感染」係指在急性感染期間感染因子(例如病原體,諸如病毒、細菌、原蟲寄生蟲、真菌或其類似物)在受感染宿主中誘導免疫反應但尚未自該宿主中清除或消除之感染。慢性感染可為持續性、潛伏性或緩慢的。雖然急性感染通常在幾日或幾週內由免疫系統消除(例如流行性感冒),但持續性感染可以相對較低之程度持續幾個月、幾年、幾十年或一生(例如B型肝炎)。相反,潛伏性感染之特徵在於長期無症狀活性不時由一段快速增加之高度感染及病原體含量升高之時期打斷(例如單純性疱疹)。最後,緩慢感染為以疾病症狀逐漸且持續增加為特徵之感染,諸如長期潛伏,之後在臨床症狀發作後,開始拖延性且進行性之臨床過程。不同於潛伏性及持續性感染,緩慢感染可能不會以急性病毒增殖期開始(例如小核糖核酸病毒感染,綿羊髓鞘脫落病毒、綿羊癢病、庫茲德-賈克氏病(Creutzfeldt-Jakob disease))。能夠誘發慢性感染之例示性感染因子包括病毒(例如細胞巨大病毒、艾伯斯坦-巴爾病毒(Epstein Barr virus)、B型肝炎病毒、C型肝炎病毒、I型單純性疱疹病毒及II型單純性疱疹病毒、1型人類免疫缺乏病毒及2型人類免疫缺乏病毒、人類乳頭狀瘤病毒、1型人類T淋巴細胞病毒及2型人類T淋巴細胞病毒、水痘帶狀疱疹病毒及其類似病毒)、細菌(例如結核分枝桿菌(Mycobacterium tuberculosis
)、李氏菌屬、肺炎克雷伯氏桿菌(Klebsiella pneumoniae
)、肺炎鏈球菌(Streptococcus pneumoniae
)、金黃色葡萄球菌(Staphylococcus aureus
)、疏螺旋體屬、幽門螺旋桿菌及其類似細菌)、原蟲寄生蟲(例如利什曼蟲屬(Leishmania spp.
)、惡性瘧原蟲(Plasmodium falciparum
)、血吸蟲屬(Schistosoma spp.
)、弓形蟲屬(Toxoplasma spp.
)、錐蟲屬(Trypanosoma spp.
)、肥頭帶絛蟲(Taenia carssiceps
)及其類似原蟲寄生蟲)及真菌(例如麯黴屬(Aspergillus spp.
)、白色念珠菌(Candida albicans
)、粗球黴菌(Coccidioides immitis
)、莢膜組織漿菌(Histoplasma capsulatum
)、肺炎肺囊蟲(Pneumocystis carinii
)及其類似真菌)。其他感染因子包括藉由進一步在此等組織中產生錯誤摺疊之蛋白質,從而導致形成致使細胞死亡、組織損傷且最終死亡之澱粉樣斑塊而影響腦或神經元結構的朊病毒或錯誤摺疊蛋白質。由朊病毒感染引起之疾病之實例包括庫茲德-賈克氏病及其變種、格-施-沙症候群(Gerstmann-Sträussler-Scheinker syndrome,GSS)、致死性家族失眠(sFI)、庫魯症(kuru)、綿羊癢病、牛中之牛腦海綿狀病(Bovine spongiform encephalopathy,BSE)(亦稱為「瘋牛」病)及腦病之各種其他動物形式[例如傳染性貂腦病(TME);白尾鹿、麋鹿及長耳鹿中之慢性消耗性疾病(CWD);貓海綿狀腦病;林羚(nyala)、羚羊及較大撚角羚中之外來有蹄類腦病(EUE)、鴕鳥之海綿狀腦病]。
「腫瘤免疫」係指腫瘤逃避免疫識別及清除之過程。因此,作為治療性概念,當該逃避減弱時,腫瘤免疫得以「治療」,且腫瘤由免疫系統識別及攻擊。腫瘤識別之實例包括腫瘤結合、腫瘤收縮及腫瘤清除。
「B7負性協同刺激拮抗劑」(「BNCA」)為降低、阻斷、抑制、消除或干擾由或經由於由B7家族成員介導表現於T淋巴細胞上之細胞表面蛋白所介導之負性協同刺激信號之藥劑。在一態樣中,BNCA可單獨或與本發明抗PD-1抗體組合使功能障礙T細胞變得非功能障礙。在另一態樣中,BNCA可為抑制B7負性協同刺激分子之核酸或蛋白質合成、表現、信號傳導及/或表現後加工之藥劑。在另一態樣中,BNCA為由B7負性協同刺激分子降低、阻斷、抑制、消除或干擾信號轉導之抗體、抗原結合抗體片段、BNCA寡肽、BNCA RNAi或BNCA小分子。B7負性協同刺激分子之實例包括:CTLA-4、PD-L1、PD-1、B7.1(表現於T細胞上)、PD-L2、B7-H3及B7-H4。
正性協同刺激促效劑為增加、增進、強化或促進由或經由表現於T淋巴細胞上之細胞表面蛋白介導之協同刺激信號之分子。在一態樣中,正性協同刺激分子可為活化正性協同刺激路徑之細胞外域、可溶性構築體或促效抗體。正性協同刺激分子之實例包括B7超家族分子,例如B7.1、B7.2、CD28及ICOS/ICOSL。其他實例包括TNFR家族協同刺激分子,例如OX40/OX40L、41-BB/41-BBL、CD27/CD27L、CD30/CD30L及HVEM/LIGHT。
「小分子」或「小有機分子」為分子量低於約500道爾頓之分子。
「干擾RNA」、「RNAi」為長度為10至50個核苷酸且降低標靶基因之表現的RNA,其中鏈之數部分充分互補(例如與標靶基因之一致性為至少80%)。RNA干涉之方法係指以轉錄後含量(例如轉譯)出現之基因表現之標靶特異性抑制(亦即「基因沉默」),且包括RNA介導之基因表現抑制之所有轉錄後機制及轉錄機制,諸如以下中所述之機制:P.D. Zamore,Science 296
: 1265 (2002);及Hannan及Rossi,Nature 431
: 371-378 (2004)。如本文所用之RNAi可呈小干擾RNA(siRNA)、短髮夾RNA(shRNA)及/或微RNA(miRNA)形式。該等RNAi分子通常為可以獨立互補或部分互補RNA鏈形式表現之雙鏈RNA複合物。此項技術中熟知設計雙鏈RNA複合物之方法。舉例而言,適合之shRNA及siRNA之設計及合成可見於Sandy等人,BioTechniques 39
: 215-224 (2005)中。
「小干擾RNA」或siRNA為長度為10至50個核苷酸且降低標靶基因之表現的雙鏈RNA(dsRNA)雙鏈體,其中第一鏈之數部分充分互補(例如與標靶基因之一致性為至少80%)。siRNA經特異性設計以避免抗病毒反應,該抗病毒反應之特徵在於干擾素合成增加、非特異性蛋白合成受抑制及RNA降解,該RNA降解通常導致與在哺乳動物細胞中使用RNAi相關之細胞自殺或死亡。Paddison等人,Proc Natl Acad Sci USA 99
(3):1443-8. (2002)。
術語「髮夾」係指具有7-20個核苷酸之環狀RNA結構。「短髮夾RNA」或shRNA為長度為10至50個核苷酸且以降低標靶基因表現之急轉彎(hairpin turn)為特徵之單鏈RNA,其中RNA鏈之數部分充分互補(例如與標靶基因之一致性為至少80%)。術語「莖環(stem-loop
)」係指同一分子鹼基對之兩個區之間配對形成在未配對短環中結束,從而得到棒棒糖形結構之雙螺旋。
「微RNA」或「miRNA」(先前稱為stRNA)為長度為約10至70個核苷酸且最初轉錄為以「莖環」結構為特徵之miRNA前體(pre-miRNA),隨後在經由RNA誘導之沉默複合物(RISC)進一步加工之後加工成成熟miRNA之單鏈RNA。
「BNCA干擾RNA」或「BNCA RNAi」較佳特異性結合BNCA核酸且降低其表現。此意謂與不存在BNCA RNAi之對照組中之B7負性協同刺激分子之表現相比,在BNCA RNAi存在下B7負性協同刺激分子之表現較低。BNCA RNAi可使用已知方法鑑別且合成(Shi Y.,Trends in Genetics 19
(1): 9-12 (2003);WO2003056012;WO2003064621;WO2001/075164;WO2002/044321)。
「BNCA寡肽」為較佳特異性結合包括分別如本文所述之受體、配位體或信號傳導組分之B7負性協同刺激多肽之寡肽。該等寡肽可使用已知寡肽合成方法化學合成或可使用重組技術製備及純化。該等寡肽長度通常為至少約5個胺基酸,或者長度為至少約6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100個或100個以上胺基酸。該等寡肽可在無過度實驗下使用熟知技術鑑別。就此點而言,應注意此項技術中熟知篩檢能夠特異性結合多肽標靶之寡肽之寡肽文庫的技術(參見例如美國專利第5,556,762號、第5,750,373號、第4,708,871號、第4,833,092號、第5,223,409號、第5,403,484號、第5,571,689號、第5,663,143號;PCT公開案第WO 84/03506號及第WO84/03564號;Geysen等人,Proc. Natl. Acad. Sci. U.S.A.
,81
:3998-4002 (1984);Geysen等人,Proc. Natl. Acad. Sci. U.S.A.
,82
:178-182 (1985);Geysen等人,Synthetic Peptides as Antigens
, 130-149 (1986);Geysen等人,J. Immunol. Meth.
,102
:259-274 (1987);Schoofs等人,J. Immunol.
,140
:611-616 (1988);Cwirla, S. E.等人,Proc. Natl. Acad. Sci. USA
,87
:6378 (1990);Lowman, H.B.等人,Biochemistry
,30
:10832 (1991);Clackson, T.等人,Nature
,352
: 624 (1991);Marks, J. D.等人,J. Mol. Biol.
,222
:581 (1991);Kang, A.S.等人,Proc. Natl. Acad. Sci. USA
,88
:8363 (1991);及Smith, G. P.,Current Opin. Biotechnol.
,2
:668 (1991)。
「BNCA小分子拮抗劑」或「BNCA小分子」為較佳特異性抑制B7負性協同刺激多肽之除本文所定義之寡肽或抗體以外的有機分子。該B7負性協同刺激信號傳導抑制較佳使功能障礙T細胞能應答抗原刺激。BNCA小分子之實例可使用已知方法鑑別及化學合成(參見例如PCT公開案第WO2000/00823號及第WO2000/39585號)。該等BNCA小分子之大小通常小於約2000道爾頓,或者大小小於約1500、750、500、250或200道爾頓,能夠較佳特異性結合如本文所述之B7負性刺激多肽且可在無過度實驗下使用熟知技術鑑別。就此點而言,應注意此項技術中熟知篩檢能夠結合多肽標靶之分子之有機分子文庫的技術(參見例如PCT公開案第WO00/00823號及第WO00/39585號)。
術語「抗生素」包括特異性抑制或消除諸如病毒、細菌、真菌或原蟲之微生物生長但在投藥濃度及給藥間隔下不會致使宿主死亡之任何分子。如本文所用之術語抗生素包括抗菌劑、抗病毒劑、抗真菌劑及抗原蟲劑。在一特定態樣中,抗生素在投藥濃度及給藥間隔下對宿主無毒。抗細菌抗生素或抗細菌劑可大致分類為殺細菌型(亦即直接殺死)或抑細菌型(亦即阻止分裂)。殺細菌型抗生素可進一步分為以下亞類:窄譜類(亦即僅影響一小類細菌子集,例如革蘭氏陰性菌(gram-negative)等)或廣譜類(亦即影響一大類)。抗生素之實例包括:(i)胺基糖苷類,例如阿米卡星(amikacin)、慶大黴素(gentamicin)、康黴素(kanamycin)、新黴素(neomycin)、奈替米星(netilmicin)、鏈黴素(streptomycin)、托普黴素(tobramycin)、嘌呤黴素(paromycin),(ii)袢黴素類(ansamycins),例如,格爾德黴素(geldanamycin)、除莠黴素(herbimycin);(iii)碳頭孢烯類(carbacephems),例如氯碳頭孢(loracarbef);(iv)碳青黴烯類(carbapenems),例如厄他培南(ertapenum)、多尼培南(doripenem)、亞胺培南(imipenem)/西司他汀(cilastatin)、美羅培南(meropenem);(v)頭孢菌素類(cephaolsporins)(第一代),例如頭孢羥胺苄(cefadroxil)、頭孢唑啉(cefazolin)、頭孢噻吩(cefalotin)、頭孢胺苄(cefalexin);(vi)頭孢菌素類(第二代),例如頭孢克洛(ceflaclor)、頭孢孟多(cefamandole)、頭孢西丁(cefoxitin)、頭孢丙烯(cefprozil)、頭孢呋辛(cefuroxime);(vi)頭孢菌素類(第三代),例如頭孢克肟(cefixime)、頭孢地尼(cefdinir)、頭孢托侖(cefditoren),頭孢哌酮(cefoperazone)、頭孢噻肟(cefotaxime)、頭孢泊肟(cefpodoxime)、頭孢他啶(ceftazidime)、頭孢布烯(ceftibuten)、頭孢唑肟(ceftizoxime)、頭孢曲松(ceftriaxone);(vii)頭孢菌素類(第四代)、例如頭孢吡肟(cefepime);(viii)頭孢菌素類(第五代),例如頭孢吡普(ceftobiprole);(ix)醣肽類(glycopeptides),例如替考拉寧(teicoplanin)、萬古黴素(vancomycin);(x)巨環內酯類,例如阿齊黴素(axithromycin)、克拉黴素(clarithromycin)、地紅黴素(dirithromycine)、紅黴素(erythromycin)、羅紅黴素(roxithromycin)、醋竹桃黴素(troleandomycin)、泰利黴素(telithromycin)、觀黴素(spectinomycin);(xi)單醯胺菌素類(monobactams),例如安曲南(axtreonam);(xii)青黴素類(penicilins),例如安莫西林(amoxicillin)、安比西林(ampicillin)、阿洛西林(axlocillin)、卡本西林(carbenicillin)、氯唑西林(cloxacillin),雙氯噁唑西林(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、甲氧西林(meticillin)、夫西林(nafcilin)、苯唑青黴素(oxacillin)、青黴素(penicillin)、哌拉西林(peperacillin)、替卡西林(ticarcillin);(xiii)抗生素多肽,例如桿菌肽(bacitracin)、黏菌素(colistin)、多黏菌素B(polymyxin B);(xiv)喹諾酮類(quinolones),例如環丙沙星(ciprofloxacin)、依諾沙星(enoxacin)、加替沙星(gatifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lemefloxacin)、莫西沙星(moxifloxacin)、諾氟沙星(norfloxacin)、氧氟沙星(orfloxacin)、曲伐沙星(trovafloxacin);(xv)磺醯胺類,例如磺胺米隆(mafenide)、百浪多息(prontosil)、磺胺醋醯胺(sulfacetamide)、磺胺甲二唑(sulfamethizole)、磺胺(sulfanilamide)、柳氮磺啶(sulfasalazine)、磺胺異噁唑(sulfisoxazole)、甲氧苄啶(trimethoprim)、甲氧苄啶-磺胺甲異噁唑(TMP-SMX);(xvi)四環素類(tetracyclines),例如地美環素(demeclocycline)、多西環素(doxycycline)、米諾環素(minocycline)、土黴素(oxytetracycline)、四環素;及(xvii)其他,諸如阿斯凡納明(arspenamine)、氯黴素(chloramphenicol)、克林黴素(clindamycin)、林可黴素(lincomycin)、乙胺丁醇(ethambutol)、磷黴素(fosfomycin)、梭鏈孢酸(fusidic acid)、呋喃唑酮(furazolidone)、異菸肼(isoniazid)、利奈唑胺(linezolid)、甲硝唑(metronidazole)、莫匹羅星(mupirocin)、硝基呋喃妥因(nitrofurantoin)、平板黴素(platensimycin)、吡嗪醯胺(pyrazinamide)、奎努普丁(quinupristin)/達福普丁(dalfopristin)、利福平(rifampin)/利福黴素(rifampicin)或替硝唑(tinidazole)。
術語「抗病毒劑」包括抑制或消除病毒生長、致病性及/或存活之任何分子。其包括抗反轉錄病毒藥物,諸如(1)逆轉錄酶抑制劑
,包括例如:(a)核苷類似物逆轉錄酶抑制劑(NRTI),例如阿昔洛韋(aciclovir/acyclovir)(ZOVIRAX®
,ZOVIR®
)、西多福韋(cidofovir)、疊氮胸苷(azidothymidine)/齊多夫定(zidovudine)(AZT,RETROVIR®
)、去羥肌苷(didanosine)(ddI、VIDEX®
);紮西他濱(zalcitabine)(ddC,HIVID®
);司他夫定(stavudine)(d4T,ZERIT®
);拉米夫定(lamivudine)(3TC,EPIVIR®
);阿巴卡韋(abacavir)(ZIAGEN®
);恩曲他濱(emtricitabine)(EMTRIVA®
);溴夫定(brivudine) (HELPIN®
);因提弗(entecavir)(BARACLUDE®
);碘苷(idoxuridine);偉拉咪定(viramidine)(Valeant Pharmacueticals之他立韋林(taribavirin))、Pharmasset/Roche之胞嘧啶核苷類似物聚合酶抑制劑PCI-6130及前藥變異體(例如R7128);Merck/Isis Pharmaceuticals之核苷類似物抑制劑MK-0608;(b)核苷酸類似物逆轉錄酶抑制劑(NtRTI),例如泰諾福韋(tenofovir)(VIREAD®
);阿德福韋(adefovir)(PREVEON®
,HEPSERA®
);福米韋生(fomivirsen) (VITRAVENE®
);(c)非核苷逆轉錄酶抑制劑(NNRTI),依發韋侖(efavirenz)(SUSTIVA®
,STOCRIN®
);奈韋拉平(nevirapine) (VIRAMUNE®
)、地拉韋啶(delavirdine) (RESCRIPTOR®
)、依曲韋林(etravirine)(INTELENCE®
)、洛韋胺(loviride);ViroChem Pharma之HCV RNA依賴性核糖核酸聚合酶之非核苷抑制劑VCH-759,Pfizer之HCV聚合酶抑制劑之非核苷抑制劑PF-868554;及(d)聚合酶抑制劑,包括:Boehringer Ingelheim之C型肝炎病毒之RNA依賴性核糖核酸聚合酶BILB-1941、Roche之核糖核酸聚合酶抑制劑R1626;Achillion Pharmaceuticals之複製酶抑制劑ACH-0137171、Roche/Pharmasset之聚合酶抑制劑R7128、Abbott之聚合酶抑制劑ABT-333及ABT-072、Boehringer Ingelheim之聚合酶抑制劑BI 207127、Pharmasset之聚合酶抑制劑PSI-7851、Anadys Pharmaceuticals之聚合酶抑制劑ANA598、Merck之聚合酶抑制劑MK-3281、Idenix之聚合酶抑制劑IDX184、Glaxo Smith Kline之聚合酶抑制劑GSK 625433、Inhibitex之聚合酶抑制劑INX-189、Idenix之聚合酶抑制劑NM283、Wyeth之聚合酶抑制劑HCV796、Gilead之聚合酶抑制劑GL60667及GS9190、Pfizer之聚合酶抑制劑PF-00868554、Virochem之聚合酶抑制劑VCH759、VCH916、VX222及VX759、Idenix之聚合酶抑制劑IDX184及IDX375、Bristol Myers Squibb之聚合酶抑制劑BMS650032;(2)蛋白酶抑制劑
,包括例如:沙奎那韋(saquinavir)(FOROVASE®
/INVIRASE®
)、利托那韋(ritonavir)(NORVIR®
)、茚地那韋(indinavir)(CRIXIVAN®
)、奈非那韋(nelfinavir)(VIRACEPT®
)、安普那韋(amprenavir) (AGENERASE®
)、洛匹那韋(lopinavir)(KALETRA®
)、阿紮那韋(atazanavir)(REYATAZ®
)、夫沙那韋(fosamprenavir) (LEXIVA®
)、替拉那韋(tipranavir)(APTIVUS®
)、地瑞那韋(darunavir)(PREZISTA®
)、特拉匹韋(telapravir)(VX-950);Vertex Pharmaceuticals之第二代HCV蛋白酶抑制劑VX-500及VX-813;Intermune/Roche之NS3/4A蛋白酶抑制劑ITMN-191/R-7227、波沙匹韋(boceprevir)、Schering-Plough之蛋白酶抑制劑SCH 503034、Medivir/Tibotec之HCV NS3/4A蛋白酶抑制劑TMC435/TMC435350、Achillion Pharmaceuticals之蛋白酶抑制劑ACH-1625、Achillion/Gilead之蛋白酶抑制劑ACH-806、Boehringer Ingelheim之蛋白酶抑制劑BI201335及BILN 2061、Schering-Plough之蛋白酶抑制劑SCH 900518/SP900518(那拉匹韋(narlaprevir))、Merck之蛋白酶抑制劑MK-7009、Bristol Myeres Squibb之蛋白酶抑制劑BMS-650032、BMS-790052及BMS-791325、Roche之蛋白酶抑制劑R7227、Phenomix之蛋白酶抑制劑PHX1766、Avila Therapeutics之蛋白酶抑制劑AVL-181、膽綠素(biliverdin)、Roche Biosciences之蛋白酶抑制劑CTS-1027、Vertex之蛋白酶抑制劑VX985、Virochem/Vertex之蛋白酶抑制劑VCH-759及VCH-917、Idenix之蛋白酶抑制劑IDX-136及316、Abbott之蛋白酶抑制劑ABT-450、Virobay之蛋白酶抑制劑VBY 376;(3)整合酶抑制劑
,包括例如:雷特格韋(raltegravir) ISENTRESS®
)、依維拉韋(elvitegravir);(4)核苷類似物/核苷酸類似物抑制劑之組合療法,阿曲普(atripla)(泰諾福韋+恩曲他濱+依發韋侖)、卡貝滋(combivir)(拉米夫定+齊多夫定);(5)進入或融合抑制劑
,包括例如:馬拉韋羅(maraviroc)、恩夫韋地(enfuvirtide)、多可沙諾(docosanol)、抗CD4抗體、抗gp120抗體、抗CCR5抗體、HCV NS5a拮抗劑:(a)Arrow Therapeutics之A-831、A-689及AZD 2836,(b)Bristol Myers Squibb之BMS-790052及BMS-824393,(c)Glaxo Smith Kline之GSK-625433,(d)NS4a拮抗劑ACH-1095;(5)成熟抑制劑
,包括例如:貝韋立馬(bevirimat)及維韋克(vivecon);(6)病毒釋放抑制劑
,包括例如:紮那米韋(zanamivir)(RELENZA®
)、奧司他韋(oseltamivir)(TAMIFLU®
)、阿比朵爾(arbidol);(7)免疫反應增強劑
,包括例如干擾素-α,例如Biolex Therapeutics之BLX-883及BLX 883 CR,Nautilus Biotech之貝洛芬(belerofon),LG Life Sciences之長效IFN-α、IFN-αSR,Flamel Technologies之長效IFN-α2b CR及IFN-α2b XL,聚乙二醇化IFN-α(例如PEG-IFN-α-2a,PEGASYS®;PEG-IFN-α-2b,PEGINTRON®),IFN-a2b-人血清白蛋白融合蛋白(ALBUFERON®
);干擾素-β(包括IFN-β-1b(BETASERON®
))、干擾素-γ、干擾素-λ、聚乙二醇化干擾素-λ(例如ZymoGenetics/Novo Nordisk之PEG-rIL-29)、干擾素-ω/白血球II干擾素(例如Intarcia Therapeutics)、鐘樣受體7促效劑(包括Anadys Pharmaceuticals之咪喹莫特(imiquimod)、艾沙托立濱(isatoribine)及其前藥變異體(例如ANA-975及ANA-971))、Implicit Bioscience之奧穀凡尼(oglufanide)(IM862、L-Glu-L-Trp-OH)及其脂質或醣基結合變異體、NOV-205(例如Molixan®,NovelosTherapeutics, Inc.之一種抗病毒肽)、Enzo Biochem之抗病毒EHC18、γ-D-麩胺醯基-L-色胺酸(例如SCV-07,SciClone Pharmaceuticals/Verta)、阿洛夫隆(aloferon)(例如阿洛夫隆-1-HGVSGHGQHGVHG、阿洛夫隆-2-GVSGHGQHGVHG)、Coley Pharmaceuticals/Actilon之TLR-9促效劑CPG 10101;(8)抗病毒協同增強劑
,亦即雖然單獨時具有極小抗病毒性質或無抗病毒性質,但增進其他抗病毒劑之作用,例如氯奎寧(choroquine)、葡萄柚汁(grapefruit juice)、羥基尿素(hydroxyurea),來氟米特(leflunomide)、黴酚酸(mycophenolic acid)、白藜蘆醇(resveratrol)、利托那韋(ritonavi);以及其他抗病毒藥物,諸如三環癸胺(amantadine)、依度尿苷(edoxudine)、泛昔洛韋(famciclovir)(FAMVIR®
)、噴昔洛韋(penciclovir)、膦甲酸鈉(fascarnet)、膦乙酸(fosfonet)、更昔洛韋(ganciclovir)(CYTOVENE®
、CYMEVENE®
、VITRASERT®
)、嘉喜(gardasil)、伊巴他濱(ibacitabine)、異丙肌苷(imunovir)、嗎啉胍(moroxydine)、多吉美(nexavir)、帕拉米韋(peramivir)、普來可那利(pleconaril)、足葉草毒素(podophyllotoxin)、病毒唑(ribavirin)、金剛乙胺(rimantadine)、曲氟尿苷(trifluridine)、三協唯(trizivir)、曲金剛胺(tromantadine)、特魯瓦達(truvada),伐昔洛韋(valaciclovir)、纈更昔洛韋(valganciclovir)、阿糖腺苷(vidarabine)及干擾素增強劑,諸如Transition Therapeutics之EMZ702、組胺二鹽酸鹽(例如Ceplene® + IFN-α);及(9)雜項或未分類抗病毒劑
,諸如:Kemin Pharmaceuticals之KPE-02003002(雙氫青蒿素(Artenimol))、Antipodean Pharmaceuticals之輔酶Q10抗氧化促效劑米托喹酮(mitoquinone)、I型α-葡萄糖苷酶抑制劑(例如Migenix Pharmaceuticals之塞而高斯(celgosivir)MX-3253、栗樹精胺(castanospermine))、糖皮質激素拮抗劑(例如HCV IRES抑制劑、米非司酮(mifepristone)、VGX Pharmaceuticals之VGX-410C)、肝臟促效劑(例如Phynova Pharmaceuticals之PYN17)、衍生自傳統草本療法之抗病毒劑(例如Phynova Pharmaceuticals之PYN18)、卡斯蛋白酶抑制劑(caspase inhibitor)(例如LG Life Sciences之LB-84451、Pfizer之依莫瑞生(emricasan)PF-03491390/IDN-6556)、藉由阻止與親環蛋白A(cyclophilin A)結合來抑制病毒複製之環孢素類似物(例如Novartis之SDZ NIM 911、Debiopharm之Debio-025)。
術語「抗真菌劑」包括抑制或消除真菌生長、致病性及/或存活之任何分子。其包括例如(1)多烯抗真菌劑,諸如納他黴素(natamyin)、龜裂殺菌素(rimocidin)、菲律賓菌素(filipin)、製真菌素(nystatin)、兩性黴素B(Amphotericin B)、坎底辛(candicin);(2)咪唑類,諸如咪康唑(miconazole)、酮康唑(ketoconazole)(LOTRIMIN®
)、益康唑(econazole)、聯苯苄唑(bifonazole)、布康唑(butoconazole)、芬替康唑(fenticonazole)、異康唑(isoconazole)、奧昔康唑(oxiconazole)、舍他康唑(sertaconazole)(ERTACZO®)、硫康唑(sulconazole)、噻康唑(tioconazole);(3)三唑類,諸如氟康唑(fluconazole)、伊曲康唑(itraconazole)、艾沙康唑(isavuconazole)、拉夫康唑(ravuconazole)、泊沙康唑(posaconazole)、伏立康唑(voriconazole)、特康唑(terconazole);(4)烯丙胺類,諸如特比萘芬(terbinafine)(LAMISIL®
)、阿莫羅芬(amorolfine)、萘替芬(naftifine)(Naftin®
)、布替萘芬(butenafine)(LOTRIMIN ULTRA®
);(5)棘白菌素類(Echinocandins),諸如阿尼芬淨(anidulafungin)、卡泊芬淨(caspofungin)、米卡芬淨(micafungin)及具有抗真菌性質之其他物質,諸如苯甲酸、環吡酮(cicclopix)、氟胞嘧啶(flucytosine)、灰黃黴素(griseofulvin)、甲基紫(gentian violet)、鹵普羅近(haloprogin)、托萘酯(tolnaftate)(TINACTIN®
、DESENEX®
、AFTATE®
)、十一烯酸、茶樹油ISO 4730(茶樹精油,萜品烯-4-醇型)、香茅油、檸檬草、橙油、玫瑰草油、天竺薄荷油、檸檬桃金娘油、苦楝油、椰子油。
術語「抗原蟲劑」包括抑制或消除原蟲生物體之生長、致病性及/或存活之任何分子。抗原蟲劑之實例包括(1)抗瘧疾劑,例如奎寧(quinine)、奎寧麥克斯(quinimax)、奎尼丁(quinidine)、奎寧麥克斯、氯奎寧(ARALEN®)、脛氯奎寧(Hydroxycloroquine)(PLAQUENIL®)、阿莫地奎寧、乙胺嘧啶(pyrimethamine)(DARAPRIM®)、磺胺多辛(sulphadoxine)、氯胍(proguanil)、美爾奎寧(mefloquine) (LARIAM®)、鹵泛群(halofantrine)、伯胺奎(primaquine)、青蒿素(artemesinin)及其衍生物(例如蒿甲醚(artemether)、青蒿琥酯(artensunate)、雙氫青蒿素(dihydroartemisinin)、蒿乙醚(arteether))、克林黴素(clindamycin)及其組合;(2)蛋白酶抑制劑及藥物,苄硝唑(benznidaole)、布帕伐醌(buparvaquone)、卡巴胂(carbarsone)、氯碘羥喹(clioquinol)、雙硫侖(disulfiram)、依氟鳥胺酸(eflornithine)、依米丁(emetine)、呋喃唑酮(furazolidone)、葡甲胺銻酸鹽(meglumine antimoniate)、美拉胂醇(melarsoprol)、甲硝唑(metronidazole)(FLAGYL®)、米替福新(miltefosine)、硝呋替莫(nifurtimox)、硝唑尼特(nitazoxanide)、奧硝唑(ornidazole)、硫酸巴龍黴素(paromomycin sulfate)、噴他脒(pentamidine)、乙胺嘧啶(pyrimethamine)(DARAPRIM®)、塞克硝唑(secnidazole)、替硝唑(tinidazole)。
如本文所用之術語「疫苗」包括當接種至宿主中時誘導針對特異性病原體之保護性免疫的任何非病原性免疫原。疫苗可採用許多形式。疫苗可為與病原體共享重要抗原但本身不具病原性之完整生物體(例如牛痘)。疫苗亦可藉由殺死(例如沙克小兒麻痹疫苗(Salk polio vaccine))或減毒(損失產生疾病之能力,例如沙賓小兒麻痹疫苗(Sabin polio vaccine))來製備。疫苗亦可由自病原生物體分離之經純化大分子製備。舉例而言,含有失活形式之可溶性細菌毒素之類毒素疫苗(例如破傷風及白喉症),其引起產生抗毒素抗體,但對完整細菌不具有免疫力。次單位疫苗(例如B型肝炎)僅含有自相關病原體分離之單一免疫原性蛋白質。半抗原結合疫苗使自相關病原體分離之某些碳水化合物或多肽抗原決定基附著於免疫原運載體(諸如破傷風類毒素)。此等策略基本上使用抗原決定基作為半抗原來誘導抗體產生,該等抗體接著識別天然病原體中之相同抗原決定基。然而,為使效果最佳,該等疫苗必須合併有B與T細胞抗原決定基,且T細胞抗原決定基必須經選擇以確保其可由宿主個體之免疫系統識別、由該免疫系統呈現且應答該免疫系統。
DNA疫苗利用宿主細胞溶解及表現肌內注射之編碼病原性蛋白質之DNA的能力。
可與抗PD-L1抗體組合用於本文所述之方法中的抗病毒疫苗之實例包括:Pevion Biotech.之HCV疫苗(病毒顆粒)、經設計以增進細胞(細胞毒性T淋巴細胞CD4+及CD8+)針對NS3、NS4及NS5B之免疫反應的Transgene viron之TG4040(MVA-HCV)、Inovio Biomedical之密碼子經優化之NS3/4a DNA疫苗CHRONVAC®、Novartis之HCV/CpG疫苗、Globeimmune之HCV疫苗GI-5005、Intercell之具有HCV CD4及CD8 T抗原決定基之合成肽與聚L-精胺酸組合之混合物IC41。
若以與佐劑之混合物形式投與,則可增強宿主對免疫原之反應。免疫佐劑以一或多種以下方式起作用:(1)延長免疫原留存時間,(2)增加免疫原之有效大小(且因此促進對巨噬細胞之吞噬及呈現),(3)刺激巨噬細胞或其他免疫細胞流入注射部位,或(4)促進局部細胞激素產生及其他免疫活性。佐劑之實例包括:傅氏完全佐劑(CFA)、鋁鹽及分支桿菌衍生蛋白(諸如胞壁醯二肽或胞壁醯三肽)。
術語「抗體」包括單株抗體(包括具有免疫球蛋白Fc區之全長抗體)、具有多抗原決定基特異性之抗體組合物、多特異性抗體(例如雙特異性抗體、雙功能抗體及單鏈分子)以及抗體片段(例如Fab、F(ab')2
及Fv)。本文中術語「免疫球蛋白」(Ig)可與「抗體」互換使用。
基本四鏈抗體單位為雜四聚醣蛋白,其由兩條相同之輕(L)鏈及兩條相同之重(H)鏈構成。IgM抗體由5個基本雜四聚體單位以及稱為J鏈之另一多肽組成,且含有10個抗原結合位點,而IgA抗體包含2-5個可與J鏈組合聚合形成多價裝配體(assemblage)之基本四鏈單位。在IgG之情況下,四鏈單位一般為約150,000道爾頓。各L鏈經由一個共價雙硫鍵與H鏈鍵聯,而視H鏈同型而定,兩條H鏈經由一或多個雙硫鍵彼此鍵聯。各H及L鏈亦具有規則間隔之鏈內雙硫橋。各H鏈在N末端具有可變域(VH
),繼之以各α及γ鏈之三個恆定域(CH
)及μ及ε同型之四個CH
域。各L鏈在N末端具有可變域(VL
),繼之以位於其另一端之恆定域。VL
對準VH
且CL
對準重鏈之第一恆定域(CH
1)。咸信特定胺基酸殘基在輕鏈與重鏈可變域之間形成界面。VH
與VL
一起配對形成單一抗原結合位點。關於不同種類抗體之結構及性質,參見例如Basic and Clinical Immunology
, 第8版,Daniel P. Stites, Abba I. Terr及Tristram G. Parslow(編),Appleton & Lange, Norwalk, Conn., 1994, 第71頁及第6章。基於恆定域之胺基酸序列,任何脊椎動物物種之L鏈均可歸為稱為κ及λ之兩個明顯不同之類型中的一者中。視重鏈之恆定域(CH)之胺基酸序列而定,免疫球蛋白可歸為不同類別或同型中。免疫球蛋白有五種類別:IgA、IgD、IgE、IgG及IgM,其分別具有以α、δ、ε、γ及μ表示之重鏈。基於CH序列及功能之相對較小之差異,γ及α類別進一步細分成亞類,例如人類表現以下亞類:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1及IgA2。
「經分離」抗體為已自其產生環境(例如天然或重組)之組分中鑑別、分離及/或回收之抗體。較佳地,經分離多肽不與其產生環境之所有其他組分締合。其產生環境之污染組分(諸如由重組轉染細胞產生之污染組分)為通常將干擾抗體之研究、診斷或治療性用途之物質,且可包括酶、激素及其他蛋白質或非蛋白質溶質。在較佳實施例中,將多肽(1)純化至如藉由例如勞立(Lowry)方法所測定,95重量%以上之抗體,且在某些實施例中,純化至99重量%以上;(1)純化至藉由使用旋杯式序列分析儀足以獲得N末端或內部胺基酸序列之至少15個殘基的程度,或(3)純化至使用考馬斯藍(Coomassie blue)或較佳銀染在非還原或還原條件下由SDS-PAGE鑑定為均質(homogeneity)。由於抗體天然環境之至少一種組分將不存在,故經分離抗體包括原位(in situ
)處於重組細胞內之抗體。然而,經分離多肽或抗體通常將由至少一個純化步驟來製備。
抗體之「可變區」或「可變域」係指抗體之重鏈或輕鏈之胺基末端域。重鏈及輕鏈之可變域可分別稱為「VH」及「VL」。此等域一般為抗體之最可變部分(相對於同一類別之其他抗體)且含有抗原結合位點。
術語「可變」係指抗體中可變域之某些區段在序列上廣泛不同。V域介導抗原結合且定義特定抗體對其特定抗原之特異性。然而,可變性並非均勻分布於整個可變域中。相反,其集中於輕鏈可變域與重鏈可變域中稱為高變區(HVR)之三個區段中。可變域之更高保守部分稱作構架區(FR)。天然重鏈及輕鏈之可變域各包含四個主要採用β-摺疊構型之FR區,該等FR區由三個HVR連接,該等HVR形成連接β-摺疊結構之環,且在一些情況下形成β-摺疊結構之一部分。各鏈中之HVR與另一鏈中之HVR藉由FR區緊密結合在一起,促使形成抗體之抗原結合位點(參見Kabat等人,Sequences of Immunological Interest
, 第五版, National Institute of Health, Bethesda, MD (1991))。雖然恆定域並不直接參與抗體與抗原之結合,但展現各種效應功能,諸如使抗體參與抗體依賴性細胞毒性。
如本文所用之術語「單株抗體」係指自實質上均質之抗體群體所獲得之抗體,亦即,構成該群體之個別抗體除可微量存在之可能的天然存在之突變及/或轉譯後修飾(例如異構化、醯胺化)外相同。單株抗體針對單一抗原位點具有高特異性。與通常包括針對不同決定子(抗原決定基)之不同抗體的多株抗體製劑相反,各單株抗體針對抗原上之單一決定子。除其特異性以外,單株抗體之有利之處在於其藉由融合瘤培養合成,不受其他免疫球蛋白污染。修飾語「單株」指示如同獲自實質上均質之抗體群體之抗體特徵,且不應理解為需要由任何特定方法產生抗體。舉例而言,根據本發明欲使用之單株抗體可由多種技術製備,該等技術包括例如融合瘤方法(例如,Kohler及Milstein.
,Nature
, 256:495-97 (1975);Hongo等人,Hybridoma,
14(3): 253-260 (1995);Harlow等人,Antibodies: A Laboratory Manual
, (Cold Spring Harbor Laboratory Press, 第2版, 1988);Hammerling等人,Monoclonal Antibodies and T-Cell Hybridomas
563-681 (Elsevier, N.Y., 1981))、重組DNA方法(參見例如美國專利第4,816,567號)、噬菌體呈現技術(參見例如Clackson等人,Nature
, 352: 624-628 (1991);Marks等人,J. Mol. Biol.
222: 581-597 (1992);Sidhu等人,J. Mol. Biol.
338(2): 299-310(2004);Lee等人,J. Mol. Biol.
340(5): 1073-1093 (2004);Fellouse,Proc. Natl. Acad. Sci. USA
101(34): 12467-12472 (2004);及Lee等人,J. Immunol. Methods
284(1-2): 119-132 (2004))及在動物中產生具有部分或所有編碼人類免疫球蛋白序列之人類免疫球蛋白基因座或基因之人類或人類樣抗體的技術(參見例如WO 1998/24893;WO 1996/34096;WO 1996/33735;WO 1991/10741;Jakobovits等人,Proc. Natl. Acad. Sci. USA
90: 2551 (1993);Jakobovits等人,Nature
362: 255-258 (1993);Bruggemann等人,Year in Immunol.
7:33 (1993);美國專利第5,545,807號;第5,545,806號;第5,569,825號;第5,625,126號;第5,633,425號及第5,661,016號;Marks等人,Bio/Technology
10: 779-783 (1992);Lonberg等人,Nature
368: 856-859 (1994);Morrison,Nature
368: 812-813 (1994);Fishwild等人,Nature Biotechnol.
14: 845-851 (1996);Neuberger,Nature Biotechnol.
14: 826 (1996);及Lonberg及Huszar,Intern. Rev. Immunol.
13: 65-93 (1995)。
術語「裸抗體」係指未與細胞毒性部分或放射性標記結合之抗體。
術語「全長抗體」、「完整抗體」及「全抗體」可互換使用,指與如抗體片段相對之大體上為完整形式的抗體。特定言之,全抗體包括具有包括Fc區之重鏈及輕鏈之抗體。恆定域可為天然序列恆定域(例如人類天然序列恆定域)或其胺基酸序列變異體。在一些情況下,完整抗體可具有一或多種效應功能。
「抗體片段」包含完整抗體之一部分,較佳為完整抗體之抗原結合區及/或可變區。抗體片段之實例包括Fab、Fab'、F(ab')2
及Fv片段;雙功能抗體;線性抗體(參見美國專利5,641,870,實例2;Zapata等人,Protein Eng. 8(10)
: 1057-1062 [1995]);單鏈抗體分子及由抗體片段形成之多特異性抗體。木瓜蛋白酶消化抗體產生稱為「Fab」片段之兩個相同之抗原結合片段及殘餘「Fc」片段,該名稱反映容易地結晶之能力。Fab片段由整個L鏈以及H鏈之可變區之域(VH
)及一條重鏈之第一恆定域(CH
1)組成。各Fab片段對抗原結合而言為單價的,亦即其具有單一抗原結合位點。用胃蛋白酶處理抗體產生單一大F(ab')2
片段,其大致對應於具有不同抗原結合活性之兩個雙硫鍵鍵聯之Fab片段且仍能夠交聯抗原。Fab'片段與Fab片段之不同之處在於在包括一或多個來自抗體鉸鏈區之半胱胺酸的CH
1域之羧基末端具有少量其他殘基。Fab'-SH在本文中為恆定域之半胱胺酸殘基帶有游離硫醇基之Fab'的名稱。最初F(ab')2
抗體片段以其間具有鉸鏈半胱胺酸之Fab'片段對形式產生。亦已知抗體片段之其他化學偶合。
Fc片段包含經由雙硫鍵結合在一起之兩條H鏈之羧基末端部分。抗體之效應功能由Fc區中之序列決定,該區亦由某些類型細胞上所發現之Fc受體(FcR)識別。
「Fv」為含有完全抗原識別及結合位點之最小抗體片段。此片段由緊密非共價締合之一重鏈可變區之域與一輕鏈可變區之域之二聚體組成。此兩個域之摺疊產生6個高變環(H及L鏈各3個環),該等環提供胺基酸殘基供抗原結合且賦予抗原結合抗體之特異性。然而,甚至單一可變域(或僅包含三個對抗原具有特異性之HVR的Fv的一半)亦具有識別及結合抗原之能力,但親和力比整個結合位點低。
「單鏈Fv」亦縮寫為「sFv」或「scFv」,其為包含連接於單一多肽鏈中之VH
及VL
抗體域之抗體片段。較佳地,sFv多肽進一步包含VH
與VL
域之間使sFv能夠形成抗原結合所要之結構的多肽連接子。關於sFv之綜述,參見Pluckthun,The Pharmacology of Monoclonal Antibodies
, 第113卷, Rosenburg及Moore編,Springer-Verlag, New York, 第269-315頁 (1994)。
本發明抗體之「功能片段」包含完整抗體之一部分,一般包括完整抗體之抗原結合區或可變區或保留FcR結合能力或具有改良之FcR結合能力之抗體的Fc區。抗體片段之實例包括線性抗體、單鏈抗體分子及由抗體片段形成之多特異性抗體。
術語「雙功能抗體」係指藉由在VH
與VL
域之間用短連接子(約5-10個殘基)構築sFv片段(參見先前段落)以致實現V域之鏈間配對而非鏈內配對,藉此產生二價片段(亦即具有兩個抗原結合位點之片段)所製備之小抗體片段。雙特異性雙功能抗體為具有兩個「交叉」sFv片段之雜二聚體,其中兩個抗體之VH
及VL
域存在於不同多肽鏈上。雙功能抗體更詳細描述於例如EP 404,097;WO 93/11161;Hollinger等人,Proc. Natl. Acad. Sci. USA 90
: 6444-6448 (1993)中。
本文之單株抗體特定包括「嵌合」抗體(免疫球蛋白),其中重鏈及/或輕鏈的一部分與衍生自特定物種或屬於特定抗體類別或亞類之抗體中的相應序列相同或同源,而該(該等)鏈之其餘部分與衍生自另一物種或屬於另一抗體類別或亞類之抗體中的相應序列相同或同源;以及該等抗體之片段,只要其展現出所要的生物活性即可(美國專利第4,816,567號;Morrison等人,Proc. Natl. Acad. Sci. USA
,81
:6851-6855 (1984))。本文之相關嵌合抗體包括PRIMATIZED®
抗體,其中抗體之抗原結合區係衍生自藉由例如用相關抗原使獼猴免疫所產生之抗體。如本文所用之「人類化抗體」為「嵌合抗體」之子集。
非人類(例如鼠類)抗體之「人類化」形式為含有衍生自非人類免疫球蛋白之最小序列的嵌合抗體。在一實施例中,人類化抗體為人類免疫球蛋白(接受者抗體),其中來自接受者之HVR(下文定義)的殘基經來自具有所要特異性、親和力及/或能力之非人類物種(供體抗體)(諸如小鼠、大鼠、兔或非人類靈長類動物)之HVR的殘基置換。在一些情況下,人類免疫球蛋白之構架(「FR」)殘基經相應非人類殘基置換。此外,人類化抗體可包含接受者抗體或供體抗體中未發現之殘基。可進行此等修飾以進一步改進抗體效能,諸如結合親和力。一般而言,人類化抗體將包含實質上所有至少一個且通常兩個可變域,其中所有或實質上所有高變環對應於非人類免疫球蛋白序列之高變環,且所有或實質上所有FR區為人類免疫球蛋白序列之FR區,但FR區可包括一或多種改良抗體效能(諸如結合親和力、異構化作用、免疫原性等)之個別FR殘基取代。FR之H鏈中之此等胺基酸取代的數目通常不超過6,且在L鏈中不超過3。人類化抗體視情況亦將包含至少一部分免疫球蛋白恆定區(Fc),通常為人類免疫球蛋白之恆定區。關於更多詳情,參見例如Jones等人,Nature
321:522-525 (1986);Riechmann等人,Nature
332:323-329 (1988);及Presta,Curr. Op. Struct. Biol.
2:593-596 (1992)。亦參見例如Vaswani及Hamilton,Ann. Allergy, Asthma & Immunol
. 1:105-115 (1998);Harris,Biochem. Soc. Transactions
23:1035-1038 (1995);Hurle及Gross,Curr. Op. Biotech
. 5:428-433 (1994);及美國專利第6,982,321號及第7,087,409號。
「人類抗體」為具有對應於人類所產生之抗體之胺基酸序列的胺基酸序列的抗體及/或已使用如本文所揭示之用於製造人類抗體之技術中之任一種製成的抗體。人類抗體之此定義特定排除包含非人類抗原結合殘基之人類化抗體。可使用此項技術中已知之各種技術(包括噬菌體呈現文庫)產生人類抗體。Hoogenboom及Winter,J. Mol. Biol
., 227:381 (1991);Marks等人,J. Mol. Biol
., 222:581 (1991)。亦可用於製備人類單株抗體之方法為Cole等人,Monoclonal Antibodies and Cancer Therapy
, Alan R. Liss, 第77頁 (1985);Boerner等人,J. Immunol.
, 147(1):86-95 (1991)中所述之方法。亦參見van Dijk及van de Winkel,Curr. Opin. Pharmacol., 5
: 368-74 (2001)。人類抗體可藉由向已經修飾以應答抗原攻擊產生該等抗體但內源性基因座已喪失能力之轉殖基因動物(例如經免疫異種小鼠)投與抗原來製備(關於XENOMOUSETM
技術,參見例如美國專利第6,075,181號及第6,150,584號)。關於經由人類B細胞融合瘤技術產生之人類抗體,亦參見例如Li等人,Proc. Natl. Acad. Sci. USA
,103
:3557-3562 (2006)。
術語「高變區」、「HVR」或「HV」在本文中使用時係指序列高變且/或形成結構確定之環之抗體可變域的區。一般而言,抗體包含6個HVR;三個位於VH中(H1,H2、H3),且三個位於VL中(L1、L2,L3)。在天然抗體中,H3及L3在六個HVR中顯示最具多樣性,且咸信尤其H3在賦予抗體精細特異性方面發揮獨特作用。參見例如Xu等人,Immunity 13
:37-45 (2000);Johnson及Wu,Methods in Molecular Biology 248:
1-25 (Lo編,Human Press, Totowa, NJ, 2003)。實際上,僅由重鏈組成之天然存在之駱駝抗體無輕鏈存在下亦具功能性且穩定。參見例如Hamers-Casterman 等人, Nature 363
:446-448 (1993);Sheriff等人, Nature Struct. Biol. 3
:733-736 (1996)。
有許多HVR描繪在使用且其為本文中所涵蓋。Kabat互補決定區(CDR)係基於序列可變性且最常使用(Kabat等人,Sequences of Proteins of Immunological Interest
, 第5版, Public Health Service, National Institutes of Health, Bethesda, MD.(1991))。Chothia另外指出結構環之位置(Chothia及LeskJ. Mol. Biol
.196
:901-917(1987))。AbM HVR表示Kabat HVR與Chothia結構環之間的折衷,且藉由Oxford Molecular之AbM抗體模型化軟體使用。「contact」HVR係基於對可用複雜晶體結構之分析。此等HVR中之每一者之殘基如下所說明。
環 Kabat AbM Chothia Contact
---- ----- --- ------- -------
L1 L24-L34 L24-L34 L26-L32 L30-L36
L2 L50-L56 L50-L56 L50-L52 L46-L55
L3 L89-L97 L89-L97 L91-L96 L89-L96
H1 H31-H35B H26-H35B H26-H32 H30-H35B
(Kabat編號)
H1 H31-H35 H26-H35 H26-H32 H30-H35
(Chothia編號)
H2 H50-H65 H50-H58 H53-H55 H47-H58
H3 H95-H102 H95-H102 H96-H101 H93-H101
HVR可包含如下「延長HVR」:VL中之24-36或24-34(L1)、46-56或50-56(L2)及89-97或89-96(L3);及VH中之26-35(H1)、50-65或49-65(H2)及93-102、94-102或95-102(H3)。可變域殘基係根據Kabat等人,同上關於此等定義中之每一者所述編號。
表述「如Kabat中編號之可變域殘基」或「如Kabat中編號之胺基酸位置」及其變化形式係指Kabat等人,同上中用於抗體彙編之重鏈可變域或輕鏈可變域的編號系統。使用此編號系統,實際的線性胺基酸序列可含有更少或額外的胺基酸,相當於縮短可變域之FR或HVR或在其中進行插入。舉例而言,重鏈可變域可包括H2之殘基52之後的單一胺基酸插入(根據Kabat之殘基52a)及重鏈FR殘基82之後的插入殘基(例如,根據Kabat之殘基82a、82b及82c等)。可藉由將既定抗體之序列同源區與「標準」Kabat編號序列比對來確定該抗體殘基的Kabat編號。
「構架」或「FR」殘基為除如本文所定義之HVR殘基以外的彼等可變域殘基。
「人類共同構架」或「受體人類構架」為在選擇人類免疫球蛋白VL或VH構架序列時表示最通常存在之胺基酸殘基的構架。一般而言,人類免疫球蛋白VL或VH序列係選自可變域序列之亞群。一般而言,序列之亞群為如Kabat等人,Sequences of Proteins of Immunological Interest
, 第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991)中之亞群。對於VL,實例包括該亞群可為如Kabat等人,同上中之亞群κI、κII、κIII或κIV。另外,對於VH,亞群可為如Kabat等人,同上中之亞群I、亞群II或亞群III。或者,人類共同構架可衍生自諸如當人類構架殘基係基於與供體構架之同源性藉由比對供體構架序列與許多各種人類構架序列而選擇時具有特定殘基之以上亞群。「衍生自」人類免疫球蛋白構架或人類共同構架之受體人類構架可包含其相同胺基酸序列或其可含有預先存在之胺基酸序列變化。在一些實施例中,預先存在之胺基酸變化之數目為10個或更少、9個或更少、8個或更少、7個或更少、6個或更少、5個或更少、4個或更少、3個或更少或2個或更少。
「VH亞群III共同構架」包含獲自Kabat等人,同上之可變重鏈亞群III之胺基酸序列中的共同序列。在一實施例中,VH亞群III共同構架胺基酸序列包含以下每一序列之至少一部分或全部:EVQLVESGGGLVQPGGSLRLSCAAS(HC-FR1)(SEQ ID NO:4)、WVRQAPGKGLEWV(HC-FR2)(SEQ ID NO:5)、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(HC-FR3,SEQ ID NO:6)、WGQGTLVTVSA(HC-FR4)(SEQ ID NO:7)。
「VL κI共同構架」包含獲自Kabat等人,同上之可變輕鏈κ亞群I之胺基酸序列中的共同序列。在一實施例中,VH亞群I共同構架胺基酸序列包含以下每一序列之至少一部分或全部: DIQMTQSPSSLSASVGDRVTITC(LC-FR1)(SEQ ID NO:11)、WYQQKPGKAPKLLIY(LC-FR2)(SEQ ID NO:12)、GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(LC-FR3)(SEQ ID NO:13)、FGQGTKVEIKR(LC-FR4)(SEQ ID NO:14)。
指定位置(例如,Fc區域之指定位置)之「胺基酸修飾」係指指定殘基之取代或缺失或至少一個胺基酸殘基鄰接指定殘基插入。「鄰接」指定殘基插入意謂在其一至兩個殘基範圍內插入。插入可在指定殘基之N末端或C末端。本文中之較佳胺基酸修飾為取代。
「親和力成熟」抗體為在其一或多個HVR中具有一或多處可使得抗體對抗原之親和力改良之變化的抗體(與不具有彼等變化之親本抗體相比)。在一實施例中,親和力成熟抗體對標靶抗原具有奈莫耳(nanomolar)或甚至皮莫耳(picomolar)親和力。親和力成熟抗體由此項技術中已知之程序產生。舉例而言,Marks等人,Bio/Technology
10:779-783 (1992)描述藉由VH及VL域改組(shuffling)達成之親和力成熟。HVR及/或構架殘基之隨機突變誘發例如描述於Barbas等人,Proc Nat. Acad. Sci. USA
91:3809-3813 (1994);Schier等人,Gene
169:147-155 (1995);Yelton等人,J. Immunol.
155:1994-2004 (1995);Jackson等人,J. Immunol.
154(7):3310-9 (1995);及Hawkins等人,J. Mol. Biol.
226:889-896 (1992)。
如本文所用之術語「特異性結合」或「具有特異性」係指諸如標靶與抗體之間的結合之可量測且可重現之相互作用,其在包括生物分子之分子之異質群體存在下確定標靶之存在。舉例而言,特異性結合標靶(可為抗原決定基)之抗體為與結合其他標靶相比以較大親和力(affinity、avidity)、更容易及/或以更長持續時間結合此標靶之抗體。在一實施例中,如例如放射性免疫檢定(RIA)所量測,抗體與無關標靶結合之程度為抗體與該標靶之結合之約10%以下。在某些實施例中,特異性結合標靶之抗體的解離常數(Kd)≤1 μM、≤100 nM、≤10 nM、≤1 nM或≤0.1 nM。在某些實施例中,抗體特異性結合在來自不同物種之蛋白質中為保守的蛋白質上之抗原決定基。在另一實施例中,特異性結合可包括(但不必需)排他性結合。
「阻斷」抗體或「拮抗」抗體為抑制或降低所結合之抗原之生物活性的抗體。在某些實施例中,阻斷抗體或拮抗抗體實質上或完全抑制抗原之生物活性。本發明抗PD-L1抗體阻斷經由PD-1之信號傳導以便使T細胞之功能反應自功能障礙狀態恢復至抗原刺激。
「促效」或活化抗體為增強或引發所結合之抗原之信號傳導的抗體。在一些實施例中,在無天然配位體存在下,促效抗體引起或活化信號傳導。
術語「固相」描述本發明抗體可黏著之非水性基質。本文中所涵蓋之固相之實例包括部分或完全由玻璃(例如受控微孔玻璃)、多醣(例如瓊脂糖)、聚丙烯醯胺、聚苯乙烯、聚乙烯醇及聚矽氧形成之固相。在某些實施例中,視上下文而定,固相可包含檢定板之孔;在其他實施例中,其為純化管柱(例如親和層析管柱)。此術語亦包括離散粒子之不連續固相,諸如美國專利第4,275,149號中所述之固相。
「抗體效應功能」係指彼等可歸功於抗體之Fc區(天然序列Fc區或胺基酸序列變異Fc區)之生物活性,且隨抗體同型而變化。抗體效應功能之實例包括:C1q結合及補體依賴性細胞毒性、Fc受體結合、抗體依賴性細胞介導之細胞毒性(ADCC)、吞噬作用、細胞表面受體(例如B細胞受體)調降及B細胞活化。「降低或最小化」抗體效應功能意謂比野生型或未經修飾之抗體減少至少50%(或者60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)。抗體效應功能之測定可由一般熟習此項技術者容易地測定及量測。在一較佳實施例中,補體結合、補體依賴性細胞毒性及抗體依賴性細胞毒性之抗體效應功能受到影響。在本發明之某些實施例中,經由消除糖基化之恆定區中之突變(例如「無效應突變(effector-less mutation)」)消除效應功能。在一態樣中,無效應突變為CH2區中之N297A或DANA突變(D265A+N297A)。Shields等人,J. Biol. Chem. 276
(9): 6591-6604 (2001)。或者,導致效應功能降低或消除之其他突變包括:K322A及L234A/L235A(LALA)。或者,可經由諸如表現於不糖基化或產生對促進效應功能無效或效果較差之改變之糖基化模式之宿主細胞(例如大腸桿菌)中的產生技術來降低或消除效應功能(例如Shinkawa等人,J. Biol. Chem. 278
(5): 3466-3473 (2003))。
「抗體依賴性細胞介導之細胞毒性」或ADCC係指一種細胞毒性形式,其中所分泌之結合於存在於某些細胞毒性細胞(例如天然殺傷(NK)細胞、嗜中性白血球及巨噬細胞)上之Fc受體(FcR)的Ig使得此等細胞毒效應細胞能夠與帶有抗原之標靶細胞特異性結合且隨後以細胞毒素殺傷該標靶細胞。該等抗體「武裝」細胞毒性細胞且為利用此機制殺死標靶細胞所需。介導ADCC之初級細胞NK細胞僅表現FcγRIII,而單核細胞表現FcγRI、FcγRII及FcγRIII。Fc在造血細胞上之表現概述於Ravetch及Kinet,Annu. Rev. Immunol
.9
: 457-92 (1991)之第464頁之表3中。為評估相關分子之ADCC活性,可執行活體外ADCC檢定,諸如美國專利第5,500,362號或第5,821,337號中所述之檢定。適用於該等檢定之效應細胞包括周邊血液單核細胞(PBMC)及自然殺傷(NK)細胞。或者或另外,可例如在諸如Clynes等人,PNAS USA 95
:652-656 (1998)中所揭示之動物模型中活體內評估相關分子之ADCC活性。
除非本文另有指示,否則免疫球蛋白重鏈中之殘基編號為如Kabat等人,同上中之EU索引編號。「如Kabat中之EU索引」係指人類IgG1 EU抗體之殘基編號。
本文中之術語「Fc區」用以定義免疫球蛋白重鏈之C末端區,包括天然序列Fc區及變異Fc區。儘管免疫球蛋白重鏈之Fc區之邊界可變化,但人類IgG重鏈Fc區通常定義為自位置Cys226處之胺基酸殘基或自Pro230至其羧基末端的一段。可例如在抗體產生或純化期間或藉由重組工程改造編碼抗體重鏈之核酸來移除Fc區之C末端離胺酸(根據EU編號系統為殘基447)。因此,完整抗體之組合物可包含已移除所有K447殘基之抗體群體、未移除任何K447殘基之抗體群體及具有有及無K447殘基之抗體之混合物的抗體群體。適用於本發明抗體之天然序列Fc區包括人類IgG1、IgG2(IgG2A、IgG2B)、IgG3及IgG4。
「Fc受體」或「FcR」描述結合抗體Fc區之受體。較佳FcR為天然序列人類FcR。此外,較佳FcR為結合IgG抗體(γ受體)且包括FcγRI、FcγRII及FcγRIII亞類之受體(包括此等受體之對偶基因變異體及替代性剪接形式)的FcR,FcγRII受體包括FcγRIIA(「活化受體」)及FcγRIIB(「抑制受體」),其具有主要其細胞質域不同之類似胺基酸序列。活化受體FcγRIIA在其細胞質域中含有基於免疫受體酪胺酸之活化基元(ITAM)。抑制受體FcγRIIB在其細胞質域中含有基於免疫受體酪胺酸之抑制基元(ITIM)。(參見M. Daëron,Annu. Rev. Immunol. 15
:203-234 (1997))。FcR綜述於Ravetch及Kinet,Annu. Rev. Immunol. 9
: 457-92 (1991);Capel等人,Immunomethods 4
: 25-34 (1994);及de Haas等人,J. Lab. Clin. Med. 126
: 330-41 (1995)中。本文之術語「FcR」涵蓋其他FcR,包括有待將來鑑別之FcR。
術語「Fc受體」或「FcR」亦包括新生兒受體FcRn,其負責將母體IgG轉移至胎兒。Guyer等人,J. Immunol. 117
: 587 (1976)及Kim等人,J. Immunol. 24
: 249 (1994)。已知量測與FcRn之結合之方法(參見例如Ghetie及Ward,Immunol. Today 18
: (12): 592-8 (1997);Ghetie等人,Nature Biotechnology 15
(7): 637-40 (1997);Hinton等人,J. Biol. Chem
.279
(8): 6213-6 (2004);WO 2004/92219 (Hinton等人))。可例如在表現人類FcRn之轉殖基因小鼠或經轉染人類細胞株中,或在投與具有變異Fc區之多肽的靈長類動物中,檢定活體內與FcRn之結合及人類FcRn高親和力結合多肽之血清半衰期。WO 2004/42072(Presta)描述與FcR之結合提高或降低之抗體變異體。亦參見例如Shields等人,J. Biol. Chem. 9
(2): 6591-6604 (2001)。
「效應細胞」為表現一或多個FcR且執行效應功能之白血球。在一態樣中,效應細胞至少表現FcγRIII且執行ADCC效應功能。介導ADCC之人類白血球之實例包括周圍血液單核細胞(PBMC)、天然殺傷(NK)細胞、單核細胞、細胞毒性T細胞及嗜中性白血球。效應細胞可自例如血液之天然來源分離。效應細胞一般為與效應期相關之淋巴細胞,且用以產生細胞激素(輔助T細胞)、殺死受病原體感染之細胞(細胞毒性T細胞)或分泌抗體(分化B細胞)。
「補體依賴性細胞毒性」或「CDC」係指在補體存在下標靶細胞之溶解。藉由使補體系統之第一組分(C1q)結合至與其同源抗原結合之抗體(屬於適當亞類)引發典型補體路徑之活化。為評估補體活化,可執行CDC檢定,例如如Gazzano-Santoro等人,J. Immunol. Methods 202
: 163 (1996)中所述。具有改變之Fc區胺基酸序列及增強或降低之C1q結合能力的抗體變異體描述於美國專利第6,194,551B1號及WO99/51642中。彼等專利公開案之內容特別地以引用的方式併入本文中。亦參見Idusogie等人,J. Immunol.
164: 4178-4184 (2000)。
IgG中之N糖基化位點位於CH2域中之Asn297處。本發明亦提供具有效應功能降低或無效應功能之Fc區的結合抗原之人類化抗體之組合物。可實現此舉之一種方式為A297N取代,先前已展示其消除抗CD20抗體中之補體結合及效應功能(「無效應Fc突變」)。Idusgie等人,同上。由於此突變,在諸如CHO之哺乳動物細胞中產生含有此Fc突變之本發明抗PD-L1抗體無任何糖基化,且此又產生降低的或最小效應功能。或者,可在無CH2取代下藉由表現於諸如大腸桿菌之非哺乳動物細胞中消除抗體效應功能。
「結合親和力」一般係指分子(例如抗體)之單一結合位點與其結合搭配物(例如抗原)間之非共價相互作用的總強度。除非另作指示,否則如本文所用之「結合親和力」係指反映結合對(例如抗體與抗原)成員之間1:1相互作用之固有結合親和力。分子X對其搭配物Y之親和力一般可由解離常數(Kd)表示。親和力可由此項技術中已知之常用方法(包括本文所述之彼等方法)量測。低親和力抗體一般緩慢地結合抗原且傾向於容易地解離,而高親和力抗體一般較快地結合抗原且傾向於長時間保持結合。此項技術中已知多種量測結合親和力之方法,該等方法中之任一者皆可用於達成本發明之目的。量測結合親和力之具體說明性及例示性實施例描述於下文中。
在一實施例中,由放射性標記抗原結合檢定(RIA)量測本發明之「Kd」或「Kd值」,該檢定用抗體之Fab形式與抗原分子如以下檢定所述執行:藉由在一系列用於滴定之未標記抗原存在下以最低濃度之經(125
I)標記抗原平衡Fab、接著以塗有抗Fab抗體之板捕捉結合抗原來量測Fab對抗原之溶液結合親和力(Chen等人,(1999)J. Mol Biol
293:865-881)。為建立檢定條件,將微量滴定板(Dynex)以50 mM碳酸鈉(pH 9.6)中之5 μg/ml之捕捉抗Fab抗體(Cappel Labs)塗布隔夜,且隨後在室溫下(約23℃)以2%(w/v)牛血清白蛋白之PBS溶液阻斷2至5小時。在非吸附性板(Nunc #269620)中,將100 pM或26 pM [125
I]抗原與相關Fab之連續稀釋液混合(與抗VEGF抗體Fab-12之評估一致,Presta等人,(1997)Cancer Res.
57:4593-4599)。接著培育相關Fab隔夜;然而,培育可持續一段較長之時間(例如65小時)以確保達到平衡。此後,將混合物轉移至捕捉板中,在室溫下培育1小時。接著移除溶液且用0.1% Tween-20之PBS溶液洗滌板8次。當乾燥板時,每孔添加150 μl閃爍體(MicroScint-20;Packard),且在Topcount γ計數器(Packard)上對板計數10分鐘。選擇提供小於或等於20%最大結合之各Fab濃度用於競爭性結合檢定。
根據另一實施例,使用表面電漿共振檢定,使用BIACORE®
-2000或BIACORE®
-3000儀器(BIAcore, Inc., Piscataway, NJ),在25℃下,以約10個反應單位(RU)之固定抗原CM5晶片量測Kd。簡言之,根據供應商之說明書用N-乙基-N'-(3-二甲基胺基丙基)-碳化二亞胺鹽酸鹽(EDC)及N-羥基丁二醯亞胺(NHS)使羧甲基化葡聚糖生物感測器晶片(CM5,BIAcore Inc.)活化。用10 mM乙酸鈉(pH 4.8)稀釋抗原至5微克/毫升(約0.2 μM),之後以5微升/分鐘之流速注射,以獲得約10個反應單位(RU)之偶合蛋白。注射抗原後,注射1 M乙醇胺以阻斷未反應基團。為進行動力學量測,在25℃下以約25 μL/min之流速注射Fab於有0.05% TWEEN 20TM
界面活性劑(PBST)之PBS中之兩倍連續稀釋液(0.78 nM至500 nM)。使用簡單的一對一朗繆爾結合模型(BIAcore®
評估軟體3.2版)藉由同時擬合締合及解離感測器圖譜計算締合速率(kon
)及解離速率(koff
)。以比率koff
/kon
計算平衡解離常數(kd)。參見例如Chen等人,J. Mol. Biol.
293:865-881 (1999)。若藉由以上表面電漿共振檢定測定時,締合速率超過106
M-1
S-1
,則締合速率可使用螢光淬滅技術量測,該技術係如分光計(諸如具有攪拌式光析管之止流裝備型分光光度計(Aviv Instruments)或8000-系列SLM-AMINCOTM
分光光度計(ThermoSpectronic))中所量測,在遞增濃度之抗原存在下,在25℃下量測PBS(pH 7.2)中之20 nM抗抗原抗體(Fab形式)之螢光發射強度(激發= 295 nm;發射= 340 nm,16 nm帶通)之增或減。
本發明之「締合速率」或「kon
」亦可如上所述在25℃下,使用BIACORE®
-2000或BIACORE®
-3000系統(BIAcore, Inc., Piscataway, NJ),以約10個反應單位(RU)之固定抗原CM5晶片測定。簡言之,根據供應商之說明書用N-乙基-N'-(3-二甲胺基丙基)-碳化二亞胺鹽酸鹽(ECD)及N-羥基丁二醯亞胺(NHS)使羧甲基化葡聚糖生物感測器晶片(CM5,BIAcore Inc.)活化。用10 mM乙酸鈉(pH 4.8)稀釋抗原至5 mg/ml(約0.2 mM),之後以5 ml/min之流速注射以獲得約10個反應單位(RU)之偶合蛋白。注射抗原後,添加1 M乙醇胺以阻斷未反應基團。為進行動力學量測,在25℃下以約25 ul/min之流速注射Fab於有0.05% Tween 20(PBST)之PBS中之兩倍連續稀釋液(0.78 nM至500 nM)。使用簡單的一對一朗繆爾結合模型(BIAcore評估軟體3.2版)藉由同時擬合締合及解離感測器圖譜計算締合速率(kon
)及離解速率(koff
)。以比率koff
/kon
計算平衡解離常數(kd)。參見例如Chen, Y.,等人,(1999)J. Mol Biol 293
:865-881。然而,若由上述表面電漿共振檢定測定時,締合速率超過106
M-1
S-1
,則締合速率較佳使用螢光淬滅技術測定,該技術係如分光計(諸如具有攪拌式光析管之止流裝備型分光光度計(Aviv Instruments)或8000-系列SLM-Aminco分光光度計(ThermoSpectronic))中所量測,在遞增濃度之抗原存在下,在25℃下量測PBS(pH 7.2)中之20 nM抗抗原抗體(Fab形式)之螢光發射強度(激發=295 nm;發射=340 nm,16 nm帶通)之增或減。
如本文中所用之短語「實質上減少」或「實質上不同」表示兩個數值之間的差異足夠大(通常,一數值與一分子相關而另一數值與參考/對比分子相關),以致熟習該項技術者認為兩個值之間的差異在該等值(例如Kd值)所量度之生物學特徵之範圍內具有統計顯著性。該兩個數值之間的差異作為參考/對比分子之值的函數例如大於約10%、大於約20%、大於約30%、大於約40%及/或大於約50%。
如本文所用之術語「實質上類似」或「實質上相同」表示兩個數值之間具有足夠高之類似性(例如,一數值與本發明抗體相關而另一數值與參考/對比抗體相關),以致熟習此項技術者認為兩個值之間的差異在該等值(例如Kd值)所量度之生物學特徵之範圍內具有極小或不具有生物及/或統計顯著性。該兩個數值之間的差異作為參考/比較值的函數例如小於約50%、小於約40%、小於約30%、小於約20%及/或小於約10%。
肽、多肽或抗體序列之「胺基酸序列一致性百分比(%)」及「同源性」係定義為:在比對序列及(若需要)引入缺口以獲得最大序列一致性百分比,且不將任何保守性取代視為序列一致性之一部分之後,候選序列中與特定肽或多肽序列中胺基酸殘基相同之胺基酸殘基的百分比。為測定胺基酸序列一致性百分比而進行之比對可以此項技術中熟知之多種方式實現,例如使用公用電腦軟體,諸如BLAST、BLAST-2、ALIGN或MEGALIGNTM
(DNASTAR)軟體。熟習此項技術者可確定用於量測比對之適當參數,包括為獲得與所比較序列全長範圍內之最大比對所需的任何算法。然而,出於本文之目的,使用Genentech, Inc.設計之序列比較電腦程式ALIGN-2產生胺基酸序列一致性百分比值。ALIGN-2之源代碼已以使用者文件(user documentation)於美國版權局(U.S. Copyright Office, Washington D.C., 20559)中申請,其中其以美國版權註冊號TXU510087註冊。ALIGN-2程式可自Genentech, Inc., South San Francisco, California公開獲得。ALIGN-2程式應編譯以用於UNIX操作系統,較佳數位UNIX V4.0D中。所有序列比較參數由ALIGN-2程式設定且不改變。
在使用ALIGN-2進行胺基酸序列比較之情況下,既定胺基酸序列A與既定胺基酸序列B之胺基酸序列一致性百分比(或者其可表述成與既定胺基酸序列B具有或包含某胺基酸序列一致性百分比之既定胺基酸序列A)如下計算:
100乘以分數X/Y
其中X為由序列比對程式ALIGN-2在該程式之A及B比對中評分為一致匹配的胺基酸殘基之數目,且其中Y為B中胺基酸殘基之總數。應瞭解,若胺基酸序列A之長度不同於胺基酸序列B之長度,則A對B之胺基酸序列一致性百分比將不等於B對A之胺基酸序列一致性百分比。
除非另外明確規定,否則本文所用之所有胺基酸序列一致性百分比值係如先前段落使用ALIGN-2電腦程式所述獲得。
編碼本文之抗體之「經分離」核酸分子為經鑑別且與在該核酸之產生環境中通常與其締合之至少一種污染核酸分子分離的核酸分子。較佳地,經分離核酸不與與產生環境相關之所有組分締合。編碼本文之多肽及抗體之經分離核酸分子呈除自然界中所發現之形式或設定以外之形式。因此,經分離核酸分子不同於編碼天然存在於細胞中之本文之多肽及抗體的核酸。
術語「控制序列」係指在特定宿主生物體內表現可操作連接之編碼序列所需的DNA序列。適用於原核生物之控制序列例如包括啟動子、視情況存在之操縱子序列(operator sequence)及核糖體結合位點。已知真核細胞利用啟動子、聚腺苷酸化信號及強化子。
當核酸置於與另一核酸序列之功能關係中時,其係經「可操作連接」。舉例而言,若前序列或分泌性前導序列之DNA表現為參與多肽分泌之前體蛋白,則其與該多肽之DNA可操作連接;若啟動子或強化子影響編碼序列之轉錄,則其與該序列可操作連接;或若核糖體結合位點經定位以有利於轉譯,則其與編碼序列可操作連接。一般而言,「可操作連接」意謂所連接之DNA序列相鄰且在分泌性前導序列之情況下為相鄰的且在閱讀相(reading phase)中。然而,強化子不必為相鄰的。連接係藉由在適宜限制性位點處連接來實現。若該等位點不存在,則根據習知實踐使用合成寡核苷酸接附子或連接子。
術語「經抗原決定基標記」在本文中使用時係指包含與「標籤多肽」融合之本文所述之多肽或抗體的嵌合多肽。標籤多肽具有足夠的殘基來提供產生抗體時可針對之抗原決定基,而其足夠短使得其不干擾其所融合之多肽的活性。標籤多肽較佳亦相當獨特以便使抗體實質上不與其他抗原決定基交叉反應。適合之標籤多肽一般具有至少6個胺基酸殘基,且通常介於約8個與50個胺基酸殘基之間(較佳介於約10個與20個胺基酸殘基之間)。
如本文所用之術語「免疫黏附素」表示將異源蛋白(「黏附素」)之結合特異性與免疫球蛋白恆定域之效應功能組合的抗體樣分子。在結構上,免疫黏附素包含具有所要結合特異性(其不為抗體之抗原識別及結合位點,亦即「異源」)之胺基酸序列與免疫球蛋白恆定域序列的融合體。免疫黏附素分子之黏附素部分通常為至少包含受體或配位體之結合位點之相鄰胺基酸序列。免疫黏附素中之免疫球蛋白恆定域序列可自任何免疫球蛋白獲得,諸如IgG-1、IgG-2(包括IgG2A及IgG2B)、IgG-3或IgG-4亞型、IgA(包括IgA-1及IgA-2)、IgE、IgD或IgM。Ig融合體較佳包括用本文所述之多肽或抗體域替代Ig分子內之至少一個可變區。在一尤佳實施例中,免疫球蛋白融合體包括IgG1分子之鉸鏈區、CH2區及CH3區,或鉸鏈區、CH1區、CH2區及CH3區。關於免疫球蛋白融合體之產生,亦參見1995年6月27日頒布之美國專利第5,428,130號。舉例而言,適用作適用於本文之組合療法之第二藥劑之免疫黏附素包括包含PD-L1或PD-L2之細胞外或PD-1結合部分或反之與免疫球蛋白序列之恆定域融合之多肽。
「融合蛋白」及「融合多肽」係指具有共價連接在一起之兩部分的多肽,其中每一部分為具有不同性質之多肽。該性質可為生物性質,諸如活體外或活體內活性。該性質亦可為簡單的化學或物理性質,諸如與標靶分子結合、催化反應等。兩部分可經由單一肽鍵直接鍵聯或經由肽連接子(將位於閱讀框架中)相互鍵聯。
「穩定」調配物為儲存後蛋白質基本上保持其物理及化學穩定性及完整性之調配物。此項技術中可利用各種量測蛋白質穩定性之分析技術且該等技術綜述於Peptide and Protein Drug Delivery,
247-301, Vincent Lee編,Marcel Dekker, Inc., New York, New York, Pubs. (1991)及Jones, A.Adv. Drug Delivery Rev. 10
: 29-90 (1993)中。可在選定溫度下量測一段選定時期的穩定性。對於快速篩檢,可將調配物保持在40℃下2週至1個月,此時量測穩定性。在將調配物儲存於2-8℃下之情況下,調配物一般在30℃或40℃下應穩定至少1個月及/或在2-8℃下應穩定至少2年。在調配物儲存於30℃之情況下,調配物一般在30℃下應穩定至少2年及/或在40℃下應穩定至少6個月。舉例而言,儲存期間之聚集程度可用作蛋白質穩定性之指示。因此,「穩定」調配物可為在調配物中約10%以下且較佳約5%以下之蛋白質呈現聚集體者。在其他實施例中,可測定調配物儲存期間聚集體形成之任何增加。
「復原」調配物為已藉由將冷凍乾燥蛋白質或抗體調配物溶解於稀釋劑中以致蛋白質完全分散所製備之調配物。復水調配物適用於投與(例如皮下投與)經相關蛋白質治療之患者,且在本發明之某些實施例中,可為適用於非經腸或靜脈內投與之調配物。
「等張」調配物為與人類血液具有基本相同之滲透壓的調配物。等張調配物一般具有約250至350 mOsm之滲透壓。術語「低張」描述滲透壓低於人體血液之滲透壓的調配物。相應地,術語「高張」係用於描述滲透壓高於人體血液之滲透壓的調配物。等張性可使用例如蒸氣壓或冰凍型滲壓計來量測。由於本發明調配物中添加鹽及/或緩衝液,故其為高張的。
如本文所用之「載劑」包括在所採用之劑量及濃度下,對暴露於其中之細胞或哺乳動物無毒之醫藥學上可接受之載劑、賦形劑或穩定劑。生理學上可接受之載劑一般為pH緩衝水溶液。生理學上可接受之載劑之實例包括:緩衝液,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸;低分子量(小於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖醇,諸如甘露糖醇或山梨糖醇;成鹽相對離子,諸如鈉;及/或非離子型界面活性劑,諸如TWEEN™、聚乙二醇(PEG)及PLURONICS™。
「包裝插頁」係指通常包括於藥劑之商業包裝中之說明書,其含有關於使用該等藥劑之適應症、用法、劑量、投藥、禁忌、與所包裝產品組合之其他藥劑及/或注意事項等資訊。
「醫藥學上可接受之酸」包括無機酸及有機酸,該等酸在其調配濃度及方式下無毒。舉例而言,適合之無機酸包括鹽酸、過氯酸、氫溴酸、氫碘酸、硝酸、硫酸、磺酸、亞磺酸,對胺基苯磺酸、磷酸、碳酸等。適合之有機酸包括直鏈及分支鏈烷基、芳族、環狀、環脂族、芳基脂族、雜環、飽和、不飽和的單羧酸、二羧酸及三羧酸,包括例如甲酸、乙酸、2-羥基乙酸、三氟乙酸、苯乙酸、三甲基乙酸、第三丁基乙酸、鄰胺基苯甲酸、丙酸、2-羥基丙酸、2-側氧基丙酸、丙二酸(propandioic)、環戊烷丙酸、環戊烷丙酸、3-苯基丙酸、丁酸、丁二酸(butandioic)、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、2-乙醯氧基-苯甲酸、抗壞血酸、肉桂酸、月桂基硫酸、硬脂酸、黏康酸、杏仁酸、丁二酸、亞甲基雙羥萘酸(embonic)、反丁烯二酸、蘋果酸、順丁烯二酸、羥基順丁烯二酸、丙二酸(malonic)、乳酸、檸檬酸、酒石酸、乙醇酸、甘醇酸、葡萄糖酸、丙酮酸、乙醛酸、草酸、甲磺酸、丁二酸、水楊酸、鄰苯二甲酸、雙羥萘酸(palmoic)、棕櫚酸(palmeic)、硫氰酸、甲烷磺酸、乙烷磺酸、1,2-乙烷二磺酸、2-羥基乙烷磺酸、苯磺酸、4-氯苯磺酸、萘-2-磺酸、對甲苯磺酸、樟腦磺酸、4-甲基二環[2.2.2]-辛-2-烯-1-甲酸、葡糖庚酸、4,4'-亞甲基雙-3-(羥基-2-烯-1-甲酸)、羥基萘甲酸。
「醫藥學上可接受之鹼」包括無機鹼及有機鹼,該等鹼在其調配濃度及方式下無毒。舉例而言,適合之鹼包括彼等由以下形成之鹼:無機鹼形成金屬,諸如鋰、鈉、鉀、鎂、鈣、銨、鐵、鋅、銅、錳、鋁;N-甲基葡萄胺;嗎啉;哌啶及有機無毒鹼,包括一級胺、二級胺及三級胺、經取代之胺、環胺及鹼離子交換樹脂[例如N(R')4 +
(其中R'獨立地為H或C1-4
烷基,例如銨、Tris)],例如異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺,2-二乙胺基乙醇、緩血酸胺、二環己胺、離胺酸、精胺酸、組胺酸、咖啡鹼、普魯卡因(procaine)、海卓胺(hydrabamine)、膽鹼、甜菜鹼、乙二胺、葡糖胺、甲基葡萄胺、可可豆鹼、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺樹脂及其類似鹼。尤佳有機無毒鹼為異丙胺、二乙胺、乙醇胺、緩血酸胺、二環己胺、膽鹼及咖啡鹼。本發明可使用之其他醫藥學上可接受之酸及鹼包括彼等衍生自例如組胺酸、甘胺酸、苯丙胺酸、天冬胺酸、麩胺酸、離胺酸及天冬醯胺之胺基酸之酸及鹼。
「醫藥學上可接受」之緩衝液及鹽包括彼等衍生自上述酸及鹼之酸加成鹽與鹼加成鹽之緩衝液及鹽。特定緩衝液及/或鹽包括組胺酸、丁二酸鹽及乙酸鹽。
「醫藥學上可接受之糖」為當與相關蛋白質組合時儲存後顯著阻止或降低蛋白質之化學及/或物理不穩定性之分子。當意欲將調配物冷凍乾燥且接著復原時,「醫藥學上可接受之糖」亦可稱為「冷凍乾燥保護劑」。例示性糖及其相應糖醇包括:胺基酸,諸如麩胺酸一鈉或組胺酸;甲基胺,諸如甜菜鹼;感膠離子鹽,諸如硫酸鎂;多元醇,諸如三元或更高分子量糖醇,例如丙三醇、葡聚糖、赤藻糖醇、甘油、阿糖醇、木糖醇、山梨糖醇及甘露糖醇;丙二醇;聚乙二醇;PLURONICS®
;及其組合。其他例示性冷凍乾燥保護劑包括丙三醇;及明膠;及糖類,蜜二糖、松三糖、棉子糖、甘露三糖及水蘇糖。還原糖之實例包括葡萄糖、麥芽糖、乳糖、麥芽酮糖、異麥芽酮糖及乳果糖。非還原糖之實例包括選自糖醇及其他直鏈多元醇之多羥基化合物之非還原糖苷。較佳糖醇為單糖苷、尤其彼等藉由還原諸如乳糖、麥芽糖、乳果糖及麥芽酮糖之雙醣獲得之化合物。糖苷側基可為葡萄糖苷或半乳糖苷。糖醇之其他實例為葡糖醇、麥芽糖醇、乳糖醇及異麥芽酮糖。較佳醫藥學上可接受之糖為非還原糖海藻糖或蔗糖。將醫藥學上可接受之糖以「保護量」添加至調配物中(例如預先冷凍乾燥),保護量意謂在儲存期間(例如復原及儲存後)蛋白質基本上保持其物理及化學穩定性及完整性。
本文相關之「稀釋劑」為醫藥學上可接受(對投與人類而言為安全且無毒的)且適用於液體調配物(諸如在冷凍乾燥後之復原之調配物)之製備的稀釋劑。例示性稀釋劑包括無菌水、抑菌注射用水(BWFI)、pH緩衝溶液(例如磷酸鹽緩衝生理食鹽水)、無菌生理食鹽水溶液、林格氏溶液(Ringer's solution)或右旋糖溶液。在一替代實施例中,稀釋劑可包括鹽及/或緩衝液之水溶液。
「防腐劑」為可添加至本文之調配物中以降低細菌活性之化合物。添加防腐劑可例如有助於多次使用(多次劑量)之調配物的生產。潛在防腐劑之實例包括十八烷基二甲基苄基氯化銨、氯化六羥季銨、氯化苯甲烴銨(烷基為長鏈化合物之氯化烷基苯甲基二甲基銨之混合物)及苄索氯銨。其他類型之防腐劑包括芳醇,諸如苯酚、丁醇及苯甲醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯、兒茶酚、間苯二酚、環己醇、3-戊醇及間甲酚。本文之最佳防腐劑為苯甲醇。
「治療」係指經設計以改變所治療之個體或細胞之自然過程的臨床介入,且可出於預防之目的或在臨床病理學過程中進行。所需治療作用包括阻止疾病發生或復發、阻止轉移、降低疾病進展速率、改善或緩解疾病狀態及減輕或改良預後。在某些實施例中,使用本發明抗體延遲疾病或病症之發展。若減輕與T細胞功能障礙病症相關之一或多種症狀,則例如使用本發明細胞凋亡型抗PD-L1抗體成功「治療」個體。
「有效量」係指在一定劑量下且經歷一段必要時間有效達成所要或指示作用(包括治療性或預防性結果)之至少量。舉例而言,本發明抗PD-L1抗體之有效量至少為抑制經由T細胞上之PD-1或其他APC上之B7.1或兩者自PD-L1信號傳導的最小濃度。
「治療有效量」至少為實現特定病症之可量測改良或預防所需之最小濃度。本文之治療有效量可隨以下因素而變化,諸如患者之疾病狀態、年齡、性別及體重以及抗體在個體中引發所要反應之能力。治療有效量亦為抗體之治療上有益作用勝過任何有毒或有害作用之量。舉例而言,本發明抗PD-L1抗體之治療有效量至少為抑制T細胞功能障礙病症之至少一種症狀之最小濃度。
「預防有效量」係指在一定劑量下且經歷一段必要時間有效達成所要預防性結果之量。舉例而言,本發明抗PD-L1抗體之預防有效量至少為阻止或減弱T細胞功能障礙病症之至少一種症狀發展之最小濃度。
「慢性」投藥係指以與急性模式相反之連續藥劑投與,以使最初治療作用(活性)維持一段較長之時間。「間歇」投藥為不中斷而是實際上循環之不連續進行的治療。
用於治療之「哺乳動物」係指歸類為哺乳動物的任何動物,包括人類、家畜及農畜,及動物園、運動或玩賞動物,諸如犬、馬、兔、牛、豬、倉鼠、沙鼠、小鼠、雪貂、大鼠、貓等。哺乳動物較佳為人類。
術語「醫藥調配物」係指呈使活性成份之生物活性有效之形式且不含有對將投與該調配物的個體具有不可接受之毒性之其他組分的製劑。該等調配物為無菌的。
「無菌」調配物為滅菌的或不含所有活微生物及其孢子。
如本文所用之術語「約」係指容易地為熟習此技術領域者所知之各別值之常見誤差範圍。
「自體免疫病症」為由個體自身組織或器官或其共分離體或表現形式或由其所引起之病狀產生且針對個體自身組織或器官或其共分離體或表現形式或由其所引起之病狀的疾病或病症。自體免疫病可為器官特異性疾病(亦即,免疫反應特異性針對某一器官系統,諸如內分泌系統、造血系統、皮膚、心肺系統、胃腸與肝系統、腎系統、甲狀腺、耳、神經肌肉系統、中樞神經系統等)或可影響多個器官系統之全身性疾病(例如全身性紅斑性狼瘡(SLE)、類風濕性關節炎(RA)、多發性肌炎等)。較佳之該等疾病包括自體免疫性風濕病症(諸如RA、修格連氏症候群(Sjögren's syndrome)、硬皮病、狼瘡(諸如SLE)及狼瘡腎炎、多發性肌炎-皮膚肌炎、冷球蛋白血症、抗磷脂抗體症候群及牛皮癬性關節炎)、自體免疫性胃腸及肝病症(諸如發炎性腸病(例如潰瘍性結腸炎及克羅恩氏病(Crohn's disease))、自體免疫性胃炎及惡性貧血、自體免疫性肝炎、原發性膽汁性肝硬化症、原發性硬化性膽管炎及乳糜瀉)、血管炎(諸如ANCA陰性血管炎及ANCA相關血管炎,包括丘-施氏血管炎(Churg-Strauss vasculitis)、韋格納氏肉芽腫病(Wegener's granulomatosis)及顯微鏡下多血管炎)、自體免疫性神經性病症(諸如多發性硬化症、眼陣攣肌陣攣症候群、重症肌無力、視神經脊髓炎、帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)及自體免疫性多發性神經病)、腎病症(諸如絲球體腎炎、古德帕斯氏症候群(Goodpasture's syndrome)及貝爾氏病(Berger's disease))、自體免疫性皮膚病症(諸如牛皮癬、風疹、蕁麻疹、尋常型天疱瘡、大皰性類天疱瘡及皮膚紅斑狼瘡)、血液病症(諸如血小板減少性紫癜、血栓性血小板減少性紫癜、輸血後紫癜及自體免疫性溶血性貧血)、動脈粥樣硬化、葡萄膜炎、自體免疫性聽覺疾病(諸如內耳病及聽力喪失)、貝西氏病(Behcet's disease)、雷諾氏症候群(Raynaud's syndrome)、器官移植及自體免疫性內分泌病症(諸如糖尿病相關自體免疫疾病,諸如胰島素依賴性糖尿病(IDDM)、阿狄森氏病(Addison's disease)及自體免疫性甲狀腺疾病(例如葛瑞夫茲氏病(Graves'disease)及甲狀腺炎))。更佳之該等疾病包括例如RA、潰瘍性結腸炎、ANCA相關血管炎、狼瘡、多發性硬化症、修格連氏症候群、葛瑞夫茲氏病、IDDM、惡性貧血、甲狀腺炎及絲球體腎炎。
如本文所用之術語「細胞毒性劑」係指抑制或阻止細胞功能及/或導致細胞破壞之物質。該術語包括放射性同位素(例如At211
、I131
、I125
、Y90
、Re186
、Re188
、Sm153
、Bi212
、P32
及Lu之放射性同位素);及毒素,諸如小分子毒素或細菌、真菌、植物或動物來源之酶促活性毒素,或其片段。
「化學治療劑」為適用於癌症治療之化合物。化學治療劑之實例包括:烷基化劑,諸如噻替派(thiotepa)及環磷醯胺(CYTOXAN®);烷基磺酸酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);乙烯亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、三伸乙基蜜胺(triethylenemelamine)、三伸乙基磷醯胺(trietylenephosphoramide)、三伸乙基硫代磷醯胺(triethylenethiophosphoramide)及三甲密胺(trimethylolomelamine);多聚乙醯(acetogenin)(尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));δ-9-四氫大麻酚(delta-9-tetrahydrocannabinol)(屈大麻酚(dronabinol),MARINOL®);β-拉帕醌(beta-lapachone);拉帕醇(lapachol);秋水仙鹼(colchicine);樺木酸(betulinic acid);喜樹鹼(camptothecin)(包括合成類似物拓朴替康(topotecan)(HYCAMTIN®)、CPT-11(伊立替康(irinotecan),CAMPTOSAR®)、乙醯基喜樹鹼(acetylcamptothecin)、斯考普萊汀(scopolectin)及9-胺基喜樹鹼);苔蘚抑素(bryostatin);培美曲唑(pemetrexed);卡利他汀(callystatin);CC-1065(包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物);足葉草毒素(podophyllotoxin);足葉草酸(podophyllinic acid);替尼泊苷(teniposide);自念珠藻環肽(cryptophycin)(尤其自念珠藻環肽1及自念珠藻環肽8);海兔毒素(dolastatin);多卡米新(duocarmycin)(包括合成類似物KW-2189及CB1-TM1);艾榴塞洛素(eleutherobin);盤克斯坦汀(pancratistatin);TLK-286;CDP323,一種口服α-4整合素抑制劑;沙考地汀(sarcodictyin);海綿抑素(spongistatin);氮芥,諸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、環磷醯胺、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、氮芥(mechlorethamine)、鹽酸氧化氮芥、美法侖(melphalan)、新恩比興(novembichin)、膽固醇苯乙酸氮芥(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、烏拉莫司汀(uracil mustard);亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及拉甯司汀(ranimnustine);抗生素,諸如烯二炔抗生素(例如卡奇黴素(calicheamicin),尤其卡奇黴素γ1I及卡奇黴素ωI1(參見例如Nicolaou等人,Angew. Chem Intl. Ed. Engl
., 33: 183-186 (1994));達米辛(dynemicin),包括達米辛A;埃斯培拉黴素(esperamicin);以及新製癌菌素(neocarzinostatin)發色團及相關色蛋白烯二炔抗生素發色團)、克拉斯米辛(aclacinomysin)、放線菌素(actinomycin)、奧斯拉菌素(authramycin)、偶氮絲胺酸(azaserine)、博萊黴素(bleomycin)、放線菌素C(cactinomycin)、卡拉比星(carabicin)、洋紅黴素(carminomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycinis)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、小紅莓(包括ADRIAMYCIN®、N-嗎啉基-小紅莓(morpholino-doxorubicin)、氰基(N-嗎啉基)小紅莓、2-吡咯啉并小紅莓、鹽酸小紅莓脂質體注射劑(DOXIL®)及去氧小紅莓(deoxydoxorubicin))、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(諸如絲裂黴素C)、黴酚酸、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤、吉西他濱(gemcitabine)(GEMZAR®)、喃氟啶(tegafur)(UFTORAL®)、卡西他濱(capecitabine) (XELODA®)、埃博黴素(epothilone)及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、喋羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、噻咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮雜尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)及伊馬替尼(imatinib)(2-苯基胺基嘧啶衍生物),以及其他c-Kit抑制劑;抗腎上腺藥劑,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如夫羅林酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);倍思塔布(bestrabucil);比生群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾弗利散(elfornithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);羅尼達寧(lonidainine);美登醇(maytansinoid),諸如美登素(maytansine)及安絲菌素(ansamitocin);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidanmol);硝拉維林(nitraerine);噴司他丁(pentostatin);凡那明(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙醯肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK®多醣複合物(JHS Natural Products, Eugene, OR);雷佐生(razoxane);根瘤菌素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2"-三氯三乙胺;單端孢黴烯族毒素(trichothecene)(尤其T-2毒素、弗納庫林A(verracurin A)、桿孢菌素A(roridin A)及胺癸叮(anguidine));烏拉坦(urethan);長春地辛(vindesine)(ELDISINE®、FILDESIN®);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);雙溴丙基哌嗪(pipobroman);甲托辛(gacytosine);阿糖胞苷(arabinoside)(「Ara-C」);噻替哌;紫杉醇,例如太平洋紫杉醇(TAXOL®)、白蛋白工程改造之太平洋紫杉醇奈米粒子調配物(ABRAXANE™
)及多西紫杉醇(TAXOTERE®);苯丁酸氮芥(chloranbucil);6-硫鳥嘌呤;巰基嘌呤(mercaptopurine);甲胺喋呤;鉑類似物,諸如順鉑(cisplatin)及卡鉑(carboplatin);長春鹼(vinblastine) (VELBAN®);鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺;米托蒽醌;長春新鹼(ONCOVIN®);奧賽力鉑(oxaliplatin);盧考弗文(leucovovin);長春瑞濱(NAVELBINE®);諾凡特龍(novantrone);依達曲沙(edatrexate);道諾黴素(daunomycin);胺基喋呤(aminopterin);伊班膦酸鹽(ibandronate);拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(difluoromethylornithine)(DMFO);類視色素,諸如視黃酸(retinoic acid);上述化學治療劑中之任一者之醫藥學上可接受之鹽、酸或衍生物;以及上述化學治療劑中之兩者或兩者以上之組合,諸如CHOP(環磷醯胺、小紅莓、長春新鹼及潑尼松龍(prednisolone)之組合療法之縮寫)及FOLFOX(奧賽力鉑(ELOXATIN™
)與5-FU及盧考弗文組合之治療方案之縮寫)。尤其在腫瘤免疫治療中與本發明抗PD-L1抗體組合使用之尤佳化學治療劑為吉西他濱。
該定義中亦包括起調控、降低、阻斷或抑制可促進癌症生長之激素之效應的作用且通常為全身性治療之形式的抗激素劑。其本身可為激素。實例包括抗雌激素藥及選擇性雌激素受體調節劑(SERM),包括例如他莫昔芬(tamoxifen)(包括NOLVADEX®他莫昔芬)、雷諾昔芬(raloxifene)(EVISTA®)、曲洛昔芬(droloxifene)、4-羥基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、雷諾昔芬鹽酸鹽(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(FARESTON®);抗孕酮;雌激素受體調降劑(ERD);雌激素受體拮抗劑,諸如氟維司群(FASLODEX®);用以抑制或制止卵巢功能之藥劑,例如黃體生成激素釋放激素(LHRH)促效劑,諸如乙酸亮丙瑞林(leuprolide acetate)(LUPRON®及ELIGARD®)、乙酸戈舍瑞林(goserelin acetate)、乙酸布舍瑞林(buserelin acetate)及曲特瑞林(tripterelin);抗雄激素藥,諸如氟他胺(flutamide)、尼魯米特(nilutamide)及比卡魯胺(bicalutamide);及抑制芳香酶(其調控腎上腺中雌激素之產生)之芳香酶抑制劑,諸如4(5)-咪唑、胺魯米特(aminoglutethimide)、乙酸甲地孕酮(megestrol acetate) (MEGASE®)、依西美坦(exemestane)(AROMASIN®)、福美斯坦(formestanie)、法屈唑(fadrozole)、伏羅唑(vorozole)(RIVISOR®)、來曲唑(letrozole)(FEMARA®)及安美達錠(anastrozole)(ARIMIDEX®)。此外,該化學治療劑之定義包括:雙膦酸鹽,諸如氯屈膦酸鹽(clodronate)(例如,BONEFOS®或OSTAC®)、依替膦酸鹽(etidronate)(DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(zoledronic acid/zoledronate)(ZOMETA®)、阿侖膦酸鹽(alendronate)(FOSAMAX®)、帕米膦酸鹽(pamidronate) (AREDIA®)、替魯膦酸鹽(tiludronate)(SKELID®)或利塞膦酸鹽(risedronate)(ACTONEL®);以及曲沙他濱(troxacitabine)(1,3-二氧戊環核苷胞嘧啶類似物);反義寡核苷酸,尤其抑制異常細胞增殖所牽涉之信號傳導路徑中基因之表現的彼等反義寡核苷酸,諸如PKC-α、Raf、H-Ras及表皮生長因子受體(EGF-R);疫苗,諸如THERATOPE®疫苗及基因治療疫苗,例如ALLOVECTIN®疫苗、LEUVECTIN®疫苗及VAXID®疫苗;拓撲異構酶1抑制劑(例如LURTOTECAN®);抗雌激素藥,諸如氟維司群(fulvestrant);Kit抑制劑,諸如伊馬替尼(imatinib)或EXEL-0862(酪胺酸激酶抑制劑);EGFR抑制劑,諸如埃羅替尼(erlotinib)或西妥昔單抗(cetuximab);抗VEGF抑制劑,諸如貝伐單抗(bevacizumab);瑞諾替康(arinotecan);rmRH(例如ABARELIX®);拉帕替尼(lapatinib)及拉帕替尼對甲苯磺酸鹽(lapatinib ditosylate)(ErbB-2與EGFR雙重酪胺酸激酶小分子抑制劑,亦稱為GW572016);17AAG(作為熱休克蛋白(Hsp)90毒劑之格爾德黴素(geldanamycin)衍生物);及上述化學治療劑中之任一者之醫藥學上可接受之鹽、酸或衍生物。
「生長抑制劑」係指抑制細胞生長之化合物或組合物,該生長視活體外或活體內受體活化而定。因此,生長抑制劑包括顯著降低S期中受體依賴性細胞之百分比的生長抑制劑。生長抑制劑之實例包括阻斷細胞週期進程(在不同於S期之其他時期)之藥劑,諸如誘導G1停滯及M期停滯之藥劑。經典M期阻斷劑包括長春鹼類及長春生物鹼(長春新鹼及長春鹼)、紫杉烷及拓撲異構酶II抑制劑(諸如小紅莓、表柔比星、道諾黴素、依託泊苷及博萊黴素)。使G1停滯之彼等藥劑亦使S期停滯,例如DNA烷基化劑,諸如他莫昔芬、潑尼松(prednisone)、達卡巴嗪、氮芥、順鉑、甲胺喋呤、5-氟尿啶及ara-C。其他資訊可見於T he Molecular Basis of Cancer
, Mendelsohn及Israel編,第1章, 標題為「Cell cycle regulation, oncogenes, and antineoplastic drugs」Murakami等人,(WB Saunders: Philadelphia, 1995), 尤其第13頁中。紫杉烷(太平洋紫杉醇及多烯紫杉醇)皆為源自紫杉之抗癌藥。衍生自歐洲紫杉之多烯紫杉醇(TAXOTERE®, Rhone-Poulenc Rorer)為太平洋紫杉醇(TAXOL®, Bristol-Myers Squibb)之半合成類似物。
術語「細胞激素」為有關由一個細胞群體所釋放並作為細胞間介體對另一細胞起作用之蛋白質的通用術語。該等細胞激素之實例為淋巴介質、單核球激素;介白素(IL),諸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-11、IL-12、IL-13、IL-15、IL-35,包括PROLEUKIN® rIL-2;腫瘤壞死因子,諸如TNF-α或TNF-β;及其他多肽因子,包括LIF及套組配位體(KL),而目前術語「介白素」基本上為細胞激素之同義詞。如本文所用之術語細胞激素包括來自天然來源或來自重組細胞培養物之蛋白質及天然序列細胞激素之生物活性等效物,包括合成產生之小分子實體及其醫藥學上可接受之衍生物及鹽。細胞激素可根據預定標靶之近端位置進行分類,其中自分泌係指對分泌細胞激素之同一細胞之作用,旁分泌係指侷限於分泌有細胞激素之鄰近區域的作用,且內分泌係指對身體之遠區域的作用。免疫細胞激素亦可藉由其增進有利於細胞免疫之I型反應與否(例如IFN-γ、TGF-β等)或有利於抗體或體液免疫之II型反應與否(IL-4、IL-10、IL-13等)進行分類。免疫細胞激素在各種免疫細胞之協同刺激、成熟、增殖、活化、發炎、生長、分化、細胞激素產生及分泌、存活中發揮作用。
術語「激素」係指一般由具有管道之腺器官分泌之多肽激素。激素包括例如生長激素,諸如人生長激素、N-甲硫胺醯基人生長激素及牛生長激素;甲狀旁腺激素;甲狀腺素;胰島素;胰島素原;鬆弛素;雌二醇;激素替代治療;雄激素,諸如卡普睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)或睾內酯(testolactone);鬆弛素原(prorelaxin);醣蛋白激素,諸如促濾泡激素(FSH)、促甲狀腺激素(TSH)及促黃體生成激素(LH);促乳素、胎盤生乳素、小鼠促性腺激素相關肽、促性腺激素釋放激素;抑制素;活化素;苗勒氏管抑制物質(mullerian-inhibiting substance);及血小板生成素。如本文所用之術語激素包括來自天然來源或來自重組細胞培養物之蛋白質,及天然序列激素之生物活性等效物,其包括合成產生之小分子實體及其醫藥學上可接受之衍生物及鹽。III. 本發明之實施方式
A.使用噬菌體呈現進行人類化
由編碼人類受體序列之核酸的孔克突變誘發(Kunkel mutagenesis)使用各高變區之獨立的寡核苷酸產生本文所述之高變區移植變異體。Kunkel等人,Methods Enzymol. 154
:367-382 (1987)。可使用常規技術在構架及/或高變區內引入適當變化,以校正及重建適當的高變區-抗原相互作用。
可使用噬菌體(噬菌粒)呈現(本文亦稱作噬菌體呈現)作為產生及篩檢由序列隨機化所產生之文庫中之許多不同的潛在變異抗體之方便且快速的方法。然而,熟習此項技術者可利用製造及篩檢已改變之抗體之其他方法。
可使用噬菌體(噬菌粒)呈現(在一些情形下,本文亦稱作噬菌體呈現)作為產生及篩檢由序列隨機化所產生之文庫中之許多不同的潛在變異抗體之方便且快速的方法。然而,熟習此項技術者可利用製造及篩檢已改變之抗體之其他方法。
噬菌體(噬菌粒)呈現技術已提供產生及選擇結合配位體(諸如抗原)之新穎蛋白質的強有力工具。使用噬菌體(噬菌粒)呈現技術允許產生可迅速分選出彼等以高親和力與標靶分子結合之序列的大型蛋白質變異體文庫。一般使編碼變異多肽之核酸與編碼病毒鞘蛋白(諸如基因III蛋白或基因VIII蛋白)之核酸序列融合。已開發出使編碼蛋白質或多肽之核酸序列與編碼一部分基因III蛋白之核酸序列融合之單價噬菌粒呈現系統。(Bass, S.,Proteins,
8:309 (1990);Lowman及Wells,Methods: A Companion to Methods in Enzymology,
3:205 (1991))。在單價噬菌粒呈現系統中,以低含量表現基因融合體,且亦表現野生型基因III蛋白以使粒子之感染力得以保持。許多專利(例如美國專利第5,723,286號、美國專利第5,432,018號、美國專利第5,580,717號、美國專利第5,427,908號及美國專利第5,498,530號)中已揭示產生肽文庫及篩檢彼等文庫之方法。
已以多種方法製備抗體或抗原結合多肽之文庫,該等方法包括藉由插入隨機DNA序列改變單個基因或藉由選殖相關基因家族。使用噬菌體(噬菌粒)呈現來呈現抗體或抗原結合片段之方法已描述於美國專利第5,750,373號、美國專利第5,733,743號、美國專利第5,837,242號、美國專利第5,969,108號、美國專利第6,172,197號、美國專利第5,580,717號及美國專利第5,658,727號中。接著針對具有所要特徵之抗體或抗原結合蛋白之表現篩檢文庫。
此項技術中已完善建立將所選胺基酸代入模板核酸中之方法,本文描述其中一些方法。舉例而言,可使用孔克方法取代高變區殘基。參見例如Kunkel等人,Methods Enzymol
. 154:367-382 (1987)。
寡核苷酸之序列包括一或多個用於待改變之高變區殘基之經設計密碼子組。密碼子組為一組用以編碼所要變異胺基酸之不同核苷酸三聯體序列。根據以下IUB代碼所示,密碼子組可使用符號表示來指定特定核苷酸或核苷酸之等莫耳混合物。IUB 代碼
可使用標準方法合成寡核苷酸或引子組。一組寡核苷酸可例如由固相合成來合成,其含有代表由密碼子組提供之核苷酸三聯體之所有可能的組合且將編碼所要胺基酸群組的序列。此項技術中熟知在某些位置具有所選核苷酸「簡併性」之寡核苷酸的合成。該等具有某些密碼子組之核苷酸組可使用商業核酸合成器(可自例如Applied Biosystems, Foster City, CA獲得)合成或可購得(例如自Life Technologies, Rockville, MD購得)。因此,所合成之一組具有特定密碼子組之寡核苷酸通常將包括複數個具有不同序列之寡核苷酸,該等差異由整個序列內之密碼子組產生。根據本發明使用之寡核苷酸具有允許與可變域核酸模板雜交且亦可包括用於選殖目的之限制酶位點的序列。
在一方法中,編碼變異胺基酸之核酸序列可由寡核苷酸介導之突變誘發產生。如Zoller等人,Nucleic Acids Res
. 10:6487-6504(1987)所述,在此項技術中熟知此技術。簡言之,藉由使編碼所要密碼子組之寡核苷酸組與DNA模板雜交產生編碼變異胺基酸之核酸序列,其中該模板為含有可變區核酸模板序列之質體之單鏈形式。雜交後,使用DNA聚合酶合成模板之整個第二條互補鏈,因此該鏈將合併寡核苷酸引子且將含有由寡核苷酸組所提供之密碼子組。
一般而言,使用長度為至少25個核苷酸之寡核苷酸。最佳寡核苷酸將具有在編碼突變之核苷酸之任一側與模板完全互補之12至15個核苷酸。此確保寡核苷酸將與單鏈DNA模板分子適當雜交。寡核苷酸易於使用此項技術中已知之諸如Crea等人,Proc. Nat'l. Acad. Sci. USA
, 75:5765 (1978)所述之技術合成。
由彼等衍生自噬菌體M13載體(適合的為市售M13mp18及M13mp19載體)之載體或彼等如Viera等人,Meth. Enzymol.,
153:3 (1987)所述含有單鏈噬菌體複製起點之載體產生DNA模板。因此,可將待突變之DNA插入一種該等載體中以產生單鏈模板。單鏈模板之產生描述於上述Sambrook等人之4.21-4.41章節中。
為改變天然DNA序列,在適合之雜交條件下使寡核苷酸與單鏈模板雜交。接著添加DNA聚合酶(通常T7 DNA聚合酶或DNA聚合酶I之Klenow片段)以使用寡核苷酸作為合成引子來合成該模板之互補鏈。由此形成異源雙鏈分子從而使得一條DNA鏈編碼突變形式之基因1,且另一條鏈(原始模板)編碼基因1之天然的未改變序列。接著將此異源雙鏈分子轉形於適合之宿主細胞中,該宿主細胞通常為原核生物,諸如大腸桿菌JM101。使細胞生長後,將其塗鋪於瓊脂糖板上且使用以32
-磷酸鹽作放射性標記之寡核苷酸引子篩檢以鑑別含有突變DNA之菌落。
可對上文剛描述之方法進行修改以便產生質體之兩條鏈均含有突變之同源雙鏈分子。修改如下:使單鏈寡核苷酸與上述單鏈模板黏接。將三種去氧核糖核苷酸(去氧核糖腺苷(dATP)、去氧核糖鳥苷(dGTP)及去氧核糖胸苷(dTT))之混合物與稱作dCTP-(aS)之經修飾硫代去氧核糖胞嘧啶(其可自Amersham獲得)組合。將此混合物添加至模板-寡核苷酸複合物中。向此混合物中添加DNA聚合酶後,產生除突變鹼基以外皆與模板相同之DNA鏈。另外,此新DNA鏈將含有dCTP-(aS)而非dCTP,該dCTP-(aS)用以保護該DNA鏈以免由限制核酸內切酶消化。在雙鏈異源雙鏈體(heteroduplex)之模板鏈經適當限制酶形成缺口後,可用ExoIII核酸酶或另一在不為含待突變誘發位點之區處切斷之適當核酸酶消化模板鏈。接著終止反應留下僅為部分單鏈之分子。接著在所有四種三磷酸去氧核糖核苷酸、ATP及DNA連接酶存在下使用DNA聚合酶形成完整雙鏈DNA同源雙鏈體。接著可使此同源雙鏈分子轉形於適合之宿主細胞中。
如先前所指示,寡核苷酸組之序列具有足以與模板核酸雜交的長度且亦可(但不必)含有限制位點。可由彼等衍生自噬菌體M13載體之載體或彼等如Viera等人,Meth. Enzymol
., 153:3 (1987)所述之含有單鏈噬菌體複製起點之載體產生DNA模板。因此,必須將待突變之DNA插入一種該等載體中以產生單鏈模板。單鏈模板之產生描述於Sambrook等人,同上之4.21-4.41章節中。
根據另一方法,可藉由提供上游及下游寡核苷酸組來產生文庫,各組具有複數個具有不同序列之寡核苷酸,該等不同序列係由寡核苷酸之序列內所提供之密碼子組產生。上游及下游寡核苷酸組以及可變域模板核酸序列可用於聚合酶鏈反應中以產生PCR產物之「文庫」。該等PCR產物可稱作「核酸卡匣(nucleic acid cassette)」,此係由於可使用已建立之分子生物技術使其與其他相關或不相關核酸序列(例如病毒鞘蛋白及二聚合域)融合。
PCR引子之序列包括一或多個針對高變區中之溶劑可接近且高度不同的位置之經設計密碼子組。如上所述,密碼子組為一組用於編碼所要變異胺基酸之不同核苷酸三聯體序列。可使用標準重組技術分離及選殖如經適當篩檢/選擇步驟選擇之符合所要標準之抗體選擇物。
B.重組製備
本發明亦提供一種編碼抗PD-L1抗體之經分離核酸、包含該等核酸之載體及宿主細胞及產生該抗體之重組技術。
對於重組產生抗體,分離編碼該抗體之核酸且插入可複製載體中以便進一步選殖(DNA擴增)或表現。使用習知程序(例如藉由使用能夠特異性結合編碼抗體之重鏈及輕鏈之基因之寡核苷酸探針)容易地分離編碼單株抗體之DNA並測序。可利用許多載體。載體之選擇部分視待使用之宿主細胞而定。一般而言,較佳宿主細胞起源於原核生物或真核生物(一般哺乳動物)。1. 在原核細胞中產生抗體 a) 載體構築
可使用標準重組技術獲得編碼本發明抗體之多肽組分的聚核苷酸序列。可自產生抗體之細胞(諸如融合瘤細胞)中分離所要聚核苷酸序列並測序。或者,可使用核苷酸合成器或PCR技術合成聚核苷酸。一旦獲得編碼多肽之序列,即將其插入能夠在原核宿主中複製且表現異源聚核苷酸之重組載體中。出於本發明之目的,可使用許多可利用且為此項技術中所知之載體。適當載體之選擇將主要視待插入載體中之核酸的大小及待經載體轉形之特定宿主細胞而定。各載體視其功能(異源聚核苷酸之擴增或表現或兩者)及其與其所駐留之特定宿主細胞之相容性而定含有多種組分。載體組分一般包括(但不限於):複製起點、選擇標記基因、啟動子、核糖體結合位點(RBS)、信號序列、異源核酸插入物及轉錄終止序列。
含有衍生自與宿主細胞相容之物種之複製子及控制序列的質體載體一般聯合此等宿主使用。載體通常帶有複製位點以及能夠在轉形細胞中提供表型選擇之標記序列。舉例而言,通常使用衍生自大腸桿菌物種之質體pBR322使大腸桿菌轉形。pBR322含有編碼安比西林(Amp)及四環素(Tet)抗性之基因,且因此提供鑑別經轉形細胞之容易方式。pBR322、其衍生物或其他微生物質體或噬菌體亦可含有或經修飾含有可由微生物使用以供表現內源蛋白質之啟動子。Carter等人之美國專利第5,648,237號中詳細描述用於表現特定抗體之pBR322衍生物之實例。
此外,含有與宿主微生物相容之複製子及控制序列的噬菌體載體可聯合此等宿主用作轉形載體。舉例而言,可利用諸如GEM.TM.-11之噬菌體製備可用以使諸如大腸桿菌LE392之易感宿主細胞轉形的重組載體。
本發明之表現載體可包含兩種或兩種以上編碼各多肽組分之啟動子-順反子(cistron)對。啟動子為位於調節其表現之順反子上游(5')的未經轉譯之調控序列。原核啟動子通常分為兩類:誘導型及組成型。誘導型啟動子為一種啟動子,在該啟動子控制下應答培養條件之改變(例如在有或無營養物存在下或溫度改變)開始順反子之增加含量之轉錄。
熟知由多種潛在宿主細胞所識別之大量啟動子。可藉由經限制酶消化自來源DNA移出所選擇之啟動子且將所分離之啟動子序列插入本發明載體中而使該啟動子可操作連接至編碼輕鏈或重鏈之順反子DNA。可使用天然啟動子序列與許多異源啟動子來引導標靶基因之擴增及/或表現。在一些實施例中,利用異源啟動子,此係因為一般而言,與天然標靶多肽啟動子相比,異源啟動子所允許之經表現之標靶基因的轉錄較大且產率較高。
適於原核宿主使用之啟動子包括PhoA啟動子、β-半乳糖苷酶及乳糖啟動子系統、色胺酸(trp)啟動子系統及雜交啟動子(諸如tac或trc啟動子)。然而,在細菌中起作用之其他啟動子(諸如其他已知細菌或噬菌體啟動子)亦適合。已公開其核苷酸序列,藉此使得熟練技術者能夠使用連接子或接附子(adaptor)提供任何所需限制位點使該等序列與編碼標靶輕鏈及重鏈之順反子可操作連接(Siebenlist等人,(1980)Cell 20
: 269)。
在一態樣中,重組載體中之各順反子包含引導所表現多肽跨膜移位之分泌信號序列組分。一般而言,信號序列可為載體之組分,或其可為插入載體中之標靶多肽DNA之一部分。出於本發明之目的所選擇之信號序列應為由宿主細胞識別及加工(亦即由信號肽酶裂解)之信號序列。對於不識別及加工異源多肽之天然信號序列的原核宿主細胞而言,使信號序列經例如選自由以下組成之群的原核信號序列取代:鹼性磷酸酶、青黴素酶、Ipp或熱穩定腸毒素II(STII)前導序列、LamB、PhoE、PelB、OmpA及MBP。在本發明之一實施例中,用於表現系統之該兩種順反子中之信號序列為STII信號序列或其變異體。
在另一態樣中,本發明之免疫球蛋白的產生可發生在宿主細胞之細胞質中,且因此無需各順反子內均存在分泌信號序列。就此而言,免疫球蛋白輕鏈及重鏈皆在細胞質內表現、摺疊及裝配以形成功能性免疫球蛋白。某些宿主菌株(例如大腸桿菌trxB-
菌株)提供有利於雙硫鍵形成之細胞質條件,藉此允許適當摺疊及裝配經表現之蛋白質次單元。Proba及PluckthunGene
,159
:203 (1995)。
本發明提供一種表現系統,其中可調節所表現多肽組分之定量比例以最大化所分泌及適當裝配之本發明抗體之產率。該調節可至少部分藉由同時調節多肽組分之轉譯強度來完成。
調節轉譯強度之一種技術揭示於Simmons等人,美國專利第5,840,523號中。其利用順反子內之轉譯起始區(TIR)之變異體。對於既定TIR,可在一定範圍之轉譯強度下產生一系列胺基酸或核酸序列變異體,藉此提供針對特定鏈之所要表現含量調節此因子的方便方式。TIR變異體可由引起可改變胺基酸序列之密碼子改變的習知突變誘發技術產生,但在核苷酸序列中靜默改變較佳。TIR改變可包括例如Shine-Dalgarno序列之編號或間隔改變以及信號序列改變。一種產生突變信號序列之方法為在不改變信號序列之胺基酸序列的編碼序列起始處產生「密碼子庫」(亦即,改變為靜默型)。此可藉由改變各密碼子之第三核苷酸位置來實現;另外,諸如白胺酸、絲胺酸及精胺酸之一些胺基酸具有多個可增加製庫複雜性的第一及第二位置。此突變誘發方法詳細描述於Yansura等人,(1992)METHODS: A Companion to Methods in Enzymol.
4:151-158中。
較佳地,產生一組載體,其內部各順反子具有一系列TIR強度。此有限的組提供各鏈之表現含量的比較以及各種TIR強度組合下所要抗體產物的產率。如Simmons等人,美國專利第5,840,523中詳細描述,TIR強度可藉由定量報導基因之表現含量來確定。基於轉譯強度比較,可選擇所要的個別TIR以組合於本發明之表現載體構築體中。b) 原核宿主細胞
適於表現本發明抗體之原核宿主細胞包括古細菌(Archaebacteria)及真細菌(Eubacteria),諸如革蘭氏陰性(Gram-negative)或革蘭氏陽性生物體。適用細菌之實例包括埃希氏桿菌屬(例如大腸桿菌)、芽孢桿菌屬(Bacilli)(例如枯草芽孢桿菌(B. subtilis))(例如枯草芽孢桿菌(B. subtilis
))、腸細菌(Enterobacteria)、假單胞菌屬(Pseudomonas
)物種(例如銅綠假單胞菌(P. aeruginosa
))、鼠傷寒沙門氏桿菌(Salmonella typhimurium
)、黏質沙雷菌(Serratia marcescans
)、克雷伯氏菌屬、變形菌屬、志賀氏菌屬(Shigella
)、根瘤菌屬(Rhizobia
)、透明顫菌(Vitreoscilla
)或副球菌屬(Paracoccus
)。在一實施例中,使用革蘭氏陰性細胞。在一實施例中,使用大腸桿菌細胞作為本發明宿主。大腸桿菌菌株之實例包括菌株W3110(Bachmann,Cellular and Molecular Biology
, 第2卷(Washington, D.C.: American Society for Microbiology, 1987), 第1190-1219頁;ATCC寄存編號27,325)及其衍生物,包括具有基因型W3110ÿfhuA
(ÿtonA
)ptr3 lac Iq lacL8 ÿompTÿ(nmpc-fepE) degP41 kanR
之菌株33D3(美國專利第5,639,635號)。其他菌株及其衍生物(諸如大腸桿菌294(ATCC 31,446)、大腸桿菌B、大腸桿菌1776(ATCC 31,537)及大腸桿菌RV308(ATCC 31,608))亦適合。此等實例為說明性的而非限制性的。構築具有確定的基因型之任何以上提及之細菌的衍生物的方法在此項技術中為已知的且描述於例如Bass等人,Proteins
,8
:309-314 (1990)中。一般需要考慮複製子在細菌細胞中之可複製性來選擇適當細菌。舉例而言,當使用熟知質體(諸如pBR322、pBR325、pACYC177或pKN410)提供複製子時,適合地可使用大腸桿菌、沙雷氏菌或沙門氏菌物種作為宿主。
宿主細胞通常應分泌最少量之蛋白水解酶,且理想地,可將額外蛋白酶抑制劑併入細胞培養物中。c) 抗體產生
用上述表現載體使宿主細胞轉形,且在適當時經修飾之習知培養基中培養以誘導啟動子、選擇轉形體或擴增編碼所要序列之基因。轉形意謂將DNA引入原核宿主中,以便DNA可作為染色體外要素或由染色體成分複製。視所使用之宿主細胞而定,使用適於該等細胞之標準技術進行轉形。對含有實質細胞壁障壁之細菌細胞而言,一般使用採用氯化鈣之鈣處理。另一轉形方法採用聚乙二醇/DMSO。所使用之另一技術為電穿孔法。
使用以產生本發明抗體的原核細胞在此項技術中已知且適於培養所選宿主細胞之培養基中生長。適合之培養基之實例包括溶菌培養液(luria broth,LB)加必需營養補充劑。在一些實施例中,培養基亦含有基於表現載體之構築而選擇之選擇劑,以選擇性允許含有表現載體之原核細胞生長。舉例而言,向培養基中添加安比西林以使表現安比西林抗性基因之細胞生長。
亦可包括除碳、氮及無機磷酸鹽來源以外之任何必需補充劑,其單獨或以與另一補充劑或培養基(諸如複合氮源)之混合物的形式以適當濃度引入。視情況,培養基可含有一或多種選自由以下組成之群的還原劑:麩胱甘肽、半胱胺酸、胱胺、巰基乙酸酯、二硫赤蘚糖醇及二硫蘇糖醇。
在適合之溫度下培養原核宿主細胞。對大腸桿菌生長而言,例如,較佳溫度係在約20℃至約39℃、更佳約25℃至約37℃之範圍內,甚至更佳在約30℃下。培養基之pH值主要視宿主生物體而定,可為約5至約9範圍內之任何pH值。對於大腸桿菌而言,pH值較佳為約6.8至約7.4,且更佳為約7.0。
若本發明之表現載體中使用誘導型啟動子,則在適於活化該啟動子之條件下誘導蛋白質表現。在本發明之一態樣中,使用PhoA啟動子控制多肽轉錄。因此,在磷酸鹽限制培養基中培養經轉形之宿主細胞以誘導。較佳地,磷酸鹽限制培養基為C.R.A.P培養基(參見例如Simmons等人,J. Immunol. Methods
(2002), 263:133-147)。如此項技術中所知,可根據所用載體構築體使用多種其他誘導劑。
本發明之經表現抗體蛋白質分泌至宿主細胞之周質中且自其中回收。蛋白質回收通常涉及一般由諸如滲透壓衝擊、音波處理或溶解之方式使微生物碎裂。一旦細胞碎裂,即可藉由離心或過濾來移除細胞碎片或完整細胞。蛋白質可例如由親和樹脂層析進一步純化。或者,可將蛋白質傳輸至培養基中且在其中進行分離。可自培養物中移除細胞,且過濾培養物上清液且濃縮以進一步純化所產生之蛋白質。可使用諸如聚丙烯醯胺凝膠電泳(PAGE)及西方墨點檢定之通常已知的方法進一步分離經表現之多肽且加以鑑別。
或者,藉由醱酵過程實現抗體大批量產生。可利用多種大規模分批饋料醱酵程序來產生重組蛋白質。大規模醱酵具有至少1000公升之容量,較佳約1,000至100,000公升之容量。此等醱酵器使用攪拌葉輪來分配氧氣及養分,尤其葡萄糖(較佳碳/能量來源)。小規模醱酵一般係指在體積容量不超過約100公升且可在約1公升至約100公升範圍內之醱酵器中進行的醱酵。
在醱酵過程中,通常在已使細胞在適合條件下生長至所需密度(例如OD550
為約180-220,在此階段細胞處於穩定期早期)後開始誘導蛋白質表現。如此項技術中已知且如上文所述,可根據所用載體構築體使用多種誘導劑。可在誘導細胞之前使細胞生長較短時間。誘導細胞之時間通常為約12-50小時,但可使用更長或更短之誘導時間。
為改良本發明抗體的產率及品質,可改變各種醱酵條件。舉例而言,為改良所分泌之抗體多肽之適當裝配及摺疊,可使用過度表現伴侶蛋白(chaperone protein)之其他載體使宿主原核細胞共轉形,該等伴侶蛋白諸如Dsb蛋白(DsbA、DsbB、DsbC、DsbD及/或DsbG)或FkpA(具有伴侶活性之肽基脯胺醯基順式/反式異構酶)。已說明伴侶蛋白有助於所產生之異源蛋白質在細菌宿主細胞中之適當摺疊及溶解。Chen等人,(1999)J Bio Chem
274:19601-19605;Georgiou等人,美國專利第6,083,715號;Georgiou等人,美國專利第6,027,888號;Bothmann及Pluckthun (2000)J. Biol. Chem.
275:17100-17105;Ramm及Pluckthun (2000)J. Biol. Chem.
275:17106-17113;Arie等人,(2001)Mol. Microbiol
. 39:199-210。
為使所表現之異源蛋白質(尤其彼等對易蛋白水解之蛋白質)之蛋白水解降至最低,本發明可使用某些缺乏蛋白水解酶之宿主菌株。舉例而言,宿主細胞菌株可經修飾以在編碼已知細菌蛋白酶(諸如蛋白酶III、OmpT、DegP、Tsp、蛋白酶I、蛋白酶Mi、蛋白酶V、蛋白酶VI及其組合)之基因中實現基因突變。可利用一些缺乏大腸桿菌蛋白酶之菌株且其描述於例如Joly等人,(1998), 同上;Georgiou等人,美國專利第5,264,365號;Georgiou等人,美國專利第5,508,192號;Hara等人,Microbial Drug Resistance
,2
:63-72 (1996)中。
可使用缺乏蛋白水解酶且經過度表現一或多種伴侶蛋白之質體轉形的大腸桿菌菌株作為編碼本發明抗體之表現系統中之宿主細胞。d) 抗體純化
本文中所產生之抗體蛋白質可進一步經純化以獲得實質上均質的製劑來進行其他檢定及使用。可利用此項技術中已知之標準蛋白質純化方法。以下程序為適合之純化程序的例示性實例:免疫親和管柱或離子交換管柱分級分離、乙醇沈澱、逆相HPLC、二氧化矽或陽離子交換樹脂(諸如DEAE)層析、層析聚焦、SDS-PAGE、硫酸銨沈澱及使用例如Sephadex G-75之凝膠過濾。
在一態樣中,使用固定於固相上之蛋白質A進行本發明全長抗體產物的免疫親和純化。蛋白質A為來自金黃色葡萄球菌(Staphylococcus aureas
)之41 kD細胞壁蛋白,其以高親和力結合抗體之Fc區。Lindmark等人 (1983)J. Immunol. Meth
. 62:1-13。蛋白質A所固定之固相較佳為包含玻璃或二氧化矽表面之管柱,更佳為受控微孔玻璃管柱或矽酸管柱。在一些應用中,管柱已塗布有諸如甘油之試劑以力圖防止污染物之非特異性黏附。接著洗滌固相以移除與固相非特異性結合之污染物。最後,藉由溶離自固相回收相關抗體。
2.在真核細胞中產生抗體
對於真核表現,載體組分一般包括(但不限於)以下之一或多者:信號序列、複製起點、一或多個標記基因及強化子元件(enhancer element)、啟動子及轉錄終止序列。a) 信號序列組分
用於真核宿主中之載體亦可為編碼信號序列之插入物或在成熟蛋白質或多肽之N末端具有特異性裂解位點之其他多肽。所選擇之異源信號序列較佳為由宿主細胞識別及加工(亦即由信號肽酶裂解)之信號序列。在哺乳動物細胞表現中,可利用哺乳動物信號序列以及病毒分泌前導序列(例如單純性疱疹gD信號)。
該前驅區之DNA在閱讀框架中與編碼本發明抗體之DNA連接。b) 複製起點
一般而言,哺乳動物表現載體無需複製起點組分(因SV40起點含有早期啟動子,故通常可僅使用該起點)。c) 選擇基因組分
表現及選殖載體可含有亦稱為可選擇標記物之選擇基因。典型選擇基因編碼具有下列作用之蛋白質:(a)賦予針對抗生素或其他毒素(例如安比西林、新黴素、甲胺喋呤或四環素)之抗性;(b)補充營養缺陷型不足;或(c)供應不可自複合培養基獲得之關鍵養分,例如對芽孢桿菌而言,為編碼D-丙胺酸消旋酶之基因。
選擇方案之一個實例利用藥物來阻滯宿主細胞生長。彼等經異源基因成功轉形之細胞產生賦予耐藥性之蛋白質,且因此在經歷選擇方案之後存活。該類顯性選擇之實例使用藥物新黴素、黴酚酸及潮黴素(hygromycin)。
哺乳動物細胞之適合之可選擇標記物的另一實例為彼等能夠鑑別能吸收編碼本發明抗體之核酸之細胞的標記物,諸如DHFR、胸苷激酶、金屬硫蛋白-I及金屬硫蛋白-II(較佳為靈長類動物金屬硫蛋白基因)、腺苷去胺酶、鳥胺酸脫羧酶等。
舉例而言,首先藉由在含有甲胺喋呤(Mtx)(DHFR之競爭性拮抗劑)之培養基中培養所有轉形體來鑑別經DHFR選擇基因轉形之細胞。當採用野生型DHFR時,適當之宿主細胞為缺乏DHFR活性之中國倉鼠卵巢(CHO)細胞株(例如ATCC CRL-9096)。
或者,可藉由使細胞在含有可選擇標記物之選擇劑(諸如胺基糖苷抗生素,例如康黴素(kanamycin)、新黴素或G418)的培養基中生長來選擇經編碼抗體之DNA序列、野生型DHFR蛋白及另一可選擇標記物(諸如,胺基糖苷3'-磷酸轉移酶(APH))轉形或共轉形之宿主細胞(尤其含有內源DHFR之野生型宿主)。參見美國專利第4,965,199號。d ) 啟動子組分
表現及選殖載體通常含有由宿主生物體所識別且可操作連接至編碼所要抗體序列之核酸的啟動子。實際上所有真核基因均具有位於轉錄起始位點上游約25至30個鹼基處之富集AT之區。在許多基因轉錄起始處上游70至80個鹼基處發現的另一序列為CNCAAT區,其中N可為任何核苷酸。大部分真核基因之3'端為AATAAA序列,該序列可為用於將聚腺苷酸尾(poly A tail)添加至編碼序列之3'端的信號。所有此等序列均可插入真核表現載體中。
適於原核宿主使用之其他啟動子包括phoA
啟動子、β-內醯胺酶及乳糖啟動子系統、鹼性磷酸酶啟動子、色胺酸(trp)啟動子系統及雜交啟動子,諸如tac啟動子。然而,其他已知細菌啟動子亦適合。用於細菌系統中之啟動子亦將含有可操作連接至編碼抗體多肽之DNA的夏因-達爾加諾(Shine-Dalgarno,S.D.)序列。
抗體多肽自哺乳動物宿主細胞中之載體之轉錄例如受以下啟動子控制:自病毒(諸如多瘤病毒、禽痘病毒、腺病毒(諸如腺病毒2)、牛乳頭狀瘤病毒、禽肉瘤病毒、細胞巨大病毒、反轉錄病毒、B型肝炎病毒且最佳猿病毒40(Simian Virus 40,SV40))之基因組獲得的啟動子、異源哺乳動物啟動子(例如肌動蛋白啟動子或免疫球蛋白啟動子)、熱休克啟動子,其限制條件為該等啟動子與宿主細胞系統相容。
SV40病毒之早期及晚期啟動子宜作為亦含有SV40病毒複製起點之SV40限制片段獲得。人巨細胞病毒之即刻早期啟動子宜作為HindIII E限制片段獲得。美國專利第4,419,446號中揭示在哺乳動物宿主中使用牛乳頭狀瘤病毒作為載體來表現DNA之系統。美國專利第4,601,978號中描述此系統之修改。關於小鼠細胞中之人類-干擾素cDNA在單純性疱疹病毒之胸苷激酶啟動子控制下之表現,亦參見Reyes等人,Nature
297:598-601 (1982)。或者,可使用勞氏肉瘤病毒(Rous Sarcoma Virus)長末端重複單元作為啟動子。e) 強化子元件組分
由高級真核細胞轉錄編碼本發明抗體之DNA通常藉由將強化子序列插入載體中來增強。目前已知許多強化子序列來自哺乳動物基因(血球蛋白、彈性蛋白酶、白蛋白、α-胎蛋白及胰島素)。然而,通常將使用來自真核細胞病毒之強化子。實例包括位於複製起點晚期側之SV40強化子(bp 100-270)、細胞巨大病毒早期啟動子強化子、複製起點晚期側的多瘤病毒強化子及腺病毒強化子。關於活化真核啟動子之強化元件,亦參見Yaniv,Nature
297:17-18(1982)。雖然可在抗體編碼序列之位置5'或3'處將強化子剪接至載體中,但較佳定位於啟動子之5'位點處。f) 轉錄終止組分
用於真核宿主細胞(酵母菌、真菌、昆蟲、植物、動物、人類或來自其他多細胞生物體之有核細胞)之表現載體亦將含有終止轉錄及穩定mRNA所必需之序列。該等序列通常可自真核或病毒DNA或cDNA之5'及偶爾3'之未經轉譯區獲得。此等區含有在編碼抗體之mRNA之未經轉譯部分中轉錄為聚腺苷酸化片段的核苷酸區段。一種適用之轉錄終止組分為牛生長激素聚腺苷酸化區。參見WO94/11026及其中所揭示之表現載體。g) 宿主細胞之選擇及轉形
適於選殖或表現DNA於本文載體中之宿主細胞包括本文所述之高級真核細胞,包括脊椎動物宿主細胞。使脊椎動物細胞於培養物(組織培養物)中繁殖已成為常規程序。適用之哺乳動物宿主細胞株之實例為由SV40轉形之猴腎CV1細胞株(COS-7,ATCC CRL 1651);人胚腎細胞株(經次選殖在懸浮培養物中生長之293或293細胞,Graham等人,J. Gen Virol.
36:59(1977));幼倉鼠腎細胞(BHK,ATCC CCL 10);中國倉鼠卵巢細胞/-DHFR(CHO,Urlaub等人,Proc. Natl. Acad. Sci. USA
77:4216(1980));小鼠足細胞(TM4,Mather, Biol. Reprod.
23:243-251(1980));猴腎細胞(CV1 ATCC CCL 70);非洲綠猴腎細胞(VERO-76,ATCC CRL-1587);人宮頸癌細胞(HELA,ATCC CCL 2);犬腎細胞(MDCK,ATCC CCL 34);布法羅大鼠肝細胞(buffalo rat liver cell)(BRL 3A,ATCC CRL 1442);人肺細胞(W138,ATCC CCL 75);人肝細胞(Hep G2,HB 8065);小鼠乳腺腫瘤(MMT 060562,ATCC CCL51);TRI細胞(Mather等人,Annals N.Y. Acad. Sci.
383:44-68(1982));MRC 5細胞;FS4細胞;及人肝癌細胞株(Hep G2)。
用產生抗體之上述表現載體或選殖載體使宿主細胞轉形,且在適當時經修飾之習知培養基中培養以誘導啟動子、選擇轉形體或擴增編碼所要序列之基因。h) 培養宿主細胞
可在多種培養基中培養用以產生本發明抗體之宿主細胞。諸如漢姆氏F10(Ham's F10)(Sigma)、最低必需培養基((MEM),Sigma)、RPMI-1640(Sigma)及達爾伯克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle's Medium) ((DMEM),Sigma)之市售培養基適於培養宿主細胞。此外,Ham等人,Meth. Enz
. 58:44 (1979);Barnes等人,Anal. Biochem
.102:255 (1980);美國專利第4,767,704號、第4,657,866號、第4,927,762號、第4,560,655號或第5,122,469號;WO 90/03430;WO 87/00195;或美國專利Re. 30,985中所述之任何培養基均可用作宿主細胞之培養基。任何此等培養基均可視需要補充激素及/或其他生長因子(諸如胰島素、運鐵蛋白或表皮生長因子)、鹽(諸如氯化鈉、鈣鹽、鎂鹽及磷酸鹽)、緩衝液(諸如HEPES)、核苷酸(諸如腺苷及胸苷)、抗生素(諸如GENTAMYCIN™藥物)、微量元素(定義為通常以在微莫耳濃度範圍內之最終濃度存在的無機化合物)及葡萄糖或等效能源。亦可包括熟習此項技術者已知之適當濃度之任何其他必要補充劑。諸如溫度、pH值及其類似條件之培養條件為彼等先前供選擇用於表現之宿主細胞使用之條件且對一般熟習此項技術者而言將顯而易見。i) 純化抗體
當使用重組技術時,抗體可在細胞內產生於周質間隙中或直接分泌至培養基中。若抗體在細胞內產生,則作為第一步,藉由例如離心或超濾移除微粒碎片(宿主細胞或溶解片段)。Carter等人,Bio/Technology 10
:163-167 (1992)描述分離分泌至大腸桿菌之周質間隙中之抗體的程序。簡言之,在乙酸鈉(pH 3.5)、EDTA及苯基甲基磺醯氟(PMSF)存在下經約30分鐘使細胞糊狀物解凍。可藉由離心移除細胞碎片。當抗體分泌至培養基中時,一般首先使用市售蛋白質濃縮過濾器(例如Amicon或Millipore Pellicon超濾單元)濃縮該等表現系統之上清液。在任何先前步驟中均可包括諸如PMSF之蛋白酶抑制劑以抑制蛋白水解,且可包括抗生素以阻止外來污染物生長。
可使用例如羥磷灰石層析法、凝膠電泳法、透析及親和層析法純化自細胞製備之抗體組合物,其中親和層析法為較佳純化技術。蛋白質A作為親和配位體之適宜性視存在於抗體中之任何免疫球蛋白Fc域的種類及同型而定。可使用蛋白質A純化基於含有1、2或4條重鏈之人類免疫球蛋白之抗體(Lindmark等人,J. Immunol. Meth.
62:1-13(1983))。對所有小鼠同型及人類3型而言,推薦蛋白質G(Guss等人,EMBO J.
5:15671575(1986))。雖然親和配位體所附著之基質最常為瓊脂糖,但可利用其他基質。機械穩定基質(諸如受控微孔玻璃或聚(苯乙烯-二乙烯基)苯)所允許之流動速率比瓊脂糖可達成的快,且所允許之處理時間比瓊脂糖可達成的短。當抗體包含CH
3域時,Bakerbond ABX™樹脂(J. T. Baker, Phillipsburg, NJ)適用於純化。視待回收之抗體而定,亦可利用其他蛋白質純化技術,諸如離子交換管柱分級分離、乙醇沈澱、逆相HPLC、二氧化矽層析、肝素SEPHAROSE™層析、陰離子或陽離子交換樹脂(諸如聚天冬胺酸管柱)層析、層析聚焦、SDS-PAGE及硫酸銨沈澱。
在任何初步純化步驟後,可使包含相關抗體及污染物之混合物經受使用pH值介於約2.5-4.5之間的溶離緩衝液之低pH值疏水相互作用層析,較佳在低鹽濃度(例如約0-0.25 M鹽)下進行該層析。
C.抗體製備
1) 多株抗體
一般藉由多次皮下(sc)或腹膜內(ip)注射相關抗原及佐劑在動物中產生多株抗體。可能適用於使用雙功能或衍生化藥劑(例如順丁烯二醯亞胺苯甲醯磺基丁二醯亞胺酯(經由半胱胺酸殘基結合)、N-羥基丁二醯亞胺(經由離胺酸殘基)、戊二醛、丁二酸酐、SOCl2
或R1
N=C=NR,其中R及R1
獨立地為低碳烷基)使相關抗原結合與在待免疫之物種中具免疫原性之蛋白質結合,該等蛋白質例如匙孔螺血氰蛋白(KLH)、血清白蛋白、牛甲狀腺球蛋白或大豆胰蛋白酶抑制劑。可使用之佐劑之實例包括傅氏完全佐劑(Freund's complete adjuvant)及MPL-TDM佐劑(單磷醯基脂質A、合成繭蜜糖二黴菌酸酯(trehalose dicorynomycolate))。熟習此項技術者可在無過度實驗之情況下選擇免疫方案。
藉由使例如100 μg或5 μg蛋白質或結合物(分別用於兔或小鼠)與3體積傅氏完全佐劑組合且在多個部位皮內注射該溶液使動物對抗原、免疫原結合物或衍生物免疫。1個月後,在多個部位以1/5至1/10初始量之於傅氏完全佐劑中之肽或結合物皮下注射來加強動物。7至14天後,對動物進行抽血且檢定血清之抗體效價。加強動物直至達到效價平線區。結合物亦可在重組細胞培養物中作為蛋白融合體製得。諸如明礬之凝集劑亦適於增強免疫反應。
2) 單株抗體
單株抗體係自一群實質上均質之抗體獲得,亦即構成此群體之個別抗體除可少量存在之可能的天然存在之突變及/或轉譯後修飾(例如異構化、醯胺化)外均相同。因此,修飾語「單株」指示抗體不為離散抗體之混合物的特徵。
舉例而言,可使用由Kohler等人,Nature, 256
:495 (1975)首次描述之融合瘤方法製備單株抗體,或可由重組DNA方法(美國專利第4,816,567號)製備單株抗體。
在融合瘤方法中,如上文所述使小鼠或諸如倉鼠之其他適當宿主動物免疫以激發產生或能夠產生將與用於免疫之蛋白質特異性結合的抗體的淋巴細胞。或者,可活體外使淋巴細胞免疫。接著使用諸如聚乙二醇之適合融合劑使淋巴細胞與骨髓瘤細胞融合以形成融合瘤細胞(Goding,Monoclonal Antibodies: Principles and Practice
, 第59-103頁 (Academic Press, 1986))。
免疫劑通常將包括抗原蛋白質或其融合變異體。一般而言,若需要具有人類起源之細胞,則使用周邊血淋巴細胞(「PBL」);或若需要非人類哺乳動物來源,則使用脾臟細胞或淋巴結細胞。接著,使用諸如聚乙二醇之適合融合劑使淋巴細胞與永生化細胞株融合以形成融合瘤細胞。Goding,Monoclonal Antibodies: Principles and Practice
, Academic Press (1986), 第59-103頁。
永生化細胞株通常為經轉形之哺乳動物細胞,尤其齧齒動物、牛及人類起源之骨髓瘤細胞。通常使用大鼠或小鼠骨髓瘤細胞株。接種由此製備之融合瘤細胞且使之在較佳含有一或多種抑制未融合之親本骨髓瘤細胞生長或存活之物質的適合之培養基中生長。舉例而言,若親本骨髓瘤細胞缺乏酶次黃嘌呤鳥嘌呤磷酸核糖基轉移酶(HGPRT或HPRT),則用於融合瘤之培養基通常將包括次黃嘌呤、胺基喋呤及胸苷(HAT培養基),該等物質為阻止缺乏HGPRT之細胞生長的物質。
較佳永生化骨髓瘤細胞為高效融合、支持由所選擇之抗體產生細胞穩定高含量產生抗體的骨髓瘤細胞,且其對諸如HAT培養基之培養基敏感。其中,較佳為鼠類骨髓瘤細胞株,諸如可自Salk Institute Cell Distribution Center, San Diego, California USA獲得之源自MOPC-21及MPC-11小鼠腫瘤之細胞株及可自American Type Culture Collection, Manassas, Virginia USA獲得之SP-2細胞(及其衍生物,例如X63-Ag8-653)。亦已描述人類骨髓瘤及小鼠-人類雜骨髓瘤細胞株用於產生人類單株抗體(Kozbor,J. Immunol.
,133
:3001 (1984);Brodeur等人,Monoclonal Antibody Production Techniques and Applications
, 第51-63頁 (Marcel Dekker, Inc., New York, 1987))。
檢定融合瘤細胞生長之培養基的針對抗原之單株抗體之產生。由融合瘤細胞產生之單株抗體之結合特異性較佳由免疫沈澱或由諸如放射免疫檢定(RIA)或酶聯免疫吸附檢定(ELISA)之活體外結合檢定來測定。
可檢定培養融合瘤細胞之培養基中針對所要抗原之單株抗體的存在。較佳地,可藉由免疫沈澱或藉由活體外結合檢定(諸如放射免疫檢定(RIA)或酶聯免疫吸附檢定(ELISA))來測定單株抗體之結合親和力及特異性。此項技術中已知該等技術及檢定。舉例而言,可由Munson等人,Anal. Biochem.
,107:
220 (1980)之斯卡查德分析(Scatchard analysis)測定結合親和力。
鑑別產生具有所要特異性、親和力及/或活性之抗體的融合瘤細胞之後,可由限制稀釋程序次選殖純系且經由標準方法使其生長(Goding, 同上)。出於此目的,適合之培養基包括例如D-MEM或RPMI-1640培養基。另外,融合瘤細胞可在哺乳動物中活體內生長為腫瘤。
由諸如蛋白質A-瓊脂糖、羥基磷灰石層析、凝膠電泳、透析或親和層析之習知免疫球蛋白純化程序適合地使由次純系分泌之單株抗體與培養基、腹水流體或血清分離。
亦可由諸如美國專利第4,816,567號中所述之彼等方法之重組DNA方法來製備單株抗體。使用習知程序(例如,藉由使用能夠與編碼鼠類抗體之重鏈及輕鏈之基因特異性結合之寡核苷酸探針)容易地分離編碼單株抗體之DNA並測序。融合瘤細胞充當該DNA之較佳來源。一旦分離後,即可將DNA置放於表現載體中,接著將該等表現載體轉染於不另外產生免疫球蛋白之諸如大腸桿菌細胞、猿猴COS細胞、中國倉鼠卵巢(CHO)細胞或骨髓瘤細胞之宿主細胞中,以在該類重組宿主細胞中合成單株抗體。關於編碼抗體之DNA之細菌中的重組表現的綜述文章包括Skerra等人,Curr. Opinion in Immunol.
, 5:256-262 (1993)及Plückthun,Immunol. Revs.
, 130:151-188 (1992)。
在另一實施例中,可使用McCafferty等人,Nature
,348
:552-554 (1990)中所述之技術自所產生之抗體噬菌體文庫中分離抗體。Clackson等人,Nature
,352
:624-628 (1991)及Marks等人,J. Mol. Biol.
,222
:581-597 (1991)分別描述使用噬菌體文庫分離鼠類及人類抗體。後續公開案描述藉由鏈改組(Marks等人,Bio/Technology
,10
:779-783 (1992)),以及作為構築極大噬菌體文庫之策略的組合感染及活體內重組(Waterhouse等人,Nuc. Acids. Res.
,21
:2265-2266 (1993))產生高親和力(奈莫耳濃度(nM)範圍)人類抗體。因此,該等技術為分離單株抗體之傳統單株抗體融合瘤技術之可行替代方案。
亦可例如藉由用人類重鏈及輕鏈恆定域之編碼序列取代同源鼠類序列(美國專利第4,816,567號;Morrison,等人,Proc. Natl Acad. Sci. USA
,81
:6851 (1984))或藉由使整個或部分非免疫球蛋白多肽之編碼序列共價連接於免疫球蛋白編碼序列來修飾DNA。通常,該等非免疫球蛋白多肽取代抗體之恆定域,或其取代抗體之一個抗原組合位點之可變域以產生包含一個對抗原具有特異性之抗原組合位點及另一個對不同抗原具有特異性之抗原組合位點的嵌合二價抗體。
本文所述之單株抗體可為單價的,其製備在此項技術中為熟知的。舉例而言,一種方法包括重組表現免疫球蛋白輕鏈及經修飾重鏈。一般在Fc區之任一點截斷重鏈以阻止重鏈交聯。或者,相關半胱胺酸殘基可經另一胺基酸殘基取代或經缺失以阻止交聯。活體外方法亦適於製備單價抗體。消化抗體以產生其片段(尤其Fab片段)可使用此項技術中已知之常規技術來實現。
亦可使用合成蛋白質化學中之已知方法(包括彼等涉及交聯劑之方法)活體外製備嵌合或雜交抗體。舉例而言,可使用雙硫鍵交換反應或藉由形成硫醚鍵來構築免疫毒素。適於此目的之試劑之實例包括亞胺基硫醇酯(iminothiolate)及甲基-4-巰基丁醯亞胺酯(methyl-4-mercaptobutyrimidate)。
3) 人類化抗體
本發明抗體可進一步包含人類化或人類抗體。非人類(例如鼠類)抗體之人類化形式為含有衍生自非人類免疫球蛋白之最小序列之嵌合免疫球蛋白、其免疫球蛋白鏈或片段(諸如Fv、Fab、Fab'、F(ab')2
或抗體之其他抗原結合子序列)。人類化抗體包括來自接受者之互補決定區(CDR)(如本文使用之HVR)之殘基經來自非人類物種(供體抗體)(諸如具有所要特異性、親和力及能力之小鼠、大鼠或兔)之CDR之殘基置換的人類免疫球蛋白(接受者抗體)。在一些情況下,人類免疫球蛋白之Fv構架殘基經相應非人類殘基置換。人類化抗體亦可包含既不可見於接受者抗體中亦不可見於輸入CDR或構架序列中之殘基。一般而言,人類化抗體將包含實質上全部至少一個及通常兩個可變域,其中全部或實質上全部CDR區對應於非人類免疫球蛋白之彼等區,且全部或實質上全部FR區為人類免疫球蛋白共同序列之彼等區。人類化抗體最佳亦包含至少一部分免疫球蛋白恆定區(Fc),通常為人類免疫球蛋白之恆定區。Jones等人,Nature 321
: 522-525 (1986);Riechmann等人,Nature 332
: 323-329 (1988)及Presta,Curr. Opin. Struct. Biol. 2
: 593-596 (1992)。
此項技術中熟知使非人類抗體人類化之方法。人類化抗體一般具有一或多個自非人類來源引入之胺基酸殘基。該等非人類胺基酸殘基通常稱為「輸入」殘基,其通常取自「輸入」可變域。人類化大體上可根據Winter及合作者之方法(Jones等人,Nature 321
:522-525 (1986);Riechmann等人,Nature 332
:323-327 (1988);Verhoeyen等人,Science 239
:1534-1536 (1988)),或藉由用齧齒動物CDR序列取代人類抗體之對應序列來進行。因此,該等「人類化」抗體為嵌合抗體(美國專利第4,816,567號),其中實質上近似完整之人類可變域已經來自非人類物種之對應序列取代。實際上,人類化抗體通常為一些CDR殘基及可能一些FR殘基經齧齒動物抗體類似位點之殘基取代的人類抗體。
待用於製備人類化抗體之人類輕鏈及重鏈可變域之選擇對降低抗原性而言極重要。根據所謂的「最佳匹配」方法,針對整個已知人類可變域序列文庫篩檢齧齒動物抗體之可變域序列。接著將最接近齧齒動物序列之人類序列接受為人類化抗體之人類構架(FR)。Sims等人,J. Immunol.
,151
:2296 (1993);Chothia等人,J. Mol. Biol.
,196
:901 (1987)。另一方法使用衍生自具有輕鏈或重鏈之特定亞群之所有人類抗體的共同序列的特定構架區。若干不同人類化抗體可使用同一構架。Carter等人,Proc. Natl. Acad. Sci. USA
,89
:4285 (1992);Presta等人,J. Immunol.
,151
:2623 (1993)。
另外,經人類化抗體保留對抗原之高親和力及其他有利生物性質係重要的。為達成此目標,根據一較佳方法,藉由使用親本序列及人類化序列之三維模型來分析親本序列及各種概念性人類化產物的方法製備人類化抗體。三維免疫球蛋白模型普遍可得且為熟習此項技術者所熟知。可獲得說明及呈現所選擇之候選免疫球蛋白序列之可能三維構型結構的電腦程式。該等呈現之檢驗准許分析殘基在候選免疫球蛋白序列之功能中之可能作用,亦即,分析影響候選免疫球蛋白結合其抗原之能力的殘基。以此方式,可自接受者序列及輸入序列選擇FR殘基且將其加以組合,以便達成所要抗體特徵,諸如對標靶抗原之親和力增加。CDR殘基通常直接且大部分實質上涉及對抗原結合之影響。
涵蓋各種形式之人類化抗體。舉例而言,人類化抗體可為諸如Fab之抗體片段,其視情況與一或多種細胞毒性劑結合以產生免疫結合物。或者,人類化抗體可為完整抗體,諸如完整IgG1抗體。
4) 人類抗體
作為人類化之替代,可產生人類抗體。舉例而言,現有可能產生在免疫後在不存在產生內源免疫球蛋白之情況下能夠產生全譜系人類抗體之轉殖基因動物(例如,小鼠)。舉例而言,已描述嵌合及生殖系突變小鼠中抗體重鏈連接區(JH
)基因之同型純合子缺失導致內源抗體產生之完全抑制。將人類生殖系免疫球蛋白基因陣列轉移至該等生殖系突變小鼠中將會在抗原攻擊後產生人類抗體。參見例如Jakobovits等人,Proc. Natl. Acad. Sci. USA
, 90:2551 (1993);Jakobovits等人,Nature
,362
:255-258 (1993);Bruggermann等人,Year in Immuno.
,7
:33 (1993);美國專利第5,591,669號及WO 97/17852。
或者,可使用噬菌體呈現技術由未免疫供體之免疫球蛋白可變(V)域基因譜系活體外產生人類抗體及抗體片段。McCafferty等人,Nature 348
:552-553 (1990);Hoogenboom及Winter,J. Mol. Biol. 227
: 381 (1991)。根據該技術,將抗體V域基因同框(in-frame)選殖於絲狀噬菌體之主要或次要鞘蛋白基因(諸如M13或fd)中且呈現為噬菌體顆粒之表面上之功能抗體片段。因為絲狀顆粒含有噬菌體基因組之單鏈DNA複本,所以基於抗體之功能性質進行選擇亦促使選擇編碼展示彼等性質之抗體之基因。因此,噬菌體模擬B-細胞之一些性質。可以多種格式進行噬菌體呈現;綜述於例如Johnson, Kevin S.及Chiswell, David J.,Curr. Opin Struct. Biol. 3
:564-571 (1993)中。噬菌體呈現可使用若干V基因區段來源。Clackson等人,Nature
352:
624-628 (1991)自衍生自免疫小鼠之脾之V基因之小隨機組合文庫分離抗噁唑酮抗體之多樣性陣列。可構築未免疫人類供體之V基因譜系且可大體上根據Marks等人,J. Mol. Biol.
222:581-597 (1991)或Griffith等人,EMBO J.
12:725-734 (1993)所述之技術分離多樣性抗原(包括自體抗原)陣列之抗體。亦參見美國專利第5,565,332號及第5,573,905號。
亦可利用Cole等人及Boerner等人之技術製備人類單株抗體(Cole等人,Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 第77頁(1985)及Boerner等人,J. Immunol. 147
(1):86-95(1991)。類似地,亦可藉由將人類免疫球蛋白基因座引入轉殖基因動物中來製備人類抗體,該轉殖基因動物例如內源性免疫球蛋白基因已部分或完全失活之小鼠。攻擊後,觀察人類抗體產生,其在各方面均與人類中所見極其類似,包括基因重排、裝配及抗體譜系。此方法描述於例如美國專利第5,545,807號;第5,545,806號;第5,569,825號;第5,625,126號;第5,633,425號;第5,661,016號及以下科學出版物中:Marks等人,Bio/Technology 10
: 779-783 (1992);Lonberg等人,Nature 368
: 856-859 (1994);Morrison,Nature 368
: 812-13 (1994);Fishwild等人,Nature Biotechnology 14
: 845-51 (1996);Neuberger,Nature Biotechnology 14
: 826 (1996)及Lonberg及Huszar,Intern. Rev. Immunol. 13
: 65-93 (1995)。
最後,亦可由經活化B細胞活體外產生人類抗體(參見美國專利第5,567,610號及第5,229,275號)。
5) 抗體片段
在某些情形下,使用抗體片段而非全抗體具有優勢。較小片段尺寸可允許快速清除且可產生改進之通向實體腫瘤之通道。
已開發多種產生抗體片段之技術。該等片段傳統上經由完整抗體之蛋白水解消化獲得(參見例如Morimoto等人,J Biochem Biophys. Method. 24
:107-117 (1992);及Brennan等人,Science
,229
:81 (1985))。然而,現可由重組宿主細胞直接產生該等片段。Fab、Fv及ScFv抗體片段所有皆可表現於大腸桿菌中且自大腸桿菌分泌,因此容易地產生大量此等片段。可自以上所討論之抗體噬菌體文庫分離抗體片段。或者,可直接自大腸桿菌回收Fab'-SH片段且使其化學偶合以形成F(ab')2
片段(Carter等人,Bio/Technology 10
:163-167 (1992))。根據另一方法,可自重組宿主細胞培養物直接分離F(ab')2
片段。活體內半衰期增加之Fab及F(ab')2
描述於美國專利第5,869,046號中。在其他實施例中,所選擇之抗體為單鏈Fv片段(scFv)。參見WO 93/16185;美國專利第5,571,894號及美國專利第5,587,458號。抗體片段亦可為「線性抗體」,例如如美國專利5,641,870中所述。該等線性抗體片段可為單特異性或雙特異性抗體。
6) 抗體依賴性酶介導之前藥療法(ADEPT)
本發明抗體亦可藉由使抗體與前藥活化酶結合而用於ADEPT中,該前藥活化酶使前藥(例如肽基化學治療劑,參見WO 81/01145)轉化為活性抗癌藥。參見例如WO 88/07378及美國專利第4,975,278號。
適用於ADEPT之免疫結合物之酶組分包括能夠對前藥起作用以便使其轉化為其更具活性之細胞毒性形式之任何酶。
適用於本發明方法之酶包括(但不限於)糖苷酶、葡萄糖氧化酶、人類溶菌酶、人類葡糖醛酸酶、適用於使含磷酸酯前藥轉化為游離藥物之鹼性磷酸酶;適用於使含硫酸酯前藥轉化為游離藥物之芳基硫酸酯酶;適用於使無毒5-氟胞嘧啶轉化為抗癌藥物5-氟尿嘧啶之胞嘧啶去胺酶;適用於使含肽前藥轉化為游離藥物之蛋白酶,諸如沙雷氏菌蛋白酶(serratia protease)、嗜熱菌蛋白酶、枯草桿菌蛋白酶、羧肽酶(例如羧肽酶G2及羧基肽酶A)及組織蛋白酶(諸如組織蛋白酶B及L);適用於轉化含有D-胺基酸取代基之前藥的D-丙胺醯基羧肽酶;適用於使糖基化前藥轉化為游離藥物之碳水化合物裂解酶,諸如β-半乳糖苷酶及神經胺糖酸苷酶;適用於使經β-內醯胺衍生之藥物轉化為游離藥物之β-內醯胺酶;及適用於使分別在胺氮處經苯氧基乙醯基或苯乙醯基衍生之藥物轉化為游離藥物之青黴素醯胺酶,諸如青黴素V醯胺酶或青黴素G醯胺酶。或者,可使用在此項技術中亦稱為「抗體酶」之具有酶促活性之抗體使本發明前藥轉化為游離活性藥物(參見例如Massey,Nature 328
: 457-458 (1987))。可如本文所述製備抗體-抗體酶結合物以將抗體酶傳遞至腫瘤細胞群體中。
上述酶可由此項技術中熟知之技術(諸如使用以上所討論之異雙功能交聯劑)與本文所述之多肽或抗體共價結合。或者,可使用此項技術中熟知之重組DNA技術構築包含與本發明酶之至少一個功能活性部分連接之本發明抗體之至少一個抗原結合區的融合蛋白(參見例如Neuberger等人,Nature 312
: 604-608 (1984))。
7) 雙特異性及多特異性抗體
雙特異性抗體(BsAb)為對至少兩個不同抗原決定基(包括同一或另一蛋白質上之抗原決定基)具有結合特異性之抗體。或者,一個臂可與標靶抗原結合,且另一臂可與結合白血球上之觸發分子(諸如T細胞受體分子(例如CD3)或IgG之Fc受體(FcγR),諸如FcγR1(CD64)、FcγRII(CD32)及FcγRIII(CD16))之臂組合,以便將細胞防禦機制聚焦且定位於標靶抗原表現細胞。該等抗體可衍生自全長抗體或抗體片段(例如F(ab')2
雙特異性抗體)。
雙特異性抗體亦可用於將細胞毒性劑定位於表現標靶抗原之細胞。該等抗體具有一個結合所要抗原之臂及另一結合細胞毒性劑(例如沙泊寧(saporin)、抗干擾素-α、長春生物鹼、篦麻毒素A鏈(ricin A chain)、甲胺喋呤或放射性同位素半抗原)之臂。已知雙特異性抗體之實例包括抗ErbB2/抗FcgRIII(WO 96/16673)、抗ErbB2/抗FcgRI(U.S.P. 5,837,234)、抗ErbB2/抗CD3(U.S.P. 5,821,337)。
此項技術中已知製造雙特異性抗體之方法。全長雙特異性抗體之傳統產生係基於兩個免疫球蛋白重鏈/輕鏈對之共表現,其中兩個鏈具有不同特異性。Millstein等人,Nature
,305
:537-539 (1983)。由於免疫球蛋白重鏈及輕鏈之隨機分配,因此該等融合瘤(四融合瘤(quadromas))產生10種不同抗體分子之潛在混合物,其中僅一個具有正確的雙特異性結構。通常由親和層析步驟進行之正確分子之純化相當繁瑣且產物產率低。類似程序揭示於WO 93/08829中及Traunecker等人,EMBO J.
,10
:3655-3659 (1991)中。
根據一種不同方法,使具有所要結合特異性(抗體-抗原組合位點)之抗體可變域與免疫球蛋白恆定域序列融合。較佳與包含鉸鏈區、CH2及CH3區中之至少部分之免疫球蛋白重鏈恆定域融合。較佳具有第一重鏈恆定區(CH1),該恆定區含有輕鏈結合所必需之位點(存在於融合中之至少一者中)。將編碼免疫球蛋白重鏈融合及必要時編碼免疫球蛋白輕鏈之DNA插入獨立表現載體中且共轉染於適合之宿主生物體中。在構築中所使用之3個多肽鏈之不相等比率提供最佳產率之實施例中,此舉提供調節3個多肽片段之相互比例之高靈活性。然而,當等比率之至少兩個多肽鏈之表現產生高產率時或當比率不具有特殊顯著性時,有可能將兩個或所有三個多肽鏈之編碼序列插入一個表現載體中。
在該方法之一較佳實施例中,雙特異性抗體包含一臂中之具有第一結合特異性之雜交免疫球蛋白重鏈及另一臂中之雜交免疫球蛋白重鏈-輕鏈對(提供第二結合特異性)。已發現該不對稱結構有利於分離所要雙特異性化合物與非所要免疫球蛋白鏈組合,因為雙特異性分子之僅一半中存在免疫球蛋白輕鏈提供容易的分離方法。該方法揭示於WO 94/04690中。關於產生雙特異性抗體之其他詳情,參見例如Suresh等人,Methods in Enzymology
,121
:210 (1986)。
根據WO 96/27011或美國專利5,731,168中所述之另一方法,可使一對抗體分子之間的界面工程化以最大化自重組細胞培養物回收之雜二聚體的百分率。較佳界面包含抗體恆定域之CH3區之至少一部分。在該方法中,用較大側鏈(例如酪胺酸或色胺酸)置換一或多個來自第一抗體分子界面之小胺基酸側鏈。藉由用較小側鏈(例如丙胺酸或蘇胺酸)置換大胺基酸側鏈在第二抗體分子界面上產生具有與大側鏈相同或相似大小之補償「空穴」。此舉提供使雜二聚體之產率增加超過諸如均二聚體之非所要最終產物之機制。
文獻中已描述由抗體片段產生雙特異性抗體之技術。舉例而言,可使用化學鍵聯製備雙特異性抗體。Brennan等人,Science 229
: 81 (1985)描述使完整抗體蛋白水解裂解以產生F(ab')2
片段之程序。在二硫醇錯合劑亞砷酸鈉存在下,該等片段被還原以使鄰二硫醇穩定且阻止形成分子間二硫化物。接著使所產生之Fab'片段轉化為硫基硝基苯甲酸酯(TNB)衍生物。接著使Fab'-TNB衍生物中之一者再轉化為Fab'-TNB衍生物以形成雙特異性抗體。所產生之雙特異性抗體可用作酶選擇性固定化之試劑。
可自大腸桿菌中直接回收Fab'片段且使該等片段化學偶合形成雙特異性抗體。Shalaby等人,J. Exp. Med.
,175
: 217-225 (1992)描述完全人類化雙特異性抗體F(ab')2
分子之產生。各Fab'片段係獨立地自大腸桿菌分泌且使其活體外經受直接化學偶合以形成雙特異性抗體。所形成之雙特異性抗體能夠與過度表現ErbB2受體之細胞及正常人類T細胞結合,以及觸發人類細胞毒性淋巴細胞對人類乳房腫瘤標靶之溶解活性。
亦已描述多種直接自重組細胞培養物製備及分離二價抗體片段之技術。舉例而言,已使用白胺酸拉鏈產生二價雜二聚體。Kostelny等人,J. Immunol.
,148
(5):1547-1553 (1992)。藉由基因融合使來自Fos蛋白質及Jun蛋白質之白胺酸拉鏈肽與兩個不同抗體之Fab'部分連接。使抗體均二聚體在鉸鏈區處還原以形成單體且接著再氧化以形成抗體雜二聚體。Hollinger等人,Proc. Natl. Acad. Sci. USA
,90
:6444-6448 (1993)所述之「雙功能抗體」技術已提供製備雙特異性/二價抗體片段之替代機制。該等片段包含經由過短而無法使同一鏈上之兩個域配對之連接子與輕鏈可變域(VL
)連接之重鏈可變域(VH
)。因此,一個片段之VH
域及VL
域被迫與另一片段之互補VL
域及VH
配對,從而形成兩個抗原結合位點。亦已報導利用單鏈Fv(sFv)二聚體製備雙特異性/二價抗體片段之另一策略。參見Gruber等人,J. Immunol.
,152
:5368 (1994)。
涵蓋具有超過兩個價數之抗體。舉例而言,可製備三特異性抗體。Tutt等人,J. Immunol. 147
: 60 (1991)。
例示性雙特異性抗體可與既定分子上之兩個不同抗原決定基結合。或者,抗蛋白質臂可與結合白血球上之觸發分子(諸如T細胞受體分子(例如CD2、CD3、CD28或B7);或IgG之Fc受體(FcγR),諸如FcγRI(CD64)、FcγRII(CD32)及FcγRIII(CD16))的臂組合以便將細胞防禦機制聚焦於表現特定蛋白質之細胞。雙特異性抗體亦可用於將細胞毒性劑定位於表現特定蛋白質之細胞。該等抗體具有蛋白結合臂及結合細胞毒性劑或放射性核素螯合劑(諸如EOTUBE、DPTA、DOTA或TETA)之臂。另一相關雙特異性抗體結合相關蛋白質且進一步結合組織因子(TF)。
8) 多價抗體
與二價抗體相比,表現抗體所結合之抗原的細胞可能更快地內化(及/或異化(catabolized))多價抗體。本發明抗體可為具有三個或三個以上抗原結合位點之多價抗體(其為除IgM類別以外之抗體)(例如四價抗體),其可容易地藉由重組表現編碼抗體多肽鏈之核酸產生。多價抗體可包含一個二聚化域及三個或三個以上抗原結合位點。較佳二聚化域包含一Fc區或一鉸鏈區(或由其組成)。在此情況下,抗體將包含一Fc區及在Fc區胺基末端之三個或三個以上抗原結合位點。本文之較佳多價抗體包含3至約8個、但較佳4個抗原結合位點(或由其組成)。多價抗體包含至少一條多肽鏈(且較佳兩條多肽鏈),其中該(等)多肽鏈包含兩個或兩個以上可變域。舉例而言,多肽鏈可包含VD1-(X1)n
-VD2-(X2)n
-Fc,其中VD1為第一可變域,VD2為第二可變域,Fc為Fc區之一條多肽鏈,X1及X2表示胺基酸或多肽,且n為0或1。舉例而言,多肽鏈可包含VH-CH1-可撓性連接子-VH-CH1-Fc區鏈或VH-CH1-VH-CH1-Fc區鏈。本文之多價抗體較佳進一步包含至少2個(且較佳4個)輕鏈可變域多肽。本文之多價抗體可例如包含約2至約8個輕鏈可變域多肽。此處涵蓋之輕鏈可變域多肽包含輕鏈可變域且視情況進一步包含CL域。
9) 雜結合抗體
雜結合抗體亦在本發明之範疇內。雜結合抗體由兩個共價連接之抗體構成。舉例而言,雜結合物中之一個抗體可與抗生物素蛋白偶合,另一抗體與生物素偶合。舉例而言,提出該等抗體使免疫系統細胞靶向不合需要之細胞(U.S.P. 4,676,980)且治療HIV感染。WO 91/00360、WO 92/200373及EP 0308936。預期可使用合成蛋白質化學中已知之方法(包括涉及交聯劑之方法)活體外製備抗體。舉例而言,可使用雙硫鍵交換反應或藉由形成硫醚鍵來構築免疫毒素。適於此目之試劑之實例包括亞胺硫醇酯及甲基-4-巰基丁亞胺酯及例如美國專利第4,676,980號中所揭示之試劑。可使用任何方便之交聯方法製備雜結合抗體。適合之交聯劑以及許多交聯技術在此項技術中為熟知的且揭示於美國專利第4,676,980號中。
10) 效應功能工程改造
可能需要在Fc效應功能方面對本發明抗體進行修飾,例如以便改良(例如增進或消除)抗體之抗原依賴性細胞介導細胞毒性(antigen-dependent cell-mediated cyotoxicity,ADCC)及/或補體依賴性細胞毒性(complement dependent cytotoxicity,CDC))。在一較佳實施例中,降低或消除抗PD-L1抗體之Fc效應功能。此舉可藉由將一或多個胺基酸取代引入抗體之Fc區中來達成。或者或另外,可將半胱胺酸殘基引入Fc區中,藉此允許在此區中形成鏈間雙硫鍵。由此產生之均二聚抗體可具有改良之內化能力及/或增加之補體介導細胞殺死及抗體依賴性細胞毒性(antibody-dependent cellular cytotoxicity,ADCC)。參見Caron等人,J. Exp Med.
176:1191-1195 (1992)及Shopes, B.J. Immunol.
148:2918-2922 (1992)。亦可使用如Wolff等人,Cancer Research
53:2560-2565 (1993)中所述之異雙功能交聯劑來製備抗腫瘤活性增強之均二聚抗體。或者,抗體可經工程改造,具有雙Fc區且藉此可具有增強之補體溶解及ADCC能力。參見Stevenson等人,Anti-Cancer Drug Design
3:219-230 (1989)。
舉例而言,如美國專利第5,739,277號中所述,為增加抗體之血清半衰期,可將救助受體結合抗原決定基併入抗體(尤其抗體片段)中。如本文所用之術語「救助受體結合抗原決定基」係指IgG分子(例如IgG1
、IgG2
、IgG3
或IgG4
)之Fc區之抗原決定基,其負責增加IgG分子之活體內血清半衰期。
11) 其他胺基酸序列修飾
涵蓋本文所述之抗體之胺基酸序列修飾。舉例而言,可能需要改良抗體之結合親和力及/或其他生物性質。抗體之胺基酸序列變異體係藉由將適當核苷酸變化引入抗體核酸中製備或由肽合成製備。該等修飾包括例如使抗體之胺基酸序列內的殘基缺失及/或在該等殘基中插入其他殘基及/或使該等殘基被取代。可進行缺失、插入及取代之任何組合以獲得最終構築體,其限制條件為最終構築體具有所要特徵。胺基酸變化在抗體之轉譯過程後亦可能改變,諸如糖基化位點之編號或位置變化。
鑑別抗體之某些為突變誘發之較佳位置的殘基或區的適用方法如Cunningham及Wells,Science
,244
:1081-1085 (1989)所述稱為「丙胺酸掃描突變誘發」。此處,鑑別殘基或標靶殘基組(例如,帶電殘基,諸如arg、asp、his、lys及glu)且用中性或帶負電胺基酸(最佳為丙胺酸或聚丙胺酸)將其置換以影響胺基酸與抗原之相互作用。隨後藉由在取代位點處或針對取代位點引入其他變異體來改進彼等對取代證實功能敏感性之胺基酸位置。因此,雖然預先確定引入胺基酸序列變化之位點,但不必預先確定突變之性質本身。舉例而言,為分析給定位點處之突變效能,在標靶密碼子或區處進行ala掃描或隨機突變誘發,且就所要活性篩檢所表現之抗體變異體。
胺基酸序列插入包括長度在1個殘基至含有一百個或以上之殘基之多肽範圍內的胺基及/或羧基末端融合,以及單一或多個胺基酸殘基之序列內插入。末端插入之實例包括具有N末端甲硫胺醯基殘基之抗體或與細胞毒性多肽融合之抗體。抗體分子之其他插入變異體包括抗體之N末端或C末端與酶(例如,對於ADEPT而言)或多肽的融合體,其增加抗體之血清半衰期。
另一類變異體為胺基酸取代變異體。該等變異體在抗體分子中具有至少一個經不同殘基置換之胺基酸殘基。雖然最受關注之取代性突變誘發之位點包括高變區,但亦涵蓋FR變化。保守取代展示於下表A中之「較佳取代」之標題下。若該等取代導致生物活性變化,則可引入表A中稱為「例示性取代」或如以下關於胺基酸類別之進一步所描述之更實質性變化且篩檢產物。 表 A 胺基酸取代
抗體之生物性質之實質性修飾係藉由選擇對維持以下之作用顯著不同的取代來實現:(a)取代區域中之多肽主鏈之結構,例如呈摺疊片或螺旋構型;(b)標靶位點處分子之電荷或疏水性;或(c)側鏈大小。基於常見側鏈性質將天然存在之殘基分為以下群組:
(1) 疏水性:正白胺酸、met、ala、val、leu、ile;
(2) 中性親水性:cys、ser、thr;
(3) 酸性:asp、glu;
(4) 鹼性:asn、gln、his、lys、arg;
(5) 影響鏈取向之殘基:gly、pro;及
(6) 芳族:trp、tyr、phe。
非保守取代將必然使該等類別中之一者之成員換成另一類別。
通常亦可用絲胺酸取代任何不涉及維持抗體之適當構型之半胱胺酸殘基以改良分子之氧化穩定性且阻止異常交聯。相反地,可將半胱胺酸鍵添加至抗體中以改良其穩定性(尤其當抗體為諸如Fv片段之抗體片段時)。
一類尤其較佳取代性變異體涉及取代親本抗體(例如,人類化抗體或人類抗體)之一或多個高變區殘基。相對於產生該等變異體之親本抗體,選擇用於進一步研發之所得變異體通常將具有改良之生物性質。產生該等取代性變異體之方便方法涉及使用噬菌體呈現之親和力成熟。簡言之,使若干高變區位點(例如,6-7個位點)突變以在各位點處產生所有可能的胺基酸取代。使如此產生之抗體變異體與封裝於各絲狀噬菌體顆粒內之M13之基因III產物融合而由絲狀噬菌體顆粒以單價形式呈現。隨後,如本文所揭示,就生物活性(例如,結合親和力)篩檢噬菌體呈現變異體。為鑑別用於修飾之候選高變區位點,可進行丙胺酸掃描突變誘發以鑑別顯著有助於抗原結合之高變區殘基。或者或另外,分析抗原-抗體複合物之晶體結構可有益於鑑別抗體與其標靶(例如PD-L1、B7.1)之間的接觸點。根據本文詳述之技術,該等接觸殘基及相鄰殘基為取代候選物。一旦產生該等變異體,則如本文所述使一系列變異體經受篩檢,且可選擇在一或多個相關檢定中具有優良性質之抗體以用於進一步研發。
另一類抗體胺基酸變異體改變抗體之原始糖基化模式。改變意謂使抗體中發現之一或多個碳水化合物部分缺失及/或添加抗體中不存在之一或多個糖基化位點。
抗體之糖基化通常為N-連接型或O-連接型。N-連接型係指碳水化合物部分與天冬醯胺酸殘基之側鏈的連接。三肽序列天冬醯胺酸-X-絲胺酸及天冬醯胺酸-X-蘇胺酸(其中X為除脯胺酸以外之任何胺基酸)為碳水化合物部分與天冬醯胺酸側鏈之酶促連接的識別序列。因此,在多肽中存在該等三肽序列中之任一者產生潛在糖基化位點。雖然O-連接型糖基化係指糖N-乙醯基半乳胺糖、半乳糖或木糖中之一者與羥基胺基酸(最常見為絲胺酸或蘇胺酸)的連接,但亦可使用5-羥基脯胺酸或5-羥基離胺酸。
宜藉由改變胺基酸序列將糖基化位點添加至抗體中從而使其含有上述三肽序列中之一或多者來實現(就N-連接型糖基化位點而言)。該改變亦可藉由向原始抗體之序列添加一或多個絲胺酸或蘇胺酸殘基或用一或多個絲胺酸或蘇胺酸殘基取代來實現(就O-連接型糖基化位點而言)。
編碼本發明抗體胺基酸序列變異體之核酸分子由此項技術中已知之多種方法製備。此等方法包括(但不限於)自天然來源分離(在天然存在之胺基酸序列變異體之情況下),或藉由早期製備之變異體或非變異體形式發生寡核苷酸介導(或定點特異性)之突變誘發、PCR突變誘發及卡匣突變誘發來製備。
12) 其他抗體修飾
本發明抗體可經進一步修飾以含有此項技術中已知且易於利用之其他非蛋白質部分。較佳地,適於衍生抗體之部分為水可溶聚合物。水可溶聚合物之非限制性實例包括(但不限於)聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纖維素、葡聚糖、聚乙烯醇、聚乙烯吡咯啶酮、聚-1,3-二氧戊環、聚-1,3,6-三噁烷、乙烯/順丁烯二酸酐共聚物、聚胺基酸(均聚物或無規共聚物)及葡聚糖或聚(N-乙烯吡咯啶酮)聚乙二醇、聚丙二醇均聚物、聚氧化丙烯/氧化乙烯共聚物、聚乙氧基化多元醇(例如甘油)、聚乙烯醇及其混合物。聚乙二醇丙醛因其於水中之穩定性而可在製造中具有優勢。聚合物可具有任何分子量,且可為分支或未分支聚合物。與抗體連接之聚合物的數目可變化,且若連接一個以上聚合物,則聚合物可為相同或不同分子。一般而言,用於衍生化之聚合物之數目及/或類型可基於以下考慮因素來確定,該等考慮因素包括(但不限於)待改良之抗體之特定性質或功能、抗體衍生物是否將在規定條件下用於療法中等。該等技術及其他適合之調配物揭示於Remington: The Science and Practice of Pharmacy
, 第20版, Alfonso Gennaro編,Philadelphia College of Pharmacy and Science (2000)中。
D.醫藥調配物
藉由混合具有所要純度之活性成份與視情況選用之醫藥學上可接受之載劑、賦形劑或穩定劑來製備治療調配物以儲存(Remington: The Science and Practice of Pharmacy
, 第20版, Lippincott Williams & Wiklins, Pub., Gennaro編,Philadelphia, PA 2000)。可接受之載劑、賦形劑或穩定劑在所用劑量及濃度下對接受者而言無毒,且包括緩衝液、抗氧化劑(包括抗壞血酸、甲硫胺酸、維生素E、偏亞硫酸氫鈉)、防腐劑、等張劑、穩定劑、金屬錯合物(例如Zn-蛋白質錯合物)、螯合劑(諸如EDTA)及/或非離子型界面活性劑。
當治療劑為抗體片段時,特異性結合標靶蛋白質之結合域之最小抑制性片段較佳。舉例而言,可基於抗體之可變區序列設計保留結合標靶蛋白質序列之能力的抗體片段或甚至肽分子。該等肽可藉由化學上合成及/或利用DNA重組技術產生(參見例如Marasco等人,Proc. Natl. Acad. Sci. USA 90
: 7889-7893 [1993])。
使用緩衝液將pH值控制在使療效最佳之範圍內,當穩定性具有pH依賴性時尤其如此。緩衝液之濃度較佳在約50 mM至約250 mM範圍內。適用於本發明之緩衝劑包括有機酸與無機酸及其鹽。舉例而言,檸檬酸鹽、磷酸鹽、丁二酸鹽、酒石酸鹽、反丁烯二酸鹽、葡糖酸鹽、草酸鹽、乳酸鹽、乙酸鹽。另外,緩衝液可包含組胺酸及三甲胺鹽(諸如Tris)。
添加防腐劑以延遲微生物生長,且添加量通常在0.2%-1.0% (w/v)範圍內。適用於本發明之防腐劑包括氯化十八基二甲基苯甲基銨;氯化六烴季銨;鹵化苯甲烴銨(例如氯化苯甲烴銨、溴化苯甲烴銨,碘化苯甲烴銨)、苄索氯銨(benzethonium chloride);硫柳汞、苯酚、丁醇或苯甲醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇、3-戊醇及間甲酚。
存在張力劑(有時稱為「穩定劑」)以調整或維持組合物中液體之張力。當與大帶電生物分子(諸如蛋白質及抗體)使用時,其通常稱為「穩定劑」,此係因為其可與胺基酸側鏈之帶電基團相互作用,藉此減小分子間及分子內相互作用之潛能。考慮到其他成份之相對量,張力劑可以0.1重量%至25重量%、較佳地1重量%至5重量%之間的任何量存在。較佳張力劑包括多元糖醇,較佳三元或三元以上糖醇(higher sugar alcohol),諸如甘油、赤藻糖醇、阿糖醇、木糖醇、山梨糖醇及甘露糖醇。
其他賦形劑包括可充當一或多種以下之試劑:(1)增積劑,(2)溶解增強劑,(3)穩定劑,及(4)阻止變性或黏著於容器壁之試劑。該等賦形劑包括:多元糖醇(以上所列舉);胺基酸,諸如丙胺酸、甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸、離胺酸、鳥胺酸、白胺酸、2-苯丙胺酸、麩胺酸、蘇胺酸等;有機糖或糖醇,諸如蔗糖、乳糖、乳糖醇、海藻糖、水蘇糖、甘露糖、山梨糖、木糖、核糖、核糖醇、肌糖(myoinisitose)、肌糖醇(myoinisitol)、半乳糖、半乳糖醇、甘油、環多醇(例如肌醇)、聚乙二醇;含硫還原劑,諸如尿素、麩胱甘肽、硫辛酸、硫代羥乙酸鈉、硫代甘油、α-單硫代甘油及硫代硫酸鈉;低分子量蛋白質,諸如人血清白蛋白、牛血清白蛋白、明膠或其他免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;單醣(例如木糖、甘露糖、果糖、葡萄糖);雙醣(例如乳糖、麥芽糖、蔗糖);三醣,諸如棉子糖;及多醣,諸如糊精或葡聚糖。
存在非離子型界面活性劑或清潔劑(亦稱為「濕潤劑」)以有助於使治療劑增溶以及保護治療蛋白質以免發生攪動誘導之聚集,其亦允許調配物暴露於剪切表面應力而不引起活性治療蛋白質或抗體變性。非離子型界面活性劑之存在量在約0.05 mg/ml至約1.0 mg/ml、較佳約0.07 mg/ml至約0.2 mg/ml範圍內。
適合之非離子型界面活性劑包括聚山梨醇酯(20、40、60、65、80等)、泊洛沙姆(polyoxamer)(184、188等)、PLURONIC®
多元醇、TRITON®
、聚氧化乙烯脫水山梨糖醇單醚(TWEEN®
-20、TWEEN®
-80等)、聚桂醇400、硬脂酸聚乙二醇40、聚氧化乙烯氫化蓖麻油10、50及60、單硬脂酸甘油酯、蔗糖脂肪酸酯、甲基纖維素及羧甲基纖維素。可使用之陰離子清潔劑包括月桂基硫酸鈉、丁二酸二辛酯磺酸鈉及二辛基磺酸鈉。陽離子清潔劑包括氯化苯甲烴銨或苄索氯銨。
為使調配物用於活體內投藥,其必須為無菌的。可藉由經無菌過濾膜過濾使調配物無菌。一般將本文之治療組合物置放於具有無菌接取口之容器中,例如具有可由皮下注射針刺穿之塞子的靜脈內溶液袋或小瓶。
投藥途徑與已知且公認之方法一致,諸如藉由在一段長時間內以適合之方式單次或多次快速注射或輸注(例如藉由皮下、靜脈內、腹膜內、肌肉內、動脈內、病灶內或關節內途徑注射或輸注)、表面投藥、吸入或藉由持續釋放或延長釋放方式。
本文之調配物亦可含有所治療之特定適應症所必需的一種以上活性化合物,較佳具有彼此並無不利影響之互補活性之活性化合物。或者或另外,組合物可包含細胞毒性劑、細胞激素或生長抑制劑。該等分子適當以對預定目的有效之量組合存在。
亦可例如藉由凝聚技術或藉由界面聚合將活性成份截留在所製備之微囊(例如分別為羥甲基纖維素或明膠微囊及聚(甲基丙烯酸甲酯)微囊)中、截留在膠狀藥物傳遞系統(例如脂質體、白蛋白微球體、微乳液、奈米粒子及奈米膠囊)中或截留在巨乳液中。該等技術揭示於Remington's Pharmaceutical Sciences
第18版, 同上中。
可經由使用無毒「水可溶多價金屬鹽」增進本文所述蛋白質及抗體之穩定性。鹽之實例包括Ca2+
、Mg2+
、Zn2+
、Fe2+
、Fe3+
、Cu2+
、Sn2+
、Sn4+
、Al2+
及Al3+
。可與上述多價金屬陽離子形成水可溶鹽之陰離子的實例包括彼等由無機酸及/或有機酸形成之陰離子。該等水可溶鹽於水中之溶解度(在20℃下)為至少約20 mg/ml,或者至少約100 mg/ml,或者至少約200 mg/ml。
可用於形成「水可溶多價金屬鹽」之適合之無機酸包括鹽酸、乙酸、硫酸、硝酸、硫氰酸及磷酸。可使用之適合有機酸包括脂族羧酸及芳族酸。此定義中之脂族酸可定義為飽和或不飽和C2-9
羧酸(例如脂族單羧酸、脂族二羧酸及脂族三羧酸)。舉例而言,此定義中之例示性單羧酸包括飽和C2-9
單羧酸(乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸及癸酸)及不飽和C2-9
單羧酸(丙烯酸、丙炔酸、甲基丙烯酸、丁烯酸及異巴豆酸)。例示性二羧酸包括飽和C2-9
二羧酸(丙二酸、丁二酸、戊二酸、己二酸及庚二酸),而不飽和C2-9
二羧酸包括順丁烯二酸、反丁烯二酸的、甲基順丁烯二酸及甲基反丁烯二酸。例示性三羧酸包括飽和C2-9
三羧酸(丙三羧酸及1,2,3-丁烷三羧酸)。另外,此定義之羧酸亦可含有一或兩個羥基以形成羥基羧酸。例示性羥基羧酸包括乙醇酸、乳酸、甘油酸、羥丙二酸、蘋果酸、酒石酸及檸檬酸。此定義中之芳族酸包括苯甲酸及水楊酸。
通常使用之可用於幫助使經囊封本發明多肽穩定的水可溶多價金屬鹽包括例如:(1)無機酸金屬鹽:鹵化物(例如氯化鋅、氯化鈣)、硫酸鹽、硝酸鹽、磷酸鹽及硫氰酸鹽;(2)脂族羧酸金屬鹽(例如乙酸鈣、乙酸鋅、丙酸鈣、羥乙酸鋅、乳酸鈣、乳酸鋅及酒石酸鋅);及(3)芳族羧酸金屬鹽:苯甲酸鹽(例如苯甲酸鋅)及水楊酸鹽。
E.治療方法:
對於疾病之預防或治療,活性劑之適當劑量將視以下而定:如上所定義之待治療疾病之類型、疾病嚴重程度及過程、投與藥劑用於預防性目的還是治療性目的、先前療法、患者臨床病史及對藥劑之反應及主治醫師之判斷。適合地,將藥劑一次性或經一系列治療投與患者。
在一特定實施例中,本發明係關於藉由減弱經由PD-1之信號傳導引起協同刺激,尤其藉由施用阻止結合PD-1及/或B7.1之PD-L1抗體來減弱,以及關於T細胞功能障礙病症之治療性治療。
1. 感染
PD-1及其配位體(「PD-1:PD-L」)在調控針對引起急性及慢性感染之病原體之免疫防禦中發揮重要作用。PD-1:PD-L信號傳導在調控有效抗微生物免疫防禦與免疫介導之組織損傷之間的平衡中發揮關鍵作用。舉例而言,雖然PD-1基因剔除小鼠清除腺病毒感染比其野生型對應小鼠快,但其發展更嚴重之肝細胞損傷。Iwai等人,J. Exp. Med. 198
: 39-50 (2003)。在疱疹基質性角膜炎小鼠模型中,阻斷抗PD-L1抗體使角膜炎惡化,從而增強HSV-1特異性效應CD4 T細胞之擴充及IFN-γ之產生及存活。Jun等人,FEBS Lett. 579
: 6259-64 (2005)。
引起慢性感染之微生物利用PD-1:PD-L信號傳導路徑逃避宿主免疫反應,此導致慢性感染。引起慢性感染之病毒可使病毒特異性T細胞變成非功能性細胞,且藉此使抗病毒T細胞反應沉默。Barber等人,Nature 439
: 682-87 (2006);Wherry等人,J. Virol. 78
: 5535-45 (2004)。CD8+
T細胞之T細胞耗竭或無反應為慢性感染期間病毒控制無效之重要原因,且為小鼠慢性LCMV感染以及人類HIV、HBV、HCV及HTLV感染及靈長類動物SIV感染的特徵。在病毒特異性CD8+
T細胞已耗竭之表型內似乎存在階層式進行性功能損失,其中首先細胞毒性及IL-2產生損失,接著效應細胞激素產生損失。
PD-1在活化後調升,且在患有LCMV慢性感染之小鼠中,表現因CD8+
T細胞耗竭而維持在高含量下。Barber等人,同上。投與阻斷PD-1:PD-L1結合之抗體引起T細胞反應增強且病毒負荷實質性減少。在CD4+
TH
反應無效之持續性感染小鼠中,阻斷PD-1:PD-L1使CD8+
T細胞自導致增殖、細胞激素分泌、殺死受感染細胞之功能障礙狀態中恢復,且降低病毒負荷,從而強有力地提出一種治療慢性病毒感染之治療方法。
由於PD-1:PD-L在LCMV中之作用,因此對將此路徑靶向人類慢性感染治療展示強烈關注。在HIV特異性T細胞[Petrovas等人,J. Exp. Med. 203
: 2281-92 (2006);Day等人,Nature 443
: 350-54 (2006);Traumann等人, Nat. Med. 12
: 1198-202 (2006)]、HBV特異性T細胞[Boettler等人,J. Virol. 80
: 3532-40 (2006);Boni等人,J. Virol. 81
: 4215-25 (2007)]及HCV特異性T細胞[Urbani等人,J. Virol. 80:
11398-403 (2006)]上,PD-L1高度表現。在患有慢性HBV感染之患者的周邊血液CD14+
單核細胞及骨髓DC[Chen等人,J. Immunol. 178
: 6634-41 (2007);Geng等人,J. Viral Hepat. 13
: 725-33 (2006)]HIV患者之CD14+細胞及T細胞[Trabattoni等人,Blood 101
: 2514-20 (2003)]上,PD-L1亦調升。活體外阻斷PD-1:PD-L1相互作用逆轉HIV特異性、HBV特異性、HCV特異性及SIV特異性CD8+及CD4+ T細胞之耗竭,且恢復增殖及細胞激素之產生。Petrovas等人,J. Exp. Med.
203: 2281-92 (2006);Day等人,同上;Trautmann等人,同上;Boni等人,同上;Urbani等人,同上;Velu等人,J. Virol. 81
: 5819-28 (2007)。
PD-1表現含量亦可為病毒特異性CD8+
T細胞之指示T細胞耗竭及疾病嚴重程度的有效診斷指標。HIV特異性CD8+
T細胞上之PD-1表現含量與病毒負荷、CD4+
計數減少及CD8+
T細胞活體外應答HIV抗原增殖之能力降低有關。對應於活體內觀察結果,HIV特異性CD4+
T細胞上之PD-1表現與病毒負荷之間直接相關。D'Souza等人,J. Immunol. 179
: 1979-87 (2007)。與表現顯著調升之PD-1之典型進展者(progressor)相反,長期非進展者(nonprogressor)具有PD-1表現明顯降低之功能性HIV特異性記憶CD8+
T細胞,調升之PD-1與CD4+ T細胞數目減少、CD4+
T細胞數目減少、HIV特異性效應記憶CD8+
T細胞功能降低及血漿病毒負荷增加相關。Zhang等人,Blood 109
: 4671-78 (2007)。
PD-1:PD-L路徑亦涉及慢性細菌感染。幽門螺旋桿菌引起慢性胃炎及胃十二指腸潰瘍,且為發展胃癌之風險因素。在幽門螺旋桿菌感染期間,T細胞反應不足以清除感染,從而引起持續性感染。活體外或活體內暴露於幽門螺旋桿菌之後,調升胃上皮細胞上之PD-L1。胃上皮細胞表現MHC II類分子,且認為在幽門螺旋桿菌感染期間,發揮重要的APC作用。阻斷PD-1與PD-L1相互作用之抗PD-L1抗體增強暴露於幽門螺旋桿菌之胃上皮細胞及CD4 T細胞之培養物中的T細胞增殖及IL-2產生。用抗體或siRNA阻斷PD-L1阻止調控性T細胞產生,從而表明在幽門螺旋桿菌感染期間,PD-L1可藉由控制調控性T細胞與效應T細胞之間的動力學來促進T細胞抑制及持續性感染。Beswick等人,Infect. Immun. 75
: 4334-41 (2007)。
寄生蠕蟲亦利用PD-1:PD-L1路徑誘導抑制免疫反應之巨噬細胞。在小鼠肥頭絛蟲(Taenia crassiceps
)(亦即絛蟲)感染期間,調升經活化巨噬細胞上之PD-1及PD-L2,且CD4+ T細胞表現PD-1。阻斷PD-1、PD-L1或PD-L2顯著降低由感染絛蟲之小鼠的巨噬細胞所致的活體外T細胞增殖抑制。Terrazas等人,Int. J. Parasitol. 35
: 1349-58 (2005)。在小鼠曼氏血吸蟲(Shistosoma mansoni
)感染期間,巨噬細胞表現高含量之PD-L1及較適中含量之PD-L2。抗PD-L1移除此等巨噬細胞活體外抑制T細胞增殖之能力,然而抗PD-L2無作用。在感染12週後,受感染小鼠巨噬細胞上之PD-L1表現下降,此與T細胞無反應受破壞有關。Smith等人,J. Immunol. 173
: 1240-48 (2004)。
2. 腫瘤免疫
腫瘤免疫之經驗證據包括(i)觀察到自發緩解;(ii)存在可偵測但無效之對腫瘤的宿主免疫反應;(iii)增加免疫缺陷患者之原發性及繼發性惡性腫瘤之發病率;(iv)偵測到腫瘤患者之抗體及T淋巴細胞之含量增加;及(v)觀察到測試動物可對各種類型腫瘤具有免疫力。
研究已顯示大部分人類腫瘤表現可由T細胞識別且因此潛在能夠誘導免疫反應之腫瘤相關抗原(TAA)。Boon等人,Immunol. Today 16
:334-336 (1995)。已藉由用TAA或經TAA脈衝之專業抗原呈現細胞為癌症患者接種疫苗開始早期臨床試驗。Dudley等人,Science 298
: 850-854 (2002);Gajewski等人,Clin. Cancer Res. 7
: 895s-901s (2001);Marincola等人,Adv. Immunol. 74
: 181-273 (2000);Peterson等人,J. Clin. Oncol. 21
: 2342-2348 (2003)。在許多此等試驗中已實現誘導腫瘤抗原特異性CD8+ T細胞。Mackensen等人,Eur. Cytokine Netw 10
: 329-336 (1999);Peterson等人,同上。亦已繼續研究將腫瘤抗原特異性T細胞接受性轉移至患者中,且已揭示使所擴充細胞毒性T淋巴細胞(CTL)回到腫瘤位點。Meidenbauer等人,J. Immunol. 170
: 2161-2169 (2003)。然而,儘管腫瘤經免疫效應細胞浸潤,但腫瘤生長顯少得到控制。
充分確定,腫瘤微環境可保護腫瘤細胞免受免疫破壞。Ganss等人,Cancer Res. 58
: 4673-4681 (1998);Singh等人,J. Exp. Med. 175
: 139-146 (1992)。已發現,腫瘤表現可溶性因子以及膜結合分子,包括轉化生長因子β(TGF-β)、介白素(IL)-10、前列腺素E2
、FASL、CTLA-4配位體、誘導腫瘤壞死因子相關細胞凋亡之配位體(TRAIL)及漸進式死亡受體配位體1(PD-L1,亦稱為B7-H1),且咸信因子介導免疫逃避。因此,阻斷腫瘤細胞上之此負性免疫調控信號為增進活體內腫瘤特異性CD8+ T細胞免疫之有前景的方法。
許多腫瘤上之PD-L1表現為此抑制之組成部分且可與其他免疫抑制信號協同起作用。PD-L1負性調控T細胞受體信號傳導。已展示PD-L1原位表現於各種實體腫瘤上,該等實體腫瘤包括乳癌、肺癌、結腸癌、卵巢癌、黑素瘤、膀胱癌、肝癌、唾液腺癌、胃癌、神經膠質瘤、甲狀腺癌、胸腺癌、上皮癌、頭頸癌。Brown等人,J. Immunol. 170
: 1257-66 (2003);Dong等人,Nat. Med. 8
: 793-800 (2002);Hamanishi等人,PNAS 104
: 3360-65 (2007);Strome等人,Cancer Res. 63
: 6501-5 (2003);Inman等人,Cancer 109
: 1499-505 (2007);Konishi等人,Clin. Cancer Res. 10
: 5094-100 (2004);Nakanishi等人,Cancer Immunol. Immunother. 56
: 1173-82 (2007);Nomi等人,Clin. Cancer Res. 13
: 2151-57 (2004);Thompson等人,PNAS 101
: 17174-79 (2004);Wu等人,Acta Histochem. 108
: 19-24 (2006)。
免疫染色亦揭示PD-1:PD-L表現於各種癌症上之表現。
有趣的是,癌症亦視為慢性發炎疾病。Coussens等人,Nature 420
: 860-867 (2002)。雖然全世界多達15%之癌症具有直接感染性起源[Kuper等人,J. Intern. Med. 248
: 171-183 (2000)],但許多人類腫瘤與慢性刺激及發炎有關。Zou等人,Ntu. Rev. Cancer 5
: 263-274 (2005)。
雖然使腫瘤上PD-L1表現與疾病結果相關之研究顯示PD-L1表現與腎癌、卵巢癌、膀胱癌、乳癌、胃癌及胰臟癌之不利預後密切相關,但可能不與小細胞肺癌之不利預後相關。Hamanishi等人,Proc. Natl. Acad. Sci. USA 104
: 3360-65 (2007);Inman等人,Cancer 109
: 1499-505 (2007);Konishi等人,Clin. Cancer Res. 10
:5094-100 (2004);Nakanishi等人,Cancer Immunol. Immunother. 56
: 1173-82 (2007);Nomi等人,Clin. Cancer Res. 13
: 2151-57 (2007);Thompson等人,Proc. Natl. Acad. Sci. USA 101
: 17174-79 (2004);Wu等人,Acta Histochem. 108
: 19-24 (2006)。此外,此等研究表明腫瘤上之較高含量之PD-L1表現可能有助於推進腫瘤期別且侵入更深組織結構中。
PD-1:PD-L路徑亦可能在血液惡性腫瘤中發揮作用。雖然PD-1或PD-L1很少表現於B細胞惡性腫瘤中,但PD-L2過度表現於套細胞惡性腫瘤中。Brown等人,同上;Rosenwald等人,J. Exp. Med. 198
: 851-62 (2003)。雖然PD-L1表現於多發性骨髓瘤細胞上,但不表現於正常漿細胞上。PD-L1阻斷活體外增加應答骨髓瘤細胞之T細胞擴充。Liu等人,Blood 110
: 296-304 (2007)。PD-L1表現於一些原發性T細胞淋巴瘤上,尤其多形性大T細胞淋巴瘤上,且PD-L1表現於相關濾泡性樹突狀細胞網狀結構上。Dorfman等人,Am. J. Surg. Pathol. 30
: 802-10 (2006)。微陣列分析進一步表明在霍奇金淋巴瘤(Hodgkin lymphoma)中腫瘤相關T細胞原位應答PD-1信號。Chemnitz等人,Blood 110
: 3226-33 (2007)。PD-1及PD-L1表現於HTLV-1介導之成人T細胞白血病及淋巴瘤中之CD4+
T細胞上。Shimauchi等人,Int. J. Cancer 121
: 2585-90 (2007)。此等腫瘤細胞對TCR信號之反應不足,且PD-1阻斷增加其TNF-α之表現,但不增加IFN-γ之表現。動物模型之研究說明腫瘤上之PD-L1表現抑制T細胞活化及腫瘤細胞溶解,且在一些情況下,使得腫瘤特異性T細胞死亡增加。Dong等人,Nat. Med. 8
: 793-800 (2006);Hirano等人,Cancer Res. 65:
1089-96 (2005)。
因此,用本發明抗PD-L1抗體抑制經由PD-L1之信號傳導以便增進T細胞功能展示有希望減弱腫瘤免疫,且因此,可有效治療癌症。
F.組合療法
本發明方法可與治療慢性感染或癌症之已知方法組合作為經組合或額外治療步驟或作為治療性調配物之額外組分。
1. 癌症:
增進宿主之免疫功能以對抗腫瘤為日益受到關注之主題。習知方法包括(i)APC增進,諸如(a)向腫瘤中注射編碼外來MHC同種異體抗原之DNA,或(b)用增加腫瘤之免疫抗原識別(例如免疫刺激細胞激素、GM-CSF、協同刺激分子B7.1、B7.2)可能性的基因轉染活組織檢查腫瘤細胞,(iii)授受性細胞免疫療法或用經活化腫瘤特異性T細胞治療。授受性細胞免疫療法包括分離腫瘤浸潤性宿主T淋巴細胞,諸如藉由用IL-2或腫瘤或兩者刺激活體外擴充該群體。另外,亦可藉由活體外施用本發明抗PD-L1抗體活化功能障礙性經分離T細胞。接著可將由此活化之T細胞再投與宿主。
癌症之傳統療法包括以下:(i)輻射療法
(例如放射線療法、X射線療法、照射)或使用電離輻射殺死癌細胞及使腫瘤縮小。輻射療法可經由外粒子束放射線療法(EBRT)外部投與或經由近接治療(brachytherapy)內部投與;(ii)化學療法
,或施用一般影響快速分裂之細胞之細胞毒性藥物;(iii)靶向療法
,或特異性影響癌細胞之不受調控之蛋白質的藥劑(例如酪胺酸激酶抑制劑伊馬替尼(imatinib)、吉非替尼(gefitinib);單株抗體;光動力療法);(iv)免疫療法
,或增強宿主之免疫反應(例如疫苗);(v)激素療法
,或阻斷激素(例如當腫瘤對激素敏感時);(vi)血管生成抑制劑
,或阻斷血管形成及生長;及(vii)緩解性護理
,或針對改良護理品質以降低疼痛、噁心、嘔吐、腹瀉及出血之治療。諸如嗎啡鹼(morphine)及羥可待酮(oxycodone)之疼痛藥物、諸如昂丹司瓊(ondansetron)及阿瑞匹坦(aprepitant)之抗嘔吐藥可允許更具侵襲性之治療方案。
在癌症治療中,可在投與本發明抗PD-L1抗體之前、之後或同時進行癌症免疫治療之任何前述習知治療。另外,本發明抗PD-L1抗體可在習知癌症治療(諸如投與腫瘤結合抗體(例如單株抗體、毒素結合單株抗體)及/或投與化學治療劑)之前、之後或同時投與。
2. 感染:
在感染(例如急性感染及/或慢性感染)治療中,除刺激對感染之天然宿主免疫防禦以外或代代該刺激,可將本發明抗PD-L1抗體投藥與習知治療相組合。對感染之天然宿主免疫防禦包括(但不限於)發炎、發熱、抗體介導之宿主防禦、T淋巴細胞介導之宿主防禦(包括淋巴介質分泌及細胞毒性T細胞(尤其在病毒感染期間))、補體介導之溶解及助噬作用(促進吞噬)及吞噬作用。本發明抗PD-L1抗體使功能障礙性T細胞再活化之能力將特別適用於治療慢性感染、尤其細胞介導之免疫對完全康復而言至關重要之感染。
a.細菌
對於由細菌性感染引起之感染,本發明抗PD-L1抗體可與治療細菌性感染之標準療法同時、在其之前或之後投與來組合。雖然現今細菌性感染最通常用抗細菌性抗生素治療,但來自經免疫宿主之含病原體特異性抗體之血清亦會有效。
因分泌毒素(產毒素細菌)、用失活毒素接種及/或投與阻斷毒素之毒性的治療劑而具有病原性之細菌通常有效(例如多株血清、抗體、抗生素等)。此等生物體包括梭菌屬(Clostridium spp.
)、芽孢桿菌屬(bacillus spp.
)、棒狀桿菌屬(Corynebacterium spp.
)、霍亂弧菌(Vibrio chloerae
)、百日咳桿菌(Bordetella pertussis
)、葡萄球菌屬(Staphylococcus spp.
)、鏈球菌屬。通常亦應答該等傳統療法之革蘭氏陰性細菌包括腸細菌(Enterobacteria)(例如埃希氏桿菌、克雷伯氏菌、變形菌屬、耶氏桿菌(Yersinia
)、伊文氏桿菌(Erwina
))、沙門氏桿菌(Salmonella
)及綠膿假單胞桿菌(Pseudomonas aeruginosa
)。對吞噬作用及助噬作用有抗性且因此通常阻止對免疫清除之更顯著攻擊的有莢膜細菌包括:鏈球菌屬、嗜血桿菌屬、奈瑟菌屬、克雷伯氏菌屬及鬆脆桿菌。
藉由侵入細胞中而逃避宿主防禦以逃避血清抗體及補體之細菌顯示特定攻擊。清除此等感染幾乎完全依賴於T淋巴細胞介導之免疫,且尤其易變為慢性感染。特定實例包括沙門氏桿菌(傷寒沙門氏桿菌(S. typhi
)、豬霍亂沙門氏桿菌(S. choleraesuis
)、腸炎沙門氏桿菌(S. enteritidis
))、退伍軍人菌桿屬(Legionella spp.
)、李氏菌屬、布魯菌屬(Brucella spp.
)及分枝桿菌(結核分枝桿菌(M. tuberculosis
)、鳥分枝桿菌(M. avium
)及麻瘋分枝桿菌(M. leprae
))。
包括密螺旋體屬、疏螺旋體屬及鉤端螺旋體屬(Leptospira spp
.)之螺旋體為引起持續性及潛伏性感染之細菌。引起梅毒疾病之病原體梅毒螺旋體(Treponema palladium
)為若不加以治療,則可產生嚴重病理性後果的性傳播疾病。該疾病經由不同階段進行。最初臨床階段為螺旋體接種部位之潰瘍或下疳。此後為螺旋體血症及微生物轉移性分布時期,該時期持續進行,包括重複病狀感染週期及消除週期,此稱為二期梅毒。在消除二期梅毒之後,疾病進入無症狀潛伏期,該潛伏期在三期梅毒時結束,三期梅毒為嚴重且通常致死之病狀。三期梅毒可表現於以下中:(i)心臟,如主動脈炎及動脈瘤形成及二級主動脈瓣不足,(ii)中樞神經系統(脊髓癆、麻痹性癡呆),(iii)眼睛(間質性角膜炎),或(iv)耳(神經性耳聾)。非性交形式類似於性交形式之臨床表現形式,但主要經由直接接觸及不良衛生傳播。其包括莓疹病(yaws)(梅毒密螺旋體細弱亞種(T. pallidum
subp.pertenue
))、品他病(pinta)(品他密螺旋體(T. carateum
))及貝耶病(bejel)(梅毒密螺旋體地方亞種(T. pallidum
subsp.endemicum
))。
梅毒之治療包括青黴素(例如青黴素G)、四環素、多西環素、頭孢曲松及阿奇黴素(azithromycin)。最宜投與本發明抗PD-L1抗體來治療潛伏性感染時期。
由伯氏疏螺旋菌(Borrelia burgdorferi
)引起之萊姆病(Lyme disease)經由壁虱叮咬傳播給人類。該疾病最初表現為局部皮疹,之後為流行性感冒樣症狀,包括不適、發熱、頭痛、頸強直及關節痛。隨後的表現表式可包括遷移性或多關節性關節炎、神經及心臟受累伴有腦神經麻痹及神經根病變、心肌炎及心律不齊。萊姆病之一些病例變成持續性的,產生類似於三期梅毒之不可逆損害。
萊姆病之當前療法主要包括投與抗生素。可用羥氯奎或甲胺喋呤(methotrexate)治療抗生素抗性菌株。可用加巴噴丁(gabapentin)治療患有神經痛之抗生素不應患者。米諾環素對具有神經學或其他發炎性表現形式之晚期/慢性萊姆病有幫助。最宜投與抗PD-L1抗體來治療潛伏性感染時期。
除非血液效價達到導致肝內阻塞之濃度,否則其他形式之疏螺旋體病(諸如由回歸熱疏螺旋體(B. recurentis
)、赫姆斯疏螺旋體(B. hermsii
)、北美回歸熱包柔氏疏螺旋體(B. turicatae
)、派可瑞疏螺旋體(B. parikeri
)、西班牙疏螺旋體(B. hispanica
)、杜通疏螺旋體(B. duttonii
)及波斯疏螺旋體(B. persica
)引起之疏螺旋體病)以及鉤端螺旋體病(例如問號狀鉤端螺旋體(L. interrogans
))通常自發消除。
b.病毒
對於由病毒原因引起之感染,本發明抗PD-L1抗體可藉由與施用治療病毒感染之標準療法同時、在其之前或之後施用來組合。該等標準療法視病毒類型而變化,但在幾乎所有的情況下,投與含對病毒具特異性之抗體(例如IgA、IgG)之人類血清均會有效。1) 流行性感冒
流行性感冒感染引起發熱、咳嗽、肌痛、頭痛及不適,其通常出現在季節性流行病中。流行性感冒亦與許多感染後病症相關,諸如腦炎、心肌心包炎、古德巴斯德症候群(Goodpasture's syndrome)及雷爾氏症候群(Reye's syndrome)。流行性感冒感染亦抑制正常肺部抗細菌防禦,以致患者自流行性感冒康復時發展細菌性肺炎的風險增加。
流行性感冒病毒表面蛋白展示由突變及重組產生之顯著抗原變異。因此,細胞溶解T淋巴細胞為宿主在感染後消除病毒之主要媒介物。流行性感冒主要分為三類:A、B及C。A型流行性感冒之獨特之處在於其感染人類與許多其他動物(例如豬、馬、鳥及海豹)且為泛流行性感冒之主要原因。此外,當細胞由兩種不同A型流行性感冒病毒株感染時,在複製期間兩種親代病毒類型之區段RNA基因組混合產生雜交複製體,從而產生新流行性病毒株。B型流行性感冒不在動物中複製且因此具有較小的遺傳變異,且C型流行性感冒僅具有單一血清型。
最習知之療法為緩解由感染引起之症狀,而宿主之免疫反應實際上清除該疾病。然而,某些病毒株(例如A型流行性感冒)可引起更嚴重的疾病及死亡。A型流行性感冒可藉由投與抑制病毒複製之環胺抑制劑三環癸胺及金剛乙胺臨床上與預防性處理。然而,由於有害反應發生率相對較高、抗病毒譜較窄(僅A型流行性感冒)且病毒有耐藥傾向,因此該等藥物之臨床效用有限。向主要流行性感冒表面蛋白、血球凝集素及神經胺糖酸苷酶投與血清IgG抗體可預防肺部感染,然而需要黏膜IgA以預防上呼吸道及氣管感染。當前最有效之流行性感冒之治療為藉由投與經福馬林(formalin)或β-丙內酯失活之病毒接種。2) 麻疹病毒
培育9-11天後,感染麻疹病毒之宿主會發展發熱、咳嗽,鼻炎及結膜炎。在1-2天內,發展紅斑斑丘疹,其快速遍布全身。因為感染亦抑制細胞免疫,所以宿主有較大風險發展細菌重複感染(bacterial superinfection),包括中耳炎、肺炎及感染後腦脊髓炎。急性感染與高發病率及死亡率有關,在營養不良青少年中尤其如此。
麻疹之治療包括被動投與混合人類IgG,其即使在暴露之後長達一週才給予,亦可在非免疫個體中預防感染。然而,預先用活的減毒病毒免疫為最有效的治療且在95%以上之經免疫個體中預防疾病。因為存在一種此病毒之血清型,所以單一免疫或感染通常產生終身保護免受後續感染。
在小部分受感染宿主中,麻疹可發展成SSPE,SSPE為由中樞神經系統之持續性感染引起之慢性進行性神經病症。SSPE由具有干擾病毒粒子裝配及出芽之缺陷的麻疹病毒純系變異體引起。對於此等患者,將需要用本發明抗PD-L1抗體使T細胞再活化以有助於病毒清除。3) B 型肝炎病毒
B型肝炎病毒(HB-V)為最具傳染性之已知血源性病原體。其為急性及慢性肝炎及肝癌以及終身慢性感染之主要原因。感染後,病毒在肝細胞中複製,其接著亦排出表面抗原HBsAg。偵測血清中之過量HBsAg為用於診斷B型肝炎感染之標準方法。急性感染可消除或其可發展成慢性持續性感染。
慢性HBV之當前治療包括α-干擾素,其增加I類人類白血球抗原(HLA)在肝細胞表面上之表現,藉此有助於細胞毒性T淋巴細胞對其之識別。另外,在臨床試驗中核苷類似物更昔洛韋、泛昔洛韋及拉米夫定亦展示一定的治療HBV感染之功效。HBV之其他治療包括聚乙二醇化α-干擾素、阿德福韋(adenfovir)、因提弗及喜必福(telbivudine)。雖然可經由非經腸投與抗HBsAg血清抗體賦予被動免疫,但用失活或重組HBsAg接種亦賦予抗感染性。可使本發明抗PD-L1抗體與B型肝炎感染之習知治療組合來達成治療優勢。4) C 型肝炎病毒
C型肝炎病毒(HC-V)感染可導致慢性形式之肝炎,從而導致肝硬化。雖然症狀類似於由B型肝炎引起之感染,但與HB-V明顯不同,受感染宿主可能10-20年均無症狀。HC-V感染之治療包括投與α-干擾素及病毒唑之組合。HC-V感染之有前景之潛在療法為蛋白酶抑制劑替普瑞韋(telapravir)(VX-960)。其他治療包括:抗PD-1抗體(MDX-1106,Medarex),巴維昔單抗(bavituximab)(一種以B2-醣蛋白I依賴性方式結合陰離子磷脂磷脂醯絲胺酸之抗體,Peregrine Pharmaceuticals)、抗HPV病毒鞘蛋白E2抗體(例如ATL 6865-Ab68+Ab65,XTL Pharmaceuticals)及Civacir®
多株抗HCV人免疫球蛋白)。可使本發明抗PD-L1抗體與C型肝炎感染之一或多種此等治療組合來達成治療優勢。5) 人類免疫缺乏病毒 (HIV)
HIV攻擊CD4+細胞,包括T淋巴細胞、單核細胞-巨噬細胞、濾泡性樹突狀細胞及蘭氏細胞(Langerhan's cells),且耗盡CD4+輔助/誘導細胞。因此,宿主獲得嚴重的細胞介導之免疫缺陷。HIV感染在至少50%的個體中導致AIDS,且經由性接觸、投與受感染血液或血液製品、用受感染精液人工授精、暴露於含有血液之針或注射器及分娩期間由受感染母親傳播給嬰兒而傳播。
感染HIV之宿主可能無症狀或可能發展類似於單核細胞增多症之急性疾病:發熱、頭痛、喉嚨痛、不適及皮疹。症狀可發展成進行性免疫功能障礙,包括持續性發熱、盜汗、體重下降、不明原因腹瀉、濕疹、牛皮癬、脂溢性皮炎、帶狀疱疹、口腔念珠菌病及口腔毛狀白斑。感染發展成AIDS之患者中常見由許多寄生蟲引起之機會性感染。
HIV之治療包括抗病毒療法,包括核苷類似物,單獨或與去羥肌苷或紮西他濱組合之齊多夫定(AST)、雙去氧肌苷(dideoxyinosine)、雙去氧胞苷(dideoxycytidine)、拉脈優錠(lamidvudine)、司他夫定;逆轉錄抑制劑,諸如地拉韋啶、奈韋拉平、洛韋胺;及蛋白酶抑制因子,諸如沙奎那韋、利托那韋、茚地那韋及奈非那韋。可使本發明抗PD-L1抗體與HIV感染之習知治療組合來達成治療優勢。6) 細胞巨大病毒
細胞巨大病毒(CMV)感染通常與持續性、潛伏性及復發性感染相關。CMV感染單核細胞及粒細胞-單核細胞祖細胞且潛伏其中。CMV之臨床症狀包括單核細胞增多症樣症狀(亦即發熱、腺腫脹、不適)及易於發展針對抗生素之過敏性皮疹。病毒經由直接接觸擴散。病毒於尿、唾液、精液中排出及較小程度上於其他體液中排出。亦可自受感染母體傳播至其胎兒或新生兒及經由輸血及器官移植傳播。CMV感染引起一般細胞免疫受損,其特徵為對非特異性有絲分裂原及特異性CMV抗原之胚芽生殖反應減弱、細胞毒性能力減弱及CD4+淋巴細胞之CD8淋巴細胞數目增加。
CMV感染之治療包括抗病毒劑更昔洛韋、膦甲酸(foscarnet)及西多韋(cidovir),但此等藥物通常僅開立於免疫受之患者的處方中。可使本發明抗PD-L1抗體與細胞巨大病毒感染之習知治療組合來達成治療優勢。7) 艾伯斯坦 - 巴爾病毒
艾伯斯坦-巴爾病毒(EBV)可產生持續性及潛伏性感染且主要攻擊B細胞。EBV感染引起傳染性單核細胞增多症之臨床病狀,包括發熱、喉嚨痛、通常有分泌物、全身性淋巴腺病及脾腫大。亦出現肝炎,其可發展成黃疸。
雖然EBV感染之典型治療緩解症狀,但EBV與某些癌症(諸如伯基特淋巴瘤(Burkitt's lymphoma)及鼻咽癌)之發展相關。因此,在此等併發症產生之前清除病毒感染具有重大益處。可使本發明抗PD-L1抗體與艾伯斯坦-巴爾病毒感染之習知治療組合來達成治療優勢。8) 疱疹病毒
單純性疱疹病毒(HSV)經由與受感染宿主直接接觸而傳播。雖然直接感染可能無症狀,但通常產生含傳染性粒子之水皰。該疾病表現為疾病活動期之循環,其中病變隨病毒潛伏性感染神經節後續爆發而出現及消失。病變可位於臉、生殖器,眼睛及/或手上。在一些情況下,感染亦可引起腦炎。
疱疹感染之治療主要針對消除症狀爆發,且包括全身抗病毒藥,諸如:阿昔洛韋(例如Zovirax®)、伐昔洛韋、泛昔洛韋、噴昔洛韋及表面藥物,諸如多可沙諾(Abreva®)、曲金剛胺及吉拉克定(zilactin)。清除疱疹之潛伏性感染將具有重大臨床益處。可使本發明抗PD-L1抗體與疱疹病毒感染之習知治療組合來達成治療優勢。9) HTLV
人類T淋巴細胞病毒(HTLV-1、HTLV-2)經由性接觸、母乳餵養或暴露於受污染血液來傳播。病毒活化使稱為Th1細胞之TH
細胞子集活化,從而導致其過度增殖及過度產生Th1相關細胞激素(例如IFN-γ及TNF-α)。此舉又導致抑制Th2淋巴細胞及降低Th2細胞激素產生(例如IL-4、IL-5、IL-10及IL-13),從而引起受感染宿主對清除時需要Th2依賴性反應之侵入生物體(例如寄生蟲感染、黏膜及體液抗體產生)產生適當免疫反應之能力下降。
HTLV感染引起機會性感染,引發支氣管擴張症、皮炎及由葡萄球菌屬(Staphylococcus spp.
)及圓線蟲屬(Strongyloides spp.
)重複感染,從而導致因多微生物性敗血症而死亡。HTLV感染亦可直接引發成人T細胞白血病/淋巴瘤及進行性脫髓鞘上運動神經原疾病(稱為HAM/TSP)。清除HTLV潛伏性感染將具有重大臨床益處。可使本發明抗PD-L1抗體與HTLV感染之習知治療組合來達成治療優勢。10) HPV
人類乳頭狀瘤病毒(HPV)主要影響角質細胞且以兩種形式存在:皮膚形式及生殖器形式。咸信經由直接接觸及/或性行為傳播。皮膚與生殖器HPV感染可引起疣及潛伏性感染及有時引起復發感染,其雖然受控制症狀且阻斷疣出現之宿主免疫控制,但宿主仍能夠將感染傳播給其他人。
HPV感染亦可引發某些癌症,諸如子宮頸癌、肛門癌、外陰癌、陰莖癌及口咽癌。尚無已知之HPV感染治療,但當前治療為表面施用咪喹莫特,其刺激免疫系統攻擊受感染區域。清除HPV潛伏性感染將具有重大臨床益處。可使本發明抗PD-L1抗體與HPV感染之習知治療組合來達成治療優勢。
c. 真菌
真菌感染或黴菌病可因免疫系統受內源性菌叢損害之宿主的初次感染或機會性移生而引起。對黴菌病之免疫主要為細胞免疫,包括嗜中性白細胞、巨噬細胞、淋巴細胞及可能自然殺傷(NK)之細胞。黴菌病通常不易由抗體及補體直接殺死。由初次感染引起之全身侵襲性黴菌病包括芽生菌病、球黴菌病、組織漿菌病及副球黴菌病。對於由真菌感染引起之慢性感染,本發明抗PD-L1可在此等黴菌病之任何習知治療之前、與其同時或在其之後投與。
由皮炎芽生菌(Blastomyces dermatitis
)所引起之芽生菌病經由吸入獲得且產生原發性肺部感染或血原性傳播疾病(主要包括皮膚、骨及男性泌尿生殖道)。最初暴露可能無症狀,或其可產生流行性感冒樣症候群。此疾病可以慢性無痛形式表現。該疾病亦與諸如患AIDS之患者之受損免疫相關。皮炎芽生菌感染之習知療法包括伊曲康唑、酮康唑或靜脈內注射雙性黴素B。
由粗球黴菌引起之球黴菌病經由吸入獲得且可引起原發性肺部感染、進行性肺病或血原性傳播疾病(主要包括皮膚、皮下組織、骨、關節及腦膜)。最初暴露可能無症狀(60%)或與流行性感冒樣症候群相關。可能出現肺炎、胸膜炎及肺空洞形成。轉移性表現形式包括皮膚損害,包括節結、潰瘍、深處及疣狀肉芽瘤之竇道、骨、關節、腱鞘及腦膜(包括腦膜炎)。該疾病亦與諸如患AIDS之患者之受損免疫相關。球黴菌病之治療包括酮康唑、伊曲康唑及氟康唑,尤其用於非腦膜病之長期維持療法。腦膜形式通常由鞘內投與雙性黴素B來治療。
由莢膜組織漿菌引起之組織漿菌病為網狀內皮系統之經由吸入獲得之疾病,其中極少酵母菌駐留於巨噬細胞中。此可產生原發性肺部感染、進行性肺病或血原性傳播疾病(主要包括網狀內皮系統、黏膜表面及腎上腺)。潛伏性感染之再活化通常出現在諸如患AIDS之患者的免疫受損患者中。最初暴露可能無症狀或與流行性感冒樣症候群相關,包括肺炎、胸膜炎、肺空洞形成及縱隔腺病。轉移性部位包括網狀內皮系統(肝脾腫大、淋巴腺病、貧血、白血球減少症及血小板減少症)、黏膜(鼻咽旁潰瘍)、胃腸道(吸收障礙)及腎上腺機能不全。雖然大部分初次感染自發消除,但當與諸如患AIDS之患者之受損免疫相關時,不停復發且通常與血原性肺炎、ARDS、散播性血管內凝血(DIC)、血原性分布丘疹膿皰及腦膜炎相關。組織漿菌病用雙性黴素B(尤其患急性血原性播散病之免疫受損患者)、伊曲康唑及酮康唑治療。
由巴西副球黴菌(Paracoccidioides brasiliensis
)引起之副球黴菌病為可產生原發性肺部感染或血原性傳播疾病(主要包括皮膚、黏膜、網狀內皮系統及腎上腺)之經由吸入獲得之黴菌病。感染最初可能無症狀,但休眠,且接著復活。此感染之治療使用酮康唑、伊曲康唑及磺醯胺。
出現於免疫受損宿主中之由機會性病原體引起之全身侵襲性黴菌病包括念珠菌病、隱球菌病、麯黴病、白黴菌病及肺囊蟲病。因本發明抗PD-L1抗體增強受損免疫系統之免疫反應,故其在此等病狀之治療中亦可具有治療性價值,尤其當與習知療法組合時。
念珠菌病(由白色念珠菌、熱帶念珠菌(C. tropicalis
)、光滑念珠菌(C. glabrata
)引起)、隱球菌病(由新型隱球酵母(Cryptococcus neoformans
)引起)、麯黴病(由黃麴黴(Aspergillus flavus
)、菸麯黴(A. fumigatus
)、土麯黴(A. tereus
)及黑麯黴(A. niger
)引起)及白黴菌病(由少根根黴(Rhizopus arrhizus
)、根毛黴屬(Rhizomuco
)、犁頭黴屬(Absidia
)、小克銀漢黴屬(Cunninghamella
)、被孢黴屬(Mortierella
)、瓶黴屬(Saksenaea spp.
)引起)之治療可在用或不用氟胞嘧啶下用一或多種以下咪唑來治療:酮康唑、伊曲康唑、氟康唑、雙性黴素B。最近自原蟲重新分類為真菌之肺囊蟲病(由肺炎肺囊蟲(penumocystis carnii)引起)係用甲氧苄啶-磺胺甲異噁唑(TMP-SMZ)及靜脈內噴他脒羥乙磺酸鹽以及胺苯碸、TMP-胺苯碸、三甲曲沙(trimetrexate)、克林黴素-伯胺奎(clindamycin-primaquine)及阿維尼農(atovagnone)治療。
由微孢子寄生蟲引起之微孢子蟲病最近自原蟲重新分類為真菌。其為具有殘留紡錘體而非線粒體之單細胞生物體。可在人類中引起疾病之生物體包括:比氏腸微孢子蟲(Enterocytozoon bieneusi
)、海倫腦炎微孢子蟲(Encephalitozoon hellem
)、小腸腦炎微孢子蟲(Encephalitozoon intestinalis
)、兔子腦炎微孢子蟲(Encephalitozoon cuniculi
)、孢蟲屬(Pleistophora spp
)、人微孢子蟲(Trachipleistophora hominis
)、吸血微孢子蟲(Trachipleistophora anthropophthera
)、人小孢子蟲(Nosema connori
)、眼小孢子蟲(Nosema ocularum
)、泡狀小孢子蟲(Brachiola vesicularum
)、角膜小孢子蟲(Vittaforma corneae
)、錫蘭微孢子蟲(Microsporidium ceylonensis
)、非洲微孢子蟲(Microsporidium africanum
)、小孢子蟲屬真菌(Brachiola algerae
)。
咸信感染因與動物、受污染水或另一感染宿主直接接觸而傳播給人類。感染宿主細胞之後,孢原質生長,分裂或形成可具有複雜生命週期(包括無性與有性繁殖)之多核變形體。繼代自體感染及慢性衰弱性疾病通常為微孢子感染之特徵。
疾病之臨床表現形式可視物種及宿主之免疫狀態而變化,且包括結膜炎(例如角膜小孢子蟲)、慢性腹瀉、吸收障礙及消耗病(例如比氏腸微孢子蟲、小腸腦炎微孢子蟲)。
眼、腸及傳播性微孢子菌病之治療包括投與阿苯達唑(albendazole)。表面施用菸黴素(fumagillin)亦可有效用於治療微孢子性角膜結膜炎。其他藥物包括驅蠕蟲劑(例如阿苯達唑)、抗生素(例如菸黴素)、免疫調節劑(例如沙立度胺(thalidomide))、抗原蟲藥(例如甲硝唑)。
d.原蟲
在發展中國家,由寄生蟲病症(諸如瘧疾、血吸蟲病及利什曼體病)引起之疾病為最普遍且重要之健康問題之一。此等疾病構成特別挑戰,此係因為其可經由各種方式逃避宿主免疫,該等方式包括1)生存在宿主細胞內部(例如利什曼蟲),2)快速改變表面抗原(例如錐蟲),及3)藉由顯示宿主抗原將其自身「偽裝」成宿主細胞(例如肝血吸蟲病)。癌症治療中免疫抑制藥物的使用及器官移植以及AID之全球流行會使瘧原蟲屬(Plasmodium spp.
)、弓形蟲屬、利什曼蟲屬、隱胞子蟲屬、錐蟲屬及蠕蟲屬之潛伏性或亞臨床感染再活化。
對於由原蟲寄生蟲感染引起之慢性感染,本發明抗PD-L1抗體可藉由與標準抗原蟲療法組合、在其之前或之後投與來組合。
由瘧原蟲屬寄生蟲(例如蛋形瘧原蟲(P. ovale
)、三日瘧原蟲(P. malariae
)、惡性瘧原蟲(P. falciparum
)、間日瘧原蟲(P. vivax
))引起之瘧疾
以在雌性按蚊之腸中發育之孢子體開始感染週期。當傳播給人類後,此等孢子體侵入肝細胞內且在其中繁殖,但不誘導發炎反應。此等生物體之子代(稱為裂殖子)接著侵入紅血球細胞中且開始通常以發熱及發寒為特徵之疾病之臨床期。在感染為地方病之世界的某些區域,幾乎所有居民均隱藏低至中等病原性之連續低程度之慢性感染,其中遞增含量之IgG抗體阻止裂殖子進入紅血球中。
目前可用於臨床疾病治療與預防之抗瘧疾藥物包括:蒿甲醚-苯芴醇(Artemether-lumefantrine)(治療,例如Coartem®及Riamet®)、青蒿琥酯-阿莫地奎寧(artesunate-amodiaquine)(治療)、青蒿琥酯-美爾奎寧(artesunate-mefloquine)(治療)、青蒿琥酯-磺胺多辛/乙胺嘧啶(artesunate-Sulfadoxine/pyrimethamine)(治療)、阿托伐醌-氯胍(atovaquone-proguanil)(治療及預防,例如Malarone®),奎寧(治療)、氯奎寧(治療及預防)、可曲齊特(cotrifazid)(治療及預防)、多西環素(治療及預防)、美爾奎寧(治療及預防,例如Lariam®)、伯胺奎(僅治療間日瘧原蟲及蛋形瘧原蟲;不用於預防)、氯胍(預防)、磺胺多辛-乙胺嘧啶(sulfadoxine-pyrimethamine)(治療及預防)、羥氯奎(治療及預防,例如Plaquenil®)。
因為本發明抗PD-L1抗體使無反應性T細胞再活化,所以其尤其可在輔助瘧原蟲清除中具有治療性。
雖然由弓形蟲(Toxoplasma
)屬寄生蟲引起之弓蟲病
(Toxoplasmosis
)通常無症狀,但小部分可發展臨床疾病,該臨床疾病可在急性良性淋巴腺病至中樞神經系統之致死感染變動。感染源包括生的或部分烹熟的豬肉或羊肉中之包囊及受感染貓之糞便中傳播之卵母細胞。感染通常經由胃腸道發生於人類中,且原蟲可鑽入身體之幾乎每個細胞中並在其中增殖(作為速殖子)。此等速殖子可產生充滿可長時間保持生活力之微小緩慢生長之感染體(緩殖子)之包囊,從而引起潛伏性慢性感染。免疫系統受損之宿主(諸如服用免疫抑制藥物或患HIV之宿主)尤其易患弓蟲病。
用於治療原發性弓蟲病之藥物包括以下:有與無伴隨抗生素(例如磺胺嘧啶、克林黴素、螺旋黴素(spiramycin)及米諾環素)之乙胺嘧啶。潛伏性弓蟲病可在用與不用克林黴素下用抗生素阿托伐醌治療。
由利什曼蟲屬寄生蟲引起之利什曼體病感染皮膚及內臟之巨噬細胞且經由白蛉(sandfly)傳播給人類。因為存在少量或不存在特異性血清抗體,所以經由活化T細胞之細胞介導之免疫似乎為清除感染之關鍵途徑。亦稱為熱帶瘡之舊大陸型利什曼體病(Old World Leishmaniasis)係由若干利什曼蟲物種引起:熱帶利什曼原蟲(L. tropica
)、碩大利什曼原蟲(L. major
)及埃塞俄比亞利什曼原蟲(L. aethiopica
)。新大陸型利什曼病(New World Leishmaniasis)係由墨西哥利什曼原蟲(L. Mexicana
)及巴西利什曼原蟲(L. braziliensis
)之各種亞種引起。雖然此等寄生蟲誘導強細胞介導之免疫反應,但臨床疾病之結果亦部分引起宿主反應。若宿主出現經抑制或不適當之細胞介導之反應,則引發自愈希望渺茫之彌漫性慢性皮膚利什曼病(例如埃塞俄比亞利什曼原蟲、墨西哥利什曼原蟲)。若宿主出現過度細胞介導之反應,則反應為類狼瘡或瑞什地伐(recidiva)利什曼原蟲病,在主要病變邊緣(例如熱帶利什曼原蟲)出現持續性非潰瘍性淋巴節結。瑞什地伐利什曼原蟲病可在最初病變之後1至10年出現。有兩種形式之疾病,即皮膚疾病及內臟疾病,其中表現形式為具有細胞介導之免疫之皮膚病變之皮膚形式對清除而言至關重要。在內臟形式中,細胞介導之免疫不充分或不存在,且該疾病臨床表現為多株B細胞高γ-球蛋白血症、白血球減少症、脾腫大及TNF-α產生增加。
米替福新(例如Impavido®)及副肌凝蛋白(paramyocin)為皮膚與內臟利什曼病之現用治療。
由隱孢子蟲屬(Crytosporidia
)原蟲感染所引起之隱孢子蟲病係因人類與受感染宿主之糞便排泄物直接接觸引起。腸黏膜組織之感染可引起腹瀉。該疾病通常表現為急性感染,但其可變成慢性的,尤其在免疫受損之個體中。雖然治療(尤其水療)通常為舒減性的,但巴龍黴素、阿奇黴素及血清Ig(例如Lactobin-R®
)已成功清除感染。
由錐蟲屬寄生蟲(例如布氏錐蟲甘比亞亞種(T. Brucei,
subsp.gambiense
)、布氏錐蟲羅得西亞亞種(T. Brucei,
subsp.rodesiense
))引起之錐蟲病經由采采蠅(Tsetse-fly)叮咬感染人類及牛。此病原體引起之攻擊係由顯示不同表面抗原之群體的繼代引起。感染之特徵在於非特異性及非保護性血清免疫球蛋白之含量升高。
錐蟲病之治療包括下列靜脈內投與:噴他脒(用於布氏甘比亞錐蟲),靜脈內蘇拉明(用於布氏羅得西亞錐蟲),依氟鳥胺酸、美拉胂醇,兩者與及不與硝呋替莫。
由吸蟲(例如血吸蟲屬(Schistomsoma spp.
))、絛蟲及線蟲引起之蠕蟲感染共有嗜酸性球增多症及反應抗體(reaginic antibody)之常見免疫反應,該等反應為T細胞依賴性的。
由曼氏血吸蟲(Shistosoma mansoni
)、日本血吸蟲(S. japonicum
)、埃及血吸蟲(S. haematobium
)及湄公血吸蟲(S. mekongi
)引起之血吸蟲病(亦稱為住血裂體蛭病)於水中以卵開始其生命週期,接著孵化成纖毛幼蟲(miracidia),鑽入蝸牛中且產生多代孢子囊。此等孢子囊又產生叉尾尾動幼蟲(cercariae),該等尾動幼蟲可以幼蟲(schistosomula)形式感染人類宿主之血流,幼蟲最初遷移至肺,接著遷移至肝臟。此等吸蟲最終在腸系膜小靜脈中配對、交配且產卵。雖然許多此等卵行進至腸中並被排泄出,但一些截留在黏膜下層、肝臟之門小靜脈及身體之其他器官中。與所截留之卵相關之肉芽腫發炎為慢性血吸蟲病之明確症狀。
血吸蟲病之治療包括投與Praziquantel®、銻、奧沙尼喹(曼氏血吸蟲(S. mansoni))及Mirazid®。
絛蟲感染可分為兩類,一類為腸居住型成年絛蟲,諸如廣節裂頭絛蟲(Diphyllobothrium latum
)及無鉤絛蟲(Taenia saginata
),其具有限制的非體液免疫作用。第二類描述遷移型組織包囊幼期絛蟲,諸如包膜絛蟲(Hymenolepis nana
)、犬絛蟲(Echinococcus granulosus
)及有鉤絛蟲(Taenia solium
),其誘導強非經腸宿主反應及保護性血清抗體。人類之最嚴重絛蟲感染為包蟲病,當其植入肝臟、肺、腦、腎臟或身體其他部分時,可導致形成包蟲囊腫。
包蟲病之治療包括投與甲硝唑、阿苯達唑及外科介入,諸如移除、抽吸、袋形縫術或網膜固定術。
線蟲為最常見的形式多樣且分布廣泛之感染人類之蠕蟲,其引發諸如旋毛蟲病、蛔蟲病、絲蟲病及類圓線蟲病之病症。由旋毛蟲(Trichinella spiralis
)引起之旋毛蟲病可因攝入生肉或部分烹熟之肉(諸如豬肉)中之旋毛蟲幼蟲而引起。在人類中,感染引起IgM升高,之後產生IgG,之後由T淋巴細胞快速排出經抗體破壞之蠕蟲的強體液反應。
唯一已知之殺死腸中之成年蠕蟲的治療為腐絕(thiabendazole),然而尚無殺死幼蟲之已知治療。
亦稱為巨大蛔蟲(人蛔蟲(Ascaris lumbricoides
))之蛔蟲為因攝入經糞便污染之物質產生之常見人類寄生蟲。雖然患者可在很長時間內保持無症狀,但當幼蟲期穿行於身體中時,其可引起內臟損害、腹膜炎及發炎、肝臟或脾臟腫大、毒性及肺炎。
蛔蟲病之治療包括在投與或不投與哌嗪、己雷瑣辛(hexylresorcinol)、山道年(santonin)及香藜油(oil of Chenopodium)下投與甲苯達唑(mebendazole)(例如Vermox®)、哌嗪、雙羥萘酸喹嘧啶(pyrantel pamoate)(例如Antiminth®、Pin-Rid®、Pin-X®)、阿苯達唑、腐絕。本發明抗PD-L1抗體可與投與治療蛔蟲病之此等療法組合、在其之前或之後投與。
由絲蟲類線蟲引起之絲蟲病由昆蟲載體引入人類中。引起盤尾絲蟲病(onchoceriasis)或河盲症(river blindness)之旋盤尾絲蟲(Onchocerca volvulus
)經由黑蠅(blackfly)叮咬傳播。感染性幼蟲將其自身寄生在皮下且發育成成蟲,誘導致纖維化宿主反應,且排出大量微絲蟲,該等微絲蟲在皮下分散且遍及眼睛,進一步誘發角膜炎或視網膜炎,接著導致角膜不透明。淋巴絲蟲病由血絲蟲屬(Brugia spp.
)及吳策絲蟲屬(Wuchereria spp.
)感染引起。隨著時間推移,尤其腹股溝中之淋巴組織結疤可阻止引流,從而引發外貌損傷病狀象皮病。
絲蟲病之初步治療為在投與或不投與伊維菌素(ivermectin)或阿苯達唑下投與抗生素伊維菌素、阿本達唑(abendazole)及枸櫞酸乙胺嗪(diethylcarbamazine citrate)(DEC,Hetrazan®)。其他治療預期藥物(prospect)包括多西環素,其殺死共生細菌沃爾巴克氏體(wolbochia)。
由圓線蟲屬寄生蟲(例如糞類圓線蟲(S. stercoralis
)、福氏類圓線蟲(S. fülleborni
))引起之類圓線蟲病為經由糞便污染之土壤傳播給人類之疾病。其可存在於獨立生存週期(桿狀幼蟲成熟為成年蠕蟲)以及寄生週期(絲狀幼蟲成熟為成年蠕蟲)中,其鑽入皮膚中,進入肺中,接著進入咽中,且最終駐留在腸中。亦已知發生圓線蟲自體感染,此基本上為絲狀幼蟲繼代之重複感染。
感染可能無症狀,或特徵可為胃腸道疼痛及腹瀉、肺之呂佛勒症候群(Löffler's syndrome)(亦即嗜酸性球增多症)及風疹。亦可存在血液嗜酸性球增多症。因為圓線蟲持續性感染可酷似消化性潰瘍、膽囊疾病及克羅恩氏病,所以常會誤診。其為免疫受損宿主之特別問題。
類圓線蟲病之已知治療為伊維菌素、阿苯達唑或腐絕,但因為此介導作用僅殺死成年蠕蟲,所以必需重複投藥。
e.接種
通常使用接種或投與抗原物質以誘導對疾病之免疫來預防或改善病原體之感染作用。增進宿主免疫可用於不僅在感染性病原體上發現而且在已患病(例如患癌症)之宿主組織上亦發現之不想要抗原。雖然疫苗傳統上衍生自已衰弱或死亡之完整病原體,但其亦可為呈現完整病原體上之人類I類或II類主要組織相容性複合物(MHC)分子特異性識別之抗原決定基的肽。特別相關之肽抗原為T細胞特異性識別之肽抗原。
最近,已展示使治療性接種與投與PD-L1阻斷於耗竭之CD8+ T細胞上相組合會增強慢性感染小鼠模型之功能及病毒控制。Ha等人,J.Exp.Med.
205(3): 543-555 (2008)。因此,本文所述之抗PD-L1抗體亦可與抗原接種組合(例如在抗原接種之前、與其同時或在其之後投與)來治療由病毒、細菌、真菌或原蟲侵入引起之感染(例如急性感染及慢性感染)以及腫瘤免疫。
G.醫藥劑量
:
本發明醫藥組合物之劑量及所要藥物濃度可視預想之特定用途而變化。適當劑量或投藥途徑之確定完全在一般技術者之技術範圍內。動物實驗為人類療法提供確定有效劑量之可靠指導。有效劑量之種間縮放可遵循Mordenti, J.及Chappell, W. 「The Use of Interspecies Scaling in Toxicokinetics」,Toxicokinetics and New Drug Development
, Yacobi等人編,Pergamon Press, New York 1989, 第42-46頁所規定之原則進行。
當使用活體內投與本文所述之多肽或抗體時,正常劑量可能視投藥途徑而自每天每公斤哺乳動物體重約10 ng至約100 mg或100 mg以上、較佳每天每公斤約1 mg至10 mg變化。文獻中提供關於特定劑量及傳遞方法之指導;參見例如美國專利第4,657,760號;第5,206,344號或第5,225,212號。在本發明之範疇內,不同調配物將對不同治療及不同病症有效,且意欲治療特定器官或組織之投藥可能必需以不同於另一器官或組織之方式傳遞。此外,劑量可藉由一或多次獨立投藥或藉由連續輸注來投與。對於經數天或更長時間重複投藥,視病狀而定,持續治療直至實現對疾病症狀之所要抑制。然而,其他給藥方案亦可適用。此療法之進程由習知技術及檢定容易地監測。
H.投與調配物
根據已知方法,諸如在一段時間內以快速注射或藉由連續輸注靜脈內投與、經由肌肉內、腹膜內、腦脊髓內、皮下、關節內、滑膜內、鞘內、經口、表面或吸入途徑,將本發明調配物(包括但不限於復原調配物及液體調配物)投與需要用抗PD-L1抗體治療之哺乳動物(較佳人類)。
在較佳實施例中,調配物藉由皮下(亦即在皮膚之下)投藥投與哺乳動物。為達成該等目的,可使用注射器注射調配物。然而,亦可利用其他投與調配物之裝置,諸如注射裝置(例如INJECT-EASE™
及GENJECT™
裝置);注射筆(injector pen)(諸如GENPEN™
);自動注射裝置、無針裝置(例如MEDIJECTOR™
及BIOJECTOR™
);及皮下貼片傳遞系統。
在一特定實施例中,本發明係針對產生單次劑量投藥單位之套組。該等套組包含治療蛋白質或抗體之水性調配物之容器,包括單室或多室預填充注射器。例示性預填充注射器可自Vetter GmbH, Ravensburg, Germany獲得。
蛋白質之適當劑量(「治療有效量」)將視以下而定,例如待治療之病狀、病狀嚴重程度及進程、投與蛋白質用於預防性目的還是治療性目的、先前療法、患者臨床病史及對抗PD-L1抗體之反應、所用調配物之形式及主治醫師之判斷。適合地,將抗PD-L1抗體一次性或經一系列治療投與患者,且可自診斷起在任何時候投與患者。可將抗PD-L1抗體作為唯一治療投與或聯合適用於治療所討論之病狀之其他藥物或療法投與。
對於抗PD-L1抗體,投與患者之最初候選劑量可在約0.1-20 mg/kg之範圍內,其可採用一或多次獨立投藥之形式。然而,其他給藥方案亦可適用。該療法之進程由習知技術容易地監測。
I.製品
在本發明之另一實施例中,提供一種含有調配物且較佳提供其使用說明書之製品。該製品包含容器。適合之容器包括例如瓶子、小瓶(例如雙室小瓶)、注射器(諸如單室或雙室注射器)及試管。該容器可由多種材料(諸如玻璃或塑膠)形成。該容器容納調配物。容器上或與容器有關之標籤可指示復原及/或使用說明。該標籤可進一步指示調配物適用於或意欲用於皮下投與及/或治療T細胞功能障礙病症。容納調配物之容器可為允許重複投與(例如,2-6次投與)復原調配物之多次使用的小瓶。該製品可進一步包含含適合之稀釋劑(例如BWFI)之第二容器。當混合稀釋劑與冷凍乾燥調配物後,復原調配物中之最終蛋白質濃度一般應為至少50 mg/ml。該製品可進一步包括自商業性及使用者觀點需要之其他材料,包括其他緩衝液、稀釋劑、過濾器、針、注射器及附帶使用說明書之包裝插頁。
參考以下實例將更充分瞭解本發明。然而,不應將其視為限制本發明之範疇。因此,本案之所有引用明確地以引用的方式併入本文中。
在另一實施例中,本發明提供一種於自動注射裝置中投與之包含本文所述之調配物的製品。自動注射器可描述為激活後無需患者或投藥人的其他必需的動作即會傳遞內含物之注射裝置。當傳遞速率必須為常數且傳遞時間大於一定時間時,其尤其適用於治療性調配物之自我藥療。實例 1 鑑別噬菌體文庫中之抗 PD-L1 抗體 進行文庫分選及篩檢以鑑別抗 PD-L1 抗體
使用人類(R&D Systems,目錄號156-B7)及鼠類(R&D Systems,目錄號1019-B7)PD-L1-Fc融合體作為交替文庫分選之抗原。詳言之,首先針對人類抗原分選噬菌體文庫,接著在後續三輪中針對鼠類、人類及鼠類抗原分選噬菌體文庫。在4℃下將Nunc 96孔Maxisorp®
免疫板用標靶抗原(10 μg/ml)塗布隔夜且在室溫下用噬菌體阻斷緩衝液PBST(磷酸鹽緩衝生理食鹽水(PBS)及1%(w/v)牛血清白蛋白(BSA)及0.05% (v/v)tween-20)阻斷1小時。將抗體噬菌體文庫VH(參見例如Lee等人,J. Immunol. Meth. 284
:119-132, 2004)及VH/VL(參見Liang等人,J. Mol. Biol. 366
: 815-829, 2007)分別添加至抗原板中且在室溫下培育隔夜。第二天,將塗布抗原之板用PBT(具有0.05% Tween-20之PBS)洗滌十次,且用50 mM HCl及500 mM NaCl溶離結合之噬菌體30分鐘且用等體積之1 M Tris鹼(pH 7.5)中和。在大腸桿菌XL-1 Blue細胞中擴增回收之噬菌體。在後續幾輪選擇期間,將用塗布抗原之板培育抗體噬菌體縮短至2-3小時,且逐漸增加板洗滌之嚴格性。
4輪淘選後,觀測到明顯的富集。自VH及VH/VL文庫分選中各揀選96種純系來確定其是否與人類與鼠類PD-L1-Fc特異性結合。對此等純系之可變區進行PCR測序以鑑別獨特的序列純系。
藉由將個別純系之VL
及VH
區分別選殖至LPG3及LPG4載體中(Lee等人,同上)、短暫表現於哺乳動物CHO細胞中且用蛋白質A管柱純化將相關親本純系重組成IgG。評價13種噬菌體抗體之阻斷可溶性PD-1-Fc融合蛋白與表現於293細胞中之人類或小鼠PD-L1之間的相互作用之能力(IC50值表示於表1的上半部分中)。按後續親和力成熟選擇阻斷人類PD-L1與PD-1之結合的IC50
最小之抗體YW243.55來改良其對於人類與小鼠PD-L1之親和力。(表1)。針對靈長類與鼠類物種具有可比的交叉反應性(而且保持對人類之親和力)之抗體將提供具有高價值之療法,因為實驗模型中已充分表徵之相同抗體可用於人類臨床試驗中。此舉避免由使用模型特定代用品引起之不確定性。用於衍生自 VH 文庫之純系的親和力改良之構築體文庫
噬菌粒pW0703(衍生自噬菌粒pV0350-2b(Lee等人,J. Mol. Biol 340
: 1073-1093 (2004)),在所有CDR-L3位置均含有終止密碼子(TAA)且在M13噬菌體之表面上顯示單價Fab)充當自VH
文庫移植相關純系之重鏈可變域(VH
)以達成親和力成熟之文庫模板。使用硬與軟隨機突變策略進行親和力成熟。對於硬隨機突變,使用經設計以模擬天然人類抗體之胺基酸使一個具有三個輕鏈CDR之所選位置之輕鏈文庫隨機突變,且所設計之DNA簡併係如Lee等人(J. Mol. Biol
340, 1073-1093 (2004))中所述。對於軟隨機突變,靶向CDR-L3之位置91-94及96、CDR-H1之位置28-31及34-35、CDR-H2之位置50、52及53-58、CDR-H3之位置95-99及100A之殘基;且選擇CDR環之兩種不同組合L3/H1/H2及L3/H3進行隨機突變。為達成在所選位置處引入約50%之突變率的軟隨機突變條件,用有利於野生型核苷酸之鹼基之70-10-10-10混合物合成突變誘發DNA(Gallop等人,Journal of Medicinal Chemistry
37:1233-1251 (1994))。分選噬菌體以產生親和力改良
使先前所鑑別之噬菌體純系經受第一輪板分選,接著經受5或6輪溶液分選。分別針對人類及鼠類PD-L1-Fc(R&D Systems,分別為目錄號156-B7,目錄號1019-B7)分選文庫。對於人類PD-L1-Fc標靶,在第一輪板分選下,在室溫下於1% BSA及0.05% Tween 20中用約3 O.D./ml之噬菌體輸入分別針對標靶塗布板(NUNC Maxisorp®
板)分選三個文庫2小時。在第一輪板分選後,執行溶液分選以增加選擇之嚴格性。對於溶液分選,在室溫下於100 μL含有1% Superblock(Pierce Biotechnology)及0.05% Tween-20之緩衝液中與20 nM經生物素標記標靶蛋白(濃度係以親本純系噬菌體IC50
值計)一起培育自第一輪板分選繁殖之1 O.D./ml噬菌體30分鐘。進一步用1% Superblock稀釋混合物10倍,且在室溫下在輕輕震盪下向中性鏈親和素塗布之各孔(5 μg/ml)中每孔施加100微升歷時15分鐘,以致經生物素標記標靶結合噬菌體。用PBS-0.05% Tween-20洗滌各孔10次。為測定本底結合,於中性鏈親和素塗布之板上對含有噬菌體及未經生物素標記之標靶的對照孔進行捕捉。用0.1 N HCl溶離結合之噬菌體20分鐘,用1/10體積之1 M Tris pH-11中和,測定效價且繁殖以用於下一輪。接著,連同兩種增加選擇嚴格性之方法一起再進行5輪溶液分選。第一輪係藉由使經生物素標記標靶蛋白濃度自4 nM降至0.5 nM進行締合速率選擇,且第二輪係藉由在室溫下或在37℃下添加過量非生物素標記標靶蛋白(100至2000倍以上)以競爭除去較弱結合物進行解離速率選擇。同時,降低噬菌體輸入(0.1至0.5 O.D/ml)以降低本底噬菌體結合。對於鼠類PD-L1-Fc標靶而言,噬菌體分選方法類似於以上關於人類PD-L1 Fc抗原所述之噬菌體分選方法,其中稍有一些改動。詳言之,在第一輪板淘選之後即刻使用100 nM經生物素標記鼠類PD-L1-Fc進行溶液淘選。在後續4輪溶液淘選中,經生物素標記標靶自10 nM降至1 nM,且在室溫下添加200-500倍過量之非生物素標記標靶。
隨後進一步用以下實例中所述之高通量親和力篩檢ELISA程序篩檢親和力成熟純系。高通量親和力篩檢 ELISA( 單點競爭 )
分別自人類及鼠類PD-L1標靶之第7輪及第6輪篩檢中揀選菌落。使菌落在96孔板(Falcon)中在37℃下於每孔150微升含50 μg/ml卡本西林(carbenicillin)及1E10/ml KO7之2YT培養基中生長隔夜。自同一板揀選經XL-1感染之親本噬菌體之菌落作為對照組。將96孔Nunc Maxisorp®
板分別每孔用100微升於PBS中之人類及鼠類PD-L1-Fc蛋白(2 μg/ml)在4℃下塗布隔夜或在室溫下塗布2小時。用65 μL 1% BSA阻斷板30分鐘且用40 μL 1% Tween 20再阻斷30分鐘。
用有或無10 nM標靶蛋白之ELISA(酶聯免疫吸附檢定)緩衝液(含0.5% BSA、0.05% Tween-20之PBS)按1:10稀釋噬菌體上清液,總體積為100 μL,且在室溫下於F板(NUNC)中培育至少1小時。將有或無標靶蛋白之75 μL混合物並排轉移至標靶蛋白塗布之板中。將板輕輕震盪15分鐘以允許未經結合之噬菌體被捕捉至標靶蛋白塗布之板上。用PBS-0.05% Tween-20洗滌板至少5次。藉由添加與辣根過氧化酶(HRP)結合之抗M13抗體於ELISA緩衝液中之溶液(1:5000)來定量結合,且在室溫下培育30分鐘。用PBS-0.05% Tween 20洗滌板至少5次。接著,按每孔100 μL向孔中添加1:1比例之3,3',5,5'-四甲基聯苯胺(TMB)過氧化酶受質及Peroxidase Solution B(H2
O2
)(Kirkegaard-Perry Laboratories(Gaithersburg, MD)),且在室溫下培育5分鐘。藉由向各孔中添加將100 μL 1 M磷酸(H3
PO4
)使反應終止,且在室溫下培育5分鐘。在450 nm下使用標準ELISA板讀取器測定各孔中黃顏色之OD(光密度)。利用以下等式計算OD減少率(%)。
OD450nm
減少率(%)=[(有競爭者之孔的OD450nm
)/(無競爭者之孔的OD450nm
)]×100
揀選人類與鼠類標靶之與親本噬菌體之孔的OD450nm
減少率(%)(100%)相比具有低於50%之OD450nm
減少率(%)的純系用於序列分析。選擇獨特純系進行噬菌體製備以藉由與親本純系相比確定針對人類與鼠類PD-L-Fc之結合親和力(噬菌體IC50
)。材料
自R&D Systems購得hPD-1-Fc、hPD-L1-Fc、hB7.1-Fc、mPD-1-Fc、mPD-L1-Fc及mB7.1。在Genentech使用習知技術產生表現293細胞之hPD-L1。自Jackson ImmunoResearch Laboratories購得F(ab')2
山羊抗人類IgG Fc。蛋白質之結合
如製造商所述,在室溫下用EZ-Link N-羥基硫代琥珀醯亞胺-LC-LC-生物素(sulfo-NHS-LC-LC-biotin)(Pierce)對PD-1-Fc及B7.1-Fc蛋白作生物素標記30分鐘。如製造商所述,用Quick Spin高容量管柱G50-Sephadex(Roche)移除過量未反應生物素。
如製造商所述,用MSD Sulfo-Tag N-羥基琥珀醯亞胺酯(NHS-Ester)(Meso Scale Discovery)對F(ab')2
山羊抗人類IgG Fc作釕標記,且用Quick Spin高容量管柱G50-Sephadex移除過量未反應Sulfo-Tag。測試噬菌體抗體之 ECL 細胞結合檢定
利用電化學發光(ECL)細胞結合檢定量測引起hPD-1-Fc與表現hPD-L1之293細胞之結合受50%抑制之抗體濃度(IC50
)。用磷酸鹽緩衝生理食鹽水(PBS)洗滌hPD-L1表現293細胞且在96孔高度結合板(Meso Scale Discovery)上按每孔25,000個細胞接種於25 μL PBS中。在室溫下培育板以使細胞附著於板之碳表面上。向各孔中添加25 μL 30% FBS且在輕微攪拌下培育板30分鐘以阻斷非特異性結合位點。在輕輕分配及抽吸條件下在ELISA微量板洗滌機(ELx405 Select, Bio-Tek Instruments)用PBS洗滌板三次。藉由用紙巾吸乾板移除孔中之過量PBS。向含3% FBS之PBS溶液(檢定緩衝液)之各孔中添加12.5 μL 2倍濃度之抗體,接著添加12.5 μL 4 μg/mL(2倍濃度)hPD-1-生物素之檢定緩衝液溶液,且在輕微攪拌下培育板1小時。在微量板洗滌機上用PBS洗滌板3次且用紙巾吸乾板。添加25 μL 2 μg/mL抗生蛋白鏈菌素-釕(Meso Scale Discovery)且在室溫下在輕輕攪拌下於檢定緩衝液中培育30分鐘。在微量板洗滌機上用PBS洗滌3次且用紙巾吸乾板。添加150 μL 1倍無界面活性劑之MSD讀取緩衝液(Meso Scale Discovery)。在Sector Imager 6000讀取器(Meso Scale Discovery)上在620 nm下讀取所發射之發光。用檢定中所用之測試抗體的濃度使用四參數非線性最小二乘法擬合分析ECL值,獲得檢定中各競爭者之IC50
值。結果及討論:
選擇15種結合人類與鼠類PD-L1之衍生自YW243.55之獨特噬菌體抗體且重組為全長IgG1抗體以用於進一步評估。此等抗體之輕鏈及重鏈可變區序列報導於圖11A及圖11B中。
經由電化學發光(ECL)細胞結合檢定測試該15種重組抗體阻斷PD-1與表現人類或小鼠PD-L1之293細胞結合之能力。表1的下半部分:在表1中「格式1」描述可溶性人類PD-1-Fc與人類PD-L1-轉染之293細胞的結合;「格式2」描述鼠類PD-1-Fc與鼠類的PD-L1轉染之293細胞的結合,且「格式3」描述人類PD-1與鼠類PD-L1轉染之293細胞的結合。雖然所有15種親和力改良之抗體均已獲得明顯的與小鼠PD-L1之交叉反應性,但仍基於YW243.55S70阻斷人類與小鼠PD-L1結合PD-1之能力(表1:IC50
值分別為49 pM及22 pM)選擇其作為第一候選物繼續研究。
表1
實例2表徵抗 PD-L1 抗體 (BIAcore)
使用BIAcore™-3000儀器由表面電漿共振(SRP)量測抗PD-L1噬菌體抗體YW243.55及YW243.55S70針對重組人類及小鼠PD-L1之結合親和力。將重組人類PD-L1-Fc(R&D Systems,目錄號156-B7)及重組小鼠PD-L1-Fc(R&D Systems,目錄號1019-B7)直接塗布於CM5生物感測器晶片上以達到約500個應答單位(RU)。對於動力學量測,在25℃下將兩倍連續稀釋液(3.9 nm至500 nm)以30 μL/min之流動速率注射至PBT緩衝液(含0.05% Tween-20之PBS)中。使用簡單的一對一朗繆耳結合模型(Languir binding model)(BIAcore Evaluation Software 3.2版)計算締合速率(kon
)及解離速率(koff
)。以比率koff
/kon
計算平衡解離常數(kD)。
所量測之抗PD-L1噬菌體抗體純系YW243.55及YW243.55.S70之結合親和力報導於下表2中。
表2
BIAcore結合親和力
實例 3A 抗 PD-L1 抗體對人類、恆河猴及小鼠 PD-L1-FACS 之特異性及放射性配位體細胞結合檢定
此實例展示本發明之抗PD-L1抗體對人類、恆河猴及小鼠PD-L1之特異性。此外,其展示該抗體對293轉染細胞之細胞膜上所表現之小鼠及人類PD-L1之親和力。
將人類及小鼠PD-L1穩定轉染至293細胞中。收集細胞且按每孔150,000個細胞塗鋪於96孔板中以進行結合研究。
自美國生物醫學研究西南基金會(Southwest Foundation for Biomedical Research)(San Antonio, Texas)獲得恆河猴血液。用等體積PBS稀釋血液且塗覆在96% Ficoll-Paque(GE Healthcare)上以分離單核細胞。使用紅血球溶解緩衝液(Qiagen)溶解紅血球得到單核細胞,且以每毫升1.5×106
個細胞與5 ng/ml PMA加1 μM依諾黴素(ionomycin)一起在6孔板中培養隔夜。培養基為含10%胎牛血清、20 μM HEPES及來自Gibco之以下補充劑之1:100稀釋液的RPMI 1640:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。第二天收集細胞,且等分至96孔板中以進行結合研究(每孔約120,000個細胞)。
由三倍連續稀釋液以10 μg/ml起始滴定PD-L1抗體YW243.55.S70或Herceptin®
抗體對照組,且在冰上於50 μl體積中與細胞結合25分鐘。洗滌細胞,且接著在冰上與20 μg/ml抗人類IgG PE(Caltag)結合25分鐘。亦用CD3 FITC及CD4 APC(BD Biosciences)使恆河猴細胞共同染色以區別CD4+ T細胞。
所有樣品均在Beckman Dickinson FACSCalibur上操作,且使用Tree Star, Inc. FlowJo®
軟體分析隨抗PD-L1抗體濃度變化之PD-L1結合資料之平均螢光強度;使用Kaleidagraph計算EC50
值(與半最大結合相關的抗體濃度)。此外,執行平衡結合研究以確定YW24355S70與293細胞上表現之人類及小鼠PD-L1之結合的精確親和力(Kd)(實例3B)。此等值概述於以下表3中:
表3
EC50
概述
實例 3B 抗 PD-L1 抗體與人類及小鼠 PD-L1 之親和力量測 - 平衡結合放射性配位體細胞結合檢定
在37℃下於5% CO2
中,在生長培養基中培養經人類或小鼠PD-L1轉染之293細胞,該生長培養基係由補充有10%胎牛血清(FBS)、2 mM L-麩胺醯胺、1×青黴素-鏈黴素之RPMI 1640培養基組成。用結合緩衝液(含2% FBS及50 mM Hepes(pH 7.2)之50:50 DMEM/F12)洗滌細胞,且將約230,000個細胞於0.2 mL結合緩衝液中置放於96孔板中。使用四氯二苯基苷脲(Iodogen)法碘化抗PD-L1抗體YW243.55.S70.hIgG。藉由凝膠過濾使用NAP-5管柱自游離125
I-NA純化經放射性標記之抗PD-L1抗體;經純化之抗體之比活性為17.41 μCi/μg。將體積為50 μL之含固定濃度之碘化抗體及遞減濃度之連續稀釋未標記抗體的競爭反應混合物置放於96孔板中。在37℃下在5% CO2
中,在生長培養基中培養表現人類PD-L1及鼠類PD-L1之293穩定轉染細胞株,該生長培養基係由補充有10%胎牛血清(FBS)、2 mM L-麩胺醯胺、1×青黴素-鏈黴素之50:50 DMEM/F12培養基組成。用結合緩衝液(含2% FBS、50 mM HEPES(pH 7.2)及2 mM疊氮化鈉之50:50 DMEM/F12)洗滌細胞,且於0.2 mL結合緩衝液中以約200,000個細胞之密度添加至50 μL競爭反應混合物中。各含細胞之競爭反應物中碘化抗體之最終濃度為約150 pM(約120,000 cpms/0.25 mL),且含細胞之競爭反應物中未經標記之抗體的最終濃度不等,以500 nM起始,隨後按2倍遞減,獲得10個濃度。在室溫下培育含細胞之競爭反應物2小時。一式三份檢定含細胞之競爭反應物的未經標記之抗體的各濃度。培育2小時後,將競爭反應物轉移至Millipore Multiscreen過濾板中,且用結合緩衝液洗滌4次以分離游離碘化抗體與結合碘化抗體。在Wallac Wizard 1470γ計數器(PerkinElmer Life and Analytical Sciences Inc. Wellesley, MA)上計數過濾器。使用NewLigand軟體(Genentech)評估結合資料,該軟體使用莫森(Munson)及羅巴德(Robard)擬合算法確定抗體之結合親和力。Musson等人,Anal. Biochem. 107
: 220-39 (1980)。
由斯卡查德分析所測定之Kd值證實表3中所示之抗PD-L1抗體與人類及小鼠PD-L1之結合的EC50值。實例 4 抗 PD-L1 抗體之選擇性及親和力 (IC50
)
此實例展示用於評估本發明之全長抗PD-L1抗體阻斷PD-L1結合PD-1與B7.1之能力的結合選擇性及親和力(IC50
)檢定。方法: hB7.1-Fc- 生物素及 hPD-1-Fc- 生物素與 hPD-L1-Fc ELISA 之結合 ( 格式 4) :
將Nunc Maxisorp 384孔板用25 μL 250 ng/mL hPD-L1-Fc之PBS溶液塗布隔夜。在微量板洗滌機上用0.05% Tween之PBS溶液(洗滌緩衝液)洗滌各孔三次且用0.5% BSA之PBS溶液阻斷各孔。向含0.05% Tween、0.5% BSA之PBS溶液(檢定稀釋液)之各孔中添加12.5 μL 2倍濃度之抗體,接著添加12.5 μL 250 ng/mL(2倍濃度)hB7.1-Fc-生物素之檢定稀釋液溶液,且在攪拌下培育板一個半小時。用洗滌緩衝液洗滌各孔6次且添加25 μL抗生蛋白鏈菌素-HRP(1:40,000檢定稀釋液溶液,GE Healthcare)。在攪拌下培育板30分鐘且用洗滌緩衝液洗滌各孔6次。添加25 μL TMB受質(Kirkegaard and Perry Laboratories)歷時1小時且用25 μL 1 M磷酸終止反應。如實例1在ECL細胞結合檢定中所述,在450 nm下讀取吸光度且分析IC50
值。格式 5 、 6 、 7
:
對於hPD-1-Fc-生物素與hPD-L1-Fc之結合(格式5),該格式類似於以上檢定,其中例外為使用hPD-1-Fc-生物素代替hB7.1-Fc-生物素進行結合。TMB受質反應時間為17分鐘。
對於mB7.1-Fc-生物素與mPD-L1-Fc之結合(格式6),該格式類似於格式5,其中例外為使用mPD-L1-Fc代替hPD-L1-Fc塗布板,且使用mB7.1-Fc-生物素代替hB7.1-Fc-生物素進行結合。TMB受質反應時間為7分鐘。
對於mPD-1-Fc-生物素與mPD-L1-Fc之結合(格式7),該格式類似於以上所提及之小鼠ELISA,其中例外為使用mPD-1-Fc-生物素代替mB7.1-Fc-生物素進行結合。TMB受質反應時間為5分鐘。結果
:
親和力成熟噬菌體抗PD-L1抗體YW243.55.S70阻斷指定結合對之間的相互作用的IC50
之評定報導於表3中。YW243.55S70能夠在38 pM之半最大抑制濃度下阻斷人類PD-L1與hB7.1 Fc之結合,該濃度相對而言可比於阻斷PD-L1/PD-1相互作用之IC50
值(42 pM)。量測YW243.55S70阻斷PD-L1與PD-1及B7.1之相互作用之能力的Biacore研究與此等ELISA結果(資料未展示)一致。
表3
實例 5 由抗 PD-L1 抗體 YW243.55.S70 活體外增進 CD4+ 及
CD8+ T 細胞活性 PMEL/B16 活體外檢定
此實例展示如應答黑素細胞肽gp100之γ-IFN產生的增強所量測,本發明抗PD-L1抗體對PMEL T細胞受體轉殖基因CD8+
T細胞活化之作用。在此程序中,自CD8+ T細胞表現對gp100肽具有特異性之TCR的PMEL TCR轉殖基因小鼠獲得CD8+ T細胞。純化CD8+ T細胞之後,執行多輪刺激以產生且擴充活化之CD8+ T細胞,而CD8+ T細胞接著又將調升PD-1表現。同時,用IFN-γ處理B16黑素瘤細胞以調升其PD-L1表現。接著,在抗PD-L1抗體存在下共培養該等細胞,且評估對IFN-γ產生之作用。針對三次刺激選擇B16細胞,因為其內源性表現低含量之gp100肽(與肽之外源應用相反)。此外,因為此等細胞亦不表現PD-L2、B7.1或B7.2,所以與PD-L1無關之其他信號傳導(例如經由CD28或CTLA-4之信號傳導,或經由PD-1之PD-L2誘導之信號傳導)之作用降至最低。PMEL 檢定:
如圖3所示,抗PD-L1抗體增加產生IFN-γ之PMEL CD8+
T細胞之百分比與應答指定量之gp100肽所產生之IFN-γ的平均含量。D.011.10 活體外檢定:
利用Ova特異性TCR Tg CD4+ T細胞之類似檢定展示,在抗PD-L1抗體存在下在先前用Ova肽刺激以誘導PD-1之表現之後,T細胞增殖增強(圖4)。在最終刺激中,使用表現PD-L1之經照射A20 B細胞向DO.11.10 T細胞提供指定濃度之Ova肽。值得注意的是,在較低程度的抗原受體刺激下,PD-1/PD-L1軸之貢獻更明顯,含量更密切地反映刺激之生理學相關量值。材料及方法: PMEL 檢定 初次刺激 ( 第 0-4 天 )
自PMEL轉殖基因T細胞受體小鼠收集脾臟及腸系膜淋巴結。將器官粉碎成單細胞懸浮液且溶解紅血球。使用CD8+
T細胞分離套組及AutoMACS細胞分離器(Miltenyi Biotec)根據製造商之說明書分離CD8+
T細胞。
自非轉殖基因性別匹配之小鼠分離脾臟且粉碎成單細胞懸浮液,且溶解紅血球。在37℃下用0.1 μg/ml gp100脈衝細胞2小時且洗滌。
在96孔平底板中與200,000個PMEL CD8+
T細胞及75,000個經gp100脈衝之脾細胞一起共培養細胞4天。培養基為伊思考夫氏改良之達爾伯克氏培養基(Iscove's Modified Dulbecco's medium)+10%胎牛血清+20 μM HEPES及來自Gibco之以下補充劑之1:100稀釋液:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。二次刺激 ( 第 4-7 天 )
離心PMEL培養物,且使用多通道吸管吸出培養基。添加新鮮培養基並混合以洗滌細胞,之後再次離心。移除大部分培養基,且添加抗體(Herceptin®
、YW243.55.S70或無)至最終濃度為10 μg/ml。一式兩份在孔中設立條件以致可在終點時評定平均IFN-γ產生。
在37℃下用0.1 μg/ml gp100肽脈衝DC-1細胞2小時且洗滌。按每孔40,000個細胞向已洗滌之PMEL培養物中添加經Gp100脈衝之DC-1細胞。將PMEL及DC-1+抗體共培養3天。三次刺激 ( 第 7-8 天 )
在三次刺激的前一天,即第6天,與20 ng/ml小鼠IFN-γ(R&D Systems)一起培育B16黑素瘤細胞隔夜以調升其PD-L1表現。
第7天,離心PMEL培養物且使用多通道吸管吸出培養基。添加新鮮培養基並混合,之後再離心。移除大部分培養基,且添加抗體至最終濃度為10 μg/ml。
用IFN-γ刺激隔夜後,洗滌B16細胞且分成三組,在無gp100、1 ng/ml gp100(低gp100)及10 ng/ml gp100(高gp100)下培育兩小時。洗滌細胞,且接著按每孔40,000個細胞添加至已洗滌之PMEL+抗體培養物中且一起培育隔夜。第 8 天 IFN-γ 細胞內染色
根據製造商之說明書,添加Golgi-Plug(BD Biosciences)供培養的最後5小時使用。根使用BD Biosciences Cytofix/Cytoperm Fixation/Permeabilization Solution套組據製造商之說明書進行IFN-γ細胞內染色,且所有染色抗體亦來自BD Biosciences。用CD8a PE及Thy1.1 FITC使細胞表面染色,且用飽和濃度之IFN-γ APC使細胞細胞內染色。
所有樣品均在Beckman Dickinson FACSCalibur上操作,且使用Tree Star, Inc. FLOWJO™軟體分析資料。 D011.10 活體外檢定
收集DO11.10轉殖基因小鼠之脾臟及腸系膜淋巴結,粉碎成單細胞懸浮液且溶解紅血球。按每毫升1×106
個細胞之密度在含0.3 μM之Ova肽之6孔板中培養細胞72小時。培養基為RPMI 1640+10%胎牛血清+20 μM HEPES及來自Gibco之以下補充劑之1:100稀釋液:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。
初次刺激之後,收集細胞且使用小鼠CD4 T細胞純化套組根據製造商之說明書(Miltenyi Biotec)純化CD4+
T細胞。接著使經純化之CD4+
T細胞靜置隔夜。
次日,收集細胞,洗滌且與經照射(10,000拉德(rad))A20細胞共培養。在96孔U形底板中一式三份在孔中設立與50,000個CD4+
T細胞至40,000個A20細胞及最終濃度為20 μg/ml之經滴定Ova肽及抗體的共培養。48小時後,每孔用1 µCi 3H-胸苷脈衝培養物隔夜且次日冷凍。隨後將板解凍,在細胞收集器上收集,且在β計數器上讀數。實例 6 由抗 PD-L1 增進混合淋巴細胞反應中人類 CD8+ T 細胞之增殖
圖5說明抗PD-L1(例如YW243.55.S1)能夠應答來自MHC錯配供體之細胞增進人類CD8 T細胞之增殖。藉由首先使用CD8+ T細胞RosetteSep®
(StemCell Technologies)根據製造商之說明書自供體A之全血富集應答之CD8+ T細胞。接著用等體積磷酸鹽緩衝生理食鹽水(PBS)稀釋細胞,且藉由塗覆於Ficoll-Paque Plus(GE Healthcare)上經梯度離心分離。分離後,用CD8 APC(BD Biosciences)使細胞染色且結果為78% CD8+ T細胞染色。用2.5 μM CFSE示蹤染料(Molecular Probes)對細胞作螢光標記。
為充當同種異體抗原呈現細胞(APC),首先自供體B之全血分離單核細胞,且接著耗盡CD3+T細胞。用等體積PBS稀釋血液,且在經Ficoll梯度離心之後分離單核細胞。用CD3 FITC(BD Biosciences)使細胞染色,洗滌且接著與抗FITC微珠(Miltenyi Biotec)一起培育。接著在AutoMACS細胞分離器(Miltenyi Biotec)上耗盡CD3 FITC陽性細胞。接著在銫照射器中以2500拉德照射細胞。
在含150,000個CD8+ T細胞及150,000個APC之96孔平底板中與10 μg/ml抗體一起共培養細胞5天。培養基為RPMI 1640+10%胎牛血清+20 μM HEPES及來自Gibco之以下補充劑之1:100稀釋液:Gluta-MAX、丙酮酸鈉、青黴素/鏈黴素及非必需胺基酸。
在第5天,收集細胞,洗滌且依序用CD8-生物素及抗生蛋白鏈菌素-PerCp(BD Biosciences)使之染色。所有樣品均在Beckman Dickinson FACSCalibur上操作,且使用Tree Star, Inc. FlowJo軟體分析資料。
在抗PD-L1存在下觀察到應答MHC錯配供體之細胞的CD8 T細胞之增殖增強約45%。實例 7 活體內模型中 PD-L1 阻斷對 LCMV 之作用
已展示T細胞在慢性刺激條件下調升且維持抑制性受體PD-1之表現。PD-1與其兩種配位體PD-L1及PD-L2中之任一者的連接造成慢性活化T細胞之不應狀態(refractory state),從而減弱其對其同源抗原之反應。在持續經淋巴細胞性脈絡叢腦膜炎病毒(lymphocytic choriomeningitis virus,LCMV)感染之小鼠中,阻斷PD-1或其配位體PD-L1足以使慢性不應T細胞恢復,從而增加抗病毒T細胞反應之量值及功能品質。類似地,經HIV或HCV慢性感染之人類展現T細胞對模擬無反應,其活性可藉由阻斷PD-1或PD-L1活體外增強。因此,LCMV模型中PD-L1阻斷之活性表明具有增強抗病毒及抗腫瘤免疫之治療潛能。
對於小鼠之LCMV活體內實驗,吾人已藉由將噬菌體衍生之重鏈及輕鏈可變區序列選殖於小鼠IgG2a重鏈及小鼠κ輕鏈恆定域之上游來重組人類化抗PD-L1抗體(YW243.55S70)。為阻止PD-L1表現細胞之抗體介導之細胞毒性,藉由抑制Fcγ受體結合,將位置265(天冬胺酸)及297(天冬醯胺)改為丙胺酸(DANA)。Shields, RL等人,J. Biol Chem
2001276
(9): 6591-6604。為測試抗PD-L1抗體在慢性感染中增強抗病毒免疫之能力,在第0天,用2×106
個空斑形成單位(plaque forming unit,pfu)之純系13 LCMV或LCMV之Armstrong病毒株感染小鼠作為參考對照組。實驗設計之示意圖顯示於圖6中。用純系13感染導致慢性感染,其特徵在於T細胞擴充但不能有效清除病毒;而Armstrong LCMV在感染8-10天內即被清除。在第14天,小鼠開始受以10 mg/kg劑量傳遞之抗PD-L1或對照mIgG處理,每週3次。在第21天及第28天,執行血液及組織的CD8 T細胞功能及病毒效價之分析。
與Barber等人,Nature439
:682-7 (2006)公開之資料一致,此實例展示在慢性LCMV感染中,在2週處理方案後,抗PD-L1抗體能夠增強細胞毒性淋巴細胞對LCMV之反應。圖7A展示應答gp33 LCMV特異性肽表現CD107a於細胞表面上之CD8 T細胞的百分比。通常於細胞內表現之CD107a之質膜表現伴隨去顆粒過程,且因此充當去顆粒之代用指標。相對於來自急性Armstrong LCMV感染之細胞之反應,來自受慢性病毒株純系13感染之動物之細胞的去顆粒減弱(對照Ig組),而PD-L1阻斷能夠使CD8+之去顆粒恢復至可比於Armstrong感染中所觀測到之去顆粒的程度。類似地,7B說明在抗PD-L1處理組中應答LCMV gp33之產生IFN-γ之CD8 T細胞相對於對照Ig的增加百分比。
接著,測試抗PD-L1抗體對降低或消除血液及組織中之LCMV病毒的影響。在圖8A中,圖展示在用純系13 LCMV感染之後第21天及第28天,經對照Ig及PD-L1處理之動物之指定組織中的對數病毒效價。在感染後第14天,開始抗體處理。阻斷PD-L1引起血液、肝臟、腦、肺及腎臟中之病毒效價極顯著地降低。印象深刻的是,在5隻小鼠中之3隻中,α-PD-L1抗體使血液LCMV效價降低至偵測限值以下之含量(<1×10-5
)。在可比設計之後續實驗中,在所有5隻用劑量為10 mg/kg或2 mg/kg之抗PD-L1處理2週(每週3次)之小鼠中均觀測到血液及肝臟中之病毒根除(資料未圖示)。下圖展示血液中病毒效價降低之動力學,且說明在第28天抗PD-L1處理組相對於對照組平均降低96.8%。此等資料證明PD-1/PD-L1路徑在慢性感染中在抑制T細胞反應方面之重要性且與活體外PD-L1阻斷對自患有慢性感染(諸如C型肝炎及HIV)人類獲得之T細胞之作用一致。材料及方法: 測定 CD8 T 細胞應答 LCMV gp33 肽產生之 IFN-γ 的百分比
自經感染小鼠中分離脾臟,且藉由在完全培養基中粉碎器官產生單細胞懸浮液,該完全培養基為含10%熱失活胎牛血清、2 mM L-麩胺醯胺、100 U/ml青黴素/鏈黴素及10 mM 2-巰基乙醇之IMDM(Invitrogen Inc., Carlsbad, CA)。使用ACK溶解緩衝液(0.15 M NH4
Cl、10 mM KHCO3
、0.1 mM EDTA)溶解紅血球。為量測抗原特異性CD8 T細胞反應,用完全培養基洗滌脾細胞,且用LCMV肽GP33(KAVYNFATC, ProImmune Inc., Bradenton, FL)活體外再刺激4小時。在96孔平底板中在100單位/毫升人類介白素-2(Sigma-Aldrich, St. Louis, MO)、1微升/毫升布雷菲德菌素A(brefeldin A)及1微升/毫升莫能星(monensin)(BD pharmingen)(1:1000稀釋液)及抗CD107a FITC(純系ID4B,BD Biosciences, San Jose, CA)存在下與100奈克/毫升GP33肽一起培養1×106
個脾細胞。培育後,用含2%胎牛血清之PBS洗滌細胞一次,且使用螢光染料結合抗體使細胞表面標記物染色,該等螢光染料結合抗體為抗CD8 APC(純系53.67,BD Biosciences, San Jose, CA)、抗CD4 PerCp-Cy5.5(純系RM4-5,BD Biosciences, San Jose, CA)及抗PD-1 PE(純系J43,BD Biosciences, San Jose, CA)。使用Cytofix Cytoperm Plus套組(BD Biosciences, San Jose, CA)根據製造商之說明書使用抗IFN-γ PE-Cy7(純系XMG1.2,eBioscience Inc. San Diego, CA)進行細胞內IFN-γ染色。為偵測GP33特異性CD8 T細胞之數目,用GP33五聚物(與APC連接之H2-Db,ProImmune Inc., Bradenton, FL)根據製造商之說明書使新鮮脾細胞染色。使用BD FACSAria(BD Biosciences, San Jose, CA)收集資料,且用FlowJo軟體(Tree Star Inc. Ashland OR)分析。 測定 LCMV 病毒效價:
用於完全IMDM中之含LCMV之血液或組織勻漿的10倍連續稀釋液感染MC57纖維肉瘤細胞。接著在組織培養恆溫箱中在37℃下培育反應物2-6小時,接著用含1%甲基纖維素之DMEM塗覆。此後培育3-5天,接著藉由抽吸移除甲基纖維素層。用PBS/4%三聚甲醛固定細胞,接著用0.5%曲拉通-x(Triton-x)增加通透性歷時20分鐘,用PBS洗滌,接著在輕微搖動下於10% FCS中阻斷1小時。用VL4抗體對LCMV進行染色(1小時),洗滌2次,接著用於阻斷緩衝液中之抗大鼠HRP(1:400)顯色。此後洗滌3次,接著向各孔中添加鄰苯二胺受質(SIGMA P8806-50TAB 3毫克/錠劑)以顯色。實例 8 癌症中之 PD-L1 阻斷
目前顯而易見,許多腫瘤利用PD-1配位體之表現作為減弱抗腫瘤T細胞反應之方法。若干人類癌症之特徵在於在腫瘤與腫瘤浸潤性白血球上表現高含量之PD-L1且此高PD-L1表現通常與較差預後相關。小鼠腫瘤模型說明腫瘤內PD-L1表現類似地增加且說明PD-1/PD-L1路徑在抑制腫瘤免疫中之作用。
此處吾人提供說明阻斷PD-L1對同基因C57B6小鼠中MC38.Ova鼠類結腸直腸癌細胞之正位腫瘤生長之影響的實驗(圖9A)。如流式細胞儀所評定,此等細胞經由逆轉錄病毒轉導表現卵清蛋白且表現PD-L1(但不表現PD-L2)於其細胞表面上(直方圖-圖10A)。在第0天,用50萬個MC38.Ova細胞經皮下給小鼠接種。在第1天或第14天,用10 mg/kg抗PD-L1(YW243.55S70-小鼠IgG2a-DANA)、對照Ig或阻斷抗CTLA4抗體(UC10-4F10-11)處理小鼠(當腫瘤平均大小達到250 mm3
時)(每組10隻小鼠),每週3次,歷時研究持續時間。早期或在後期介入中阻斷PD-L1均極有效作為單一藥劑療法阻止腫瘤生長。相反,阻斷CTLA4(T細胞上表現之另一抑制性分子)展示無抑制腫瘤生長之跡象。此等結果說明PD-1/PD-L1軸優於CTLA4/B7之抑制抗腫瘤免疫反應之獨特作用,且證明用阻斷PD-L1與PD-1及B7.1相互作用之抗體具有治療人類癌症之潛能。MC38.Ova 同基因腫瘤模型:方法。
在第0天,用於100微升HBSS+基質膠(matrigel)中之50萬個MC38.Ova細胞經皮下給70隻動物接種。第1天開始,將20隻小鼠招募至2個處理組(參見下文:第1組或第2組)中之一個中。使其餘40隻小鼠生長腫瘤直至第14天。在此等40隻小鼠中,將30隻具有類似大小之腫瘤的小鼠招募至3個處理組(第3組至第5組)中之一個中。每週2次量測腫瘤且稱重小鼠。對因腫瘤體積不相似而未招募至以下處理組中之小鼠實行安樂死。
第1組:抗gp120抗體,10 mg/kg(腹膜內),100 μL,第1天,每週3次
第2組:抗PD-L1抗體,10 mg/kg(腹膜內),100 μL,第1天,每週3次
第3組:抗gp120抗體,10 mg/kg(腹膜內),100 μL,第14天,每週3次
第4組:抗PD-L1抗體,10 mg/kg(腹膜內),100 μL,第14天,每週3次
第5組:抗CTLA-4抗體,10 mg/kg(腹膜內),100 μL,第14天,每週3次
***第1組及第2組在第1天開始給藥;第3組、第4組及第5組在第14天開始給藥。實例 9 抗 PD-L1 與提供抗腫瘤作用或免疫增進療法之其他藥劑之組合 (MC38.Ova 模型 )
在第0天,用於100微升HBSS+基質膠中之50萬個MC38.Ova細胞經皮下給150隻動物接種。使小鼠生長腫瘤。每週2次稱重小鼠且量測直至第11天(當腫瘤體積介於100 mm3
與200 mm3
之間時)。在第11天,腫瘤量測之後,將小鼠招募至以下12個處理組中之一個中。對因腫瘤體積不相似而未招募至以下處理組中之小鼠實行安樂死。吉西他濱(第4組)處理在第12天開始,而其餘抗體組之處理在第14天開始。所有體積均為100 μl(於惰性媒劑中),其他詳情如下所報導:
第1組:抗gp120抗體,10 mg/kg(腹膜內),100 μL,每週3次共5次,n=10
第2組:抗PD-L1抗體,10 mg/kg(腹膜內),100 μL,每週3次共5次,n=10
第3組:抗VEGF抗體,5 mg/kg(腹膜內),100 μL,每週2次共5次,n=10
第4組:吉西他濱,40 mg/kg(腹膜內),100 μl,第12、16、20天投與,n=10
第5組:抗PD-L1抗體+抗gp120抗體,n=10
第6組:抗PD-L1抗體+抗VEGF抗體,n=10
第7組:抗PD-L1抗體+吉西他濱,n=10
第8組:抗gp120抗體+吉西他濱,n=10
第9組:抗gp120抗體+抗VEGF,n=10
第12天:在麻醉下自第1組之小鼠眼後抽血(100微升)用於CBC分析。
第14天及第22天:在麻醉下自第4組之小鼠眼後抽血(100微升)用於CBC分析。
第19天:在麻醉下自除第4組以外之所有小鼠眼後抽血(100微升)用於CBC分析。
第26天:在麻醉下自除第4組以外之所有小鼠眼後抽血(100微升)用於PK分析。
每週2次量測腫瘤且稱重小鼠。每天將稱重展現體重減輕>15%之動物,且若其體重減輕>20%,則實行安樂死。當腫瘤體積超過3,000 mm3
時或3個月之後尚未形成腫瘤時,將對小鼠實行安樂死。
此研究展示(圖10),與單獨的α-VEGF及吉西他濱誘導性方案相比,PD-L1阻斷更有效。實例 10 於哺乳動物細胞中表現抗 PD-L1 抗體
此實例說明藉由於哺乳動物細胞中重組表現製備潛在糖基化之形式之抗PD-L1抗體。
使用載體pRK5(參見1989年3月15日公開之EP 307,247)作為表現載體。視情況,使編碼抗體輕鏈及/或重鏈之DNA連接於含所選限制酶之pRK5中以允許使用諸如Sambrook等人,同上中所述之連接方法插入該DNA。
在一實施例中,所選宿主細胞可為293細胞。在組織培養板中使人類293細胞(ATCC CCL 1573)在諸如補充有胎牛血清及視情況選用之營養組分及/或抗生素之DMEM的培養基中生長至匯合。混合約10 μg編碼pRK5抗體之DNA與約1 μg編碼VA RNA基因之DNA[Thimmappaya等人,Cell
,31
:543 (1982)],且溶解於500 μL 1 mM Tris-HCl、0.1 mM EDTA、0.227 M CaCl2
中。向此混合物中逐滴添加500 μL 50 mM HEPES(pH 7.35)、280 mM NaCl、1.5 mM NaPO4
,且在25℃下形成沈澱歷時10分鐘。將沈澱懸浮且添加至293細胞中且在37℃下沈降約4小時。吸出培養基且添加2 ml 20%甘油之PBS溶液歷時30秒。接著用無血清培養基洗滌293細胞,添加新鮮培養基且培育細胞約5天。
轉染後約24小時,移除培養基且用培養基(單獨)或含200 μCi/ml35
S-半胱胺酸及200 μCi/ml35
S-甲硫胺酸之培養基更換。培育12小時後,收集改良之培養基,在旋轉過濾器上濃縮且裝載於15% SDS凝膠上。可乾燥經加工凝膠且暴露於薄膜一段所選時間來揭示抗體之存在性。含經轉染細胞之培養物可經受進一步培育(於無血清培養基中),且在所選生物檢定中測試培養基。
在替代技術中,可使用Somparyrac等人,Proc. Natl. Acad. Sci.
,12
:7575 (1981)所述之硫酸葡聚糖法(dextran sulfate method)將抗體短暫引入293細胞中。使293細胞在旋轉燒瓶中生長至最大密度,且添加700 μg編碼pRK5抗體之DNA。首先藉由離心自旋轉燒瓶中濃縮細胞且用PBS洗滌。在細胞離心塊上培育DNA-葡聚糖沈澱4小時。用20%甘油處理細胞90秒,用組織培養基洗滌且再引入含有組織培養基、5 μg/ml牛胰島素及0.1 μg/ml牛運鐵蛋白之旋轉燒瓶中。約4天後,離心改良之培養基並過濾以移除細胞及碎片。接著可濃縮含經表現抗體之樣品且利用諸如透析及/或管柱層析法之任何所選方法進行純化。
在另一實施例中,可表現抗體於CHO細胞中。可使用諸如CaPO4
或DEAE-葡聚糖之已知試劑將編碼連接於pRK5中之抗體的DNA轉染至CHO細胞中。如上所述,可培育細胞培養物,且用培養基(單獨)或含有諸如35
S-甲硫胺酸之放射性標記之培養基更換培養基。確定抗體之存在性後,可用無血清培養基更換培養基。較佳培育培養物約6天,且接著收集改良之培養基。接著可濃縮含經表現抗體之培養基且利用任何所選方法純化。
亦可表現抗體之標記抗原決定基之變異體於宿主CHO細胞中。可將編碼連接於pRK5中之抗體的DNA次選殖於pRK5載體外部。次選殖插入物可經受PCR以與諸如poly-his標籤之所選抗原決定基標籤同框融合於桿狀病毒表現載體中。接著可將編碼抗體插入物之標記poly-his之DNA次選殖於含有用於選擇穩定純系之諸如DHFR之選擇標記物的SV40驅動載體中。最終,可用SV40驅動載體轉染(如上所述)CHO細胞。可如上所述作標記來驗證表現。接著可濃縮含經表現之標記poly-His之抗體的培養基且利用任何所選方法(諸如利用Ni2+
-螯合親和層析法)純化。
亦可利用短暫表現程序表現抗體於CHO及/或COS細胞中,或利用另一穩定表現程序表現抗體於CHO細胞中。
使用以下程序進行於CHO細胞中之穩定表現。該等蛋白質表現為IgG構築體(免疫黏附素),其中各別蛋白質之可溶性形式(例如細胞外域)之編碼序列與含鉸鏈、CH2及CH2域之IgG1恆定區序列融合,及/或該等蛋白質為標記poly-His之形式。
PCR擴增後,使用如Ausubel等人,Current Protocols of Molecular Biology
, Unit 3.16, John Wiley and Sons (1997)中所述之標準技術將各別DNA次選殖於CHO表現載體中。CHO表現載體經構築具有相關DNA之相容性限制位點5=及3=以允許cDNA=s方便穿梭(shuttling)。用於在CHO細胞中表現之載體係如Lucas等人,Nucl. Acids Res. 24
:9 (1774-1779) (1996)中所述,且使用SV40早期啟動子/強化子驅動相關cDNA及二氫葉酸還原酶(DHFR)之表現。DHFR表現允許選擇轉染後穩定維持之質體。
使用市售轉染試劑SUPERFECT®
(Quiagen)、DOSPER®
或FUGENE®
(Boehringer Mannheim),將12微克所要質體DNA引入約1000萬個CHO細胞中。如Lucas等人,同上所述使細胞生長。於安瓿中冷凍約3×10-7
個細胞以如下所述進行進一步生長及生產。
藉由置放於水浴中將含質體DNA之安瓿解凍,且藉由渦旋混合。將內含物吸移至含10 mL培養基之離心管中,且在1000 rpm下離心5分鐘。吸出上清液,且將細胞再懸浮於10 mL選擇性培養基(含5%經0.2 μm滲濾之胎牛血清的經0.2 μm過濾之PS20)中。接著將細胞等分至含90 mL選擇性培養基之100 mL旋轉器中。1-2天後,將細胞轉移至填充有150 mL選擇性生長培養基之250 mL旋轉器中,且在37℃下培育。再過2-3天後,按每毫升3×105
個細胞給250 mL,500 mL及2000 mL旋轉器接種。藉由離心及再懸浮於生產培養基中,用新鮮培養基更換細胞培養基。儘管可使用任何適合之CHO培養基,但實際上可使用1992年6月16日頒布之美國專利第5,122,469號中所述之生產培養基。按每毫升1.2×106
個細胞給3 L生產旋轉器接種。在第0天,測定細胞數量及pH值。在第1天,獲取旋轉器樣品且開始用經過濾空氣噴氣。在第2天,獲取旋轉器樣品,溫度變至33℃,且取30 mL 500 g/L葡萄糖及0.6 mL 10%消泡劑(例如35%聚二甲基矽氧烷乳液,Dow Corning 365 Medical Grade Emulsion)。在整個生產過程中,必要時,調節pH值以使其維持在約7.2。10天後或直至生活力降至70%以下,藉由離心且經由0.22 μm過濾器過濾收集細胞培養物。將濾液儲存在4℃下或立即裝載於管柱上進行純化。
對於標記poly-His之構築體,使用Ni-NTA管柱(Qiagen)純化蛋白質。純化之前,向改良之培養基中添加咪唑直至濃度為5 mM。將改良之培養基以4-5 ml/min之流動速率泵送至在4℃下於含0.3 M NaCl及5 mM咪唑之20 mM Hepes(pH 7.4)緩衝液中平衡之6 ml Ni-NTA管柱上。裝載後,再用平衡緩衝液洗滌管柱,且用含0.25 M咪唑之平衡緩衝液溶離蛋白質。隨後將高度純化之蛋白質脫鹽於含10 mM Hepes,0.14 M NaCl及4%甘露糖醇之儲存緩衝液(pH 6.8)中及25 ml G25超細(Pharmacia)管柱中,且儲存於-80℃下。
如下自改良之培養基中純化免疫黏附素(含Fc)構築體。將改良之培養基泵送至已於20 mM磷酸鈉緩衝液(pH 6.8)中平衡之5 ml蛋白質A管柱(Pharmacia)上。裝載後,用平衡緩衝液澈底洗滌管柱,之後用100 mM檸檬酸(pH 3.5)溶離。立即藉由收集1 ml溶離份於含275 μL 1 M Tris緩衝液(pH 9)之管中來中和經溶離蛋白質。隨後將高度純化之蛋白質脫鹽於以上關於標記poly-His之蛋白質所述之儲存緩衝液中。利用SDS聚丙烯醯胺凝膠及利用埃德曼降解(Edman degradation)測定N末端胺基酸序列來評定均質性。實例 11 於大腸桿菌中表現抗 PD-L1 抗體
此實例說明藉由於大腸桿菌中重組表現製備未糖基化之形式之抗PD-L1抗體。
最初使用所選PCR引子擴增編碼抗PD-L1抗體之DNA序列。引子應含有對應於所選表現載體之限制酶位點的限制酶位點。可利用多種表現載體。適合之載體之實例為pBR322(衍生自大腸桿菌;參見Bolivar等人,Gene,2
:95 (1977)),其含有安比西林(ampicillin)及四環素(tetracycline)抗性基因。用限制酶消化載體,且脫去磷酸。接著使PCR擴增序列連接於載體中。載體較佳應包括編碼抗生素抗性基因、trp啟動子、polyhis前導序列(包括頭6個STII密碼子、polyhis序列及腸激酶裂解位點)、NPOR編碼區、λ轉錄終止子及argU基因的序列。
接著使用Sambrook等人,同上中所述之方法使用連接混合物使所選大腸桿菌菌株轉形。根據於LB板上生長之能力鑑別轉形體,且接著選擇抗生素抗性菌落。可分離質體DNA且藉由限制分析及DNA測序證實。
可使所選純系在諸如補充有抗生素之LB培養液之液體培養基中生長隔夜。隨後可使用隔夜培養物接種較大規模培養物。接著使細胞生長至所要光學密度,在此期間開啟表現啟動子。
再培養細胞若干小時後,可藉由離心收集細胞。可使用此項技術中已知之各種試劑溶解由離心獲得之細胞離心塊,且接著使用金屬螯合管柱在允許緊密結合抗體之條件下純化經溶解抗體。
亦可使用以下程序將抗PD-L1抗體以標記poly-His之形式表現於大腸桿菌中。最初使用所選PCR引子擴增DNA編碼抗體。引子含有對應於所選表現載體上之限制酶位點之限制酶位點,及提供有效且可靠之轉譯起始、在金屬螯合管柱上快速純化及用腸激酶蛋白水解移除的其他適用序列。接著使經PCR擴增之標記poly-His的序列連接於表現載體中,基於菌株52(W3110 fuhA(tonA) lon galE rpoHts (htpRts) clpP(lacIq))使用該表現載體使大腸桿菌宿主轉形。首先在30℃下在震盪下使轉形體在含有50 mg/ml卡本西林之LB中生長直至O.D.600達到3-5。接著在CRAP培養基(藉由混合3.57 g (NH4
)2
SO4
、0.71 g二水合檸檬酸鈉、1.07 g KCl、5.36 g Difco酵母提取物、於500 mL水中之5.36 g Sheffield hycase SF以及110 mM MPOS(pH 7.3)、0.55%(w/v)葡萄糖及7 mM MgSO4
製備)中稀釋培養物50-100倍,且使之在震盪下在30℃下生長約20-30小時。移除樣品以藉由SDS-PAGE分析驗證表現,且離心大量培養物使細胞形成離心塊。冷凍細胞離心塊直至純化及再摺疊(refolding)。
將來自0.5至1 L醱酵物之大腸桿菌糊狀物(6-10 g離心塊)再懸浮於10倍體積(w/v)之7 M胍、20 mM Tris(pH 8)緩衝液中。分別添加固體亞硫酸鈉及四硫磺酸鈉以使得最終濃度為0.1 M及0.02 M,且在4℃下攪拌溶液隔夜。此步驟產生所有半胱胺酸殘基均經亞硫酸鹽化(sulfitolization)阻斷之變性蛋白質。在40,000 rpm下於Beckman Ultracentifuge中離心溶液30分鐘。用3-5倍體積之金屬螯合管柱緩衝液(6 M胍、20 mM Tris,pH 7.4)稀釋上清液,且經由0.22微米過濾器過濾使之澄清。視條件而定,將經澄清萃取物裝載於以金屬螯合管柱緩衝液平衡之5 ml Qiagen Ni-NTA金屬螯合管柱上。再用含50 mM咪唑緩衝液(Calbiochem, Utrol grade)(pH 7.4)洗滌管柱。用含250 mM咪唑緩衝液溶離蛋白質。彙集含所要蛋白質之溶離份且儲存於4℃下。基於蛋白質之胺基酸序列使用所計算之消光係數由其280 nm下之吸光度估算蛋白質濃度。
藉由於新近製備之再摺疊緩衝液中緩慢稀釋樣品使蛋白質再摺疊,該再摺疊緩衝液由20 mM Tris(pH 8.6)、0.3 M NaCl、2.5 M尿素、5 mM半胱胺酸、20 mM甘胺酸及1 mM EDTA組成。選擇再摺疊體積以便最終蛋白質濃度介於50至100微克/毫升之間。在4℃下輕輕攪拌再摺疊溶液12-36小時。藉由添加TFA至最終濃度為0.4%(pH值為約3)中止再摺疊反應。在進一步純化蛋白質之前,經由0.22微米過濾器過濾溶液,且添加乙腈至最終濃度為2-10%。在Poros R1/H逆相管柱上使用0.1% TFA之移動緩衝液以10%至80%之乙腈梯度溶離,層析分離再摺疊蛋白質。在SDS聚丙烯醯胺凝膠上分析具有A280吸光度之溶離份等分試樣,且彙集含均質再摺疊蛋白質之溶離份。一般而言,在最小濃度之乙腈下溶離大部分蛋白質之適當再摺疊物質,因為彼等物質之疏水性內部最緊實受到保護而不與逆相樹脂相互作用。通常在較高乙腈濃度下溶離聚集之物質。除自所要形式消除錯誤摺疊形式之蛋白質以外,逆相步驟亦自樣品中移除內毒素。
彙集含所要摺疊抗PD-L1抗體之溶離份,且使用對準溶液之輕柔氮氣流移除乙腈。藉由透析或藉由使用於調配緩衝液中平衡之G25超細(Pharmacia)樹脂之凝膠過濾將蛋白質調配於20 mM Hepes(pH 6.8)及0.14 M氯化鈉及4%甘露糖醇中且無菌過濾。
G(鳥嘌呤) | Y(C或T) | H(A或C或T) |
A(腺嘌呤) | M(A或C) | B(C或G或T) |
T(胸嘧啶) | K(G或T) | V(A或C或G) |
C(胞嘧啶) | S(C或G) | D(A或G或T) |
R(A或G) | W(A或T) | N(A或C或G或T) |
舉例而言,在密碼子組DVK中,D可為核苷酸A或G或T;V可為A或G或C;且K可為G或T。此密碼子組可提供18種不同密碼子且可編碼胺基酸Ala、Trp、Tyr、Lys、Thr、Asn、Lys、Ser、Arg、Asp、Glu、Gly及Cys。 |
原始殘基 | 例示性取代 | 較佳取代 |
Ala(A) | val;leu;ile | val |
Arg(R) | lys;gln;asn | lys |
Asn(N) | gln;his;asp;lys;arg | gln |
Asp(D) | glu;asn | glu |
Cys(C) | ser;ala | ser |
Gln(Q) | asn;glu | asn |
Glu(E) | asp;gln | asp |
Gly(G) | ala | ala |
His(H) | asn;gln;lys;arg | arg |
Ile(I) | leu;val;met;ala;phe;正白胺酸 | leu |
Leu(L) | 正白胺酸;ile;val;met;ala;phe | ile |
Lys(K) | arg;gln;asn | arg |
Met(M) | leu;phe;ile | leu |
Phe(F) | leu;val;ile;ala;tyr | tyr |
Pro(P) | Ala | ala |
Ser(S) | Thr | thr |
Thr(T) | Ser | ser |
Trp(W) | tyr;phe | tyr |
Tyr(Y) | trp;phe;thr;ser | phe |
Val(V) | ile;leu;met;phe;ala;正白胺酸 | leu |
純系 | 格式1 | 格式2 | 格式3 |
hPD1-Fc-生物素/hPDL1-293 IC50 (nM) | mPD1-Fc-生物素/mPDL1-293 IC50 (nM) | hPD1-Fc-生物素/mPDL1-293 IC50 (nM) | |
YW251.11 | 8.6 | ||
YW 243.1 | 0.234 | ||
YW243.55 | 0.099 | >100 | |
YW254.1 | >100 | 0.795 | |
YW254.2 | >100 | 3.76 | |
YW254.3 | >100 | >100 | |
YW254.4 | 1.73 | 15.6 | |
YW254.9 | >100 | 0.224 | |
YW254.33 | 2.2 | >100 | |
YW262.4 | 50 | 1.42 | |
YW262.5 | 90 | 25 | |
YW262.16 | 7.5 | 0.626 | |
YW262.64 | 0.256 | 100 | |
YW243.55.5 | 0.104 | 0.141 | |
YW243.55.8 | 0.061 | 0.063 | |
YW243.55.30 | 0.108 | 0.100 | |
YW243.55.34 | 0.084 | 0.049 | |
YW243.55.49 | 0.08 | 0.032 | |
YW243.55.51 | 0.078 | 0.031 | |
YW243.55.62 | 0.096 | 0.066 | |
YW243.55.84 | 0.124 | 0.051 | |
YW243.55.89 | 0.066 | 0.13 | |
YW243.55.H12 | 0.103 | 0.156 | |
YW243.55.H37 | 0.109 | 0.163 | |
YW243.55.H70 | 0.084 | 0.042 | |
YW243.55.S1 | 0.114 | 0.074 | |
YW243.55.S37 | 0.100 | 0.024 | |
YW243.55.S70 | 0.049 | 0.022 |
純系 | 固定之rhPD-L1 Fc | 固定之rmPD-L1 Fc | ||||
kon /(1/Ms) | koff /(1/s) | kD(M) | kon /(1/Ms) | koff /(1/s) | kD(M) | |
YW243.55(Fab) | 5.80×105 | 7.30×10-3 | 1.26×10-8 | -- | -- | >1×10-6 |
YW243.55(IgG) | 2.70×105 | 2.60×10-4 | 9.63×10-10 | 5.80×104 | 9.20×10-3 | 1.59×10-7 |
YW243.55.S70(Fab) | 5.30×105 | 1.00×10-4 | 1.89×10-10 | 4.80×105 | 1.40×10-3 | 2.92×10-9 |
YW243.55.S70(IgG) | 3.90×105 | 6.30×10-5 | 1.62×10-10 | 2.80×105 | 1.80×10-4 | 6.43×10-10 |
物種 | FACS之EC50 (nm) | 平衡放射性配位體結合之Kd(nM) |
人類 | 0.4 | 0.4 |
恆河猴 | 0.3 | |
小鼠 | 0.3 | 0.13 |
大鼠 | 0.8 |
抗體 | 格式4 | 格式5 | 格式6 | 格式7 |
hB7.1-生物素/hPD-L1 IC50 (pM) | hPD-1-生物素/hPD-L1 IC50 (pM) | mB7.1-生物素/mPD-L1 IC50 (pM) | mPD-1-生物素/mPD-L1 IC50 (pM) | |
YW243.55.S70 | 38 | 42 | 29 | 48 |
圖1為描繪由B7家族細胞表面分子協同刺激T細胞之圖解說明;
圖2為展示PMEL/B16 T細胞刺激檢定之實驗設計之示意圖;
圖3為經由應答黑素細胞肽gp100增進PMEL CD8+ T細胞中之IFN-γ產生展示抗PD-L1抗體對抗原特異性T細胞功能之作用的條形圖。在抗PD-L1抗體存在下在刺激期間,產生IFN-γ之CD8+ T細胞之百分比與其IFN-γ產生含量均增加;
圖4為經由在經Ova脈衝之A20 B細胞/mPD-L1 APC二次刺激時抗PD-L1抗體YW243.55.S1增強Ova特異性CD4+ T細胞增殖展示抗PD-L1抗體對抗原特異性T細胞功能之作用的條形圖;
圖5為一系列FACS圖,其展示在混合淋巴細胞反應中,抗PD-L1抗體YW243.55S1增進人類CD8 T細胞增殖。亦報導如由CFSE強度之稀釋倍數所量測之增殖細胞的百分比;
圖6為用嵌合形式之抗PD-L1抗體YW243.55S70治療慢性LCMV之實驗設計的示意圖。箭頭表示用2×106
pfu 純系13 LCMV感染後14天開始的抗PD-L1之6次劑量之計時;
圖7A及圖7B為展示由抗PD-L1抗體YW243.55.S70活體內治療慢性LCMV感染後離體細胞中CD8效應功能增進之圖。由YW243.55.S70阻斷PD-L1增加CD8+
T細胞之去顆粒(如由表面CD107A之增加所量測)(圖7A)且應答LCMV肽gp33增加產生IFN-γ之細胞的百分比(圖7B)。用H2-Db gp33五聚物染色揭示gp33特異性細胞之出現率;
圖8A及圖8B展示用抗PD-L1抗體活體內治療後,慢性LCMV感染中血液及組織LCMV效價之降低。在圖8A中,分別在抗體治療之後第21天及第28天、一週及兩週分析各種指定組織之病毒效價。在圖8B中,在第0天、第7天、第14天、第21天及第28天分析血清病毒效價,其中第0天進行LCMV接種且第14天開始治療;
圖9A展示在治療性治療所建立之腫瘤(治療在第14天開始,此時腫瘤為250 mm3
)之後,MC38.Ova結腸癌腫瘤生長因施用抗PD-L1抗體而顯著減慢。圖9B為展示如流式細胞儀所量測之組織培養物中MC38.Ova細胞上之PD-L1表面表現含量的直方圖。MC38.Ova細胞不表現PD-L2;
圖10為展示C57BL/6小鼠中PD-L1阻斷治療單獨及與抗VEGF或吉西他濱組合時對MC38.Ova腫瘤生長之作用的圖;及
圖11A-圖11B分別為噬菌體呈現所鑑別之11種抗PD-L1抗體之重鏈及輕鏈可變區序列。陰影條展示具有各種定義之CDR,而方框區域展示HVR之範圍。
Claims (96)
- 一種經分離之重鏈可變區多肽,其包含HVR-H1、HVR-H2及HVR-H3序列,其中: (a) 該HVR-H1序列為GFTFSX1 SWIH (SEQ ID NO: 1); (b) 該HVR-H2序列為AWIX2 PYGGSX3 YYADSVKG (SEQ ID NO:2); (c) 該HVR-H3序列為RHWPGGFDY (SEQ ID NO: 3); 另外其中:X1 為D或G;X2 為S或L;X3 為T或S。
- 如請求項1之多肽,其中X1 為D;X2 為S;X3 為T。
- 如請求項1之多肽,其進一步包含根據下式並列(juxtaposed)於該等HVRs之間的可變區重鏈構架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4)。
- 如請求項3之多肽,其中該等構架序列係衍生自人類共同(consensus)構架序列。
- 如請求項4之多肽,其中該等構架序列為VH亞群III共同構架。
- 如請求項5之多肽,其中一或多個該等構架序列如下: HC-FR1為EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4); HC-FR2為WVRQAPGKGLEWV (SEQ ID NO:5); HC-FR3為RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO:6); HC-FR4為WGQGTLVTVSA (SEQ ID NO:7)。
- 如請求項1之經分離之重鏈多肽,其與包含HVR-L1、HVR-L2及HVR-L3之可變區輕鏈組合,其中: (a) 該HVR-L1序列為RASQX4 X5 X6 TX7 X8 A (SEQ ID NO:8); (b) 該HVR-L2序列為SASX9 LX10 S (SEQ ID NO: 9);及 (c) 該HVR-L3序列為QQX11 X12 X13 X14 PX15 T (SEQ ID NO:10); 另外其中:X4 為D或V;X5 為V或I;X6 為S或N;X7 為A或F;X8 為V或L;X9 為F或T;X10 為Y或A;X11 為Y、G、F或S;X12 為L、Y、F或W;X13 為Y、N、A、T、G、F或I;X14 為H、V、P、T或I;X15 為A、W、R、P或T。
- 如請求項7之多肽,其中X4 為D;X5 為V;X6 為S;X7 為A;X8 為V;X9 為F;X10 為Y;X11 為Y;X12 為L;X13 為Y;X14 為H;X15 為A。
- 如請求項7之多肽,其進一步包含根據下式並列於該等HVRs之間的可變區輕鏈構架序列:(LC-FR1)-(HVR-L1) -(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。
- 如請求項9之多肽,其中該等構架序列係衍生自人類共同構架序列。
- 如請求項10之多肽,其中該等構架序列為VLκI共同構架。
- 如請求項11之多肽,其中一或多個該等構架序列如下: LC-FR1為DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11); LC-FR2為WYQQKPGKAPKLLIY (SEQ ID NO:12); LC-FR3為GVPSRFSGSGSGTDFTLTISSLQPEDFATY YC (SEQ ID NO:13); LC-FR4為FGQGTKVEIKR (SEQ ID NO:14)。
- 一種經分離之抗PD-L1抗體或抗原結合片段,其包含重鏈及輕鏈可變區序列,其中: (a) 該重鏈包含HVR-H1、HVR-H2及HVR-H3,另外其中: (i) 該HVR-H1序列為GFTFSX1 SWIH(SEQ ID NO: 1); (ii) 該HVR-H2序列為AWIX2 PYGGSX3 YYADSVKG(SEQ ID NO:2); (iii) 該HVR-H3序列為RHWPGGFDY(SEQ ID NO:3);及 (b) 該輕鏈包含HVR-L1、HVR-L2及HVR-L3,另外其中: (iv) 該HVR-L1序列為RASQX4 X5 X6 TX7 X8 A(SEQ ID NO:8); (v) 該HVR-L2序列為SASX9 LX10 S(SEQ ID NO: 9); (vi) 該HVR-L3序列為QQX11 X12 X13 X14 PX15 T(SEQ ID NO:10); 其中:X1 為D或G;X2 為S或L;X3 為T或S;X4 可為D或V;X5 可為V或I;X6 可為S或N;X7 可為A或F;X8 可為V或L;X9 可為F或T;X10 可為Y或A;X11 可為Y、G、F或S;X12 可為L、Y、F或W;X13 可為Y、N、A、T、G、F或I;X14 可為H、V、P、T或I;X15 可為A、W、R、P或T。
- 如請求項13之抗體或抗體片段,其中X1 為D;X2 為S;X3 為T。
- 如請求項13之抗體或抗體片段,其中X4 =D,X5 =V,X6 =S,X7 =A且X8 =V,X9 =F且X10 =Y,X11 =Y,X12 =L,X13 =Y,X14 =H且X15 =A。
- 如請求項13之抗體或抗體片段,其中X1 =D,X2 =S且X3 =T,X4 =D,X5 =V,X6 =S,X7 =A且X8 =V,X9 =F且X10 =Y,X11 =Y,X12 =L,X13 =Y,X14 =H且X15 =A。
- 如請求項13至16中任一項之抗體或抗體片段,其進一步包含: (a) 根據下式並列於該等HVRs之間的可變區重鏈構架序列: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3) -(HVR-H3)-(HC-FR4),及 (b) 根據下式並列於該等HVRs之間的可變區輕鏈構架序列: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。
- 如請求項17之抗體或抗體片段,其中該等構架序列係衍生自人類共同構架序列。
- 如請求項18之抗體或抗體片段,其中該等可變區重鏈構架序列為VH亞群III共同構架。
- 如請求項19之抗體或抗體片段,其中一或多個該等構架序列如下: HC-FR1為EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4); HC-FR2為WVRQAPGKGLEWV (SEQ ID NO:5); HC-FR3為RFTISADTSKNTAYLQMNSLRAEDTAVYYC AR (SEQ ID NO:6); HC-FR4為WGQGTLVTVSA (SEQ ID NO:7)。
- 如請求項18之抗體或抗體片段,其中該等可變區輕鏈構架序列為VL κ I共同構架。
- 如請求項21之抗體或抗體片段,其中一或多個該等構架序列如下: LC-FR1為DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11); LC-FR2為WYQQKPGKAPKLLIY (SEQ ID NO:12); LC-FR3為GVPSRFSGSGSGTDFTLTISSLQPEDFATY YC (SEQ ID NO:13);及 LC-FR4為FGQGTKVEIKR (SEQ ID NO:14)。
- 如請求項18之抗體或抗體片段,其中: (a) 該等可變重鏈構架序列如下: (i) HC-FR1為EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4); (ii) HC-FR2為WVRQAPGKGLEWV (SEQ ID NO: 5); (iii) HC-FR3為RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO:6); (iv) HC-FR4為WGQGTLVTVSA (SEQ ID NO: 7); (b) 該等可變輕鏈構架序列如下: (i) LC-FR1為DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11); (ii) LC-FR2為WYQQKPGKAPKLLIY (SEQ ID NO: 12); LC-FR3為GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:13); (iv) LC-FR4為FGQGTKVEIKR (SEQ ID NO: 14)。
- 如請求項23之抗體或抗體片段,其進一步包含人類恆定區。
- 如請求項24之抗體或抗體片段,其中該恆定區係選自由IgG1、IgG2、IgG3及IgG4組成之群。
- 如請求項25之抗體或抗體片段,其中該恆定區為IgG1。
- 如請求項23之抗體或抗體片段,其進一步包含鼠類恆定區。
- 如請求項27之抗體或抗體片段,其中該恆定區係選自由IgG1、IgG2A、IgG2B及IgG3組成之群。
- 如請求項28之抗體或抗體片段,其中該恆定區為IgG2A。
- 如請求項25之抗體或抗體片段,其具有減小或最小效應功能。
- 如請求項30之抗體或抗體片段,其中該最小效應功能由無效應Fc突變(effector-less Fc mutation)產生。
- 如請求項31之抗體或抗體片段,其中該無效應Fc突變為N297A。
- 如請求項31之抗體或抗體片段,其中該無效應Fc突變為D265A/N297A。
- 如請求項30之抗體或抗體片段,其中該最小效應功能由非糖基化(aglycosylation)產生。
- 一種抗體或抗原結合片段,其包含重鏈及輕鏈可變區序列,其中: (a) 該重鏈包含HVR-H1、HVR-H2及HVR-H3,分別與GFTFSDSWIH(SEQ ID NO:15)、AWISPYGGSTYYA DSVKG(SEQ ID NO:16)及RHWPGGFDY(SEQ ID NO: 3)具有至少85%之總序列一致性,及 (b) 該輕鏈包含HVR-L1、HVR-L2及HVR-L3,分別與RASQDVSTAVA(SEQ ID NO:17)、SASFLYS(SEQ ID NO:18)及QQYLYHPAT(SEQ ID NO:19)具有至少85%之總序列一致性。
- 如請求項35之抗體或抗體片段,其中該序列一致性為至少90%。
- 如請求項36之抗體或抗體片段,其進一步包含: (a) 根據下式並列於該等HVRs之間的可變區重鏈(VH)構架序列: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),及 (b) 根據下式並列於該等HVRs之間的可變區輕鏈(VL)構架序列: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。
- 如請求項37之抗體或抗體片段,其進一步包含衍生自人類共同序列之VH及VL構架區。
- 如請求項38之抗體或抗體片段,其中該VH構架序列係衍生自Kabat亞群I、II或III序列。
- 如請求項39之抗體或抗體片段,其中該VH構架序列係衍生自Kabat亞群III共同構架序列。
- 如請求項40之抗體或抗體片段,其中該等VH構架序列如下: HC-FR1為EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:4); HC-FR2為WVRQAPGKGLEWV (SEQ ID NO:5); HC-FR3為RFTISADTSKNTAYLQMNSLRAEDTAVYYC AR (SEQ ID NO:6); HC-FR4為WGQGTLVTVSA (SEQ ID NO:7)。
- 如請求項38之抗體或抗體片段,其中該VL構架序列係衍生自Kabat κ I、II、III或IV亞群序列。
- 如請求項42之抗體或抗體片段,其中該該VL構架序列為Kabat κ I共同構架序列。
- 如請求項43之抗體或抗體片段,其中該等VL構架序列如下: LC-FR1為DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11); LC-FR2為WYQQKPGKAPKLLIY (SEQ ID NO:12); LC-FR3為GVPSRFSGSGSGTDFTLTISSLQPEDFATY YC (SEQ ID NO:13); LC-FR4為FGQGTKVEIKR (SEQ ID NO:14)。
- 一種經分離之抗PD-L1抗體或抗原結合片段,其包含重鏈及輕鏈可變區序列,其中: (a) 該重鏈序列與以下重鏈序列具有至少85%之序列一致性:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDS WIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(SEQ ID NO:20),及 (b) 該輕鏈序列與以下輕鏈序列具有至少85%之序列一致性:DIQMTQSPSSLSASVGDRVTITCRASQDVSTAV AWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO:21)。
- 如請求項45之抗體或抗原結合片段,其中該序列一致性為至少90%。
- 一種經分離之抗PD-L1抗體或抗原結合片段,其包含重鏈及輕鏈可變區序列,其中: (a)該重鏈包含以下序列:EVQLVESGGGLVQPGGSLRLS CAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(SEQ ID NO:20),及 (b)該輕鏈包含以下序列:DIQMTQSPSSLSASVGDRVTITC RASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO:21)。
- 一種組合物,其包含如請求項13至47中任一項之抗PD-L1抗體或抗原結合片段及至少一種醫藥學上可接受之載劑。
- 一種經分離之核酸,其編碼如請求項1至11中任一項之多肽。
- 一種經分離之核酸,其編碼抗PD-L1抗體或抗原結合片段之輕鏈或重鏈可變序列,其中: (a) 該重鏈進一步包含HVR-H1、HVR-H2及HVR-H3序列,分別與GFTFSDSWIH(SEQ ID NO:15)、AWISP YGGSTYYADSVKG(SEQ ID NO:16)及RHWPGGFDY(SEQ ID NO:3)具有至少85%之序列一致性,或 (b) 該輕鏈進一步包含HVR-L1、HVR-L2及HVR-L3序列,分別與RASQDVSTAVA(SEQ ID NO:17)、SASF LYS(SEQ ID NO:18)及QQYLYHPAT(SEQ ID NO: 19)具有至少85%之序列一致性。
- 如請求項50之核酸,其中序列一致性為90%。
- 如請求項50之核酸,其中該抗PD-L1抗體進一步包含衍生自人類共同序列之VL及VH構架區。
- 如請求項52之核酸,其中該VH序列係衍生自Kabat亞群I、II或III序列。
- 如請求項52之核酸,其中該VL序列係衍生自Kabat κ I、II、III或IV亞群序列。
- 如請求項50之核酸,其中該抗PD-L1抗體包含衍生自鼠類抗體之恆定區。
- 如請求項50之核酸,其中該抗PD-L1抗體包含衍生自人類抗體之恆定區。
- 如請求項56之核酸,其中該恆定區為IgG1。
- 如請求項57之核酸,其具有減小或最小效應功能。
- 如請求項58之核酸,其中該最小效應功能由無效應Fc突變產生。
- 如請求項59之核酸,其中該無效應Fc突變為N297A。
- 一種載體,其包含如請求項49至60中任一項之核酸。
- 一種宿主細胞,其包含如請求項61之載體。
- 如請求項62之宿主細胞,其為真核細胞。
- 如請求項63之宿主細胞,其為哺乳動物細胞。
- 如請求項64之宿主細胞,其為中國倉鼠卵巢(CHO)細胞。
- 如請求項62之宿主細胞,其為原核細胞。
- 如請求項66之宿主細胞,其為大腸桿菌(E. coli )。
- 一種製造抗PD-L1抗體之方法,該方法包含如請求項62至67中任一項之宿主細胞在適於表現編碼該抗PD-L1抗體或抗原結合片段之載體的條件下培養,及回收該抗體或片段。
- 一種製品,其包含如請求項48之組合物及至少一種BNCA分子。
- 一種製品,其包含如請求項48之組合物及至少一種化學治療劑。
- 如請求項70之製品,其中該化學治療劑為吉西他濱(gemcitabine)。
- 一種製品,其包含如請求項48之組合物及至少一種針對正協同刺激(positive costimulatory)分子之促效劑。
- 如請求項72之製品,其進一步包含BNCA拮抗劑。
- 一種製品,其包含如請求項48之組合物及至少一種抗生素。
- 如請求項74之製品,其中該抗生素為抗病毒劑。
- 如請求項75之製品,其中抗病毒劑為逆轉錄酶抑制劑。
- 如請求項76之製品,其中該逆轉錄酶抑制劑為聚合酶抑制劑。
- 如請求項75之製品,其中該抗病毒劑為蛋白酶抑制劑。
- 一種製品,其包含如請求項48之組合物及至少一種疫苗。
- 一種活體外增進T細胞功能之方法,該方法包含向功能障礙T細胞施用有效量之如請求項48之組合物。
- 一種如請求項48之組合物的用途,其用於製造供治療T細胞功能障礙病症之藥劑。
- 如請求項81之用途,其中該T細胞功能障礙病症為感染。
- 如請求項82之用途,其中該感染為慢性的。
- 如請求項81之用途,其中該T細胞功能障礙病症為腫瘤免疫。
- 如請求項83之用途,其中該慢性感染為持續性的。
- 如請求項83之用途,其中該慢性感染為潛伏性的。
- 如請求項83之用途,其中該慢性感染為緩慢的(slow)。
- 如請求項82之用途,其中該感染由選自由細菌、病毒、真菌及原蟲組成之群的病原體引起。
- 如請求項88之用途,其中該病原體為細菌且該藥劑與抗細菌劑組合使用。
- 如請求項88之用途,其中該病原體為病毒且該藥劑與抗病毒劑組合使用。
- 如請求項88之用途,其中該病原體為真菌且該藥劑與抗真菌劑組合使用。
- 如請求項88之用途,其中該病原體為原蟲且該藥劑與抗原蟲劑組合使用。
- 如請求項88之用途,其中該藥劑與疫苗組合使用。
- 如請求項84之用途,其中該藥劑與選自由以下組成之群的治療方案組合使用:輻射療法、化學療法、靶向療法、免疫療法、激素療法、血管生成抑制及舒減護理(palliative care)。
- 如請求項84之用途,其中該腫瘤免疫由選自由以下組成之群的癌症引起:乳癌、肺癌、結腸癌、卵巢癌、黑素瘤、膀胱癌、腎癌、肝癌、唾液腺癌、胃癌、神經膠質瘤、甲狀腺癌、胸腺癌、上皮癌、頭頸癌、胃癌及胰臟癌。
- 如請求項28之抗體或抗體片段,其具有減小或最小效應功能。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12109208P | 2008-12-09 | 2008-12-09 | |
US61/121,092 | 2008-12-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202206454A true TW202206454A (zh) | 2022-02-16 |
Family
ID=42097246
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW108135242A TWI729512B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
TW102134843A TWI605828B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
TW110115088A TW202206454A (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
TW105118618A TWI686405B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
TW098141907A TWI419705B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW108135242A TWI729512B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
TW102134843A TWI605828B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105118618A TWI686405B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
TW098141907A TWI419705B (zh) | 2008-12-09 | 2009-12-08 | 抗pd-l1抗體及其於增進t細胞功能之用途 |
Country Status (40)
Country | Link |
---|---|
US (11) | US8217149B2 (zh) |
EP (7) | EP3929216A1 (zh) |
JP (6) | JP5681638B2 (zh) |
KR (8) | KR20230070055A (zh) |
CN (4) | CN104479018B (zh) |
AR (2) | AR074563A1 (zh) |
AU (5) | AU2009333580B2 (zh) |
BR (1) | BRPI0917592B1 (zh) |
CA (2) | CA3120172A1 (zh) |
CL (1) | CL2011001382A1 (zh) |
CO (1) | CO6390023A2 (zh) |
CR (2) | CR20160570A (zh) |
CY (2) | CY1118943T1 (zh) |
DK (2) | DK2376535T3 (zh) |
EC (1) | ECSP11011115A (zh) |
ES (1) | ES2628095T3 (zh) |
FI (1) | FI4209510T3 (zh) |
FR (1) | FR17C1050I2 (zh) |
HK (3) | HK1163130A1 (zh) |
HR (1) | HRP20170908T1 (zh) |
HU (2) | HUE034832T2 (zh) |
IL (4) | IL213353A (zh) |
LT (3) | LT4209510T (zh) |
LU (1) | LUC00051I2 (zh) |
MA (1) | MA32948B1 (zh) |
MX (3) | MX356367B (zh) |
MY (1) | MY188826A (zh) |
NL (1) | NL300914I2 (zh) |
NO (1) | NO2018006I1 (zh) |
NZ (2) | NZ717213A (zh) |
PE (2) | PE20141722A1 (zh) |
PL (1) | PL2376535T3 (zh) |
PT (1) | PT2376535T (zh) |
RU (2) | RU2636023C2 (zh) |
SG (3) | SG196798A1 (zh) |
SI (1) | SI2376535T1 (zh) |
TW (5) | TWI729512B (zh) |
UA (1) | UA109108C2 (zh) |
WO (1) | WO2010077634A1 (zh) |
ZA (1) | ZA201102417B (zh) |
Families Citing this family (1491)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7030219B2 (en) | 2000-04-28 | 2006-04-18 | Johns Hopkins University | B7-DC, Dendritic cell co-stimulatory molecules |
EP2277532A1 (en) | 2002-09-11 | 2011-01-26 | Genentech, Inc. | Novel composition and methods for the treatment of immune related diseases |
ES2500921T3 (es) | 2003-04-29 | 2014-10-01 | Sarepta Therapeutics, Inc. | Composiciones para potenciar el transporte y la eficacia antisentido de análogos de ácidos nucleicos en células |
US8067571B2 (en) | 2005-07-13 | 2011-11-29 | Avi Biopharma, Inc. | Antibacterial antisense oligonucleotide and method |
US20100016215A1 (en) | 2007-06-29 | 2010-01-21 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
WO2009079592A2 (en) * | 2007-12-17 | 2009-06-25 | California Institute Of Technology | Modulating immune system development and function through microrna mir-146 |
ES2848323T3 (es) | 2008-01-31 | 2021-08-06 | Inst Nat Sante Rech Med | Anticuerpos contra CD39 humano y uso de los mismos para inhibir la actividad de las células T reguladoras |
WO2009114085A2 (en) | 2008-03-03 | 2009-09-17 | The University Of Miami | Allogeneic cancer cell-based immunotherapy |
CA3179151A1 (en) | 2008-04-09 | 2009-10-15 | Genentech, Inc. | Novel compositions and methods for the treatment of immune related diseases |
US9017660B2 (en) | 2009-11-11 | 2015-04-28 | Advaxis, Inc. | Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors |
JP5757863B2 (ja) | 2008-05-19 | 2015-08-05 | アドバクシス インコーポレイテッド | 異種抗原のための二重送達システム |
US9650639B2 (en) | 2008-05-19 | 2017-05-16 | Advaxis, Inc. | Dual delivery system for heterologous antigens |
PL2350129T3 (pl) | 2008-08-25 | 2015-12-31 | Amplimmune Inc | Kompozycje antagonistów PD-1 i sposoby stosowania |
US8268314B2 (en) | 2008-10-08 | 2012-09-18 | Hoffmann-La Roche Inc. | Bispecific anti-VEGF/anti-ANG-2 antibodies |
SG196798A1 (en) | 2008-12-09 | 2014-02-13 | Genentech Inc | Anti-pd-l1 antibodies and their use to enhance t-cell function |
WO2011041613A2 (en) | 2009-09-30 | 2011-04-07 | Memorial Sloan-Kettering Cancer Center | Combination immunotherapy for the treatment of cancer |
US8741591B2 (en) | 2009-10-09 | 2014-06-03 | The Research Foundation For The State University Of New York | pH-insensitive glucose indicator protein |
US10016617B2 (en) | 2009-11-11 | 2018-07-10 | The Trustees Of The University Of Pennsylvania | Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers |
CA2778714C (en) * | 2009-11-24 | 2018-02-27 | Medimmune Limited | Targeted binding agents against b7-h1 |
EP2504028A4 (en) * | 2009-11-24 | 2014-04-09 | Amplimmune Inc | SIMULTANEOUS INHIBITION OF PD-L1 / PD-L2 |
CN102791738B (zh) | 2009-12-10 | 2015-10-07 | 霍夫曼-拉罗奇有限公司 | 优先结合人csf1r胞外域4的抗体及其用途 |
JP5894538B2 (ja) * | 2010-02-04 | 2016-03-30 | ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア | 炎症性ヒトTh17細胞の増殖および機能を決定的に調節するICOS |
CA3090304A1 (en) * | 2010-05-13 | 2011-11-17 | Sarepta Therapeutics, Inc. | Antisense modulation of interleukins 17 and 23 signaling |
EP2575818A4 (en) | 2010-06-03 | 2013-11-06 | Pharmacyclics Inc | USE OF INHIBITORS OF BRUTON TYROSINE KINASE (BTK) |
US9226958B2 (en) | 2010-10-01 | 2016-01-05 | University Of Georgia Research Foundation, Inc. | Use of Listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals |
AR083847A1 (es) | 2010-11-15 | 2013-03-27 | Novartis Ag | Variantes de fc (fragmento constante) silenciosas de los anticuerpos anti-cd40 |
EP3332804A1 (en) | 2011-03-11 | 2018-06-13 | Advaxis, Inc. | Listeria-based adjuvants |
WO2012149540A1 (en) | 2011-04-28 | 2012-11-01 | The Broad Institute Inc | Inhibitors of histone deacetylase |
US9161948B2 (en) | 2011-05-05 | 2015-10-20 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
EP2709453B1 (en) * | 2011-05-16 | 2019-10-23 | Romark Laboratories, L.C. | Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections |
AU2016201747B2 (en) * | 2011-05-16 | 2017-06-01 | Romark Laboratories, L.C. | Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections |
EP2723380B1 (en) | 2011-06-24 | 2019-08-21 | Stephen D. Gillies | Light chain immunoglobulin fusion proteins and methods of use thereof |
CN107519486B (zh) * | 2011-06-24 | 2021-06-11 | 台北荣民总医院 | 于感染性与恶性疾病的治疗中提升免疫反应的方法 |
PL3409278T3 (pl) | 2011-07-21 | 2021-02-22 | Sumitomo Pharma Oncology, Inc. | Heterocykliczne inhibitory kinazy białkowej |
JP6238459B2 (ja) | 2011-08-01 | 2017-11-29 | ジェネンテック, インコーポレイテッド | Pd−1軸結合アンタゴニストとmek阻害剤を使用する癌の治療方法 |
PT2785375T (pt) * | 2011-11-28 | 2020-10-29 | Merck Patent Gmbh | Anticorpos anti-pd-l1 e usos destes |
WO2013102123A2 (en) * | 2011-12-28 | 2013-07-04 | Novelmed Therapeutics, Inc. | Aglycosylated human antibody and fusion protein and uses thereof |
EP2804619B1 (en) * | 2012-01-16 | 2021-10-13 | Atox Bio Ltd. | Reltecimod for treatment of bacterial infections |
CN104411327A (zh) | 2012-03-12 | 2015-03-11 | 阿德瓦希斯公司 | 李斯特菌疫苗治疗以后的抑制细胞功能抑制 |
US20140004131A1 (en) | 2012-05-04 | 2014-01-02 | Novartis Ag | Antibody formulation |
SG10201700698WA (en) | 2012-05-15 | 2017-02-27 | Bristol Myers Squibb Co | Cancer immunotherapy by disrupting pd-1/pd-l1 signaling |
ES2742379T3 (es) | 2012-05-31 | 2020-02-14 | Hoffmann La Roche | Procedimientos de tratamiento del cáncer usando antagonistas de unión al eje de PD-1 y antagonistas de VEGF |
EP2854843A4 (en) | 2012-05-31 | 2016-06-01 | Sorrento Therapeutics Inc | ANTIGEN BINDING PROTEINS THAT BIND PD-L1 |
BR112014030812B1 (pt) | 2012-06-13 | 2022-11-08 | Incyte Holdings Corporation | Compostos tricíclicos substituídos como inibidores de fgfr, seus usos, composição farmacêutica e método para inibir uma enzima fgfr |
AR091649A1 (es) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos |
CN104428315B (zh) | 2012-07-13 | 2017-09-29 | 罗氏格黎卡特股份公司 | 双特异性抗‑vegf/抗‑ang‑2抗体及其在治疗眼血管疾病中的应用 |
JP6575950B2 (ja) | 2012-07-24 | 2019-09-18 | ファーマサイクリックス エルエルシー | Bruton型チロシンキナーゼ(Btk)阻害剤に対する耐性を伴う変異 |
EP2877444B1 (en) | 2012-07-27 | 2020-09-02 | The Broad Institute, Inc. | Inhibitors of histone deacetylase |
WO2014028502A1 (en) * | 2012-08-13 | 2014-02-20 | ImmunGene Inc. | Engineered antibody-interferon fusion molecules for treatment of autoimmune diseases |
CN114984062A (zh) | 2012-08-30 | 2022-09-02 | 安姆根有限公司 | 使用单纯疱疹病毒和免疫检查点抑制剂治疗黑色素瘤的方法 |
RS56624B1 (sr) | 2012-10-02 | 2018-03-30 | Bristol Myers Squibb Co | Kombinacija anti-kir antitela i anti-pd-1 antitela u lečenju kancera |
AU2013337277B2 (en) | 2012-11-05 | 2018-03-08 | Foundation Medicine, Inc. | Novel NTRK1 fusion molecules and uses thereof |
WO2014083178A1 (en) * | 2012-11-30 | 2014-06-05 | F. Hoffmann-La Roche Ag | Identification of patients in need of pd-l1 inhibitor cotherapy |
CA2896797A1 (en) | 2013-01-11 | 2014-07-17 | Dingfu Biotarget Co., Ltd | Agents for treating tumours, use and method thereof |
EP2945652B1 (en) | 2013-01-18 | 2021-07-07 | Foundation Medicine, Inc. | Methods of treating cholangiocarcinoma |
EP2950814A4 (en) | 2013-01-31 | 2016-06-08 | Univ Jefferson | PD-L1 AND PD-L2 BASED FUSION PROTEINS AND USES THEREOF |
EP3626741A1 (en) | 2013-02-20 | 2020-03-25 | The Trustees Of The University Of Pennsylvania | Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor |
US9573988B2 (en) | 2013-02-20 | 2017-02-21 | Novartis Ag | Effective targeting of primary human leukemia using anti-CD123 chimeric antigen receptor engineered T cells |
LT2964638T (lt) | 2013-03-06 | 2017-12-27 | Astrazeneca Ab | Epidermio augimo faktoriaus receptoriaus aktyvinančių mutacijų formų chinazolino inhibitoriai |
AR095363A1 (es) * | 2013-03-15 | 2015-10-14 | Genentech Inc | Biomarcadores y métodos para el tratamiento de condiciones relacionadas con pd-1 y pd-l1 |
KR20230070054A (ko) | 2013-03-15 | 2023-05-19 | 제넨테크, 인크. | Pd-1 및 pd-l1 관련 상태를 치료하기 위한 바이오마커 및 방법 |
UY35468A (es) | 2013-03-16 | 2014-10-31 | Novartis Ag | Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19 |
AU2014251087B2 (en) | 2013-04-09 | 2019-05-02 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
MX2015014181A (es) | 2013-04-09 | 2016-05-24 | Boston Biomedical Inc | 2-acetilnafto [2,3-b]furano -4,9-diona para uso en el tratamiento del cáncer. |
SG10201708520YA (en) | 2013-04-19 | 2017-12-28 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
AR095882A1 (es) | 2013-04-22 | 2015-11-18 | Hoffmann La Roche | Terapia de combinación de anticuerpos contra csf-1r humano con un agonista de tlr9 |
WO2014195852A1 (en) | 2013-06-03 | 2014-12-11 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations of an anti-pd-l1 antibody and a mek inhibitor and/or a braf inhibitor |
EP3004877A4 (en) | 2013-06-06 | 2017-04-19 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for identification, assessment prevention, and treatment of cancer using pd-l1 isoforms |
CN103304638B (zh) * | 2013-07-08 | 2014-12-03 | 郑州大学 | 具有抗肿瘤活性的pd-l1亲和肽及其应用 |
US9873740B2 (en) * | 2013-07-16 | 2018-01-23 | Genentech, Inc. | Methods of treating cancer using PD-1 axis binding antagonists and TIGIT inhibitors |
CA2917858A1 (en) * | 2013-08-02 | 2015-02-05 | Aduro Biotech Holdings, Europe B.V. | Combining cd27 agonists and immune checkpoint inhibition for immune stimulation |
ES2760249T3 (es) * | 2013-08-08 | 2020-05-13 | Cytune Pharma | Composición farmacéutica combinada |
DK3030575T3 (en) | 2013-08-08 | 2018-10-22 | Cytune Pharma | IL-15 AND IL-15R-ALFA-SUSHI DOMAIN-BASED MODULOKINES |
RU2705795C2 (ru) | 2013-08-20 | 2019-11-12 | Мерк Шарп И Доум Корп. | Лечение рака комбинацией антагониста pd-1 и динациклиба |
AR097306A1 (es) | 2013-08-20 | 2016-03-02 | Merck Sharp & Dohme | Modulación de la inmunidad tumoral |
CA2922607C (en) | 2013-09-06 | 2022-08-30 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
PL3041468T3 (pl) | 2013-09-06 | 2018-12-31 | Aurigene Discovery Technologies Limited | Pierścieniowe związki peptydomimetyczne jako immunomodulatory |
EP3041828B1 (en) | 2013-09-06 | 2018-05-23 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
WO2015038538A1 (en) * | 2013-09-10 | 2015-03-19 | Medimmune, Llc | Compositions and methods for treating sepsis |
AR097584A1 (es) * | 2013-09-12 | 2016-03-23 | Hoffmann La Roche | Terapia de combinación de anticuerpos contra el csf-1r humano y anticuerpos contra el pd-l1 humano |
EP4130044A1 (en) | 2013-09-13 | 2023-02-08 | BeiGene Switzerland GmbH | Anti-pd1 antibodies and their use as therapeutics and diagnostics |
KR20240033088A (ko) | 2013-09-20 | 2024-03-12 | 브리스톨-마이어스 스큅 컴퍼니 | 종양을 치료하기 위한 항-lag-3 항체 및 항-pd-1 항체의 조합물 |
CA2925421C (en) | 2013-09-24 | 2023-08-29 | Medicenna Therapeutics, Inc. | Interleukin-2 fusion proteins and uses thereof |
EP3049442A4 (en) | 2013-09-26 | 2017-06-28 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
EP3626742A1 (en) | 2013-09-27 | 2020-03-25 | F. Hoffmann-La Roche AG | Anti-pdl1 antibody formulations |
CN104558177B (zh) * | 2013-10-25 | 2020-02-18 | 苏州思坦维生物技术股份有限公司 | 拮抗抑制程序性死亡受体pd-1与其配体结合的单克隆抗体及其编码序列与用途 |
CA2926856A1 (en) | 2013-10-25 | 2015-04-30 | Dana-Farber Cancer Institute, Inc. | Anti-pd-l1 monoclonal antibodies and fragments thereof |
WO2015066413A1 (en) | 2013-11-01 | 2015-05-07 | Novartis Ag | Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections |
BR112016010716A8 (pt) | 2013-11-13 | 2020-04-22 | Novartis Ag | dose de reforço imunológico, baixa, de um inibidor de mtor, seu uso, e adjuvante de vacina |
EP3071697B1 (en) | 2013-11-22 | 2019-10-16 | DNAtrix, Inc. | Adenovirus expressing immune cell stimulatory receptor agonist(s) |
WO2015088930A1 (en) | 2013-12-10 | 2015-06-18 | Merck Sharp & Dohme Corp. | Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue |
WO2015094992A1 (en) | 2013-12-17 | 2015-06-25 | Merck Sharp & Dohme Corp. | Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists |
DE202014010499U1 (de) | 2013-12-17 | 2015-10-20 | Kymab Limited | Targeting von humaner PCSK9 zur Cholesterinbehandlung |
US20150210772A1 (en) | 2013-12-17 | 2015-07-30 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody |
CN105934253A (zh) * | 2013-12-17 | 2016-09-07 | 豪夫迈·罗氏有限公司 | 使用pd-1轴结合拮抗剂和抗her2抗体治疗her2阳性癌症的方法 |
AU2014364606A1 (en) * | 2013-12-17 | 2016-07-07 | Genentech, Inc. | Combination therapy comprising OX40 binding agonists and PD-1 axis binding antagonists |
US10689432B2 (en) | 2013-12-18 | 2020-06-23 | Albert Einstein College Of Medicine | B7X and its derivatives for treating and preventing cardiovascular disease |
WO2015090230A1 (en) | 2013-12-19 | 2015-06-25 | Novartis Ag | Human mesothelin chimeric antigen receptors and uses thereof |
US10023636B2 (en) | 2013-12-20 | 2018-07-17 | Intervet Inc. | Caninized murine antibodies to human PD-1 |
EP3087071B1 (en) | 2013-12-24 | 2018-09-05 | Bristol-Myers Squibb Company | Tricyclic compounds as anticancer agents |
CA3193936A1 (en) * | 2014-01-15 | 2015-07-23 | Kadmon Corporation, Llc | Immunomodulatory agents |
JO3517B1 (ar) | 2014-01-17 | 2020-07-05 | Novartis Ag | ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2 |
TWI681969B (zh) | 2014-01-23 | 2020-01-11 | 美商再生元醫藥公司 | 針對pd-1的人類抗體 |
TWI680138B (zh) | 2014-01-23 | 2019-12-21 | 美商再生元醫藥公司 | 抗pd-l1之人類抗體 |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
JOP20200096A1 (ar) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | جزيئات جسم مضاد لـ tim-3 واستخداماتها |
RU2744880C1 (ru) | 2014-02-04 | 2021-03-16 | Инсайт Корпорейшн | Комбинация антагониста pd-1 и ингибитора ido1 для лечения рака |
AU2015214390B2 (en) | 2014-02-04 | 2020-05-07 | Merck Sharp & Dohme LLC. | Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer |
EP3686219A1 (en) | 2014-02-04 | 2020-07-29 | Pfizer Inc | Combination of a pd-1 antagonist and a 4-1bb agonist for treating cancer |
CA2934979A1 (en) | 2014-02-10 | 2015-08-13 | Merck Patent Gmbh | Targeted tgf.beta. inhibition |
WO2015131176A1 (en) * | 2014-02-28 | 2015-09-03 | Podack Eckhard R | Compositions, methods, and kits for treatment of cancer |
EP2915569A1 (en) | 2014-03-03 | 2015-09-09 | Cytune Pharma | IL-15/IL-15Ralpha based conjugates purification method |
GB201403775D0 (en) | 2014-03-04 | 2014-04-16 | Kymab Ltd | Antibodies, uses & methods |
EP3114144A1 (en) | 2014-03-05 | 2017-01-11 | Bristol-Myers Squibb Company | Treatment of renal cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent |
US10519237B2 (en) | 2014-03-12 | 2019-12-31 | Yeda Research And Development Co. Ltd | Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS |
CN108025068A (zh) * | 2014-03-12 | 2018-05-11 | 耶达研究与开发有限公司 | 降低系统性调节性t细胞水平或活性来治疗cns的疾病和损伤 |
US10618963B2 (en) | 2014-03-12 | 2020-04-14 | Yeda Research And Development Co. Ltd | Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS |
LT3116909T (lt) | 2014-03-14 | 2020-02-10 | Novartis Ag | Antikūno molekulės prieš lag-3 ir jų panaudojimas |
EP3119423B1 (en) | 2014-03-15 | 2022-12-14 | Novartis AG | Treatment of cancer using chimeric antigen receptor |
AP2016009374A0 (en) | 2014-03-24 | 2016-08-31 | Novartis Ag | Monobactam organic compounds for the treatment of bacterial infections |
SG11201607969XA (en) | 2014-03-31 | 2016-10-28 | Genentech Inc | Anti-ox40 antibodies and methods of use |
BR112016022345A2 (pt) | 2014-03-31 | 2017-10-10 | Genentech Inc | terapia de combinação compreendendo agentes antiangiogênese e agonistas de ligação de ox40 |
IL280215B (en) | 2014-04-07 | 2022-07-01 | Novartis Ag | Cancer treatment using a chimeric receptor antigen (car) against cd19 |
US20150307620A1 (en) * | 2014-04-16 | 2015-10-29 | University Of Connecticut | Linked immunotherapeutic agonists that costimulate multiple pathways |
CA2946398A1 (en) | 2014-04-24 | 2015-10-29 | The Board Of Trustees Of The Leland Stanford Junior University | Superagonists, partial agonists and antagonists of interleukin-2 |
CN103936835B (zh) * | 2014-04-29 | 2016-03-30 | 郑州大学 | 具有抗肿瘤活性的靶向PD-L1IgV亲和肽D1 |
CN103936836B (zh) * | 2014-04-29 | 2016-03-30 | 郑州大学 | 具有抗肿瘤活性的靶向PD-L1IgV亲和肽D2 |
CA2949121A1 (en) | 2014-05-15 | 2015-11-19 | Bristol-Myers Squibb Company | Treatment of lung cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent |
US20170182003A1 (en) | 2014-05-23 | 2017-06-29 | Eisai R&D Management Co., Ltd. | Combination therapies for the treatment of cancer |
JP2017516779A (ja) | 2014-05-28 | 2017-06-22 | アイデニクス・ファーマシューティカルズ・エルエルシー | 癌治療のためのヌクレオシド誘導体 |
MA40041B1 (fr) | 2014-05-28 | 2021-03-31 | Memorial Sloan Kettering Cancer Center | Anticorps anti-gitr et leurs procédés d'utilisation |
JP6666905B2 (ja) | 2014-05-29 | 2020-03-18 | スプリング バイオサイエンス コーポレーション | Pd−l1抗体及びその使用 |
JP2017525753A (ja) | 2014-06-06 | 2017-09-07 | フレクサス・バイオサイエンシーズ・インコーポレイテッドFlexus Biosciences, Inc. | 免疫調節剤 |
MX2016015456A (es) | 2014-06-06 | 2017-02-23 | Bristol Myers Squibb Co | Anticuerpos contra el receptor del factor de necrosis tumoral inducido por glucocorticoides (gitr) y sus usos. |
CA2951278A1 (en) | 2014-06-19 | 2015-12-23 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized programmed cell death 1 gene |
CN104098651B (zh) * | 2014-06-30 | 2016-06-29 | 郑州大学 | 具有抗肿瘤活性的PD-L1 IgV亲和肽及其应用 |
KR102130600B1 (ko) * | 2014-07-03 | 2020-07-08 | 베이진 엘티디 | Pd-l1 항체와 이를 이용한 치료 및 진단 |
CA2954868C (en) * | 2014-07-11 | 2023-08-29 | Genentech, Inc. | Anti-pd-l1 antibodies and diagnostic uses thereof |
RU2733735C2 (ru) | 2014-07-15 | 2020-10-06 | Дженентек, Инк. | Композиции для лечения рака с применением антагонистов, связывающихся с компонентом сигнального пути pd-1, и ингибиторов mek |
CN106999561A (zh) | 2014-07-18 | 2017-08-01 | 阿德瓦希斯股份有限公司 | 用于治疗前列腺癌的pd‑1拮抗剂和基于李斯特菌的疫苗的组合 |
EP3172237A2 (en) | 2014-07-21 | 2017-05-31 | Novartis AG | Treatment of cancer using humanized anti-bcma chimeric antigen receptor |
EP3193915A1 (en) | 2014-07-21 | 2017-07-26 | Novartis AG | Combinations of low, immune enhancing. doses of mtor inhibitors and cars |
ES2805475T3 (es) | 2014-07-21 | 2021-02-12 | Novartis Ag | Tratamiento del cáncer utilizando un receptor antigénico quimérico de CD33 |
WO2016014553A1 (en) | 2014-07-21 | 2016-01-28 | Novartis Ag | Sortase synthesized chimeric antigen receptors |
WO2016014688A2 (en) | 2014-07-22 | 2016-01-28 | Junzhuan Qiu | Anti-pd-1 antibodies |
EP3660042B1 (en) | 2014-07-31 | 2023-01-11 | Novartis AG | Subset-optimized chimeric antigen receptor-containing t-cells |
JP6909153B2 (ja) | 2014-08-05 | 2021-07-28 | アポロミクス インコーポレイテッド | 抗pd−l1抗体 |
EP3177593A1 (en) | 2014-08-06 | 2017-06-14 | Novartis AG | Quinolone derivatives as antibacterials |
DK3179992T3 (da) | 2014-08-11 | 2022-07-11 | Acerta Pharma Bv | Terapeutisk kombination af en btk-inhibitor, en pd-1-inhibitor og/eller en pd-l1-inhibitor |
AU2015301460B2 (en) | 2014-08-14 | 2021-04-08 | Novartis Ag | Treatment of cancer using GFR alpha-4 chimeric antigen receptor |
EP3070102A1 (en) | 2015-03-18 | 2016-09-21 | F. Hoffmann-La Roche AG | Combination therapy of antibodies human cd40 activating antibodies and anti human pld-1 antibodies |
AU2015303239A1 (en) * | 2014-08-14 | 2016-12-15 | F. Hoffmann-La Roche Ag | Combination therapy of antibodies activating human CD40 and antibodies against human PD-L1 |
EP3712171A1 (en) | 2014-08-19 | 2020-09-23 | Novartis AG | Treatment of cancer using a cd123 chimeric antigen receptor |
US10695426B2 (en) | 2014-08-25 | 2020-06-30 | Pfizer Inc. | Combination of a PD-1 antagonist and an ALK inhibitor for treating cancer |
WO2016033555A1 (en) | 2014-08-28 | 2016-03-03 | Halozyme, Inc. | Combination therapy with a hyaluronan-degrading enzyme and an immune checkpoint inhibitor |
EP3186284B1 (en) | 2014-08-28 | 2022-04-06 | BioAtla, Inc. | Conditionally active chimeric antigen receptors for modified t-cells |
DK3186283T3 (da) * | 2014-08-29 | 2020-03-02 | Hoffmann La Roche | Kombinationsbehandling med tumormålrettede IL-2- immuncytokinervarianter og antistoffer mod humant PD-L1 |
US9535074B2 (en) | 2014-09-08 | 2017-01-03 | Merck Sharp & Dohme Corp. | Immunoassay for soluble PD-L1 |
EP3659621A1 (en) | 2014-09-13 | 2020-06-03 | Novartis AG | Combination therapies for cancer |
DK3193931T3 (da) | 2014-09-16 | 2020-10-19 | Innate Pharma | Neutralisering af hæmmende veje i lymfocytter |
MX2017003645A (es) | 2014-09-17 | 2017-05-30 | Novartis Ag | Direccion de celulas citotoxicas con receptores quimericos para inmunoterapia adoptiva. |
AU2015320678B2 (en) | 2014-09-23 | 2021-07-22 | Genentech, Inc. | Method of using anti-CD79b immunoconjugates |
US20170209574A1 (en) | 2014-10-03 | 2017-07-27 | Novartis Ag | Combination therapies |
MA41044A (fr) | 2014-10-08 | 2017-08-15 | Novartis Ag | Compositions et procédés d'utilisation pour une réponse immunitaire accrue et traitement contre le cancer |
WO2016057705A1 (en) | 2014-10-08 | 2016-04-14 | Novartis Ag | Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof |
EP3736294A3 (en) | 2014-10-10 | 2021-02-17 | Innate Pharma | Cd73 blockade |
ES2908056T3 (es) | 2014-10-10 | 2022-04-27 | Idera Pharmaceuticals Inc | Tratamiento del cáncer por agonistas del TLR9 con inhibidores del punto de control |
KR102122463B1 (ko) | 2014-10-14 | 2020-06-15 | 할로자임, 아이엔씨 | 아데노신 디아미네이즈-2(ada2)의 조성물, 이의 변이체 및 이를 사용하는 방법 |
PE20171067A1 (es) | 2014-10-14 | 2017-07-24 | Novartis Ag | Moleculas de anticuerpo que se unen a pd-l1 y usos de las mismas |
JP6687612B2 (ja) | 2014-10-24 | 2020-04-22 | アストラゼネカ アクチボラグ | 組合せ |
GB201419084D0 (en) | 2014-10-27 | 2014-12-10 | Agency Science Tech & Res | Anti-PD-1 antibodies |
TWI711463B (zh) | 2014-10-29 | 2020-12-01 | 美商戊瑞治療有限公司 | 用於癌症之組合療法 |
WO2016070001A1 (en) * | 2014-10-31 | 2016-05-06 | Jounce Therapeutics, Inc. | Methods of treating conditions with antibodies that bind b7-h4 |
KR20170086540A (ko) | 2014-11-03 | 2017-07-26 | 제넨테크, 인크. | T 세포 면역 하위세트를 검출하기 위한 검정 및 그의 사용 방법 |
US20160160290A1 (en) | 2014-11-03 | 2016-06-09 | Genentech, Inc. | Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment |
JP7305300B2 (ja) | 2014-11-05 | 2023-07-10 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 併用免疫療法 |
UY36390A (es) | 2014-11-05 | 2016-06-01 | Flexus Biosciences Inc | Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen |
JP2017538678A (ja) | 2014-11-05 | 2017-12-28 | フレクサス・バイオサイエンシーズ・インコーポレイテッドFlexus Biosciences, Inc. | 免疫調節剤 |
AR102537A1 (es) | 2014-11-05 | 2017-03-08 | Flexus Biosciences Inc | Agentes inmunomoduladores |
US20190076452A1 (en) * | 2014-11-11 | 2019-03-14 | Medimmune Limited | Therapeutic combinations for treating neoplasia |
WO2016075670A1 (en) | 2014-11-14 | 2016-05-19 | Novartis Ag | Antibody drug conjugates |
CN106999583A (zh) * | 2014-11-17 | 2017-08-01 | 豪夫迈·罗氏有限公司 | 包含ox40结合激动剂和pd‑1轴结合拮抗剂的组合疗法 |
PT3220927T (pt) | 2014-11-20 | 2022-02-07 | Promega Corp | Sistemas e métodos para avaliar moduladores de pontos de verificação imunitária |
MX2017006610A (es) | 2014-11-20 | 2017-09-29 | Hoffmann La Roche | Terapia combinada de moleculas de union a antigeno biespecificas activadoras de celulas t y antagonistas de union de eje de pd-1. |
HUE050596T2 (hu) | 2014-11-21 | 2020-12-28 | Bristol Myers Squibb Co | Antitestek CD73 ellen és azok felhasználásai |
MX2017006323A (es) | 2014-11-21 | 2017-08-21 | Bristol Myers Squibb Co | Anticuerpos que comprenden regiones constantes pesadas modificadas. |
JP6771464B2 (ja) | 2014-11-27 | 2020-10-21 | ジェネンテック, インコーポレイテッド | Cbpおよび/またはep300インヒビターとしての、4,5,6,7−テトラヒドロ−1h−ピラゾロ[4,3−c]ピリジン−3−アミン化合物 |
WO2016090034A2 (en) | 2014-12-03 | 2016-06-09 | Novartis Ag | Methods for b cell preconditioning in car therapy |
US10442819B2 (en) | 2014-12-05 | 2019-10-15 | Merck Sharp & Dohme Corp. | Tricyclic compounds as inhibitors of mutant IDH enzymes |
US20160158360A1 (en) | 2014-12-05 | 2016-06-09 | Genentech, Inc. | Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists |
US10508108B2 (en) | 2014-12-05 | 2019-12-17 | Merck Sharp & Dohme Corp. | Tricyclic compounds as inhibitors of mutant IDH enzymes |
US10086000B2 (en) | 2014-12-05 | 2018-10-02 | Merck Sharp & Dohme Corp. | Tricyclic compounds as inhibitors of mutant IDH enzymes |
AU2015360736A1 (en) | 2014-12-09 | 2017-06-01 | Merck Sharp & Dohme Corp. | System and methods for deriving gene signature biomarkers of response to PD-1 antagonists |
CA2969803A1 (en) | 2014-12-16 | 2016-06-23 | Novartis Ag | Isoxazole hydroxamic acid compounds as lpxc inhibitors |
IL300202B2 (en) | 2014-12-18 | 2024-04-01 | Amgen Inc | Stable frozen formulation for herpes simplex virus |
US20170340733A1 (en) | 2014-12-19 | 2017-11-30 | Novartis Ag | Combination therapies |
WO2016100975A1 (en) | 2014-12-19 | 2016-06-23 | Massachsetts Institute Ot Technology | Molecular biomarkers for cancer immunotherapy |
AR103232A1 (es) | 2014-12-22 | 2017-04-26 | Bristol Myers Squibb Co | ANTAGONISTAS DE TGFbR |
BR112017013385A2 (pt) | 2014-12-23 | 2018-02-06 | Bristol-Myers Squibb Company | anticorpos para tigit |
GB201500319D0 (en) | 2015-01-09 | 2015-02-25 | Agency Science Tech & Res | Anti-PD-L1 antibodies |
US11161907B2 (en) | 2015-02-02 | 2021-11-02 | Novartis Ag | Car-expressing cells against multiple tumor antigens and uses thereof |
WO2016124558A1 (en) | 2015-02-03 | 2016-08-11 | Ventana Medical Systems, Inc. | Histochemical assay for evaluating expression of programmed death ligand 1 (pd-l1) |
US10983128B2 (en) | 2015-02-05 | 2021-04-20 | Bristol-Myers Squibb Company | CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy |
AU2016215175B2 (en) | 2015-02-06 | 2021-09-16 | Heat Biologics, Inc. | Vector co-expressing vaccine and costimulatory molecules |
WO2016128912A1 (en) | 2015-02-12 | 2016-08-18 | Acerta Pharma B.V. | Therapeutic combinations of a btk inhibitor, a pi3k inhibitor, a jak-2 inhibitor, a pd-1 inhibitor, and/or a pd-l1 inhibitor |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
AU2016219822B2 (en) | 2015-02-20 | 2020-07-09 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
EP4279087A3 (en) | 2015-02-26 | 2024-01-31 | Merck Patent GmbH | Pd-1 / pd-l1 inhibitors for the treatment of cancer |
MX371167B (es) | 2015-03-02 | 2020-01-21 | Rigel Pharmaceuticals Inc | Inhibidores de inhibidores del factor beta de crecimiento de transformacion (tgf-beta). |
WO2016141209A1 (en) | 2015-03-04 | 2016-09-09 | Merck Sharp & Dohme Corp. | Combination of a pd-1 antagonist and eribulin for treating cancer |
KR20170122809A (ko) | 2015-03-04 | 2017-11-06 | 머크 샤프 앤드 돔 코포레이션 | 암을 치료하기 위한 pd-1 길항제 및 vegfr/fgfr/ret 티로신 키나제 억제제의 조합 |
MX2017011374A (es) | 2015-03-06 | 2018-01-23 | Beyondspring Pharmaceuticals Inc | Método de tratamiento de cáncer asociado con una mutación de ras. |
MX2017011375A (es) | 2015-03-06 | 2018-01-23 | Beyondspring Pharmaceuticals Inc | Método para tratar un tumor cerebral. |
US20180044429A1 (en) | 2015-03-09 | 2018-02-15 | Celldex Therapeutics, Inc. | Cd27 agonists |
US10449211B2 (en) | 2015-03-10 | 2019-10-22 | Aduro Biotech, Inc. | Compositions and methods for activating “stimulator of interferon gene”—dependent signalling |
WO2016142833A1 (en) | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
IL292449B2 (en) | 2015-03-13 | 2024-02-01 | Cytomx Therapeutics Inc | Nucleic acids encoding antibodies against PDL1 and methods for their preparation |
EP3067062A1 (en) | 2015-03-13 | 2016-09-14 | Ipsen Pharma S.A.S. | Combination of tasquinimod or a pharmaceutically acceptable salt thereof and a pd1 and/or pdl1 inhibitor, for use as a medicament |
US20180133327A1 (en) | 2015-03-16 | 2018-05-17 | Amal Therapeutics Sa | Cell Penetrating Peptides and Complexes Comprising the Same |
KR20170128567A (ko) | 2015-03-23 | 2017-11-22 | 바이엘 파마 악티엔게젤샤프트 | 항-ceacam6 항체 및 그의 용도 |
KR102610592B1 (ko) * | 2015-03-30 | 2023-12-07 | 주식회사 에스티큐브 | 당화 pd-l1에 특이적인 항체 및 그의 사용 방법 |
WO2016161286A1 (en) | 2015-04-03 | 2016-10-06 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer |
ES2820768T3 (es) | 2015-04-03 | 2021-04-22 | Xoma Technology Ltd | Tratamiento del cáncer usando inhibidores de TGF-beta y PD-1 |
JP6955445B2 (ja) | 2015-04-07 | 2021-10-27 | ジェネンテック, インコーポレイテッド | アゴニスト性の活性を有する抗原結合複合体及びその使用方法 |
EP3280439A1 (en) * | 2015-04-07 | 2018-02-14 | INSERM - Institut National de la Santé et de la Recherche Médicale | Anti-pd-l1 immunotoxin for use in therapy |
TWI738646B (zh) | 2015-04-07 | 2021-09-11 | 日商賽多利克公司 | 醫藥組成物 |
EP3280795B1 (en) | 2015-04-07 | 2021-03-24 | Novartis AG | Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives |
WO2016162505A1 (en) | 2015-04-08 | 2016-10-13 | F-Star Biotechnology Limited | Her2 binding agent therapies |
BR112017021688A2 (pt) | 2015-04-17 | 2018-08-14 | Bristol-Myers Squibb Company | composições compreendendo uma combinação de um anticorpo anti-pd-1 e outro anticorpo |
US20180094058A1 (en) * | 2015-04-17 | 2018-04-05 | Bioxcel Corporation | Compositions and methods for preventing tumor growth and treating cancer by targeting lectin galactoside-binding soluble 3 binding protein |
CN108473957A (zh) | 2015-04-17 | 2018-08-31 | 诺华股份有限公司 | 改善嵌合抗原受体表达细胞的功效和扩增的方法 |
ES2844799T3 (es) | 2015-04-17 | 2021-07-22 | Merck Sharp & Dohme | Biomarcadores sanguíneos de sensibilidad tumoral a antagonistas de PD-1 |
EP3286211A1 (en) | 2015-04-23 | 2018-02-28 | Novartis AG | Treatment of cancer using chimeric antigen receptor and protein kinase a blocker |
CN107406502A (zh) * | 2015-04-23 | 2017-11-28 | 豪夫迈·罗氏有限公司 | 结合血管生成素2的抗体与结合编程性死亡配体1的抗体的组合疗法 |
US20160362489A1 (en) | 2015-04-28 | 2016-12-15 | Bristol-Myers Squibb Company | Treatment of PD-L1-Positive Melanoma Using an Anti-PD-1 Antibody |
US10174113B2 (en) | 2015-04-28 | 2019-01-08 | Bristol-Myers Squibb Company | Treatment of PD-L1-negative melanoma using an anti-PD-1 antibody and an anti-CTLA-4 antibody |
US10683290B2 (en) | 2015-05-11 | 2020-06-16 | Bristol-Myers Squibb Company | Tricyclic compounds as anticancer agents |
ES2770349T3 (es) | 2015-05-12 | 2020-07-01 | Bristol Myers Squibb Co | Compuestos de 5H-pirido[3,2-b]indol como agentes antineoplásicos |
US9725449B2 (en) | 2015-05-12 | 2017-08-08 | Bristol-Myers Squibb Company | Tricyclic compounds as anticancer agents |
WO2016183326A1 (en) | 2015-05-12 | 2016-11-17 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2016189055A1 (en) | 2015-05-27 | 2016-12-01 | Idenix Pharmaceuticals Llc | Nucleotides for the treatment of cancer |
US20180155429A1 (en) | 2015-05-28 | 2018-06-07 | Bristol-Myers Squibb Company | Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody |
KR20180013881A (ko) | 2015-05-29 | 2018-02-07 | 제넨테크, 인크. | 암에서의 pd-l1 프로모터 메틸화 |
MX2017015046A (es) | 2015-05-29 | 2018-05-17 | Agenus Inc | Anticuerpos anti-antigeno 4 del linfocito t citotoxico (ctla-4) y metodos para uso de los mismos. |
WO2016196298A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Therapeutic and diagnolstic methods for cancer |
US10751412B2 (en) | 2015-05-29 | 2020-08-25 | Merck Sharp & Dohme Corp. | Combination of a PD-1 antagonist and CPG-C type oligonucleotide for treating cancer |
LT3303396T (lt) | 2015-05-29 | 2023-01-10 | Bristol-Myers Squibb Company | Antikūnai prieš ox40 ir jų panaudojimo būdai |
WO2016196389A1 (en) | 2015-05-29 | 2016-12-08 | Bristol-Myers Squibb Company | Treatment of renal cell carcinoma |
JP2018521979A (ja) | 2015-06-03 | 2018-08-09 | ボストン バイオメディカル, インコーポレイテッド | 癌の治療に使用するための癌幹細胞性阻害剤および免疫療法剤を含む組成物 |
WO2016196897A1 (en) | 2015-06-04 | 2016-12-08 | Sarepta Therapeutics, Inc. | Methods and compounds for treatment of lymphocyte-related diseases and conditions |
WO2016200836A1 (en) | 2015-06-08 | 2016-12-15 | Genentech, Inc. | Methods of treating cancer using anti-ox40 antibodies |
AU2016274584A1 (en) | 2015-06-08 | 2018-01-04 | Genentech, Inc. | Methods of treating cancer using anti-OX40 antibodies and PD-1 axis binding antagonists |
JP6865177B2 (ja) | 2015-06-11 | 2021-04-28 | バイオノミクス リミテッド | 医薬組み合わせおよびその使用 |
WO2016201354A1 (en) * | 2015-06-11 | 2016-12-15 | Globavir Biosciences, Inc. | Methods and compositions for treating cancer |
US10696745B2 (en) | 2015-06-11 | 2020-06-30 | Wuxi Biologics (Shanghai) Co. Ltd. | Anti-PD-L1 antibodies |
EP3307778A1 (en) | 2015-06-12 | 2018-04-18 | Bristol-Myers Squibb Company | Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways |
MX2017016324A (es) * | 2015-06-16 | 2018-03-02 | Merck Patent Gmbh | Tratamientos de combinacion de antagonista de ligando 1 de muerte programada (pd-l1). |
JP6996983B2 (ja) * | 2015-06-16 | 2022-02-21 | ジェネンテック, インコーポレイテッド | 抗cll-1抗体及び使用方法 |
WO2016203432A1 (en) | 2015-06-17 | 2016-12-22 | Novartis Ag | Antibody drug conjugates |
JP6896650B2 (ja) | 2015-06-17 | 2021-06-30 | ジェネンテック, インコーポレイテッド | Pd−1軸結合アンタゴニスト及びタキサンを使用した局所進行性または転移性乳癌の治療方法 |
WO2016209936A1 (en) | 2015-06-22 | 2016-12-29 | Duke University | Synergistic nanotherapy systems and methods of use thereof |
MX2018000261A (es) | 2015-06-24 | 2018-03-08 | Janssen Biotech Inc | Modulacion y tratamiento inmunes de tumores solidos con anticuerpos que se unen especificamente a cd38. |
EP3108897A1 (en) | 2015-06-24 | 2016-12-28 | F. Hoffmann-La Roche AG | Antibodies against human csf-1r for use in inducing lymphocytosis in lymphomas or leukemias |
JP6892443B2 (ja) | 2015-06-24 | 2021-06-23 | イモデュロン セラピューティクス リミテッド | がん治療で使用するためのチェックポイント阻害剤及び全細胞マイコバクテリウム |
AU2016285920A1 (en) | 2015-06-29 | 2018-02-01 | Bristol-Myers Squibb Company | Antibodies to CD40 with enhanced agonist activity |
EA201890199A1 (ru) | 2015-07-02 | 2018-06-29 | Селджин Корпорейшн | Комбинированная терапия для лечения гемобластозов и солидных опухолей |
GB201511790D0 (en) | 2015-07-06 | 2015-08-19 | Iomet Pharma Ltd | Pharmaceutical compound |
CA2991059C (en) | 2015-07-13 | 2024-01-16 | Beyondspring Pharmaceuticals, Inc. | Plinabulin monohydrate polymorphs |
EP3322731B1 (en) | 2015-07-14 | 2021-01-13 | Bristol-Myers Squibb Company | Method of treating cancer using immune checkpoint inhibitor; antibody that binds to programmed death-1 receptor (pd-1) or programmed death ligand 1 (pd-l1) |
CA2991628C (en) | 2015-07-16 | 2020-04-07 | Bioxcel Therapeutics, Inc. | A novel approach for treatment of cancer using immunomodulation |
KR20210089270A (ko) | 2015-07-16 | 2021-07-15 | 바이오카인 테라퓨틱스 리미티드 | 암 치료용 조성물 및 방법 |
AR105433A1 (es) | 2015-07-21 | 2017-10-04 | Novartis Ag | Métodos para mejorar la eficacia y expansión de las células inmunes |
RU2018106515A (ru) | 2015-07-21 | 2019-08-21 | Зе Чилдрен'С Медикал Сентер Корпорейшн | Pd-l1-экспрессирующие гемопоэтические стволовые клетки и применения |
KR20180034548A (ko) | 2015-07-28 | 2018-04-04 | 브리스톨-마이어스 스큅 컴퍼니 | Tgf 베타 수용체 길항제 |
EP3328407A1 (en) | 2015-07-29 | 2018-06-06 | Novartis AG | Combination of pd-1 antagonist with an egfr inhibitor |
WO2017019897A1 (en) | 2015-07-29 | 2017-02-02 | Novartis Ag | Combination therapies comprising antibody molecules to tim-3 |
ES2878188T3 (es) | 2015-07-29 | 2021-11-18 | Novartis Ag | Terapias de combinación que comprenden moléculas de anticuerpos contra LAG-3 |
CN106397592A (zh) * | 2015-07-31 | 2017-02-15 | 苏州康宁杰瑞生物科技有限公司 | 针对程序性死亡配体(pd-l1)的单域抗体及其衍生蛋白 |
WO2017020291A1 (en) * | 2015-08-06 | 2017-02-09 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
CN106432494B9 (zh) * | 2015-08-11 | 2022-02-15 | 广州誉衡生物科技有限公司 | 新型抗-pd-1抗体 |
MX2018001644A (es) | 2015-08-11 | 2018-11-09 | Wuxi Biologics Cayman Inc | Anticuerpos anti-pd-1 novedosos. |
UA123701C2 (uk) | 2015-08-13 | 2021-05-19 | Мерк Шарп І Доум Корп. | Циклічні динуклеотидні сполуки як агоністи sting |
US11453697B1 (en) | 2015-08-13 | 2022-09-27 | Merck Sharp & Dohme Llc | Cyclic di-nucleotide compounds as sting agonists |
AR105654A1 (es) | 2015-08-24 | 2017-10-25 | Lilly Co Eli | Anticuerpos pd-l1 (ligando 1 de muerte celular programada) |
US20180250303A1 (en) | 2015-08-25 | 2018-09-06 | Bristol-Myers Squibb Company | Tgf beta receptor antagonists |
ES2955775T3 (es) | 2015-08-27 | 2023-12-07 | Inst Nat Sante Rech Med | Métodos para predecir el tiempo de supervivencia de pacientes que padecen cáncer de pulmón |
EP3344996A2 (en) | 2015-09-03 | 2018-07-11 | The Trustees Of The University Of Pennsylvania | Biomarkers predictive of cytokine release syndrome |
CN108348571B (zh) | 2015-09-03 | 2022-03-22 | 艾瑞朗医疗公司 | 拟肽大环化合物及其用途 |
MA44909A (fr) | 2015-09-15 | 2018-07-25 | Acerta Pharma Bv | Association thérapeutique d'un inhibiteur du cd19 et d'un inhibiteur de la btk |
BR112018005862A2 (pt) | 2015-09-25 | 2018-10-16 | Genentech, Inc. | anticorpos, anticorpos isolados, polinucleotídeo, vetor, célula hospedeira, método de produção do anticorpo, imunoconjugado, composição, usos dos anticorpos, métodos para tratar ou retardar a progressão de um câncer e de uma doença e para aumentar, potencializar ou estimular uma resposta ou função imune e kit |
WO2017055326A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2017055484A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining the metabolic status of lymphomas |
WO2017055320A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cytotoxic lymphocytes in a tissue sample |
WO2017055325A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of nk cells in a tissue sample |
WO2017055327A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of endothelial cells in a tissue sample |
WO2017055324A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cells of monocytic origin in a tissue sample |
WO2017055321A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of fibroblasts in a tissue sample |
WO2017055322A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of neutrophils in a tissue sample |
WO2017055319A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of b cells in a tissue sample |
JP2018529719A (ja) | 2015-09-30 | 2018-10-11 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Alk陰性がんを処置するためのpd−1系結合アンタゴニストおよびalk阻害剤の組合せ |
ES2900482T3 (es) | 2015-10-01 | 2022-03-17 | Gilead Sciences Inc | Combinación de un inhibidor de Btk y un inhibidor de punto de control para el tratamiento del cáncer |
CR20180163A (es) | 2015-10-02 | 2018-05-25 | Hoffmann La Roche | Anticuerpos biespecíficos específicos para un receptor de tnf coestimulador |
WO2017060397A1 (en) | 2015-10-09 | 2017-04-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of subjects suffering from melanoma metastases |
CN106565836B (zh) * | 2015-10-10 | 2020-08-18 | 中国科学院广州生物医药与健康研究院 | 高亲和力的可溶性pdl-1分子 |
EP3362475B1 (en) | 2015-10-12 | 2023-08-30 | Innate Pharma | Cd73 blocking agents |
CN108135934A (zh) | 2015-10-19 | 2018-06-08 | 永恒生物科技股份有限公司 | 通过组合疗法治疗实体或淋巴肿瘤的方法 |
US10149887B2 (en) | 2015-10-23 | 2018-12-11 | Canbas Co., Ltd. | Peptides and peptidomimetics in combination with t cell activating and/or checkpoint inhibiting agents for cancer treatment |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
MA43186B1 (fr) | 2015-11-03 | 2022-03-31 | Janssen Biotech Inc | Anticorps se liant spécifiquement à pd-1 et leurs utilisations |
WO2017077382A1 (en) | 2015-11-06 | 2017-05-11 | Orionis Biosciences Nv | Bi-functional chimeric proteins and uses thereof |
WO2017087280A1 (en) | 2015-11-16 | 2017-05-26 | Genentech, Inc. | Methods of treating her2-positive cancer |
CN107614529B (zh) * | 2015-11-17 | 2019-11-12 | 苏州盛迪亚生物医药有限公司 | Pd-l1抗体、其抗原结合片段及其医药用途 |
JP2018538263A (ja) | 2015-11-18 | 2018-12-27 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 抗pd−1抗体および抗ctla−4抗体の組合せを用いる肺癌の処置法 |
KR20180081591A (ko) | 2015-11-19 | 2018-07-16 | 제넨테크, 인크. | B-raf 억제제 및 면역 체크포인트 억제제를 사용하여 암을 치료하는 방법 |
JP6983776B2 (ja) | 2015-11-19 | 2021-12-17 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | グルココルチコイド誘発腫瘍壊死因子受容体(gitr)に対する抗体およびその使用 |
MX2018006477A (es) | 2015-12-02 | 2018-09-03 | Agenus Inc | Anticuerpos y metodos de uso de estos. |
EP3366691A1 (en) | 2015-12-03 | 2018-08-29 | GlaxoSmithKline Intellectual Property Development Limited | Cyclic purine dinucleotides as modulators of sting |
RS61029B1 (sr) * | 2015-12-07 | 2020-12-31 | Merck Patent Gmbh | Vodena formulacija koja sadrži avelumab antitelo na pd-1 |
WO2017098421A1 (en) | 2015-12-08 | 2017-06-15 | Glaxosmithkline Intellectual Property Development Limited | Benzothiadiazine compounds |
EP3178848A1 (en) | 2015-12-09 | 2017-06-14 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody for reducing formation of anti-drug antibodies |
KR20180085740A (ko) | 2015-12-09 | 2018-07-27 | 에프. 호프만-라 로슈 아게 | 항-약물 항체의 형성을 감소시키기 위한 ii형 항-cd20 항체 |
CN108602829A (zh) | 2015-12-15 | 2018-09-28 | 百时美施贵宝公司 | Cxcr4受体拮抗剂 |
WO2017106062A1 (en) | 2015-12-15 | 2017-06-22 | Merck Sharp & Dohme Corp. | Novel compounds as indoleamine 2,3-dioxygenase inhibitors |
MX2018007423A (es) | 2015-12-17 | 2018-11-09 | Novartis Ag | Moleculas de anticuerpo que se unen a pd-1 y usos de las mismas. |
GB201522311D0 (en) | 2015-12-17 | 2016-02-03 | Photocure Asa | Use |
GB201522309D0 (en) | 2015-12-17 | 2016-02-03 | Photocure Asa | Use |
CN109069623A (zh) | 2015-12-18 | 2018-12-21 | 诺华股份有限公司 | 靶向CD32b的抗体及其使用方法 |
WO2017106630A1 (en) | 2015-12-18 | 2017-06-22 | The General Hospital Corporation | Polyacetal polymers, conjugates, particles and uses thereof |
UA126113C2 (uk) | 2015-12-22 | 2022-08-17 | Інсайт Корпорейшн | Гетероциклічні сполуки як імуномодулятори |
US11413340B2 (en) | 2015-12-22 | 2022-08-16 | Novartis Ag | Mesothelin chimeric antigen receptor (CAR) and antibody against PD-L1 inhibitor for combined use in anticancer therapy |
EP4039699A1 (en) | 2015-12-23 | 2022-08-10 | ModernaTX, Inc. | Methods of using ox40 ligand encoding polynucleotides |
CN106939047B (zh) * | 2016-01-04 | 2021-08-31 | 江苏怀瑜药业有限公司 | 一种pd-l1抗体及其制备方法 |
US20200264165A1 (en) | 2016-01-04 | 2020-08-20 | Inserm (Institut National De La Sante Et De Larecherche Medicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
US9938254B2 (en) | 2016-01-08 | 2018-04-10 | Celgene Corporation | Antiproliferative compounds, and their pharmaceutical compositions and uses |
EP3693019A1 (en) | 2016-01-08 | 2020-08-12 | Taiho Pharmaceutical Co., Ltd. | Anti-tumor agent containing immunomodulator |
KR20180097615A (ko) | 2016-01-08 | 2018-08-31 | 에프. 호프만-라 로슈 아게 | Pd-1 축 결합 길항물질 및 항-cea/항-cd3 이중특이성 항체를 사용하는 cea-양성 암의 치료 방법 |
AU2017205167B2 (en) | 2016-01-08 | 2021-07-01 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
US10189808B2 (en) | 2016-01-08 | 2019-01-29 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
US20170198051A1 (en) | 2016-01-11 | 2017-07-13 | Inhibrx Lp | Multivalent and multispecific ox40-binding fusion proteins |
SG11201805532XA (en) | 2016-01-11 | 2018-07-30 | Inhibrx Inc | Multivalent and multispecific 41bb-binding fusion proteins |
HUE052893T2 (hu) | 2016-01-13 | 2021-05-28 | Acerta Pharma Bv | Antifolát és BTK-gátló terápiás kombinációi |
KR20180101549A (ko) | 2016-01-21 | 2018-09-12 | 이나뜨 파르마 | 림프구에서의 저해 경로의 중화 |
US10822415B2 (en) | 2016-01-28 | 2020-11-03 | Inserm (Institut National De La Santéet De La Recherche Médicale) | Methods for enhancing the potency of the immune checkpoint inhibitors |
US10918737B2 (en) | 2016-01-28 | 2021-02-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of cancer |
WO2017129763A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer |
EP3411407B1 (en) | 2016-02-05 | 2024-04-03 | Orionis Biosciences BV | Bispecific signaling agents and uses thereof |
WO2017139231A1 (en) | 2016-02-08 | 2017-08-17 | Beyondspring Pharmaceuticals, Inc. | Compositions containing tucaresol or its analogs |
US11219635B2 (en) | 2016-02-19 | 2022-01-11 | City Of Hope | Bi-specific aptamer |
AU2017219216B2 (en) | 2016-02-19 | 2019-12-19 | Novartis Ag | Tetracyclic pyridone compounds as antivirals |
EP4086285A1 (en) | 2016-02-25 | 2022-11-09 | Cell Medica Switzerland AG | Binding members to pd-l1 |
MX2018010295A (es) | 2016-02-26 | 2019-06-06 | Inst Nat Sante Rech Med | Anticuerpos que tienen especificidad para atenuador de linfocitos b y t (btla) y usos de los mismos. |
CA3015913A1 (en) | 2016-02-29 | 2017-09-08 | Foundation Medicine, Inc. | Methods of treating cancer |
CN109196121B (zh) | 2016-02-29 | 2022-01-04 | 基因泰克公司 | 用于癌症的治疗和诊断方法 |
JP6918816B2 (ja) | 2016-03-01 | 2021-08-18 | ノース カロライナ ステート ユニバーシティ | マイクロニードルパッチ支援送達による強化されたがん免疫療法 |
SG10201601719RA (en) | 2016-03-04 | 2017-10-30 | Agency Science Tech & Res | Anti-LAG-3 Antibodies |
BR112018067368A2 (pt) | 2016-03-04 | 2019-01-15 | Bristol-Myers Squibb Company | terapia de combinação com anticorpos anti-cd73 |
EP3309177B1 (en) * | 2016-03-04 | 2020-05-13 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Pdl-1 antibody, pharmaceutical composition thereof, and uses thereof |
RU2018134771A (ru) | 2016-03-04 | 2020-04-06 | Новартис Аг | Клетки, экспрессирующие множество молекул химерных антигенных рецепторов (car), и их применение |
WO2017153433A1 (en) | 2016-03-08 | 2017-09-14 | Innate Pharma | Siglec neutralizing antibodies |
WO2017153952A1 (en) | 2016-03-10 | 2017-09-14 | Glaxosmithkline Intellectual Property Development Limited | 5-sulfamoyl-2-hydroxybenzamide derivatives |
WO2017156349A1 (en) | 2016-03-10 | 2017-09-14 | Cold Genesys, Inc. | Methods of treating solid or lymphatic tumors by combination therapy |
WO2017160599A1 (en) | 2016-03-14 | 2017-09-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of cd300b antagonists to treat sepsis and septic shock |
CN114085836B (zh) * | 2016-03-14 | 2024-01-26 | 豪夫迈·罗氏有限公司 | 用于减少pd-l1表达的寡核苷酸 |
US11767362B1 (en) | 2016-03-15 | 2023-09-26 | Chugai Seiyaku Kabushiki Kaisha | Methods of treating cancers using PD-1 axis binding antagonists and anti-GPC3 antibodies |
CA3016474A1 (en) | 2016-03-15 | 2017-09-21 | Mersana Therapeutics, Inc. | Napi2b-targeted antibody-drug conjugates and methods of use thereof |
WO2017161032A1 (en) | 2016-03-15 | 2017-09-21 | North Carolina State University | Nanoparticles, controlled-release dosage forms, and methods for delivering an immunotherapeutic agent |
FI3429618T3 (fi) | 2016-03-16 | 2024-03-15 | Amal Therapeutics Sa | Immuunijäjestelmän tarkistuspisteen modulaattorin ja soluun tunkeutuvan peptidin, cargon ja tlr-peptidiagonistin kompleksin yhdistelmä lääketieteelliseen käyttöön |
US11287428B2 (en) | 2016-03-16 | 2022-03-29 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | PD1 and PDL-1 expression during progression from myelodysplastic syndrome to acute myelogenous leukemia |
US10822416B2 (en) | 2016-03-23 | 2020-11-03 | Mabspace Biosciences (Suzhou) Co., Ltd | Anti-PD-L1 antibodies |
WO2017165742A1 (en) | 2016-03-24 | 2017-09-28 | Millennium Pharmaceuticals, Inc. | Methods of treating gastrointestinal immune-related adverse events in anti-ctla4 anti-pd-1 combination treatments |
US11760803B2 (en) | 2016-03-24 | 2023-09-19 | Takeda Pharmaceutical Company Limited | Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments |
FI3433257T3 (fi) | 2016-03-24 | 2024-01-08 | Novartis Ag | Alkynyylinukleosidianalogeja ihmisen rinoviruksen estäjinä |
WO2017167921A1 (en) | 2016-03-30 | 2017-10-05 | Centre Léon-Bérard | Lymphocytes expressing cd73 in cancerous patient dictates therapy |
EP3225253A1 (en) | 2016-04-01 | 2017-10-04 | Deutsches Krebsforschungszentrum Stiftung des Öffentlichen Rechts | Cancer therapy with an oncolytic virus combined with a checkpoint inhibitor |
US11209441B2 (en) | 2016-04-05 | 2021-12-28 | Bristol-Myers Squibb Company | Cytokine profiling analysis |
CA3019630A1 (en) | 2016-04-07 | 2017-10-12 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
AU2017247806B2 (en) | 2016-04-07 | 2019-11-14 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
AU2017248354A1 (en) | 2016-04-08 | 2018-10-04 | Gilead Sciences, Inc. | Compositions and methods for treating cancer, inflammatory diseases and autoimmune diseases |
CA3020830A1 (en) | 2016-04-13 | 2017-10-19 | Vivia Biotech, S.L | Ex vivo bite.rtm. activated t cells |
IL262251B2 (en) | 2016-04-14 | 2023-09-01 | Ose Immunotherapeutics | New anti-syrap antibodies and their medical applications |
CA3019921A1 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
MX2018012493A (es) | 2016-04-15 | 2019-06-06 | Genentech Inc | Métodos para controlar y tratar el cáncer. |
SG10201913248VA (en) | 2016-04-18 | 2020-02-27 | Celldex Therapeutics Inc | Agonistic antibodies that bind human cd40 and uses thereof |
RU2018140960A (ru) * | 2016-04-25 | 2020-05-26 | МЕДИММЬЮН, ЭлЭлСи | Композиции, содержащие комбинированный состав на основе антител к pd-l1 и ctla-4 |
CN105695406A (zh) * | 2016-04-27 | 2016-06-22 | 天津普瑞赛尔生物科技有限公司 | 制备具有高效肿瘤杀伤性dc-cik免疫细胞的方法及制得的dc-cik免疫细胞 |
EP3452030A4 (en) | 2016-05-04 | 2019-11-13 | Bristol-Myers Squibb Company | INHIBITORS OF INDOLEAMINE-2,3-DIOXYGENASE AND METHOD FOR THEIR USE |
EP3452450A1 (en) | 2016-05-04 | 2019-03-13 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
WO2017192874A1 (en) | 2016-05-04 | 2017-11-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Albumin-binding immunomodulatory compositions and methods of use thereof |
JP2019516681A (ja) | 2016-05-04 | 2019-06-20 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | インドールアミン2,3−ジオキシゲナーゼ阻害剤およびその使用方法 |
JP2019516687A (ja) | 2016-05-04 | 2019-06-20 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | インドールアミン2,3−ジオキシゲナーゼ阻害剤およびその使用方法 |
WO2017192840A1 (en) | 2016-05-04 | 2017-11-09 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
US10604531B2 (en) | 2016-05-05 | 2020-03-31 | Glaxosmithkline Intellectual Property (No.2) Limited | Enhancer of zeste homolog 2 inhibitors |
JP6979971B2 (ja) * | 2016-05-09 | 2021-12-15 | アイジーエム バイオサイエンシズ インコーポレイテッド | 抗pd−l1抗体 |
SG10201603721TA (en) | 2016-05-10 | 2017-12-28 | Agency Science Tech & Res | Anti-CTLA-4 Antibodies |
CN109563141A (zh) | 2016-05-13 | 2019-04-02 | 奥里尼斯生物科学公司 | 对非细胞结构的治疗性靶向 |
TWI755395B (zh) | 2016-05-13 | 2022-02-21 | 美商再生元醫藥公司 | 抗-pd-1抗體與輻射治療癌症之組合 |
ES2930255T3 (es) | 2016-05-13 | 2022-12-09 | Bioatla Inc | Anticuerpos anti-Ror2, fragmentos de anticuerpos, sus inmunoconjugados y usos de los mismos |
WO2017197243A1 (en) * | 2016-05-13 | 2017-11-16 | Ohio State Innovation Foundation | Cblb inhibition for treating fungal infections |
CA3023883A1 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Targeted mutant interferon-beta and uses thereof |
CA3024465A1 (en) | 2016-05-17 | 2017-11-23 | Genentech, Inc. | Stromal gene signatures for diagnosis and use in immunotherapy |
EP3458083B1 (en) | 2016-05-18 | 2022-11-02 | ModernaTX, Inc. | Polynucleotides encoding interleukin-12 (il12) and uses thereof |
EP3458474B1 (en) | 2016-05-18 | 2022-07-06 | ModernaTX, Inc. | Combinations of mrnas encoding immune modulating polypeptides and uses thereof |
US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
MA45025A (fr) | 2016-05-20 | 2019-03-27 | Lilly Co Eli | Traitement d'association utilisant des inhibiteurs de notch et de pd-1 ou pd-l1 |
DK3458053T3 (da) | 2016-05-20 | 2022-02-21 | Biohaven Therapeutics Ltd | Anvendelse af riluzol, riluzolprodrugs eller riluzolanaloger med immunterapier til cancerbehandling |
JP7014736B2 (ja) | 2016-05-24 | 2022-02-01 | ジェネンテック, インコーポレイテッド | がんの処置のためのピラゾロピリジン誘導体 |
MA45122A (fr) | 2016-05-24 | 2019-04-10 | Constellation Pharmaceuticals Inc | Inhibiteurs hétérocycliques de cbp/ep300 et leur utilisation dans le traitement du cancer |
WO2017202962A1 (en) | 2016-05-24 | 2017-11-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of non small cell lung cancer (nsclc) that coexists with chronic obstructive pulmonary disease (copd) |
KR20230003387A (ko) | 2016-05-25 | 2023-01-05 | 엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔 | 암 치료 방법 및 조성물 |
BR112018074463A2 (pt) | 2016-05-27 | 2019-03-06 | Agenus Inc. | anticorpos anti-tim-3 e métodos de uso dos mesmos. |
EP3463405A4 (en) | 2016-05-27 | 2020-02-26 | DNAtrix, Inc. | ADENOVIRUS AND IMMUNOMODULATORY POLYTHERAPY |
US10994033B2 (en) | 2016-06-01 | 2021-05-04 | Bristol-Myers Squibb Company | Imaging methods using 18F-radiolabeled biologics |
WO2018220099A1 (en) | 2017-06-02 | 2018-12-06 | F. Hoffmann-La Roche Ag | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
EP3252078A1 (en) | 2016-06-02 | 2017-12-06 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
PT3464368T (pt) | 2016-06-02 | 2023-08-17 | Bristol Myers Squibb Co | Utilização de um anticorpo anti-pd-1 em combinação com um anticorpo anti-cd30 no tratamento de linfoma |
KR20190015377A (ko) | 2016-06-02 | 2019-02-13 | 브리스톨-마이어스 스큅 컴퍼니 | 불응성 호지킨 림프종에서의 니볼루맙을 사용한 pd-1 차단 |
AU2017275782A1 (en) | 2016-06-02 | 2019-01-24 | Ultimovacs As | A vaccine in combination with an immune checkpoint inhibitor for use in treating cancer |
JP2019517512A (ja) | 2016-06-03 | 2019-06-24 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 結腸直腸癌を有する患者の処置における抗pd−1抗体の使用 |
WO2017210624A1 (en) | 2016-06-03 | 2017-12-07 | Bristol-Myers Squibb Company | Anti-pd-1 antibody for use in a method of treating a tumor |
EP3463454A1 (en) | 2016-06-03 | 2019-04-10 | Bristol-Myers Squibb Company | Anti-pd-1 antibody for use in a method of treatment of recurrent small cell lung cancer |
RU2760348C2 (ru) | 2016-06-06 | 2021-11-24 | Бейондспринг Фармасьютикалс, Инк. | Способ уменьшения нейтропении |
CN109563071B (zh) | 2016-06-08 | 2021-08-03 | 葛兰素史密斯克莱知识产权发展有限公司 | 作为atf4途径抑制剂的化学化合物 |
US10851053B2 (en) | 2016-06-08 | 2020-12-01 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
SG11201811003PA (en) | 2016-06-13 | 2019-01-30 | I Mab | Anti-pd-l1 antibodies and uses thereof |
AU2017283480A1 (en) | 2016-06-13 | 2019-01-24 | Torque Therapeutics, Inc. | Methods and compositions for promoting immune cell function |
HUE050796T2 (hu) | 2016-06-14 | 2021-01-28 | Novartis Ag | (R)-4-(5-(ciklopropiletinil)izoxazol-3-il)-N-hidroxi-2-metil-2-(metilszulfonil)butánamid kristályos formája baktériumellenes szerként |
WO2017216685A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | Pentacyclic pyridone compounds as antivirals |
WO2017216686A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals |
US9567399B1 (en) | 2016-06-20 | 2017-02-14 | Kymab Limited | Antibodies and immunocytokines |
WO2018029474A2 (en) | 2016-08-09 | 2018-02-15 | Kymab Limited | Anti-icos antibodies |
KR102531889B1 (ko) | 2016-06-20 | 2023-05-17 | 키맵 리미티드 | 항-pd-l1 및 il-2 사이토카인 |
MD3472167T2 (ro) | 2016-06-20 | 2023-02-28 | Incyte Corp | Compuși heterociclici ca imunomodulatori |
EP3474856B1 (en) | 2016-06-24 | 2022-09-14 | Infinity Pharmaceuticals, Inc. | Combination therapies |
WO2018006005A1 (en) | 2016-06-30 | 2018-01-04 | Oncorus, Inc. | Pseudotyped oncolytic viral delivery of therapeutic polypeptides |
AU2017293423B2 (en) | 2016-07-05 | 2023-05-25 | Beigene, Ltd. | Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer |
WO2018009466A1 (en) | 2016-07-05 | 2018-01-11 | Aduro Biotech, Inc. | Locked nucleic acid cyclic dinucleotide compounds and uses thereof |
WO2018011166A2 (en) | 2016-07-12 | 2018-01-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2018014001A1 (en) | 2016-07-14 | 2018-01-18 | Fred Hutchinson Cancer Research Center | Multiple bi-specific binding domain constructs with different epitope binding to treat cancer |
US10077306B2 (en) | 2016-07-14 | 2018-09-18 | Bristol-Myers Squibb Company | Antibodies against TIM3 and uses thereof |
GB201612520D0 (en) | 2016-07-19 | 2016-08-31 | F-Star Beta Ltd | Binding molecules |
CA3031047A1 (en) | 2016-07-20 | 2018-01-25 | Glaxosmithkline Intellectual Property Development Limited | Isoquinoline derivatives as perk inhibitors |
WO2018017708A1 (en) | 2016-07-20 | 2018-01-25 | University Of Utah Research Foundation | Cd229 car t cells and methods of use thereof |
WO2018017633A1 (en) | 2016-07-21 | 2018-01-25 | Bristol-Myers Squibb Company | TGF Beta RECEPTOR ANTAGONISTS |
CN106243223B (zh) * | 2016-07-28 | 2019-03-05 | 北京百特美博生物科技有限公司 | 抗人pdl1抗体及其用途 |
JP2019525934A (ja) | 2016-07-29 | 2019-09-12 | イーライ リリー アンド カンパニー | 癌の治療に使用するためのメレスチニブおよび抗pd−l1または抗pd−1阻害剤を用いた組み合わせ治療 |
US20210369746A1 (en) | 2016-08-01 | 2021-12-02 | Molecular Templates, Inc. | Administration of hypoxia activated prodrugs in combination with immune modulatory agents for treating cancer |
ES2899036T3 (es) | 2016-08-04 | 2022-03-09 | Innovent Biologics Suzhou Co Ltd | Nanocuerpo anti-PD-L1 y su uso |
EP3495391A4 (en) * | 2016-08-05 | 2020-08-19 | Y-Biologics Inc. | ANTIBODIES AGAINST PROGRAMMED DEATH LIGAND 1 (PD-L1) AND USE OF IT |
WO2018026249A1 (ko) * | 2016-08-05 | 2018-02-08 | 주식회사 와이바이오로직스 | 프로그램화된 세포 사멸 단백질 리간드-1 (pd-l1)에 대한 항체 및 이의 용도 |
JP2019530434A (ja) | 2016-08-05 | 2019-10-24 | ジェネンテック, インコーポレイテッド | アゴニスト活性を有する多価及び多重エピトープ抗体ならびに使用方法 |
WO2018029124A1 (en) | 2016-08-08 | 2018-02-15 | F. Hoffmann-La Roche Ag | Therapeutic and diagnostic methods for cancer |
CN116640214A (zh) | 2016-08-09 | 2023-08-25 | 科马布有限公司 | 分离抗体及其应用 |
KR20190038829A (ko) | 2016-08-12 | 2019-04-09 | 제넨테크, 인크. | Mek 억제제, pd-1 축 억제제, 및 vegf 억제제를 사용한 조합 요법 |
WO2018029336A1 (en) | 2016-08-12 | 2018-02-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining whether a subject was administered with an activator of the ppar beta/delta pathway. |
EP3497130B1 (en) | 2016-08-12 | 2021-10-27 | Merck Patent GmbH | Combination therapy for cancer |
CA3032331A1 (en) | 2016-08-17 | 2018-02-22 | Compugen Ltd. | Anti-tigit antibodies, anti-pvrig antibodies and combinations thereof |
WO2018033135A1 (en) | 2016-08-19 | 2018-02-22 | Beigene, Ltd. | Use of a combination comprising a btk inhibitor for treating cancers |
US20210284733A1 (en) * | 2016-08-22 | 2021-09-16 | Arbutus Biopharma Corporation | Anti-pd-1 antibodies, or fragments thereof, for treating hepatitis b |
JP7138094B2 (ja) | 2016-08-25 | 2022-09-15 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | マクロファージ活性化剤と組み合わせた抗csf-1r抗体の間欠投与 |
KR20190040990A (ko) | 2016-08-26 | 2019-04-19 | 브리스톨-마이어스 스큅 컴퍼니 | 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법 |
WO2018041118A1 (en) | 2016-08-31 | 2018-03-08 | Beijing Biocytogen Co., Ltd | Genetically modified non-human animal with human or chimeric pd-l1 |
CN107815466B (zh) | 2016-08-31 | 2020-03-13 | 百奥赛图江苏基因生物技术有限公司 | 人源化基因改造动物模型的制备方法及应用 |
CN110121352B (zh) | 2016-09-01 | 2020-12-11 | 嵌合体生物工程公司 | Gold优化的car t-细胞 |
CN110191720A (zh) | 2016-09-09 | 2019-08-30 | Tg治疗有限公司 | 用于治疗血液学癌症的抗-CD20抗体、PI 3激酶-δ抑制剂以及抗-PD-1或抗-PD-L1抗体的组合 |
WO2018048975A1 (en) | 2016-09-09 | 2018-03-15 | Bristol-Myers Squibb Company | Use of an anti-pd-1 antibody in combination with an anti-mesothelin antibody in cancer treatment |
WO2018047109A1 (en) | 2016-09-09 | 2018-03-15 | Novartis Ag | Polycyclic pyridone compounds as antivirals |
WO2018046736A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
WO2018046738A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
KR20230109771A (ko) * | 2016-09-13 | 2023-07-20 | 노쓰 캐롤라이나 스테이트 유니버시티 | 혈소판 조성물 및 치료제의 전달 방법 |
KR20190053909A (ko) | 2016-09-16 | 2019-05-20 | 바이오노믹스 리미티드 | 항체와 체크포인트 면역 억제제의 병용 요법 |
KR20230131498A (ko) | 2016-09-21 | 2023-09-13 | 아말 테라퓨틱스 에스에이 | 암 치료를 위한, 세포 투과 펩타이드, 멀티 에피토프 및 tlr 펩타이드 작용제를 포함하는 융합체 |
AU2017332161A1 (en) | 2016-09-21 | 2019-04-04 | The United States Government As Represented By The Department Of Veterans Affairs | Chimeric antigen receptor (car) that targets chemokine receptor CCR4 and its use |
WO2018055080A1 (en) | 2016-09-22 | 2018-03-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof |
WO2018057955A1 (en) | 2016-09-23 | 2018-03-29 | Elstar Therapeutics, Inc. | Multispecific antibody molecules comprising lambda and kappa light chains |
CN117510643A (zh) | 2016-09-23 | 2024-02-06 | 美勒斯公司 | 调节细胞表达的生物活性的结合分子 |
CN109844536B (zh) | 2016-09-26 | 2023-04-14 | 豪夫迈·罗氏有限公司 | 预测对pd-1轴抑制剂的响应 |
MX2019003569A (es) | 2016-09-27 | 2020-07-22 | Oncologie Inc | Metodos para tratar el cancer con bavituximab en funcion de niveles de b2 glucoproteina 1 y ensayos de estos. |
JOP20190061A1 (ar) | 2016-09-28 | 2019-03-26 | Novartis Ag | مثبطات بيتا-لاكتاماز |
JP2019534251A (ja) | 2016-09-29 | 2019-11-28 | ジェネンテック, インコーポレイテッド | Mek阻害剤、pd−1軸阻害剤、及びタキサンを用いた併用療法 |
ES2893532T3 (es) | 2016-10-04 | 2022-02-09 | Merck Sharp & Dohme | Compuestos de benzo[b]tiofeno como agonistas de STING |
MX2019003934A (es) | 2016-10-06 | 2019-07-10 | Genentech Inc | Métodos terapéuticos y de diagnóstico para el cáncer. |
CA3039451A1 (en) | 2016-10-06 | 2018-04-12 | Pfizer Inc. | Dosing regimen of avelumab for the treatment of cancer |
EP3523331A1 (en) | 2016-10-07 | 2019-08-14 | Novartis AG | Chimeric antigen receptors for the treatment of cancer |
US11712465B2 (en) | 2016-10-07 | 2023-08-01 | Enterome S.A. | Microbiota sequence variants of tumor-related antigenic epitopes |
EP3522916A2 (en) | 2016-10-07 | 2019-08-14 | Enterome S.A. | Immunogenic compounds for cancer therapy |
KR20240007316A (ko) | 2016-10-07 | 2024-01-16 | 엔터롬 에스.에이. | 암 치료를 위한 면역원성 화합물 |
US11666649B2 (en) | 2016-10-11 | 2023-06-06 | University Of Miami | Vectors and vaccine cells for immunity against Zika virus |
EP3527216B1 (en) | 2016-10-11 | 2024-02-14 | NEC Corporation | A medicine comprising a toll-like receptor agonist, lag-3 protein, a hsp70-derived peptide and a gpc3-derived peptide |
IL265800B2 (en) | 2016-10-11 | 2023-10-01 | Agenus Inc | Anti-LAG-3 antibodies and methods of using them |
CA3040465A1 (en) | 2016-10-14 | 2018-04-19 | Merck Sharp & Dohme Corp. | Combination of a pd-1 antagonist and eribulin for treating urothelial cancer |
WO2018071576A1 (en) | 2016-10-14 | 2018-04-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Treatment of tumors by inhibition of cd300f |
WO2018073753A1 (en) | 2016-10-18 | 2018-04-26 | Novartis Ag | Fused tetracyclic pyridone compounds as antivirals |
WO2018075447A1 (en) | 2016-10-19 | 2018-04-26 | The Trustees Of Columbia University In The City Of New York | Combination of braf inhibitor, talimogene laherparepvec, and immune checkpoint inhibitor for use in the treatment cancer (melanoma) |
CN110114368A (zh) | 2016-10-24 | 2019-08-09 | 奥睿尼斯生物科学公司 | 靶向突变干扰素-γ及其用途 |
CN110099925A (zh) | 2016-10-28 | 2019-08-06 | 百时美施贵宝公司 | 使用抗pd-1抗体治疗尿道上皮癌的方法 |
WO2018081531A2 (en) | 2016-10-28 | 2018-05-03 | Ariad Pharmaceuticals, Inc. | Methods for human t-cell activation |
EP3532091A2 (en) | 2016-10-29 | 2019-09-04 | H. Hoffnabb-La Roche Ag | Anti-mic antibidies and methods of use |
JP7011657B2 (ja) * | 2016-10-30 | 2022-02-10 | シャンハイ・ヘンリウス・バイオテック・インコーポレイテッド | 抗pd-l1抗体および変異型 |
TWI788307B (zh) | 2016-10-31 | 2023-01-01 | 美商艾歐凡斯生物治療公司 | 用於擴增腫瘤浸潤性淋巴細胞之工程化人造抗原呈現細胞 |
MX2019004621A (es) | 2016-11-02 | 2019-11-28 | Engmab Sarl | Anticuerpo biespecifico contra bcma y cd3 y un farmaco inmunologico para uso combinado en el tratamiento del mieloma multiple. |
EP3534947A1 (en) | 2016-11-03 | 2019-09-11 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses & methods |
CN110072890B (zh) | 2016-11-03 | 2022-11-29 | 百时美施贵宝公司 | 可活化的抗ctla-4抗体及其用途 |
AU2017355512A1 (en) | 2016-11-04 | 2019-05-23 | Aximmune, Inc. | Beta-alethine, immune modulators, and uses thereof |
US10342785B2 (en) | 2016-11-04 | 2019-07-09 | Askat Inc. | Use of EP4 receptor antagonists for the treatment of NASH-associated liver cancer |
EP3538140A1 (en) | 2016-11-14 | 2019-09-18 | Institut National de la Sante et de la Recherche Medicale (INSERM) | Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation |
TWI791471B (zh) | 2016-11-15 | 2023-02-11 | 美商建南德克公司 | 用於用抗cd20/抗cd3雙特異性抗體進行治療之給藥 |
US10660909B2 (en) | 2016-11-17 | 2020-05-26 | Syntrix Biosystems Inc. | Method for treating cancer using chemokine antagonists |
US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
WO2018091542A1 (en) | 2016-11-21 | 2018-05-24 | Idenix Pharmaceuticals Llc | Cyclic phosphate substituted nucleoside derivatives for the treatment of liver diseases |
WO2018098352A2 (en) | 2016-11-22 | 2018-05-31 | Jun Oishi | Targeting kras induced immune checkpoint expression |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
WO2018102427A1 (en) | 2016-11-29 | 2018-06-07 | Boston Biomedical, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
WO2018099539A1 (en) | 2016-11-29 | 2018-06-07 | Horst Lindhofer | Combination of t-cell redirecting multifunctional antibodies with immune checkpoint modulators and uses thereof |
AU2017368155B2 (en) | 2016-11-30 | 2022-02-24 | Oncomed Pharmaceuticals, Inc. | Methods for treatment of cancer comprising TIGIT-binding agents |
KR20190090822A (ko) | 2016-12-01 | 2019-08-02 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | 조합 요법 |
JP2020511407A (ja) | 2016-12-01 | 2020-04-16 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | 併用療法 |
CN110248678A (zh) | 2016-12-03 | 2019-09-17 | 朱诺治疗学股份有限公司 | 调节car-t细胞的方法 |
WO2018106738A1 (en) | 2016-12-05 | 2018-06-14 | Massachusetts Institute Of Technology | Brush-arm star polymers, conjugates and particles, and uses thereof |
LT3551660T (lt) | 2016-12-07 | 2023-12-27 | Agenus Inc. | Antikūnai prieš ctla-4 ir jų naudojimo būdai |
KR102603681B1 (ko) | 2016-12-07 | 2023-11-17 | 아게누스 인코포레이티드 | 항체 및 이의 사용방법 |
EP3552626A4 (en) | 2016-12-12 | 2020-06-10 | Daiichi Sankyo Company, Limited | ASSOCIATION OF AN ANTIBODY DRUG CONJUGATE AND AN IMMUNE CONTROL POINT INHIBITOR |
CN110366562A (zh) | 2016-12-12 | 2019-10-22 | 豪夫迈·罗氏有限公司 | 使用抗pd-l1抗体和抗雄激素治疗癌症的方法 |
AU2017378226A1 (en) | 2016-12-14 | 2019-06-20 | Janssen Biotech, Inc. | CD8A-binding fibronectin type III domains |
US10597438B2 (en) | 2016-12-14 | 2020-03-24 | Janssen Biotech, Inc. | PD-L1 binding fibronectin type III domains |
US10611823B2 (en) | 2016-12-14 | 2020-04-07 | Hanssen Biotech, Inc | CD137 binding fibronectin type III domains |
WO2018112360A1 (en) | 2016-12-16 | 2018-06-21 | Evelo Biosciences, Inc. | Combination therapies for treating cancer |
WO2018112364A1 (en) | 2016-12-16 | 2018-06-21 | Evelo Biosciences, Inc. | Combination therapies for treating melanoma |
CN117752798A (zh) | 2016-12-19 | 2024-03-26 | 豪夫迈·罗氏有限公司 | 用靶向性4-1bb(cd137)激动剂的组合疗法 |
MY197635A (en) | 2016-12-22 | 2023-06-29 | Incyte Corp | Benzooxazole derivatives as immunomodulators |
CN110072553B (zh) | 2016-12-22 | 2023-09-15 | 豪夫迈·罗氏有限公司 | 在抗pd-l1/pd1治疗失败之后抗csf-1r抗体与抗pd-l1抗体组合对肿瘤的治疗 |
MX2019007615A (es) | 2016-12-23 | 2019-11-05 | Univ Johns Hopkins | Imagenología de celulas tumorales e inmunitarias basadas en expresion de pd-l1. |
EP3558377A1 (en) | 2016-12-23 | 2019-10-30 | Virttu Biologics Limited | Treatment of cancer |
EP3559032A1 (en) | 2016-12-23 | 2019-10-30 | Innate Pharma | Heterodimeric antigen binding proteins |
EP3559045A4 (en) * | 2016-12-23 | 2020-08-19 | REMD Biotherapeutics, Inc. | IMMUNOTHERAPY USING ANTIBODIES THAT BIND TO A TIMED DEATH LIGAND 1 (PD-L1) |
WO2018122245A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting the survival time of patients suffering from cms3 colorectal cancer |
WO2018122249A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from a microsatellite stable colorectal cancer |
US20190315852A1 (en) | 2017-01-05 | 2019-10-17 | Netris Pharma | Combined treatment with netrin-1 interfering drug and immune checkpoint inhibitors drugs |
US10961239B2 (en) | 2017-01-05 | 2021-03-30 | Bristol-Myers Squibb Company | TGF beta receptor antagonists |
CN110431135A (zh) | 2017-01-06 | 2019-11-08 | 大连万春布林医药有限公司 | 微管蛋白结合化合物及其治疗用途 |
US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
EP3565560A4 (en) | 2017-01-09 | 2021-01-13 | Bioxcel Therapeutics, Inc. | PREDICTIVE AND DIAGNOSTIC PROCEDURES FOR PROSTATE CANCER |
US11034667B2 (en) | 2017-01-09 | 2021-06-15 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
MX2019008346A (es) | 2017-01-13 | 2019-09-09 | Agenus Inc | Receptores de celulas t que se unen a ny-eso-1 y metodos de uso de estos. |
AU2018211064A1 (en) | 2017-01-18 | 2019-09-05 | Genentech, Inc. | Idiotypic antibodies against anti-PD-L1 antibodies and uses thereof |
EP3570840A1 (en) | 2017-01-20 | 2019-11-27 | Exelixis, Inc. | Combinations of cabozantinib and atezolizumab to treat cancer |
TWI812494B (zh) | 2017-01-20 | 2023-08-11 | 美商阿克思生物科學有限公司 | 用於治療癌症相關病症之唑嘧啶 |
WO2018137681A1 (en) | 2017-01-25 | 2018-08-02 | Beigene, Ltd. | Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof |
AU2018212788A1 (en) | 2017-01-27 | 2019-07-25 | Janssen Biotech, Inc. | Cyclic dinucleotides as STING agonists |
AU2018212787B2 (en) | 2017-01-27 | 2023-10-26 | Janssen Biotech, Inc. | Cyclic dinucleotides as sting agonists |
WO2018140671A1 (en) | 2017-01-27 | 2018-08-02 | Celgene Corporation | 3-(1-oxo-4-((4-((3-oxomorpholino) methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione and isotopologues thereof |
CA3052190A1 (en) | 2017-02-01 | 2018-08-09 | Beyondspring Pharmaceuticals, Inc. | Method of reducing neutropenia |
JOP20190187A1 (ar) | 2017-02-03 | 2019-08-01 | Novartis Ag | مترافقات عقار جسم مضاد لـ ccr7 |
EP3577138A1 (en) | 2017-02-06 | 2019-12-11 | Innate Pharma | Immunomodulatory antibody drug conjugates binding to a human mica polypeptide |
JP2020505955A (ja) | 2017-02-06 | 2020-02-27 | オリオンズ バイオサイエンス インコーポレイテッド | 標的化改変型インターフェロン及びその使用 |
KR102642385B1 (ko) | 2017-02-06 | 2024-03-04 | 오리오니스 바이오사이언시스 엔브이 | 표적화된 키메라 단백질 및 이의 용도 |
WO2018146148A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A method for predicting the response to checkpoint blockade cancer immunotherapy |
WO2018146128A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Detection of kit polymorphism for predicting the response to checkpoint blockade cancer immunotherapy |
EP3579874B1 (en) | 2017-02-10 | 2021-07-21 | Novartis AG | 1-(4-amino-5-bromo-6-(1 h-pyrazol-1-yl)pyrimidin-2-yl)-1 h-pyrazol-4-ol and use thereof in the treatment of cancer |
ES2895641T3 (es) * | 2017-02-10 | 2022-02-22 | Chiome Bioscience Inc | Método para fomentar la diversificación de una región variable de anticuerpos |
WO2018151820A1 (en) | 2017-02-16 | 2018-08-23 | Elstar Therapeutics, Inc. | Multifunctional molecules comprising a trimeric ligand and uses thereof |
CN110662764B (zh) * | 2017-02-16 | 2023-08-22 | 湘潭腾华生物科技有限公司 | 抗程序性死亡配体1(pd-l1)抗体及其治疗用途 |
TWI674261B (zh) | 2017-02-17 | 2019-10-11 | 美商英能腫瘤免疫股份有限公司 | Nlrp3 調節劑 |
EP3585812A1 (en) | 2017-02-21 | 2020-01-01 | Regeneron Pharmaceuticals, Inc. | Anti-pd-1 antibodies for treatment of lung cancer |
CN108456251A (zh) * | 2017-02-21 | 2018-08-28 | 上海君实生物医药科技股份有限公司 | 抗pd-l1抗体及其应用 |
CA3052767A1 (en) | 2017-02-27 | 2018-08-30 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors |
EP3585486A1 (en) | 2017-02-27 | 2020-01-01 | Novartis AG | Dosing schedule for a combination of ceritinib and an anti-pd-1 antibody molecule |
WO2018160538A1 (en) | 2017-02-28 | 2018-09-07 | Mersana Therapeutics, Inc. | Combination therapies of her2-targeted antibody-drug conjugates |
MX2019010295A (es) | 2017-03-01 | 2019-11-21 | Genentech Inc | Métodos de diagnóstico y terapéuticos para el cáncer. |
EP3592769A1 (en) | 2017-03-09 | 2020-01-15 | Genmab A/S | Antibodies against pd-l1 |
SG11201908391XA (en) | 2017-03-15 | 2019-10-30 | Cue Biopharma Inc | Methods for modulating an immune response |
AU2018235944B2 (en) | 2017-03-15 | 2024-01-04 | Amgen Inc. | Use of oncolytic viruses, alone or in combination with a checkpoint inhibitor, for the treatment of cancer |
EP3596075B1 (en) | 2017-03-15 | 2023-10-11 | F. Hoffmann-La Roche AG | Azaindoles as inhibitors of hpk1 |
JP7308150B2 (ja) | 2017-03-16 | 2023-07-13 | イナート・ファルマ・ソシエテ・アノニム | 癌を処置するための組成物及び方法 |
US20210186982A1 (en) | 2017-03-24 | 2021-06-24 | Universite Nice Sophia Antipolis | Methods and compositions for treating melanoma |
US20200048321A1 (en) * | 2017-03-24 | 2020-02-13 | Orpheus Bioscience Inc. | Pantids for treatment of autoimmune disorders |
CN108623686A (zh) | 2017-03-25 | 2018-10-09 | 信达生物制药(苏州)有限公司 | 抗ox40抗体及其用途 |
JP7029822B2 (ja) * | 2017-03-29 | 2022-03-04 | タイペイ・メディカル・ユニバーシティ | 抗原特異的t細胞及びその使用 |
KR102644408B1 (ko) | 2017-03-30 | 2024-03-07 | 메르크 파텐트 게엠베하 | 암의 치료를 위한 항-pd-l1 항체 및 dna-pk 억제제의 병용 |
MX2019011511A (es) | 2017-03-30 | 2019-11-18 | Hoffmann La Roche | Naftiridinas como inhibidores de cinasa 1 progenitora hematopoyetica (hpk1). |
US20200033324A1 (en) * | 2017-03-31 | 2020-01-30 | Sony Corporation | Information processing device, information processing method, and cell analyzing system |
EP3601355A1 (en) | 2017-03-31 | 2020-02-05 | Bristol-Myers Squibb Company | Methods of treating tumor |
KR20200020662A (ko) | 2017-04-03 | 2020-02-26 | 온콜로지, 인크. | 면역-종양학 제제와 함께 ps-표적화 항체를 사용하여 암을 치료하는 방법 |
WO2018187260A1 (en) | 2017-04-04 | 2018-10-11 | Heat Biologics, Inc. | Intratumoral vaccination |
US11603407B2 (en) | 2017-04-06 | 2023-03-14 | Regeneron Pharmaceuticals, Inc. | Stable antibody formulation |
TWI788340B (zh) | 2017-04-07 | 2023-01-01 | 美商必治妥美雅史谷比公司 | 抗icos促效劑抗體及其用途 |
KR102629972B1 (ko) | 2017-04-13 | 2024-01-29 | 아게누스 인코포레이티드 | 항-cd137 항체 및 이의 사용 방법 |
MX2019012187A (es) | 2017-04-13 | 2019-11-25 | Hoffmann La Roche | Un inmunoconjugado de interleuquina-2, un agonista de cd40 y opcionalmente un antagonista de union al eje pd-1 para uso en metodos para tratar cancer. |
CA3058478A1 (en) | 2017-04-14 | 2018-10-18 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
RU2665790C1 (ru) * | 2017-04-17 | 2018-09-04 | Закрытое Акционерное Общество "Биокад" | Моноклональное антитело к pd-l1 |
SG11201909041SA (en) * | 2017-04-18 | 2019-11-28 | R Pharm Overseas Inc | Anti-pd-l1 antibody and use thereof |
US11738009B2 (en) | 2017-04-18 | 2023-08-29 | Tempest Therapeutics, Inc. | Bicyclic compounds and their use in the treatment of cancer |
EP3612563A1 (en) | 2017-04-19 | 2020-02-26 | Elstar Therapeutics, Inc. | Multispecific molecules and uses thereof |
CN106939049B (zh) | 2017-04-20 | 2019-10-01 | 苏州思坦维生物技术股份有限公司 | 拮抗抑制人pd-1抗原与其配体结合的单克隆抗体及其制备方法与应用 |
BR112019022009A2 (pt) | 2017-04-21 | 2020-05-12 | Sillajen, Inc. | Terapia de combinação de vírus vaccinia oncolítico e inibidor de ponto de verificação |
TWI778050B (zh) | 2017-04-21 | 2022-09-21 | 美商醫肯納腫瘤學公司 | 吲哚ahr抑制劑及其用途 |
JP2020517699A (ja) | 2017-04-26 | 2020-06-18 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | ジスルフィド結合の還元を最小限にする抗体製造法 |
AR111419A1 (es) | 2017-04-27 | 2019-07-10 | Novartis Ag | Compuestos fusionados de indazol piridona como antivirales |
EP3615068A1 (en) | 2017-04-28 | 2020-03-04 | Novartis AG | Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor |
US20200385472A1 (en) | 2017-04-28 | 2020-12-10 | Elstar Therapeutics, Inc. | Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof |
US20200055948A1 (en) | 2017-04-28 | 2020-02-20 | Novartis Ag | Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor |
AR111651A1 (es) | 2017-04-28 | 2019-08-07 | Novartis Ag | Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación |
UY37695A (es) | 2017-04-28 | 2018-11-30 | Novartis Ag | Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo |
CA3062061A1 (en) | 2017-05-01 | 2018-11-08 | Agenus Inc. | Anti-tigit antibodies and methods of use thereof |
AR111658A1 (es) | 2017-05-05 | 2019-08-07 | Novartis Ag | 2-quinolinonas tricíclicas como agentes antibacteriales |
WO2018209049A1 (en) | 2017-05-12 | 2018-11-15 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
EP3623389A4 (en) * | 2017-05-12 | 2021-01-20 | Jiangsu Hengrui Medicine Co., Ltd. | FUSION PROTEIN WITH TGF RECEPTOR AND ITS MEDICAL USES |
EP3621624B1 (en) | 2017-05-12 | 2023-08-30 | Merck Sharp & Dohme LLC | Cyclic di-nucleotide compounds as sting agonists |
JP7090347B2 (ja) | 2017-05-12 | 2022-06-24 | ハープーン セラピューティクス,インク. | メソテリン結合タンパク質 |
CA3062487A1 (en) * | 2017-05-16 | 2018-11-22 | Jiangsu Hengrui Medicine Co., Ltd. | Pd-l1 antibody pharmaceutical composition and use thereof |
KR20200006115A (ko) | 2017-05-16 | 2020-01-17 | 브리스톨-마이어스 스큅 컴퍼니 | 항-gitr 효능제 항체에 의한 암의 치료 |
EP3634417B1 (en) | 2017-05-17 | 2023-07-12 | Arcus Biosciences, Inc. | Quinazoline-pyrazole derivatives for the treatment of cancer-related disorders |
JP2020520923A (ja) | 2017-05-17 | 2020-07-16 | ボストン バイオメディカル, インコーポレイテッド | がんを処置するための方法 |
MA49144A (fr) | 2017-05-18 | 2020-03-25 | Tesaro Inc | Polythérapies pour le traitement du cancer |
WO2018213731A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof |
JP2020521751A (ja) | 2017-05-25 | 2020-07-27 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 修飾重鎖定常領域を含む抗体 |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
MX2019014192A (es) | 2017-05-29 | 2021-04-12 | Gamamabs Pharma | Inhibidor de inmunosupresion asociado al cancer. |
CA3065304A1 (en) | 2017-05-30 | 2018-12-06 | Bristol-Myers Squibb Company | Compositions comprising an anti-lag-3 antibody or an anti-lag-3 antibody and an anti-pd-1 or anti-pd-l1 antibody |
MX2019012038A (es) | 2017-05-30 | 2019-11-18 | Bristol Myers Squibb Co | Composiciones que comprenden una combinacion de un anticuerpo anti gen 3 de activacion del linfocito (lag-3), un inhibidor de la trayectoria del receptor de muerte programada 1 (pd-1), y un agente inmunoterapeutico. |
BR112019020610A2 (pt) | 2017-05-30 | 2020-04-22 | Bristol-Myers Squibb Company | tratamento de tumores positivos para o lag-3 |
WO2018222901A1 (en) | 2017-05-31 | 2018-12-06 | Elstar Therapeutics, Inc. | Multispecific molecules that bind to myeloproliferative leukemia (mpl) protein and uses thereof |
JOP20190279A1 (ar) | 2017-05-31 | 2019-11-28 | Novartis Ag | الصور البلورية من 5-برومو -2، 6-داي (1h-بيرازول -1-يل) بيريميدين -4- أمين وأملاح جديدة |
JP2020522512A (ja) | 2017-05-31 | 2020-07-30 | ストキューブ アンド シーオー., インコーポレイテッド | Btn1a1に免疫特異的に結合する抗体及び分子を用いて癌を治療する方法 |
WO2018223004A1 (en) | 2017-06-01 | 2018-12-06 | Xencor, Inc. | Bispecific antibodies that bind cd20 and cd3 |
BR112019025035A2 (pt) | 2017-06-01 | 2020-06-30 | Compugen Ltd. | método para tratar câncer |
EP3630839A1 (en) | 2017-06-01 | 2020-04-08 | Xencor, Inc. | Bispecific antibodies that bind cd 123 cd3 |
KR20200016899A (ko) | 2017-06-01 | 2020-02-17 | 싸이톰스 테라퓨틱스, 인크. | 활성화가능 항-pdl1 항체, 및 이의 이용 방법 |
CN110678483B (zh) | 2017-06-01 | 2023-09-22 | 百时美施贵宝公司 | 用抗pd-1抗体治疗肿瘤的方法 |
BR112019025403A2 (pt) | 2017-06-02 | 2020-08-18 | Juno Therapeutics Inc | artigos de fabricação e métodos para tratamento usando terapia celular adotiva |
US11542331B2 (en) | 2017-06-06 | 2023-01-03 | Stcube & Co., Inc. | Methods of treating cancer using antibodies and molecules that bind to BTN1A1 or BTN1A1-ligands |
EP3634496A4 (en) * | 2017-06-06 | 2021-09-08 | Dana-Farber Cancer Institute, Inc. | METHOD FOR RISING AWARENESS IN CANCER CELLS AGAINST T-CELL-MEDIATED KILLING BY MODULATING MOLECULAR SIGNAL PATHS |
WO2018225093A1 (en) | 2017-06-07 | 2018-12-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds as atf4 pathway inhibitors |
WO2018225033A1 (en) | 2017-06-09 | 2018-12-13 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy |
CA3061959A1 (en) | 2017-06-09 | 2018-12-13 | Providence Health & Services - Oregon | Utilization of cd39 and cd103 for identification of human tumor reactive t cells for treatment of cancer |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
EP3641814A4 (en) | 2017-06-19 | 2021-06-23 | Medicenna Therapeutics Inc. | USES AND METHODS FOR IL-2 SUPERAGONISTS, AGONISTS, AND FUSIONS THEREOF |
GB201709808D0 (en) | 2017-06-20 | 2017-08-02 | Kymab Ltd | Antibodies |
JP2020524157A (ja) | 2017-06-20 | 2020-08-13 | アンスティテュート キュリー | がん併用療法における使用のためのsuv39h1ヒストンメチルトランスフェラーゼの阻害剤 |
BR112019027402A2 (pt) | 2017-06-22 | 2020-07-07 | Celgene Corporation | tratamento de carcinoma hepatocelular caracterizado por infecção pelo vírus da hepatite b |
EP3642240A1 (en) | 2017-06-22 | 2020-04-29 | Novartis AG | Antibody molecules to cd73 and uses thereof |
PE20200717A1 (es) | 2017-06-22 | 2020-07-21 | Novartis Ag | Moleculas de anticuerpo que se unen a cd73 y usos de las mismas |
WO2018235056A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER |
TW201904993A (zh) | 2017-06-22 | 2019-02-01 | 瑞士商諾華公司 | IL-1β 結合抗體之用途 |
CN110831972B (zh) * | 2017-06-25 | 2023-05-12 | 西雅图免疫公司 | 抗pd-l1抗体及其制备和使用方法 |
CA3066518A1 (en) | 2017-06-26 | 2019-01-03 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
CA3066747A1 (en) | 2017-06-27 | 2019-01-03 | Novartis Ag | Dosage regimens for anti-tim-3 antibodies and uses thereof |
EP3645040A4 (en) | 2017-06-27 | 2021-05-05 | Neuracle Science Co., Ltd | USE OF ANTI-FAM19A5 ANTIBODIES FOR THE TREATMENT OF CANCERS |
JP2020526194A (ja) | 2017-06-29 | 2020-08-31 | ジュノー セラピューティクス インコーポレイテッド | 免疫療法薬と関連する毒性を評価するためのマウスモデル |
EP3644993B1 (en) | 2017-06-30 | 2023-08-02 | Bristol-Myers Squibb Company | Amorphous and crystalline forms of ido inhibitors |
MX2019015886A (es) | 2017-06-30 | 2020-09-10 | Celgene Corp | Composiciones y metodos de uso de 2-(4-clorofenil)-n-((2-(2,6-diox opiperidin-3-il)-1-0xoisoindolin-5-il)metil)-2,2-difluoroacetamid a. |
CA3068395A1 (en) | 2017-07-03 | 2019-01-10 | Glaxosmithkline Intellectual Property Development Limited | 2-(4-chlorophenoxy)-n-((1-(2-(4-chlorophenoxy)ethynazetidin-3-yl)methyl)acetamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases |
JP2020525513A (ja) | 2017-07-03 | 2020-08-27 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | 癌および他の疾患を治療するためのatf4阻害剤としてのn−(3−(2−(4−クロロフェノキシ)アセトアミドビシクロ[1.1.1]ペンタン−1−イル)−2−シクロブタン−1−カルボキサミド誘導体および関連化合物 |
JP7438098B2 (ja) * | 2017-07-06 | 2024-02-26 | メルス ナムローゼ フェンノートシャップ | 細胞により発現される生物学的活性を調節する結合分子 |
AU2018298676A1 (en) | 2017-07-10 | 2019-12-19 | Innate Pharma | Siglec-9-neutralizing antibodies |
WO2019014100A1 (en) | 2017-07-10 | 2019-01-17 | Celgene Corporation | ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF |
SG11202000248UA (en) | 2017-07-14 | 2020-02-27 | Innate Tumor Immunity Inc | Nlrp3 modulators |
WO2019016174A1 (en) | 2017-07-18 | 2019-01-24 | Institut Gustave Roussy | METHOD FOR ASSESSING RESPONSE TO TARGETING DRUG PD-1 / PDL-1 MEDICINES |
JP2020527572A (ja) | 2017-07-20 | 2020-09-10 | ノバルティス アーゲー | 抗lag−3抗体の投薬量レジメンおよびその使用 |
AU2018304458B2 (en) | 2017-07-21 | 2021-12-09 | Foundation Medicine, Inc. | Therapeutic and diagnostic methods for cancer |
US11926664B2 (en) | 2017-07-25 | 2024-03-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for modulating monocytopoiesis |
WO2019021208A1 (en) | 2017-07-27 | 2019-01-31 | Glaxosmithkline Intellectual Property Development Limited | USEFUL INDAZOLE DERIVATIVES AS PERK INHIBITORS |
EP3658914A1 (en) | 2017-07-28 | 2020-06-03 | Bristol-Myers Squibb Company | Predictive peripheral blood biomarker for checkpoint inhibitors |
WO2019023525A1 (en) * | 2017-07-28 | 2019-01-31 | Dana-Farber Cancer Institute, Inc. | ENHANCED IMMUNOTHERAPY OF CANCER USING TARGETED TRANSCRIPTION MODULATORS |
AU2018311966A1 (en) | 2017-08-04 | 2020-02-13 | Merck Sharp & Dohme Llc | Benzo[b]thiophene sting agonists for cancer treatment |
CN116333131A (zh) | 2017-08-04 | 2023-06-27 | 健玛保 | 与pd-l1和cd137结合的结合剂及其用途 |
WO2019027857A1 (en) | 2017-08-04 | 2019-02-07 | Merck Sharp & Dohme Corp. | COMBINATIONS OF PD-1 ANTAGONISTS AND STING BENZO [B] THIOPHENIC AGONISTS FOR THE TREATMENT OF CANCER |
JP2020530003A (ja) | 2017-08-07 | 2020-10-15 | アムジェン インコーポレイテッド | 抗pd−l1抗体及び腫瘍溶解性ウイルスでの、肝転移を伴う三種陰性乳がん又は結腸直腸がんの処置 |
WO2019035938A1 (en) | 2017-08-16 | 2019-02-21 | Elstar Therapeutics, Inc. | MULTISPECIFIC MOLECULES BINDING TO BCMA AND USES THEREOF |
MX2020001793A (es) | 2017-08-17 | 2020-07-22 | Ikena Oncology Inc | Inhibidores del receptor de hidrocarburos de arilo (ahr) y usos de los mismos. |
TWI785098B (zh) | 2017-08-18 | 2022-12-01 | 開曼群島商科賽睿生命科學公司 | Tg02之多晶型 |
CN111094982A (zh) | 2017-08-28 | 2020-05-01 | 百时美施贵宝公司 | 用于治疗和诊断癌症的tim-3拮抗剂 |
CN111278854A (zh) | 2017-09-04 | 2020-06-12 | 艾吉纳斯公司 | 与混合谱系白血病(mll)特异性磷酸肽结合的t细胞受体和其使用方法 |
UY37866A (es) | 2017-09-07 | 2019-03-29 | Glaxosmithkline Ip Dev Ltd | Nuevos compuestos derivados de benzoimidazol sustituidos que reducen la proteína myc (c-myc) en las células e inhiben la histona acetiltransferasa de p300/cbp. |
WO2019053617A1 (en) | 2017-09-12 | 2019-03-21 | Glaxosmithkline Intellectual Property Development Limited | CHEMICAL COMPOUNDS |
US11497756B2 (en) | 2017-09-12 | 2022-11-15 | Sumitomo Pharma Oncology, Inc. | Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib |
EP3684410A1 (en) | 2017-09-19 | 2020-07-29 | Institut Curie | Agonist of aryl hydrocarbon receptor for use in cancer combination therapy |
EP3684413A1 (en) | 2017-09-20 | 2020-07-29 | Chugai Seiyaku Kabushiki Kaisha | Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent |
JP7366031B2 (ja) | 2017-09-22 | 2023-10-20 | カイメラ セラピューティクス, インコーポレイテッド | タンパク質分解剤およびそれらの使用 |
WO2019060693A1 (en) | 2017-09-22 | 2019-03-28 | Kymera Therapeutics, Inc. | CRBN LIGANDS AND USES THEREOF |
WO2019060708A1 (en) * | 2017-09-22 | 2019-03-28 | The Children's Medical Center Corporation | TREATMENT OF TYPE 1 DIABETES AND AUTOIMMUNE DISEASES OR DISORDERS |
WO2019061324A1 (en) | 2017-09-29 | 2019-04-04 | Curis Inc. | CRYSTALLINE FORMS OF IMMUNOMODULATORS |
MX2020003770A (es) | 2017-09-30 | 2020-07-29 | Tesaro Inc | Terapias de combinacion para tratar cancer. |
EA039662B1 (ru) | 2017-10-03 | 2022-02-24 | Закрытое Акционерное Общество "Биокад" | Антитела, специфичные к cd47 и pd-l1 |
JP7291130B2 (ja) | 2017-10-05 | 2023-06-14 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド | インターフェロン遺伝子の刺激物質(sting)の調節物質 |
EP3692033A1 (en) | 2017-10-05 | 2020-08-12 | GlaxoSmithKline Intellectual Property Development Limited | Modulators of stimulator of interferon genes (sting) useful in treating hiv |
US11801240B2 (en) | 2017-10-06 | 2023-10-31 | Tesaro, Inc. | Combination therapies and uses thereof |
BR112020006809A2 (pt) | 2017-10-06 | 2020-10-06 | Innate Pharma | anticorpos, agente, uso, composto, composição farmacêutica, kits e composição ou uso |
EP3694541A2 (en) | 2017-10-09 | 2020-08-19 | Enterome S.A. | Microbiota sequence variants of tumor-related antigenic epitopes |
US11649212B2 (en) | 2017-10-09 | 2023-05-16 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
WO2019074824A1 (en) | 2017-10-09 | 2019-04-18 | Bristol-Myers Squibb Company | INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS AND METHODS OF USE |
KR20200063153A (ko) | 2017-10-10 | 2020-06-04 | 누맙 세러퓨틱스 아게 | Cd137을 표적화하는 항체 및 이의 사용 방법 |
EP3470426A1 (en) | 2017-10-10 | 2019-04-17 | Numab Therapeutics AG | Multispecific antibody |
WO2019072868A1 (en) | 2017-10-10 | 2019-04-18 | Numab Therapeutics AG | MULTISPECIFIC ANTIBODIES |
US11230601B2 (en) | 2017-10-10 | 2022-01-25 | Tilos Therapeutics, Inc. | Methods of using anti-lap antibodies |
BR112020006669A2 (pt) | 2017-10-11 | 2020-09-24 | Aurigene Discovery Technologies Limited | formas cristalinas de 1,2,4-oxadiazol 3-substituído |
CN111511766A (zh) | 2017-10-13 | 2020-08-07 | Ose免疫疗法 | 修饰的抗SIRPa抗体及其应用 |
US20200239577A1 (en) | 2017-10-15 | 2020-07-30 | Bristol-Myers Squibb Company | Methods of treating tumor |
CA3079310A1 (en) | 2017-10-18 | 2019-04-25 | Vivia Biotech, S.L. | Bite-activated car-t cells |
TW201925223A (zh) | 2017-10-18 | 2019-07-01 | 美商艾爾潘免疫科學有限公司 | 變異型icos 配位體免疫調節蛋白及相關組合物及方法 |
MX2020004074A (es) | 2017-10-19 | 2020-10-16 | Debiopharm Int Sa | Producto de combinacion para el tratamiento de cancer. |
EP3700933A1 (en) | 2017-10-25 | 2020-09-02 | Novartis AG | Antibodies targeting cd32b and methods of use thereof |
US11718679B2 (en) | 2017-10-31 | 2023-08-08 | Compass Therapeutics Llc | CD137 antibodies and PD-1 antagonists and uses thereof |
US20210132042A1 (en) | 2017-11-01 | 2021-05-06 | Juno Therapeutics, Inc. | Methods of assessing or monitoring a response to a cell therapy |
WO2019089921A1 (en) | 2017-11-01 | 2019-05-09 | Bristol-Myers Squibb Company | Immunostimulatory agonistic antibodies for use in treating cancer |
BR112020008323A2 (pt) | 2017-11-01 | 2020-11-03 | Juno Therapeutics Inc | anticorpos e receptores de antígenos quiméricos específicos para antígeno de maturação de células b |
EP3703692A4 (en) | 2017-11-01 | 2021-04-28 | Merck Sharp & Dohme Corp. | NEW SUBSTITUTED TETRAHYDROQUINOLINE COMPOUNDS USED AS INDOLEAMINE 2,3-DIOXYGENASE (IDO) INHIBITORS |
KR20200116077A (ko) | 2017-11-01 | 2020-10-08 | 주노 쎄러퓨티크스 인코퍼레이티드 | B 세포 성숙 항원에 특이적인 키메라 항원 수용체 및 암호화 폴리뉴클레오타이드 |
US20200237906A1 (en) * | 2017-11-02 | 2020-07-30 | Nanjing Shunxin Pharmaceutical Co., Ltd. | Pharmaceutical Composition of Humanized Monoclonal Anti-PD-L1 Antibody |
EA202090746A1 (ru) | 2017-11-03 | 2020-08-17 | Ориджен Дискавери Текнолоджис Лимитед | Двойные ингибиторы путей tim-3 и pd-1 |
CN111213059B (zh) | 2017-11-06 | 2024-01-09 | 豪夫迈·罗氏有限公司 | 用于癌症的诊断和治疗方法 |
ES2925450T3 (es) | 2017-11-06 | 2022-10-18 | Bristol Myers Squibb Co | Compuestos de isofuranona útiles como inhibidores de HPK1 |
KR20200084333A (ko) | 2017-11-06 | 2020-07-10 | 오리진 디스커버리 테크놀로지스 리미티드 | 면역조절을 위한 병행 요법 |
US20210292415A1 (en) | 2017-11-06 | 2021-09-23 | Bristol-Myers Squibb Company | Methods of treating a tumor |
AU2018363880B2 (en) * | 2017-11-08 | 2022-04-07 | Epiaxis Therapeutics Pty Ltd | Immunogenic compositions and uses therefor |
US20200353050A1 (en) | 2017-11-10 | 2020-11-12 | Armo Biosciences, Inc. | Compositions and methods of use of interleukin-10 in combination with immune check-point pathway inhibitors |
MX2020004930A (es) | 2017-11-14 | 2020-08-27 | Merck Sharp & Dohme | Compuestos de biarilo sustituido novedosos como inhibidores de indolamina 2,3-dioxigenasa (ido). |
WO2019099294A1 (en) | 2017-11-14 | 2019-05-23 | Merck Sharp & Dohme Corp. | Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
TWI698238B (zh) | 2017-11-14 | 2020-07-11 | 美商輝瑞股份有限公司 | Ezh2抑制劑組合治療 |
US20210079015A1 (en) | 2017-11-17 | 2021-03-18 | Novartis Ag | Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b |
AU2018367524B2 (en) | 2017-11-17 | 2022-09-15 | Merck Sharp & Dohme Llc | Antibodies specific for immunoglobulin-like transcript 3 (ILT3) and uses thereof |
BR112020010020A2 (pt) * | 2017-11-20 | 2020-11-10 | Taizhou Mabtech Pharmaceutical Co., Ltd | uma proteína de fusão bifuncional direcionada a cd47 e pd-l1 |
US11679148B2 (en) | 2017-11-24 | 2023-06-20 | Institut National De La Santé Et De La Recherche Médicale (Inserm) | Methods and compositions for treating cancers |
US11638760B2 (en) | 2017-11-27 | 2023-05-02 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
US11786529B2 (en) | 2017-11-29 | 2023-10-17 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors |
TW201925782A (zh) | 2017-11-30 | 2019-07-01 | 瑞士商諾華公司 | 靶向bcma之嵌合抗原受體及其用途 |
MX2020005562A (es) | 2017-11-30 | 2020-08-20 | Genentech Inc | Anticuerpos anti-pd-l1 y métodos para utilizarlos para la detección de pd-l1. |
MY181242A (en) * | 2017-12-01 | 2020-12-21 | Sbi Pharmaceuticals Co Ltd | Pharmaceutical composition for enhancing antitumor effect by immune checkpoint inhibitor |
CN111615521A (zh) * | 2017-12-04 | 2020-09-01 | 北京韩美药品有限公司 | 抗pd-l1/抗cd47天然抗体结构样异源二聚体形式双特异抗体及其制备 |
EP3720881A1 (en) | 2017-12-08 | 2020-10-14 | Elstar Therapeutics, Inc. | Multispecific molecules and uses thereof |
KR20200099178A (ko) | 2017-12-15 | 2020-08-21 | 얀센 바이오테크 인코포레이티드 | Sting 작용제로서의 환상 다이뉴클레오티드 |
WO2019118937A1 (en) | 2017-12-15 | 2019-06-20 | Juno Therapeutics, Inc. | Anti-cct5 binding molecules and methods of use thereof |
US11629189B2 (en) | 2017-12-19 | 2023-04-18 | Kymab Limited | Bispecific antibody for ICOS and PD-L1 |
GB201721338D0 (en) | 2017-12-19 | 2018-01-31 | Kymab Ltd | Anti-icos Antibodies |
CN111741976A (zh) | 2017-12-19 | 2020-10-02 | F星贝塔有限公司 | 包括pd-l1抗原结合位点的fc结合片段 |
JP2021507906A (ja) | 2017-12-20 | 2021-02-25 | ノバルティス アーゲー | 抗ウイルス剤としての融合三環式ピラゾロ−ジヒドロピラジニル−ピリドン化合物 |
US11685761B2 (en) | 2017-12-20 | 2023-06-27 | Merck Sharp & Dohme Llc | Cyclic di-nucleotide compounds as sting agonists |
TW201929908A (zh) | 2017-12-21 | 2019-08-01 | 美商梅爾莎納醫療公司 | 吡咯并苯并二氮呯抗體共軛物 |
BR112020012997A2 (pt) | 2017-12-26 | 2020-12-01 | Kymera Therapeutics, Inc. | degradadores de irak e usos dos mesmos |
CN109970857B (zh) | 2017-12-27 | 2022-09-30 | 信达生物制药(苏州)有限公司 | 抗pd-l1抗体及其用途 |
WO2019129054A1 (zh) | 2017-12-27 | 2019-07-04 | 信达生物制药(苏州)有限公司 | 三链抗体、其制备方法及其用途 |
WO2019129137A1 (zh) | 2017-12-27 | 2019-07-04 | 信达生物制药(苏州)有限公司 | 抗lag-3抗体及其用途 |
CN111788227A (zh) | 2017-12-27 | 2020-10-16 | 百时美施贵宝公司 | 抗cd40抗体及其用途 |
CN109970856B (zh) | 2017-12-27 | 2022-08-23 | 信达生物制药(苏州)有限公司 | 抗lag-3抗体及其用途 |
WO2019129136A1 (zh) | 2017-12-27 | 2019-07-04 | 信达生物制药(苏州)有限公司 | 抗pd-l1抗体及其用途 |
TW201930350A (zh) * | 2017-12-28 | 2019-08-01 | 大陸商南京傳奇生物科技有限公司 | 針對pd-l1之抗體及其變異體 |
US11865081B2 (en) | 2017-12-29 | 2024-01-09 | Virogin Biotech Canada Ltd. | Oncolytic viral delivery of therapeutic polypeptides |
CN111867619A (zh) * | 2018-01-03 | 2020-10-30 | 曲生物制品公司 | 过继性细胞治疗的先天寻靶 |
EP3735590A1 (en) | 2018-01-04 | 2020-11-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
WO2019136112A1 (en) | 2018-01-05 | 2019-07-11 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
EP3737408A1 (en) | 2018-01-08 | 2020-11-18 | Novartis AG | Immune-enhancing rnas for combination with chimeric antigen receptor therapy |
WO2019139921A1 (en) | 2018-01-09 | 2019-07-18 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
WO2019137397A1 (zh) * | 2018-01-10 | 2019-07-18 | 江苏恒瑞医药股份有限公司 | Pd-l1抗体、其抗原结合片段及医药用途 |
CA3084370A1 (en) | 2018-01-12 | 2019-07-18 | Bristol-Myers Squibb Company | Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer |
US20210177781A9 (en) | 2018-01-12 | 2021-06-17 | KDAc Therapeutics, Inc. | Combination of a selective histone deacetylase 3 (hdac3) inhibitor and an immunotherapy agent for the treatment of cancer |
CN111886255A (zh) | 2018-01-12 | 2020-11-03 | 百时美施贵宝公司 | 抗tim3抗体及其用途 |
US11485743B2 (en) | 2018-01-12 | 2022-11-01 | Kymera Therapeutics, Inc. | Protein degraders and uses thereof |
WO2019140387A1 (en) | 2018-01-12 | 2019-07-18 | Kymera Therapeutics, Inc. | Crbn ligands and uses thereof |
KR20200109339A (ko) | 2018-01-16 | 2020-09-22 | 브리스톨-마이어스 스큅 컴퍼니 | Tim3에 대한 항체를 사용하여 암을 치료하는 방법 |
EP3740509A4 (en) | 2018-01-17 | 2022-06-22 | Apexigen, Inc. | ANTI-PD-L1 ANTIBODIES AND METHODS OF USE |
WO2019144126A1 (en) | 2018-01-22 | 2019-07-25 | Pascal Biosciences Inc. | Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells |
BR112020014574A2 (pt) | 2018-01-22 | 2020-12-08 | Bristol-Myers Squibb Company | Composições e métodos para o tratamento do câncer |
US11786523B2 (en) | 2018-01-24 | 2023-10-17 | Beyondspring Pharmaceuticals, Inc. | Composition and method for reducing thrombocytopenia |
CA3089769A1 (en) | 2018-01-29 | 2019-08-01 | Merck Patent Gmbh | Gcn2 inhibitors and uses thereof |
SG11202006701TA (en) | 2018-01-29 | 2020-08-28 | Merck Patent Gmbh | Gcn2 inhibitors and uses thereof |
JP7383620B2 (ja) | 2018-01-31 | 2023-11-20 | セルジーン コーポレイション | 養子細胞療法およびチェックポイント阻害剤を使用する併用療法 |
EP3746116A1 (en) | 2018-01-31 | 2020-12-09 | Novartis AG | Combination therapy using a chimeric antigen receptor |
WO2019152979A1 (en) | 2018-02-05 | 2019-08-08 | Orionis Biosciences, Inc. | Fibroblast binding agents and use thereof |
WO2019157124A1 (en) | 2018-02-08 | 2019-08-15 | Bristol-Myers Squibb Company | Combination of a tetanus toxoid, anti-ox40 antibody and/or anti-pd-1 antibody to treat tumors |
EP3752203A1 (en) | 2018-02-13 | 2020-12-23 | Novartis AG | Chimeric antigen receptor therapy in combination with il-15r and il15 |
EP3756012A1 (en) | 2018-02-21 | 2020-12-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
WO2019165315A1 (en) | 2018-02-23 | 2019-08-29 | Syntrix Biosystems Inc. | Method for treating cancer using chemokine antagonists alone or in combination |
AU2019225249A1 (en) | 2018-02-26 | 2020-09-17 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-PD-L1 antagonist antibodies |
TW202000666A (zh) | 2018-02-27 | 2020-01-01 | 美商英塞特公司 | 作為a2a/a2b抑制劑之咪唑并嘧啶及三唑并嘧啶 |
US20200405763A1 (en) * | 2018-02-27 | 2020-12-31 | The Methodist Hospital System | Irf-4 engineered t cells and uses thereof in treating cancer |
CN111801331A (zh) | 2018-02-28 | 2020-10-20 | 诺华股份有限公司 | 吲哚-2-羰基化合物及其用于治疗乙型肝炎的用途 |
CA3090620A1 (en) | 2018-03-06 | 2019-09-12 | Institut Curie | Inhibitor of setdb1 histone methyltransferase for use in cancer combination therapy |
RU2020133451A (ru) | 2018-03-12 | 2022-04-12 | Инститьют Насьонал Де Ла Санте Et De La Решерш Медикаль (Инсерм) | Применение терапевтически эффективной комбинации химиотерапиии и ингибитора контрольной точки иммунного ответа с миметиком ограничения калорийности для лечения рака |
JP2021517130A (ja) | 2018-03-13 | 2021-07-15 | オーセ イミュノセラピューティクスOse Immunotherapeutics | 抗ヒトSIRPav1抗体の使用および抗v1抗体を製造する方法 |
EP3766499A4 (en) * | 2018-03-13 | 2021-04-21 | Osaka University | TUMOR IMMUNE STIMULATOR |
WO2019178362A1 (en) | 2018-03-14 | 2019-09-19 | Elstar Therapeutics, Inc. | Multifunctional molecules that bind to calreticulin and uses thereof |
US20210009711A1 (en) | 2018-03-14 | 2021-01-14 | Elstar Therapeutics, Inc. | Multifunctional molecules and uses thereof |
WO2019175243A1 (en) | 2018-03-14 | 2019-09-19 | Merck Patent Gmbh | Compounds and uses thereof to treat tumors in a subject |
MX2021015518A (es) | 2018-03-14 | 2022-07-21 | Surface Oncology Inc | Anticuerpos que se unen a cd39 y sus usos. |
US20210017283A1 (en) | 2018-03-21 | 2021-01-21 | Five Prime Therapeutics, Inc. | Antibodies Binding to Vista at Acidic pH |
US11332524B2 (en) | 2018-03-22 | 2022-05-17 | Surface Oncology, Inc. | Anti-IL-27 antibodies and uses thereof |
AU2019236865A1 (en) | 2018-03-23 | 2020-10-01 | Bristol-Myers Squibb Company | Antibodies against MICA and/or MICB and uses thereof |
WO2019184909A1 (zh) | 2018-03-27 | 2019-10-03 | 信达生物制药(苏州)有限公司 | 新型抗体分子、其制备方法及其用途 |
CN110305210B (zh) | 2018-03-27 | 2023-02-28 | 信达生物制药(苏州)有限公司 | 新型抗体分子、其制备方法及其用途 |
CN108546298B (zh) * | 2018-03-29 | 2021-05-14 | 中国人民解放军军事科学院军事医学研究院 | 一种特异性结合pd-1的单克隆抗体 |
WO2019185792A1 (en) | 2018-03-29 | 2019-10-03 | Philogen S.P.A | Cancer treatment using immunoconjugates and immune check-point inhibitors |
CN108546299B (zh) * | 2018-03-29 | 2019-09-24 | 中国人民解放军军事科学院军事医学研究院 | 解除pd-1对机体免疫抑制的靶向分子 |
JP2021519771A (ja) | 2018-03-30 | 2021-08-12 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 腫瘍を処置する方法 |
US11952424B2 (en) | 2018-03-30 | 2024-04-09 | Merus N.V. | Multivalent antibody |
EP3774765A4 (en) | 2018-04-03 | 2021-12-29 | Merck Sharp & Dohme Corp. | Aza-benzothiophene compounds as sting agonists |
KR20200139203A (ko) | 2018-04-03 | 2020-12-11 | 머크 샤프 앤드 돔 코포레이션 | Sting 효능제로서의 벤조티오펜 및 관련 화합물 |
JP2021520201A (ja) | 2018-04-04 | 2021-08-19 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 抗cd27抗体およびその使用 |
US11874276B2 (en) | 2018-04-05 | 2024-01-16 | Dana-Farber Cancer Institute, Inc. | STING levels as a biomarker for cancer immunotherapy |
WO2019193540A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Heteroaryl derivatives of formula (i) as atf4 inhibitors |
WO2019193541A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors |
CN112218657A (zh) | 2018-04-12 | 2021-01-12 | 百时美施贵宝公司 | Cd73拮抗剂抗体和pd-1/pd-l1轴拮抗剂抗体的抗癌组合疗法 |
US20210147547A1 (en) | 2018-04-13 | 2021-05-20 | Novartis Ag | Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof |
AU2019254237A1 (en) | 2018-04-16 | 2020-12-03 | Onquality Pharmaceuticals China Ltd. | Method for preventing or treating side effects of cancer therapy |
CN108727504B (zh) * | 2018-04-16 | 2021-08-27 | 泉州向日葵生物科技有限公司 | 一种ifn与抗pd-l1抗体的融合蛋白及其应用 |
WO2019204257A1 (en) | 2018-04-16 | 2019-10-24 | Arrys Therapeutics, Inc. | Ep4 inhibitors and use thereof |
US10968201B2 (en) | 2018-04-17 | 2021-04-06 | Tempest Therapeutics, Inc. | Bicyclic carboxamides and methods of use thereof |
MX2020010910A (es) | 2018-04-18 | 2021-02-09 | Xencor Inc | Proteinas de fusion heterodimericas dirigidas a pd-1 que contienen proteinas de fusion il-15 / il-15ra fc y dominios de union al antigeno pd-1 y usos de los mismos. |
CA3097625A1 (en) | 2018-04-18 | 2019-10-24 | Xencor, Inc. | Il-15/il-15ra heterodimeric fc fusion proteins and uses thereof |
EP3781689A1 (en) | 2018-04-19 | 2021-02-24 | Checkmate Pharmaceuticals, Inc. | Synthetic rig-i-like receptor agonists |
EP3781687A4 (en) | 2018-04-20 | 2022-02-09 | Merck Sharp & Dohme Corp. | NEW RIG-I SUBSTITUTED AGONISTS: COMPOSITIONS AND METHODS THEREOF |
BR112020021539A2 (pt) | 2018-04-25 | 2021-01-19 | Innate Tumor Immunity, Inc. | Moduladores de nlrp3 |
EP3784688A2 (en) | 2018-04-26 | 2021-03-03 | Agenus Inc. | Heat shock protein-binding peptide compositions and methods of use thereof |
WO2019207030A1 (en) | 2018-04-26 | 2019-10-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting a response with an immune checkpoint inhibitor in a patient suffering from a lung cancer |
EP3784351A1 (en) | 2018-04-27 | 2021-03-03 | Novartis AG | Car t cell therapies with enhanced efficacy |
EP3788369A1 (en) | 2018-05-01 | 2021-03-10 | Novartis Ag | Biomarkers for evaluating car-t cells to predict clinical outcome |
WO2019213340A1 (en) | 2018-05-03 | 2019-11-07 | Bristol-Myers Squibb Company | Uracil derivatives as mer-axl inhibitors |
WO2019211492A1 (en) | 2018-05-04 | 2019-11-07 | Tollys | Tlr3 ligands that activate both epithelial and myeloid cells |
TW202014201A (zh) | 2018-05-04 | 2020-04-16 | 德商馬克專利公司 | 用於治療癌症之PD-1/PD-L1,TGFβ及DNA-PK之組合抑制 |
KR20210018265A (ko) | 2018-05-04 | 2021-02-17 | 인사이트 코포레이션 | Fgfr 억제제의 고체 형태 및 이의 제조 방법 |
SG11202010882XA (en) | 2018-05-04 | 2020-11-27 | Incyte Corp | Salts of an fgfr inhibitor |
SG11202011117VA (en) | 2018-05-15 | 2020-12-30 | Medimmune Ltd | Treatment of cancer |
GB201807924D0 (en) | 2018-05-16 | 2018-06-27 | Ctxt Pty Ltd | Compounds |
CA3100731A1 (en) | 2018-05-18 | 2019-11-21 | Incyte Corporation | Fused pyrimidine derivatives as a2a / a2b inhibitors |
BR112020023756A2 (pt) | 2018-05-23 | 2021-02-09 | Celgene Corporation | tratamento de mieloma múltiplo e uso de biomarcadores para 4-(4-(4-(((2-(2,6-dioxopiperidin-3-il)-1-oxoisoindolin-4-il)oxi)metil)benzil)piperazin-1-il)-3-fluorobenzonitrila |
JP7293256B2 (ja) | 2018-05-23 | 2023-06-19 | セルジーン コーポレイション | 併用のためのbcma及びcd3に対する抗増殖性化合物及び二重特異性抗体 |
AR126019A1 (es) | 2018-05-30 | 2023-09-06 | Novartis Ag | Anticuerpos frente a entpd2, terapias de combinación y métodos de uso de los anticuerpos y las terapias de combinación |
WO2019232244A2 (en) | 2018-05-31 | 2019-12-05 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
TW202017569A (zh) | 2018-05-31 | 2020-05-16 | 美商佩樂敦治療公司 | 用於抑制cd73之組合物及方法 |
US11352320B2 (en) | 2018-05-31 | 2022-06-07 | Merck Sharp & Dohme Corp. | Substituted [1.1.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors |
CN112165974A (zh) | 2018-05-31 | 2021-01-01 | 诺华股份有限公司 | 乙型肝炎抗体 |
TW202016136A (zh) | 2018-06-01 | 2020-05-01 | 瑞士商諾華公司 | 針對bcma之結合分子及其用途 |
CN112512578A (zh) | 2018-06-01 | 2021-03-16 | 诺华股份有限公司 | 结合cd123和cd3的双特异性抗体的给药 |
CN112566938A (zh) | 2018-06-03 | 2021-03-26 | 拉姆卡普生物测试有限公司 | 针对ceacam5和cd47的双特异性抗体 |
CN110563842B (zh) * | 2018-06-06 | 2022-07-29 | 浙江博锐生物制药有限公司 | 针对程序性死亡配体(pd-l1)的抗体及其应用 |
US11266615B2 (en) | 2018-06-08 | 2022-03-08 | Harrow Ip, Llc | Pyrimethamine-based pharmaceutical compositions and methods for fabricating thereof |
EP3813803A1 (en) | 2018-06-08 | 2021-05-05 | Harrow IP, LLC | Pyrimethamine-based pharmaceutical compositions and methods for fabricating thereof |
MX2020013443A (es) | 2018-06-13 | 2021-02-26 | Novartis Ag | Receptores de antigeno quimerico de bcma y usos de los mismos. |
KR20210035805A (ko) | 2018-06-15 | 2021-04-01 | 플래그쉽 파이어니어링 이노베이션스 브이, 인크. | 세포후 신호전달 인자의 조절을 통한 면역 활성의 증가 |
CN112334486A (zh) | 2018-06-18 | 2021-02-05 | 先天制药公司 | 用于治疗癌症的组合物和方法 |
JP7097465B2 (ja) | 2018-06-19 | 2022-07-07 | アルモ・バイオサイエンシーズ・インコーポレイテッド | キメラ抗原受容体細胞療法と併用するil-10剤の組成およびその使用方法 |
US11180531B2 (en) | 2018-06-22 | 2021-11-23 | Bicycletx Limited | Bicyclic peptide ligands specific for Nectin-4 |
MA52968A (fr) | 2018-06-23 | 2021-04-28 | Hoffmann La Roche | Méthodes de traitement du cancer du poumon à l'aide d'un antagoniste de liaison à l'axe pd-1, d'un agent de platine et d'un inhibiteur de la topoisomérase ii |
WO2020006016A1 (en) | 2018-06-27 | 2020-01-02 | Bristol-Myers Squibb Company | Naphthyridinone compounds useful as t cell activators |
PE20210469A1 (es) | 2018-06-27 | 2021-03-08 | Bristol Myers Squibb Co | Compuestos de naftiridinona sustituidos utiles como activadores de celulas t |
CA3105448A1 (en) | 2018-07-03 | 2020-01-09 | Elstar Therapeutics, Inc. | Anti-tcr antibody molecules and uses thereof |
EP3818082A1 (en) | 2018-07-04 | 2021-05-12 | F. Hoffmann-La Roche AG | Novel bispecific agonistic 4-1bb antigen binding molecules |
WO2020010177A1 (en) | 2018-07-06 | 2020-01-09 | Kymera Therapeutics, Inc. | Tricyclic crbn ligands and uses thereof |
TWI819024B (zh) | 2018-07-09 | 2023-10-21 | 美商戊瑞治療有限公司 | 結合至ilt4的抗體 |
US20210253528A1 (en) | 2018-07-09 | 2021-08-19 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
AU2019301944B2 (en) | 2018-07-10 | 2022-02-24 | Novartis Ag | 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of IKAROS Family Zinc Finger 2 (IKZF2)-dependent diseases |
CN112673092B (zh) | 2018-07-11 | 2024-03-29 | 阿克蒂姆治疗有限公司 | 工程化的免疫刺激性细菌菌株及其用途 |
PE20210687A1 (es) | 2018-07-11 | 2021-04-08 | Bristol Myers Squibb Co | Anticuerpos de union a vista a ph acido |
GB201811408D0 (en) | 2018-07-12 | 2018-08-29 | F Star Beta Ltd | CD137 Binding Molecules |
WO2020011966A1 (en) | 2018-07-12 | 2020-01-16 | F-Star Beta Limited | Antibody molecules that bind cd137 and ox40 |
BR112021000394A2 (pt) | 2018-07-12 | 2021-04-06 | F-Star Beta Limited | Moléculas de anticorpo que se ligam a pd-l1 e cd137 |
WO2020014583A1 (en) | 2018-07-13 | 2020-01-16 | Bristol-Myers Squibb Company | Ox-40 agonist, pd-1 pathway inhibitor and ctla-4 inhibitor combination for use in a mehtod of treating a cancer or a solid tumor |
KR20210034622A (ko) | 2018-07-18 | 2021-03-30 | 제넨테크, 인크. | Pd-1 축 결합 길항제, 항 대사제, 및 백금 제제를 이용한 폐암 치료 방법 |
KR20210032488A (ko) | 2018-07-20 | 2021-03-24 | 서피스 온콜로지, 인크. | 항-cd112r 조성물 및 방법 |
US20210355113A1 (en) | 2018-07-23 | 2021-11-18 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
WO2020023355A1 (en) | 2018-07-23 | 2020-01-30 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
TW202012405A (zh) | 2018-07-24 | 2020-04-01 | 瑞士商赫孚孟拉羅股份公司 | 萘啶化合物及其用途 |
US20210301020A1 (en) | 2018-07-24 | 2021-09-30 | Amgen Inc. | Combination of lilrb1/2 pathway inhibitors and pd-1 pathway inhibitors |
EP3826722A1 (en) | 2018-07-24 | 2021-06-02 | F. Hoffmann-La Roche AG | Isoquinoline compounds and uses thereof |
CN112041348B (zh) | 2018-07-25 | 2023-09-22 | 天境生物科技(上海)有限公司 | 抗cd73抗pd-l1双特异性抗体 |
EP3826660A1 (en) | 2018-07-26 | 2021-06-02 | Bristol-Myers Squibb Company | Lag-3 combination therapy for the treatment of cancer |
US20210236633A1 (en) | 2018-08-06 | 2021-08-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
WO2020031107A1 (en) | 2018-08-08 | 2020-02-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
JP2021534101A (ja) | 2018-08-09 | 2021-12-09 | ヴェルソー セラピューティクス, インコーポレイテッド | Ccr2及びcsf1rを標的とするためのオリゴヌクレオチド組成物ならびにその使用 |
CN112601761A (zh) | 2018-08-13 | 2021-04-02 | 印希比股份有限公司 | 结合ox40的多肽及其用途 |
CN113038989A (zh) | 2018-08-16 | 2021-06-25 | 先天肿瘤免疫公司 | 咪唑并[4,5-c]喹啉衍生的nlrp3调节剂 |
CN112888677A (zh) | 2018-08-16 | 2021-06-01 | 先天肿瘤免疫公司 | 被取代的4-氨基-1H-咪唑并[4,5-c]喹啉化合物及其改进的制备方法 |
CN112996567A (zh) | 2018-08-16 | 2021-06-18 | 先天肿瘤免疫公司 | 咪唑并[4,5-c]喹啉衍生的nlrp3-调节剂 |
AU2019324388A1 (en) * | 2018-08-20 | 2021-03-18 | 1Globe Biomedical Co., Ltd. | Novel cancer immunotherapy antibody compositions |
EP3843849A1 (en) | 2018-08-27 | 2021-07-07 | Pieris Pharmaceuticals GmbH | Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof |
US10959986B2 (en) | 2018-08-29 | 2021-03-30 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
WO2020044206A1 (en) | 2018-08-29 | 2020-03-05 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors for use in the treatment cancer |
US11253525B2 (en) | 2018-08-29 | 2022-02-22 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
JP7397874B2 (ja) | 2018-08-30 | 2023-12-13 | エイチシーダブリュー バイオロジックス インコーポレイテッド | 多鎖キメラポリペプチドおよびその使用 |
SG11202101780WA (en) | 2018-08-30 | 2021-03-30 | Hcw Biologics Inc | Single-chain chimeric polypeptides and uses thereof |
CA3109361A1 (en) | 2018-08-30 | 2020-03-05 | HCW Biologics, Inc. | Single-chain and multi-chain chimeric polypeptides and uses thereof |
TW202031273A (zh) | 2018-08-31 | 2020-09-01 | 美商艾歐凡斯生物治療公司 | 抗pd-1抗體難治療性之非小細胞肺癌(nsclc)病患的治療 |
TW202024023A (zh) | 2018-09-03 | 2020-07-01 | 瑞士商赫孚孟拉羅股份公司 | 治療性化合物及其使用方法 |
WO2020048942A1 (en) | 2018-09-04 | 2020-03-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cytotoxic t lymphocyte-dependent immune responses |
WO2020051333A1 (en) | 2018-09-07 | 2020-03-12 | Pfizer Inc. | Anti-avb8 antibodies and compositions and uses thereof |
JP2021536476A (ja) * | 2018-09-07 | 2021-12-27 | ザ ジェネラル ホスピタル コーポレイション | 免疫チェックポイント阻害のための組成物および方法 |
EP3846793B1 (en) | 2018-09-07 | 2024-01-24 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
WO2020053742A2 (en) | 2018-09-10 | 2020-03-19 | Novartis Ag | Anti-hla-hbv peptide antibodies |
CA3112326A1 (en) | 2018-09-12 | 2020-03-19 | Novartis Ag | Antiviral pyridopyrazinedione compounds |
CA3111401A1 (en) | 2018-09-19 | 2020-03-26 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
EP3852752A1 (en) | 2018-09-19 | 2021-07-28 | F. Hoffmann-La Roche AG | Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof |
JP2022511337A (ja) | 2018-09-19 | 2022-01-31 | インサーム (インスティテュート ナショナル デ ラ サンテ エ デ ラ ルシェルシェ メディカル) | 免疫チェックポイント治療に抵抗性のある癌の治療のための方法および医薬組成物 |
BR112021003678A2 (pt) | 2018-09-20 | 2021-05-18 | Iovance Biotherapeutics, Inc. | métodos para criopreservar tecido de tumor, para fabricar, para preparar e para expandir linfócitos infiltrantes de tumor, para tratar um indivíduo com câncer e para tratar câncer para um indivíduo humano, e, fragmento de tumor criopreservado . |
EP3857230B1 (en) | 2018-09-21 | 2023-06-07 | F. Hoffmann-La Roche AG | Diagnostic methods for triple-negative breast cancer |
JP7425049B2 (ja) | 2018-09-25 | 2024-01-30 | ハープーン セラピューティクス,インク. | Dll3結合タンパク質および使用方法 |
KR20210066837A (ko) | 2018-09-26 | 2021-06-07 | 메르크 파텐트 게엠베하 | 암 치료를 위한 pd-1 안타고니스트, atr 억제제 및 백금화제의 조합 |
JP7465272B2 (ja) | 2018-09-27 | 2024-04-10 | マレンゴ・セラピューティクス,インコーポレーテッド | Csf1r/ccr2多特異性抗体 |
US20210347851A1 (en) | 2018-09-28 | 2021-11-11 | Novartis Ag | Cd19 chimeric antigen receptor (car) and cd22 car combination therapies |
CN110960679A (zh) * | 2018-09-28 | 2020-04-07 | 江苏康缘药业股份有限公司 | 一种抗肿瘤的药物组合物及其应用 |
US20220047633A1 (en) | 2018-09-28 | 2022-02-17 | Novartis Ag | Cd22 chimeric antigen receptor (car) therapies |
IL305106A (en) | 2018-09-29 | 2023-10-01 | Novartis Ag | A process for producing a compound to inhibit the activity of SHP2 |
JP7433304B2 (ja) | 2018-09-30 | 2024-02-19 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | シンノリン化合物および癌などのhpk1依存性障害の治療 |
WO2020070053A1 (en) | 2018-10-01 | 2020-04-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of inhibitors of stress granule formation for targeting the regulation of immune responses |
TW202024053A (zh) | 2018-10-02 | 2020-07-01 | 美商建南德克公司 | 異喹啉化合物及其用途 |
WO2020072695A1 (en) | 2018-10-03 | 2020-04-09 | Genentech, Inc. | 8-aminoisoquinoline compounds and uses thereof |
EP3861016A2 (en) | 2018-10-03 | 2021-08-11 | Xencor, Inc. | Il-12 heterodimeric fc-fusion proteins |
CN112839962A (zh) | 2018-10-09 | 2021-05-25 | 百时美施贵宝公司 | 用于治疗癌症的抗mertk抗体 |
TW202035445A (zh) | 2018-10-10 | 2020-10-01 | 美商帝洛斯療法股份有限公司 | 抗lap抗體變異體及其用途 |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11377477B2 (en) | 2018-10-12 | 2022-07-05 | Xencor, Inc. | PD-1 targeted IL-15/IL-15RALPHA fc fusion proteins and uses in combination therapies thereof |
CN112867803A (zh) | 2018-10-16 | 2021-05-28 | 诺华股份有限公司 | 单独的或与免疫标志物组合的肿瘤突变负荷作为生物标志物用于预测对靶向疗法的应答 |
WO2020081493A1 (en) | 2018-10-16 | 2020-04-23 | Molecular Templates, Inc. | Pd-l1 binding proteins |
CA3116324A1 (en) | 2018-10-18 | 2020-04-23 | Genentech, Inc. | Diagnostic and therapeutic methods for sarcomatoid kidney cancer |
JP2022505113A (ja) | 2018-10-18 | 2022-01-14 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 固形腫瘍の処置のためのβig-h3アンタゴニストと免疫チェックポイント阻害剤との組み合わせ |
CN113286611A (zh) | 2018-10-19 | 2021-08-20 | 百时美施贵宝公司 | 用于黑色素瘤的组合疗法 |
MX2021004603A (es) | 2018-10-22 | 2021-09-08 | Glaxosmithkline Ip Dev Ltd | Dosificacion. |
JP2022505647A (ja) | 2018-10-23 | 2022-01-14 | ブリストル-マイヤーズ スクイブ カンパニー | 腫瘍の処置方法 |
US11564995B2 (en) | 2018-10-29 | 2023-01-31 | Wisconsin Alumni Research Foundation | Peptide-nanoparticle conjugates |
CA3117050A1 (en) | 2018-10-29 | 2020-05-07 | Mersana Therapeutics, Inc. | Cysteine engineered antibody-drug conjugates with peptide-containing linkers |
KR20210084552A (ko) | 2018-10-29 | 2021-07-07 | 위스콘신 얼럼나이 리서어치 화운데이션 | 향상된 암 면역요법을 위한 면역관문 억제제와 복합체화된 덴드리틱 폴리머 |
WO2020089811A1 (en) | 2018-10-31 | 2020-05-07 | Novartis Ag | Dc-sign antibody drug conjugates |
JP2022512917A (ja) | 2018-11-01 | 2022-02-07 | ジュノー セラピューティクス インコーポレイテッド | B細胞成熟抗原に特異的なキメラ抗原受容体を使用する処置方法 |
EP3873464A4 (en) | 2018-11-01 | 2022-06-08 | Merck Sharp & Dohme Corp. | NOVEL SUBSTITUTED PYRAZOLE COMPOUNDS AS INDOLAMINE-2,3-DIOXYGENASE INHIBITORS |
JP2022506598A (ja) | 2018-11-01 | 2022-01-17 | ジュノー セラピューティクス インコーポレイテッド | Gタンパク質共役受容体クラスcグループ5メンバーd(gprc5d)に特異的なキメラ抗原受容体 |
US20210403469A1 (en) | 2018-11-06 | 2021-12-30 | Merck Sharp & Dohme Corp. | Novel substituted tricyclic compounds as indoleamine 2,3-dioxygenase inhibitors |
CN113454111A (zh) | 2018-11-06 | 2021-09-28 | 健玛保 | 抗体配制剂 |
US20220001026A1 (en) | 2018-11-08 | 2022-01-06 | Modernatx, Inc. | Use of mrna encoding ox40l to treat cancer in human patients |
KR20210091152A (ko) | 2018-11-14 | 2021-07-21 | 바이엘 악티엔게젤샤프트 | 암의 치료를 위한 항-ceacam6 및 항-pd-1 또는 항-pd-l1 항체의 제약 조합물 |
WO2020102375A1 (en) | 2018-11-14 | 2020-05-22 | Regeneron Pharmaceuticals, Inc. | Intralesional administration of pd-1 inhibitors for treating skin cancer |
TW202028222A (zh) | 2018-11-14 | 2020-08-01 | 美商Ionis製藥公司 | Foxp3表現之調節劑 |
AU2019380307A1 (en) | 2018-11-16 | 2021-07-01 | Bristol-Myers Squibb Company | Anti-NKG2A antibodies and uses thereof |
EP3880231A1 (en) | 2018-11-16 | 2021-09-22 | NeoImmuneTech, Inc. | Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor |
KR20210104713A (ko) | 2018-11-16 | 2021-08-25 | 주노 쎄러퓨티크스 인코퍼레이티드 | B 세포 악성 종양 치료를 위한 조작된 t 세포 투약 방법 |
WO2020102804A2 (en) | 2018-11-16 | 2020-05-22 | Arqule, Inc. | Pharmaceutical combination for treatment of cancer |
WO2020106560A1 (en) | 2018-11-20 | 2020-05-28 | Merck Sharp & Dohme Corp. | Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use |
WO2020104496A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Bispecific antibody targeting transferrin receptor 1 and soluble antigen |
JP2022507734A (ja) | 2018-11-20 | 2022-01-18 | メルク・シャープ・アンド・ドーム・コーポレーション | 置換アミノトリアゾロピリミジン及びアミノトリアゾロピラジンアデノシン受容体アンタゴニスト、医薬組成物及びそれらの使用 |
AU2019385497A1 (en) | 2018-11-20 | 2021-06-17 | Cornell University | Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer |
WO2020104479A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies |
EP3886842A1 (en) | 2018-11-26 | 2021-10-06 | Debiopharm International SA | Combination treatment of hiv infections |
EP3887397A1 (en) | 2018-11-28 | 2021-10-06 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
US20230008022A1 (en) | 2018-11-28 | 2023-01-12 | Merck Sharp & Dohme Corp. | Novel substituted piperazine amide compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
US20220018828A1 (en) | 2018-11-28 | 2022-01-20 | Inserm (Institut National De La Santé Et La Recherche Médicale | Methods and kit for assaying lytic potential of immune effector cells |
WO2020109570A1 (en) | 2018-11-30 | 2020-06-04 | Gbg Forschungs Gmbh | Method for predicting the response to cancer immunotherapy in cancer patients |
JOP20210117A1 (ar) | 2018-11-30 | 2023-01-30 | Merck Sharp & Dohme | مشتقات أمينو ترايازولو كوينازولين بها استبدال في الموضع-9 كمضادات مستقبل أدينوزين، تركيبات صيدلانية واستخدامها |
KR20210117260A (ko) | 2018-11-30 | 2021-09-28 | 주노 쎄러퓨티크스 인코퍼레이티드 | 입양 세포 요법을 사용한 치료방법 |
IL310831A (en) | 2018-11-30 | 2024-04-01 | Glaxosmithkline Ip Dev Ltd | Compounds useful in curing HIV |
WO2020113233A1 (en) | 2018-11-30 | 2020-06-04 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
EP3891508A1 (en) | 2018-12-04 | 2021-10-13 | Bristol-Myers Squibb Company | Methods of analysis using in-sample calibration curve by multiple isotopologue reaction monitoring |
EP3890749A4 (en) | 2018-12-04 | 2022-08-03 | Sumitomo Dainippon Pharma Oncology, Inc. | CDK9 INHIBITORS AND POLYMORPHS THEREOF FOR USE AS CANCER TREATMENT AGENT |
JP2022511502A (ja) | 2018-12-05 | 2022-01-31 | ジェネンテック, インコーポレイテッド | がんの免疫療法のための診断方法及び診断用組成物 |
WO2020115261A1 (en) | 2018-12-07 | 2020-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2020115262A1 (en) | 2018-12-07 | 2020-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of cd26 and cd39 as new phenotypic markers for assessing maturation of foxp3+ t cells and uses thereof for diagnostic purposes |
EP3894401A2 (en) | 2018-12-11 | 2021-10-20 | Theravance Biopharma R&D IP, LLC | Naphthyridine and quinoline derivatives useful as alk5 inhibitors |
WO2020120592A1 (en) | 2018-12-12 | 2020-06-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating melanoma |
EP3897624A1 (en) | 2018-12-17 | 2021-10-27 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Use of sulconazole as a furin inhibitor |
WO2020127411A1 (en) | 2018-12-19 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d |
TW202039542A (zh) | 2018-12-19 | 2020-11-01 | 美商庫爾生物製藥有限公司 | 多聚體t細胞調節多肽及其使用方法 |
EP3670659A1 (en) | 2018-12-20 | 2020-06-24 | Abivax | Biomarkers, and uses in treatment of viral infections, inflammations, or cancer |
CN113438961A (zh) | 2018-12-20 | 2021-09-24 | Xencor股份有限公司 | 含有IL-15/IL-15Rα和NKG2D抗原结合结构域的靶向异二聚体Fc融合蛋白 |
CN109627336A (zh) * | 2018-12-20 | 2019-04-16 | 南京昂科利医药科技创新研究院有限公司 | 一种表达pd-l1单链抗体的新城疫溶瘤病毒的制备方法及应用 |
EP3897637A1 (en) | 2018-12-20 | 2021-10-27 | Novartis AG | Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives |
WO2020128637A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1 binding antibodies in the treatment of a msi-h cancer |
US20220025036A1 (en) | 2018-12-21 | 2022-01-27 | Novartis Ag | Use of il-1beta binding antibodies |
WO2020127885A1 (en) | 2018-12-21 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compositions for treating cancers and resistant cancers |
CN113474048A (zh) | 2018-12-21 | 2021-10-01 | Aim免疫科技有限公司 | 用于癌症治疗的组合物和方法 |
US20200369762A1 (en) | 2018-12-21 | 2020-11-26 | Novartis Ag | Use of il-1beta binding antibodies |
BR112021011900A2 (pt) | 2018-12-21 | 2021-09-08 | Novartis Ag | Anticorpos para pmel17 e conjugados dos mesmos |
WO2020128893A1 (en) | 2018-12-21 | 2020-06-25 | Pfizer Inc. | Combination treatments of cancer comprising a tlr agonist |
KR20210108422A (ko) | 2018-12-21 | 2021-09-02 | 노파르티스 아게 | IL-1β 결합 항체의 용도 |
CA3124690A1 (en) | 2018-12-27 | 2020-07-02 | Amgen Inc. | Lyophilized virus formulations |
KR20210110838A (ko) | 2018-12-28 | 2021-09-09 | 트랜스진 에스.에이. | M2 결함성 폭스바이러스 |
WO2020141199A1 (en) | 2019-01-03 | 2020-07-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer |
US11660297B2 (en) | 2019-01-09 | 2023-05-30 | Celgene Corporation | Antiproliferative compounds and second active agents for combined use |
CA3125756A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Solid forms comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and salts thereof, and compositions comprising and methods of using the same |
CN113597301A (zh) | 2019-01-09 | 2021-11-02 | 细胞基因公司 | 包含(s)-4-(4-(4-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)甲基)苄基)哌嗪-1-基)-3-氟苄腈的药物组合物以及使用它的方法 |
CN113301963A (zh) | 2019-01-14 | 2021-08-24 | 先天肿瘤免疫公司 | 用于治疗癌症的作为nlrp3调节剂的取代的喹唑啉类 |
EP3911417B1 (en) | 2019-01-14 | 2022-10-26 | Innate Tumor Immunity, Inc. | Heterocyclic nlrp3 modulators , for use in the treatment of cancer |
CN113286786A (zh) | 2019-01-14 | 2021-08-20 | 先天肿瘤免疫公司 | Nlrp3调节剂 |
JP2022517112A (ja) | 2019-01-14 | 2022-03-04 | イネイト・テューマー・イミュニティ・インコーポレイテッド | Nlrp3モジュレーター |
CN113710702A (zh) | 2019-01-14 | 2021-11-26 | 健泰科生物技术公司 | 用pd-1轴结合拮抗剂和rna疫苗治疗癌症的方法 |
CA3126741A1 (en) | 2019-01-15 | 2020-07-23 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy |
MA54863A (fr) | 2019-01-29 | 2021-12-08 | Juno Therapeutics Inc | Anticorps et récepteurs antigéniques chimériques spécifiques du récepteur orphelin-1 de type récepteur à tyrosine kinase (ror1) |
TWI829857B (zh) | 2019-01-29 | 2024-01-21 | 美商英塞特公司 | 作為a2a / a2b抑制劑之吡唑并吡啶及三唑并吡啶 |
JP7442536B2 (ja) | 2019-01-30 | 2024-03-04 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | ガンを患っている被験体が免疫チェックポイント阻害剤で反応を達成するかを特定するための方法及び組成物 |
WO2020161083A1 (en) | 2019-02-04 | 2020-08-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating blood-brain barrier |
JP2022519649A (ja) | 2019-02-08 | 2022-03-24 | ジェネンテック, インコーポレイテッド | がんの診断および治療方法 |
WO2020167990A1 (en) | 2019-02-12 | 2020-08-20 | Tolero Pharmaceuticals, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
US20220098674A1 (en) | 2019-02-13 | 2022-03-31 | Inserm (Institut National De La Santé Et Dr La Recherch Médicale) | Methods and compositions for selecting a cancer treatment in a subject suffering from cancer |
EP3924521A4 (en) | 2019-02-15 | 2023-03-29 | IncellDx, Inc. | BLADDER-ASSOCIATED SPECIMEN ASSAY, IDENTIFICATION AND TREATMENT OF BLADDER-ASSOCIATED NEOPLASIA, AND KITS FOR USE THEREOF |
EA202192019A1 (ru) | 2019-02-15 | 2021-11-02 | Новартис Аг | Производные 3-(1-оксо-5-(пиперидин-4-ил)изоиндолин-2-ил)пиперидин-2,6-диона и пути их применения |
CN113329792A (zh) | 2019-02-15 | 2021-08-31 | 诺华股份有限公司 | 取代的3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途 |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
TW202045181A (zh) | 2019-02-15 | 2020-12-16 | 美商英塞特公司 | 細胞週期蛋白依賴性激酶2生物標記物及其用途 |
WO2020169472A2 (en) | 2019-02-18 | 2020-08-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of inducing phenotypic changes in macrophages |
CN113710270A (zh) | 2019-02-19 | 2021-11-26 | 迈斯特治疗公司 | 产生可用于治疗癌症的自体t细胞的方法及其组合物 |
EP3929213A4 (en) * | 2019-02-21 | 2023-03-08 | Eucure (Beijing) Biopharma Co., Ltd | ANTI-PD-L1 ANTIBODIES AND ITS USE |
MX2021010228A (es) | 2019-02-28 | 2021-10-26 | Regeneron Pharma | Administracion de inhibidores de pd-1 para el tratamiento de cancer de piel. |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
MX2021010458A (es) | 2019-03-05 | 2021-09-21 | Amgen Inc | Uso de virus oncoliticos para el tratamiento del cancer. |
CN113677707A (zh) | 2019-03-06 | 2021-11-19 | 瑞泽恩制药公司 | 用于在治疗癌症中增强效力的il-4/il-13途径抑制剂 |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
EP3938403A1 (en) | 2019-03-14 | 2022-01-19 | F. Hoffmann-La Roche AG | Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab |
WO2020187998A1 (en) | 2019-03-19 | 2020-09-24 | Fundació Privada Institut D'investigació Oncològica De Vall Hebron | Combination therapy with omomyc and an antibody binding pd-1 or ctla-4 for the treatment of cancer |
JP2022525149A (ja) | 2019-03-20 | 2022-05-11 | スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド | ベネトクラクスが失敗した急性骨髄性白血病(aml)の処置 |
EP3941463A1 (en) | 2019-03-22 | 2022-01-26 | Sumitomo Dainippon Pharma Oncology, Inc. | Compositions comprising pkm2 modulators and methods of treatment using the same |
JP2022527298A (ja) | 2019-03-26 | 2022-06-01 | ザ リージェンツ オブ ザ ユニヴァシティ オブ ミシガン | Stat3の低分子分解誘導剤 |
KR20210146349A (ko) | 2019-03-28 | 2021-12-03 | 브리스톨-마이어스 스큅 컴퍼니 | 종양을 치료하는 방법 |
EP3946625A1 (en) | 2019-03-28 | 2022-02-09 | Bristol-Myers Squibb Company | Methods of treating tumor |
JP2022526565A (ja) | 2019-03-29 | 2022-05-25 | ウニヴェルズィテート チューリッヒ | コンパートメント、特にCNSへの局所送達のためのFc修飾生物学的製剤 |
US20220185831A1 (en) | 2019-03-29 | 2022-06-16 | The Regents Of The University Of Michigan | Stat3 protein degraders |
WO2020205662A1 (en) | 2019-03-29 | 2020-10-08 | Myst Therapeutics, Inc. | Ex vivo methods for producing a t cell therapeutic and related compositions and methods |
EP3948289A1 (en) | 2019-03-29 | 2022-02-09 | F. Hoffmann-La Roche AG | Modulators of cell surface protein interactions and methods and compositions related to same |
US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
TW202102543A (zh) | 2019-03-29 | 2021-01-16 | 美商安進公司 | 溶瘤病毒在癌症新輔助療法中之用途 |
WO2020201362A2 (en) | 2019-04-02 | 2020-10-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting and preventing cancer in patients having premalignant lesions |
EP3946462A1 (en) | 2019-04-02 | 2022-02-09 | BicycleTX Limited | Bicycle toxin conjugates and uses thereof |
AU2020253955A1 (en) | 2019-04-03 | 2021-09-09 | Targimmune Therapeutics Ag | Immunotherapy for the treatment of cancer |
WO2020205688A1 (en) | 2019-04-04 | 2020-10-08 | Merck Sharp & Dohme Corp. | Inhibitors of histone deacetylase-3 useful for the treatment of cancer, inflammation, neurodegeneration diseases and diabetes |
SG11202110829YA (en) | 2019-04-05 | 2021-10-28 | Kymera Therapeutics Inc | Stat degraders and uses thereof |
WO2020208060A1 (en) | 2019-04-09 | 2020-10-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk2 inhibitors in combination with immune checkpoint blockade therapy for the treatment of cancer |
EA202192800A1 (ru) | 2019-04-12 | 2022-03-30 | Васкулар Биодженикс Лтд | Способы противоопухолевой терапии |
WO2020212484A1 (en) | 2019-04-17 | 2020-10-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treatment of nlrp3 inflammasome mediated il-1beta dependent disorders |
JP2022529269A (ja) * | 2019-04-18 | 2022-06-20 | キューエルエスエフ バイオセラピューティック インコーポレイテッド | ヒト化抗pd-l1抗体 |
CA3134522A1 (en) | 2019-04-19 | 2020-10-22 | Genentech, Inc. | Anti-mertk antibodies and their methods of use |
EP3725370A1 (en) * | 2019-04-19 | 2020-10-21 | ImmunoBrain Checkpoint, Inc. | Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease |
CA3136698A1 (en) | 2019-04-23 | 2020-10-29 | Innate Pharma | Cd73 blocking antibodies |
JP7212990B2 (ja) | 2019-04-26 | 2023-01-26 | アイ-エムエービー バイオファーマ ユーエス リミテッド | ヒトpd‐l1抗体 |
US20220220565A1 (en) | 2019-04-30 | 2022-07-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2020223233A1 (en) | 2019-04-30 | 2020-11-05 | Genentech, Inc. | Prognostic and therapeutic methods for colorectal cancer |
WO2020223469A1 (en) | 2019-05-01 | 2020-11-05 | Incyte Corporation | N-(1-(methylsulfonyl)piperidin-4-yl)-4,5-di hydro-1h-imidazo[4,5-h]quinazolin-8-amine derivatives and related compounds as cyclin-dependent kinase 2 (cdk2) inhibitors for treating cancer |
WO2020223558A1 (en) | 2019-05-01 | 2020-11-05 | Incyte Corporation | Tricyclic amine compounds as cdk2 inhibitors |
AU2020270376A1 (en) | 2019-05-03 | 2021-10-07 | Genentech, Inc. | Methods of treating cancer with an anti-PD-L1 antibody |
WO2020227159A2 (en) | 2019-05-03 | 2020-11-12 | Flagship Pioneering Innovations V, Inc. | Methods of modulating immune activity |
WO2020225552A1 (en) | 2019-05-06 | 2020-11-12 | Medimmune Limited | Combination of monalizumab, durvalumab, chemotherapy and bevacizumab or cetuximab for the treatment of colorectal cancer |
IL287801A (en) | 2019-05-07 | 2022-07-01 | Immunicom Inc | Augmentation of responses to checkpoint inhibitors using in vitro apheresis |
JP2022533194A (ja) | 2019-05-16 | 2022-07-21 | スティングセラ インコーポレイテッド | ベンゾ[b][1,8]ナフチリジン酢酸誘導体および使用方法 |
EP3969438A1 (en) | 2019-05-16 | 2022-03-23 | Stingthera, Inc. | Oxoacridinyl acetic acid derivatives and methods of use |
IL266728B (en) | 2019-05-19 | 2020-11-30 | Yeda Res & Dev | Identification of recurrent mutant neopeptides |
CN114555610A (zh) | 2019-05-20 | 2022-05-27 | 麻省理工学院 | 硼酸酯前药及其用途 |
JP2022534889A (ja) | 2019-05-24 | 2022-08-04 | ファイザー・インコーポレイテッド | Cdk阻害剤を使用した組合せ療法 |
EP3976832A1 (en) | 2019-05-30 | 2022-04-06 | Bristol-Myers Squibb Company | Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy |
JP2022534967A (ja) | 2019-05-30 | 2022-08-04 | ブリストル-マイヤーズ スクイブ カンパニー | 多腫瘍遺伝子シグネチャーおよびその使用 |
JP2022534981A (ja) | 2019-05-30 | 2022-08-04 | ブリストル-マイヤーズ スクイブ カンパニー | 細胞局在化シグネチャーおよび組み合わせ治療 |
CA3141826A1 (en) | 2019-05-31 | 2020-12-03 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
US11246906B2 (en) | 2019-06-11 | 2022-02-15 | Alkermes Pharma Ireland Limited | Compositions and methods for subcutaneous administration of cancer immunotherapy |
EP3983084A1 (en) | 2019-06-12 | 2022-04-20 | Vanderbilt University | Amino acid transport inhibitors and the uses thereof |
CN114269715A (zh) | 2019-06-12 | 2022-04-01 | 范德比尔特大学 | 作为氨基酸转运抑制剂的二苄基胺 |
WO2020248156A1 (zh) * | 2019-06-12 | 2020-12-17 | 苏州工业园区唯可达生物科技有限公司 | Pd-l1靶向结合剂及其用途 |
AU2020294797A1 (en) | 2019-06-21 | 2021-12-23 | HCW Biologics, Inc. | Multi-chain chimeric polypeptides and uses thereof |
KR20220036998A (ko) | 2019-06-25 | 2022-03-23 | 이노벤트 바이오로직스 (쑤저우) 컴퍼니, 리미티드 | 항 cd47/pd-l1 이중특이성 항체를 포함하는 제제, 이의 제조 방법 및 용도 |
WO2020260547A1 (en) | 2019-06-27 | 2020-12-30 | Rigontec Gmbh | Design method for optimized rig-i ligands |
AU2020298572A1 (en) | 2019-07-02 | 2021-11-18 | Fred Hutchinson Cancer Center | Recombinant Ad35 vectors and related gene therapy improvements |
WO2021003417A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
KR20220029651A (ko) | 2019-07-09 | 2022-03-08 | 다케다 야쿠힌 고교 가부시키가이샤 | Sting 작용제 및 관문 저해제의 투여 |
CA3138560A1 (en) | 2019-07-16 | 2021-01-21 | Shaomeng Wang | Imidazopyrimidines as eed inhibitors and the use thereof |
GB201910304D0 (en) | 2019-07-18 | 2019-09-04 | Ctxt Pty Ltd | Compounds |
GB201910305D0 (en) | 2019-07-18 | 2019-09-04 | Ctxt Pty Ltd | Compounds |
US11083705B2 (en) | 2019-07-26 | 2021-08-10 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumor |
WO2021019526A1 (en) | 2019-07-29 | 2021-02-04 | Yeda Research And Development Co. Ltd. | Methods of treating and diagnosing lung cancer |
WO2021026009A1 (en) | 2019-08-02 | 2021-02-11 | Mersana Therapeutics, Inc. | Bis-[n-((5-carbamoyl)-1h-benzo[d]imidazol-2-yl)-pyrazol-5-carboxamide] derivatives and related compounds as sting (stimulator of interferon genes) agonists for the treatment of cancer |
EP4007592A1 (en) | 2019-08-02 | 2022-06-08 | LanthioPep B.V. | Angiotensin type 2 (at2) receptor agonists for use in the treatment of cancer |
WO2021024020A1 (en) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
AU2020328507A1 (en) | 2019-08-12 | 2022-03-17 | Purinomia Biotech, Inc. | Methods and compositions for promoting and potentiating T-cell mediated immune responses through ADCC targeting of CD39 expressing cells |
EP4013750A1 (en) | 2019-08-14 | 2022-06-22 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors |
GB201912107D0 (en) | 2019-08-22 | 2019-10-09 | Amazentis Sa | Combination |
US20220305048A1 (en) | 2019-08-26 | 2022-09-29 | Dana-Farber Cancer Institute, Inc. | Use of heparin to promote type 1 interferon signaling |
CA3151824A1 (en) | 2019-08-27 | 2021-03-04 | The Regents Of The University Of Michigan | Cereblon e3 ligase inhibitors |
AR119821A1 (es) | 2019-08-28 | 2022-01-12 | Bristol Myers Squibb Co | Compuestos de piridopirimidinonilo sustituidos útiles como activadores de células t |
CA3114467A1 (en) | 2019-08-29 | 2021-03-04 | Remegen Co., Ltd. | Anti pd-l1 antibody and use thereof |
CR20220076A (es) | 2019-08-30 | 2022-06-24 | Agenus Inc | Anticuerpos anti-cd96 y sus métodos de uso |
WO2021048292A1 (en) | 2019-09-11 | 2021-03-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2021050964A1 (en) | 2019-09-13 | 2021-03-18 | Nimbus Saturn, Inc. | Hpk1 antagonists and uses thereof |
WO2021055329A1 (en) | 2019-09-16 | 2021-03-25 | Surface Oncology, Inc. | Anti-cd39 antibody compositions and methods |
CA3151022A1 (en) | 2019-09-17 | 2021-03-25 | Bial - R&D Investments, S.A. | Substituted n-heterocyclic carboxamides as acid ceramidase inhibitors and their use as medicaments |
CA3150700A1 (en) | 2019-09-17 | 2021-03-25 | Renato T. Skerlj | IMIDAZOLE SUBSTITUTE CARBOXAMIDES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS |
CA3150906A1 (en) | 2019-09-17 | 2021-03-25 | Renato T. Skerlj | Substituted, saturated and unsaturated n-heterocyclic carboxamides and related compounds for their use in the treatment of medical disorders |
KR20220064983A (ko) | 2019-09-18 | 2022-05-19 | 노파르티스 아게 | Nkg2d 융합 단백질 및 이의 용도 |
TW202124446A (zh) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | 與entpd2抗體之組合療法 |
WO2021055816A1 (en) | 2019-09-18 | 2021-03-25 | Molecular Templates, Inc. | Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds |
KR20220113353A (ko) | 2019-09-18 | 2022-08-12 | 람캅 바이오 알파 에이지 | Ceacam5 및 cd3에 대한 이중특이적 항체 |
EP4031578A1 (en) | 2019-09-18 | 2022-07-27 | Novartis AG | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
EP4031576A1 (en) | 2019-09-18 | 2022-07-27 | Molecular Templates, Inc. | Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds |
US20220380368A1 (en) | 2019-09-19 | 2022-12-01 | The Regents Of The University Of Michigan | Spirocyclic androgen receptor protein degraders |
KR20220065816A (ko) | 2019-09-19 | 2022-05-20 | 브리스톨-마이어스 스큅 컴퍼니 | 산성 pH에서 VISTA에 결합하는 항체 |
CA3155090A1 (en) | 2019-09-20 | 2021-03-25 | Transgene | Combination of a poxvirus encoding hpv polypeptides and il-2 with an anti-pd-l1 antibody |
AU2020350795A1 (en) | 2019-09-22 | 2022-03-31 | Bristol-Myers Squibb Company | Quantitative spatial profiling for LAG-3 antagonist therapy |
AU2020353079A1 (en) | 2019-09-25 | 2022-04-14 | Bristol-Myers Squibb Company | Composite biomarker for cancer therapy |
TW202128752A (zh) | 2019-09-25 | 2021-08-01 | 美商表面腫瘤學公司 | 抗il﹘27抗體及其用途 |
TW202126649A (zh) | 2019-09-26 | 2021-07-16 | 瑞士商諾華公司 | 抗病毒吡唑并吡啶酮化合物 |
EP4034562A2 (en) | 2019-09-27 | 2022-08-03 | GlaxoSmithKline Intellectual Property Development Limited | Antigen binding proteins |
CR20220127A (es) | 2019-09-27 | 2022-05-27 | Genentech Inc | Administración de dosis para tratamiento con anticuerpos antagonistas anti-tigit y anti-pd-l1 |
EP4037693A1 (en) | 2019-09-30 | 2022-08-10 | Astrazeneca AB | Combination treatment for cancer |
EP3800201A1 (en) | 2019-10-01 | 2021-04-07 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cd28h stimulation enhances nk cell killing activities |
EP4037700A2 (en) | 2019-10-03 | 2022-08-10 | Xencor, Inc. | Targeted il-12 heterodimeric fc-fusion proteins |
US20220354811A1 (en) | 2019-10-03 | 2022-11-10 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating macrophages polarization |
US20220363776A1 (en) | 2019-10-04 | 2022-11-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of ovarian cancer, breast cancer or pancreatic cancer |
TW202128757A (zh) | 2019-10-11 | 2021-08-01 | 美商建南德克公司 | 具有改善之特性的 PD-1 標靶 IL-15/IL-15Rα FC 融合蛋白 |
EP4041731A1 (en) | 2019-10-11 | 2022-08-17 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
US20210106649A1 (en) * | 2019-10-11 | 2021-04-15 | TOBEBIO Novel Drug Laboratory Co., Ltd. | Synergistic combination of chemotherapy and peptide for treating cancer |
CN114786682A (zh) | 2019-10-14 | 2022-07-22 | Aro生物疗法公司 | 结合cd71的纤维粘连蛋白iii型结构域 |
WO2021076574A2 (en) | 2019-10-14 | 2021-04-22 | Aro Biotherapeutics Company | Fn3 domain-sirna conjugates and uses thereof |
JP2022552324A (ja) | 2019-10-14 | 2022-12-15 | インサイト・コーポレイション | Fgfr阻害剤としての二環式複素環 |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
WO2021074391A1 (en) | 2019-10-17 | 2021-04-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing nasal intestinal type adenocarcinomas |
BR112022007376A2 (pt) | 2019-10-21 | 2022-07-05 | Novartis Ag | Terapias de combinação com venetoclax e inibidores de tim-3 |
JP2022553306A (ja) | 2019-10-21 | 2022-12-22 | ノバルティス アーゲー | Tim-3阻害剤およびその使用 |
EP4048795A1 (en) | 2019-10-23 | 2022-08-31 | Checkmate Pharmaceuticals, Inc. | Synthetic rig-i-like receptor agonists |
TW202128761A (zh) | 2019-10-25 | 2021-08-01 | 日商第一三共股份有限公司 | 抗garp抗體與免疫調節劑之組合 |
CN112724127B (zh) | 2019-10-28 | 2023-02-17 | 中国科学院上海药物研究所 | 五元杂环氧代羧酸类化合物及其医药用途 |
WO2021083959A1 (en) | 2019-10-29 | 2021-05-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating uveal melanoma |
MX2022005056A (es) | 2019-10-29 | 2022-05-18 | Eisai R&D Man Co Ltd | Combinacion de un antagonista de pd-1, un inhibidor tirosina cinasa de vegfr/fgfr/ret y un inhibidor de cbp/beta-catenina para el tratamiento del cancer. |
US20220409642A1 (en) | 2019-11-04 | 2022-12-29 | Astrazeneca Ab | Combination therapy for treating cancer |
WO2021092220A1 (en) | 2019-11-06 | 2021-05-14 | Bristol-Myers Squibb Company | Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy |
WO2021092221A1 (en) | 2019-11-06 | 2021-05-14 | Bristol-Myers Squibb Company | Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy |
MX2022005400A (es) | 2019-11-06 | 2022-05-24 | Genentech Inc | Metodos de diagnostico y terapeuticos para el tratamiento de canceres hematologicos. |
EP4055609A1 (en) | 2019-11-07 | 2022-09-14 | Oncxerna Therapeutics, Inc. | Classification of tumor microenvironments |
BR112022008191A2 (pt) | 2019-11-08 | 2022-07-12 | Bristol Myers Squibb Co | Terapia com antagonista de lag-3 para melanoma |
BR112022009031A2 (pt) | 2019-11-11 | 2022-10-11 | Incyte Corp | Sais e formas cristalinas de um inibidor de pd-1/pd-l1 |
TW202130618A (zh) | 2019-11-13 | 2021-08-16 | 美商建南德克公司 | 治療性化合物及使用方法 |
EP4058465A1 (en) | 2019-11-14 | 2022-09-21 | Cohbar Inc. | Cxcr4 antagonist peptides |
MX2022005839A (es) | 2019-11-19 | 2022-06-09 | Bristol Myers Squibb Co | Compuestos utiles como inhibidores de la proteina helios. |
US20230000864A1 (en) | 2019-11-22 | 2023-01-05 | Sumitomo Pharma Oncology, Inc. | Solid dose pharmaceutical composition |
MX2022006213A (es) | 2019-11-22 | 2022-06-22 | Theravance Biopharma R&D Ip Llc | Piridinas sustituidas y metodos de uso. |
CN115279764A (zh) | 2019-11-26 | 2022-11-01 | 医肯纳肿瘤学公司 | 多晶型咔唑衍生物及其用途 |
WO2021108109A1 (en) * | 2019-11-26 | 2021-06-03 | Beijing Xuanyi Pharmasciences Co., Ltd. | Modulators of t-cell activity |
JP2023504400A (ja) | 2019-11-26 | 2023-02-03 | ブリストル-マイヤーズ スクイブ カンパニー | (r)-n-(4-クロロフェニル)-2-((1s,4s)-4-(6-フルオロキノリン-4-イル)シクロヘキシル)プロパンアミドの塩/共結晶 |
KR20220104217A (ko) | 2019-11-26 | 2022-07-26 | 노파르티스 아게 | Cd19 및 cd22 키메라 항원 수용체 및 이의 용도 |
US20220401540A1 (en) | 2019-11-27 | 2022-12-22 | Cytlimic Inc. | Pharmaceutical composition |
IL293350A (en) | 2019-11-27 | 2022-07-01 | Myst Therapeutics Llc | A method for producing tumor-reactive t cells using modulatory substances |
EP3831849A1 (en) | 2019-12-02 | 2021-06-09 | LamKap Bio beta AG | Bispecific antibodies against ceacam5 and cd47 |
EP4069695A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Derivatives of an fgfr inhibitor |
CA3163875A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
EP4069683A1 (en) | 2019-12-06 | 2022-10-12 | Mersana Therapeutics, Inc. | Dimeric compounds as sting agonists |
CR20220322A (es) | 2019-12-09 | 2022-07-28 | Genentech Inc | Formulaciones de anticuerpos anti-pd-l1 |
US20230114107A1 (en) | 2019-12-17 | 2023-04-13 | Flagship Pioneering Innovations V, Inc. | Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly |
WO2021127283A2 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
JP2023509366A (ja) | 2019-12-17 | 2023-03-08 | カイメラ セラピューティクス, インコーポレイテッド | Irak分解剤およびそれらの使用 |
MX2022006932A (es) | 2019-12-19 | 2022-07-11 | Bristol Myers Squibb Co | Combinaciones de inhibidores de diacilglicerol cinasas (dgk) y antagonistas de puntos de control. |
EP4076508A1 (en) | 2019-12-19 | 2022-10-26 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and vaccine compositions to treat cancers |
BR112022011902A2 (pt) | 2019-12-20 | 2022-09-06 | Novartis Ag | Terapias de combinação |
AR120823A1 (es) | 2019-12-23 | 2022-03-23 | Bristol Myers Squibb Co | Compuestos bicíclicos sustituidos útiles como activadores de células t |
EP4081524A1 (en) | 2019-12-23 | 2022-11-02 | Bristol-Myers Squibb Company | Substituted heteroaryl compounds useful as t cell activators |
KR20220120624A (ko) | 2019-12-23 | 2022-08-30 | 브리스톨-마이어스 스큅 컴퍼니 | T 세포 활성화제로서 유용한 치환된 피페라진 유도체 |
JP2023507847A (ja) | 2019-12-23 | 2023-02-27 | ブリストル-マイヤーズ スクイブ カンパニー | T細胞アクティベーターとして有用な置換キナゾリニル化合物 |
JP2023509394A (ja) | 2019-12-23 | 2023-03-08 | カイメラ セラピューティクス, インコーポレイテッド | Smarca分解剤およびそれらの使用 |
US20230061608A1 (en) | 2019-12-23 | 2023-03-02 | Bristol-Myers Squibb Company | Substituted quinolinonyl piperazine compounds useful as t cell activators |
CN110974958B (zh) * | 2019-12-25 | 2020-08-21 | 北京东方百泰生物科技有限公司 | 一种抗pd-l1单克隆抗体的注射制剂 |
CN113045655A (zh) | 2019-12-27 | 2021-06-29 | 高诚生物医药(香港)有限公司 | 抗ox40抗体及其用途 |
CA3166549A1 (en) | 2020-01-03 | 2021-07-08 | Incyte Corporation | Combination therapy comprising a2a/a2b and pd-1/pd-l1 inhibitors |
EP4084821A4 (en) | 2020-01-03 | 2024-04-24 | Marengo Therapeutics Inc | CD33-BINDING MULTIFUNCTIONAL MOLECULES AND THEIR USES |
JP2023517794A (ja) | 2020-01-06 | 2023-04-27 | ハイファイバイオ(ホンコン)リミテッド | 抗tnfr2抗体及びその使用 |
JP2023510429A (ja) | 2020-01-07 | 2023-03-13 | ハイファイバイオ (エイチケー) リミテッド | 抗ガレクチン-9抗体およびその使用 |
MX2022008214A (es) | 2020-01-09 | 2022-08-08 | Hoffmann La Roche | Nuevas moleculas de union al antigeno que contienen el trimero de 4-1bbl. |
US20230348458A1 (en) | 2020-01-10 | 2023-11-02 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2021146370A1 (en) | 2020-01-15 | 2021-07-22 | Blueprint Medicines Corporation | Map4k1 inhibitors |
EP4090770A1 (en) | 2020-01-17 | 2022-11-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
CA3167413A1 (en) | 2020-01-17 | 2021-07-22 | Novartis Ag | Combination comprising a tim-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia |
WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
CA3166407A1 (en) | 2020-01-29 | 2021-08-05 | Merus N.V. | Means and method for modulating fimmune cell engaging effects |
AU2021213969A1 (en) | 2020-01-30 | 2022-09-01 | ONA Therapeutics S.L. | Combination therapy for treatment of cancer and cancer metastasis |
WO2021152400A1 (en) | 2020-01-30 | 2021-08-05 | Gnubiotics Sciences Sa | Compositions comprising pig stomach mucins and uses thereof |
AU2021212197A1 (en) | 2020-01-31 | 2022-08-04 | BioNTech SE | Methods of inducing neoepitope-specific T cells with a PD-1 axis binding antagonist and an RNA vaccine |
WO2021156360A1 (en) | 2020-02-05 | 2021-08-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki) |
CN115362167A (zh) | 2020-02-06 | 2022-11-18 | 百时美施贵宝公司 | Il-10及其用途 |
EP4100016A1 (en) | 2020-02-07 | 2022-12-14 | AI Therapeutics, Inc. | Anti-viral compositions and methods of use |
WO2021167885A1 (en) * | 2020-02-21 | 2021-08-26 | Macrogenics, Inc. | Cd137 binding molecules and uses thereof |
IL295896A (en) | 2020-02-26 | 2022-10-01 | Biograph 55 Inc | c19 c38 bispecific antibodies |
JP2023516636A (ja) | 2020-02-27 | 2023-04-20 | ミスト セラピューティクス リミテッド ライアビリティ カンパニー | 腫瘍反応性t細胞のエクスビボ富化および増大のための方法ならびに関連するその組成物 |
CN116568341A (zh) | 2020-02-28 | 2023-08-08 | 百时美施贵宝公司 | 基于纤连蛋白的放射性标记的支架和抗体及其治疗诊断用途 |
US20230113705A1 (en) | 2020-02-28 | 2023-04-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing, prognosing and managing treatment of breast cancer |
TW202146452A (zh) | 2020-02-28 | 2021-12-16 | 瑞士商諾華公司 | 結合cd123和cd3之雙特異性抗體的給藥 |
AR121506A1 (es) | 2020-03-03 | 2022-06-08 | Pic Therapeutics Inc | Inhibidores del eif4e y sus usos |
KR20220150353A (ko) | 2020-03-05 | 2022-11-10 | 네오티엑스 테라퓨틱스 엘티디. | 면역 세포를 사용하여 암을 치료하기 위한 방법 및 조성물 |
AU2021230385A1 (en) | 2020-03-06 | 2022-09-22 | Incyte Corporation | Combination therapy comprising AXL/MER and PD-1/PD-L1 inhibitors |
MX2022010912A (es) | 2020-03-06 | 2022-11-09 | Celgene Quanticel Res Inc | Combinacion de un inhibidor de desmetilasa-1 especifica de lisina (lsd-1) y nivolumab para usarse en el tratamiento de cancer de pulmon de celulas peque?as (sclc) o cancer de pulmon de celulas no peque?as escamosas (sqnsclc). |
US20230235073A1 (en) | 2020-03-06 | 2023-07-27 | Ona Therapeutics, S.L. | Anti-cd36 antibodies and their use to treat cancer |
WO2021177980A1 (en) | 2020-03-06 | 2021-09-10 | Genentech, Inc. | Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist |
US20230093147A1 (en) | 2020-03-09 | 2023-03-23 | President And Fellows Of Harvard College | Methods and compositions relating to improved combination therapies |
EP3878446A1 (en) | 2020-03-09 | 2021-09-15 | Universite De Geneve | Hsd11b1 inhibitors for use in immunotherapy and uses thereof |
US20230140384A1 (en) | 2020-03-09 | 2023-05-04 | Bristol-Myers Squibb Company | Antibodies to cd40 with enhanced agonist activity |
IL295569A (en) | 2020-03-19 | 2022-10-01 | Arcus Biosciences Inc | Tetralin and tetrahydroquinoline compounds as inhibitors of hif-2alpha |
IL296451A (en) | 2020-03-19 | 2022-11-01 | Kymera Therapeutics Inc | mdm2 joints and their uses |
JP2023519254A (ja) | 2020-03-23 | 2023-05-10 | ブリストル-マイヤーズ スクイブ カンパニー | がんを処置するための抗ccr8抗体 |
TW202140441A (zh) | 2020-03-23 | 2021-11-01 | 美商必治妥美雅史谷比公司 | 經取代之側氧基異吲哚啉化合物 |
US20230159573A1 (en) | 2020-03-26 | 2023-05-25 | The Regents Of The University Of Michigan | Small molecule stat protein degraders |
WO2021203131A1 (en) | 2020-03-31 | 2021-10-07 | Theravance Biopharma R&D Ip, Llc | Substituted pyrimidines and methods of use |
CN115698717A (zh) | 2020-04-03 | 2023-02-03 | 基因泰克公司 | 癌症的治疗和诊断方法 |
WO2021205444A1 (en) | 2020-04-06 | 2021-10-14 | Yeda Research And Development Co. Ltd. | Methods of diagnosing cancer and predicting responsiveness to therapy |
US20230272056A1 (en) | 2020-04-09 | 2023-08-31 | Merck Sharp & Dohme Llc | Affinity matured anti-lap antibodies and uses thereof |
WO2021207689A2 (en) | 2020-04-10 | 2021-10-14 | Juno Therapeutics, Inc. | Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen |
US20230149543A1 (en) | 2020-04-14 | 2023-05-18 | Glaxosmithkline Intellectual Property Development Limited | Combination treatment for cancer based upon an icos antbody and a pd-l1 antibody tgf-bets-receptor fusion protein |
AU2021254794A1 (en) | 2020-04-16 | 2022-12-15 | Incyte Corporation | Fused tricyclic KRAS inhibitors |
WO2021216920A1 (en) | 2020-04-22 | 2021-10-28 | Iovance Biotherapeutics, Inc. | Systems and methods for coordinating manufacturing of cells for patient-specific immunotherapy |
TW202206100A (zh) | 2020-04-27 | 2022-02-16 | 美商西健公司 | 癌症之治療 |
JP2023523450A (ja) | 2020-04-28 | 2023-06-05 | ジェネンテック, インコーポレイテッド | 非小細胞肺がん免疫療法のための方法及び組成物 |
US20230181756A1 (en) | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
EP4147052A1 (en) | 2020-05-05 | 2023-03-15 | F. Hoffmann-La Roche AG | Predicting response to pd-1 axis inhibitors |
BR112022022335A2 (pt) | 2020-05-05 | 2023-01-10 | Teon Therapeutics Inc | Moduladores de receptor canabinoide tipo 2 (cb2) e usos dos mesmos |
US20230183214A1 (en) | 2020-05-06 | 2023-06-15 | Merck Sharp & Dohme Llc | Il4i1 inhibitors and methods of use |
US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
US20230192867A1 (en) | 2020-05-15 | 2023-06-22 | Bristol-Myers Squibb Company | Antibodies to garp |
WO2021239838A2 (en) | 2020-05-26 | 2021-12-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) polypeptides and uses thereof for vaccine purposes |
IL298273A (en) | 2020-05-26 | 2023-01-01 | Regeneron Pharma | Methods for the treatment of cervical cancer using the administration of the pd-1 inhibitory antibody Semilimb |
WO2021243207A1 (en) | 2020-05-28 | 2021-12-02 | Modernatx, Inc. | Use of mrnas encoding ox40l, il-23 and il-36gamma for treating cancer |
US20230173095A1 (en) | 2020-05-29 | 2023-06-08 | President And Fellows Of Harvard College | Living cells engineered with polyphenol-functionalized biologically active nanocomplexes |
IL298608A (en) | 2020-06-01 | 2023-01-01 | Hcw Biologics Inc | Methods for treating disorders related to aging |
WO2021247003A1 (en) | 2020-06-01 | 2021-12-09 | HCW Biologics, Inc. | Methods of treating aging-related disorders |
PE20231078A1 (es) | 2020-06-02 | 2023-07-17 | Arcus Biosciences Inc | Anticuerpos anti-tigit |
TW202210483A (zh) | 2020-06-03 | 2022-03-16 | 美商凱麥拉醫療公司 | Irak降解劑之結晶型 |
WO2021245071A1 (en) | 2020-06-03 | 2021-12-09 | Mv Biotherapeutics Sa | Combination of an atp-hydrolyzing enzyme and an immune checkpoint modulator and uses thereof |
WO2021249969A1 (en) | 2020-06-10 | 2021-12-16 | Merck Patent Gmbh | Combination product for the treatment of cancer diseases |
TW202214623A (zh) | 2020-06-10 | 2022-04-16 | 美商施萬生物製藥研發 Ip有限責任公司 | 結晶型alk5抑制劑及其用途 |
JP2023529206A (ja) | 2020-06-12 | 2023-07-07 | ジェネンテック, インコーポレイテッド | がん免疫療法のための方法及び組成物 |
CA3181820A1 (en) | 2020-06-16 | 2021-12-23 | Genentech, Inc. | Methods and compositions for treating triple-negative breast cancer |
TW202200616A (zh) | 2020-06-18 | 2022-01-01 | 美商建南德克公司 | 使用抗tigit抗體及pd-1軸結合拮抗劑之治療 |
WO2021258010A1 (en) | 2020-06-19 | 2021-12-23 | Gossamer Bio Services, Inc. | Oxime compounds useful as t cell activators |
MX2022015852A (es) | 2020-06-23 | 2023-01-24 | Novartis Ag | Regimen de dosificacion que comprende derivados de 3-(1-oxoisoindolin-2-il)piperidina-2,6-diona. |
WO2021262969A1 (en) | 2020-06-24 | 2021-12-30 | The General Hospital Corporation | Materials and methods of treating cancer |
KR20230027082A (ko) | 2020-06-25 | 2023-02-27 | 셀진 코포레이션 | 조합 요법을 사용한 암의 치료 방법 |
MX2022016548A (es) | 2020-06-26 | 2023-03-14 | Amgen Inc | Muteínas de il-10 y proteínas de fusión de las mismas. |
WO2022006179A1 (en) | 2020-06-29 | 2022-01-06 | Flagship Pioneering Innovations V, Inc. | Viruses engineered to promote thanotransmission and their use in treating cancer |
WO2022004760A1 (ja) * | 2020-06-30 | 2022-01-06 | 塩野義製薬株式会社 | 抗ccr8抗体と化学療法剤の併用 |
JP2023531305A (ja) | 2020-06-30 | 2023-07-21 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 術前補助療法後の固形癌患者の再発及び/又は死亡のリスクを予測するための方法。 |
US20230266322A1 (en) | 2020-06-30 | 2023-08-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapy and radical surgery |
WO2022003554A1 (en) | 2020-07-01 | 2022-01-06 | Pfizer Inc. | Biomarkers for pd-1 axis binding antagonist therapy |
WO2022010854A1 (en) | 2020-07-07 | 2022-01-13 | Celgene Corporation | Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)m ethyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same |
JP2023532768A (ja) | 2020-07-07 | 2023-07-31 | バイオエヌテック エスエー | Hpv陽性癌の治療用rna |
US20230257365A1 (en) | 2020-07-10 | 2023-08-17 | The Regents Of The University Of Michigan | Small molecule androgen receptor protein degraders |
WO2022011205A1 (en) | 2020-07-10 | 2022-01-13 | The Regents Of The University Of Michigan | Androgen receptor protein degraders |
US11787775B2 (en) | 2020-07-24 | 2023-10-17 | Genentech, Inc. | Therapeutic compounds and methods of use |
US20230266332A1 (en) | 2020-07-28 | 2023-08-24 | Inserm (Institut National De La Santè Et De La Recherch Médicale) | Methods and compositions for preventing and treating a cancer |
KR20230044480A (ko) | 2020-07-30 | 2023-04-04 | 카이메라 쎄라퓨틱스 인코포레이티드 | 돌연변이 림프종의 치료 방법 |
EP4188549A1 (en) | 2020-08-03 | 2023-06-07 | Novartis AG | Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
WO2022031710A2 (en) * | 2020-08-04 | 2022-02-10 | Exelixis, Inc. | Multispecific binding agents and uses thereof |
AU2021320226A1 (en) | 2020-08-05 | 2023-03-23 | Synthekine, Inc. | gp130 binding molecules and methods of use |
CA3190415A1 (en) | 2020-08-05 | 2022-02-10 | Synthekine, Inc. | Il2rb/il2rg synthetic cytokines |
EP4192880A2 (en) | 2020-08-05 | 2023-06-14 | Synthekine, Inc. | Il10 receptor binding molecules and methods of use |
EP4192866A2 (en) | 2020-08-10 | 2023-06-14 | GV20 Therapeutics LLC | Compositions and methods for treating autoimmune diseases and cancers by targeting igsf8 |
WO2022036146A1 (en) | 2020-08-12 | 2022-02-17 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
JP2023537412A (ja) | 2020-08-13 | 2023-08-31 | ブリストル-マイヤーズ スクイブ カンパニー | 目的の細胞を標的とするためのil-2の向け直し方法 |
AU2021327130A1 (en) | 2020-08-17 | 2023-03-02 | Bicycletx Limited | Bicycle conjugates specific for Nectin-4 and uses thereof |
KR20230074487A (ko) | 2020-08-26 | 2023-05-30 | 마렝고 테라퓨틱스, 인크. | Trbc1 또는 trbc2를 검출하는 방법 |
CA3168743A1 (en) | 2020-08-26 | 2022-03-03 | Matthew G. Fury | Methods of treating cancer by administering a pd-1 inhibitor |
WO2022047189A1 (en) | 2020-08-28 | 2022-03-03 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for hepatocellular carcinoma |
WO2022047093A1 (en) | 2020-08-28 | 2022-03-03 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of kras |
EP4204453A1 (en) | 2020-08-31 | 2023-07-05 | Bristol-Myers Squibb Company | Cell localization signature and immunotherapy |
CN111808196B (zh) * | 2020-08-31 | 2020-12-29 | 北京百奥赛图基因生物技术有限公司 | 抗pd-1抗体及其用途 |
EP4208482A1 (en) | 2020-09-02 | 2023-07-12 | Pharmabcine Inc. | Combination therapy of a pd-1 antagonist and an antagonist for vegfr-2 for treating patients with cancer |
US11932692B2 (en) | 2020-09-03 | 2024-03-19 | Regeneron Pharmaceuticals, Inc. | Methods of treating cancer pain by administering a PD-1 inhibitor |
CR20230155A (es) | 2020-09-14 | 2023-06-27 | Boehringer Ingelheim Int | Vacuna heteróloga de estímulo primario |
KR20230070256A (ko) | 2020-09-17 | 2023-05-22 | 상하이 린-크레스트 엔터프라이즈 매니지먼트 컴퍼니 리미티드 | 이중특이성 재조합 단백질 및 이의 용도 |
CN111920948B (zh) * | 2020-09-25 | 2021-02-02 | 安可瑞(山西)生物细胞有限公司 | 包含免疫细胞的药物组合物用于治疗癌症 |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
CN116406369A (zh) | 2020-10-05 | 2023-07-07 | 百时美施贵宝公司 | 用于浓缩蛋白质的方法 |
WO2022076596A1 (en) | 2020-10-06 | 2022-04-14 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting stat6 |
WO2022074152A1 (en) | 2020-10-08 | 2022-04-14 | Targimmune Therapeutics Ag | Immunotherapy for the treatment of cancer |
CN116685325A (zh) | 2020-10-20 | 2023-09-01 | 豪夫迈·罗氏有限公司 | Pd-1轴结合拮抗剂和lrrk2抑制剂的组合疗法 |
AR123855A1 (es) | 2020-10-20 | 2023-01-18 | Genentech Inc | Anticuerpos anti-mertk conjugados con peg y métodos de uso |
US20240101666A1 (en) | 2020-10-23 | 2024-03-28 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for lung cancer |
WO2022084531A1 (en) | 2020-10-23 | 2022-04-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating glioma |
WO2022093981A1 (en) | 2020-10-28 | 2022-05-05 | Genentech, Inc. | Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists |
WO2022094567A1 (en) | 2020-10-28 | 2022-05-05 | Ikena Oncology, Inc. | Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine |
AU2021374590A1 (en) | 2020-11-04 | 2023-06-01 | Genentech, Inc. | Subcutaneous dosing of anti-cd20/anti-cd3 bispecific antibodies |
IL302396A (en) | 2020-11-04 | 2023-06-01 | Genentech Inc | Dosage for treatment with bispecific anti-CD20/anti-CD3 antibodies |
EP4240493A2 (en) | 2020-11-04 | 2023-09-13 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates |
MX2023005362A (es) | 2020-11-06 | 2023-06-22 | Incyte Corp | Proceso para hacer un inhibidor de proteina de muerte programada 1 (pd-1)/ligando de muerte programada 1 (pd-l1) y sales y formas cristalinas del mismo. |
WO2022099018A1 (en) | 2020-11-06 | 2022-05-12 | Incyte Corporation | Process of preparing a pd-1/pd-l1 inhibitor |
WO2022099075A1 (en) | 2020-11-06 | 2022-05-12 | Incyte Corporation | Crystalline form of a pd-1/pd-l1 inhibitor |
WO2022097060A1 (en) | 2020-11-06 | 2022-05-12 | Novartis Ag | Cd19 binding molecules and uses thereof |
TW202233248A (zh) | 2020-11-08 | 2022-09-01 | 美商西健公司 | 組合療法 |
KR20230106645A (ko) | 2020-11-11 | 2023-07-13 | 다이이찌 산쿄 가부시키가이샤 | 항체-약물 콘주게이트와 항 SIRPα 항체의 조합 |
JP2023554587A (ja) | 2020-11-12 | 2023-12-28 | アンセルム(アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル) | Sars-cov-2 スパイクタンパク質の受容体結合ドメインにコンジュゲートまたは融合している抗体およびワクチン目的でのそれらの使用 |
WO2022103904A1 (en) | 2020-11-13 | 2022-05-19 | Genentech, Inc. | Methods and compositions comprising a krasg12c inhibitor and a pd-l1 binding antagonist for treating lung cancer |
EP4244391A1 (en) | 2020-11-16 | 2023-09-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
EP4244392A1 (en) | 2020-11-16 | 2023-09-20 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022101463A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of the last c-terminal residues m31/41 of zikv m ectodomain for triggering apoptotic cell death |
CA3200671A1 (en) | 2020-11-17 | 2022-05-27 | Seagen Inc. | Methods of treating cancer with a combination of tucatinib and an anti-pd-1/anti-pd-l1 antibody |
KR20230110254A (ko) | 2020-11-18 | 2023-07-21 | 다케다 야쿠힌 고교 가부시키가이샤 | Sting 작용제, 관문 저해제, 및 방사선의 투여 |
AU2021392040A1 (en) | 2020-12-02 | 2023-06-29 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
WO2022119830A1 (en) | 2020-12-02 | 2022-06-09 | Genentech, Inc. | Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy |
WO2022120353A1 (en) | 2020-12-02 | 2022-06-09 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
WO2022120179A1 (en) | 2020-12-03 | 2022-06-09 | Bristol-Myers Squibb Company | Multi-tumor gene signatures and uses thereof |
CA3201219A1 (en) | 2020-12-04 | 2022-06-09 | Mir Ali | Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof |
WO2022125497A1 (en) | 2020-12-08 | 2022-06-16 | Infinity Pharmaceuticals, Inc. | Eganelisib for use in the treatment of pd-l1 negative cancer |
TW202237119A (zh) | 2020-12-10 | 2022-10-01 | 美商住友製藥腫瘤公司 | Alk﹘5抑制劑和彼之用途 |
CA3202416A1 (en) | 2020-12-16 | 2022-06-23 | Pieter Fokko VAN LOO | Multispecific antibodies for the treatment of cancer |
EP4262986A1 (en) | 2020-12-16 | 2023-10-25 | Gossamer Bio Services, Inc. | Compounds useful as t cell activators |
IL301701A (en) | 2020-12-18 | 2023-05-01 | Lamkap Bio Beta Ag | Bispecific antibodies against CEACAM5 and CD47 |
TW202245808A (zh) | 2020-12-21 | 2022-12-01 | 德商拜恩迪克公司 | 用於治療癌症之治療性rna |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022135666A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
AU2021416156A1 (en) | 2020-12-28 | 2023-06-22 | Bristol-Myers Squibb Company | Methods of treating tumors |
JP2024503265A (ja) | 2020-12-28 | 2024-01-25 | ブリストル-マイヤーズ スクイブ カンパニー | 抗体組成物およびその使用の方法 |
KR20230157940A (ko) | 2020-12-29 | 2023-11-17 | 인사이트 코포레이션 | A2a/a2b 저해제, pd-1/pd-l1 저해제 및 항-cd73 항체를포함하는 병용 요법 |
WO2022148736A1 (en) | 2021-01-05 | 2022-07-14 | Transgene | Vectorization of muc1 t cell engager |
EP4274850A1 (en) | 2021-01-08 | 2023-11-15 | Bristol-Myers Squibb Company | Combination therapy using an anti-fucosyl-gm1 antibody |
KR20230146528A (ko) | 2021-01-11 | 2023-10-19 | 바이사이클티엑스 리미티드 | 암을 치료하기 위한 방법 |
WO2022150788A2 (en) | 2021-01-11 | 2022-07-14 | Synthekine, Inc. | Compositions and methods related to receptor pairing |
JP2024503654A (ja) | 2021-01-13 | 2024-01-26 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 併用療法 |
CN116963773A (zh) | 2021-01-21 | 2023-10-27 | 浙江养生堂天然药物研究所有限公司 | 治疗肿瘤的组合物及方法 |
TW202241508A (zh) | 2021-01-29 | 2022-11-01 | 美商艾歐凡斯生物治療公司 | 細胞介素相關之腫瘤浸潤性淋巴球組合物及方法 |
WO2022162569A1 (en) | 2021-01-29 | 2022-08-04 | Novartis Ag | Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof |
WO2022167445A1 (en) | 2021-02-02 | 2022-08-11 | Liminal Biosciences Limited | Gpr84 antagonists and uses thereof |
EP4288427A1 (en) | 2021-02-02 | 2023-12-13 | Liminal Biosciences Limited | Gpr84 antagonists and uses thereof |
WO2022171121A1 (zh) | 2021-02-10 | 2022-08-18 | 同润生物医药(上海)有限公司 | 治疗肿瘤的方法和组合 |
CR20230382A (es) | 2021-02-12 | 2023-09-06 | Hoffmann La Roche | Derivados de tetrahidroazepina bicíclicos para el tratamiento del cáncer |
TW202245789A (zh) | 2021-02-15 | 2022-12-01 | 美商凱麥拉醫療公司 | Irak4降解劑及其用途 |
CN116917273A (zh) | 2021-03-02 | 2023-10-20 | 葛兰素史克知识产权发展有限公司 | 作为dnmt1抑制剂的经取代的吡啶 |
WO2022187419A1 (en) | 2021-03-03 | 2022-09-09 | The Regents Of The University Of Michigan | Small molecule degraders of androgen receptor |
WO2022187423A1 (en) | 2021-03-03 | 2022-09-09 | The Regents Of The University Of Michigan | Cereblon ligands |
JP2024510947A (ja) | 2021-03-05 | 2024-03-12 | レアダルティス、ソシエダッド リミターダ | 三量体ポリペプチドおよびがん治療におけるその使用 |
JP2024509192A (ja) | 2021-03-05 | 2024-02-29 | ニンバス サターン, インコーポレイテッド | Hpk1アンタゴニスト及びその使用 |
EP4305041A1 (en) | 2021-03-08 | 2024-01-17 | Blueprint Medicines Corporation | Map4k1 inhibitors |
WO2022197641A1 (en) | 2021-03-15 | 2022-09-22 | Rapt Therapeutics, Inc. | 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine derivatives as hematopoietic progenitor kinase 1 (hpk1) modulators and/or inhibitors for the treatment of cancer and other diseases |
WO2022194908A1 (en) | 2021-03-17 | 2022-09-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
CN117321418A (zh) | 2021-03-18 | 2023-12-29 | 诺华股份有限公司 | 癌症生物标志物及其使用方法 |
CA3212571A1 (en) | 2021-03-19 | 2022-09-22 | Trained Therapeutix Discovery, Inc. | Compounds for regulating trained immunity, and their methods of use |
KR20230159590A (ko) | 2021-03-23 | 2023-11-21 | 리제너론 파아마슈티컬스, 인크. | Pd-1 억제제를 투여함에 의한 면역억제 또는 면역손상된 환자에서 암을 치료하는 방법 |
TW202304506A (zh) | 2021-03-25 | 2023-02-01 | 日商安斯泰來製藥公司 | 涉及抗claudin 18.2抗體的組合治療以治療癌症 |
EP4314348A1 (en) | 2021-03-25 | 2024-02-07 | Oncxerna Therapeutics, Inc. | Targeted therapies in cancer |
CA3207652A1 (en) | 2021-03-26 | 2022-09-29 | Stephanie Cornen | Cytokine anchors for nkp46-binding nk cell engager proteins |
EP4316518A1 (en) * | 2021-03-29 | 2024-02-07 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Drug combination of toll-like receptor 7 agonist and anti-pd-l1 antibody |
IL307262A (en) | 2021-03-29 | 2023-11-01 | Juno Therapeutics Inc | METHODS FOR DOSAGE AND THERAPY IN COMBINATION OF CHECKPOINT INHIBITOR AND CAR T CELL THERAPY |
EP4314060A1 (en) | 2021-03-31 | 2024-02-07 | GlaxoSmithKline Intellectual Property Development Limited | Antigen binding proteins and combinations thereof |
KR20230165276A (ko) | 2021-03-31 | 2023-12-05 | 플래그쉽 파이어니어링 이노베이션스 브이, 인크. | 타노트랜스미션 폴리펩티드 및 암의 치료에서의 이의 용도 |
EP4314068A1 (en) | 2021-04-02 | 2024-02-07 | The Regents Of The University Of California | Antibodies against cleaved cdcp1 and uses thereof |
KR20230167067A (ko) | 2021-04-05 | 2023-12-07 | 브리스톨-마이어스 스큅 컴퍼니 | 암의 치료를 위한 피리디닐 치환된 옥소이소인돌린 화합물 |
JP2024515243A (ja) | 2021-04-06 | 2024-04-08 | ブリストル-マイヤーズ スクイブ カンパニー | ピリジニル置換されたオキソイソインドリン化合物 |
TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途 |
JP2024514836A (ja) | 2021-04-08 | 2024-04-03 | ニューリックス セラピューティクス,インコーポレイテッド | Cbl-b阻害化合物との組み合わせ療法 |
WO2022216993A2 (en) | 2021-04-08 | 2022-10-13 | Marengo Therapeutics, Inc. | Multifuntional molecules binding to tcr and uses thereof |
IL307419A (en) | 2021-04-09 | 2023-12-01 | Ose Immunotherapeutics | A new scaffold for bifunctional molecules with improved properties |
JP2024513246A (ja) | 2021-04-09 | 2024-03-22 | ジェネンテック, インコーポレイテッド | Raf阻害剤及びpd-1軸阻害剤を用いた併用治療 |
TW202304999A (zh) | 2021-04-09 | 2023-02-01 | 美商思進公司 | 以抗tigit抗體治療癌症之方法 |
WO2022214652A1 (en) | 2021-04-09 | 2022-10-13 | Ose Immunotherapeutics | Scaffold for bifunctioanl molecules comprising pd-1 or cd28 and sirp binding domains |
EP4323405A1 (en) | 2021-04-12 | 2024-02-21 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
KR20230170039A (ko) | 2021-04-13 | 2023-12-18 | 뉴베일런트, 아이엔씨. | Egfr 돌연변이를 지니는 암을 치료하기 위한 아미노-치환된 헤테로사이클 |
EP4322938A1 (en) | 2021-04-14 | 2024-02-21 | Institut National de la Santé et de la Recherche Médicale (INSERM) | New method to improve nk cells cytotoxicity |
EP4074835A1 (en) | 2021-04-15 | 2022-10-19 | Deutsches Krebsforschungszentrum - Stiftung des öffentlichen Rechts / Universität Heidelberg | H-1 pv expressing rnai effectors |
AU2022258829A1 (en) | 2021-04-16 | 2023-10-26 | Novartis Ag | Antibody drug conjugates and methods for making thereof |
KR20230172548A (ko) | 2021-04-16 | 2023-12-22 | 이케나 온콜로지, 인코포레이티드 | Mek 억제제 및 이의 용도 |
WO2022226100A1 (en) | 2021-04-20 | 2022-10-27 | Seagen Inc. | Modulation of antibody-dependent cellular cytotoxicity |
EP4326903A1 (en) | 2021-04-23 | 2024-02-28 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and compositions for treating cell senescence accumulation related disease |
WO2022229966A1 (en) | 2021-04-29 | 2022-11-03 | Yeda Research And Development Co. Ltd. | T cell receptors directed against ras-derived recurrent neoantigens and methods of identifying same |
JP2024516230A (ja) | 2021-04-30 | 2024-04-12 | ジェネンテック, インコーポレイテッド | がんのための治療及び診断方法並びに組成物 |
EP4330282A1 (en) | 2021-04-30 | 2024-03-06 | F. Hoffmann-La Roche AG | Dosing for combination treatment with anti-cd20/anti-cd3 bispecific antibody and anti-cd79b antibody drug conjugate |
WO2022227015A1 (en) | 2021-04-30 | 2022-11-03 | Merck Sharp & Dohme Corp. | Il4i1 inhibitors and methods of use |
KR20240005809A (ko) | 2021-05-07 | 2024-01-12 | 서피스 온콜로지, 엘엘씨 | 항-il-27 항체 및 이의 용도 |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
WO2022243378A1 (en) | 2021-05-18 | 2022-11-24 | Kymab Limited | Uses of anti-icos antibodies |
EP4341261A1 (en) | 2021-05-21 | 2024-03-27 | Arcus Biosciences, Inc. | Axl compounds |
WO2022242737A1 (zh) | 2021-05-21 | 2022-11-24 | 天津立博美华基因科技有限责任公司 | 药物组合及其用途 |
TW202313603A (zh) | 2021-05-21 | 2023-04-01 | 美商阿克思生物科學有限公司 | Axl抑制劑化合物 |
CN117412767A (zh) | 2021-05-25 | 2024-01-16 | 雪绒花免疫公司 | C-x-c基序趋化因子受体6(cxcr6)结合分子及其使用方法 |
WO2022247972A2 (es) | 2021-05-26 | 2022-12-01 | Centro De Inmunologia Molecular | Uso de composiciones terapéuticas para el tratamiento de pacientes con tumores de origen epitelial |
WO2022251359A1 (en) | 2021-05-26 | 2022-12-01 | Theravance Biopharma R&D Ip, Llc | Bicyclic inhibitors of alk5 and methods of use |
TW202307210A (zh) | 2021-06-01 | 2023-02-16 | 瑞士商諾華公司 | Cd19和cd22嵌合抗原受體及其用途 |
CA3218692A1 (en) | 2021-06-04 | 2022-12-08 | Boehringer Ingelheim International Gmbh | Anti-sirp-alpha antibodies |
GB202107994D0 (en) | 2021-06-04 | 2021-07-21 | Kymab Ltd | Treatment of cancer |
CA3218590A1 (en) | 2021-06-07 | 2022-12-15 | Providence Health & Services - Oregon | Cxcr5, pd-1, and icos expressing tumor reactive cd4 t cells and their use |
AR126102A1 (es) | 2021-06-09 | 2023-09-13 | Incyte Corp | Heterociclos tricíclicos como inhibidores de fgfr |
WO2022258691A1 (en) | 2021-06-09 | 2022-12-15 | Innate Pharma | Multispecific proteins binding to nkg2d, a cytokine receptor, a tumour antigen and cd16a |
WO2022258678A1 (en) | 2021-06-09 | 2022-12-15 | Innate Pharma | Multispecific proteins binding to nkp30, a cytokine receptor, a tumour antigen and cd16a |
TW202313610A (zh) | 2021-06-09 | 2023-04-01 | 美商英塞特公司 | 作為fgfr抑制劑之三環雜環 |
EP4352098A1 (en) | 2021-06-09 | 2024-04-17 | Innate Pharma | Multispecific proteins binding to nkp46, a cytokine receptor, a tumour antigen and cd16a |
KR20240026507A (ko) | 2021-06-29 | 2024-02-28 | 플래그쉽 파이어니어링 이노베이션스 브이, 인크. | 타노트랜스미션을 촉진시키도록 엔지니어링된 면역 세포 및 이의 용도 |
BR112023026966A2 (pt) | 2021-07-02 | 2024-03-12 | Hoffmann La Roche | Métodos para tratar um indivíduo com melanoma, para alcançar uma resposta clínica, para tratar um indivíduo com linfoma não hodgkin, para tratar uma população de indivíduos com linfoma não hodgkin e para tratar um indivíduo com câncer colorretal metastático |
WO2023280790A1 (en) | 2021-07-05 | 2023-01-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Gene signatures for predicting survival time in patients suffering from renal cell carcinoma |
TW202317565A (zh) | 2021-07-07 | 2023-05-01 | 美商英塞特公司 | 作為kras抑制劑的三環化合物 |
WO2023285552A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
TW202321237A (zh) | 2021-07-14 | 2023-06-01 | 美商纜圖藥品公司 | Map4k1抑制劑 |
WO2023287896A1 (en) | 2021-07-14 | 2023-01-19 | Incyte Corporation | Tricyclic compounds as inhibitors of kras |
WO2023288264A1 (en) | 2021-07-15 | 2023-01-19 | Blueprint Medicines Corporation | Map4k1 inhibitors |
KR20240038991A (ko) | 2021-07-19 | 2024-03-26 | 리제너론 파마슈티칼스 인코포레이티드 | 암을 치료하기 위한 체크포인트 저해제 및 종양용해 바이러스의 조합 |
CA3224180A1 (en) | 2021-07-28 | 2023-02-02 | F. Hoffmann-La Roche Ag | Methods and compositions for treating cancer |
WO2023010094A2 (en) | 2021-07-28 | 2023-02-02 | Genentech, Inc. | Methods and compositions for treating cancer |
AU2022320051A1 (en) | 2021-07-30 | 2024-01-25 | ONA Therapeutics S.L. | Anti-cd36 antibodies and their use to treat cancer |
WO2023010080A1 (en) | 2021-07-30 | 2023-02-02 | Seagen Inc. | Treatment for cancer |
CN113413464A (zh) * | 2021-08-09 | 2021-09-21 | 中国人民解放军海军军医大学第一附属医院 | 抗pd-l1抗体在急性呼吸窘迫综合征治疗药物中的应用 |
WO2023016564A1 (zh) | 2021-08-12 | 2023-02-16 | 上海才致药成生物科技有限公司 | 靶向GPC3的抗体干扰素α融合蛋白及其用途 |
IL310662A (en) | 2021-08-23 | 2024-04-01 | Immunitas Therapeutics Inc | Anti-CD161 antibodies and their uses |
IL310924A (en) | 2021-08-25 | 2024-04-01 | Pic Therapeutics Inc | EIF4E inhibitors and their uses |
WO2023028238A1 (en) | 2021-08-25 | 2023-03-02 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
CA3229855A1 (en) | 2021-08-31 | 2023-03-09 | Incyte Corporation | Naphthyridine compounds as inhibitors of kras |
TW202325306A (zh) | 2021-09-02 | 2023-07-01 | 美商天恩治療有限公司 | 改良免疫細胞之生長及功能的方法 |
WO2023031366A1 (en) | 2021-09-02 | 2023-03-09 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Anti-cecam6 antibodies with reduced side-effects |
WO2023039089A1 (en) | 2021-09-08 | 2023-03-16 | Twentyeight-Seven, Inc. | Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives |
US20230151005A1 (en) | 2021-09-21 | 2023-05-18 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of kras |
WO2023056403A1 (en) | 2021-09-30 | 2023-04-06 | Genentech, Inc. | Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists |
WO2023051926A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
CA3234375A1 (en) | 2021-10-01 | 2023-04-06 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
TW202327595A (zh) | 2021-10-05 | 2023-07-16 | 美商輝瑞大藥廠 | 用於治療癌症之氮雜內醯胺化合物的組合 |
TW202333802A (zh) | 2021-10-11 | 2023-09-01 | 德商拜恩迪克公司 | 用於肺癌之治療性rna(二) |
US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
CA3234821A1 (en) | 2021-10-28 | 2023-05-04 | Suman Kumar VODNALA | Methods for culturing immune cells |
AU2022375806A1 (en) | 2021-10-29 | 2023-12-14 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for hematological cancer |
WO2023078900A1 (en) | 2021-11-03 | 2023-05-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating triple negative breast cancer (tnbc) |
WO2023079428A1 (en) | 2021-11-03 | 2023-05-11 | Pfizer Inc. | Combination therapies using tlr7/8 agonist |
WO2023081730A1 (en) | 2021-11-03 | 2023-05-11 | Teon Therapeutics, Inc. | 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer |
WO2023080900A1 (en) | 2021-11-05 | 2023-05-11 | Genentech, Inc. | Methods and compositions for classifying and treating kidney cancer |
WO2023083439A1 (en) | 2021-11-09 | 2023-05-19 | BioNTech SE | Tlr7 agonist and combinations for cancer treatment |
WO2023088968A1 (en) | 2021-11-17 | 2023-05-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Universal sarbecovirus vaccines |
TW202320792A (zh) | 2021-11-22 | 2023-06-01 | 美商英塞特公司 | 包含fgfr抑制劑及kras抑制劑之組合療法 |
US20230203062A1 (en) | 2021-11-24 | 2023-06-29 | Genentech, Inc. | Therapeutic compounds and methods of use |
WO2023097195A1 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic indazole compounds and methods of use in the treatment of cancer |
WO2023097211A1 (en) | 2021-11-24 | 2023-06-01 | The University Of Southern California | Methods for enhancing immune checkpoint inhibitor therapy |
US20230203010A1 (en) | 2021-12-03 | 2023-06-29 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
WO2023104910A1 (en) | 2021-12-08 | 2023-06-15 | Tessa Therapeutics Ltd. | Treatment of lymphoma |
US20230183251A1 (en) | 2021-12-10 | 2023-06-15 | Incyte Corporation | Bicyclic amines as cdk12 inhibitors |
WO2023114984A1 (en) | 2021-12-17 | 2023-06-22 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
WO2023118165A1 (en) | 2021-12-21 | 2023-06-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2023122772A1 (en) | 2021-12-22 | 2023-06-29 | Gossamer Bio Services, Inc. | Oxime derivatives useful as t cell activators |
WO2023122777A1 (en) | 2021-12-22 | 2023-06-29 | Gossamer Bio Services, Inc. | Oxime derivatives useful as t cell activators |
WO2023122778A1 (en) | 2021-12-22 | 2023-06-29 | Gossamer Bio Services, Inc. | Pyridazinone derivatives useful as t cell activators |
US20230192722A1 (en) | 2021-12-22 | 2023-06-22 | Incyte Corporation | Salts and solid forms of an fgfr inhibitor and processes of preparing thereof |
WO2023129438A1 (en) | 2021-12-28 | 2023-07-06 | Wisconsin Alumni Research Foundation | Hydrogel compositions for use for depletion of tumor associated macrophages |
WO2023130081A1 (en) | 2021-12-30 | 2023-07-06 | Neoimmunetech, Inc. | Method of treating a tumor with a combination of il-7 protein and vegf antagonist |
WO2023137161A1 (en) | 2022-01-14 | 2023-07-20 | Amgen Inc. | Triple blockade of tigit, cd112r, and pd-l1 |
WO2023147371A1 (en) | 2022-01-26 | 2023-08-03 | Bristol-Myers Squibb Company | Combination therapy for hepatocellular carcinoma |
WO2023143478A1 (en) * | 2022-01-27 | 2023-08-03 | Crown Bioscience Inc. | Novel anti-cd4 and anti-pd-l1 bispecific antibodies |
JP7444182B2 (ja) | 2022-01-28 | 2024-03-06 | トヨタ自動車株式会社 | 車両用スロープ展開装置 |
WO2023147488A1 (en) | 2022-01-28 | 2023-08-03 | Iovance Biotherapeutics, Inc. | Cytokine associated tumor infiltrating lymphocytes compositions and methods |
WO2023150186A1 (en) | 2022-02-01 | 2023-08-10 | Arvinas Operations, Inc. | Dgk targeting compounds and uses thereof |
WO2023154799A1 (en) | 2022-02-14 | 2023-08-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Combination immunotherapy for treating cancer |
TW202342474A (zh) | 2022-02-14 | 2023-11-01 | 美商基利科學股份有限公司 | 抗病毒吡唑并吡啶酮化合物 |
CN114181310B (zh) * | 2022-02-14 | 2022-07-05 | 中山康方生物医药有限公司 | 抗tigit抗体、其药物组合物及用途 |
WO2023159102A1 (en) | 2022-02-17 | 2023-08-24 | Regeneron Pharmaceuticals, Inc. | Combinations of checkpoint inhibitors and oncolytic virus for treating cancer |
WO2023161453A1 (en) | 2022-02-24 | 2023-08-31 | Amazentis Sa | Uses of urolithins |
WO2023164638A1 (en) | 2022-02-25 | 2023-08-31 | Bristol-Myers Squibb Company | Combination therapy for colorectal carcinoma |
WO2023166418A2 (en) | 2022-03-03 | 2023-09-07 | Pfizer Inc. | Multispecific antibodies and uses thereof |
WO2023168404A1 (en) | 2022-03-04 | 2023-09-07 | Bristol-Myers Squibb Company | Methods of treating a tumor |
US20230279004A1 (en) | 2022-03-07 | 2023-09-07 | Incyte Corporation | Solid forms, salts, and processes of preparation of a cdk2 inhibitor |
WO2023170606A1 (en) | 2022-03-08 | 2023-09-14 | Alentis Therapeutics Ag | Use of anti-claudin-1 antibodies to increase t cell availability |
WO2023173057A1 (en) | 2022-03-10 | 2023-09-14 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023173053A1 (en) | 2022-03-10 | 2023-09-14 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023174210A1 (en) | 2022-03-14 | 2023-09-21 | Laekna Limited | Combination treatment for cancer |
WO2023178192A1 (en) | 2022-03-15 | 2023-09-21 | Compugen Ltd. | Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer |
WO2023178329A1 (en) | 2022-03-18 | 2023-09-21 | Bristol-Myers Squibb Company | Methods of isolating polypeptides |
WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023192478A1 (en) | 2022-04-01 | 2023-10-05 | Bristol-Myers Squibb Company | Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer |
WO2023196988A1 (en) | 2022-04-07 | 2023-10-12 | Modernatx, Inc. | Methods of use of mrnas encoding il-12 |
WO2023196987A1 (en) | 2022-04-07 | 2023-10-12 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2023196964A1 (en) | 2022-04-08 | 2023-10-12 | Bristol-Myers Squibb Company | Machine learning identification, classification, and quantification of tertiary lymphoid structures |
WO2023194656A1 (en) | 2022-04-08 | 2023-10-12 | Tilt Biotherapeutics Oy | Monoclonal pd-l1 antibodies |
US20230406930A1 (en) | 2022-04-13 | 2023-12-21 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
WO2023201291A1 (en) | 2022-04-13 | 2023-10-19 | Genentech, Inc. | Pharmaceutical compositions of mosunetuzumab and methods of use |
WO2023211889A1 (en) | 2022-04-25 | 2023-11-02 | Ikena Oncology, Inc. | Polymorphic compounds and uses thereof |
WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023220703A1 (en) | 2022-05-12 | 2023-11-16 | Genentech, Inc. | Methods and compositions comprising a shp2 inhibitor and a pd-l1 binding antagonist |
WO2023222854A1 (en) | 2022-05-18 | 2023-11-23 | Kymab Limited | Uses of anti-icos antibodies |
WO2023228095A1 (en) | 2022-05-24 | 2023-11-30 | Daiichi Sankyo Company, Limited | Dosage regimen of an anti-cdh6 antibody-drug conjugate |
WO2023230205A1 (en) | 2022-05-25 | 2023-11-30 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023230541A1 (en) | 2022-05-27 | 2023-11-30 | Viiv Healthcare Company | Piperazine derivatives useful in hiv therapy |
WO2023235847A1 (en) | 2022-06-02 | 2023-12-07 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
WO2023240156A1 (en) | 2022-06-08 | 2023-12-14 | Tidal Therapeutics, Inc. | Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof |
TW202402279A (zh) | 2022-06-08 | 2024-01-16 | 美商英塞特公司 | 作為dgk抑制劑之三環三唑并化合物 |
WO2023242351A1 (en) | 2022-06-16 | 2023-12-21 | Lamkap Bio Beta Ag | Combination therapy of bispecific antibodies against ceacam5 and cd47 and bispecific antibodies against ceacam5 and cd3 |
WO2023250430A1 (en) | 2022-06-22 | 2023-12-28 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
WO2023250400A1 (en) | 2022-06-22 | 2023-12-28 | Juno Therapeutics, Inc. | Treatment methods for second line therapy of cd19-targeted car t cells |
WO2024015731A1 (en) | 2022-07-11 | 2024-01-18 | Incyte Corporation | Fused tricyclic compounds as inhibitors of kras g12v mutants |
WO2024015803A2 (en) | 2022-07-11 | 2024-01-18 | Autonomous Therapeutics, Inc. | Encrypted rna and methods of its use |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024015372A1 (en) | 2022-07-14 | 2024-01-18 | Teon Therapeutics, Inc. | Adenosine receptor antagonists and uses thereof |
WO2024020432A1 (en) | 2022-07-19 | 2024-01-25 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024023740A1 (en) | 2022-07-27 | 2024-02-01 | Astrazeneca Ab | Combinations of recombinant virus expressing interleukin-12 with pd-1/pd-l1 inhibitors |
WO2024023750A1 (en) | 2022-07-28 | 2024-02-01 | Astrazeneca Uk Limited | Combination of antibody-drug conjugate and bispecific checkpoint inhibitor |
WO2024028364A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Aryl-triazolyl and related gpr84 antagonists and uses thereof |
WO2024028365A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Substituted pyridone gpr84 antagonists and uses thereof |
WO2024028363A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Heteroaryl carboxamide and related gpr84 antagonists and uses thereof |
US20240041929A1 (en) | 2022-08-05 | 2024-02-08 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for gprc5d and bcma |
WO2024036100A1 (en) | 2022-08-08 | 2024-02-15 | Bristol-Myers Squibb Company | Substituted tetrazolyl compounds useful as t cell activators |
WO2024036101A1 (en) | 2022-08-09 | 2024-02-15 | Bristol-Myers Squibb Company | Tertiary amine substituted bicyclic compounds useful as t cell activators |
WO2024033400A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sk2 inhibitor for the treatment of pancreatic cancer |
WO2024033399A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sigmar1 ligand for the treatment of pancreatic cancer |
WO2024033458A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydroazepine derivatives |
WO2024033389A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033388A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033457A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024049949A1 (en) | 2022-09-01 | 2024-03-07 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2024052356A1 (en) | 2022-09-06 | 2024-03-14 | Institut National de la Santé et de la Recherche Médicale | Inhibitors of the ceramide metabolic pathway for overcoming immunotherapy resistance in cancer |
WO2024054992A1 (en) | 2022-09-09 | 2024-03-14 | Bristol-Myers Squibb Company | Methods of separating chelator |
WO2024056716A1 (en) | 2022-09-14 | 2024-03-21 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy |
WO2024069009A1 (en) | 2022-09-30 | 2024-04-04 | Alentis Therapeutics Ag | Treatment of drug-resistant hepatocellular carcinoma |
WO2024077166A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating lung cancer |
WO2024077191A1 (en) | 2022-10-05 | 2024-04-11 | Flagship Pioneering Innovations V, Inc. | Nucleic acid molecules encoding trif and additionalpolypeptides and their use in treating cancer |
WO2024077095A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating bladder cancer |
CN116444675B (zh) * | 2023-05-11 | 2023-12-22 | 亲和(武汉)生命科技有限责任公司 | 一种Pfu DNA聚合酶纳米抗体及其制备方法和应用 |
Family Cites Families (421)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US30985A (en) | 1860-12-18 | Thomas l | ||
US5432A (en) | 1848-02-01 | Improvement in machinery for knitting | ||
US18A (en) | 1836-08-31 | Thomas blanchard | ||
USRE30985E (en) | 1978-01-01 | 1982-06-29 | Serum-free cell culture media | |
US4275149A (en) | 1978-11-24 | 1981-06-23 | Syva Company | Macromolecular environment control in specific receptor assays |
US4657760A (en) | 1979-03-20 | 1987-04-14 | Ortho Pharmaceutical Corporation | Methods and compositions using monoclonal antibody to human T cells |
WO1981001145A1 (en) | 1979-10-18 | 1981-04-30 | Univ Illinois | Hydrolytic enzyme-activatible pro-drugs |
US4419446A (en) | 1980-12-31 | 1983-12-06 | The United States Of America As Represented By The Department Of Health And Human Services | Recombinant DNA process utilizing a papilloma virus DNA as a vector |
US4601978A (en) | 1982-11-24 | 1986-07-22 | The Regents Of The University Of California | Mammalian metallothionein promoter system |
US4560655A (en) | 1982-12-16 | 1985-12-24 | Immunex Corporation | Serum-free cell culture medium and process for making same |
US4657866A (en) | 1982-12-21 | 1987-04-14 | Sudhir Kumar | Serum-free, synthetic, completely chemically defined tissue culture media |
EP0138854B1 (en) | 1983-03-08 | 1992-11-04 | Chiron Mimotopes Pty. Ltd. | Antigenically active amino acid sequences |
NZ207394A (en) | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
WO1984003506A1 (en) | 1983-03-08 | 1984-09-13 | Commw Serum Lab Commission | Antigenically active amino acid sequences |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4767704A (en) | 1983-10-07 | 1988-08-30 | Columbia University In The City Of New York | Protein-free culture medium |
US4965199A (en) | 1984-04-20 | 1990-10-23 | Genentech, Inc. | Preparation of functional human factor VIII in mammalian cells using methotrexate based selection |
NZ215865A (en) | 1985-04-22 | 1988-10-28 | Commw Serum Lab Commission | Method of determining the active site of a receptor-binding analogue |
US5206344A (en) | 1985-06-26 | 1993-04-27 | Cetus Oncology Corporation | Interleukin-2 muteins and polymer conjugation thereof |
GB8516415D0 (en) | 1985-06-28 | 1985-07-31 | Celltech Ltd | Culture of animal cells |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US6548640B1 (en) | 1986-03-27 | 2003-04-15 | Btg International Limited | Altered antibodies |
US4927762A (en) | 1986-04-01 | 1990-05-22 | Cell Enterprises, Inc. | Cell culture medium with antioxidant |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
GB8705477D0 (en) | 1987-03-09 | 1987-04-15 | Carlton Med Prod | Drug delivery systems |
US4975278A (en) | 1988-02-26 | 1990-12-04 | Bristol-Myers Company | Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells |
IL87737A (en) | 1987-09-11 | 1993-08-18 | Genentech Inc | Method for culturing polypeptide factor dependent vertebrate recombinant cells |
ES2058199T3 (es) | 1987-09-23 | 1994-11-01 | Bristol Myers Squibb Co | Heteroconjugados de anticuerpos para la eliminacion de celulas infectadas por el vih. |
US5571689A (en) | 1988-06-16 | 1996-11-05 | Washington University | Method of N-acylating peptide and proteins with diheteroatom substituted analogs of myristic acid |
US5663143A (en) | 1988-09-02 | 1997-09-02 | Dyax Corp. | Engineered human-derived kunitz domains that inhibit human neutrophil elastase |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
EP0435911B1 (en) | 1988-09-23 | 1996-03-13 | Cetus Oncology Corporation | Cell culture medium for enhanced cell growth, culture longevity and product expression |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5175384A (en) | 1988-12-05 | 1992-12-29 | Genpharm International | Transgenic mice depleted in mature t-cells and methods for making transgenic mice |
US5225538A (en) | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
CA2062795A1 (en) | 1989-06-29 | 1990-12-30 | Michael W. Fanger | Bispecific reagents for aids therapy |
US5225212A (en) | 1989-10-20 | 1993-07-06 | Liposome Technology, Inc. | Microreservoir liposome composition and method |
US5859205A (en) * | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
CA2050918A1 (en) | 1990-01-12 | 1991-07-13 | Raju Kucherlapati | Generation of xenogeneic antibodies |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
US5723286A (en) | 1990-06-20 | 1998-03-03 | Affymax Technologies N.V. | Peptide library and screening systems |
WO1992000373A1 (en) | 1990-06-29 | 1992-01-09 | Biosource Genetics Corporation | Melanin production by transformed microorganisms |
US6172197B1 (en) | 1991-07-10 | 2001-01-09 | Medical Research Council | Methods for producing members of specific binding pairs |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
ES2108048T3 (es) | 1990-08-29 | 1997-12-16 | Genpharm Int | Produccion y utilizacion de animales inferiores transgenicos capaces de producir anticuerpos heterologos. |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5122469A (en) | 1990-10-03 | 1992-06-16 | Genentech, Inc. | Method for culturing Chinese hamster ovary cells to improve production of recombinant proteins |
US5264365A (en) | 1990-11-09 | 1993-11-23 | Board Of Regents, The University Of Texas System | Protease-deficient bacterial strains for production of proteolytically sensitive polypeptides |
US5508192A (en) | 1990-11-09 | 1996-04-16 | Board Of Regents, The University Of Texas System | Bacterial host strains for producing proteolytically sensitive polypeptides |
DE69130831T2 (de) | 1990-11-21 | 1999-09-16 | Iterex Pharma Lp | Synthese äquimolarer mischungen vielzähliger oligomere, speziell oligopeptidmischungen |
DE69129154T2 (de) | 1990-12-03 | 1998-08-20 | Genentech Inc | Verfahren zur anreicherung von proteinvarianten mit geänderten bindungseigenschaften |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
AU662148B2 (en) | 1991-04-10 | 1995-08-24 | Scripps Research Institute, The | Heterodimeric receptor libraries using phagemids |
JPH06507398A (ja) | 1991-05-14 | 1994-08-25 | リプリジェン コーポレーション | Hiv感染治療のための異種複合抗体 |
EP0590058B1 (en) | 1991-06-14 | 2003-11-26 | Genentech, Inc. | HUMANIZED Heregulin ANTIBODy |
JP3951062B2 (ja) | 1991-09-19 | 2007-08-01 | ジェネンテック・インコーポレーテッド | 少なくとも遊離のチオールとして存在するシステインを有する抗体フラグメントの大腸菌での発現、2官能性F(ab’)2抗体の産生のための使用 |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
US5270170A (en) | 1991-10-16 | 1993-12-14 | Affymax Technologies N.V. | Peptide library and screening method |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
AU3178993A (en) | 1991-11-25 | 1993-06-28 | Enzon, Inc. | Multivalent antigen-binding proteins |
ATE419355T1 (de) | 1992-02-06 | 2009-01-15 | Novartis Vaccines & Diagnostic | Marker für krebs und biosynthetisches bindeprotein dafür |
US5733743A (en) | 1992-03-24 | 1998-03-31 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
JPH08500017A (ja) | 1992-08-17 | 1996-01-09 | ジェネンテク,インコーポレイテッド | 二特異的免疫アドヘジン |
DK0669836T3 (da) | 1992-11-13 | 1996-10-14 | Idec Pharma Corp | Terapeutisk anvendelse af kimære og radioaktivt mærkede antistoffer og humant B-lymfocytbegrænset differentieringsantigen til behandling af B-cellelymfom |
EP0672142B1 (en) | 1992-12-04 | 2001-02-28 | Medical Research Council | Multivalent and multispecific binding proteins, their manufacture and use |
CA2143491C (en) * | 1994-03-01 | 2011-02-22 | Yasumasa Ishida | A novel peptide related to human programmed cell death and dna encoding it |
US5639635A (en) | 1994-11-03 | 1997-06-17 | Genentech, Inc. | Process for bacterial production of polypeptides |
EP1241264A1 (en) | 1994-12-02 | 2002-09-18 | Chiron Corporation | Monoclonal antibodies to colon cancer antigen |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US5840523A (en) | 1995-03-01 | 1998-11-24 | Genetech, Inc. | Methods and compositions for secretion of heterologous polypeptides |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
US5739277A (en) | 1995-04-14 | 1998-04-14 | Genentech Inc. | Altered polypeptides with increased half-life |
KR100654645B1 (ko) | 1995-04-27 | 2007-04-04 | 아브게닉스, 인크. | 면역화된 제노마우스 유래의 인간 항체 |
EP0823941A4 (en) | 1995-04-28 | 2001-09-19 | Abgenix Inc | HUMAN ANTIBODIES DERIVED FROM IMMUNIZED XENO MOUSES |
US5837234A (en) | 1995-06-07 | 1998-11-17 | Cytotherapeutics, Inc. | Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane |
DE19544393A1 (de) | 1995-11-15 | 1997-05-22 | Hoechst Schering Agrevo Gmbh | Synergistische herbizide Mischungen |
AU2660397A (en) | 1996-04-05 | 1997-10-29 | Board Of Regents, The University Of Texas System | Methods for producing soluble, biologically-active disulfide bond-containing eukaryotic proteins in bacterial cells |
ATE549918T1 (de) | 1996-12-03 | 2012-04-15 | Amgen Fremont Inc | Menschliche antikörper, die ausdrücklich menschliches tnf alpha binden |
WO2001034629A1 (en) | 1999-11-12 | 2001-05-17 | Human Genome Sciences, Inc. | 21 human secreted proteins |
US6083715A (en) | 1997-06-09 | 2000-07-04 | Board Of Regents, The University Of Texas System | Methods for producing heterologous disulfide bond-containing polypeptides in bacterial cells |
PT1034298E (pt) | 1997-12-05 | 2012-02-03 | Scripps Research Inst | Humanização de anticorpo murino |
DE69937291T2 (de) | 1998-04-02 | 2008-07-10 | Genentech, Inc., South San Francisco | Antikörpervarianten und fragmente davon |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6335155B1 (en) | 1998-06-26 | 2002-01-01 | Sunesis Pharmaceuticals, Inc. | Methods for rapidly identifying small organic molecule ligands for binding to biological target molecules |
WO2000026227A1 (en) | 1998-10-30 | 2000-05-11 | Millennium Pharmaceuticals, Inc. | Ldl related protein and uses thereof |
US6406884B1 (en) | 1999-06-18 | 2002-06-18 | Millennium Pharmaceuticals, Inc. | Secreted proteins and uses thereof |
US20030027998A1 (en) | 1998-10-30 | 2003-02-06 | Holtzman Douglas A. | Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses |
US20060205034A1 (en) | 1998-10-30 | 2006-09-14 | Millennium Pharmaceuticals, Inc. | Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses |
EP1141708A1 (en) | 1998-12-28 | 2001-10-10 | Sunesis Pharmaceuticals Inc. | Identifying small organic molecule ligands for binding |
US20080213778A1 (en) | 1998-12-30 | 2008-09-04 | Millennium Pharmaceuticals, Inc. | Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses |
EP1710299A3 (en) | 1998-12-30 | 2007-01-10 | Millennium Pharmaceuticals, Inc. | Secreted proteins and nucleic acids encoding them |
EP1140976A4 (en) | 1998-12-30 | 2003-05-21 | Millennium Pharm Inc | SECRETED PROTEINS AND THEIR USES |
US7041474B2 (en) * | 1998-12-30 | 2006-05-09 | Millennium Pharmaceuticals, Inc. | Nucleic acid encoding human tango 509 |
AU2396700A (en) | 1998-12-30 | 2000-07-31 | Millennium Pharmaceuticals, Inc. | Secreted proteins and uses thereof |
US20120270219A1 (en) | 1998-12-30 | 2012-10-25 | Millennium Pharmaceuticals, Inc. | Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses |
WO2000050442A2 (en) | 1999-02-26 | 2000-08-31 | Millennium Pharmaceuticals, Inc. | Secreted proteins and uses thereof |
EP1173456A4 (en) | 1999-03-01 | 2005-10-12 | Millennium Pharm Inc | SECRETED PROTEINS AND NUCLEIC ACIDS ENCODING THEM |
EP1444260A4 (en) | 1999-05-14 | 2004-08-25 | Millennium Pharm Inc | SECRETED PROTEINS AND THEIR USE |
WO2001000672A1 (en) | 1999-06-29 | 2001-01-04 | Millennium Pharmaceuticals, Inc. | Secreted proteins and uses thereof |
WO2001000673A1 (en) | 1999-06-30 | 2001-01-04 | Millennium Pharmaceuticals, Inc. | Membrane-associated and secreted proteins and uses thereof |
EP1074617A3 (en) | 1999-07-29 | 2004-04-21 | Research Association for Biotechnology | Primers for synthesising full-length cDNA and their use |
JP2002171977A (ja) | 1999-07-29 | 2002-06-18 | Herikkusu Kenkyusho:Kk | 新規なヒトsh2蛋白質 |
JP2002191363A (ja) | 1999-07-29 | 2002-07-09 | Herikkusu Kenkyusho:Kk | 全長cDNA合成用プライマー、およびその用途 |
US6908748B2 (en) | 1999-07-29 | 2005-06-21 | Kenji Sobue | Genes associated with the maintenance of differentiation of smooth muscle cells |
AU6180900A (en) | 1999-07-29 | 2001-02-19 | Chugai Seiyaku Kabushiki Kaisha | Novel genes encoding protein kinase/protein phosphatase |
WO2001009346A1 (fr) | 1999-07-29 | 2001-02-08 | Ota, Toshio | Gene codant pour une nouvelle proteine de type adenylate kinase 3 (ak3) |
AU6181000A (en) | 1999-07-29 | 2001-02-19 | Chugai Research Institute For Molecular Medicine, Inc. | Novel genes encoding protein kinase/protein phosphatase |
WO2001009317A1 (fr) | 1999-07-29 | 2001-02-08 | Helix Research Institute | Gene associe au cancer de l'estomac |
WO2001009319A1 (fr) | 1999-07-29 | 2001-02-08 | Helix Research Institute | Gene exprime specifiquement dans le muscle cardiaque foetal humain |
WO2001009349A1 (fr) | 1999-07-29 | 2001-02-08 | Helix Research Institute | Nouveaux genes codant pour une proteine de type serine protease |
AU6394400A (en) | 1999-07-30 | 2001-02-19 | Millennium Pharmaceuticals, Inc. | Secreted proteins and uses thereof |
JP4896327B2 (ja) * | 1999-08-23 | 2012-03-14 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | Pd−1、b7−4の受容体、およびその使用 |
WO2001014556A1 (en) * | 1999-08-23 | 2001-03-01 | Dana-Farber Cancer Institute, Inc. | Novel b7-4 molecules and uses therefor |
EP1218411A4 (en) | 1999-09-20 | 2004-09-01 | Millennium Pharm Inc | SECRETED PROTEINS AND THEIR USES |
WO2001023523A2 (en) | 1999-09-30 | 2001-04-05 | Millennium Pharmaceuticals, Inc. | Secreted proteins and uses thereof |
US20070219125A1 (en) | 1999-11-17 | 2007-09-20 | Cojocaru Gad S | Novel thrombospondin-1 polynucleotides encoding variant thrombospondin-1 polypeptides and methods using same |
WO2001036632A2 (en) | 1999-11-17 | 2001-05-25 | Compugen Ltd. | Variants of alternative splicing |
WO2001039722A2 (en) | 1999-11-30 | 2001-06-07 | Mayo Foundation For Medical Education And Research | B7-h1, a novel immunoregulatory molecule |
US6803192B1 (en) * | 1999-11-30 | 2004-10-12 | Mayo Foundation For Medical Education And Research | B7-H1, a novel immunoregulatory molecule |
EP1908780B1 (en) * | 2000-01-03 | 2012-08-15 | The Trustees Of The University Of Pennsylvania | Novel chimeric proteins and methods for using the same |
WO2001068134A2 (en) * | 2000-03-14 | 2001-09-20 | Genetics Institute, Inc. | Therapies that improve graft survival, using antibodies against a b7 antigen |
NZ522045A (en) | 2000-03-30 | 2007-05-31 | Whitehead Biomedical Inst | RNA sequence-specific mediators of RNA interference |
JP2003530839A (ja) * | 2000-04-12 | 2003-10-21 | プリンシピア ファーマスーティカル コーポレイション | アルブミン融合タンパク質 |
US6936450B2 (en) | 2000-04-12 | 2005-08-30 | Compugen Ltd. | Variants of protein kinases |
US7030219B2 (en) * | 2000-04-28 | 2006-04-18 | Johns Hopkins University | B7-DC, Dendritic cell co-stimulatory molecules |
US20030031675A1 (en) | 2000-06-06 | 2003-02-13 | Mikesell Glen E. | B7-related nucleic acids and polypeptides useful for immunomodulation |
EP1292619B1 (en) | 2000-06-06 | 2008-02-06 | Bristol-Myers Squibb Company | B7-related nucleic acids and polypeptides and their uses for immunomodulation |
US7323174B1 (en) * | 2000-06-12 | 2008-01-29 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Modulation of immune response and methods based thereon |
NZ522844A (en) | 2000-06-28 | 2005-02-25 | Brigham & Womens Hospital | PD-L2 molecules: novel PD-1 ligands and methods to identify compounds to modulate T cell activation |
US6635750B1 (en) * | 2000-07-20 | 2003-10-21 | Millennium Pharmaceuticals, Inc. | B7-H2 nucleic acids, members of the B7 family |
EP1328624B1 (en) | 2000-09-20 | 2011-11-09 | Amgen Inc. | B7-like molecules and uses thereof |
WO2002039813A1 (fr) * | 2000-11-15 | 2002-05-23 | Ono Pharmaceutical Co., Ltd. | Souris sans pd-1 et utilisation de celle-ci |
US20060014166A1 (en) | 2004-01-27 | 2006-01-19 | Yossi Cohen | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of endometriosis |
US7601692B2 (en) | 2000-11-28 | 2009-10-13 | Compugen Ltd. | MCP-1 splice variants and methods of using same |
JP3523245B1 (ja) | 2000-11-30 | 2004-04-26 | メダレックス,インコーポレーテッド | ヒト抗体作製用トランスジェニック染色体導入齧歯動物 |
ES2728168T3 (es) | 2000-12-01 | 2019-10-22 | Max Planck Gesellschaft | Moléculas pequeñas de ARN que median en la interferencia de ARN |
US9249229B2 (en) | 2000-12-08 | 2016-02-02 | Alexion Pharmaceuticals, Inc. | Polypeptides and antibodies derived from chronic lymphocytic leukemia cells and uses thereof |
US20060057651A1 (en) | 2000-12-08 | 2006-03-16 | Bowdish Katherine S | Polypeptides and antibodies derived from chronic lymphocytic leukemia cells and uses thereof |
AU2002246632B2 (en) | 2000-12-08 | 2007-04-05 | Alexion Pharmaceuticals, Inc. | Chronic lymphocytic leukemia cell line and its use for producing an antibody |
US7408041B2 (en) | 2000-12-08 | 2008-08-05 | Alexion Pharmaceuticals, Inc. | Polypeptides and antibodies derived from chronic lymphocytic leukemia cells and uses thereof |
US20040198661A1 (en) | 2000-12-08 | 2004-10-07 | Bowdish Katherine S. | Polypeptides and antibodies derived from chronic lymphocytic leukemia cells and uses thereof |
US20030180309A1 (en) | 2001-01-08 | 2003-09-25 | Baum Peter R. | Human B7 polypeptides |
US20040005557A1 (en) | 2001-01-16 | 2004-01-08 | Muralidhara Padigaru | Proteins, polynucleotides encoding them and methods of using the same |
WO2002068647A2 (en) | 2001-01-16 | 2002-09-06 | Curagen Corporation | Proteins, polynucleotides encoding them and methods of using the same |
US7754208B2 (en) * | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
AU2002240818C1 (en) | 2001-03-14 | 2008-11-06 | Agilent Technologies, Inc. | MHC molecule constructs and their uses for diagnosis and therapy |
WO2002077208A1 (de) | 2001-03-27 | 2002-10-03 | Genethor Gmbh | Antigen-abhängige reduktion von spezifischen immunreaktionen durch beeinflussung der co-stimulation |
AR036993A1 (es) * | 2001-04-02 | 2004-10-20 | Wyeth Corp | Uso de agentes que modulan la interaccion entre pd-1 y sus ligandos en la submodulacion de respuestas inmunologicas |
WO2002079499A1 (en) | 2001-04-02 | 2002-10-10 | Wyeth | Pd-1, a receptor for b7-4, and uses therefor |
WO2002080952A2 (en) | 2001-04-09 | 2002-10-17 | Lorantis Limited | Therapeutic use and identification of modulators of a hedgehog signalling pathway or one of its target pathways |
AU2002258941A1 (en) * | 2001-04-20 | 2002-11-05 | Mayo Foundation For Medical Education And Research | Methods of enhancing cell responsiveness |
FR2824567B1 (fr) * | 2001-05-11 | 2003-08-08 | Inst Nat Sante Rech Med | Procede d'obtention de lymphocytes tr1 regulateurs specifiques d'antigene |
WO2002092792A2 (de) | 2001-05-16 | 2002-11-21 | Genethor Gmbh | Antigen-abhängige reduktion von spezifischen immunreaktionen durch beeinflussung der co-stimulation |
US20060276422A1 (en) * | 2001-05-18 | 2006-12-07 | Nassim Usman | RNA interference mediated inhibition of B7-H1 gene expression using short interfering nucleic acid (siNA) |
US20030003953A1 (en) * | 2001-06-18 | 2003-01-02 | Comverse Network Systems Ltd. | Multi-user chat service in a cellular network |
ATE524495T1 (de) | 2001-07-31 | 2011-09-15 | Ono Pharmaceutical Co | Pd-1-spezifische substanz |
US20040033497A1 (en) * | 2002-08-13 | 2004-02-19 | Alarcon-Riquelme Marta E. | Polymorphisms of PD-1 |
US20040101876A1 (en) | 2002-05-31 | 2004-05-27 | Liat Mintz | Methods and systems for annotating biomolecular sequences |
US7678769B2 (en) | 2001-09-14 | 2010-03-16 | Compugen, Ltd. | Hepatocyte growth factor receptor splice variants and methods of using same |
US20040248157A1 (en) | 2001-09-14 | 2004-12-09 | Michal Ayalon-Soffer | Novel polynucleotides encoding soluble polypeptides and methods using same |
US20100183573A1 (en) | 2001-09-14 | 2010-07-22 | Compugen Ltd. | Hepatocyte growth factor receptor splice variants and methods of using same |
US20040142325A1 (en) | 2001-09-14 | 2004-07-22 | Liat Mintz | Methods and systems for annotating biomolecular sequences |
CA2842429A1 (en) | 2001-10-19 | 2003-05-01 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of inflammatory bowel disorders |
WO2003042402A2 (en) * | 2001-11-13 | 2003-05-22 | Dana-Farber Cancer Institute, Inc. | Agents that modulate immune cell activation and methods of use thereof |
GB0130955D0 (en) | 2001-12-24 | 2002-02-13 | Cancer Res Ventures | Expression system |
US7638326B2 (en) * | 2002-01-03 | 2009-12-29 | The Trustees Of The University Of Pennsylvania | Activation and expansion of T-cells using an engineered multivalent signaling platform |
US20030166282A1 (en) | 2002-02-01 | 2003-09-04 | David Brown | High potency siRNAS for reducing the expression of target genes |
AR038568A1 (es) | 2002-02-20 | 2005-01-19 | Hoffmann La Roche | Anticuerpos anti-a beta y su uso |
EP2865688A1 (en) | 2002-03-01 | 2015-04-29 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
IL148993A0 (en) | 2002-04-04 | 2002-11-10 | Yissum Res Dev Co | Broad-spectrum in-vivo effective superantigen toxin antagonists based on the interaction between cd28 and the superantigen and uses thereof |
US8535672B2 (en) * | 2002-04-04 | 2013-09-17 | Yissum Research Development Of The Hebrew University Of Jerusalem | Broad-spectrum in-vivo effective superantigen toxin antagonists based on the interaction between CD28 and the superantigen and uses thereof |
EP2305710A3 (en) * | 2002-06-03 | 2013-05-29 | Genentech, Inc. | Synthetic antibody phage libraries |
CA2388441A1 (en) * | 2002-06-10 | 2003-12-10 | Wei-Ping Min | Immunomodulation using rna interference |
US7595048B2 (en) * | 2002-07-03 | 2009-09-29 | Ono Pharmaceutical Co., Ltd. | Method for treatment of cancer by inhibiting the immunosuppressive signal induced by PD-1 |
JP2004121218A (ja) * | 2002-08-06 | 2004-04-22 | Jenokkusu Soyaku Kenkyusho:Kk | 気管支喘息または慢性閉塞性肺疾患の検査方法 |
US7217797B2 (en) | 2002-10-15 | 2007-05-15 | Pdl Biopharma, Inc. | Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis |
CA2502413A1 (en) | 2002-11-01 | 2004-05-21 | The Regents Of The University Of Colorado, A Body Corporate | Quantitative analysis of protein isoforms using matrix-assisted laser desorption/ionization time of flight mass spectrometry |
US7449300B2 (en) * | 2002-11-21 | 2008-11-11 | Mayo Foundation For Medical Education And Research | Detection of antibodies specific for B7-H1 in subjects with diseases or pathological conditions mediated by activated T cells |
US7439042B2 (en) * | 2002-12-16 | 2008-10-21 | Globeimmune, Inc. | Yeast-based therapeutic for chronic hepatitis C infection |
CN1753912B (zh) | 2002-12-23 | 2011-11-02 | 惠氏公司 | 抗pd-1抗体及其用途 |
US6808748B2 (en) | 2003-01-23 | 2004-10-26 | Applied Materials, Inc. | Hydrogen assisted HDP-CVD deposition process for aggressive gap-fill technology |
JP4532409B2 (ja) * | 2003-01-23 | 2010-08-25 | 小野薬品工業株式会社 | ヒトpd−1に対し特異性を有する物質 |
KR20120084343A (ko) | 2003-03-04 | 2012-07-27 | 알렉시온 파마슈티칼스, 인코포레이티드 | 만성 림프성 백혈병 세포로부터 유래된 폴리펩티드와 항체 및 이들의 용도 |
AU2003272065A1 (en) | 2003-04-03 | 2004-10-25 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Broad-spectrum in-vivo effective superantigen toxin antagonists based on the interaction between cd28 and the superantigen and uses thereof |
US20040248205A1 (en) * | 2003-04-16 | 2004-12-09 | Stern Lawrence J. | Major histocompatibility complex (MHC)-peptide arrays |
PT1698642E (pt) * | 2003-12-26 | 2009-01-13 | Shinetsu Chemical Co | Processo para a produção de polímero de cloreto de vinilo |
US20090075257A1 (en) | 2004-01-27 | 2009-03-19 | Compugen Ltd. | Novel nucleic acid sequences and methods of use thereof for diagnosis |
US20090215046A1 (en) | 2004-01-27 | 2009-08-27 | Compugen Ltd. | Novel nucleotide and amino acid sequences, and assays methods of use thereof for diagnosis of colon cancer |
US20060040278A1 (en) | 2004-01-27 | 2006-02-23 | Cojocaru Gad S | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of ovarian cancer |
US20060183131A1 (en) | 2004-01-27 | 2006-08-17 | Amir Toporik | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of breast cancer |
US20080182299A1 (en) | 2004-01-27 | 2008-07-31 | Compugent Ltd. | Novel brain natriuretic peptide variants and methods of use thereof |
US7569662B2 (en) | 2004-01-27 | 2009-08-04 | Compugen Ltd | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of lung cancer |
US7368548B2 (en) | 2004-01-27 | 2008-05-06 | Compugen Ltd. | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer |
EP1749025A2 (en) | 2004-01-27 | 2007-02-07 | Compugen Ltd. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of colon cancer |
AU2005206389A1 (en) | 2004-01-27 | 2005-08-04 | Compugen Ltd. | Methods of identifying putative gene products by interspecies sequence comparison and biomolecular sequences uncovered thereby |
WO2005072055A2 (en) | 2004-01-27 | 2005-08-11 | Compugen Usa, Inc. | Novel brain natriuretic peptide variants and methods of use thereof |
US7345142B2 (en) | 2004-01-27 | 2008-03-18 | Compugen Ltd. | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of cardiac disease |
WO2005072340A2 (en) | 2004-01-27 | 2005-08-11 | Compugen Ltd. | Novel polynucleotides encoding polypeptides and methods using same |
EP1735342A2 (en) | 2004-01-27 | 2006-12-27 | Compugen USA, Inc. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis |
EP1713900A4 (en) | 2004-01-27 | 2009-06-17 | Compugen Ltd | METHOD AND SYSTEMS FOR COMMENTING BIOMOLECULAR SEQUENCES |
AU2005248530A1 (en) | 2004-01-27 | 2005-12-08 | Compugen Ltd. | Differential expression of markers in ovarian cancer |
US7667001B1 (en) | 2004-01-27 | 2010-02-23 | Compugen Ltd. | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of lung cancer |
WO2006035273A2 (en) | 2004-01-27 | 2006-04-06 | Compugen Usa, Inc. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis |
WO2006021874A2 (en) | 2004-01-27 | 2006-03-02 | Compugen Usa, Inc. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer |
CA2555509A1 (en) | 2004-01-27 | 2005-07-27 | Compugen Usa, Inc. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of lung cancer |
US7842459B2 (en) | 2004-01-27 | 2010-11-30 | Compugen Ltd. | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis |
US20060263786A1 (en) | 2004-01-27 | 2006-11-23 | Rotem Sorek | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of colon cancer |
US7332569B2 (en) | 2004-01-27 | 2008-02-19 | Compugen Ltd. | Brain natriuretic peptide spliced variant |
WO2005072050A2 (en) | 2004-01-27 | 2005-08-11 | Compugen Usa, Inc. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of breast cancer |
US7714100B2 (en) | 2004-01-27 | 2010-05-11 | Compugen Ltd | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of cardiac disease |
EP1713827A2 (en) | 2004-01-27 | 2006-10-25 | Compugen Ltd. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of cardiac disease |
KR20050082389A (ko) * | 2004-02-18 | 2005-08-23 | 메덱스젠 주식회사 | 직렬 연쇄체를 갖는 면역접합체를 포함하는 장기이식합병증 치료용 약제학적 조성물 |
AU2005250408B2 (en) * | 2004-05-27 | 2010-09-23 | The Trustees Of The University Of Pennsylvania | Novel artificial antigen presenting cells and uses therefor |
EP2481750A1 (en) | 2004-06-30 | 2012-08-01 | Mayo Foundation for Medical Education and Research | B7-DC binding antibody |
US20060099203A1 (en) | 2004-11-05 | 2006-05-11 | Pease Larry R | B7-DC binding antibody |
US7501119B2 (en) | 2004-06-30 | 2009-03-10 | Mayo Foundation For Medical Education And Research | Methods and molecules for modulating an immune response |
US20060003452A1 (en) * | 2004-07-01 | 2006-01-05 | Virxsys Corporation | Vector packaging cell line |
PT1810026T (pt) * | 2004-10-06 | 2018-06-11 | Mayo Found Medical Education & Res | B7-h1 e pd-1 no tratamento do carcinona de células renais |
WO2006043271A1 (en) | 2004-10-22 | 2006-04-27 | Compugen Ltd. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis |
WO2006054297A2 (en) | 2004-11-17 | 2006-05-26 | Compugen Ltd. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis |
KR20070086218A (ko) * | 2004-12-17 | 2007-08-27 | 제넨테크, 인크. | 자가면역 질환에 대한 이전 요법에 실패했던 환자에서의,자가면역 질환의 항-혈관신생 요법 |
AU2005323025A1 (en) * | 2004-12-31 | 2006-07-13 | Biogen Idec Ma Inc. | Polypeptides that bind BR3 and uses thereof |
WO2006072954A2 (en) | 2005-01-05 | 2006-07-13 | Compugen Ltd. | Novel il-6 polynucleotides encoding variant il-6 polypeptides and methods using same |
US7906635B2 (en) | 2005-01-27 | 2011-03-15 | Compugen Ltd. | Nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of ovarian cancer |
EP1851543A2 (en) | 2005-02-24 | 2007-11-07 | Compugen Ltd. | Novel diagnostic markers, especially for in vivo imaging, and assays and methods of use thereof |
CN105315373B (zh) | 2005-05-09 | 2018-11-09 | 小野药品工业株式会社 | 程序性死亡-1(pd-1)的人单克隆抗体及使用抗pd-1抗体来治疗癌症的方法 |
ES2609429T3 (es) * | 2005-05-12 | 2017-04-20 | Zymogenetics, Inc. | Composiciones y métodos para modular respuestas inmunitarias |
CA2545557A1 (en) * | 2005-05-31 | 2006-11-30 | Mcgill University | Stromal antigen-presenting cells and use thereof |
PL2397156T3 (pl) | 2005-06-08 | 2017-07-31 | Dana-Farber Cancer Institute, Inc. | Sposoby i kompozycje do leczenia uporczywych infekcji i nowotworu poprzez hamowanie ścieżki zaprogramowanej śmierci komórki 1 (PD-1) |
EP1891218A2 (en) | 2005-06-08 | 2008-02-27 | Compugen Ltd. | Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis |
JP2006345852A (ja) * | 2005-06-16 | 2006-12-28 | Virxsys Corp | 抗体複合体 |
KR101607288B1 (ko) | 2005-07-01 | 2016-04-05 | 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. | 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날 항체 |
CA2624535A1 (en) | 2005-09-30 | 2007-04-05 | Compugen Ltd. | Hepatocyte growth factor receptor splice variants and methods of using same |
EP1777523A1 (en) | 2005-10-19 | 2007-04-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | An in vitro method for the prognosis of progression of a cancer and of the outcome in a patient and means for performing said method |
ES2618543T3 (es) * | 2005-11-23 | 2017-06-21 | Genentech, Inc. | Métodos y composiciones relacionados con ensayos de linfocitos B |
AU2006321888A1 (en) * | 2005-12-08 | 2007-06-14 | University Of Louisville Research Foundation, Inc. | Immunostimulatory compositions and methods |
WO2007082154A2 (en) | 2006-01-05 | 2007-07-19 | Mayo Foundation For Medical Education And Research | B7-h1 and b7-h4 in cancer |
US20100015642A1 (en) | 2006-01-05 | 2010-01-21 | Kwon Eugene D | B7-h1 and survivin in cancer |
US20100015143A1 (en) | 2006-03-22 | 2010-01-21 | Tracy Hussell | Compositions and Methods Relating to Modulation of Immune System Components |
US20070243548A1 (en) * | 2006-03-28 | 2007-10-18 | Elias Georges | Calumenin-directed diagnostics and therapeutics for cancer and chemotherapeutic drug resistance |
WO2007124361A2 (en) | 2006-04-20 | 2007-11-01 | Mayo Foundation For Medical Education And Research | Soluble b7-h1 |
US20100166741A1 (en) | 2006-07-13 | 2010-07-01 | Genentech , Inc. | Altered br-3 binding polypeptides |
WO2008011344A2 (en) | 2006-07-17 | 2008-01-24 | Nationwide Children's Hospital Inc. | Disruption of programmed death-1 (pd-1) ligands to adjuvant adeno-associated virus vector vaccines |
GB0615662D0 (en) * | 2006-08-07 | 2006-09-13 | Affitech As | Antibody |
WO2008034076A2 (en) | 2006-09-15 | 2008-03-20 | The Johns Hopkins University | Cyclophosphamide in combination with immune therapeutics |
WO2008085562A2 (en) * | 2006-09-20 | 2008-07-17 | The Johns Hopkins University | Combinatorieal therapy of cancer and infectious diseases with anti-b7-h1 antibodies |
WO2008057632A1 (en) | 2006-11-09 | 2008-05-15 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Differential gene expression in physiological and pathological angiogenesis |
AU2007325283B2 (en) | 2006-11-27 | 2012-08-30 | Diadexus, Inc. | Ovr110 antibody compositions and methods of use |
CA2672595A1 (en) | 2006-12-15 | 2008-06-19 | Guy Hermans | Amino acid sequences that modulate the interaction between cells of the immune system |
NZ629273A (en) | 2006-12-27 | 2015-02-27 | Harvard College | Compositions and methods for the treatment of infections and tumors |
WO2008091643A2 (en) | 2007-01-23 | 2008-07-31 | Altarex Medical Corp. | In vitro culture system to evaluate synergy in targeting immune suppressive pathways concurrent to immunotherapy |
JP2010516786A (ja) | 2007-01-26 | 2010-05-20 | ユニバーシティー オブ ルイヴィル リサーチ ファウンデーション,インコーポレーテッド | ワクチンとしての使用のためのエキソソーム成分の改変 |
KR20090114443A (ko) | 2007-02-09 | 2009-11-03 | 제넨테크, 인크. | 항-Robo4 항체 및 그의 용도 |
WO2008116468A2 (en) | 2007-03-26 | 2008-10-02 | Dako Denmark A/S | Mhc peptide complexes and uses thereof in infectious diseases |
EP3023436A1 (en) | 2007-07-03 | 2016-05-25 | Dako Denmark A/S | Improved methods for generation, labeling and use of mhc multimers |
US9243052B2 (en) | 2007-08-17 | 2016-01-26 | Daniel Olive | Method for treating and diagnosing hematologic malignancies |
EP2195342A1 (en) | 2007-09-07 | 2010-06-16 | Ablynx N.V. | Binding molecules with multiple binding sites, compositions comprising the same and uses thereof |
US8062852B2 (en) | 2007-10-01 | 2011-11-22 | The Children's Hospital And Regional Medical Center | Detection and treatment of autoimmune disorders |
BRPI0819349B1 (pt) | 2007-10-31 | 2018-05-08 | Idexx Lab Inc | métodos de distinguir entre animais que foram ou não infectados com e. canis, e de determinar a presença de um anticorpo ou fragmentos de ligação de antígeno, composição e kit |
CA2742926A1 (en) | 2007-11-28 | 2009-06-04 | Universite De Montreal | Pd-1 modulation and uses thereof |
US20100285039A1 (en) | 2008-01-03 | 2010-11-11 | The Johns Hopkins University | B7-H1 (CD274) Antagonists Induce Apoptosis of Tumor Cells |
WO2009108341A1 (en) | 2008-02-28 | 2009-09-03 | Argos Therapeutics, Inc. | Transient expression of immunomodulatory polypeptides for the prevention and treatment of autoimmune disease, allergy and transplant rejection |
US20110020325A1 (en) | 2008-02-29 | 2011-01-27 | Kwon Eugene D | Methods for reducing granulomatous inflammation |
WO2009114335A2 (en) | 2008-03-12 | 2009-09-17 | Merck & Co., Inc. | Pd-1 binding proteins |
US8246016B2 (en) | 2008-07-18 | 2012-08-21 | Uop Llc | Downcomer for a gas-liquid contacting device |
WO2010014784A2 (en) | 2008-08-01 | 2010-02-04 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with diverse therapeutic regimens for the synergistic treatment of proliferative diseases |
PL2350129T3 (pl) | 2008-08-25 | 2015-12-31 | Amplimmune Inc | Kompozycje antagonistów PD-1 i sposoby stosowania |
WO2010027828A2 (en) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Pd-1 antagonists and methods of use thereof |
KR101050829B1 (ko) | 2008-10-02 | 2011-07-20 | 서울대학교산학협력단 | 항 pd-1 항체 또는 항 pd-l1 항체를 포함하는 항암제 |
WO2010056735A1 (en) | 2008-11-11 | 2010-05-20 | The Trustees Of The University Of Pennsylvania | Compositions and methods for inhibiting an oncogenic protein to enhance immunogenicity |
US20110229411A1 (en) | 2008-11-27 | 2011-09-22 | Institut Gustave Roussy | Use of p2x7 pathway for assessing the sensitivity of a subject to a cancer treatment |
CA2744449C (en) | 2008-11-28 | 2019-01-29 | Emory University | Methods for the treatment of infections and tumors |
SG196798A1 (en) * | 2008-12-09 | 2014-02-13 | Genentech Inc | Anti-pd-l1 antibodies and their use to enhance t-cell function |
LT2769737T (lt) | 2009-07-20 | 2017-06-26 | Bristol-Myers Squibb Company | Anti-ctla4 antikūno derinys su etopozidu, skirtas sinerginiam proliferacinių ligų gydymui |
CA2778714C (en) | 2009-11-24 | 2018-02-27 | Medimmune Limited | Targeted binding agents against b7-h1 |
EP2504028A4 (en) | 2009-11-24 | 2014-04-09 | Amplimmune Inc | SIMULTANEOUS INHIBITION OF PD-L1 / PD-L2 |
PL2542590T5 (pl) | 2010-03-05 | 2020-08-10 | The Johns Hopkins University | Kompozycje i sposoby dla ukierunkowanych immunomodulatorowych przeciwciał i białek fuzyjnych |
EP2571577A1 (en) | 2010-05-17 | 2013-03-27 | Bristol-Myers Squibb Company | Improved immunotherapeutic dosing regimens and combinations thereof |
WO2012037551A2 (en) | 2010-09-17 | 2012-03-22 | Irx Therapeutics, Inc. | Primary cell-derived biologic and wt1 synthetic long peptide vaccine |
HUE051674T2 (hu) | 2010-09-24 | 2021-03-29 | Niels Grabe | Eszközök és eljárások rákos beteg kezelésére adott válaszának elõrejelzésére |
ES2669310T3 (es) | 2011-04-20 | 2018-05-24 | Medimmune, Llc | Anticuerpos y otras moléculas que se unen con B7-H1 y PD-1 |
JP6238459B2 (ja) | 2011-08-01 | 2017-11-29 | ジェネンテック, インコーポレイテッド | Pd−1軸結合アンタゴニストとmek阻害剤を使用する癌の治療方法 |
PT2785375T (pt) | 2011-11-28 | 2020-10-29 | Merck Patent Gmbh | Anticorpos anti-pd-l1 e usos destes |
WO2013085893A1 (en) | 2011-12-05 | 2013-06-13 | Immunomedics, Inc. | Therapeutic use of anti-cd22 antibodies for inducing trogocytosis |
US9757458B2 (en) | 2011-12-05 | 2017-09-12 | Immunomedics, Inc. | Crosslinking of CD22 by epratuzumab triggers BCR signaling and caspase-dependent apoptosis in hematopoietic cancer cells |
US20140212425A1 (en) | 2011-12-05 | 2014-07-31 | Immunomedics, Inc. | Therapeutic use of anti-cd22 antibodies for inducing trogocytosis |
US20150004175A1 (en) | 2011-12-13 | 2015-01-01 | Yale University | Compositions and Methods for Reducing CTL Exhaustion |
CA2862390A1 (en) | 2012-01-25 | 2013-08-01 | Dnatrix, Inc. | Biomarkers and combination therapies using oncolytic virus and immunomodulation |
WO2013164754A2 (en) | 2012-05-04 | 2013-11-07 | Pfizer Inc. | Prostate-associated antigens and vaccine-based immunotherapy regimens |
WO2013172926A1 (en) | 2012-05-14 | 2013-11-21 | Yale University | Immune biomarkers and assays predictive of clinical response to immunotherapy for cancer |
SG10201700698WA (en) | 2012-05-15 | 2017-02-27 | Bristol Myers Squibb Co | Cancer immunotherapy by disrupting pd-1/pd-l1 signaling |
AU2013262655A1 (en) | 2012-05-16 | 2014-12-04 | John Wayne Cancer Institute | Immunological markers for adjuvant therapy in melanoma |
EP2854843A4 (en) | 2012-05-31 | 2016-06-01 | Sorrento Therapeutics Inc | ANTIGEN BINDING PROTEINS THAT BIND PD-L1 |
ES2742379T3 (es) | 2012-05-31 | 2020-02-14 | Hoffmann La Roche | Procedimientos de tratamiento del cáncer usando antagonistas de unión al eje de PD-1 y antagonistas de VEGF |
US9845356B2 (en) | 2012-08-03 | 2017-12-19 | Dana-Farber Cancer Institute, Inc. | Single agent anti-PD-L1 and PD-L2 dual binding antibodies and methods of use |
JP6559566B2 (ja) | 2012-08-06 | 2019-08-14 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 癌患者をスクリーニングするための方法及びキット |
WO2014028560A2 (en) | 2012-08-14 | 2014-02-20 | Ibc Pharmaceuticals, Inc. | T-cell redirecting bispecific antibodies for treatment of disease |
US9682143B2 (en) | 2012-08-14 | 2017-06-20 | Ibc Pharmaceuticals, Inc. | Combination therapy for inducing immune response to disease |
US9382329B2 (en) | 2012-08-14 | 2016-07-05 | Ibc Pharmaceuticals, Inc. | Disease therapy by inducing immune response to Trop-2 expressing cells |
US20150231241A1 (en) | 2012-08-14 | 2015-08-20 | Ibc Pharmaceuticals, Inc. | Combination therapy for inducing immune response to disease |
WO2014083178A1 (en) | 2012-11-30 | 2014-06-05 | F. Hoffmann-La Roche Ag | Identification of patients in need of pd-l1 inhibitor cotherapy |
AR093984A1 (es) | 2012-12-21 | 2015-07-01 | Merck Sharp & Dohme | Anticuerpos que se unen a ligando 1 de muerte programada (pd-l1) humano |
CA2896797A1 (en) | 2013-01-11 | 2014-07-17 | Dingfu Biotarget Co., Ltd | Agents for treating tumours, use and method thereof |
WO2014122271A1 (en) | 2013-02-07 | 2014-08-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from diffuse large b-cell lymphomas |
EP2958571B1 (en) | 2013-02-21 | 2024-04-10 | Michele Maio | Dna hypomethylating agents for cancer therapy |
WO2014165082A2 (en) | 2013-03-13 | 2014-10-09 | Medimmune, Llc | Antibodies and methods of detection |
EP2971128B1 (en) | 2013-03-15 | 2023-03-01 | Veracyte, Inc. | Biomarkers for diagnosis of lung diseases and methods of use thereof |
KR20230070054A (ko) | 2013-03-15 | 2023-05-19 | 제넨테크, 인크. | Pd-1 및 pd-l1 관련 상태를 치료하기 위한 바이오마커 및 방법 |
US20160084839A1 (en) | 2013-04-02 | 2016-03-24 | Marisa Dolled-Filhart | Immunohistochemical assay for detecting expression of programmed death ligand 1 (pd-l1) in tumor tissue |
JP6361039B2 (ja) | 2013-04-03 | 2018-07-25 | アイビーシー ファーマスーティカルズ,インコーポレイテッド | 疾患に対する免疫反応を誘導するための併用療法 |
WO2014194293A1 (en) | 2013-05-30 | 2014-12-04 | Amplimmune, Inc. | Improved methods for the selection of patients for pd-1 or b7-h4 targeted therapies, and combination therapies thereof |
EP3003316B1 (en) | 2013-05-31 | 2020-07-22 | Merck Sharp & Dohme Corp. | Combination therapies for cancer |
EP3004877A4 (en) | 2013-06-06 | 2017-04-19 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for identification, assessment prevention, and treatment of cancer using pd-l1 isoforms |
WO2015035112A1 (en) | 2013-09-05 | 2015-03-12 | The Johns Hopkins University | Cancer therapy via a combination of epigenetic modulation and immune modulation |
GB201316024D0 (en) | 2013-09-09 | 2013-10-23 | Almac Diagnostics Ltd | Molecular diagnostic test for lung cancer |
WO2015035365A1 (en) | 2013-09-09 | 2015-03-12 | The Nohns Hopkins University | Targeting the m2-tumor associated macrophage for cancer therapy |
WO2015038538A1 (en) | 2013-09-10 | 2015-03-19 | Medimmune, Llc | Compositions and methods for treating sepsis |
EP3626742A1 (en) | 2013-09-27 | 2020-03-25 | F. Hoffmann-La Roche AG | Anti-pdl1 antibody formulations |
WO2015050663A1 (en) | 2013-10-01 | 2015-04-09 | Mayo Foundation For Medical Education And Research | Methods for treating cancer in patients with elevated levels of bim |
CA2926690A1 (en) | 2013-10-11 | 2015-04-16 | Sloan-Kettering Institute For Cancer Research | Methods and compositions for regulatory t-cell ablation |
EP3060919A4 (en) | 2013-10-25 | 2018-02-14 | Nodality, Inc. | Methods and compositions for immunomodulation |
CN104558177B (zh) | 2013-10-25 | 2020-02-18 | 苏州思坦维生物技术股份有限公司 | 拮抗抑制程序性死亡受体pd-1与其配体结合的单克隆抗体及其编码序列与用途 |
CA2926856A1 (en) | 2013-10-25 | 2015-04-30 | Dana-Farber Cancer Institute, Inc. | Anti-pd-l1 monoclonal antibodies and fragments thereof |
WO2015069770A1 (en) | 2013-11-05 | 2015-05-14 | Cognate Bioservices, Inc. | Combinations of checkpoint inhibitors and therapeutics to treat cancer |
US20160299146A1 (en) | 2013-11-20 | 2016-10-13 | Dana-Farber Cancer Institute, Inc. | Kynurenine Pathway Biomarkers Predictive of Anti-Immune Checkpoint Inhibitor Response |
WO2015081158A1 (en) | 2013-11-26 | 2015-06-04 | Bristol-Myers Squibb Company | Method of treating hiv by disrupting pd-1/pd-l1 signaling |
WO2015088930A1 (en) | 2013-12-10 | 2015-06-18 | Merck Sharp & Dohme Corp. | Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue |
WO2015088847A1 (en) | 2013-12-11 | 2015-06-18 | Glaxosmithkline Llc | Treating cancer with a combination of a pd-1 antagonist and a vegfr inhibitor |
RS59480B1 (sr) | 2013-12-12 | 2019-12-31 | Shanghai hengrui pharmaceutical co ltd | Pd-1 antitelo, njegov fragment koji se vezuje na antigen, i njegova medicinska primena |
US8986691B1 (en) | 2014-07-15 | 2015-03-24 | Kymab Limited | Method of treating atopic dermatitis or asthma using antibody to IL4RA |
US9045548B1 (en) | 2014-07-15 | 2015-06-02 | Kymab Limited | Precision Medicine by targeting rare human PCSK9 variants for cholesterol treatment |
AU2014364606A1 (en) | 2013-12-17 | 2016-07-07 | Genentech, Inc. | Combination therapy comprising OX40 binding agonists and PD-1 axis binding antagonists |
US9067998B1 (en) | 2014-07-15 | 2015-06-30 | Kymab Limited | Targeting PD-1 variants for treatment of cancer |
US8945560B1 (en) | 2014-07-15 | 2015-02-03 | Kymab Limited | Method of treating rheumatoid arthritis using antibody to IL6R |
US9017678B1 (en) | 2014-07-15 | 2015-04-28 | Kymab Limited | Method of treating rheumatoid arthritis using antibody to IL6R |
US8992927B1 (en) | 2014-07-15 | 2015-03-31 | Kymab Limited | Targeting human NAV1.7 variants for treatment of pain |
EP2886558A1 (en) | 2013-12-17 | 2015-06-24 | Kymab Limited | Antibodies for use in treating conditions related to specific PCSK9 variants in specific patient populations |
US9045545B1 (en) | 2014-07-15 | 2015-06-02 | Kymab Limited | Precision medicine by targeting PD-L1 variants for treatment of cancer |
US9914769B2 (en) | 2014-07-15 | 2018-03-13 | Kymab Limited | Precision medicine for cholesterol treatment |
EP2975058A1 (en) | 2014-07-15 | 2016-01-20 | Kymab Limited | Antibodies for use in treating conditions related to specific PCSK9 variants in specific patient populations |
CN105934253A (zh) | 2013-12-17 | 2016-09-07 | 豪夫迈·罗氏有限公司 | 使用pd-1轴结合拮抗剂和抗her2抗体治疗her2阳性癌症的方法 |
US9051378B1 (en) | 2014-07-15 | 2015-06-09 | Kymab Limited | Targeting rare human PCSK9 variants for cholesterol treatment |
US8883157B1 (en) | 2013-12-17 | 2014-11-11 | Kymab Limited | Targeting rare human PCSK9 variants for cholesterol treatment |
US20150210772A1 (en) | 2013-12-17 | 2015-07-30 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody |
US9034332B1 (en) | 2014-07-15 | 2015-05-19 | Kymab Limited | Precision medicine by targeting rare human PCSK9 variants for cholesterol treatment |
US9023359B1 (en) | 2014-07-15 | 2015-05-05 | Kymab Limited | Targeting rare human PCSK9 variants for cholesterol treatment |
US8986694B1 (en) | 2014-07-15 | 2015-03-24 | Kymab Limited | Targeting human nav1.7 variants for treatment of pain |
WO2015092393A2 (en) | 2013-12-17 | 2015-06-25 | Kymab Limited | Human targets |
WO2015095868A1 (en) | 2013-12-20 | 2015-06-25 | Wake Forest University Health Sciences | Methods and compositions for increasing protective antibody levels induced by pneumococcal polysaccharide vaccines |
GB201322725D0 (en) | 2013-12-20 | 2014-02-05 | Immodulon Therapeutics Ltd | Cancer therapy |
US20160340407A1 (en) | 2014-01-14 | 2016-11-24 | Dana-Farber Camcer Institute, Inc. | Compositions and methods for identification, assessment, prevention, and treatment of melanoma using pd-l1 isoforms |
CA3193936A1 (en) | 2014-01-15 | 2015-07-23 | Kadmon Corporation, Llc | Immunomodulatory agents |
TWI680138B (zh) | 2014-01-23 | 2019-12-21 | 美商再生元醫藥公司 | 抗pd-l1之人類抗體 |
TWI681969B (zh) | 2014-01-23 | 2020-01-11 | 美商再生元醫藥公司 | 針對pd-1的人類抗體 |
US20170175197A1 (en) | 2014-01-29 | 2017-06-22 | Caris Mpi, Inc. | Molecular profiling of immune modulators |
WO2015117164A1 (en) | 2014-02-03 | 2015-08-06 | Memorial Sloan-Kettering Cancer Center | Tumor-associated macrophages and methods and compositions for targeting cancer therapy and identifying potential responders |
WO2015114146A1 (en) | 2014-02-03 | 2015-08-06 | Sividon Diagnostics Gmbh | Method for predicting the response to an anti-her2 containing therapy and/or chemotherapy in patients with breast cancer |
EP3102233A4 (en) | 2014-02-05 | 2017-11-22 | Cedars-Sinai Medical Center | Methods and compositions for treating cancer and infectious diseases |
US10619210B2 (en) | 2014-02-07 | 2020-04-14 | The Johns Hopkins University | Predicting response to epigenetic drug therapy |
CA2937236C (en) | 2014-02-21 | 2023-03-07 | Ibc Pharmaceuticals, Inc. | Disease therapy by inducing immune response to trop-2 expressing cells |
US20170107577A1 (en) | 2014-03-11 | 2017-04-20 | The Council Of The Queensland Institute Of Medical Research | Determining Cancer Aggressiveness, Prognosis and Responsiveness to Treatment |
CN114081946A (zh) | 2014-03-12 | 2022-02-25 | 耶达研究与开发有限公司 | 降低系统性调节性t细胞水平或活性来治疗cns疾病和损伤 |
WO2015157623A1 (en) | 2014-04-11 | 2015-10-15 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Immune gene signatures in urothelial carcinoma (uc) |
WO2015164743A2 (en) | 2014-04-24 | 2015-10-29 | Dana-Farber Cancer Institute, Inc. | Tumor suppressor and oncogene biomarkers predictive of anti-immune checkpoint inhibitor response |
WO2015162596A1 (en) | 2014-04-25 | 2015-10-29 | Immunid | Use of immune diversity as a predictive marker for identifying patients likely to respond to an anti-ctla4 treatment |
US10302653B2 (en) | 2014-05-22 | 2019-05-28 | Mayo Foundation For Medical Education And Research | Distinguishing antagonistic and agonistic anti B7-H1 antibodies |
WO2015178746A1 (ko) | 2014-05-23 | 2015-11-26 | 주식회사 제넥신 | Pd-l1 융합 단백질 및 이의 용도 |
US20170115291A1 (en) | 2014-05-28 | 2017-04-27 | Dana-Farber Cancer Institute, Inc. | Activating JAK Kinase Biomarkers Predictive of Anti-Immune Checkpoint Inhibitor Response |
US20160031990A1 (en) | 2014-05-29 | 2016-02-04 | Medlmmune, Llc | Antagonists of pdl-1 and pd-1 for the treatment of hpv-negative cancers |
JP6666905B2 (ja) | 2014-05-29 | 2020-03-18 | スプリング バイオサイエンス コーポレーション | Pd−l1抗体及びその使用 |
CA2951278A1 (en) | 2014-06-19 | 2015-12-23 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized programmed cell death 1 gene |
KR102130600B1 (ko) | 2014-07-03 | 2020-07-08 | 베이진 엘티디 | Pd-l1 항체와 이를 이용한 치료 및 진단 |
DK3166976T3 (da) | 2014-07-09 | 2022-04-11 | Birdie Biopharmaceuticals Inc | Anti-pd-l1-kombinationer til behandling af tumorer |
JP6279733B2 (ja) | 2014-07-09 | 2018-02-14 | 日本全薬工業株式会社 | 抗イヌpd−1抗体又は抗イヌpd−l1抗体 |
CN112546230A (zh) | 2014-07-09 | 2021-03-26 | 博笛生物科技有限公司 | 用于治疗癌症的联合治疗组合物和联合治疗方法 |
US9150660B1 (en) | 2014-07-15 | 2015-10-06 | Kymab Limited | Precision Medicine by targeting human NAV1.8 variants for treatment of pain |
US9139648B1 (en) | 2014-07-15 | 2015-09-22 | Kymab Limited | Precision medicine by targeting human NAV1.9 variants for treatment of pain |
DE202015008974U1 (de) | 2014-07-15 | 2016-06-30 | Kymab Limited | Targeting von humaner PCSK9 zur Cholesterinbehandlung |
EP3332790A1 (en) | 2014-07-15 | 2018-06-13 | Kymab Limited | Antibodies for use in treating conditions related to specific pcsk9 variants in specific patients populations |
GB201413162D0 (en) | 2014-07-24 | 2014-09-10 | Immusmol Sas | Prediction of cancer treatment based on determination of enzymes or metabolites of the kynurenine pathway |
US11186640B2 (en) | 2014-07-31 | 2021-11-30 | The University Of Western Australia | Method for the identification of immunotherapy-drug combinations using a network approach |
ES2847311T3 (es) | 2014-08-05 | 2021-08-02 | MabQuest SA | Reactivos inmunológicos que se unen a PD-1 |
JP6909153B2 (ja) | 2014-08-05 | 2021-07-28 | アポロミクス インコーポレイテッド | 抗pd−l1抗体 |
CN106794246B (zh) | 2014-08-08 | 2021-10-15 | OncoQuest制药有限公司 | 肿瘤抗原特异性抗体和tlr3刺激以增强检查点干扰癌症疗法的性能 |
WO2016023916A1 (en) | 2014-08-12 | 2016-02-18 | Kymab Limited | Treatment of disease using ligand binding to targets of interest |
AU2015303239A1 (en) | 2014-08-14 | 2016-12-15 | F. Hoffmann-La Roche Ag | Combination therapy of antibodies activating human CD40 and antibodies against human PD-L1 |
WO2016027273A1 (en) | 2014-08-19 | 2016-02-25 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd | Methods for predicting and monitoring cancer patients' response to treatment by measuring myeloid derived suppressor cells (mdscs) |
DK3186283T3 (da) | 2014-08-29 | 2020-03-02 | Hoffmann La Roche | Kombinationsbehandling med tumormålrettede IL-2- immuncytokinervarianter og antistoffer mod humant PD-L1 |
CN112546238A (zh) | 2014-09-01 | 2021-03-26 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-pd-l1结合物 |
WO2016034718A1 (en) | 2014-09-05 | 2016-03-10 | Medimmune Limited | Methods for identifying patients responsive to anti-pd-l1 antibody therapy using markers (cxcl9, krt8.trim29, and ifngamma) |
US9535074B2 (en) | 2014-09-08 | 2017-01-03 | Merck Sharp & Dohme Corp. | Immunoassay for soluble PD-L1 |
EP3659621A1 (en) | 2014-09-13 | 2020-06-03 | Novartis AG | Combination therapies for cancer |
WO2016044736A1 (en) | 2014-09-18 | 2016-03-24 | Cell Signaling Technology, Inc. | Altered antibodies and methods of making the same |
WO2016049385A1 (en) | 2014-09-24 | 2016-03-31 | Apellis Pharmaceuticals, Inc. | Methods and compositions for cancer treatment and treatment selection |
AU2015326996B2 (en) | 2014-09-30 | 2021-05-20 | Intervet International B.V. | PD-L1 antibodies binding canine PD-L1 |
US20170209574A1 (en) | 2014-10-03 | 2017-07-27 | Novartis Ag | Combination therapies |
WO2016057933A1 (en) | 2014-10-10 | 2016-04-14 | Global Biopharma, Inc. | Methods for treating and/or preventing a tumor growth, invasion and/or metastasis |
WO2016061256A1 (en) | 2014-10-14 | 2016-04-21 | The University Of Chicago | Nanoparticles for photodynamic therapy, x-ray induced photodynamic therapy, radiotherapy, chemotherapy, immunotherapy, and any combination thereof |
PE20171067A1 (es) | 2014-10-14 | 2017-07-24 | Novartis Ag | Moleculas de anticuerpo que se unen a pd-l1 y usos de las mismas |
US20170242016A1 (en) | 2014-10-15 | 2017-08-24 | Epic Sciences, Inc. | Circulating tumor cell diagnostics for therapy targeting pd-l1 |
WO2016059602A2 (en) | 2014-10-16 | 2016-04-21 | Glaxo Group Limited | Methods of treating cancer and related compositions |
AU2015343425A1 (en) | 2014-11-04 | 2017-05-25 | Dana-Farber Cancer Institute, Inc. | Anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses |
WO2016073760A1 (en) | 2014-11-05 | 2016-05-12 | The Regents Of The University Of California | Methods for stratifying non-responders to therapies that block pd1/pdl1 axis |
WO2016071701A1 (en) | 2014-11-07 | 2016-05-12 | Kymab Limited | Treatment of disease using ligand binding to targets of interest |
US20190076452A1 (en) | 2014-11-11 | 2019-03-14 | Medimmune Limited | Therapeutic combinations for treating neoplasia |
CN106999583A (zh) | 2014-11-17 | 2017-08-01 | 豪夫迈·罗氏有限公司 | 包含ox40结合激动剂和pd‑1轴结合拮抗剂的组合疗法 |
MA40737A (fr) | 2014-11-21 | 2017-07-04 | Memorial Sloan Kettering Cancer Center | Déterminants de la réponse d'un cancer à une immunothérapie par blocage de pd-1 |
WO2016089873A1 (en) | 2014-12-02 | 2016-06-09 | Celgene Corporation | Combination therapies |
AU2016274584A1 (en) | 2015-06-08 | 2018-01-04 | Genentech, Inc. | Methods of treating cancer using anti-OX40 antibodies and PD-1 axis binding antagonists |
JP6996983B2 (ja) | 2015-06-16 | 2022-02-21 | ジェネンテック, インコーポレイテッド | 抗cll-1抗体及び使用方法 |
-
2009
- 2009-12-08 SG SG2014001614A patent/SG196798A1/en unknown
- 2009-12-08 KR KR1020237015324A patent/KR20230070055A/ko not_active Application Discontinuation
- 2009-12-08 CN CN201410743500.4A patent/CN104479018B/zh active Active
- 2009-12-08 RU RU2011128399A patent/RU2636023C2/ru not_active Application Discontinuation
- 2009-12-08 BR BRPI0917592-0A patent/BRPI0917592B1/pt active IP Right Grant
- 2009-12-08 UA UAA201108595A patent/UA109108C2/uk unknown
- 2009-12-08 EP EP21169871.7A patent/EP3929216A1/en not_active Withdrawn
- 2009-12-08 EP EP22180770.4A patent/EP4169951A1/en not_active Withdrawn
- 2009-12-08 ES ES09764997.4T patent/ES2628095T3/es active Active
- 2009-12-08 HU HUE09764997A patent/HUE034832T2/hu unknown
- 2009-12-08 WO PCT/US2009/067104 patent/WO2010077634A1/en active Application Filing
- 2009-12-08 EP EP23214687.8A patent/EP4331604A2/en active Pending
- 2009-12-08 US US12/633,339 patent/US8217149B2/en active Active
- 2009-12-08 LT LTEP22215991.5T patent/LT4209510T/lt unknown
- 2009-12-08 PL PL09764997T patent/PL2376535T3/pl unknown
- 2009-12-08 DK DK09764997.4T patent/DK2376535T3/en active
- 2009-12-08 LT LTEP09764997.4T patent/LT2376535T/lt unknown
- 2009-12-08 EP EP18177113.0A patent/EP3447073A1/en not_active Withdrawn
- 2009-12-08 RU RU2017132160A patent/RU2017132160A/ru not_active Application Discontinuation
- 2009-12-08 CA CA3120172A patent/CA3120172A1/en active Pending
- 2009-12-08 MX MX2016009486A patent/MX356367B/es unknown
- 2009-12-08 AU AU2009333580A patent/AU2009333580B2/en active Active
- 2009-12-08 KR KR1020197016653A patent/KR20190069615A/ko active Application Filing
- 2009-12-08 FI FIEP22215991.5T patent/FI4209510T3/fi active
- 2009-12-08 KR KR1020227011061A patent/KR20220047668A/ko not_active Application Discontinuation
- 2009-12-08 SG SG2011042173A patent/SG172059A1/en unknown
- 2009-12-08 EP EP17162438.0A patent/EP3255060A1/en not_active Withdrawn
- 2009-12-08 TW TW108135242A patent/TWI729512B/zh active
- 2009-12-08 CN CN200980149532.9A patent/CN102245640B/zh active Active
- 2009-12-08 KR KR1020177026686A patent/KR20170113681A/ko active Application Filing
- 2009-12-08 KR KR1020217015160A patent/KR20210060670A/ko not_active Application Discontinuation
- 2009-12-08 CR CR20160570A patent/CR20160570A/es unknown
- 2009-12-08 CN CN202210551253.2A patent/CN114835812A/zh active Pending
- 2009-12-08 KR KR1020117013128A patent/KR101782570B1/ko active IP Right Grant
- 2009-12-08 JP JP2011540819A patent/JP5681638B2/ja active Active
- 2009-12-08 TW TW102134843A patent/TWI605828B/zh active
- 2009-12-08 KR KR1020207012431A patent/KR20200047793A/ko active Application Filing
- 2009-12-08 MA MA33995A patent/MA32948B1/fr unknown
- 2009-12-08 CA CA2740806A patent/CA2740806C/en active Active
- 2009-12-08 MX MX2013001859A patent/MX342591B/es unknown
- 2009-12-08 PT PT97649974T patent/PT2376535T/pt unknown
- 2009-12-08 KR KR1020187022311A patent/KR20180089573A/ko active Application Filing
- 2009-12-08 DK DK22215991.5T patent/DK4209510T3/da active
- 2009-12-08 PE PE2014001134A patent/PE20141722A1/es active IP Right Grant
- 2009-12-08 TW TW110115088A patent/TW202206454A/zh unknown
- 2009-12-08 MX MX2011005853A patent/MX2011005853A/es not_active Application Discontinuation
- 2009-12-08 EP EP09764997.4A patent/EP2376535B9/en not_active Revoked
- 2009-12-08 SG SG10201708690SA patent/SG10201708690SA/en unknown
- 2009-12-08 SI SI200931672A patent/SI2376535T1/sl unknown
- 2009-12-08 MY MYPI2011002606A patent/MY188826A/en unknown
- 2009-12-08 EP EP22215991.5A patent/EP4209510B1/en active Active
- 2009-12-08 PE PE2011001188A patent/PE20120341A1/es not_active Application Discontinuation
- 2009-12-08 NZ NZ717213A patent/NZ717213A/en unknown
- 2009-12-08 TW TW105118618A patent/TWI686405B/zh active
- 2009-12-08 NZ NZ592119A patent/NZ592119A/xx unknown
- 2009-12-08 TW TW098141907A patent/TWI419705B/zh active
- 2009-12-08 CN CN201810947420.9A patent/CN108997498A/zh active Pending
- 2009-12-09 AR ARP090104766A patent/AR074563A1/es active IP Right Grant
-
2011
- 2011-03-31 ZA ZA2011/02417A patent/ZA201102417B/en unknown
- 2011-05-24 CO CO11064204A patent/CO6390023A2/es active IP Right Grant
- 2011-06-05 IL IL213353A patent/IL213353A/en active Protection Beyond IP Right Term
- 2011-06-07 CR CR20110316A patent/CR20110316A/es unknown
- 2011-06-08 CL CL2011001382A patent/CL2011001382A1/es unknown
- 2011-06-08 EC EC2011011115A patent/ECSP11011115A/es unknown
-
2012
- 2012-04-16 HK HK12103694.9A patent/HK1163130A1/zh unknown
- 2012-05-23 US US13/478,511 patent/US20130045201A1/en not_active Abandoned
- 2012-05-23 US US13/478,421 patent/US20130045200A1/en not_active Abandoned
- 2012-05-24 US US13/479,470 patent/US20130045202A1/en not_active Abandoned
-
2013
- 2013-07-30 US US13/954,796 patent/US20140065135A1/en not_active Abandoned
-
2014
- 2014-11-11 US US14/538,072 patent/US20150322153A1/en not_active Abandoned
-
2015
- 2015-01-09 JP JP2015003298A patent/JP6178349B2/ja active Active
- 2015-08-17 HK HK15107929.4A patent/HK1207387A1/zh unknown
- 2015-09-04 US US14/846,457 patent/US20160222117A1/en not_active Abandoned
-
2016
- 2016-06-09 AU AU2016203867A patent/AU2016203867B2/en active Active
- 2016-10-26 US US15/335,278 patent/US9920123B2/en active Active
- 2016-11-22 IL IL249127A patent/IL249127B/en active IP Right Grant
-
2017
- 2017-04-06 JP JP2017075787A patent/JP6509935B2/ja active Active
- 2017-06-14 HR HRP20170908TT patent/HRP20170908T1/hr unknown
- 2017-06-28 CY CY20171100689T patent/CY1118943T1/el unknown
- 2017-11-27 FR FR17C1050C patent/FR17C1050I2/fr active Active
- 2017-11-28 HU HUS1700049C patent/HUS1700049I1/hu unknown
- 2017-11-29 NL NL300914C patent/NL300914I2/nl unknown
- 2017-11-29 LU LU00051C patent/LUC00051I2/fr unknown
- 2017-12-06 CY CY2017043C patent/CY2017043I2/el unknown
- 2017-12-19 LT LTPA2017041C patent/LTC2376535I2/lt unknown
-
2018
- 2018-01-26 US US15/881,611 patent/US20190016807A1/en not_active Abandoned
- 2018-02-14 NO NO2018006C patent/NO2018006I1/no unknown
- 2018-05-09 AU AU2018203226A patent/AU2018203226B2/en active Active
- 2018-05-30 HK HK18107040.5A patent/HK1247621A1/zh unknown
- 2018-12-24 IL IL263931A patent/IL263931B/en active IP Right Grant
-
2019
- 2019-04-03 JP JP2019071460A patent/JP2019122409A/ja active Pending
-
2020
- 2020-04-01 AR ARP200100913A patent/AR118559A2/es unknown
- 2020-04-21 US US16/854,707 patent/US20210032345A1/en not_active Abandoned
- 2020-07-09 AU AU2020204593A patent/AU2020204593B2/en active Active
- 2020-10-13 IL IL278007A patent/IL278007A/en unknown
-
2021
- 2021-12-02 JP JP2021196323A patent/JP7332671B2/ja active Active
-
2023
- 2023-01-26 US US18/160,094 patent/US20230287127A1/en active Pending
- 2023-08-10 JP JP2023131222A patent/JP2023154034A/ja active Pending
-
2024
- 2024-02-12 AU AU2024200864A patent/AU2024200864A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7332671B2 (ja) | 抗pd-l1抗体およびt細胞機能を増強するためのそれらの使用 |