WO2011066389A1 - Targeted binding agents against b7-h1 - Google Patents
Targeted binding agents against b7-h1 Download PDFInfo
- Publication number
- WO2011066389A1 WO2011066389A1 PCT/US2010/058007 US2010058007W WO2011066389A1 WO 2011066389 A1 WO2011066389 A1 WO 2011066389A1 US 2010058007 W US2010058007 W US 2010058007W WO 2011066389 A1 WO2011066389 A1 WO 2011066389A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- amino acid
- seq
- human
- acid sequence
- Prior art date
Links
- 239000011230 binding agent Substances 0.000 title description 281
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims abstract description 330
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 claims abstract description 286
- 241000282414 Homo sapiens Species 0.000 claims abstract description 198
- 210000004027 cell Anatomy 0.000 claims abstract description 195
- 238000011282 treatment Methods 0.000 claims abstract description 60
- 230000027455 binding Effects 0.000 claims description 222
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 claims description 121
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 121
- 238000000034 method Methods 0.000 claims description 105
- 150000001413 amino acids Chemical class 0.000 claims description 89
- 241001465754 Metazoa Species 0.000 claims description 81
- 102000048776 human CD274 Human genes 0.000 claims description 78
- 206010028980 Neoplasm Diseases 0.000 claims description 77
- 239000012634 fragment Substances 0.000 claims description 68
- 238000003556 assay Methods 0.000 claims description 64
- 108091033319 polynucleotide Proteins 0.000 claims description 61
- 102000040430 polynucleotide Human genes 0.000 claims description 61
- 239000002157 polynucleotide Substances 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 59
- 230000005764 inhibitory process Effects 0.000 claims description 52
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 51
- 201000011510 cancer Diseases 0.000 claims description 45
- 239000013612 plasmid Substances 0.000 claims description 41
- 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 39
- 125000000539 amino acid group Chemical group 0.000 claims description 33
- 239000013598 vector Substances 0.000 claims description 28
- 150000007523 nucleic acids Chemical class 0.000 claims description 27
- 230000001404 mediated effect Effects 0.000 claims description 25
- 230000004614 tumor growth Effects 0.000 claims description 25
- 102000039446 nucleic acids Human genes 0.000 claims description 24
- 108020004707 nucleic acids Proteins 0.000 claims description 24
- 201000001441 melanoma Diseases 0.000 claims description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- 241000282693 Cercopithecidae Species 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 241000024188 Andala Species 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 238000002794 lymphocyte assay Methods 0.000 claims description 2
- 230000000754 repressing effect Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 59
- 201000010099 disease Diseases 0.000 abstract description 55
- 210000004408 hybridoma Anatomy 0.000 abstract description 37
- 230000014509 gene expression Effects 0.000 abstract description 34
- 239000000427 antigen Substances 0.000 description 104
- 235000001014 amino acid Nutrition 0.000 description 103
- 108091007433 antigens Proteins 0.000 description 103
- 102000036639 antigens Human genes 0.000 description 103
- 108090000623 proteins and genes Proteins 0.000 description 96
- 229940024606 amino acid Drugs 0.000 description 92
- 210000004602 germ cell Anatomy 0.000 description 81
- 102000004169 proteins and genes Human genes 0.000 description 76
- 235000018102 proteins Nutrition 0.000 description 67
- 108090000765 processed proteins & peptides Proteins 0.000 description 62
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 46
- 102000004196 processed proteins & peptides Human genes 0.000 description 46
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 45
- 229920001184 polypeptide Polymers 0.000 description 40
- 241000699670 Mus sp. Species 0.000 description 34
- 108060003951 Immunoglobulin Proteins 0.000 description 33
- 102000018358 immunoglobulin Human genes 0.000 description 33
- 239000003814 drug Substances 0.000 description 32
- 238000006467 substitution reaction Methods 0.000 description 29
- 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 28
- 230000006870 function Effects 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 26
- 239000003112 inhibitor Substances 0.000 description 24
- 125000003729 nucleotide group Chemical group 0.000 description 23
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 22
- 241000699666 Mus <mouse, genus> Species 0.000 description 22
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 22
- 238000009472 formulation Methods 0.000 description 22
- 239000003446 ligand Substances 0.000 description 22
- 239000002773 nucleotide Substances 0.000 description 22
- 241001529936 Murinae Species 0.000 description 21
- 239000012636 effector Substances 0.000 description 21
- 210000004881 tumor cell Anatomy 0.000 description 21
- 238000013459 approach Methods 0.000 description 19
- 230000001225 therapeutic effect Effects 0.000 description 19
- 230000000295 complement effect Effects 0.000 description 18
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 18
- 230000002401 inhibitory effect Effects 0.000 description 18
- 230000035772 mutation Effects 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- 230000001613 neoplastic effect Effects 0.000 description 17
- 238000007792 addition Methods 0.000 description 16
- 230000001965 increasing effect Effects 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 15
- 230000004071 biological effect Effects 0.000 description 15
- 230000009545 invasion Effects 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 241000894007 species Species 0.000 description 15
- 239000006228 supernatant Substances 0.000 description 15
- 239000003053 toxin Substances 0.000 description 15
- 231100000765 toxin Toxicity 0.000 description 15
- 108700012359 toxins Proteins 0.000 description 15
- 241000124008 Mammalia Species 0.000 description 14
- 108091034117 Oligonucleotide Proteins 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- 230000004927 fusion Effects 0.000 description 14
- 238000003752 polymerase chain reaction Methods 0.000 description 14
- 210000002966 serum Anatomy 0.000 description 14
- 210000003719 b-lymphocyte Anatomy 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 12
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 12
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 12
- 229960004397 cyclophosphamide Drugs 0.000 description 12
- -1 e.g. Proteins 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 12
- 229940088598 enzyme Drugs 0.000 description 12
- 238000001727 in vivo Methods 0.000 description 12
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 11
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 11
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 11
- 241000282567 Macaca fascicularis Species 0.000 description 11
- 239000011324 bead Substances 0.000 description 11
- 230000004709 cell invasion Effects 0.000 description 11
- 229960004679 doxorubicin Drugs 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- 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 10
- 230000004663 cell proliferation Effects 0.000 description 10
- 230000009260 cross reactivity Effects 0.000 description 10
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 10
- 230000035755 proliferation Effects 0.000 description 10
- 230000008685 targeting Effects 0.000 description 10
- 238000012447 xenograft mouse model Methods 0.000 description 10
- 108010006654 Bleomycin Proteins 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 9
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 9
- 206010035226 Plasma cell myeloma Diseases 0.000 description 9
- 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 9
- 229960001561 bleomycin Drugs 0.000 description 9
- 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 9
- 238000012217 deletion Methods 0.000 description 9
- 230000037430 deletion Effects 0.000 description 9
- 230000013595 glycosylation Effects 0.000 description 9
- 238000006206 glycosylation reaction Methods 0.000 description 9
- 210000004698 lymphocyte Anatomy 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 210000001616 monocyte Anatomy 0.000 description 9
- 238000002703 mutagenesis Methods 0.000 description 9
- 231100000350 mutagenesis Toxicity 0.000 description 9
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 9
- 230000002062 proliferating effect Effects 0.000 description 9
- 230000011664 signaling Effects 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 229960004528 vincristine Drugs 0.000 description 9
- 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 9
- 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 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 8
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 8
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 8
- 229940045513 CTLA4 antagonist Drugs 0.000 description 8
- 241000283707 Capra Species 0.000 description 8
- 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 8
- 238000002965 ELISA Methods 0.000 description 8
- 108010074328 Interferon-gamma Proteins 0.000 description 8
- 206010027476 Metastases Diseases 0.000 description 8
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 8
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000012452 Xenomouse strains Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 235000018417 cysteine Nutrition 0.000 description 8
- 231100000433 cytotoxic Toxicity 0.000 description 8
- 230000001472 cytotoxic effect Effects 0.000 description 8
- 210000004443 dendritic cell Anatomy 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 8
- 238000009396 hybridization Methods 0.000 description 8
- 230000028993 immune response Effects 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 230000009401 metastasis Effects 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 235000002374 tyrosine Nutrition 0.000 description 8
- 102000008096 B7-H1 Antigen Human genes 0.000 description 7
- 108010074708 B7-H1 Antigen Proteins 0.000 description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 7
- 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 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 208000036142 Viral infection Diseases 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 230000001413 cellular effect Effects 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 238000002649 immunization Methods 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- 229960000485 methotrexate Drugs 0.000 description 7
- 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 7
- 229960004618 prednisone Drugs 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 7
- 230000009385 viral infection Effects 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 6
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 6
- 239000012980 RPMI-1640 medium Substances 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 6
- 108010090804 Streptavidin Proteins 0.000 description 6
- 230000006044 T cell activation Effects 0.000 description 6
- 230000005867 T cell response Effects 0.000 description 6
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 6
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products 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 6
- 230000003213 activating effect Effects 0.000 description 6
- 230000000692 anti-sense effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000001900 immune effect Effects 0.000 description 6
- 229940127121 immunoconjugate Drugs 0.000 description 6
- 230000005847 immunogenicity Effects 0.000 description 6
- 229940072221 immunoglobulins Drugs 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 201000000050 myeloid neoplasm Diseases 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- 210000004180 plasmocyte Anatomy 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D 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)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 5
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 5
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 206010014733 Endometrial cancer Diseases 0.000 description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 description 5
- 108010087819 Fc receptors Proteins 0.000 description 5
- 102000009109 Fc receptors Human genes 0.000 description 5
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 5
- 102100037850 Interferon gamma Human genes 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
- 101001117316 Mus musculus Programmed cell death 1 ligand 1 Proteins 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- 230000006052 T cell proliferation Effects 0.000 description 5
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 5
- 230000005809 anti-tumor immunity Effects 0.000 description 5
- 150000001720 carbohydrates Chemical class 0.000 description 5
- 235000014633 carbohydrates Nutrition 0.000 description 5
- 229960004630 chlorambucil Drugs 0.000 description 5
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 5
- 229940127089 cytotoxic agent Drugs 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 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 5
- 238000000432 density-gradient centrifugation Methods 0.000 description 5
- 229960005420 etoposide Drugs 0.000 description 5
- 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 5
- 102000048362 human PDCD1 Human genes 0.000 description 5
- 230000002637 immunotoxin Effects 0.000 description 5
- 239000002596 immunotoxin Substances 0.000 description 5
- 229940051026 immunotoxin Drugs 0.000 description 5
- 231100000608 immunotoxin Toxicity 0.000 description 5
- 229960000310 isoleucine Drugs 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 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 5
- 229960001924 melphalan Drugs 0.000 description 5
- 229960004857 mitomycin Drugs 0.000 description 5
- 230000003472 neutralizing effect Effects 0.000 description 5
- 210000005259 peripheral blood Anatomy 0.000 description 5
- 239000011886 peripheral blood Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 235000004400 serine Nutrition 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 239000004474 valine Substances 0.000 description 5
- 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 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
- 239000004475 Arginine Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 4
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 206010018338 Glioma Diseases 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 241000711549 Hepacivirus C Species 0.000 description 4
- 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 4
- 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 4
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 4
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 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
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 230000004988 N-glycosylation Effects 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 206010038389 Renal cancer Diseases 0.000 description 4
- 108010039491 Ricin Proteins 0.000 description 4
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
- 239000004473 Threonine Substances 0.000 description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 description 4
- 101100323865 Xenopus laevis arg1 gene Proteins 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 229940045799 anthracyclines and related substance Drugs 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000000340 anti-metabolite Effects 0.000 description 4
- 210000000612 antigen-presenting cell Anatomy 0.000 description 4
- 229940100197 antimetabolite Drugs 0.000 description 4
- 239000002256 antimetabolite Substances 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 230000007910 cell fusion Effects 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 239000012997 ficoll-paque Substances 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000005090 green fluorescent protein Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 229960000908 idarubicin Drugs 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 4
- 201000010982 kidney cancer Diseases 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 235000008476 powdered milk Nutrition 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000009870 specific binding Effects 0.000 description 4
- 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 4
- 235000008521 threonine Nutrition 0.000 description 4
- 238000012384 transportation and delivery Methods 0.000 description 4
- 229960004355 vindesine Drugs 0.000 description 4
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 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
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 3
- 108010032595 Antibody Binding Sites Proteins 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 206010005949 Bone cancer Diseases 0.000 description 3
- 208000018084 Bone neoplasm Diseases 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- 108091035707 Consensus sequence Proteins 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- 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 3
- 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 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
- 241000588724 Escherichia coli Species 0.000 description 3
- 229910052693 Europium Inorganic materials 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 3
- 208000032612 Glial tumor Diseases 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
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 102000008070 Interferon-gamma Human genes 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
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 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 3
- 108010000817 Leuprolide Proteins 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- 108010084592 Saporins Proteins 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 108091008874 T cell receptors Proteins 0.000 description 3
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 description 3
- 206010057644 Testis cancer Diseases 0.000 description 3
- 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 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 description 3
- 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 3
- 229940122803 Vinca alkaloid Drugs 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D 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)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229940009456 adriamycin Drugs 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 3
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 235000009697 arginine Nutrition 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 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 3
- 230000001588 bifunctional effect Effects 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000006664 bond formation reaction Methods 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- 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 3
- 229930195731 calicheamicin Natural products 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 201000007455 central nervous system cancer Diseases 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 229960000640 dactinomycin Drugs 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 210000003162 effector t lymphocyte Anatomy 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 229960001904 epirubicin Drugs 0.000 description 3
- 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 3
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 3
- 229960000390 fludarabine Drugs 0.000 description 3
- 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 3
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound 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 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 3
- 235000008191 folinic acid Nutrition 0.000 description 3
- 239000011672 folinic acid Substances 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 235000004554 glutamine Nutrition 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 201000010536 head and neck cancer Diseases 0.000 description 3
- 208000014829 head and neck neoplasm Diseases 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229960003130 interferon gamma Drugs 0.000 description 3
- 229960001691 leucovorin Drugs 0.000 description 3
- 208000032839 leukemia Diseases 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
- 210000004185 liver Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 238000000491 multivariate analysis Methods 0.000 description 3
- 231100000219 mutagenic Toxicity 0.000 description 3
- 230000003505 mutagenic effect Effects 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 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 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000013610 patient sample Substances 0.000 description 3
- 102000013415 peroxidase activity proteins Human genes 0.000 description 3
- 108040007629 peroxidase activity proteins Proteins 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 238000007747 plating Methods 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 238000002741 site-directed mutagenesis Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229940063683 taxotere Drugs 0.000 description 3
- 229960004964 temozolomide Drugs 0.000 description 3
- 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 3
- 229960001278 teniposide Drugs 0.000 description 3
- 201000003120 testicular cancer Diseases 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 206010046766 uterine cancer Diseases 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine 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-XQKSVPLYSA-N 0.000 description 3
- GBABOYUKABKIAF-GHYRFKGUSA-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-GHYRFKGUSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 108010066676 Abrin Proteins 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 210000004366 CD4-positive T-lymphocyte Anatomy 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- 150000008574 D-amino acids Chemical class 0.000 description 2
- 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 2
- 102000053602 DNA Human genes 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- 101100456896 Drosophila melanogaster metl gene Proteins 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 229930189413 Esperamicin Natural products 0.000 description 2
- 102100037362 Fibronectin Human genes 0.000 description 2
- 102000002090 Fibronectin type III Human genes 0.000 description 2
- 108050009401 Fibronectin type III Proteins 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 2
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 2
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- 101150089646 Hpdl gene Proteins 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 2
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 2
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 108030005449 Polo kinases Proteins 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 102000006382 Ribonucleases Human genes 0.000 description 2
- 108010083644 Ribonucleases Proteins 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 241000713311 Simian immunodeficiency virus Species 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 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 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 2
- 206010047741 Vulval cancer Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 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 2
- 229960001220 amsacrine Drugs 0.000 description 2
- 230000003432 anti-folate effect Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 230000002137 anti-vascular effect Effects 0.000 description 2
- 229940124691 antibody therapeutics Drugs 0.000 description 2
- 229940127074 antifolate Drugs 0.000 description 2
- 239000003080 antimitotic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000001754 blood buffy coat Anatomy 0.000 description 2
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229940127093 camptothecin Drugs 0.000 description 2
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 2
- 229930188550 carminomycin Natural products 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
- 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
- 239000000969 carrier Substances 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229960002412 cediranib Drugs 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 229940046044 combinations of antineoplastic agent Drugs 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000004940 costimulation Effects 0.000 description 2
- 230000000139 costimulatory effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 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 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 201000005619 esophageal carcinoma Diseases 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 150000005699 fluoropyrimidines Chemical class 0.000 description 2
- 239000004052 folic acid antagonist Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 201000010175 gallbladder cancer Diseases 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 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 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 229940049906 glutamate Drugs 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 102000048770 human CD276 Human genes 0.000 description 2
- 102000043321 human CTLA4 Human genes 0.000 description 2
- 102000046492 human ICOSLG Human genes 0.000 description 2
- 102000048119 human PDCD1LG2 Human genes 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 230000008629 immune suppression Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052747 lanthanoid Inorganic materials 0.000 description 2
- 150000002602 lanthanoids Chemical class 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 235000018977 lysine Nutrition 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 210000003071 memory t lymphocyte Anatomy 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin 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=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 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 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 238000007857 nested PCR Methods 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960005419 nitrogen Drugs 0.000 description 2
- 229960000435 oblimersen Drugs 0.000 description 2
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)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(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(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)N2C3=C(C(NC(N)=N3)=O)N=C2)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)N2C3=NC=NC(N)=C3N=C2)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(N=C(N)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)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 108700028325 pokeweed antiviral Proteins 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 229960004432 raltitrexed Drugs 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000001718 repressive effect Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 239000012146 running buffer Substances 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 238000012868 site-directed mutagenesis technique Methods 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 206010073373 small intestine adenocarcinoma Diseases 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 229960000814 tetanus toxoid Drugs 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 229960000303 topotecan Drugs 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
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000005030 transcription termination Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- 229950000578 vatalanib Drugs 0.000 description 2
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 201000005102 vulva cancer Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000013389 whole blood assay Methods 0.000 description 2
- BEJKOYIMCGMNRB-GRHHLOCNSA-N (2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BEJKOYIMCGMNRB-GRHHLOCNSA-N 0.000 description 1
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-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;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)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-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
- OYIWRKOSDGPKFD-XGGCRALDSA-N (7s,9s)-9-acetyl-6,9,11-trihydroxy-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 Chemical compound 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(C)=O)CCOCC1 OYIWRKOSDGPKFD-XGGCRALDSA-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
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- HHFBDROWDBDFBR-UHFFFAOYSA-N 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(CN=C(C=2C3=CC=C(Cl)C=2)C=2C(=CC=CC=2F)F)C3=N1 HHFBDROWDBDFBR-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
- HUDPLKWXRLNSPC-UHFFFAOYSA-N 4-aminophthalhydrazide Chemical compound O=C1NNC(=O)C=2C1=CC(N)=CC=2 HUDPLKWXRLNSPC-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- 102100031126 6-phosphogluconolactonase Human genes 0.000 description 1
- 108010029731 6-phosphogluconolactonase Proteins 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- HPLNQCPCUACXLM-PGUFJCEWSA-N ABT-737 Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 description 1
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 101710092462 Alpha-hemolysin Proteins 0.000 description 1
- 101710197219 Alpha-toxin Proteins 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 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 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 102100024775 Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase Human genes 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 101001011741 Bos taurus Insulin Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 101710185679 CD276 antigen Proteins 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 231100000023 Cell-mediated cytotoxicity Toxicity 0.000 description 1
- 206010057250 Cell-mediated cytotoxicity Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 108060002063 Cyclotide Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- 101150097493 D gene Proteins 0.000 description 1
- 102100037579 D-3-phosphoglycerate dehydrogenase Human genes 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 206010011968 Decreased immune responsiveness Diseases 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 108700022150 Designed Ankyrin Repeat Proteins Proteins 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
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- BVTJGGGYKAMDBN-UHFFFAOYSA-N Dioxetane Chemical class C1COO1 BVTJGGGYKAMDBN-UHFFFAOYSA-N 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 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
- 238000008157 ELISA kit Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108091006020 Fc-tagged proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)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)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 208000012766 Growth delay Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 108090001101 Hepsin Proteins 0.000 description 1
- 102000004989 Hepsin Human genes 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101100407305 Homo sapiens CD274 gene Proteins 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 1
- 101000878602 Homo sapiens Immunoglobulin alpha Fc receptor Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 1
- 101000963974 Hydrophis stokesii Alpha-elapitoxin-Ast2b Proteins 0.000 description 1
- 102100034980 ICOS ligand Human genes 0.000 description 1
- 101710093458 ICOS ligand Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 102100038005 Immunoglobulin alpha Fc receptor Human genes 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- 101150008942 J gene Proteins 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 102000019298 Lipocalin Human genes 0.000 description 1
- 108050006654 Lipocalin Proteins 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108700041567 MDR Genes Proteins 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 108010026217 Malate Dehydrogenase Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010091175 Matriptase Proteins 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- JJIHLJJYMXLCOY-BYPYZUCNSA-N N-acetyl-L-serine Chemical compound CC(=O)N[C@@H](CO)C(O)=O JJIHLJJYMXLCOY-BYPYZUCNSA-N 0.000 description 1
- PYUSHNKNPOHWEZ-YFKPBYRVSA-N N-formyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC=O PYUSHNKNPOHWEZ-YFKPBYRVSA-N 0.000 description 1
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 1
- 101000964025 Naja naja Long neurotoxin 3 Proteins 0.000 description 1
- 101000822778 Naja naja Long neurotoxin 4 Proteins 0.000 description 1
- 101000822797 Naja naja Long neurotoxin 5 Proteins 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101150030083 PE38 gene Proteins 0.000 description 1
- 108700034306 PROMACE-CytaBOM protocol Proteins 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 101710124951 Phospholipase C Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010053210 Phycocyanin Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- WDVSHHCDHLJJJR-UHFFFAOYSA-N Proflavine Chemical compound C1=CC(N)=CC2=NC3=CC(N)=CC=C3C=C21 WDVSHHCDHLJJJR-UHFFFAOYSA-N 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 108010059712 Pronase Proteins 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 102220544141 Pyrin_T20A_mutation Human genes 0.000 description 1
- 102220544143 Pyrin_T20D_mutation Human genes 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 101000677856 Stenotrophomonas maltophilia (strain K279a) Actin-binding protein Smlt3054 Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102100037942 Suppressor of tumorigenicity 14 protein Human genes 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 230000017274 T cell anergy Effects 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 102100024554 Tetranectin Human genes 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 101710182223 Toxin B Proteins 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 102220499422 Transcriptional protein SWT1_F19A_mutation Human genes 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241001629556 Tulare apple mosaic virus Species 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 108010057266 Type A Botulinum Toxins Proteins 0.000 description 1
- 108091005906 Type I transmembrane proteins Proteins 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 108091023045 Untranslated Region Proteins 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 description 1
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 101150117115 V gene Proteins 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 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 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000009824 affinity maturation Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- 239000002776 alpha toxin Substances 0.000 description 1
- 102000005840 alpha-Galactosidase Human genes 0.000 description 1
- 108010030291 alpha-Galactosidase Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000003277 amino acid sequence analysis Methods 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 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 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001740 anti-invasion Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000002927 anti-mitotic effect 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
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000000063 antileukemic agent Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 108010044540 auristatin Proteins 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000013398 bayesian method Methods 0.000 description 1
- 108700000711 bcl-X Proteins 0.000 description 1
- 102000055104 bcl-X Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 108010087667 beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase Proteins 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 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
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 description 1
- 229950004398 broxuridine Drugs 0.000 description 1
- 108010049223 bryodin Proteins 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound 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 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- UHBYWPGGCSDKFX-UHFFFAOYSA-N carboxyglutamic acid Chemical compound OC(=O)C(N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-UHFFFAOYSA-N 0.000 description 1
- 238000012219 cassette mutagenesis Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 230000005890 cell-mediated cytotoxicity Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010372 cloning stem cell Methods 0.000 description 1
- 238000007621 cluster analysis Methods 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 201000010918 connective tissue cancer Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 108091008034 costimulatory receptors Proteins 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000009402 cross-breeding Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 238000007418 data mining Methods 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229950003913 detorubicin Drugs 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- PGUYAANYCROBRT-UHFFFAOYSA-N dihydroxy-selanyl-selanylidene-lambda5-phosphane Chemical compound OP(O)([SeH])=[Se] PGUYAANYCROBRT-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery 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
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 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
- 229940082789 erbitux Drugs 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229950002017 esorubicin Drugs 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
- 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
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 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
- 150000002224 folic acids Chemical class 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000033581 fucosylation Effects 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 102000010705 glucose-6-phosphate dehydrogenase activity proteins Human genes 0.000 description 1
- 108040005050 glucose-6-phosphate dehydrogenase activity proteins Proteins 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 150000002337 glycosamines Chemical group 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=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 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000521 hyperimmunizing effect Effects 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 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 1
- 229960002411 imatinib Drugs 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 108091008042 inhibitory receptors Proteins 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000020082 intraepithelial neoplasia Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 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 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 201000004962 larynx cancer Diseases 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 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 1
- 238000002898 library design Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 238000010801 machine learning Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000035800 maturation Effects 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
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960004296 megestrol acetate Drugs 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 210000002500 microbody Anatomy 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 238000002887 multiple sequence alignment Methods 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
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000000440 neutrophil Anatomy 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
- 229960002653 nilutamide Drugs 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000003909 pattern recognition Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000002818 protein evolution Methods 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 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 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000031526 regulation of chronic inflammatory response Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000002702 ribosome display Methods 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 102220324707 rs375086772 Human genes 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- JRPHGDYSKGJTKZ-UHFFFAOYSA-K selenophosphate Chemical compound [O-]P([O-])([O-])=[Se] JRPHGDYSKGJTKZ-UHFFFAOYSA-K 0.000 description 1
- 231100000489 sensitizer Toxicity 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 108010010958 snake venom neurotoxin F Proteins 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000007755 survival signaling Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 108010013645 tetranectin Proteins 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 229960005026 toremifene 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
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 108020005087 unfolded proteins Proteins 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- 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
-
- 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
Definitions
- the invention relates to targeted binding agents against the B7-H1 protein and uses of such agents.
- the invention relates to fully human monoclonal antibodies directed to B7-H1 and uses of these antibodies.
- aspects of the invention also relate to cell lines expressing such targeted binding agents or antibodies.
- the described targeted binding agents are useful as diagnostics and for the treatment of diseases associated with the activity and/or expression of B7-H1.
- T cells and B cells Two major classes of lymphocytes termed T cells and B cells. After encountering an antigen, T cells proliferate and differentiate into antigen-specific effector cells, while B cells proliferate and differentiate into antibody-secreting cells.
- T cell activation is a multi-step process requiring several signaling events between the T cell and an antigen-presenting cell (APC).
- APC antigen-presenting cell
- T cell activation to occur two types of signals must be delivered to a resting T cell. The first type is mediated by the antigen-specific T cell receptor (TcR), and confers specificity to the immune response. The second, costimulatory, type regulates the magnitude of the response and is delivered through accessory receptors on the T cell.
- TcR antigen-specific T cell receptor
- a primary costimulatory signal is delivered through the activating CD28 receptor upon engagement of its ligands B7-1 or B7-2.
- engagement of the inhibitory CTLA-4 receptor by the same B7-1 or B7-2 ligands results in attenuation of a T cell response.
- CTLA-4 signals antagonize costimulation mediated by CD28.
- CD28 costimulation overrides the CTLA-4 inhibitory effect.
- Temporal regulation of the CD28 and CTLA-4 expression maintains a balance between activating and inhibitory signals and ensures the development of an effective immune response, while safeguarding against the development of autoimmunity.
- B7-H1 also known as PD-L1
- B7-H1 is a type I transmembrane protein of approximately 53kDa in size.
- B7-H1 is expressed on a number of immune cell types including activated and anergic/exhausted T cells, on na ' ive and activated B cells, as well as on myeloid dendritic cells (DC), monocytes and mast cells.
- DC myeloid dendritic cells
- non-immune cells including islets of the pancreas, Kupffer cells of the liver, vascular endothelium and selected epithelia, for example airway epithelia and renal tubule epithelia, where its expression is enhanced during inflammatory episodes.
- B7-H1 expression is also found at increased levels on a number of tumours including, but not limited to breast, colon, colorectal, lung, renal, including renal cell carcinoma, gastric, bladder, non-small cell lung cancer (NSCLC), hepatocellular cancer (HCC), and pancreatic cancer, as well as melanoma.
- NSCLC non-small cell lung cancer
- HCC hepatocellular cancer
- B7-H1 is a member of the B7 family of proteins, which contain two extracellular Ig domains, one N-terminal V-type domain followed by a C-type domain.
- the intracellular domain of 30 amino acids length contains no obvious signaling motifs, but does bear a potential site for protein kinase C phosphorylation.
- the murine form of B7-H1 bears 69% amino acid identity with the human form of B7-H1, and also shares a conserved structure.
- B7-H1 is known to bind two alternative ligands, the first of these, PD-1, is a 50-55 kDa type I transmembrane receptor that was originally identified in a T cell line undergoing activation-induced apoptosis. PD-1 is expressed on activated T cells, B cells, and monocytes, as well as other cells of the immune system and binds both B7-H1 (PD-L1) and the related B7-DC (PD-L2). The second is the B7 family member B7-1, which is expressed on activated T cells, B cells, monocytes and antigen presenting cells.
- PD-1 is a member of the immunoglobulin (Ig) superfamily that contains a single Ig V-like domain in its extracellular region.
- the PD-1 cytoplasmic domain contains two tyrosines, with the most membrane-proximal tyrosine (VAYEEL in mouse PD-1) located within an ITIM (immuno- receptor tyrosine-based inhibitory motif).
- ITIM immunoglobulin-based inhibitory motif
- the ITIM in the cytoplasmic region and the ITIM-like motif surrounding the carboxy-terminal tyrosine (TEYATI in human and mouse) are also conserved between human and murine orthologues.
- Signalling via the PD-1/B7-H1 axis is believed to serve critical, non-redundant functions within the immune system, by negatively regulating T cell responses. This regulation is involved in T cell development in the thymus, in regulation of chronic inflammatory responses and in maintenance of both peripheral tolerance and immune privilege.
- the critical nature of these functions is exemplified in PD-1 -deficient mice, which exhibit an autoimmune phenotype. PD-1 deficiency in the C57BL/6 mice results in chronic progressive lupus-like glomerulonephritis and arthritis.
- PD-1 deficiency leads to severe cardiomyopathy due to the presence of heart-tissue-specific self-reacting antibodies.
- the function of signaling via B7-H1/B7-1 is less clear, but is thought to also be involved in delivering negative regulatory signals to both T cells and antigen presenting cells.
- B7-H1 expression on tumour cells is believed to aid tumours in evading detection and elimination by the immune system.
- B7-H1 functions in this respect via several alternative mechanisms including driving exhaustion and anergy of tumour infiltrating T lymphocytes, stimulating secretion of immune repressive cytokines into the tumour micro-environment, stimulating repressive regulatory T cell function and protecting B7-H1 expressing tumour cells from lysis by tumour cell specific cytotoxic T cells.
- the present invention relates to targeted binding agents that specifically bind to B7-H1 and inhibit the biological activity of B7-H1.
- the invention relates to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 activity.
- the invention relates to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding of B7-H1 to PD-1.
- the invention relates to targeted binding agents that block B7-H1 induced T-cell suppression and thereby enhance anti-tumor immunity.
- the invention further relates to targeted binding agents that can further stimulate one or more of the following activities including T cell proliferation, IFN- ⁇ and/or IL-2 secretion in mixed lymphocyte reactions.
- Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit the biological activity of B7- Hl .
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the biological activity than would occur in the absence of the targeted binding agent.
- Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 activity.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 activity than would occur in the absence of the targeted binding agent.
- Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding to PD-1.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1/PD-1 receptor ligand binding compared to what would occur in the absence of the targeted binding agent.
- the targeted binding agents of the invention can inhibit binding of PD-l/Fc to human B7-H1 expressed on ES-2 cells.
- the targeted binding agent inhibits binding with an IC50 of less than 1 nM, 0.5 nM, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07 or 0.06 nM.
- the antibodies of the invention have an IC50 of about 1 nM down to about 0.06 nM; or of about 0.5 nM down to about 0.06 nM; or of about 0.1 nM down to about 0.06 nM; or of about 1 nM down to about 0.1 nM; or of about 1 nM down to about 0.5 nM.
- Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit binding to its ligand B7-1.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 95%, 96%, 97%, 98% 99% or 100% of B7-H1/B7-1 receptor ligand binding compared to what would occur in the absence of the targeted binding agent.
- Embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit B7-H1 induced tumor proliferation.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 induced tumor proliferation than would occur in the absence of the targeted binding agent.
- the targeted binding agent inhibits at least 5%, at least 10%>, at least 15%, at least 20%>, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 induced tumor cell survival than would occur in the absence of the targeted binding agent.
- Targets of the invention relate to targeted binding agents that specifically bind to B7-H1 and thereby inhibit tumour growth of A375 or HPAC cancer cell lines.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%), or at least 95% of growth of cancer cells at day 30 compared to an isotype control.
- Targeted binding agents that specifically bind to B7-H1 and thereby inhibit B7-H1 mediated suppression of tumour reactive T-cells, thereby enhancing anti-tumour cytolytic T-cell activity.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of B7-H1 mediated suppression of tumour reactive T-cell activity than would occur in the absence of the targeted binding agent.
- the targeted binding agent enhances at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of antitumor immunity than would occur in the absence of the targeted binding agent.
- the targeted binding agent inhibits at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of cell proliferation than would occur in the absence of the targeted binding agent.
- the antibodies of the invention relate to targeted binding agents that specifically bind to B7-H1 and increase specific cytolytic (CTL) activity against B7-H1 expressing tumor cells.
- the antibodies of the invention have an EC50 of less than or equal to 100 nM, 50 nM or 1 nM. Further, in another embodiment, the antibodies of the invention have an EC50 of about 100 nM down to about 1 nM; or of about 50 nM down to about 1 nM; or of about 20 nM down to about 1 nM; or of about 100 nM down to about 50 nM; or of about 100 nM down to about 70 nM.
- Further embodiments of the invention relate to targeted binding agents that specifically bind to B7-H1 and inhibit B7-H1 mediated suppression of T-cell proliferation at an EC50 less than or equal to 100 nM.
- the antibodies of the invention have an EC50 of less than or equal to 100 nM, e.g., 90, 80, 70, 60, 50, 40, 30, 20 or 10 nM.
- the antibodies of the invention have an EC50 of about 100 nM down to about 10 nM; or of about 50 nM down to about 10 nM; or of about 20 nM down to about 10 nM; or of about 100 nM down to about 50 nM; or of about 100 nM down to about 70 nM; or of about 100 nM down to about 80 nM.
- the targeted binding agents also inhibit tumour cell adhesion, motility, invasion and cellular metastasis and in addition, the targeted binding agents are useful for reducing tumour growth. Mechanisms by which this can be achieved can include, and are not limited to, inhibiting B7-H1 activity.
- the targeted binding agent is an antibody. In one embodiment of the invention, the targeted binding agent is a monoclonal antibody. In one embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody or a fragment thereof. Such monoclonal antibodies may be referred to herein as anti-B7-Hl antibodies or antibodies of the invention.
- Antibodies, monoclonal antibodies and human monoclonal antibodies include the antibodies of the IgGl, IgG2, IgG3 and IgG4 isotypes, for example IgG2.
- the targeted binding agent is a fully human monoclonal antibody of the IgG2 isotype. This isotype has reduced potential to elicit effector function in comparison with other isotypes, which may lead to reduced toxicity.
- the targeted binding agent is a fully human monoclonal antibody of the IgGl isotype.
- the IgGl isotype has increased potential to elicit Antibody Directed Cell-mediated Cytotoxicity (ADCC) in comparison with other isotypes, which may lead to improved efficacy.
- ADCC Antibody Directed Cell-mediated Cytotoxicity
- the IgGl isotype has improved stability in comparison with other isotypes, e.g. IgG4, which may lead to improved bioavailability/ease of manufacture/longer half-life.
- the fully human monoclonal antibody of the IgGl isotype is of the z, za or f allotype.
- the targeted binding agent has desirable therapeutic properties, selected from one or more of the following: high binding affinity for B7-H1, the ability to inhibit B7-H1 activity in vitro and in vivo, the ability to inhibit B7-H1 -mediated tumour cell survival, and the ability to inhibit B7-H1 mediated suppression of tumour reactive T-cells, which may in turn reduce tumour cell proliferation, motility, invasion, metastasis, and tumour growth.
- the invention includes antibodies that specifically bind to B7-H1 with very high affinities (Kd).
- the targeted binding agent binds B7-H1 with a binding affinity (Kd) of less than 5 nanomolar (nM). In other embodiments, the targeted binding agent binds with a Kd of less than 4 nM, 3 nM, 2.5nM, 2 nM or 1 nM.
- antibodies of the invention binds B7-H1 with a Kd of about 5 nM to about 1 nM; or about 5 nM to about 2 nM; or about 5 nM to about 3 nM; or about 5 nM to about 4 nM; or about 3 nM to about 1 nM; or about 2 nM to about 1 nM.
- the targeted binding agent binds B7-H1 with a Kd of less than 950 picomolar (pM).
- the targeted binding agent binds B7-H1 with a Kd of less than 900 pM.
- the targeted binding agent binds B7-H1 with a Kd of less than 800 pM, 700 pM or 600 pM. In some embodiments of the invention, the targeted binding agent binds B7-H1 with a Kd of less than 500 pM. In other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 400 pM. In still other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 300 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 200 pM.
- the targeted binding agent binds B7-H1 with a Kd of less than 100 pM.
- antibodies of the invention binds B7-H1 with a Kd of about 900 pM to about 100 pM; or about 900 pM to about 200 pM; or about 900 pM to about 300 pM; or about 900 pM to about 400 pM; or about 900 pM to about 500 pM; or about 900 pM to about 600 pM; or about 900 pM to about 700 pM; or about 200 pM to about 100 pM; or about 300 pM to about 200 pM; or about 400 pM to about 300 pM.
- the targeted binding agent binds B7-H1 with a Kd of less than 90 pM, 80 pM, 70 pM, 60 pM, 55pM or 50pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 60 pM. In some other embodiments, the targeted binding agent binds B7-H1 with a Kd of less than 55 pM.
- antibodies of the invention binds B7-H1 with a Kd of about 100 pM to about 50 pM; or about 100 pM to about 70 pM; or about 100 pM to about 80 pM; or about 100 pM to about 90 pM; or about 70 pM to about 50 pM; or about 60 pM to about 50 pM; or about 55 pM to about 50 pM.
- the Kd may be assessed using a method described herein or known to one of skill in the art (e.g., a BIAcore assay, ELISA) (Biacore International AB, Uppsala, Sweden).
- Targeted binding agents of the invention have considerably improved binding affinities for B7-H1 in comparison with the antibodies reported in the prior art.
- binding properties of the targeted binding agent or antibody of the invention may also be measured by reference to the dissociation or association rates (k 0ff and k on respectively).
- a targeted binding agent or an antibody of the invention may have a k on rate (antibody (Ab) + antigen (Ag) kon — Ab- Ag) of at least 10 4 M ' V 1 , at least 5 X 10 4 M ' V 1 , at least 10 5 M ' V 1 , at least 2 X 10 5 M ' V 1 , at least 5 X 10 5 M ' V 1 , at least 10 6 M ' V 1 , at least 5 X 10 6 M ' V 1 , at least 10 7 M ' V 1 , at least 5 X 10 7 M ' V 1 , or at least 10 8 M ' V 1 as measured by a BIAcore assay.
- antibodies of the invention have a k on rate of about 5 X 10 4 M ' V 1 to about 5 X 10 8 M ' V 1 ; or of about 5 X 10 5 M " V 1 to about 5 X 10 8 M ' V 1 ; or of about 5 X 10 6 M ' V 1 to about 5 X 10 8 M ' V 1 ; or of about 5 X 10 7 M ' V 1 to about 5 X 10 8 M ' V 1 , as measured by a BIAcore assay.
- targeted binding agent or an antibody may have a k 0 ff rate ( (Ab-Ag) ko ⁇ antibody (Ab) + antigen (Ag)) of less than 5x10 "1 s "1 , less than 10 "1 s "1 ,
- antibodies of the invention have a k 0 ff rate of about 1 X 10 "4 s “1 to about 1 X 10 "5 s “1 ; or of about 1 X 10 "4 s “1 to about 5 X 10 "4 s “1 ,as measured by a BIAcore assay.
- the targeted binding agent of the invention specifically binds human B7-H1.
- the targeted binding agent of the invention does not bind other immune co-modulatory proteins, e.g., human PD-L2, human B7-H2, human B7-H3, human CD28, human CTLA-4 and human PD1.
- the targeted binding agent of the invention is cross-reactive with other B7-H1 proteins from other species.
- the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1.
- the targeted binding agent of the invention is cross-reactive with mouse B7-H1, e.g., 2.7A4.
- the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1 and with mouse B7-H1, e.g., 2.7A4.
- the targeted binding agent of the invention is cross-reactive with cynomolgus monkey B7-H1 but not with mouse B7- Hl, e.g., 2.9D10 and 2.14H9.
- the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences (VH) shown in Table 8. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT.
- a targeted binding agent or antibody comprising a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT, or another antibody as disclosed herein, may further comprise any one of the light chain sequences (VL) shown in Table 9 or of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT or 2.14H90PT, or other antibody as disclosed herein.
- VL light chain sequences
- the targeted binding agent or antibody comprises a sequence comprising any one of the heavy chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT and further comprising the corresponding light chain sequence of antibody 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT.
- the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody comprises a sequence comprising any one of the light chain sequences shown in Table 9. In another embodiment, the targeted binding agent or antibody comprises a sequence comprising any one of the light chain sequences of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.7A4 and further comprising the light chain sequence of antibody 2.7A4. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.14H9 and further comprising the light chain sequence of antibody 2.14H9. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.9D10 and further comprising the light chain sequence of antibody 2.9D10. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.7A.40PT and further comprising the light chain sequence of antibody 2.7A.40PT. In another embodiment the targeted binding agent or antibody comprises a sequence comprising any of the heavy chain sequence of antibody 2.14H90PT and further comprising the light chain sequence of antibody 2.14H90PT.
- the targeting binding agent is any one of the monoclonal antibodies as shown in Table 1.
- the targeting binding agent is a monoclonal antibody selected from the group consisting of: 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT.
- the targeted binding agent comprises one or more of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT.
- the targeting binding agent is monoclonal antibody 2.7A4.
- the targeting binding agent is monoclonal antibody 2.14H9.
- the targeting binding agent is monoclonal antibody 2.9D10.
- the targeting binding agent is monoclonal antibody 2.7A40PT. In certain other embodiments, the targeting binding agent is monoclonal antibody 2.14H90PT. In additional embodiments, the targeted binding agent is derivable from any of the foregoing monoclonal antibodies.
- the targeted binding agent may comprise a sequence comprising any one of the CDR1, CDR2 or CDR3 of the heavy chain variable sequences encoded by a polynucleotide in a plasmid designated 2.7A4 G, 2.14H9 G, and 2.9D10 NG which were deposited at NCIMB under number 41598 on November 19, 2008, under number 41597 on November 19, 2008, and under number 41599 on November 19, 2008, respectively.
- the targeted binding agent may comprise a sequence comprising any one of the CDR1, CDR2 or CDR3 of the light chain variable domain sequences encoded by a polynucleotide in a plasmid designated 2.7A4 G, 2.14H9 G and 2.9D10 NG which were deposited under number 41598 on November 19, 2008, under number 41597 on November 19, 2008, or under number 41599 on November 19, 2008, respectively.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008 and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under deposit number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008, and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19,
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19,
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain amino acid sequence comprising a CDR3 encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain amino acid sequence comprising at least one, at least two, or at least three of the CDRs of the antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.7A4_G which was deposited at the NCIMB under number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under number 41598 on November 19, 2008 and a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.7A4 G which was deposited at the NCIMB under number 41598 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008 and a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.14H9 G which was deposited at the NCIMB under number 41597 on November 19, 2008.
- a targeted binding agent or an antibody of the invention comprises a heavy chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008 and a light chain variable domain sequence of an antibody encoded by the polynucleotide in plasmid designated 2.9D10 NG which was deposited at the NCIMB under number 41599 on November 19, 2008.
- a targeted binding agent or an antibody may comprise a sequence comprising a heavy chain CDR1 (HCDRl), heavy chain CDR2 (HCDR2) and heavy chain CDR3 (HCDR3) selected from any one of the sequences shown in Table 8.
- a targeted binding agent or an antibody may comprise a sequence comprising a light chain CDR1 (LCDRl), light chain CDR2 (LCDR2) and light chain CDR3 (LCDR3) selected from any one of the sequences shown in Table 9.
- a targeted binding agent or an antibody may comprise a sequence comprising a HCDRl, HCDR2 and HCDR3 selected from any one of the CDRs of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, or 3.18G1.
- a targeted binding agent or an antibody may comprise a sequence comprising a LCDRl, LCDR2 and LCDR3 selected from any one of the CDRs of antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, or 3.18Gl .
- a further embodiment is a targeted binding agent or an antibody that specifically binds to B7-H1 and comprises a sequence comprising one of the CDR2 and one of the CDR3 sequences shown in Table 9.
- the targeted binding agent or antibody further comprises a sequence comprising: a CDR3 sequence as shown in Table 8.
- the targeted binding agent or antibody further comprises a sequence comprising: a CDR2 and a CDR3 sequence as shown in Table 8 and/or Table 9.
- the targeted binding agent or antibody further comprises a sequence comprising: a CDRl, a CDR2 and a CDR3 sequence as shown in Table 8 and/or Table 9.
- the targeted binding agent or antibody may comprise a sequence comprising any one of a CDRl, a CDR2 or a CDR3 of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, as shown in Table 8.
- the targeted binding agent or antibody may comprise a sequence comprising any one of a CDRl, a CDR2 or a CDR3 of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, as shown in Table 9.
- the targeted binding agent or antibody may comprise a sequence comprising a CDRl, a CDR2 and a CDR3 of any one of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT, as shown in Table 8.
- the targeted binding agent or antibody may comprise a sequence comprising a CDRl, a CDR2 and a CDR3 of any one of fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT or 2.14H90PT, as shown in Table 9.
- the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.7A4 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.7A4 as shown in Table 9.
- the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.14H9 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.14H9 as shown in Table 9.
- the targeted binding agent or antibody comprises a sequence comprising the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.9D10 as shown in Table 8 and the CDRl, CDR2 and CDR3 sequence of fully human monoclonal antibody 2.9D10 as shown in Table 9.
- the antibody is a fully human monoclonal antibody.
- a further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT, or as shown in Table 8 or Table 9.
- a further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 and Table 9.
- the targeted binding agent or antibody comprises a sequence comprising the contiguous sequences spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences of monoclonal antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 or Table 9.
- a further embodiment of the invention is a targeted binding agent or antibody comprising a sequence comprising the contiguous sequence spanning the framework regions and CDRs, specifically from FRl through FR4 or CDRl through CDR3, of any one of the sequences of monoclonal antibodies 2.9D10, 2.7A4, 2.14H9, 3.15G8, 2.20A8, 3.18G1, 2.7A40PT, or 2.14H90PT or as shown in Table 8 and Table 9.
- the antibody is a fully human monoclonal antibody.
- a targeted binding agent or antibody of the invention comprises a CDR3 sequence as shown in Table 8 or 9; or any one of a CDRl, a CDR2 or a CDR3 sequence as shown in Table 8 or 9; or a CDRl, a CDR2 and a CDR3 sequence of a light chain variable domain sequence as shown in Table 8; or a CDRl, a CDR2 and a CDR3 sequence of a heavy chain variable domain sequence sequence as shown as shown in Table 9.
- One embodiment provides a targeted binding agent or antibody, or antigen-binding portion thereof, wherein the agent or antibody, or antigen-binding portion thereof, comprises a sequence comprising SEQ ID NO.:2, SEQ ID NO.:7, SEQ ID NO.: 12, SEQ ID NO.: 17, SEQ ID NO.:22, SEQ ID NO.:27, SEQ ID NO.:32, SEQ ID NO.:37, SEQ ID NO.:42, SEQ ID NO.:47, SEQ ID NO.:52, SEQ ID NO.:57, SEQ ID NO.:62, SEQ ID NO.:67, SEQ ID NO.:72, or SEQ ID NO.:77.
- One embodiment provides a targeted binding agent or antibody, or antigen-binding portion thereof, wherein the agent or antibody, or antigen-binding portion thereof, comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:2.
- the targeted binding agent or antibody, or antigen-binding portion thereof further comprises a light chain sequence comprising the sequence of SEQ ID NO.:7.
- the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:2 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:7.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.: 12. In one embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.: 17. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 12 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 17.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:22. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:27. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:22 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:27.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:32.
- the targeted binding agent or antibody, or antigen-binding portion thereof further comprises a light chain sequence comprising the sequence of SEQ ID NO.:37.
- the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:32 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:37.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:42. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:47. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:42 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:47.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:52. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:57. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO:52 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO:57.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.:62. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:67. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 62 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 67.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain sequence comprising the sequence of SEQ ID NO.: 72. In another embodiment, the targeted binding agent or antibody, or antigen-binding portion thereof, further comprises a light chain sequence comprising the sequence of SEQ ID NO.:77. In some embodiments, the antibody is a fully human monoclonal antibody.
- the targeted binding agent or antibody, or antigen-binding portion thereof comprises a heavy chain variable domain having at least 90% identity to the amino acid of SEQ ID NO: 72 and comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 77.
- the targeted binding agent or antibody comprises variants or derivatives of the CDRs disclosed herein, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3), the light or heavy chain sequences disclosed herein, or the antibodies disclosed herein.
- Variants include targeted binding agents or antibodies comprising sequences which have as many as twenty, sixteen, ten, nine or fewer, e.g.
- Variants include targeted binding agents or antibodies comprising sequences which have one, two or three, amino acid additions, substitutions, deletions, and/or insertions in any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FRl through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein.
- Variants include targeted binding agents or antibodies comprising sequences which have at least about 60, 70, 80, 85, 90, 95, 98 or about 99% amino acid sequence identity with any of the CDRl, CDR2 or CDR3s as shown in Table 8 or Table 9, the contiguous sequences spanning the framework regions and CDRs (specifically from FR1 through FR4 or CDRl through CDR3) as shown in Table 8 or Table 9, the light or heavy chain sequences disclosed herein, or with the monoclonal antibodies disclosed herein.
- the percent identity of two amino acid sequences can be determined by any method known to one skilled in the art, including, but not limited to, pairwise protein alignment.
- variants comprise changes in the CDR sequences or light or heavy chain sequences disclosed herein that are naturally occurring or are introduced by in vitro engineering of native sequences using recombinant DNA techniques or mutagenesis techniques.
- Naturally occurring variants include those which are generated in vivo in the corresponding germline nucleotide sequences during the generation of an antibody to a foreign antigen.
- variants include targeted binding agents or antibodies comprising sequences which have (a) a VH CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 3;
- VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 4;
- VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 5;
- VL CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to VL CDRl of SEQ ID NO: 8;
- VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 9;
- VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 10.
- variants include targeted binding agents or antibodies comprising sequences which have (a) a VH CDRl having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 23;
- VH CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 24
- VH CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 25;
- VL CDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to VL CDR1 of SEQ ID NO: 28;
- VL CDR2 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 29;
- VL CDR3 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 30.
- the derivative may be a heteroantibody, that is an antibody in which two or more antibodies are linked together.
- Derivatives include antibodies which have been chemically modified. Examples include covalent attachment of one or more polymers, such as water-soluble polymers, N-linked, or O-linked carbohydrates, sugars, phosphates, and/or other such molecules. The derivatives are modified in a manner that is different from naturally occurring or starting antibody, either in the type or location of the molecules attached. Derivatives further include deletion of one or more chemical groups which are naturally present on the antibody.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one, any two, any three, any four or all five of the germline residues as indicated in Table 10.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2, wherein SEQ ID NO.: 2 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 10.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7, wherein SEQ ID NO.: 7 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11 and any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7, wherein SEQ ID NO.: 7 comprises any one, any two, any three, any four, any five, for all five of the germline residues as indicated in Table 11.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12, wherein SEQ ID NO.: 12 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 12. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12, wherein SEQ ID NO.: 12 comprises any one, any two or all two of the germline residues as indicated in Table 12.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17, wherein SEQ ID NO.: 17 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 13. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17, wherein SEQ ID NO.: 17 comprises any one, any two, any three, any four or all four of the germline residues as indicated in Table 13.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27, wherein SEQ ID NO.: 27 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 14. In some embodiments of the invention, the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27, wherein SEQ ID NO.: 27 comprises any one, any two, any three or all three of the germline residues as indicated in Table 14.
- a further embodiment of the invention is a targeted binding agent or antibody which competes for binding to B7-H1 with the targeted binding agent or antibodies of the invention.
- the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
- “Competes” indicates that the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT, i.e. competition is unidirectional.
- Embodiments of the invention include a targeted binding agent or antibody which cross competes with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT for binding to B7-H1.
- Cross competes indicates that the targeted binding agent or antibody competes for binding to B7-H1 with any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT, and vice versa, i.e. competition is bidirectional.
- a further embodiment of the invention is a targeted binding agent or antibody that binds to the same epitope or epitopes on the extracellular domain of human B7-H1 as the targeted binding agent or antibodies of the invention.
- Embodiments of the invention also include a targeted binding agent or antibody that binds to the same epitope or epitopes on the extracellular domain of human B7-H1 as any one of fully human monoclonal antibodies 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
- the targeted binding agent or antibody binds an epitope on human
- B7-H1 including at least one or more of the following amino acids selected from the group consisting of Asp at position 122 and Arg at position 125.
- an antibody of the invention binds an epitope on human B7-H1 comprising at least two of the following three amino acid residues of Asp at position 122, Arg at position 125 and Arg at position 113.
- the antibody binds an epitope on human B7-H1, wherein the antibody exhibits no binding to He at position 54, Ser at position 117 and Ala at position 121 on human B7-H1.
- an antibody of the invention loses its ability to bind to human B7-H1 if the Arg at position 113 is mutated to an Ala, or to a Tyr, or to a Leu as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Arg at position 125 is mutated to an Ala, or to a Gin, or to a Ser as determined by a competition assay as compared to binding to wild-type B7-H1.
- an antibody of the invention retains its ability to bind to human B7-H1 if the Arg at position 123 is mutated to an Ala, or to a Phe, or to a Thr as determined by a competition assay as compared to binding to wild-type B7-H1.
- the antibody is 2.14H9.
- the antibody is 2.14H90PT.
- the targeted binding agent or antibody binds an epitope on the extracellular domain of human B7-H1 comprising at least one or more of the following amino acids Asp at position 122 and Thr at position 20.
- the antibody binds at least two of the following three amino acid residues of Phe at position 19, Thr at position 20 and Asp at position 122 on human B7-H1.
- an antibody of the invention loses its ability to bind to human B7-H1 if the Phe at position 19 is mutated to an Ala, or to a Gly, or to a Ser as determined by a competition assay as compared to binding to wild-type B7-H1. In yet a further embodiment, an antibody of the invention loses its ability to bind to human B7-H1 if the Thr at position 20 is mutated to an Ala, or to a Val, or to a Asp as
- an antibody of the invention loses its ability to bind to human B7-H1 if the Asp at position 122 is mutated to an Asn, or to a Glu as determined by a competition assay as compared to binding to wild-type B7-H1.
- an antibody of the invention retains its ability to bind to human B7-H1 if the Arg at position 123 is mutated to an Ala, or to a Phe, or to a Thr as determined by a competition assay as compared to binding to wild-type B7-H1.
- the antibody is 2.7A4. In another example, the antibody is 2.7A40PT.
- the targeted binding agent is a bispecific antibody.
- a bispecific antibody is an antibody that has binding specificity for at least two different epitopes on the same or on different proteins. Methods for making bispecific antibodies are known in the art. (See, for example, Millstein et al, Nature, 305:537-539 (1983); Traunecker et al., EMBO J, 10:3655- 3659 (1991); Suresh et al, Methods in Enzymology, 121 :210 (1986); Kostelny et al., J. Immunol, 148(5): 1547-1553 (1992); Hollinger et al, Proc. Natl Acad. Sci.
- Embodiments of the invention described herein relate to monoclonal antibodies that specifically bind B7-H1 and affect B7-H1 function.
- Other embodiments relate to fully human antibodies that specifically bind B7-H1 and preparations thereof with desirable properties from a therapeutic perspective, including high binding affinity for B7-H1, high selectivity for inhibition of B7-H1 signaling, low toxicity, the ability to block PD-1 receptor activity, the ability to inhibit B7-H1 -induced tumour cell survival through immune suppression, the ability to inhibit B7-H1 mediated repression of anti-tumour immunity, which may in turn inhibit proliferation or invasion -related diseases include neoplastic diseases, and/or the ability of tumour cells to grow in vitro and in vivo.
- Still other embodiments relate to a method of repressing B7-H1 -mediated T cell inhibition in an animal by administering to an animal in need thereof an effective amount of a composition comprising the antibodies of the invention. Still other embodiments relate to fully human antibodies that specifically bind B7-H1 and preparations thereof that do not result in a significant Human Anti-Chimeric Antibody (HACA) response, thereby allowing for repeated administration.
- HACA Human Anti-Chimeric Antibody
- nucleic acid molecule encoding any of the targeted binding agents or antibodies of the invention.
- nucleic acid molecule encoding the light chain or the heavy chain of an antibody of the invention.
- nucleic acid molecule encodes the light chain or the heavy chain of a fully human monoclonal antibody of any of the antibodies described herein.
- nucleic acid molecule encodes the light chain or the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- the nucleic acid molecule encodes the light chain and the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- the invention also encompasses polynucleotides that hybridize under stringent or lower stringency hybridization conditions, as defined herein, to polynucleotides that encode any of the targeted binding agents or antibodies described herein.
- a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a targeted binding agent as described hereinabove.
- a vector comprising a nucleic acid molecule or molecules as described hereinabove, wherein the vector encodes a light chain and/or a heavy chain of an antibody as defined hereinabove.
- the vector comprises a nucleic acid molecule encoding the light chain and/or the heavy chain of a fully human monoclonal antibody.
- the vector comprises a nucleic acid molecule encoding the light chain or the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT. In another embodiment, the vector comprises a nucleic acid molecule encoding the light chain and the heavy chain of any one of the fully human monoclonal antibodies 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- a host cell transformed with any of the nucleic acid molecules as described hereinabove.
- a host cell comprising the vector comprising the nucleic acid molecule as described hereinabove.
- the host cell may comprise more than one vector.
- antibodies can advantageously be, for example, polyclonal, oligoclonal, monoclonal, chimeric, humanised, and/or fully human antibodies.
- the targeted binding agent is a binding fragment of a fully human monoclonal antibody.
- the targeted binding agent can be a full-length antibody (e.g., having an intact human Fc region) or an antibody binding fragment (e.g., a Fab, Fab' or F(ab') 2 , Fv, dAb or other well known antibody fragment, as described in more detail below).
- the antibodies can be single-domain antibodies such as camelid or human single VH or VL domains that bind to B7-H1, such as a dAb fragment.
- Embodiments of the invention described herein also provide cells for producing these antibodies.
- Examples of cells include hybridomas, or recombinantly created cells, such as Chinese hamster ovary (CHO) cells, variants of CHO cells (for example DG44) and NSO cells that produce antibodies against B7-H1. Additional information about variants of CHO cells can be found in Andersen and Reilly (2004) Current Opinion in Biotechnology 15, 456-462 which is incorporated herein in its entirety by reference.
- the antibody can be manufactured from a hybridoma that secretes the antibody, or from a recombinantly engineered cell that has been transformed or transfected with a gene or genes encoding the antibody.
- one embodiment of the invention is a method of producing a targeted binding agent or an antibody of the invention by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the targeted binding agent or antibody followed by recovery of the targeted binding agent or antibody.
- a method of producing an antibody of the invention by culturing host cells under conditions wherein a nucleic acid molecule is expressed to produce the antibody, followed by recovery of the antibody.
- Still other embodiments include an antibody of the invention produced by the method of culturing a host cell which expresses an antibody encoded by a nucleic acid molecule encoding an antibody of the invention, and isolating said antibody from said culture.
- embodiments of the invention also include any nucleic acid molecule which encodes an antibody or fragment of an antibody of the invention including nucleic acid sequences optimised for increasing yields of antibodies or fragments thereof when transfected into host cells for antibody production.
- a further embodiment herein includes a method of producing antibodies that specifically bind to B7-H1 and inhibit the biological activity of B7-H1, by immunising a mammal with cells expressing B7-H1, isolated cell membranes containing B7-H1, purified B7-H1, or a fragment thereof, and/or one or more orthologous sequences or fragments thereof.
- a further embodiment herein includes a method of producing high affinity antibodies that specifically bind to B7-H1 and inhibit the biological activity of B7-H1, by immunising a mammal with cells expressing B7-H1, isolated cell membranes containing B7-H1, purified B7- Hl, or a fragment thereof, and/or one or more orthologous sequences or fragments thereof.
- Other embodiments are based upon the generation and identification of isolated antibodies that bind specifically to B7-H1 and inhibit the biological activity of B7-H1.
- B7-H1 is expressed on a number of tumour types.
- Antibodies that specifically bind to B7-H1 can prevent B7-H1 -mediated tumour cell survival and inhibit B7-H1 mediated repression of anti-tumour immune responses through immune suppression, this can in turn reduce tumour cell invasion, metastasis, tumour growth, and other properties.
- the antibody can be manufactured from a hybridoma that secretes the antibody, or from a recombinantly engineered cell that has been transformed or transfected with a gene or genes encoding the antibody.
- a hybridoma that produces the targeted binding agent or antibody of the invention there is a hybridoma that produces the light chain and/or the heavy chain of an antibody of the invention.
- the hybridoma may produce a light chain and/or a heavy chain of a fully human monoclonal antibody.
- the hybridoma produces the light chain and/or the heavy chain of the fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- the hybridoma may produce an antibody that binds to the same epitope or epitopes as fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- the hybridoma may produce an antibody that competes for binding to B7-H1 with fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- the hybridoma may produce an antibody that cross-competes for binding to B7-H1 with fully human monoclonal antibody 2.7A4, 2.14H9, 2.9D10, 2.7A40PT and 2.14H90PT.
- compositions including a targeted binding agent or antibody of the invention or binding fragment thereof, and a pharmaceutically acceptable carrier.
- Still further embodiments of the invention include methods of treating a proliferative or invasion-related disease in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for a proliferative or invasion-related disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the animal is human.
- the targeted binding agent is a fully human monoclonal antibody.
- the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
- Still further embodiments of the invention include methods of inhibiting cell proliferation or invasion -related disease, with a B7-H1 mediated component, in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for proliferation or invasion -related disease, with a B7-H1 mediated component, and administering to said animal a therapeutically effective dose of a targeted binding agent of the invention.
- the animal is human.
- the targeted binding agent is a fully human monoclonal antibody.
- the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
- Still further embodiments of the invention include methods of inhibiting tumour cell invasion, cellular metastasis or tumour growth in an animal by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for tumour cell, invasion, cellular metastasis or tumour growth, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the animal is human.
- the targeted binding agent is a fully human monoclonal antibody.
- the targeted binding agent is an antibody of the invention and may be selected from the group consisting of 2.7A4, 2.14H9 or 2.9D10, 2.7A40PT or 2.14H90PT.
- Still further embodiments of the invention include methods of treating an animal suffering from a neoplastic disease by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for a neoplastic disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- Still further embodiments of the invention include methods of treating an animal suffering from a non-neoplastic disease by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for a non-neoplastic disease, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- Still further embodiments of the invention include methods of treating an animal suffering from chronic viral infection by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for chronic viral infection, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- Still further embodiments of the invention include methods of treating an animal suffering from a malignant tumour by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for a malignant tumour, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- Still further embodiments of the invention include methods of treating an animal suffering from a disease or condition associated with B7-H1 expression by administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- the method further comprises selecting an animal in need of treatment for a disease or condition associated with B7-H1 expression, and administering to the animal a therapeutically effective dose of a targeted binding agent of the invention.
- a malignant tumour may be selected from the group consisting of: solid tumours such as melanoma, skin cancers, small cell lung cancer, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, gallbladder cancer, thyroid tumour, bone cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, testicular cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, renal cell carcinoma, colon cancer, colorectal, pancreatic cancer, esophageal carcinoma, brain/CNS cancers, head and neck cancers, neuronal cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma, sarcomas, cancer of the pleural/peritoneal membranes and le
- Treatable proliferative or invasion -related diseases include neoplastic diseases, such as, melanoma, skin cancer, small cell lung cancer, non-small cell lung cancer, salivary gland, glioma, hepatocellular (liver) carcinoma, gallbladder cancer, thyroid tumour, bone cancer, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, vulval cancer, endometrial cancer, testicular cancer, bladder cancer, lung cancer, glioblastoma, thyroid cancer, endometrial cancer, kidney cancer, colon cancer, colorectal cancer, pancreatic cancer, esophageal carcinoma, brain/CNS cancers, neuronal cancers, head and neck cancers, mesothelioma, sarcomas, biliary (cholangiocarcinoma), small bowel adenocarcinoma, pediatric malignancies, epidermoid carcinoma, sarcomas, cancer of the pleural/
- Treatable chronic viral infections include HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) in humans, simian immunodeficiency virus (SIV) in monkeys, and lymphocytic choriomeningitis virus (LCMV) in mice.
- HIV hepatitis B virus
- HCV hepatitis C virus
- SIV simian immunodeficiency virus
- LCMV lymphocytic choriomeningitis virus
- Disease-related cell invasion and/or proliferation may be any abnormal, undesirable or pathological cell invasion and/or proliferation, for example tumour-related cell invasion and/or proliferation.
- the neoplastic disease is a solid tumour selected from any one of the following carcinomas of the breast, colon, colorectal, prostate, stomach, gastric, ovary, esophagus, pancreas, gallbladder, non-small cell lung cancer, thyroid, endometrium, head and neck, renal, renal cell carcinoma, bladder and gliomas.
- the present invention is suitable for use in inhibiting B7-H1, in patients with a tumour which is dependent alone, or in part, on B7-H1.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a proliferative or invasion-related disease.
- the use further comprises selecting an animal in need of treatment for a proliferative or invasion-related disease.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of medicament for the treatment of proliferation or invasion -related disease, with a B7-H1 mediated component, in an animal.
- the use further comprises selecting an animal in need of treatment for proliferation or invasion -related disease, with a B7-H1 mediated component.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of medicament for the treatment of tumour cell invasion, cellular metastasis or tumour growth in an animal.
- the use further comprises selecting an animal in need of treatment for tumour cell invasion, cellular metastasis or tumour.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a neoplastic disease.
- the use further comprises selecting an animal in need of treatment for a neoplastic disease.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a disease where the etiology is associated with an infectious agent, such as, for example, hepatocellular cancer, gastric cancer, or cervical cancer.
- an infectious agent such as, for example, hepatocellular cancer, gastric cancer, or cervical cancer.
- the use further comprises selecting an animal in need of treatment for a neoplastic disease.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a non-neoplastic disease.
- the use further comprises selecting an animal in need of treatment for a non-neoplastic disease.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from chronic viral infection.
- the use further comprises selecting an animal in need of treatment for a non-neoplastic disease.
- the use further comprises ocular disease, inflammatory disease, cardiovascular disease and sepsis.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a malignant tumour.
- the use further comprises selecting an animal in need of treatment for a malignant tumour.
- Still further embodiments of the invention include use of a targeted binding agent or antibody of the invention in the preparation of a medicament for the treatment of an animal suffering from a disease or condition associated with B7-H1 expression.
- the use further comprises selecting an animal in need of treatment for a disease or condition associated with B7-H1 expression.
- Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from a proliferative or invasion-related disease.
- Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from tumour cell invasion, cellular metastasis or tumour growth in an animal.
- Still further embodiments of the invention include a targeted binding agent or antibody of the invention for use as a medicament for the treatment of an animal suffering from a disease or condition associated with B7-H1 expression.
- treatment of a proliferative or invasion-related disease In one embodiment treatment of a proliferative or invasion-related disease
- treatment of a neoplastic disease comprises inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, increased time to tumour recurrence, slowing of disease progression.
- treatment of a disease or condition associated with B7-H1 expression comprises inhibiting the growth of cells that express B7-H1.
- a clearing agent is administered, to remove excess circulating antibody from the blood.
- the animal to be treated is a human.
- the targeted binding agent is a fully human monoclonal antibody.
- the targeted binding agent is selected from the group consisting of fully human monoclonal antibodies 2.7A4, 2.14H9 and 2.9D10.
- Embodiments of the invention include a conjugate comprising the targeted binding agent as described herein, and a therapeutic agent.
- the therapeutic agent is a toxin.
- the therapeutic agent is a radioisotope.
- the therapeutic agent is a pharmaceutical composition.
- a method of selectively killing a cancerous cell in a patient comprises administering a fully human antibody conjugate to a patient.
- the fully human antibody conjugate comprises an antibody that can bind to B7-H1 and an agent.
- the agent is either a toxin, a radioisotope, or another substance that will kill a cancer cell.
- the antibody conjugate thereby selectively kills the cancer cell.
- a conjugated fully human antibody that specifically binds to B7-H1 is provided. Attached to the antibody is an agent, and the binding of the antibody to a cell results in the delivery of the agent to the cell.
- the above conjugated fully human antibody binds to an extracellular domain of B7-H1.
- the antibody and conjugated toxin are internalised by a cell that expresses B7-H1.
- the agent is a cytotoxic agent.
- the agent is, for example saporin, or auristatin, pseudomonas exotoxin, gelonin, ricin, calicheamicin or maytansine -based immunoconjugates, and the like.
- the agent is a radioisotope.
- the targeted binding agent or antibody of the invention can be administered alone, or can be administered in combination with additional antibodies or chemotherapeutic drugs or radiation therapy or therapeutic vaccines.
- a monoclonal, oligoclonal or polyclonal mixture of B7-H1 antibodies that block B7-H1 mediated repression of anti-tumour immunity can be administered in combination with a drug shown to inhibit tumour cell proliferation.
- a pharmaceutical composition comprising a targeted binding agent of antibody of the invention and a pharmaceutically acceptable carrier.
- Another embodiment of the invention includes a method of diagnosing diseases or conditions in which an antibody as disclosed herein is utilised to detect the presence and/or level of B7-H1 in a patient or patient sample.
- the patient sample is blood or blood serum or urine.
- methods for the identification of risk factors, diagnosis of disease, and staging of disease is presented which involves the identification of the expression and/or overexpression of B7-H1 using anti-B7-Hl antibodies.
- the methods comprise administering to a patient a fully human antibody conjugate that selectively binds to B7-H1 on a cell.
- the antibody conjugate comprises an antibody that specifically binds to B7-H1 and a label.
- the methods further comprise observing the presence of the label in the patient. A relatively high amount of the label will indicate a relatively high risk of the disease and a relatively low amount of the label will indicate a relatively low risk of the disease.
- the label is a green fluorescent protein.
- the invention further provides methods for assaying for the presence and/or level of B7- HI in a patient sample, comprising contacting an antibody as disclosed herein with a biological sample from a patient, and detecting the level of binding between said antibody and B7-H1 in said sample.
- the biological sample is blood, plasma or serum.
- Another embodiment of the invention includes a method for diagnosing a condition associated with the expression of B7-H1 in a cell by contacting the serum or a cell with an antibody as disclosed herein, and thereafter detecting the presence of B7-H1.
- the condition can be a proliferative or invasion -related disease including, but not limited to, a neoplastic disease.
- the invention includes an assay kit for detecting B7-H1 in mammalian tissues, cells, or body fluids. Such a kit would be useful to screen for B7-H1 -related diseases.
- the kit includes a targeted binding agent or antibody of the invention and a means for indicating the reaction of the targeted binding agent or antibody with B7-H1, if present.
- the antibody is a monoclonal antibody.
- the antibody that binds B7-H1 is labeled.
- the antibody is an unlabeled primary antibody and the kit further includes a means for detecting the primary antibody.
- the means for detecting includes a labeled second antibody that is an anti-immunoglobulin.
- the antibody may be labeled with a marker selected from the group consisting of a fluorochrome, an enzyme, a radionuclide and a radiopaque material.
- the targeted binding agents or antibodies as disclosed herein can be modified to enhance their capability of fixing complement and participating in complement- dependent cytotoxicity (CDC).
- the targeted binding agents or antibodies can be modified to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC).
- the targeted binding agents or antibodies can be modified both to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to enhance their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).
- the targeted binding agents or antibodies as disclosed herein can be modified to reduce their capability of fixing complement and participating in complement- dependent cytotoxicity (CDC). In other embodiments, the targeted binding agents or antibodies can be modified to reduce their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC). In yet other embodiments, the targeted binding agents or antibodies as disclosed herein can be modified both to reduce their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to reduce their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).
- ADCC antibody-dependent cytotoxicity
- the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 4 to 7 days.
- the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 2 to 5 days, 3 to 6 days, 4 to 7 days, 5 to 8 days, 6 to 9 days, 7 to 10 days, 8 to 11 days, 8 to 12, 9 to 13, 10 to 14, 11 to 15, 12 to 16, 13 to 17, 14 to 18, 15 to 19, or 16 to 20 days.
- the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 17 to 21 days, 18 to 22 days, 19 to 23 days, 20 to 24 days, 21 to 25, days, 22 to 26 days, 23 to 27 days, 24 to 28 days, 25 to 29 days, or 26 to 30 days.
- the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention can be up to about 50 days.
- the half-lives of antibodies and of compositions of the invention can be prolonged by methods known in the art. Such prolongation can in turn reduce the amount and/or frequency of dosing of the antibody compositions.
- Antibodies with improved in vivo half-lives and methods for preparing them are disclosed in U.S. Patent No. 6,277,375; and International Publication Nos. WO 98/23289 and WO 97/3461.
- the invention provides an article of manufacture including a container.
- the container includes a composition containing a targeted binding agent or antibody as disclosed herein, and a package insert or label indicating that the composition can be used to treat cell adhesion, invasion, angiogenesis, and/or proliferation -related diseases, including, but not limited to, diseases characterised by the expression or overexpression of B7-H1.
- the invention provides a kit for treating diseases involving the expression of B7-H1, comprising a targeted binding agent or antibody as disclosed herein, and instructions to administer the monoclonal antibodies to a subject in need of treatment.
- the present invention provides formulation of proteins comprising a variant Fc region. That is, a non naturally occurring Fc region, for example an Fc region comprising one or more non naturally occurring amino acid residues. Also encompassed by the variant Fc regions of present invention are Fc regions which comprise amino acid deletions, additions and/or modifications.
- the serum half-life of proteins comprising Fc regions may be increased by increasing the binding affinity of the Fc region for FcRn. In one embodiment, the Fc variant protein has enhanced serum half life relative to comparable molecule.
- the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat.
- the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat and at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 234, 235 and 331 , as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat.
- an Fc variant of the invention comprises the 234F, 235F, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat.
- an Fc variant of the invention comprises the 234F, 235 Y, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat.
- an Fc variant of the invention comprises the 234F, 235E, and 33 IS non naturally occurring amino acid residues, as numbered by the EU index as set forth in Kabat.
- the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat; at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, and 33 IS, as numbered by the EU index as set forth in Kabat, and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
- the "OPT” and “TM” designations are synonymous and are used to describe antibodies of the invention engineered to introduce the three mutations; L234F and L235E in the hinge and P331S in the CH2 domain of the IgG molecule to eliminate its ability to trigger antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity (Oganesyan V. et al. (2008), Acta Cryst., D64: 700-704).
- the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least a non naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat.
- the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid at one or more positions selected from the group consisting of 234, 235 and 331, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat.
- the Fc region may further comprise additional non naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index as set forth in Kabat.
- the present invention provides an Fc variant protein formulation, wherein the Fc region comprises at least one non naturally occurring amino acid selected from the group consisting of 234F, 235F, 235 Y, 235E and 33 IS, as numbered by the EU index as set forth in Kabat; and at least one non naturally occurring amino acid at one or more positions are selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.
- amino acid substitutions and/or deletions can be generated by mutagenesis methods, including, but not limited to, site-directed mutagenesis (Kunkel, Proc. Natl. Acad. Sci. USA 82:488-492 (1985) ), PCR mutagenesis (Higuchi, in “PCR Protocols: A Guide to Methods and Applications", Academic Press, San Diego, pp. 177-183 (1990)), and cassette mutagenesis (Wells et al, Gene 34:315-323 (1985)).
- site-directed mutagenesis is performed by the overlap-extension PCR method (Higuchi, in "PCR Technology: Principles and Applications for DNA Amplification", Stockton Press, New York, pp. 61-70 (1989)).
- the technique of overlap- extension PCR can also be used to introduce any desired mutation(s) into a target sequence (the starting DNA).
- the first round of PCR in the overlap- extension method involves amplifying the target sequence with an outside primer (primer 1) and an internal mutagenesis primer (primer 3), and separately with a second outside primer (primer 4) and an internal primer (primer 2), yielding two PCR segments (segments A and B).
- the internal mutagenesis primer (primer 3) is designed to contain mismatches to the target sequence specifying the desired mutation(s).
- the products of the first round of PCR (segments A and B) are amplified by PCR using the two outside primers (primers 1 and 4).
- the resulting full-length PCR segment (segment C) is digested with restriction enzymes and the resulting restriction fragment is cloned into an appropriate vector.
- the starting DNA e.g., encoding an Fc fusion protein, an antibody or simply an Fc region
- the primers are designed to reflect the desired amino acid substitution.
- the glycosylation patterns of the antibodies provided herein are modified to enhance ADCC and CDC effector function. See Shields RL et al, (2002) JBC. 277:26733; Shinkawa T et al, (2003) JBC. 278:3466 and Okazaki A et al, (2004) J. Mol. Biol., 336: 1239.
- an Fc variant protein comprises one or more engineered glycoforms, i.e., a carbohydrate composition that is covalently attached to the molecule comprising an Fc region.
- Engineered glycoforms may be useful for a variety of purposes, including but not limited to enhancing or reducing effector function.
- Engineered glycoforms may be generated by any method known to one skilled in the art, for example by using engineered or variant expression strains, by co-expression with one or more enzymes, for example DI N-acetylglucosaminyltransferase III (GnTIl l), by expressing a molecule comprising an Fc region in various organisms or cell lines from various organisms, or by modifying carbohydrate(s) after the molecule comprising Fc region has been expressed.
- Methods for generating engineered glycoforms are known in the art, and include but are not limited to those described in Umana et al, 1999, Nat.
- GlycoMAbTM glycosylation engineering technology GLYCART biotechnology AG, Zurich, Switzerland. See, e.g., WO 00061739; EA01229125; US 20030115614; Okazaki et al, 2004, JMB, 336: 1239-49.
- glycosylation of the Fc region can be modified to increase or decrease effector function (see for examples, Umana et al, 1999, Nat. Biotechnol 17: 176-180; Davies et al, 2001, Biotechnol Bioeng 74:288-294; Shields et al, 2002, J Biol Chem 277:26733-26740; Shinkawa et al, 2003, J Biol Chem 278:3466-3473) U.S. Pat. No. 6,602,684; U.S. Ser. No. 10/277,370; U.S. Ser. No.
- the Fc regions of the antibodies of the invention comprise altered glycosylation of amino acid residues.
- the altered glycosylation of the amino acid residues results in lowered effector function.
- the altered glycosylation of the amino acid residues results in increased effector function.
- the Fc region has reduced fucosylation.
- the Fc region is afucosylated (see for examples, U.S. Patent Application Publication No.2005/0226867).
- Fig. 1 is a bar graph showing the effects of the anti-B7-Hl antibodies of the invention on
- Fig. 2 is a bar graph showing enhancement of T-cell proliferation by anti-B7-Hl antibodies of the invention in DCMLR assay.
- Fig. 3 is a bar graph showing IFN- ⁇ release by anti-B7-Hl antibodies of the invention in DCMLR assay.
- Fig. 4 is a graph showing 95% confidence interval for anti-B7-Hl IC50 by anti-B7-Hl antibodies of the invention in the human PD1 /human B7-H1 ligand inhibition assay to evaluate the impact of IgG class switching and germlining on antibody activity.
- Fig. 5 is a line graph showing the results from an ELISA assay that was performed to evaluate anti-B7-Hl antibodies of the invention cross-reactivity to co-modulatory antigens.
- Fig. 6 is a bar graph showing the effects of anti-B7-Hl antibodies of the invention in the in-vitro Tet-recall assay.
- Fig. 7 is a bar graph showing the results form testing agonism activity of anti-B7-Hl antibodies of the invention using the Tet-recall assay.
- Fig. 8A/B/C are line graphs showing the effect of anti-B7-Hl antibodies of the invention on HPAC cells in a mouse xenograft model.
- Fig. 9A/B/C are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
- Fig. 10A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on HPAC cells in a mouse xenograft model.
- Fig. 11 is a line graph showing the effect of anti-B7-Hl antibodies of the invention on
- FIG. 12A/B/C/D are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
- Fig. 13A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model with and without the presence of T cells.
- Fig. 14A/B are line graphs showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model with and without the presence of T cells.
- Fig. 15 is a line graph showing the effect of anti-B7-Hl antibodies of the invention on A375 cells in a mouse xenograft model.
- Standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See for example, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001)), which is incorporated herein by reference.
- An antagonist or inhibitor may be a polypeptide, nucleic acid, carbohydrate, lipid, small molecular weight compound, an oligonucleotide, an oligopeptide, RNA interference (RNAi), antisense, a recombinant protein, an antibody, or fragments thereof or conjugates or fusion proteins thereof.
- RNAi RNA interference
- antisense see Opalinska JB, Gewirtz AM. (Sci STKE. 2003 Oct 28;2003 (206):pe47.)
- a compound refers to any small molecular weight compound with a molecular weight of less than about 2000 Daltons.
- B7-H1 refers to the human B7-H, B7H1, B7-H1, B7 homolog 1, CD274 antigen, PDCD1L1, PDCD1LG1, PDCD1 ligand 1, PDL1, PD-L1, Programmed cell death 1 ligand 1 precursor, or Programmed death ligand 1.
- neutralising when referring to a targeted binding agent, such as an antibody, relates to the ability of said agent to eliminate, reduce, or significantly reduce, the activity of a target antigen.
- a “neutralising” anti-B7-Hl antibody of the invention is capable of eliminating or significantly reducing the activity of B7-H1.
- a neutralising, antagonising or inhibiting antibody that specifically binds B7-H1 may, for example, act by blocking the binding of B7-H1 to its cognate ligands.
- a neutralising antibody against B7- HI inhibits B7-H1 mediated repression of T-cell immunity.
- a neutralising, antagonising or inhibiting antibody that specifically binds B7-H1 may, for example, act by inhibiting binding of B7-H1 to PD-1 and/or to B7-1.
- “Inhibiting the biological activity of B7-H1” encompasses an inhibition of B7-H1 activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%), at least 80%>, at least 85%>, at least 90%>, or at least 95%> in comparison with the biological activity in the absence of a targeted binding agent or antibody of the invention.
- polypeptide is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence.
- native protein, fragments, and analogs are species of the polypeptide genus.
- Preferred polypeptides in accordance with the invention comprise the human heavy chain immunoglobulin molecules and the human kappa light chain immunoglobulin molecules, as well as antibody molecules formed by combinations comprising the heavy chain immunoglobulin molecules with light chain immunoglobulin molecules, such as the kappa or lambda light chain immunoglobulin molecules, and vice versa, as well as fragments and analogs thereof.
- Preferred polypeptides in accordance with the invention may also comprise solely the human heavy chain immunoglobulin molecules or fragments thereof.
- naturally occurring refers to the fact that an object can be found in nature.
- a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory or otherwise is naturally occurring.
- control sequence refers to polynucleotide sequences that are necessary either to effect or to affect the expression and processing of coding sequences to which they are connected. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences may include promoters, enhancers, introns, transcription termination sequences, polyadenylation signal sequences, and 5' and '3 untranslated regions.
- control sequences is intended to include, at a minimum, all components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
- polynucleotide as referred to herein means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide, or RNA-DNA hetero-duplexes.
- the term includes single and double stranded forms of DNA.
- oligonucleotide includes naturally occurring, and modified nucleotides linked together by naturally occurring, and non naturally occurring linkages. Oligonucleotides are a polynucleotide subset generally comprising a length of 200 bases or fewer. Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in length. Oligonucleotides are usually single stranded, e.g. for probes; although oligonucleotides may be double stranded, e.g. for use in the construction of a gene mutant. Oligonucleotides can be either sense or antisense oligonucleotides.
- nucleotides includes deoxyribonucleotides and ribonucleotides.
- modified nucleotides includes nucleotides with modified or substituted sugar groups and the like.
- oligonucleotide linkages includes oligonucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res.
- oligonucleotide can include a label for detection, if desired.
- selective hybridise means to detectably and specifically bind.
- Polynucleotides, oligonucleotides and fragments thereof selectively hybridise to nucleic acid strands under hybridisation and wash conditions that minimise appreciable amounts of detectable binding to nonspecific nucleic acids.
- High stringency conditions can be used to achieve selective hybridisation conditions as known in the art and discussed herein.
- the nucleic acid sequence homology between the polynucleotides, oligonucleotides, or antibody fragments and a nucleic acid sequence of interest will be at least 80%, and more typically with preferably increasing homologies of at least 85%, 90%, 95%, 99%, and 100%.
- Stringent hybridization conditions include, but are not limited to, hybridization to filter- bound DNA in 6X sodium chloride/sodium citrate (SSC) (0.9 M NaCl/90 mM NaCitrate, pH 7.0) at about 45°C followed by one or more washes in 0.2X SSC/0.1% SDS at about 50-65°C, highly stringent conditions such as hybridization to filter-bound DNA in 6X SSC at about 45°C followed by one or more washes in 0.1X SSC/0.2%o SDS at about 60°C, or any other stringent hybridization conditions known to those skilled in the art (see, for example, Ausubel, F.M. et al., eds. 1989 Current Protocols in Molecular Biology, vol. 1, Green Publishing Associates, Inc. and John Wiley and Sons, Inc., NY at pages 6.3.1 to 6.3.6 and 2.10.3).
- SSC sodium chloride/sodium citrate
- Two amino acid sequences are "homologous" if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximising matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively and preferably, two protein sequences (or polypeptide sequences derived from them of at least about 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater.
- the two sequences or parts thereof are more preferably homologous if their amino acids are greater than or equal to 50% identical when optimally aligned using the ALIGN program. It should be appreciated that there can be differing regions of homology within two orthologous sequences. For example, the functional sites of mouse and human orthologues may have a higher degree of homology than non-functional regions.
- a polynucleotide sequence is homologous (i.e., is identical, not strictly evolutionarily related) to all or a portion of a reference polynucleotide sequence, or that a polypeptide sequence is identical to a reference polypeptide sequence.
- the term “complementary to” is used herein to mean that the complementary sequence is homologous to all or a portion of a reference polynucleotide sequence.
- the nucleotide sequence "TATAC” corresponds to a reference sequence “TATAC” and is complementary to a reference sequence "GTATA”.
- sequence identity means that two polynucleotide or amino acid sequences are identical (i.e., on a nucleotide-by-nucleotide or residue-by-residue basis) over the comparison window.
- percentage of sequence identity is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.
- substantially identical denotes a characteristic of a polynucleotide or amino acid sequence, wherein the polynucleotide or amino acid comprises a sequence that has at least 85 percent sequence identity, preferably at least 90 to 95 percent sequence identity, more preferably at least 99 percent sequence identity, as compared to a reference sequence over a comparison window of at least 18 nucleotide (6 amino acid) positions, frequently over a window of at least 24-48 nucleotide (8-16 amino acid) positions, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the comparison window.
- the reference sequence may be a subset of a larger sequence .
- the twenty conventional amino acids and their abbreviations follow conventional usage. See Immunology - A Synthesis (2 nd Edition, E.S. Golub and D.R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference.
- Stereoisomers e.g., D-amino acids
- unnatural amino acids such as ⁇ -, ⁇ -disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for polypeptides of the present invention.
- Examples of unconventional amino acids include: 4- hydroxyproline, ⁇ -carboxyglutamate, ⁇ - ⁇ , ⁇ , ⁇ -trimethyllysine, ⁇ - ⁇ -acetyllysine, O- phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ⁇ - ⁇ - methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).
- the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.
- the left-hand end of single-stranded polynucleotide sequences is the 5 ' end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5' direction.
- the direction of 5' to 3' addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA and which are 5 ' to the 5 ' end of the RNA transcript are referred to as "upstream sequences"; sequence regions on the DNA strand having the same sequence as the RNA and which are 3' to the 3' end of the RNA transcript are referred to as "downstream sequences".
- the term "substantial identity” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity, and most preferably at least 99 percent sequence identity.
- residue positions that are not identical differ by conservative amino acid substitutions.
- Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains.
- a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur- containing side chains is cysteine and methionine.
- Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic-aspartic, and asparagine-glutamine.
- minor variations in the amino acid sequences of antibodies or immunoglobulin molecules are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence maintain at least 75%, more preferably at least 80%>, 90%, 95%, and most preferably 99% sequence identity to the antibodies or immunoglobulin molecules described herein.
- conservative amino acid replacements are contemplated. Conservative replacements are those that take place within a family of amino acids that have related side chains.
- More preferred families are: serine and threonine are an aliphatic-hydroxy family; asparagine and glutamine are an amide-containing family; alanine, valine, leucine and isoleucine are an aliphatic family; and phenylalanine, tryptophan, and tyrosine are an aromatic family.
- Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases.
- computerised comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. Bowie et al. Science 253: 164 (1991).
- Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. These residues are deamidated under neutral or basic conditions. The deamidated form of these residues falls within the scope of this invention.
- cysteine residues in proteins are either engaged in cysteine-cysteine disulfide bonds or sterically protected from the disulfide bond formation when they are a part of folded protein region.
- Disulfide bond formation in proteins is a complex process, which is determined by the redox potential of the environment and specialized thiol-disulfide exchanging enzymes (Creighton, Methods Enzymol. 107, 305-329, 1984; Houee-Levin, Methods Enzymol. 353, 35- 44,2002).
- cysteine residue When a cysteine residue does not have a pair in protein structure and is not sterically protected by folding, it can form a disulfide bond with a free cysteine from solution in a process known as disulfide shuffling. In another process known as disulfide scrambling, free cysteines may also interfere with naturally occurring disulfide bonds (such as those present in antibody structures) and lead to low binding, low biological activity and/or low stability.
- Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogs.
- Analogs can include various muteins of a sequence other than the naturally occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts.
- a conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterises the parent sequence).
- Examples of art-recognised polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et at. Nature 354: 105 (1991), which are each incorporated herein by reference. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds.
- CDR region or “CDR” is intended to indicate the hypervariable regions of the heavy and light chains of an antibody which confer the antigen-binding specificity to the antibody.
- CDRs may be defined according to the Kabat system (Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th Edition. US Department of Health and Human Services, Public Service, NIH, Washington), and later editions.
- An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs.
- CDR or CDRs is used here in order to indicate, according to the case, one of these regions or several, or even the whole, of these regions which contain the majority of the amino acid residues responsible for the binding by affinity of the antibody for the antigen or the epitope which it recognises.
- the third CDR of the heavy chain (HCDR3) has a greater size variability (greater diversity essentially due to the mechanisms of arrangement of the genes which give rise to it). It may be as short as 2 amino acids although the longest size known is 26. CDR length may also vary according to the length that can be accommodated by the particular underlying framework. Functionally, HCDR3 plays a role in part in the determination of the specificity of the antibody (Segal et al, PNAS, 71 :4298-4302, 1974, Amit et al, Science, 233:747-753, 1986, Chothia et al, J. Mol.
- a "set of CDRs" referred to herein comprises CDR1, CDR2 and CDR3.
- a set of HCDRs refers to HCDR1, HCDR2 and HCDR3
- a set of LCDRs refers to LCDR1, LCDR2 and LCDR3.
- Variants of the VH and VL domains and CDRs of the present invention including those for which amino acid sequences are set out herein, and which can be employed in targeting binding agents and antibodies for B7-H1 can be obtained by means of methods of sequence alteration or mutation and screening for antigen targeting with desired characteristics.
- desired characteristics include but are not limited to: increased binding affinity for antigen relative to known antibodies which are specific for the antigen; increased neutralisation of an antigen activity relative to known antibodies which are specific for the antigen if the activity is known; specified competitive ability with a known antibody or ligand to the antigen at a specific molar ratio; ability to immunoprecipitate ligand-receptor complex; ability to bind to a specified epitope; linear epitope, e.g.
- peptide sequence identified using peptide-binding scan e.g. using peptides screened in linear and/or constrained conformation; conformational epitope, formed by non-continuous residues; ability to modulate a new biological activity of B7-H1, or downstream molecule; ability to bind and/or neutralise B7-H1 and/or for any other desired property.
- the techniques required to make substitutions within amino acid sequences of CDRs, antibody VH or VL domains and antigen binding sites are available in the art. Variants of antibody molecules disclosed herein may be produced and used in the present invention. Following the lead of computational chemistry in applying multivariate data analysis techniques to the structure/property-activity relationships (Wold, et al.
- the properties of antibodies can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of antibody sequence, functional and three-dimensional structures and these properties can be considered singly and in combination.
- An antibody antigen-binding site composed of a VH domain and a VL domain is typically formed by six loops of polypeptide: three from the light chain variable domain (VL) and three from the heavy chain variable domain (VH).
- VL light chain variable domain
- VH heavy chain variable domain
- Analysis of antibodies of known atomic structure has elucidated relationships between the sequence and three-dimensional structure of antibody combining sites. These relationships imply that, except for the third region (loop) in VH domains, binding site loops have one of a small number of main-chain conformations: canonical structures.
- the canonical structure formed in a particular loop has been shown to be determined by its size and the presence of certain residues at key sites in both the loop and in framework regions.
- sequence-structure relationship can be used for prediction of those residues in an antibody of known sequence, but of an unknown three-dimensional structure, which are important in maintaining the three-dimensional structure of its CDR loops and hence maintain binding specificity. These predictions can be backed up by comparison of the predictions to the output from lead optimisation experiments.
- a model can be created of the antibody molecule using any freely available or commercial package, such as WAM.
- a protein visualisation and analysis software package such as Insight II (Accelrys, Inc.) or Deep View may then be used to evaluate possible substitutions at each position in the CDR. This information may then be used to make substitutions likely to have a minimal or beneficial effect on activity or confer other desirable properties.
- polypeptide fragment refers to a polypeptide that has an amino- terminal and/or carboxy-terminal deletion, but where the remaining amino acid sequence is identical to the corresponding positions in the naturally occurring sequence deduced, for example, from a full-length cDNA sequence. Fragments typically are at least 5, 6, 8 or 10 amino acids long, preferably at least 14 amino acids long, more preferably at least 20 amino acids long, usually at least 50 amino acids long, and even more preferably at least 70 amino acids long.
- analog refers to polypeptides which are comprised of a segment of at least 25 amino acids that has substantial identity to a portion of a deduced amino acid sequence and which has at least one of the following properties: (1) specific binding to B7-H1, under suitable binding conditions, (2) ability to block appropriate B7-H1 -protein binding, or (3) ability to inhibit B7-H1 activity.
- polypeptide analogs comprise a conservative amino acid substitution (or addition or deletion) with respect to the naturally occurring sequence.
- Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally occurring polypeptide.
- Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics”. Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS p.392 (1985); and Evans et al. J. Med. Chem. 30: 1229 (1987), which are incorporated herein by reference. Such compounds are often developed with the aid of computerised molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent therapeutic or prophylactic effect.
- a paradigm polypeptide i.e., a polypeptide that has a biochemical property or pharmacological activity
- Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type may be used to generate more stable peptides.
- constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo and Gierasch Ann. Rev. Biochem. 61 :387 (1992), incorporated herein by reference); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclise the peptide.
- antibody and “antibodies” (immunoglobulins) may be an oligoclonal antibody, a polyclonal antibody, a monoclonal antibody (including full-length monoclonal antibodies), a camelised antibody, a chimeric antibody, a CDR-grafted antibody, a multi-specific antibody, a bi-specific antibody, a catalytic antibody, a chimeric antibody, a humanized antibody, a fully human antibody, an anti-idiotypic antibody and antibodies that can be labeled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques.
- An antibody may be from any species.
- An antibody comprises a polypeptide or group of polypeptides that are comprised of at least one binding domain that is formed from the folding of polypeptide chains having three- dimensional binding spaces with internal surface shapes and charge distributions complementary to the features of an antigenic determinant of an antigen.
- An antibody typically has a tetrameric form, comprising two identical pairs of polypeptide chains, each pair having one "light” and one "heavy” chain. The variable regions of each light/heavy chain pair form an antibody binding site.
- Native antibodies are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains.
- Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes.
- Each heavy and light chain also has regularly spaced intrachain disulfide bridges.
- Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
- Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
- Light chains are classified as either lambda chains or kappa chains based on the amino acid sequence of the light chain constant region.
- variable domain of a kappa light chain may also be denoted herein as VK.
- variable region may also be used to describe the variable domain of a heavy chain or light chain. Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains.
- the variable regions of each light/heavy chain pair form an antibody binding site.
- Such antibodies may be derived from any mammal, including, but not limited to, humans, monkeys, pigs, horses, rabbits, dogs, cats, mice, etc.
- antibody or “antibodies” includes binding fragments of the antibodies of the invention, exemplary fragments include single-chain Fvs (scFv), single-chain antibodies, single domain antibodies, domain antibodies, Fv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-stabilised variable region (dsFv), dimeric variable region (Diabody), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), intrabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope-binding fragments of any of the above.
- scFv single-chain Fvs
- dsFv disulfide-stabilised variable region
- Diabody dimeric variable region
- anti-Id antibodies including, e.g., anti-Id antibodies to antibodies of the invention
- intrabodies linear antibodies, single-chain antibody molecules and multi
- antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site.
- Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass.
- Digestion of antibodies with the enzyme, papain results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallise.
- Digestion of antibodies with the enzyme, pepsin results in the a F(ab') 2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites.
- the F(ab') 2 fragment has the ability to crosslink antigen.
- Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
- Fab when used herein refers to a fragment of an antibody that comprises the constant domain of the light chain and the CHI domain of the heavy chain.
- dAb when used herein refers to a fragment of an antibody that is the smallest functional binding unit of a human antibodies.
- a “dAb” is a single domain antibody and comprises either the variable domain of an antibody heavy chain (VH domain) or the variable domain of an antibody light chain (VL domain).
- VH domain variable domain of an antibody heavy chain
- VL domain variable domain of an antibody light chain
- Each dAb contains three of the six naturally occurring CDRs (Ward et al., Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature 341, 544-546 (1989); Holt, et al., Domain antibodies: protein for therapy, Trends Biotechnol. 21, 484-49 (2003)). With molecular weights ranging from 11 to 15 kDa, they are four times smaller than a fragment antigen binding (Fab)2 and half the size of a single chain Fv (scFv) molecule.
- Fab fragment antigen binding
- “Camelid” when used herein refers to antibody molecules are composed of heavy-chain dimers which are devoid of light chains, but nevertheless have an extensive antigen-binding repertoire (Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R (1993) Naturally occurring antibodies devoid of light chains. Nature 363:446-448).
- the term "diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V R ) connected to a light chain variable domain (V L ) in the same polypeptide chain (V H -V L ).
- Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl Acad. Sci. USA, 90:6444-6448 (1993).
- binding fragments are (Ward, E.S. et al., (1989) Nature 341, 544-546) the Fab fragment consisting of VL, VH, CL and CHI domains; (McCafferty et al (1990) Nature, 348, 552-554) the Fd fragment consisting of the VH and CHI domains; (Holt et al (2003) Trends in Biotechnology 21, 484-490) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward, E.S.
- Fv, scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains (Reiter, Y. et al, Nature Biotech, 14, 1239-1245, 1996).
- Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu, S. et al, (1996) Cancer Res., 56, 3055- 3061).
- binding fragments are Fab', which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CHI domain, including one or more cysteines from the antibody hinge region, and Fab'-SH, which is a Fab' fragment in which the cysteine residue(s) of the constant domains bear a free thiol group.
- variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are responsible for the binding specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed through the variable domains of antibodies. It is concentrated in segments called Complementarity Determining Regions (CDRs) both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework regions (FR).
- CDRs Complementarity Determining Regions
- FR framework regions
- the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a ⁇ -sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the ⁇ -sheet structure.
- the CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)).
- the constant domains are generally not involved directly in antigen binding, but may influence antigen binding affinity and may exhibit various effector functions, such as participation of the antibody in ADCC, CDC, and/or apoptosis.
- hypervariable region when used herein refers to the amino acid residues of an antibody which are associated with its binding to antigen.
- the hypervariable regions encompass the amino acid residues of the "complementarity determining regions" or "CDRs” (e.g., residues 24-34 (LI), 50-56 (L2) and 89-97 (L3) of the light chain variable domain and residues 31-35 (HI), 50-65 (H2) and 95-102 (H3) of the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.
- CDRs complementarity determining regions
- target binding agent refers to an agent, for example an antibody, or binding fragment thereof, that preferentially binds to a target site.
- the targeted binding agent is specific for only one target site. In other embodiments, the targeted binding agent is specific for more than one target site.
- the targeted binding agent may be a monoclonal antibody and the target site may be an epitope.
- a targeted binding agent may comprise at least one antigen binding domain (e.g. a CDR) of an antibody, wherein said domain is fused or contained within a heterologous protein scaffold, e.g. a non-antibody protein scaffold.
- Binding fragments of an antibody are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab') 2 , Fv, dAb and single-chain antibodies. An antibody other than a "bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. An antibody substantially inhibits adhesion of a receptor to a counter-receptor when an excess of antibody reduces the quantity of receptor bound to counter-receptor by at least about 20%, 40%>, 60%> or 80%o, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
- epitopic determinants includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor.
- Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and may, but not always, have specific three-dimensional structural characteristics, as well as specific charge characteristics.
- An antibody is said to specifically bind an antigen when the dissociation constant is ⁇ 1 ⁇ , preferably ⁇ 100 nM and most preferably ⁇ 10 nM.
- agent is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
- B7-H1 polypeptide refers to a portion of aB7-Hl polypeptide that has a biological or an immunological activity of a native B7-H1 polypeptide.
- Biological when used herein refers to a biological function that results from the activity of the native B7-H1 polypeptide.
- a preferred B7-H1 biological activity includes, for example, B7-H1 induced cell proliferation, cell adhesion and invasion.
- mammal when used herein refers to any animal that is considered a mammal. Preferably, the mammal is human.
- Animal when used herein encompasses animals considered a mammal. Preferably the animal is human.
- patient includes human and veterinary subjects.
- mAb refers to monoclonal antibody.
- Liposome when used herein refers to a small vesicle that may be useful for delivery of drugs that may include the B7-H1 polypeptide of the invention or antibodies to such a B7-H1 polypeptide to a mammal.
- Label refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label chemiluminescent labeled or a biotinyl group.
- Radioisotopes or radionuclides may include 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, m In, 125 1, 131 I, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, ⁇ -galactosidase, luciferase, alkaline phosphatase.
- Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH”), alpha-D-galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes; additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein”), dansyl, umbelliferone, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, and fiuorescamine; fluorophores such as lanthanide cryptates and chelates e.g.
- enzymes such as glucose-6-phosphate dehydrogenase (“G6PDH”), alpha-D-galactosidase, glucose oxydase,
- chemoluminescent labels or chemiluminescers such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5-bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof, sap
- pharmaceutical agent or drug refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.
- Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)), (incorporated herein by reference).
- substantially pure means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present.
- a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, more preferably more than about 85%, 90%, 95%), and 99%.
- the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
- Antibody-dependent cell-mediated cytotoxicity and “ADCC” refer to a cell-mediated reaction in which non-specific cytotoxic cells that express Ig Fc receptors (FcRs) (e.g. Natural Killer (NK) cells, monocytes, neutrophils, and macrophages) recognise bound antibody on a target cell and subsequently cause lysis of the target cell.
- FcRs Ig Fc receptors
- NK cells Natural Killer (NK) cells, monocytes, neutrophils, and macrophages
- FcRs expression on hematopoietic cells is summarised in Table 9 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
- ADCC activity of a molecule of interest can be assessed in vitro, such as that described in U.S. Patent No. 5,500,362, or 5,821,337.
- useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
- PBMC peripheral blood mononuclear cells
- NK Natural Killer
- ADCC activity of the molecule of interest can be assessed in vivo, e.g. , in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1988).
- “Complement dependent cytotoxicity” and “CDC” refer to the mechanism by which antibodies carry out their cell-killing function. It is initiated by the binding of Clq, a constituent of the first component of complement, to the Fc domain of Igs, IgG or IgM, which are in complex with antigen (Hughs- Jones, N.C., and B. Gardner. 1979. Mol. Immunol. 16:697). Clq is a large, structurally complex glycoprotein of -410 kDa present in human serum at a concentration of 70 ⁇ (Cooper, N.R. 1985. Adv. Immunol. 37: 151). Together with two serine proteases, Clr and Cls, Clq forms the complex CI, the first component of complement.
- antibody half-life means a pharmacokinetic property of an antibody that is a measure of the mean survival time of antibody molecules following their administration.
- Antibody half-life can be expressed as the time required to eliminate 50 percent of a known quantity of immunoglobulin from the patient's body or a specific compartment thereof, for example, as measured in serum or plasma, i.e., circulating half-life, or in other tissues.
- Half-life may vary from one immunoglobulin or class of immunoglobulin to another. In general, an increase in antibody half-life results in an increase in mean residence time (MRT) in circulation for the antibody administered.
- MRT mean residence time
- isotype refers to the classification of an antibody's heavy or light chain constant region.
- the constant domains of antibodies are not involved in binding to antigen, but exhibit various effector functions.
- a given human antibody or immunoglobulin can be assigned to one of five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM.
- IgA, IgD, IgE, IgG, and IgM Several of these classes may be further divided into subclasses (isotypes), e.g., IgGl (gamma 1), IgG2 (gamma 2), IgG3 (gamma 3), and IgG4 (gamma 4), and IgAl and IgA2.
- the heavy chain constant regions that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
- the structures and three-dimensional configurations of different classes of immunoglobulins are well- known.
- human immunoglobulin classes only human IgGl, IgG2, IgG3, IgG4, and IgM are known to activate complement.
- Human IgGl, IgG2, IgG3, and IgG4 are known to bind Fc gamma receptors, which mediate various effector functions including ADCC.
- Human light chain constant regions may be classified into two major classes, kappa and lambda.
- the isotype of an antibody that specifically binds B7-H1 can be switched, for example to take advantage of a biological property of a different isotype.
- the antibodies in some circumstances it can be desirable in connection with the generation of antibodies as therapeutic antibodies against B7-H1 that the antibodies be capable of fixing complement and participating in complement-dependent cytotoxicity (CDC).
- CDC complement-dependent cytotoxicity
- isotypes of antibodies that are capable of the same, including, without limitation, the following: murine IgM, murine IgG2a, murine IgG2b, murine IgG3, human IgM, human IgA, human IgGl, and human IgG3.
- antibodies can be desirable in connection with the generation of antibodies as therapeutic antibodies against B7-H1 that the antibodies be capable of binding Fc receptors on effector cells and participating in antibody-dependent cytotoxicity (ADCC).
- ADCC antibody-dependent cytotoxicity
- isotypes of antibodies that are capable of the same, including, without limitation, the following: murine IgG2a, murine IgG2b, murine IgG3, human IgGl, and human IgG3.
- antibodies that are generated need not initially possess such an isotype but, rather, the antibody as generated can possess any isotype and the antibody can be isotype switched thereafter using conventional techniques that are well known in the art. Such techniques include the use of direct recombinant techniques (see e.g., U.S. Patent No. 4,816,397), cell-cell fusion techniques (see e.g., U.S. Patent Nos. 5,916,771 and 6,207,418), among others.
- the anti- B7-H1 antibodies discussed herein are fully human antibodies. If an antibody possessed desired binding to B7-H1, it could be readily isotype switched to generate a human IgM, human IgGl, or human IgG3 isotype, while still possessing the same variable region (which defines the antibody's specificity and some of its affinity). Such molecule would then be capable of fixing complement and participating in CDC and/or be capable of binding to Fc receptors on effector cells and participating in ADCC.
- Blood assays use unfractionated blood as a source of natural effectors. Blood contains complement in the plasma, together with FcR-expressing cellular effectors, such as polymorphonuclear cells (PMNs) and mononuclear cells (MNCs). Thus, whole blood assays allow simultaneous evaluation of the synergy of both ADCC and CDC effector mechanisms in vitro.
- PMNs polymorphonuclear cells
- MNCs mononuclear cells
- a “therapeutically effective” amount as used herein is an amount that provides some improvement or benefit to the subject. Stated in another way, a “therapeutically effective” amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom. Clinical symptoms associated with the disorders that can be treated by the methods of the invention are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
- Exemplary cancers in humans include a bladder tumour, breast tumour, prostate tumour, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and CNS cancer (e.g., glioma tumour), cervical cancer, choriocarcinoma, colon and rectum cancer, connective tissue cancer, cancer of the digestive system; endometrial cancer, esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g.
- lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma, neuroblastoma, oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer, retinoblastoma; rhabdomyosarcoma; rectal cancer, renal cancer, cancer of the respiratory system; sarcoma, skin cancer; stomach cancer, testicular cancer, thyroid cancer; uterine cancer, cancer of the urinary system, as well as other carcinomas and sarcomas.
- Exemplary chronic infections in humans include HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV).
- HIV hepatitis B virus
- HCV hepatitis C virus
- the basic antibody structural unit is known to comprise a tetramer.
- Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy” chain (about 50-70 kDa).
- the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
- the carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function.
- Human light chains are classified as kappa and lambda light chains.
- Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgA, and IgE, respectively.
- variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D” region of about 10 more amino acids.
- J Fundamental Immunology Ch. 7
- D variable region of about 10 more amino acids.
- an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are the same.
- the chains all exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called CDRs.
- the CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope.
- both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
- the assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989).
- a bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites.
- Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann Clin. Exp. Immunol. 79: 315-321 (1990), Kostelny et al. J. Immunol. 148: 1547-1553 (1992). Bispecific antibodies do not exist in the form of fragments having a single binding site (e.g., Fab, Fab', and Fv).
- a VH domain is paired with a VL domain to provide an antibody antigen- binding site, although a VH or VL domain alone may be used to bind antigen.
- the VH domain (see Table 9) may be paired with the VL domain (see Table 13), so that an antibody antigen- binding site is formed comprising both the VH and VL domains
- Human antibodies avoid some of the problems associated with antibodies that possess murine or rat variable and/or constant regions.
- the presence of such murine or rat derived proteins can lead to the rapid clearance of the antibodies or can lead to the generation of an immune response against the antibody by a patient.
- fully human antibodies can be generated through the introduction of functional human antibody loci into a rodent, other mammal or animal so that the rodent, other mammal or animal produces fully human antibodies.
- XenoMouse ® strains of mice that have been engineered to contain up to but less than 1000 kb-sised germline configured fragments of the human heavy chain locus and kappa light chain locus. See Mendez et al. Nature Genetics 15: 146-156 (1997) and Green and Jakobovits J. Exp. Med. 188:483-495 (1998).
- the XenoMouse ® strains are available from Amgen, Inc. (Fremont, California, U.S.A).
- mice are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies.
- Technologies utilised for achieving the same are disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15:146-156 (1997), the disclosure of which is hereby incorporated by reference.
- minilocus In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus.
- Kirin has also demonstrated the generation of human antibodies from mice in which, through microcell fusion, large pieces of chromosomes, or entire chromosomes, have been introduced. See European Patent Application Nos. 773 288 and 843 961, the disclosures of which are hereby incorporated by reference. Additionally, KMTM- mice, which are the result of cross-breeding of Kirin's Tc mice with Medarex's minilocus (Humab) mice have been generated. These mice possess the human IgH transchromosome of the Kirin mice and the kappa chain transgene of the Genpharm mice (Ishida et al, Cloning Stem Cells, (2002) 4:91-102).
- Human antibodies can also be derived by in vitro methods. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display, and the like.
- mice were prepared through the utilization of the XenoMouse ® technology, as described below. Such mice are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilised for achieving the same are disclosed in the patents, applications, and references disclosed in the background section herein. In particular, however, a preferred embodiment of transgenic production of mice and antibodies therefrom is disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al. Nature Genetics 15: 146-156 (1997), the disclosure of which is hereby incorporated by reference.
- XenoMouse ® lines of mice are immunised with an antigen of interest (e.g. B7-H1), lymphatic cells (such as B-cells) are recovered from the hyper- immunised mice, and the recovered lymphocytes are fused with a myeloid-type cell line to prepare immortal hybridoma cell lines.
- B7-H1 an antigen of interest
- lymphatic cells such as B-cells
- myeloid-type cell line to prepare immortal hybridoma cell lines.
- These hybridoma cell lines are screened and selected to identify hybridoma cell lines that produced antibodies specific to the antigen of interest.
- Provided herein are methods for the production of multiple hybridoma cell lines that produce antibodies specific to B7-H1.
- characterisation of the antibodies produced by such cell lines including nucleotide and amino acid sequence analyses of the heavy and light chains of such antibodies.
- B cells can be directly assayed.
- CD 19+ B cells can be isolated from hyperimmune XenoMouse® mice and allowed to proliferate and differentiate into antibody-secreting plasma cells.
- Antibodies from the cell supernatants are then screened by ELISA for reactivity against the B7-H1 immunogen.
- the supernatants might also be screened for immunoreactivity against fragments of B7-H1 to further map the different antibodies for binding to domains of functional interest on B7-H1.
- the antibodies may also be screened other related human proteins and against the rat, the mouse, and non-human primate, such as Cynomolgus monkey, orthologues of B7-H1, the last to determine species cross-reactivity.
- B cells from wells containing antibodies of interest may be immortalised by various methods including fusion to make hybridomas either from individual or from pooled wells, or by infection with EBV or transfection by known immortalising genes and then plating in suitable medium.
- single plasma cells secreting antibodies with the desired specificities are then isolated using a B7-H1 -specific hemolytic plaque assay (see for example Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48 (1996)).
- Cells targeted for lysis are preferably sheep red blood cells (SRBCs) coated with the B7-H1 antigen.
- SRBCs sheep red blood cells coated with the B7-H1 antigen.
- the single antigen-specific plasma cell in the center of the plaque can be isolated and the genetic information that encodes the specificity of the antibody is isolated from the single plasma cell.
- RT-PCR reverse-transcription followed by PCR
- Such cloned DNA can then be further inserted into a suitable expression vector, preferably a vector cassette such as a pcDNA, more preferably such a pcDNA vector containing the constant domains of immunglobulin heavy and light chain.
- a suitable expression vector preferably a vector cassette such as a pcDNA, more preferably such a pcDNA vector containing the constant domains of immunglobulin heavy and light chain.
- the generated vector can then be transfected into host cells, e.g., HEK293 cells, CHO cells, and cultured in conventional nutrient media modified as appropriate for inducing transcription, selecting transformants, or amplifying the genes encoding the desired sequences.
- antibodies as described herein can be expressed in cell lines other than hybridoma cell lines. Sequences encoding particular antibodies can be used to transform a suitable mammalian host cell. Transformation can be by any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus (or into a viral vector) and transducing a host cell with the virus (or vector) or by transfection procedures known in the art, as exemplified by U.S. Patent Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents are hereby incorporated herein by reference). The transformation procedure used depends upon the host to be transformed.
- Methods for introducing heterologous polynucleotides into mammalian cells include dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.
- Mammalian cell lines available as hosts for expression are well known in the art and include many immortalised cell lines available from the NCIMB, including but not limited to Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), human epithelial kidney 293 cells (Hek293), and a number of other cell lines. Cell lines of particular preference are selected through determining which cell lines have high expression levels and produce antibodies with constitutive B7-H1 binding properties.
- CHO Chinese hamster ovary
- HeLa cells HeLa cells
- BHK baby hamster kidney
- COS monkey kidney cells
- Hep G2 human hepatocellular carcinoma cells
- Hek293 human epithelial kidney 293 cells
- a myeloma, CHO cell or other cell line is prepared that possesses a heavy chain with any desired isotype and another myeloma, CHO cell or other cell line is prepared that possesses the light chain.
- Such cells can, thereafter, be fused and a cell line expressing an intact antibody can be isolated.
- antibody candidates are generated that meet desired "structural" attributes as discussed above, they can generally be provided with at least certain of the desired "functional” attributes through isotype switching.
- a myeloma, CHO cell or other cell line is prepared that possesses a heavy chain with any desired isotype and another myeloma, CHO cell or other cell line is prepared that possesses the light chain.
- Such cells can, thereafter, be fused and a cell line expressing an intact antibody can be isolated.
- antibody candidates are generated that meet desired "structural" attributes as discussed above, they can generally be provided with at least certain of the desired "functional” attributes through isotype switching.
- Embodiments of the invention include the antibodies listed below in Table 1. This table reports the identification number of each antibody, along with the SEQ ID number of the variable domain of the corresponding heavy chain and light chain genes and polypeptides, respectively. Each antibody sequence has been given an identification number.
- Embodiments of the invention include sterile pharmaceutical formulations of anti-B7-Hl antibodies that are useful as treatments for diseases. Such formulations would inhibit the binding of B7-H1 to one or more of its cognate ligands, thereby treating pathological conditions where, for example, serum or tissue B7-H1 is abnormally elevated.
- Antibodies of the invention preferably possess adequate affinity to potently inhibit B7-H1 activity, or inhibit B7-H1 binding to one or more of its cognate ligands, and preferably have an adequate duration of action to allow for infrequent dosing in humans. A prolonged duration of action will allow for less frequent and more convenient dosing schedules by alternate parenteral routes such as subcutaneous or intramuscular injection.
- Sterile formulations can be created, for example, by filtration through sterile filtration membranes, prior to or following lyophilisation and reconstitution of the antibody.
- the antibody ordinarily will be stored in lyophilised form or in solution.
- Therapeutic antibody compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having an adapter that allows retrieval of the formulation, such as a stopper pierceable by a hypodermic injection needle.
- the route of antibody administration is in accord with known methods, e.g., injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intrathecal, inhalation or intralesional routes, direct injection to a tumour site, or by sustained release systems as noted below.
- the antibody is preferably administered continuously by infusion or by bolus injection.
- an effective amount of antibody to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred that the therapist titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Typically, the clinician will administer antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or by the assays described herein.
- Antibodies as described herein, can be prepared in a mixture with a pharmaceutically acceptable carrier.
- This therapeutic composition can be administered intravenously or through the nose or lung, preferably as a liquid or powder aerosol (lyophilised).
- the composition can also be administered parenterally or subcutaneously as desired.
- the therapeutic composition should be sterile, pyrogen-free and in a parenterally acceptable solution having due regard for pH, isotonicity, and stability. These conditions are known to those skilled in the art.
- dosage formulations of the compounds described herein are prepared for storage or administration by mixing the compound having the desired degree of purity with pharmaceutically acceptable carriers, excipients, or stabilisers.
- Such materials are non-toxic to the recipients at the dosages and concentrations employed, and include buffers such as TRIS HC1, phosphate, citrate, acetate and other organic acid salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium and/or nonionic surfactants such as TWEEN, PLURONICS or poly ethylenegly col.
- buffers such as TRIS HC1, phosphate, citrate, acetate
- Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in Remington: The Science and Practice of Pharmacy (20 th ed, Lippincott Williams & Wilkens Publishers (2003)). For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
- sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the polypeptide, which matrices are in the form of shaped articles, films or microcapsules.
- sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) as described by Langer et al, J. Biomed Mater. Res., (1981) 15: 167-277 and Langer, Chem. Tech., (1982) 12:98-105, or poly(vinylalcohol)), polylactides (U.S. Pat. No.
- Sustained-released compositions also include preparations of crystals of the antibody suspended in suitable formulations capable of maintaining crystals in suspension. These preparations when injected subcutaneous ly or intraperitonealy can produce a sustained release effect.
- Other compositions also include liposomally entrapped antibodies. Liposomes containing such antibodies are prepared by methods known per se: U.S. Pat. No. DE 3,218,121; Epstein et al, Proc. Natl. Acad. Sci. USA, (1985) 82:3688-3692; Hwang et al, Proc. Natl. Acad. Sci.
- the dosage of the antibody formulation for a given patient will be determined by the attending physician taking into consideration various factors known to modify the action of drugs including severity and type of disease, body weight, sex, diet, time and route of administration, other medications and other relevant clinical factors.
- Therapeutically effective dosages can be determined by either in vitro or in vivo methods.
- An effective amount of the antibodies, described herein, to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient. Accordingly, it is preferred for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
- a typical daily dosage might range from about 0.000 lmg/kg, O.OOlmg/kg, O.Olmg/kg, O.lmg/kg, lmg/kg, lOmg/kg to up to lOOmg/kg, lOOOmg/kg, lOOOOmg/kg or more, of the patient's body weight depending on the factors mentioned above.
- the dosage may be between 0.0001 mg/kg and 20 mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5 mg/kg, 0.0001 and 2 mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and 0.75 mg/kg, 0.0001 mg/kg and 0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg, 0.0001 to 0.15 mg/kg, 0.0001 to 0.10 mg/kg, 0.001 to 0.5 mg/kg, 0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kg of the patient's body weight depending on the factors mentioned above.
- the clinician will administer the therapeutic antibody until a dosage is reached that achieves the desired effect. The progress of this therapy is easily monitored by conventional assays or as described herein.
- Doses of antibodies of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
- compositions and methods herein will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
- suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
- formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.
- Such modalities include, without limitation, advanced antibody therapeutics, such as bispecific antibodies, immunotoxins, radiolabeled therapeutics, and single antibody V domains, antibodylike binding agent based on other than V region scaffolds, single domain antibodies, generation of peptide therapeutics, B7-H1 binding domains in novel scaffolds, gene therapies, particularly intrabodies, antisense therapeutics, and small molecules.
- advanced antibody therapeutics such as bispecific antibodies, immunotoxins, radiolabeled therapeutics, and single antibody V domains, antibodylike binding agent based on other than V region scaffolds, single domain antibodies, generation of peptide therapeutics, B7-H1 binding domains in novel scaffolds, gene therapies, particularly intrabodies, antisense therapeutics, and small molecules.
- An antigen binding site may be provided by means of arrangement of CDRs on non- antibody protein scaffolds, such as fibronectin or cytochrome B etc. (Haan & Maggos (2004) BioCentury, 12(5): A1-A6; Koide et al. (1998) Journal of Molecular Biology, 284: 1141-1151; Nygren et al. (1997) Current Opinion in Structural Biology, 7: 463-469) or by randomising or mutating amino acid residues of a loop within a protein scaffold to confer binding specificity for a desired target. Scaffolds for engineering novel binding sites in proteins have been reviewed in detail by Nygren et al. (Nygren et al.
- Protein scaffolds for antibody mimics are disclosed in WO/0034784, which is herein incorporated by reference in its entirety, in which the inventors describe proteins (antibody mimics) that include a fibronectin type III domain having at least one randomised loop.
- a suitable scaffold into which to graft one or more CDRs, e.g. a set of HCDRs, may be provided by any domain member of the immunoglobulin gene superfamily.
- the scaffold may be a human or non-human protein.
- An advantage of a non-antibody protein scaffold is that it may provide an antigen-binding site in a scaffold molecule that is smaller and/or easier to manufacture than at least some antibody molecules.
- Small size of a binding member may confer useful physiological properties, such as an ability to enter cells, penetrate deep into tissues or reach targets within other structures, or to bind within protein cavities of the target antigen.
- Use of antigen binding sites in non-antibody protein scaffolds is reviewed in Wess, 2004 (Wess, L. In: BioCentury, The Bernstein Report on BioBusiness, 12(42), A1-A7, 2004).
- Typical are proteins having a stable backbone and one or more variable loops, in which the amino acid sequence of the loop or loops is specifically or randomly mutated to create an antigen-binding site that binds the target antigen.
- Such proteins include the IgG-binding domains of protein A from S.
- a targeted binding agent may comprise other amino acids, e.g.
- Targeted binding agents of the invention may carry a detectable label, or may be conjugated to a toxin or a targeting moiety or enzyme (e.g. via a peptidyl bond or linker).
- a targeted binding agent may comprise a catalytic site (e.g. in an enzyme domain) as well as an antigen binding site, wherein the antigen binding site binds to the antigen and thus targets the catalytic site to the antigen.
- the catalytic site may inhibit biological function of the antigen, e.g. by cleavage.
- bispecific antibodies can be generated that comprise (i) two antibodies one with a specificity to B7-H1 and another to a second molecule that are conjugated together, (ii) a single antibody that has one chain specific to B7-H1 and a second chain specific to a second molecule, or (iii) a single chain antibody that has specificity to B7-H1 and the other molecule.
- Such bispecific antibodies can be generated using techniques that are well known; for example, in connection with (i) and (ii) see e.g., Fanger et al. Immunol Methods 4:72-81 (1994) and Wright and Harris, supra, and in connection with (iii) see e.g., Traunecker et al. Int. J.
- the second specificity can be made as desired.
- the second specificity can be made to the heavy chain activation receptors, including, without limitation, CD 16 or CD64 ⁇ see e.g., Deo et al. Immunol. Today 18:127 (1997)) or CD89 ⁇ see e.g., Valerius et al. Blood 90:4485-4492 (1997)).
- Antibodies can also be modified to act as immunotoxins utilising techniques that are well known in the art. See e.g., Vitetta Immunol Today 14:252 (1993). See also U.S. Patent No. 5,194,594. In connection with the preparation of radiolabeled antibodies, such modified antibodies can also be readily prepared utilising techniques that are well known in the art. See e.g., Junghans et al. in Cancer Chemotherapy and Biotherapy 655-686 (2d edition, Chafner and Longo, eds., Lippincott Raven (1996)). See also U.S. Patent Nos. 4,681,581, 4,735,210, 5,101,827, 5,102,990 (RE 35,500), 5,648,471, and 5,697,902. Each immunotoxin or radiolabeled molecule would be likely to kill cells expressing the desired multimeric enzyme subunit oligomerisation domain.
- an antibody When an antibody is linked to an agent (e.g., radioisotope, pharmaceutical composition, or a toxin) it is contemplated that the agent possesses a pharmaceutical property selected from the group of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents and combinations thereof.
- agent e.g., radioisotope, pharmaceutical composition, or a toxin
- the agent possesses a pharmaceutical property selected from the group of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents and combinations thereof.
- the agent can be selected from the group of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antimetabolites, antibiotics, enzymes, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, antagonists, endostatin, taxols, camptothecins, oxaliplatin, doxorubicins and their analogs, and a combination thereof.
- toxins further include gelonin, Pseudomonas exotoxin (PE), PE40, PE38, diphtheria toxin, ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, Pseudomonas endotoxin, members of the enediyne family of molecules, such as calicheamicin and esperamicin, as well as derivatives, combinations and modifications thereof.
- Chemical toxins can also be taken from the group consisting of duocarmycin (see, e.g., U.S. Patent No.
- chemotherapeutic agents also include Adriamycin, Doxorubicin, 5-Fluorouracil, Cytosine arabinoside (Ara-C), Cyclophosphamide, Thiotepa, Taxotere (docetaxel), Busulfan, Cytoxin, Taxol, Methotrexate, Cisplatin, Melphalan, Vinblastine, Bleomycin, Etoposide, Ifosfamide, Mitomycin C, Mitoxantrone, Vincreistine, Vinorelbine, Carboplatin, Teniposide, Daunomycin, Carminomycin, Aminopterin, Dactinomycin, Mitomycins, Esperamicins (see, U.S.
- Patent No. 4,675,187 Melphalan, and other related nitrogen mustards.
- Suitable toxins and chemotherapeutic agents are described in Remington's Pharmaceutical Sciences, 19th Ed. (Mack Publishing Co. 1995), and in Goodman And Gilman's The Pharmacological Basis of Therapeutics, 7th Ed. (MacMillan Publishing Co. 1985).
- Other suitable toxins and/or chemotherapeutic agents are known to those of skill in the art.
- radioisotopes examples include gamma-emitters, positron-emitters, and x-ray emitters that can be used for localisation and/or therapy, and beta-emitters and alpha-emitters that can be used for therapy.
- the radioisotopes described previously as useful for diagnostics, prognostics and staging are also useful for therapeutics.
- Non-limiting examples of anti-cancer or anti-leukemia agents include anthracyclines such as doxorubicin (adriamycin), daunorubicin (daunomycin), idarubicin, detorubicin, carminomycin, epirubicin, esorubicin, and morpholino and substituted derivatives, combinations and modifications thereof.
- anthracyclines such as doxorubicin (adriamycin), daunorubicin (daunomycin), idarubicin, detorubicin, carminomycin, epirubicin, esorubicin, and morpholino and substituted derivatives, combinations and modifications thereof.
- Exemplary pharmaceutical agents include cis-platinum, taxol, calicheamicin, vincristine, cytarabine (Ara-C), cyclophosphamide, prednisone, daunorubicin, idarubicin, fludarabine, chlorambucil, interferon alpha, hydroxyurea, temozolomide, thalidomide, and bleomycin, and derivatives, combinations and modifications thereof.
- the anti- cancer or anti-leukemia is doxorubicin, morpholinodoxorubicin, or morpholinodaunorubicin.
- the antibodies of the invention also encompass antibodies that have half-lives (e.g., serum half-lives) in a mammal, preferably a human, of greater than that of an unmodified antibody.
- said antibody half life is greater than about 15 days, greater than about 20 days, greater than about 25 days, greater than about 30 days, greater than about 35 days, greater than about 40 days, greater than about 45 days, greater than about 2 months, greater than about 3 months, greater than about 4 months, or greater than about 5 months.
- Antibodies or fragments thereof having increased in vivo half-lives can be generated by techniques known to those of skill in the art. For example, antibodies or fragments thereof with increased in vivo half-lives can be generated by modifying (e.g., substituting, deleting or adding) amino acid residues identified as involved in the interaction between the Fc domain and the FcRn receptor (see, e.g., International Publication Nos.
- Antibodies or fragments thereof with increased in vivo half-lives can be generated by attaching to said antibodies or antibody fragments polymer molecules such as high molecular weight polyethyleneglycol (PEG).
- PEG polymer molecules
- PEG can be attached to said antibodies or antibody fragments with or without a multifunctional linker either through site-specific conjugation of the PEG to the N- or C-terminus of said antibodies or antibody fragments or via epsilon-amino groups present on lysine residues. Linear or branched polymer derivatisation that results in minimal loss of biological activity will be used.
- the degree of conjugation will be closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of PEG molecules to the antibodies. Unreacted PEG can be separated from antibody- PEG conjugates by, e.g., size exclusion or ion-exchange chromatography.
- affinity values can be important, other factors can be as important or more so, depending upon the particular function of the antibody.
- an immunotoxin toxin associated with an antibody
- the act of binding of the antibody to the target can be useful; however, in some embodiments, it is the internalisation of the toxin into the cell that is the desired end result.
- antibodies with a high percent internalisation can be desirable in these situations.
- antibodies with a high efficiency in internalisation are contemplated.
- a high efficiency of internalisation can be measured as a percent internalised antibody, and can be from a low value to 100%.
- 0.1-5, 5-10, 10-20, 20-30, 30-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-99, and 99-100% can be a high efficiency.
- the desirable efficiency can be different in different embodiments, depending upon, for example, the associated agent, the amount of antibody that can be administered to an area, the side effects of the antibody-agent complex, the type (e.g., cancer type) and severity of the problem to be treated.
- the antibodies disclosed herein provide an assay kit for the detection of B7-H1 expression in mammalian tissues or cells in order to screen for a disease or disorder associated with changes in expression of B7-H1.
- the kit comprises an antibody that binds B7-H1 and means for indicating the reaction of the antibody with the antigen, if present.
- an article of manufacture comprising a container, comprising a composition containing an antibody that specifically binds B7-H1 , and a package insert or label indicating that the composition can be used to treat disease mediated by B7-H1 expression.
- a mammal and, more preferably, a human receives the antibody that specifically binds B7-H1.
- the anti-tumour treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery, bone marrow and peripheral stem cell transplantations or radiotherapy or chemotherapy.
- Such chemotherapy may include one or more of the following categories of anti tumour agents:
- antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vin
- cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
- antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
- antiandrogens for example
- anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
- anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetra
- metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or inhibitors of cathepsin activity, inhibitors of serine proteases for example matriptase, hepsin, urokinase and inhibitors of integrin ⁇ 6 function.
- cytotoxic agents such as fludarabine, 2-chlorodeoxyadenosine, chlorambucil or doxorubicin and combination thereoff such as Fludarabine + cyclophosphamide, CVP: cyclophosphamide + vincristine + prednisone, ACVBP: doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone, CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone, CNOP: cyclophosphamide + mitoxantrone + vincristine + prednisone, m-BACOD: methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone + leucovorin., MACOP-B: methotrexate + doxorubicin + cyclophosphamide, vin
- inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
- inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3 -chloro-4-fluorophenyl)-7-(3 -morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet
- antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM)] and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2- fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications W097/22596, WO
- vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
- antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense or G3139 (Genasense), an anti bcl2 antisense;
- (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
- GDEPT gene-directed enzyme pro-drug therapy
- (x) immunotherapy approaches including for example treatment with Alemtuzumab (campath-lHTM), a monoclonal antibody directed at CD52, or treatment with antibodies directed at CD22, ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy such as treatment with monoclonal antibodies inhibiting CTLA-4 function, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies, adoptive T-cell transfer using T-cells that have been non-specifically activated or targeted to a specific antigen of interest ex vivo;
- cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor
- approaches to decrease T cell anergy such as treatment with monoclonal antibodies inhibit
- Vaccination approaches including for example treatment with a vaccine directed against a specific viral infection such as HIV or HBV, or treatment with a vaccine directed against a specific tumour antigen;
- inhibitors of protein degradation such as proteasome inhibitor such as Velcade (bortezomid); and
- biotherapeutic therapeutic approaches for example those which use peptides or proteins (such as antibodies or soluble external receptor domain constructions) which either sequester receptor ligands, block ligand binding to receptor or decrease receptor signalling (e.g. due to enhanced receptor degradation or lowered expression levels).
- peptides or proteins such as antibodies or soluble external receptor domain constructions
- the anti-tumour treatment defined herein may involve, in addition to the compounds of the invention, treatment with other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxalip latin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
- Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
- Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range.
- the human B7-H1 cDNA (Dong, H. et al, 1999, Nat. Med. 5: 1365 - 1369) was amplified from Image clone 7262208 (ATCC) using polymerase chain reaction (PCR) and then cloned into the Nhe 1 and EcoRl sites of pcr3.1Bid vector. This construct was lipofected into CHO cells (American Type Tissue Collection, catalog # CCL-61) and the expression on the cell surface was confirmed by fluorescent activated cell sorting (FACS) analysis.
- FACS fluorescent activated cell sorting
- Monoclonal antibodies against human B7-H1 were developed by sequentially immunizing XenoMouse ® mice (XenoMouse strains: XMG2 (IgG2 kappa/lambda) and XMG4 (IgG4 kappa/lambda) Amgen, Inc. Vancouver, British Columbia, Canada) with either 5-10 ug of the B7-Hl/Fc chimera protein or 1-2x10(6) CHO cells expressing recombinant human B7-H1 as described in Example 1.
- ⁇ refers to "intraperitoneal” and "SC” refers to "subcutaneous'
- EXAMPLE 3 RECOVERY OF LYMPHOCYTES, B-CELL ISOLATIONS, FUSIONS
- Immunised mice were sacrificed by cervical dislocation, and the draining lymph nodes harvested and pooled from each cohort.
- the lymphoid cells were dissociated by grinding in DMEM to release the cells from the tissues and the cells were suspended in DMEM. The cells were counted, and 0.9 ml DMEM per 100 million lymphocytes added to the cell pellet to resuspend the cells gently but completely.
- Using 100 ⁇ of CD90+ magnetic beads per 100 million cells the cells were labeled by incubating the cells with the magnetic beads at 4°C for 15 minutes.
- the magnetically labeled cell suspension containing up to 10 8 positive cells (or up to 2xl0 9 total cells) was loaded onto a LS+ column and the column washed with DMEM. The total effluent was collected as the CD90-negative fraction (most of these cells were expected to be B cells).
- the fusion was performed by mixing washed enriched B cells from above and nonsecretory myeloma P3X63Ag8.653 cells purchased from ATCC, cat.# CRL 1580 (Kearney et al, J. Immunol. 123, 1979, 1548-1550) at a ratio of 1 :1.
- the cell mixture was gently pelleted by centrifugation at 800 x g. After complete removal of the supernatant, the cells were treated with 2-4 mL of Pronase solution (CalBiochem, cat. # 53702; 0.5 mg/ml in PBS) for no more than 2 minutes.
- Electro-cell fusion was performed using a fusion generator (model ECM2001, Genetronic, Inc., San Diego, CA).
- the fusion chamber size used was 2.0 ml, using the following instrument settings:
- the cell suspensions were carefully removed from the fusion chamber under sterile conditions and transferred into a sterile tube containing the same volume of Hybridoma Culture Medium (DMEM, JRH Biosciences), 15 % FBS (Hyclone), supplemented with L- glutamine, pen/strep, OPI (oxaloacetate, pyruvate, bovine insulin) (all from Sigma) and IL-6 (Boehringer Mannheim).
- DMEM Hybridoma Culture Medium
- FBS Hyclone
- OPI oxaloacetate, pyruvate, bovine insulin
- IL-6 Boehringer Mannheim
- Hybridoma Selection Medium Hybridoma Culture Medium supplemented with 0.5x HA (Sigma, cat. # A9666)
- Hybridoma Selection Medium 0.5x HA (Sigma, cat. # A9666)
- the cells were mixed gently and pipetted into 96-well plates and allowed to grow. On day 7 or 10, one-half the medium was removed, and the cells re-fed with Hybridoma Selection Medium.
- Hybridomas were grown as routine in the selective medium. Exhaustive supernatants collected from the hybridomas were tested in various assays as described in Examples 4-5. Just to note, antibodies that begin with a 3 digit, e.g., 3.15G8, are IgG4 and antibodies that begin with a 2, e.g., 2.9D10, are IgG2.
- EXAMPLE 4 BINDING TO CELL BOUND HUMAN AND CYNOMOLGUS MONKEY
- Supernatants collected from hybridoma cells were tested to assess the ability of the secreted antibodies to bind to 293T cells transiently expressing either full length human or cynomolgus monkey B7-H1.
- a mock-transfected 293T cell line was used as a negative control.
- Cells diluted in PBS containing 2% FBS were seeded at a density of 2500-3000 expressing and 15000-17500 mock transfected cells in 40 ⁇ /well in 384 well plates (Corning Costar, catalog # 3712). Immediately after plating, 10 ⁇ /well of hybridoma supernatants were added and plates incubated for 1.5 hr at room temperature.
- Biotinylated human PD-l/Fc protein (R&D Systems, catalog #1086-PD) was added to a final concentration of 1.25 ug/ml and plates were incubated at 4C for 1 hour on a shaker. Cells were washed and fixed in 100 ul of PBS containing 3.7% formaldehyde and 3% bovine serum albumin for 20 min at room temperature. Cells were washed and incubated in 100 ul of PBS containing 0.6% H202 and 3% bovine serum albumin for 10 min at room temperature. Cells were washed and incubated in 50 ⁇ of horseradish peroxidase-conjugated streptavidin diluted at 1 :4000 for 30 min at 4oC.
- the ability of the purified antibodies to bind to human B7-H1, B7-DC, mouse B7H1 and cynomolgus monkey B7-H1 was determined by FACS analysis. Briefly, 293T cells were either mock-transfected or transiently transfected with either human B7-H1 or human B7-DC using Lipofectamine 2000 (Invitrogen, catalog #11668). Mouse J558 cells expressing mouse B7-H1 were obtained from ATCC (catalog #TIB-6). Cells were resuspended in PBS containing 2%> FBS (FACS buffer) and seeded at 50000 cells/well into V-bottomed plates.
- FACS buffer FACS buffer
- Anti-B7-Hl and isotype control antibodies diluted in FACS buffer were added at a final concentration of 5 ⁇ g/ml and plates were incubated for 1 h at 4 °C. After washing with FACS buffer, goat anti-human Fc Cy5 (5 ⁇ g/ml, Jackson Immunoresearch, catalog # 109-175-098) and 7-AAD (5 ⁇ g/ml) were added and plates were incubated for 15 min at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Table 5 shows ability of purified antibodies (5 ⁇ g/ml) to bind to 293T cells transfected with human B7-H1.
- EXAMPLE 7 BINDING OF PURIFIED HUMAN ANTI-B7-H1 ANTIBODIES TO STIMULATED HUMAN AND CYNOMOLGUS MONKEY T CELLS
- 96-well high binding plates were incubated with 100 ul/well of anti-CD3 antibody diluted at 1 ug/ml in PBS (OKT3 clone, eBioscience, catalog # 160037) at 4C overnight.
- Human T cells were isolated from frozen leukopack using T cell enrichment kit (StemCell Technologies, catalog #19051).
- Anti-CD3 mAb coated plates were washed with PBS and purified T cells were added in 200 ul of ICM media at 360000 cells/well and cultured for 72 hours.
- T cells were then harvested, washed in FACS buffer and mixed with diluted purified anti-B7-Hl antibodies or irrelevant human IgG2 or IgG4 antibodies at final concentration of lug/ml in 96-well V-bottom assay plate (50 ul/well). After 2 hours incubation at 4C, T cells were washed twice in FACS buffer and then stained with Cy5 -conjugated goat anti-human IgG Fc antibody (5 ug/ml, Jackson Immunoresearch, catalog # 109-175-098) and 7-AAD (10 ug/ml). Cells were incubated for 30 min at 4 °C before being washed again with FACS buffer and being read on a FACSCalibur instrument. Live lymphocyte population was selected for analysis based on forward and side scatter as well as negative staining for 7-AAD.
- 96-well high binding plates were incubated with 100 ul/well of goat anti-mouse IgG Fc antibody diluted at 1 ug/ml in PBS at 4C overnight. Plates were washed with PBS and incubated with anti-CD3 antibody diluted at 1 ug/ml in ICM media (clone SP-34, BD catalog #556610) at 37C for 2 hours. Cynomolgus monkey PBMC were isolated from peripheral blood (Bioreclamation, catalog #CYNWBCPT). Anti-CD3 mAb coated plates were washed with PBS and isolated PBMC were added in 200 ul of ICM media at -200000 cells/well and cultured for 72 hours.
- the ability of purified human anti-B7-Hl antibodies to inhibit the binding of human PD-l/Fc protein to human B7-H1 expressed on surface of ES-2 cells was evaluated. Briefly, 50000 cells/well were plated in 50 ⁇ of PBS into wells of a 384-well tissue culture plate (Corning Costar, catalog # 3712). Next, 50 ⁇ /well of a diluted monoclonal antibody was added at final concentration of 2.5, 0.5, 0.1, 0.02, 0.004, 0.008, 0.00016 nM and plates were incubated at 4C for 1 hour.
- Biotinylated human PD-l/Fc protein (10 ug/ml, R&D Systems, catalog #1086-PD) was added and plates were incubated at 4C for 1 hour.
- EXAMPLE 9 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES
- CD3-coated beads/ml were further coupled with recombinant human IgGlFc (R&D Systems, cat# l lO-HG-100) at 160 ug/ml or with the recombinant human B7-Hl/Fc protein (R&D Systems, Cat# 156-B7-100) at 80 ug/ml combined with the human IgGlFc protein at 80 ug/ml (total concentration 160 ug/ml) and incubated at 37°C for 24 hours with shaking.
- human IgGlFc R&D Systems, cat# l lO-HG-100
- B7-Hl/Fc protein R&D Systems, Cat# 156-B7-100
- the beads were then incubated in PBS containing 0.05% bovine serum albumin at room temperature for 1 hour, washed four times in 0.1% BSA and 2mM EDTA in PBS (pH7.4) and finally resuspended in RPMI1640 media containing 10% FBS at 5x10(7) beads/ml.
- Peripheral blood monocytes were isolated from a leukapheresis pack using Ficoll-Paque
- T cells were plated at 10(5) cells/80 ul/well in 96-well plate (Corning, cat#3603) and bead-antibody mix was added at 20ul/well to a total volume of 100 ul/well.
- T cell activation in the absence of B7-H1 inhibitory effect was determined using beads coated with anti-CD3 antibody and the human IgGlFc protein.
- Cells were cultured for 5 days and supernatants were harvested and analyzed for IFN- ⁇ release by using BD Human IFN- ⁇ ELISA Kit II (BD Cat. No.550612) per manufacturer's instructions. Cell proliferation was measured on day 5 by the addition of ⁇ /well of AlamarBlue (Invitrogen DAL 1025).
- EXAMPLE 10 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON ACTIVATION OF CD4 T CELLS IN DENDRITIC CELL-T-CELL MIXED
- Dendritic cells were generated from monocytic precursors as described previously (Curr Protoc Immunol. 2001 May; Chapter 7: Unit 7.32).
- Peripheral blood monocytes were isolated from a leukapheresis pack using Ficoll-Paque Plus (GE Healthcare 17-1440-03) density gradient centrifugation, resuspended in serum-free RPMI 1640 (Gibco 22400-089), and allowed to adhere to T150 cell culture flasks (Corning 430825).
- the nonadherent cells were removed and the cells were cultured in RPMI supplemented with 5% human serum (Invitrogen 34005100).
- Cytokines were added at a final concentration of 2ng/ml GM-CSF (BD Biosciences 550068) and lOng/ml IL-4 (BD Biosciences 554605).
- Fresh media with cytokines was added every 2 - 3 days.
- cells were matured with 20ng/ml of TNF-a (BD Biosciences 554618) and allowed to incubate for 24 hours. Mature dendritic cells were harvested, phenotyped, and frozen for later use.
- CD4+ T-cells were isolated from PBMC using a magnetic isolation kit (Dynal 113.17) per manufacturer's instructions and cultured in a primary MLR as described previously (J Immunol. 2003 Apr l;170(7):3637-44).
- 1.5E5 allogeneic CD4+ responding T-cells were cultured in 96 well-flat bottom microtiter plates (Costar 3595) with dendritic cells at a T-cell: dendritic cell ratio of 1 :2.5.
- Dendritic cell preparations were treated with 100 ⁇ g/ml of mitomycin C (Sigma M4287) prior to addition to coculture to prevent any proliferation from contaminating lymphocytes.
- Antibodies were added at various concentrations in a final volume of 200 ⁇ 1 of RPMI + 10% human serum. Thymidine incorporation was measured on Day 5 by a 16-h pulse with [ 3 H] thymidine ( ⁇ ⁇ , Perkin-Elmer NET027001MC). Supernatants were harvested prior to radioactive labeling and analyzed for IFN- ⁇ release by Luminex assay (BioRad 171 -Bl 1921) per manufacturer's instructions. Enhancement of T-cell proliferation by anti-B7-Hl antibodies from repeat experiments is shown in Figure 2. Corresponding IFN- ⁇ release is shown in Figure 3.
- the heavy chain variable domain sequences and the light chain variable domain sequence s of the antibodies were sequenced to determine their DNA sequences.
- the complete sequence information for the anti-B7-Hl antibodies is provided in the sequence listing with nucleotide and amino acid sequences for each gamma and kappa or lambda chain combination.
- the variable heavy sequences were analyzed to determine the VH family and the J-region sequence.
- the sequences were then translated to determine the primary amino acid sequence and compared to the germline VH and J-region sequences to assess somatic hypermutations.
- Tables 8 and 9 are tables comparing the antibody heavy chain regions to their cognate germline heavy chain region and the antibody light chain regions to their cognate germline light chain region.
- the amino acid numbering is by numerical numbering.
- Immunoglobulin genes undergo various modifications during maturation of the immune response, including recombination between V, D and J gene segments, isotype switching, and hypermutation in the variable regions. Recombination and somatic hypermutation are the foundation for generation of antibody diversity and affinity maturation, but they can also generate sequence liabilities that may make commercial production of such immunoglobulins as therapeutic agents difficult, or increase the immunogenicity risk of the antibody.
- mutations in CDR regions are likely to contribute to improved affinity and function, while mutations in framework regions may increase the risk of immunogenicity. This risk can be reduced by reverting framework mutations to germline, while ensuring that activity of the antibody is not adversely impacted.
- Some structural liabilities may be generated by the diversification processes, or they may exist within germline sequences contributing to the heavy and light chain variable domains. Regardless of the source, it may be desirable to remove potential structural liabilities that may result in instability, aggregation, heterogeneity of product, or increased immunogenicity. Examples of undesirable liabilities include unpaired cysteines (which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation), N-linked glycosylation sites (resulting in heterogeneity of structure and activity), as well as deamidation (e.g. NG, NS), isomerization (DG), oxidation (exposed methionine), and hydrolysis (DP) sites.
- unpaired cysteines which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation
- N-linked glycosylation sites resulting in heterogeneity of structure and activity
- deamidation e.g. NG, NS
- DG isomerization
- the antibody sequence can be mutated back to the germline sequence.
- Such corrective mutations can occur at one, two, three or more positions, or a combination of any of the mutated positions, using standard molecular biological techniques.
- Tables 10-14 below illustrate the positions of such variations back to germline for mAb 2.9D10, 2.7A4 and 2.14H9. Each row represents a unique combination of germline and non-germline residues at the position indicated by bold type. The position of the amino acid is representated by numerical numbering.
- the invention includes replacing any structural liabilities in the sequence that might affect the heterogeneity of the antibodies of the invention.
- Such liabilities include glycosylation sites, un-paired cysteines, surface exposed methinones, etc.
- changes are made to remove one or more of such structural liabilities.
- N-linked glycosylation sites it may be desirable to remove one or more consensus N-linked glycosylation sites from the antibody germline or antibody sequence.
- an N-linked glycosylation consensus site sequence has the sequence of Asn-any AA- Ser or Thr where the middle amino acid cannot be a proline (Pro).
- unpaired cysteines can be replaced alone or in conjunction with other structural changes. An unpaired cysteine can be mutated to an appropriate amino acid that has comparable side chain properties such as a serine.
- a sequence that is optimized is a sequence which has been mutated at one or more positions back to its germline sequence or can be modified to remove one or more other liabilities such as structural liabilities.
- An optimized sequence can also include a sequence that has been mutated at one or more positions back to its germline sequence and which has also been further modified to remove one or more structural liabilities.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 2.
- SEQ ID NO.: 2 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 10.
- SEQ ID NO: 2 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 10.
- SEQ ID NO.: 2 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 10.
- the non germline sequence is mutated back to germline at position 80 where F is changed to a Y and at position 87 where K is changed to an R.
- a specific example of such a sequence is 2.7A4VHOPT as shown in Table 15.
- Table 11 Exemplary Mutations of 2.7A4 Light Chain (SEQ ID NO: 7) to Germline at the Indicated Residue Number
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 7.
- SEQ ID NO.: 7 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 11.
- SEQ ID NO: 7 comprises any one, any two, any three, any four, any five, or all five of the germline residues as indicated in Table 11.
- SEQ ID NO.: 7 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 11.
- 2.7A4 variable light domain which has been mutated to particular germline sequences include 2.7A4 VLOPT (optimized where the non- germline sequence has been mutated from an A to a T at position 17 and a R to a K at position 104) as shown in Table 15.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 12.
- SEQ ID NO.: 12 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 12.
- SEQ ID NO: 12 comprises any one, any two, or all two of the germline residues as indicated in Table 12.
- SEQ ID NO.: 12 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 12.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 17.
- SEQ ID NO.: 17 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 13.
- SEQ ID NO: 17 comprises any one, any two, any three, any four, or all four of the germline residues as indicated in Table 7.
- SEQ ID NO.: 17 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 13.
- SEQ ID NO: 17 can be altered or further altered by making nongermlining changes to SEQ ID NO: 17. In one example, SEQ ID NO: 17 can be altered such that from a F to a Y at position 37 and from a F to a Y at position 50.
- the targeted binding agent or antibody comprises a sequence comprising SEQ ID NO.: 27.
- SEQ ID NO.: 27 comprises any one of the combinations of germline and non-germline residues indicated by each row of Table 14.
- SEQ ID NO: 27 comprises any one, any two, any three, or all three of the germline residues as indicated in Table 14.
- SEQ ID NO.: 27 comprises any one of the unique combinations of germline and non-germline residues indicated by each row of Table 14.
- the heavy chain of 2.14H9 can be changed at amino acid 31 of SEQ ID NO:22 from a R to a S.
- Germlining of these amino acid residues was carried out using standard site directed mutagenesis techniques with the appropriate mutagenic primers.
- the germlined sequences have the prefix "OPT" after the antibody name, for example, 2.7A4VHOPT, 2.7VLOPT and 2.14H9VLOPT.
- Germlined IgG were then re-evaluated in the human B7-Hl/hPDl ligand inhibition assay to confirm there had not been a reduction in antibody in vitro activity.
- Example of gene synthesis and reformatting as IgGl and IgGl-TM Clones were converted from scFv to IgG format by sub-cloning the VH and VL domains into vectors expressing whole antibody heavy and light chains respectively.
- the VH domains were cloned into the vector pEU15.1 to express IgGl or the vector pEU15.1-TM to express IgGl-TM antibodies.
- Both vectors contain the human heavy chain constant domains and regulatory elements to express whole IgG heavy chain in mammalian cells.
- the vector pEU15.1- TM is a modified pEU15.1 human IgGl vector.
- VL domains were cloned into pEU4.4 and pEU3.4 vectors for the expression of the human lambda and kappa light chain constant domains respectively, with regulatory elements to express whole IgG light chain in mammalian cells.
- Vectors for the expression of heavy chains and light chains were originally described in Vaughan et al. (Nature Biotechnology 14(3):309- 314, 1996). These vectors have been engineered simply by introducing an OriP element.
- IgGs the heavy and light chain IgG expression vectors were transfected into EBNA-HEK293 mammalian cells (Invitrogen R620-07). IgGs were expressed and secreted into the medium. Harvests were pooled and spun down prior to purification. The IgG was purified using Protein A chromatography using an AKTA Express purification system (GE Healthcare) previously sanitised to avoid any endotoxin contamination of the sample. Culture supernatants are loaded onto lmL HiTrapTM MabSelectSureTM columns (GE Healthcare, 11-0034-93) and washed with 50 mM Tris-HCl pH 8.0, 250 mM NaCl.
- AKTA Express purification system GE Healthcare
- Bound IgG was eluted from the column using 0.1 M Sodium Citrate (pH 3.0) and neutralised by the addition of 1M Tris-HCl (pH 9.0). The eluted material was buffer exchanged into PBS using Nap 10 columns (Amersham, 17-0854- 02) and filtered before determining protein concentration and endotoxin levels. IgG concentration was determined spectrophotometrically using an extinction coefficient based on the amino acid sequence of the IgG (Vaughan et al. supra).
- Endotoxin level was determined using the Endosafe PTS Portable Test System (Charles River Laboratories) fitted with 1-0.1 EU/mL and 10- O.lEU/mL LAL cartridges (Charles River Laboratories, PT520). The purified IgG were analysed for degradation by SDS-PAGE.
- Anti-B7-Hl antibodies in the IgGl-TM format were evaluated and compared to the same antibodies but in the IgGl format in the human B7-Hl/hPDl ligand inhibition assay to confirm there had not been a reduction in antibody in vitro activity due to IgG isotype switching ( Figure 4) ⁇
- EXAMPLE 12 HUMAN B7H1/FC BINDING HUMAN PD1/FC - HTRF® ASSAY
- the assay described is a homogenous TR-FRET assay using HTRF ® assay technology requiring no wash steps.
- To a Costar 3676 microtitre plate 5 ⁇ 1 ⁇ 11 of biotinylated PDl/Fc at InM diluted into PBS was added. This was followed with the addition of 5 ⁇ 1 ⁇ 11 streptavidin XL ent (CisBio) at 4nM diluted into assay buffer (PBS + 0.1% BSA + 0.8M KF). 5 ⁇ 1 ⁇ 11 of a titration of sample material diluted in PBS was added to relevant wells. For the definition of total binding, 5 ⁇ 1 of PBS or relevant sample buffer was added per well.
- Example of IC50 determinations in the human PDl/human B7-H1 ligand inhibition assay for anti-B7-Hl antibodies are provided in Table 19. All anti-human B7-H1 antibodies are in the IgGl-TM format.
- EXAMPLE 13 HUMAN B7H1/FC BINDING HUMAN B7-1/FC - HTRF ® ASSAY
- the assay described was a homogenous TR-FRET assay using HTRF ® assay technology requiring no wash steps.
- To a Costar 3676 microtitre plate 5 ⁇ 1 ⁇ 11 of biotinylated B7-1/Fc at 8nM diluted into PBS was added. This was followed with the addition of 5 ⁇ 1 ⁇ 11 streptavidin XL ent (CisBio) at 20nM diluted into assay buffer (PBS + 0.1% BSA + 0.8M KF). 5 ⁇ 1 ⁇ 11 of a titration of sample material diluted in PBS was added to relevant wells. For the definition of total binding, 5 ⁇ 1 of PBS or relevant sample buffer per well was added.
- EXAMPLE 14 CROSS REACTIVITY OF ANTI-B7-H1 ANTIBODIES WITH OTHER
- ELISAs were performed to determine the cross-reactivity of the anti-B7-Hl IgGl-TM antibodies for other immune co-modulatory molecules.
- the ELISAs consisted of coating MaxiSorp plates (NUNC) at 4° C overnight with 250ng per well of the extracellular domain (ECD) of human B7-H1 (R&D Systems, 156-B7), human PD-L2 (R&D Systems, 1224-PL), human B7-H2 (R&D Systems, 165-B7), human B7-H3 (R&D Systems, 1027-B3), human CD28 (R&D Systems, 342-CD), human CTLA-4 (R&D Systems, 325-CT) and human PD1 (R&D Systems, 1086-PD) followed by blocking the plates with PBS containing 3% dried milk powder at room temperature for lh.
- NUNC MaxiSorp plates
- Murine cross reactivity was also investigated by coating the ECD of murine B7-H1 (R&D Systems, 1019-B7).
- Biotinylated anti-B7-Hl IgGl-TM diluted at ⁇ in PBS containing 3% dried milk powder, were incubated at room temperature for 2h to allow binding. Bound biotinylated IgGs were detected with europium Nl -labelled streptavidin (Perkin Elmer, 1244-360) at 0.2ug/mL.
- Control experiment demonstrating antigen coating to the NUNC plate was performed using the commercial antibodies mouse IgG2a anti-human B7-H1 (R&D Systems, MAB156), mouse IgG2b anti-human PD-L2 (R&D Systems, MAB1224), mouse IgG2b anti-human B7-H2 (R&D Systems, MAB165), mouse IgGl anti-human B7-H3 (R&D Systems, MAB1027), mouse IgGl anti-human CD28 (R&D Systems, MAB342), mouse IgG2a anti-human CTLA-4 (Abeam, ab33320), mouse IgG2b anti-human PD1 (R&D Systems, MAB1086) and rat IgG2a anti-mouse B7-H1 (R&D Systems, MAB1019).
- mouse IgG2a anti-human B7-H1 R&D Systems, MAB156
- mouse IgG2b anti-human PD-L2 R&D Systems, MA
- the cross-reactivity of the 3 anti-B7-Hl IgGl-TM antibodies 2.7A40PT, 2.9D10 and 2.14H90PT to the panel of eight immune co-modulatory antigens were determined in triplicate. At lOOnM of antibody concentration, all three anti-B7-Hl antibodies show no cross reactivity for any of the seven human immune co-modulatory molecules we tested ( Figure 5).
- the IgGl-TM anti-B7-Hl antibody 2.7A40PT displays a measurable cross reactivity for murine B7-H1 with a signal level of 5.3% on average compared to 100% binding to the human B7-H1.
- the other two anti-B7-Hl antibodies tested, 2.9D10 and 2.14H90PT do not show any cross reactivity for murine B7-H1 ( Figure 5).
- EXAMPLE 15 AFFINITY OF ANTI-B7-H1 ANTIBODIES FOR HUMAN AND
- the binding affinity and kinetic parameters of anti-B7-Hl antibodies in the IgGl-TM format to monomeric human and cynomologus B7-H1 were determined by surface plasmon resonance using a BIAcore T100 instrument (BIAcore, Uppsala, Sweden). In brief, experiments were performed at 25°C using HBS-EP buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% v/v surfactant P20) as running buffer.
- IgGs were affinity captured on the surface of a CM5 sensor chip (BIAcore) via protein G, which was amine coupled onto the CM5 surface to achieve the density of -500 Response Units (RU), according to the manufacturer's instructions (BIAapplications Handbook, BIAcore).
- Recombinant monomeric human or cynomologus B7-H1 FlagHisio extracellular domains (ECDs) were used as analytes. Dilutions of B7-H1 ECD (200- 3.12 nM) in the running buffer were injected at a constant flow rate of 100 ⁇ /min for 60 seconds.
- Hl is InM and 175pM respectively (Table 21).
- Affinity of anti-B7-Hl antibodies 2.7A40PT and 2.14H90PT for monomeric cynomologus B7-H1 is 835pM and 367pM respectively (Table 22). Those two antibodies are strongly cross reactive for cynomologus B7-H1 as affinities are very close to the ones for human B7-H1.
- Table 22 Affinity and kinetic parameters analysis of anti-B7-Hl antibodies for binding to cynomologus B7-H1 Reference Antibody #1 4.64 1.36xl0 6 0.0063
- EXAMPLE 16 EPITOPE MAPPING OF ANTI-B7-H1 ANTIBODIES
- Anti-B7-Hl antibodies are competing for the binding of human B7-H1 to human PD1 (Example 5, 8 and 12) so they should interact with some of those 14 residues if we assume that there are negligible differences between the B7H1 binding interface to human and mouse PD1 (62% amino acid identity between the two species extracellular domain sequence). Single amino acid B7-H1 mutants will be generated for all the 14 positions described in Table 23. Mutants will be tested for binding to anti-B7-Hl antibodies by phage ELISA and the ability to compete the binding of anti-B7-Hl antibodies to human B7-H1 in HTRF ® competition assays. All anti-B7-Hl antibodies described are in the IgGl-TM format. Cloning of the human B7-H1 extracellular domain gene in fusion with bacteriophage gene III for phage display expression
- B7H1 REV 5 '-AATAATGCGGCCGCCCTTTCGTTTGGGGGATGC-3 '
- PCR product has then been directionally cloned in the pCANTAB6 vector (McCafferty J. et al, 1994, Appl. Biochem. BiotechnoL, Vol. 47, pl57- 173) using Sfi I and Not I restriction sites.
- E. coli strain TGI were transformed with the ligation and individual colonies were screened by sequencing to identify a B7-H1 transformant named B7-Hl_pCANTA6.
- B7-H1 mutants have been generated by saturation mutagenesis at all the 14 residues of the PD1 interface using fully randomised NNS primers (Table 24) and the plasmid B7- Hl_pCANTA6 as DNA template. Mutagenesis was performed with the Stratagene's QuickChange Multi Site-Directed Mutagenesis Kit (Catalog #200513) according to the manufacturer's instructions. Mutagenic reactions were used to transform E. coli strain TGI and individual colonies were screened by sequencing to identify B7-H1 variants. A total of 252 variants were identified among the 280 possible (20 amino acids time 14 positions) and cherry picked in 3 96-wells culture plates.
- Binding of the B7-H1 mutants to anti-B7-Hl antibodies 2.14H90PT, 2.7A40PT or Reference Ab#l have been assessed by phage ELISA after assuring that the B7-H1 extracellular domain in fusion with gene III protein could be displayed at the phage surface.
- Cherry picked TGI cultures were grown and superinfected with M13K07 helper phage to produce phage particles displaying B7-H1 mutants at their surface.
- Phage supernatants were blocked in PBS+3% skimmed milk and incubated in NUNC MaxiSorb plates previously coated overnight with lug/mL 2.14H90PT, 2.7A40PT or Reference antibody#l in PBS and blocked with PBS+3% skimmed milk.
- Bound phages were detected using streptavidin coupled with europium (Perkin Elmer) after incubation with a biotinylated anti-M13 secondary antibody (Progen).
- Extracellular domain of human B7-H1 wild-type and mutants were expressed in bacteria and purified by affinity chromatography as previously described (Bannister D. et ah, 2006, Biotechnology and bioengineering, 94, 931-937).
- the HTRF® competition assays measured the binding of anti-B7-Hl antibody to HIS FLAG tagged B7-H1. Titration of non tagged B7-H1 samples, prepared as described above, will compete with HIS FLAG tagged B7-H1 for binding to anti-B7-Hl antibody, leading to a reduction in assay signal.
- the antibodies 2.14H90PT, 2.7A40PT and Reference antibody#l were used to establish competition assays for characterising the relative binding of purified wild- type or mutants B7-H1. This will confirm which B7-H1 residues are required for antibody binding. 10 ⁇ of B7-H1 sample was added to a 384 well low volume assay plate (Corning 3673).
- B7-H1 sample 2.14H90PT IgGLTM 2.7A40PT IgGLTM Reference Ab#1 wild-type B7H1 0.76 2.79 1.89
- B7H1 R125S No inhibition 2.7 9.7 Argl 13 and Argl 25 are strongly involved in the binding to 2.14H90PT.
- Replacement by an Ala or other amino acids (Tyr or Leu at position 113 and Gin or Ser at position 125) lead to a total lost of binding to that antibody.
- Binding profile of those B7-H1 mutants to 2.7A40PT or Reference antibody#l is similar to the wild-type B7-H1. This shows that the lost of binding is not due to a general structural modification of B7-H1 as for instance an unfolded protein but to a direct involvement of those residues with 2.14H90PT binding.
- Phel9, Thr20 and Aspl22 are strongly involved in the binding to 2.7A40PT. All B7-H1 mutants at those positions have no binding to that antibody but do bind 2.14H90PT or Reference antibody#l in a similar way to wild-type B7-H1, excepted B7H1 D122E mutant which binds those 2 antibodies less efficiently. Those three residues are specifics to the 2.7A40PT mAb binding epitope and are not shared by the 2.14H90PT or the Reference antibody#l epitopes. Argl 13 is also involved in the 2.7A40PT epitope but to a lesser extend. Replacement by an Ala does not affect the binding to that antibody but a Tyr or Leu mutations lead to a total lost of binding.
- EXAMPLE 17 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON A MEMORY T-CELL RESPONSE TO SUB-OPTIMAL CONCENTRATIONS OF A
- PBMCs Peripheral blood monocytes
- PBMCs Peripheral blood monocytes
- RPMI 1640 Glutamax I media Glutamax I media
- pen/strep GBCO,. 15140
- Human AB Serum Human AB Serum
- tetanus toxoid (Calbiochem582231) at a density of 1x105 cells per well.
- anti-B7-Hl antibodies in the IgGl-TM format or isotype control were added at the indicated concentrations and cultures returned to 37°C for a further 2 days, at which point supematants were harvested and analysed by DELFIA for levels of interferon- ⁇ . Enhancement of interferon- ⁇ release by anti-B7-Hl antibodies is shown in Figure 6.
- Anti-B7-Hl antibodies 2.9D10, 2.7A40PT and 2.14H90PT are able to increase the release of Interferon- ⁇ . This data confirms the ability of 2.9D10, 2.7A40PT and 2.14H90PT to enhance antigen specific T-cell responses.
- EXAMPLE 18 DETERMINATION OF THE EFFECTS OF ANTI-B7-H1 ANTIBODIES ON A MEMORY T-CELL RESPONSE TO OPTIMAL CONCENTRATIONS OF A
- PBMCs Peripheral blood monocytes
- Ficoll-Paque Plus GE Healthcare 17-1440-03 density gradient centrifugation as per manufacturers instructions. Following isolation cells were resuspended in RPMI 1640 Glutamax I media (GIBCO,.61870) supplemented with 1% pen/strep (GIBCO,.
- mice The in-vivo activity of anti-human B7-H1 antibodies was investigated in xenograft mouse models using immunocompromised NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice.
- the mice were engrafted subcutaneously (SC) with human cancer cell lines expressing human B7-H1 and human CD4+ and CD8+ T cells that were isolated from peripheral blood mononuclear cells of healthy donors and cultured to enrich for alloreactive effector T cells.
- Intraperiteneal (IP) doses of anti-human B7-H1 antibodies were given to mice inoculated with the human pancreatic cancer cell line HP AC or the human melanoma cell line A375.
- Enriched CD4+ and CD8+ T cells were cultured separately for 7- 10 days in medium supplemented with rhIL-2 and each combined with mitomyosin C treated A375 or HP AC cells. T cells were collected and separately cultured again for 7-10 days in medium supplemented with rhIL-2 and combined with mitomyosin C treated A375 or HPAC cells. CD4+ and CD8+ T cells were collected and combined at a 1 : 1 ratio.
- A375 and HPAC cancer cell lines and PBMC enriched for CD4+ and CD8+ T cells were mixed immediately before subcutaneous (SC) administration at the indicated effector-to-target (E:T) ratios.
- the inoculation number of cells for each cancer cell line was predetermined by empirical tumor forming dose studies; in general, 2.5 x 10 6 cells in a total volume of 0.2 mL were engrafted into each animal.
- IgGlTM isotype control human IgG2a or IgGlOPT (also referred to herein as "IgGlTM") antibody or the anti- B7-H1 antibodies 2.14H9 IgG2a, 2.14H90PT, 2.7A40PT or Reference antibody#l in the IgGlOPT format.
- IgGlTM isotype control human IgG2a or IgGlOPT
- Anti-B7-H1 antibodies 2.14H9 IgG2a, 2.14H90PT, 2.7A40PT or Reference antibody#l in the IgGlOPT format.
- the first dose (200 ⁇ ) of test article was administered IP 1 hour after engraftment of cancer/effector T cells; the animals received up to 4 additional doses of the test article on study days 3, 5, 8 and/or 10.
- rhIL-2 was administered IP 1 hour after engraftment of cancer/effector T cells; the animals received 4 additional daily doses of rhIL-2 for 4 consecutive days.
- the formation of tumor was observed in each animal one or two times a week. Tumors were measured by caliper; tumor volumes (V) were calculated using the following formula:
- TGI tumor growth inhibition
- % TGI [1 - (mean tumor V of treatment group) ⁇ (mean tumor V of control group)] x 100.
- Table 26 Study 1 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
- anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of HPAC (pancreas) cancer cells at day 30 by up to 60%> as compared to the isotype control group ( Figure 10 and Table 28).
- Table 28 Study 3 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
- Table 29 Study 4 - Treatment groups and percent Tumor Growth Inhibition in mice engrafted with HP AC cancer cells following intravenous administration of anti-B7-Hl antibodies
- IP administration of 2.14H9 IgG2a or 2.70PT anti-B7-Hl antibodies in the A375 (melanoma) xenograft model also significantly inhibited tumor growth at day 29 by as much as 64% and 61% respectively as compared to the isotype control group ( Figure 12 and Table 30).
- Table 30 Study-5. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies
- anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 77% as compared to the isotype control group ( Figure 13 and Table 31).
- Table 31 Study-6. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies Group Test Article Dose (mg/kg/mouse) % TGI at day 25
- anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 82% as compared to the isotype control group ( Figure 14 and Table 32).
- anti-B7-Hl antibody 2.14H90PT significantly inhibited the growth of A375 (melanoma) cancer cells when combined with T cells at day 25 by up to 93% as compared to the isotype control group ( Figure 15 and Table 33).
- Table 33 Study-8. Treatment groups and percent Tumor Growth Inhibition in mice engrafted with A375 cancer cells following intravenous administration of anti-B7-Hl antibodies
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Oncology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Hematology (AREA)
- Biotechnology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (42)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10833923.5A EP2504364B1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
CA2778714A CA2778714C (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
EP17179204.7A EP3279215B1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
KR1020157031862A KR101740171B1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
CN201080053042.1A CN102918058B (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against B7-H1 |
LTEP10833923.5T LT2504364T (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
AU2010324757A AU2010324757C1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against B7-H1 |
NZ599405A NZ599405A (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
ES10833923.5T ES2646863T3 (en) | 2009-11-24 | 2010-11-24 | B7-H1 specific binding agents |
MX2015000738A MX343747B (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1. |
KR1020177011850A KR101790767B1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
PL10833923T PL2504364T3 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
NO10833923A NO2504364T3 (en) | 2009-11-24 | 2010-11-24 | |
JP2012540171A JP5837504B2 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agent for B7-H1 |
US13/511,538 US8779108B2 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against B7-H1 |
RU2012126138A RU2571204C3 (en) | 2009-11-24 | 2010-11-24 | SPECIFIC BINDING AGENTS AGAINST B7-H1 |
BR122021025338-2A BR122021025338B1 (en) | 2009-11-24 | 2010-11-24 | ISOLATED ANTIBODY OR BINDING FRAGMENT THEREOF AGAINST B7-H1, PHARMACEUTICAL COMPOSITION AND ITS USES |
RS20171053A RS56469B1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
BR112012012465-0A BR112012012465B1 (en) | 2009-11-24 | 2010-11-24 | ISOLATED ANTIBODY OR BINDING FRAGMENT THEREOF WHICH SPECIFICALLY BINDS HUMAN B7-H1, COMPOSITION COMPRISING THE SAME AND USES |
KR1020177030381A KR101934071B1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
MX2016015254A MX359551B (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1. |
MX2012005809A MX2012005809A (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1. |
PL17179204T PL3279215T3 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
SI201031562T SI2504364T1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
DK10833923.5T DK2504364T3 (en) | 2009-11-24 | 2010-11-24 | TARGETED BINDING AGENTS B7-H1 |
IL219876A IL219876A (en) | 2009-11-24 | 2012-05-17 | Antibody or fragment thereof against human b7-h1, compositions comprising same and use thereof in the preparation of medicaments |
US14/271,108 US9493565B2 (en) | 2009-11-24 | 2014-05-06 | Targeted binding agents against B7-H1 |
IL243813A IL243813A (en) | 2009-11-24 | 2016-01-28 | Targeted binding agents against b7-h1 |
AU2016203758A AU2016203758C1 (en) | 2009-11-24 | 2016-06-06 | Targeted binding agents against b7-h1 |
US15/333,683 US10400039B2 (en) | 2009-11-24 | 2016-10-25 | Targeted binding agents against B7-H1 |
HRP20171653TT HRP20171653T1 (en) | 2009-11-24 | 2017-10-30 | Targeted binding agents against b7-h1 |
CY20171101127T CY1119743T1 (en) | 2009-11-24 | 2017-10-30 | TARGETED CONNECTIVE FACTORS AGAINST B7-H1 |
FR19C1001C FR19C1001I2 (en) | 2009-11-24 | 2019-01-09 | TARGET LIAISON AGENTS DIRECTED AGAINST B7-H1 |
LTPA2019002C LTC2504364I2 (en) | 2009-11-24 | 2019-01-09 | Target binding agents against B7-H1 |
LU00097C LUC00097I2 (en) | 2009-11-24 | 2019-01-14 | |
HUS1900002C HUS1900002I1 (en) | 2009-11-24 | 2019-01-14 | Targeted binding agents against b7-h1 |
NL300964C NL300964I2 (en) | 2009-11-24 | 2019-01-14 | Durvalumab |
NO2019002C NO2019002I1 (en) | 2009-11-24 | 2019-01-14 | |
CY2019003C CY2019003I2 (en) | 2009-11-24 | 2019-01-14 | TARGETED BINDING AGENTS AGAINST B7-H1 |
US16/519,614 US11518809B2 (en) | 2009-11-24 | 2019-07-23 | Targeted binding agents against B7-H1 |
CY20201100370T CY1122816T1 (en) | 2009-11-24 | 2020-04-22 | TARGETED BINDING AGENTS AGAINST B7-H1 |
US18/051,773 US20230235062A1 (en) | 2009-11-24 | 2022-11-01 | Targeted binding agents against b7-h1 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26406109P | 2009-11-24 | 2009-11-24 | |
US61/264,061 | 2009-11-24 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/511,538 A-371-Of-International US8779108B2 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against B7-H1 |
US14/271,108 Continuation US9493565B2 (en) | 2009-11-24 | 2014-05-06 | Targeted binding agents against B7-H1 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011066389A1 true WO2011066389A1 (en) | 2011-06-03 |
Family
ID=44066905
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2010/058007 WO2011066389A1 (en) | 2009-11-24 | 2010-11-24 | Targeted binding agents against b7-h1 |
Country Status (28)
Country | Link |
---|---|
US (5) | US8779108B2 (en) |
EP (2) | EP3279215B1 (en) |
JP (5) | JP5837504B2 (en) |
KR (4) | KR101573109B1 (en) |
CN (2) | CN102918058B (en) |
AU (2) | AU2010324757C1 (en) |
BR (2) | BR122021025338B1 (en) |
CA (2) | CA2992770A1 (en) |
CY (3) | CY1119743T1 (en) |
DK (2) | DK3279215T3 (en) |
ES (2) | ES2646863T3 (en) |
FR (1) | FR19C1001I2 (en) |
HK (1) | HK1246310A1 (en) |
HR (2) | HRP20171653T1 (en) |
HU (3) | HUE037159T2 (en) |
IL (2) | IL219876A (en) |
LT (3) | LT3279215T (en) |
LU (1) | LUC00097I2 (en) |
MX (3) | MX2012005809A (en) |
NL (1) | NL300964I2 (en) |
NO (2) | NO2504364T3 (en) |
NZ (2) | NZ599405A (en) |
PL (2) | PL2504364T3 (en) |
PT (2) | PT3279215T (en) |
RS (2) | RS56469B1 (en) |
RU (2) | RU2571204C3 (en) |
SI (2) | SI2504364T1 (en) |
WO (1) | WO2011066389A1 (en) |
Cited By (550)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013079174A1 (en) | 2011-11-28 | 2013-06-06 | Merck Patent Gmbh | Anti-pd-l1 antibodies and uses thereof |
WO2014008218A1 (en) | 2012-07-02 | 2014-01-09 | Bristol-Myers Squibb Company | Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof |
WO2014055648A1 (en) | 2012-10-02 | 2014-04-10 | Bristol-Myers Squibb Company | Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer |
WO2015016718A1 (en) | 2013-08-02 | 2015-02-05 | Bionovion Holding B.V. | Combining cd27 agonists and immune checkpoint inhibition for immune stimulation |
WO2015033303A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | Cyclic peptidomimetic compounds as immunomodulators |
WO2015033299A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
WO2015033301A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
WO2015036499A1 (en) * | 2013-09-11 | 2015-03-19 | Medimmune Limited | Anti-b7-h1 antibodies for treating tumors |
WO2015036511A1 (en) * | 2013-09-12 | 2015-03-19 | F. Hoffmann-La Roche Ag | Combination therapy of antibodies against human csf-1r and antibodies against human pd-l1 |
WO2015042246A1 (en) | 2013-09-20 | 2015-03-26 | Bristol-Myers Squibb Company | Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors |
WO2015095410A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody |
WO2015095423A2 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
WO2015095418A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
JP2015519375A (en) * | 2012-05-31 | 2015-07-09 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | Antigen binding protein that binds to PD-L1 |
WO2015112805A1 (en) | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-l1 |
EP2903641A2 (en) * | 2012-10-04 | 2015-08-12 | Dana-Farber Cancer Institute, Inc. | Human monoclonal anti-pd-l1 antibodies and methods of use |
CN104830788A (en) * | 2015-05-05 | 2015-08-12 | 杨光华 | DC cell based on HBV-HCV antigen, targeting immune cell population, preparation method and applications thereof |
KR20150094674A (en) * | 2012-12-11 | 2015-08-19 | 알버트 아인슈타인 컬리지 오브 메디신 오브 예쉬바 유니버시티 | Methods for high throughput receptor:ligand identification |
DE202014010421U1 (en) | 2013-12-17 | 2015-11-12 | Kymab Limited | Human goals |
US9192667B2 (en) | 2013-04-22 | 2015-11-24 | Hoffmann-La Roche Inc. | Method of treating cancer by administering CSF-1R antibodies and a TLR9 agonist |
US20150344577A1 (en) * | 2013-01-11 | 2015-12-03 | Dingfu Biotarget Co., Ltd | Agents for treating tumors, use and method thereof |
WO2015187835A2 (en) | 2014-06-06 | 2015-12-10 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
US9212224B2 (en) | 2012-05-15 | 2015-12-15 | Bristol-Myers Squibb Company | Antibodies that bind PD-L1 and uses thereof |
WO2015195163A1 (en) * | 2014-06-20 | 2015-12-23 | R-Pharm Overseas, Inc. | Pd-l1 antagonist fully human antibody |
WO2016007235A1 (en) | 2014-07-11 | 2016-01-14 | Genentech, Inc. | Anti-pd-l1 antibodies and diagnostic uses thereof |
WO2016004876A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
WO2016011160A1 (en) | 2014-07-15 | 2016-01-21 | Genentech, Inc. | Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors |
US20160031990A1 (en) * | 2014-05-29 | 2016-02-04 | Medlmmune, Llc | Antagonists of pdl-1 and pd-1 for the treatment of hpv-negative cancers |
JP2016504336A (en) * | 2012-12-21 | 2016-02-12 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Antibody binding to human programmed death ligand 1 (PD-L1) |
WO2016030455A1 (en) | 2014-08-28 | 2016-03-03 | Medimmune Limited | Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small lung cancer |
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) |
WO2016081384A1 (en) | 2014-11-17 | 2016-05-26 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
WO2016081748A2 (en) | 2014-11-21 | 2016-05-26 | Bristol-Myers Squibb Company | Antibodies against cd73 and uses thereof |
WO2016090300A1 (en) | 2014-12-05 | 2016-06-09 | Genentech, Inc. | Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists |
WO2016094481A1 (en) * | 2014-12-09 | 2016-06-16 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized cluster of differentiation 274 gene |
WO2016111645A1 (en) * | 2015-01-09 | 2016-07-14 | Agency For Science, Technology And Research | Anti-pd-l1 antibodies |
WO2016127052A1 (en) | 2015-02-05 | 2016-08-11 | Bristol-Myers Squibb Company | Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy |
WO2016142833A1 (en) | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
WO2016146259A1 (en) | 2015-03-16 | 2016-09-22 | Amal Therapeutics Sa | A novel complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for treatment of glioblastoma |
WO2016166348A1 (en) * | 2015-04-17 | 2016-10-20 | Elsalys Biotech | Anti-tyro3 antibodies and uses thereof |
WO2016181349A1 (en) | 2015-05-14 | 2016-11-17 | Pfizer Inc. | Combinations comprising a pyrrolidine-2,5-dione ido1 inhibitor and an anti-body |
WO2016149201A3 (en) * | 2015-03-13 | 2016-11-24 | Cytomx Therapeutics, Inc. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
WO2016196218A1 (en) | 2015-05-31 | 2016-12-08 | Curegenix Corporation | Combination compositions for immunotherapy |
WO2016196228A1 (en) | 2015-05-29 | 2016-12-08 | Bristol-Myers Squibb Company | Antibodies against ox40 and uses thereof |
WO2016196381A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Pd-l1 promoter methylation in cancer |
WO2016196298A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Therapeutic and diagnolstic methods for cancer |
WO2016197204A1 (en) | 2015-06-11 | 2016-12-15 | Bionomics Limited | Pharmaceutical combination and uses thereof |
WO2016200835A1 (en) | 2015-06-08 | 2016-12-15 | Genentech, Inc. | Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists |
WO2016201425A1 (en) | 2015-06-12 | 2016-12-15 | Bristol-Myers Squibb Company | Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways |
WO2016205320A1 (en) | 2015-06-17 | 2016-12-22 | Genentech, Inc. | Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes |
WO2017004016A1 (en) | 2015-06-29 | 2017-01-05 | The Rockefeller University | Antibodies to cd40 with enhanced agonist activity |
WO2017019897A1 (en) | 2015-07-29 | 2017-02-02 | Novartis Ag | Combination therapies comprising antibody molecules to tim-3 |
WO2017019894A1 (en) | 2015-07-29 | 2017-02-02 | Novartis Ag | Combination therapies comprising antibody molecules to lag-3 |
WO2017020858A1 (en) | 2015-08-06 | 2017-02-09 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
US9605070B2 (en) | 2014-01-31 | 2017-03-28 | Novartis Ag | Antibody molecules to TIM-3 and uses thereof |
WO2017058780A1 (en) | 2015-09-30 | 2017-04-06 | Merck Patent Gmbh | Combination of a pd-1 axis binding antagonist and an alk inhibitor for treating alk-negative cancer |
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 |
WO2017064043A1 (en) | 2015-10-12 | 2017-04-20 | Innate Pharma | Cd73 blocking agents |
WO2017077382A1 (en) | 2015-11-06 | 2017-05-11 | Orionis Biosciences Nv | Bi-functional chimeric proteins and uses thereof |
WO2017087678A2 (en) | 2015-11-19 | 2017-05-26 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
WO2017087280A1 (en) | 2015-11-16 | 2017-05-26 | Genentech, Inc. | Methods of treating her2-positive cancer |
WO2017087851A1 (en) | 2015-11-19 | 2017-05-26 | Genentech, Inc. | Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors |
WO2017075045A3 (en) * | 2015-10-30 | 2017-06-08 | Mayo Foundation For Medical Education And Research | Antibodies to b7-h1 |
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 |
US9683048B2 (en) | 2014-01-24 | 2017-06-20 | Novartis Ag | Antibody molecules to PD-1 and uses thereof |
WO2017106656A1 (en) | 2015-12-17 | 2017-06-22 | Novartis Ag | Antibody molecules to pd-1 and uses thereof |
WO2017112741A1 (en) | 2015-12-22 | 2017-06-29 | Novartis Ag | Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy |
WO2017118634A1 (en) | 2016-01-04 | 2017-07-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
WO2017125532A1 (en) | 2016-01-21 | 2017-07-27 | Innate Pharma | Neutralization of inhibitory pathways in lymphocytes |
WO2017134305A1 (en) | 2016-02-05 | 2017-08-10 | Orionis Biosciences Nv | Bispecific signaling agents and uses thereof |
WO2017144681A1 (en) | 2016-02-25 | 2017-08-31 | Cell Medica Switzerland Ag | Binding members to pd-l1 |
WO2017152085A1 (en) | 2016-03-04 | 2017-09-08 | Bristol-Myers Squibb Company | Combination therapy with anti-cd73 antibodies |
WO2017151502A1 (en) | 2016-02-29 | 2017-09-08 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2017153433A1 (en) | 2016-03-08 | 2017-09-14 | Innate Pharma | Siglec neutralizing antibodies |
WO2017159699A1 (en) | 2016-03-15 | 2017-09-21 | Chugai Seiyaku Kabushiki Kaisha | Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies |
WO2017157964A1 (en) | 2016-03-16 | 2017-09-21 | Amal Therapeutics Sa | Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine |
WO2017167921A1 (en) | 2016-03-30 | 2017-10-05 | Centre Léon-Bérard | Lymphocytes expressing cd73 in cancerous patient dictates therapy |
WO2017175156A1 (en) | 2016-04-07 | 2017-10-12 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
WO2017175147A1 (en) | 2016-04-07 | 2017-10-12 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
WO2017181111A2 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
WO2017181079A2 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
WO2017184619A2 (en) | 2016-04-18 | 2017-10-26 | Celldex Therapeutics, Inc. | Agonistic antibodies that bind human cd40 and uses thereof |
WO2017194782A2 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Therapeutic targeting of non-cellular structures |
WO2017194783A1 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Targeted mutant interferon-beta and uses thereof |
WO2017200969A1 (en) | 2016-05-20 | 2017-11-23 | Eli Lilly And Company | Combination therapy with notch and pd-1 or pd-l1 inhibitors |
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 |
WO2017210335A1 (en) | 2016-06-01 | 2017-12-07 | Bristol-Myers Squibb Company | Imaging methods using 18f-radiolabeled biologics |
WO2017220990A1 (en) | 2016-06-20 | 2017-12-28 | Kymab Limited | Anti-pd-l1 antibodies |
WO2018013818A2 (en) | 2016-07-14 | 2018-01-18 | Bristol-Myers Squibb Company | Antibodies against tim3 and uses thereof |
WO2018029474A2 (en) | 2016-08-09 | 2018-02-15 | Kymab Limited | Anti-icos antibodies |
WO2018031865A1 (en) | 2016-08-12 | 2018-02-15 | Genentech, Inc. | Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a vegf inhibitor |
WO2018029124A1 (en) | 2016-08-08 | 2018-02-15 | F. Hoffmann-La Roche Ag | Therapeutic and diagnostic methods for cancer |
WO2018049474A1 (en) | 2016-09-16 | 2018-03-22 | Bionomics Limited | Antibody and checkpoint inhibitor combination therapy |
WO2018055060A1 (en) | 2016-09-21 | 2018-03-29 | Amal Therapeutics Sa | Fusion comprising a cell penetrating peptide, a multi epitope and a tlr peptide agonist for treatment of cancer |
WO2018055145A1 (en) | 2016-09-26 | 2018-03-29 | F. Hoffmann-La Roche Ag | Predicting response to pd-1 axis inhibitors |
WO2018064299A1 (en) | 2016-09-29 | 2018-04-05 | Genentech, Inc. | Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a taxane |
WO2018068028A1 (en) | 2016-10-06 | 2018-04-12 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2018065625A2 (en) | 2016-10-07 | 2018-04-12 | Enterome | Immunogenic compounds for cancer therapy |
WO2018065628A2 (en) | 2016-10-07 | 2018-04-12 | Enterome | Microbiota sequence variants of tumor-related antigenic epitopes |
WO2018065623A2 (en) | 2016-10-07 | 2018-04-12 | Enterome | Immunogenic compounds for cancer therapy |
US9957323B2 (en) | 2016-06-20 | 2018-05-01 | Kymab Limited | Anti-ICOS antibodies |
WO2018077893A1 (en) | 2016-10-24 | 2018-05-03 | Orionis Biosciences Nv | Targeted mutant interferon-gamma and uses thereof |
WO2018081621A1 (en) | 2016-10-28 | 2018-05-03 | Bristol-Myers Squibb Company | Methods of treating urothelial carcinoma using an anti-pd-1 antibody |
WO2018085555A1 (en) | 2016-11-03 | 2018-05-11 | Bristol-Myers Squibb Company | Activatable anti-ctla-4 antibodies and uses thereof |
US9975957B2 (en) | 2014-03-31 | 2018-05-22 | Genentech, Inc. | Anti-OX40 antibodies and methods of use |
WO2018093821A1 (en) | 2016-11-15 | 2018-05-24 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies |
US9987500B2 (en) | 2014-01-23 | 2018-06-05 | Regeneron Pharmaceuticals, Inc. | Human antibodies to PD-1 |
US9988452B2 (en) | 2014-10-14 | 2018-06-05 | Novartis Ag | Antibody molecules to PD-L1 and uses thereof |
WO2018099978A1 (en) | 2016-11-29 | 2018-06-07 | Horst Lindhofer | Combination of t-cell redirecting multifunctional antibodies with immune checkpoint modulators and uses thereof |
WO2018110515A1 (en) | 2016-12-12 | 2018-06-21 | 第一三共株式会社 | Combination of antibody-drug conjugate and immune checkpoint inhibitor |
WO2018111890A1 (en) | 2016-12-12 | 2018-06-21 | Genentech, Inc. | Methods of treating cancer using anti-pd-l1 antibodies and antiandrogens |
WO2018129497A1 (en) | 2017-01-09 | 2018-07-12 | Bioxcel Therapeutics, Inc. | Predictive and diagnostic methods for prostate cancer |
WO2018127570A1 (en) | 2017-01-05 | 2018-07-12 | Netris Pharma | Combined treatment with netrin-1 interfering drug and immune checkpoint inhibitors drugs |
EP3277320A4 (en) * | 2015-03-30 | 2018-08-01 | Stcube, Inc. | Antibodies specific to glycosylated pd-l1 and methods of use thereof |
WO2018138591A1 (en) | 2017-01-24 | 2018-08-02 | Pfizer Inc. | Calicheamicin derivatives and antibody drug conjugates thereof |
WO2018144999A1 (en) | 2017-02-06 | 2018-08-09 | Orionis Biosciences, Inc. | Targeted engineered interferon and uses thereof |
WO2018141964A1 (en) | 2017-02-06 | 2018-08-09 | Orionis Biosciences Nv | Targeted chimeric proteins and uses thereof |
WO2018141959A1 (en) | 2017-02-06 | 2018-08-09 | Innate Pharma | Immunomodulatory antibody drug conjugates binding to a human mica polypeptide |
WO2018150224A1 (en) | 2017-02-16 | 2018-08-23 | Shenzhen Runshin Bioscience | Anti-programmed death-ligand 1 (pd-l1) antibodies and therapeutic uses thereof |
WO2018152396A1 (en) | 2017-02-17 | 2018-08-23 | Innate Tumor Immunity, Inc. | Substituted imidazo-quinolines as nlrp3 modulators |
WO2018154520A1 (en) | 2017-02-27 | 2018-08-30 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors |
WO2018160841A1 (en) | 2017-03-01 | 2018-09-07 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
US10072087B2 (en) | 2009-12-10 | 2018-09-11 | Hoffmann-La Roche Inc. | Antibodies against human CSF-1R and uses thereof |
US10076518B2 (en) | 2015-03-06 | 2018-09-18 | Beyondspring Pharmaceuticals, Inc. | Method of treating a brain tumor |
WO2018167147A1 (en) | 2017-03-15 | 2018-09-20 | F. Hoffmann-La Roche Ag | Azaindoles as inhibitors of hpk1 |
WO2018167267A1 (en) | 2017-03-16 | 2018-09-20 | Innate Pharma | Compositions and methods for treating cancer |
WO2018170168A1 (en) | 2017-03-15 | 2018-09-20 | Cue Biopharma, Inc. | Methods for modulating an immune response |
WO2018172508A1 (en) | 2017-03-24 | 2018-09-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2018183928A1 (en) | 2017-03-31 | 2018-10-04 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2018183956A1 (en) | 2017-03-30 | 2018-10-04 | Genentech, Inc. | Naphthyridines as inhibitors of hpk1 |
WO2018183964A1 (en) | 2017-03-30 | 2018-10-04 | Genentech, Inc. | Isoquinolines as inhibitors of hpk1 |
EP3309177A4 (en) * | 2016-03-04 | 2018-10-10 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Pdl-1 antibody, pharmaceutical composition thereof, and uses thereof |
WO2018187613A2 (en) | 2017-04-07 | 2018-10-11 | Bristol-Myers Squibb Company | Anti-icos agonist antibodies and uses thereof |
WO2018191660A1 (en) | 2017-04-14 | 2018-10-18 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2018189220A1 (en) | 2017-04-13 | 2018-10-18 | F. Hoffmann-La Roche Ag | An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer |
WO2018194496A2 (en) | 2017-04-17 | 2018-10-25 | Закрытое Акционерное Общество "Биокад" | Monoclonal antibody to pd-l1 |
WO2018200430A1 (en) | 2017-04-26 | 2018-11-01 | Bristol-Myers Squibb Company | Methods of antibody production that minimize disulfide bond reduction |
EP2926142B1 (en) | 2012-11-30 | 2018-11-07 | F.Hoffmann-La Roche Ag | Identification of patients in need of pd-l1 inhibitor cotherapy |
WO2018213297A1 (en) | 2017-05-16 | 2018-11-22 | Bristol-Myers Squibb Company | Treatment of cancer with anti-gitr agonist antibodies |
WO2018218056A1 (en) | 2017-05-25 | 2018-11-29 | Birstol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
WO2018219956A1 (en) | 2017-05-29 | 2018-12-06 | Gamamabs Pharma | Cancer-associated immunosuppression inhibitor |
WO2018222718A1 (en) | 2017-05-30 | 2018-12-06 | Bristol-Myers Squibb Company | Treatment of lag-3 positive tumors |
WO2018223040A1 (en) | 2017-06-01 | 2018-12-06 | Bristol-Myers Squibb Company | Methods of treating a tumor using an anti-pd-1 antibody |
WO2018222722A2 (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 |
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 |
WO2018222711A2 (en) | 2017-05-30 | 2018-12-06 | Bristol-Myers Squibb Company | Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent |
US10155748B2 (en) | 2015-07-13 | 2018-12-18 | Beyondspring Pharmaceuticals, Inc. | Plinabulin compositions |
US10167336B2 (en) | 2013-03-14 | 2019-01-01 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
WO2019011855A1 (en) | 2017-07-10 | 2019-01-17 | Innate Pharma | Siglec-9-neutralizing antibodies |
WO2019014402A1 (en) | 2017-07-14 | 2019-01-17 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
EP3360893A4 (en) * | 2015-10-10 | 2019-01-23 | Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences | High-affinity and soluble pdl-1 molecule |
WO2019018757A1 (en) | 2017-07-21 | 2019-01-24 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2019032431A1 (en) | 2017-08-07 | 2019-02-14 | Amgen Inc. | Treatment of triple negative breast cancer or colorectal cancer with liver metastases with an anti pd-l1 antibody and an oncolytic virus |
US10214586B2 (en) | 2015-08-24 | 2019-02-26 | Eli Lilly And Company | PD-L1 antibodies |
US10238650B2 (en) | 2015-03-06 | 2019-03-26 | Beyondspring Pharmaceuticals, Inc. | Method of treating cancer associated with a RAS mutation |
WO2019059411A1 (en) | 2017-09-20 | 2019-03-28 | Chugai Seiyaku Kabushiki Kaisha | Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent |
EP3348571A4 (en) * | 2015-07-31 | 2019-04-10 | Jiangsu Alphamab Biopharmaceuticals Co., Ltd. | Single domain antibody for programmed death-ligand (pd-l1) and derived protein thereof |
WO2019069269A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | Modulators of stimulator of interferon genes (sting) useful in treating hiv |
WO2019068907A1 (en) | 2017-10-06 | 2019-04-11 | Innate Pharma | Restoration of t cell activity via the cd39/cd73 axis |
WO2019069270A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | Modulators of stimulator of interferon genes (sting) |
US10259875B2 (en) | 2013-10-01 | 2019-04-16 | Mayo Foundation For Medical Education And Research | Methods for treating cancer in patients with elevated levels of BIM |
EP3470426A1 (en) | 2017-10-10 | 2019-04-17 | Numab Therapeutics AG | Multispecific antibody |
WO2019072871A2 (en) | 2017-10-09 | 2019-04-18 | Enterome S.A. | Microbiota sequence variants of tumor-related antigenic epitopes |
WO2019075090A1 (en) | 2017-10-10 | 2019-04-18 | Tilos Therapeutics, Inc. | Anti-lap antibodies and uses thereof |
WO2019072870A1 (en) | 2017-10-10 | 2019-04-18 | Numab Innovation Ag | Antibodies targeting cd137 and methods of use thereof |
WO2019072868A1 (en) | 2017-10-10 | 2019-04-18 | Numab Therapeutics AG | Multispecific antibody |
WO2019075468A1 (en) | 2017-10-15 | 2019-04-18 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2019079520A2 (en) | 2017-10-18 | 2019-04-25 | Alpine Immune Sciences, Inc. | Variant icos ligand immunomodulatory proteins and related compositions and methods |
EP3292873B1 (en) | 2013-02-22 | 2019-05-01 | CureVac AG | Combination of vaccination and inhibition of the pd-1 pathway |
WO2019090263A1 (en) | 2017-11-06 | 2019-05-09 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2019089921A1 (en) | 2017-11-01 | 2019-05-09 | Bristol-Myers Squibb Company | Immunostimulatory agonistic antibodies for use in treating cancer |
WO2019090330A1 (en) | 2017-11-06 | 2019-05-09 | Bristol-Myers Squibb Company | Methods of treating a tumor |
WO2019097369A1 (en) | 2017-11-14 | 2019-05-23 | Pfizer Inc. | Ezh2 inhibitor combination therapies |
US10302653B2 (en) | 2014-05-22 | 2019-05-28 | Mayo Foundation For Medical Education And Research | Distinguishing antagonistic and agonistic anti B7-H1 antibodies |
US10328158B2 (en) | 2014-01-10 | 2019-06-25 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for immunotherapy |
WO2019122884A1 (en) | 2017-12-19 | 2019-06-27 | Kymab Limited | Antibodies to icos |
CN109963589A (en) * | 2016-10-30 | 2019-07-02 | 上海复宏汉霖生物技术股份有限公司 | Anti- PD-L1 antibody and variant |
WO2019133747A1 (en) | 2017-12-27 | 2019-07-04 | Bristol-Myers Squibb Company | Anti-cd40 antibodies and uses thereof |
WO2019134946A1 (en) | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
WO2019140150A1 (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 |
WO2019140229A1 (en) | 2018-01-12 | 2019-07-18 | Bristol-Myers Squibb Company | Antibodies against tim3 and uses thereof |
WO2019144126A1 (en) | 2018-01-22 | 2019-07-25 | Pascal Biosciences Inc. | Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells |
WO2019143607A1 (en) | 2018-01-16 | 2019-07-25 | Bristol-Myers Squibb Company | Methods of treating cancer with antibodies against tim3 |
WO2019144098A1 (en) | 2018-01-22 | 2019-07-25 | Bristol-Myers Squibb Company | Compositions and methods of treating cancer |
EP3378871A4 (en) * | 2015-11-17 | 2019-08-07 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Pd-l1 antibody, antigen fragment binding thereof and pharmaceutical 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 |
WO2019165434A1 (en) | 2018-02-26 | 2019-08-29 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2019162325A1 (en) | 2018-02-21 | 2019-08-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
WO2019175113A1 (en) | 2018-03-12 | 2019-09-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers |
WO2019183040A1 (en) | 2018-03-21 | 2019-09-26 | Five Prime Therapeutics, Inc. | ANTIBODIES BINDING TO VISTA AT ACIDIC pH |
WO2019190327A2 (en) | 2018-03-30 | 2019-10-03 | Merus N.V. | Multivalent antibody |
WO2019191676A1 (en) | 2018-03-30 | 2019-10-03 | Bristol-Myers Squibb Company | Methods of treating tumor |
EP3550019A1 (en) | 2014-10-24 | 2019-10-09 | Astrazeneca AB | Combination |
CN110337449A (en) * | 2017-02-21 | 2019-10-15 | 上海君实生物医药科技股份有限公司 | Anti- PD-L1 antibody and its application |
WO2019200256A1 (en) | 2018-04-12 | 2019-10-17 | Bristol-Myers Squibb Company | Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody |
US10457725B2 (en) | 2016-05-13 | 2019-10-29 | Regeneron Pharmaceuticals, Inc. | Methods of treating skin cancer by administering a PD-1 inhibitor |
WO2019209896A1 (en) | 2018-04-25 | 2019-10-31 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2019211489A1 (en) | 2018-05-04 | 2019-11-07 | Merck Patent Gmbh | COMBINED INHIBITION OF PD-1/PD-L1, TGFβ AND DNA-PK FOR THE TREATMENT OF CANCER |
WO2019211492A1 (en) | 2018-05-04 | 2019-11-07 | Tollys | Tlr3 ligands that activate both epithelial and myeloid cells |
WO2019219820A1 (en) | 2018-05-16 | 2019-11-21 | Ctxt Pty Limited | Substituted condensed thiophenes as modulators of sting |
WO2019229699A1 (en) | 2018-05-31 | 2019-12-05 | Novartis Ag | Hepatitis b antibodies |
WO2019241730A2 (en) | 2018-06-15 | 2019-12-19 | Flagship Pioneering Innovations V, Inc. | Increasing immune activity through modulation of postcellular signaling factors |
WO2019243252A1 (en) | 2018-06-18 | 2019-12-26 | Innate Pharma | Compositions and methods for treating cancer |
WO2019246557A1 (en) | 2018-06-23 | 2019-12-26 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor |
US10517875B2 (en) | 2014-07-23 | 2019-12-31 | Mayo Foundation for Medical Engineering and Research | Targeting DNA-PKcs and B7-H1 to treat cancer |
WO2020014327A2 (en) | 2018-07-11 | 2020-01-16 | Five Prime Therapeutics, Inc. | Antibodies binding to vista at acidic ph |
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 |
WO2020014132A2 (en) | 2018-07-09 | 2020-01-16 | Five Prime Therapeutics, Inc. | Antibodies binding to ilt4 |
WO2020011964A1 (en) | 2018-07-12 | 2020-01-16 | F-Star Beta Limited | Antibody molecules that bind pd-l1 and cd137 |
WO2020018789A1 (en) | 2018-07-18 | 2020-01-23 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent |
WO2020023707A1 (en) | 2018-07-26 | 2020-01-30 | Bristol-Myers Squibb Company | Lag-3 combination therapy for the treatment of cancer |
WO2020023551A1 (en) | 2018-07-24 | 2020-01-30 | Genentech, Inc. | Naphthyridine compounds and uses thereof |
WO2020023560A1 (en) | 2018-07-24 | 2020-01-30 | F. Hoffmann-La Roche Ag | Isoquinoline compounds and uses thereof |
US10548988B2 (en) | 2012-07-18 | 2020-02-04 | Birdie Biopharmaceuticals, Inc. | Compounds for targeted immunotherapy |
WO2020037094A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Substitued 4-amino-1h-imidazo[4,5-c]quinoline compounds and improved methods for their preparation |
WO2020037091A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Imidazo[4,5-c]quinoline derived nlrp3-modulators |
WO2020037092A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Imidazo[4,5-c]quinoline derived nlrp3-modulators |
US10570204B2 (en) | 2013-09-26 | 2020-02-25 | The Medical College Of Wisconsin, Inc. | Methods for treating hematologic cancers |
EP2943507B1 (en) | 2013-01-10 | 2020-02-26 | Genmab A/S | Inert format |
WO2020043683A1 (en) | 2018-08-27 | 2020-03-05 | Pieris Pharmaceuticals Gmbh | Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof |
WO2020044206A1 (en) | 2018-08-29 | 2020-03-05 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors for use in the treatment cancer |
WO2020051099A1 (en) | 2018-09-03 | 2020-03-12 | Genentech, Inc. | Carboxamide and sulfonamide derivatives useful as tead modulators |
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 |
WO2020053742A2 (en) | 2018-09-10 | 2020-03-19 | Novartis Ag | Anti-hla-hbv peptide antibodies |
US10596257B2 (en) | 2016-01-08 | 2020-03-24 | Hoffmann-La Roche Inc. | Methods of treating CEA-positive cancers using PD-1 axis binding antagonists and anti-CEA/anti-CD3 bispecific antibodies |
WO2020061349A1 (en) | 2018-09-21 | 2020-03-26 | Genentech, Inc. | Diagnostic methods for triple-negative breast cancer |
WO2020061060A1 (en) | 2018-09-19 | 2020-03-26 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2020058372A1 (en) | 2018-09-19 | 2020-03-26 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy |
WO2020061377A1 (en) | 2018-09-19 | 2020-03-26 | Genentech, Inc. | Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof |
WO2020069402A1 (en) | 2018-09-30 | 2020-04-02 | Genentech, Inc. | Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer |
WO2020072627A1 (en) | 2018-10-02 | 2020-04-09 | Genentech, Inc. | Isoquinoline compounds for the treatment of cancer |
WO2020072695A1 (en) | 2018-10-03 | 2020-04-09 | Genentech, Inc. | 8-aminoisoquinoline compounds and uses thereof |
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 |
WO2020076969A2 (en) | 2018-10-10 | 2020-04-16 | Tilos Therapeutics, Inc. | Anti-lap antibody variants and uses thereof |
WO2020081767A1 (en) | 2018-10-18 | 2020-04-23 | Genentech, Inc. | Diagnostic and therapeutic methods for sarcomatoid kidney cancer |
WO2020081928A1 (en) | 2018-10-19 | 2020-04-23 | Bristol-Myers Squibb Company | Combination therapy for melanoma |
WO2020086724A1 (en) | 2018-10-23 | 2020-04-30 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2020092304A1 (en) | 2018-10-29 | 2020-05-07 | Wisconsin Alumni Research Foundation | Dendritic polymers complexed with immune checkpoint inhibitors for enhanced cancer immunotherapy |
US10646567B2 (en) | 2011-08-01 | 2020-05-12 | Genentech, Inc. | Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors |
WO2020102501A1 (en) | 2018-11-16 | 2020-05-22 | Bristol-Myers Squibb Company | Anti-nkg2a antibodies and uses thereof |
WO2020102728A1 (en) | 2018-11-16 | 2020-05-22 | Neoimmunetech, Inc. | Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor |
WO2020102804A2 (en) | 2018-11-16 | 2020-05-22 | Arqule, Inc. | Pharmaceutical combination for treatment of cancer |
US10662253B2 (en) | 2008-01-31 | 2020-05-26 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Antibodies against human CD39 and use thereof for inhibiting T regulatory cells activity |
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 |
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 |
WO2020112781A1 (en) | 2018-11-28 | 2020-06-04 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
WO2020109570A1 (en) | 2018-11-30 | 2020-06-04 | Gbg Forschungs Gmbh | Method for predicting the response to cancer immunotherapy in cancer patients |
WO2020109355A1 (en) | 2018-11-28 | 2020-06-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and kit for assaying lytic potential of immune effector cells |
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 |
WO2020117952A2 (en) | 2018-12-05 | 2020-06-11 | Genentech, Inc. | Diagnostic methods and compositions for cancer immunotherapy |
WO2020117849A1 (en) | 2018-12-04 | 2020-06-11 | Bristol-Myers Squibb Company | Methods of analysis using in-sample calibration curve by multiple isotopologue reaction monitoring |
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 |
EP3433277A4 (en) * | 2016-03-23 | 2020-06-17 | Mabspace Biosciences (Suzhou) Co., Ltd | Novel anti-pd-l1 antibodies |
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 |
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 |
WO2020132560A2 (en) | 2018-12-21 | 2020-06-25 | Aim Immunotech Inc. | Compositions and methods for cancer therapy |
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 |
WO2020132297A1 (en) | 2018-12-19 | 2020-06-25 | Cue Biopharma, Inc. | Multimeric t-cell modulatory polypeptides and methods of use thereof |
WO2020127059A1 (en) | 2018-12-17 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sulconazole as a furin inhibitor |
WO2020136235A1 (en) | 2018-12-28 | 2020-07-02 | Transgene Sa | M2-defective poxvirus |
WO2020136147A1 (en) | 2018-12-26 | 2020-07-02 | Innate Pharma | Compounds and methods for treatment of head and neck cancer |
WO2020150115A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2020150116A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2020148338A1 (en) | 2019-01-15 | 2020-07-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy |
WO2020150114A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Heterocyclic nlrp3 modulators, for use in the treatment of cancer |
WO2020150152A1 (en) | 2019-01-14 | 2020-07-23 | Genentech, Inc. | Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine |
WO2020150113A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Substituted quinazolines as nlrp3 modulators, for use in the treatment of cancer |
EP3478723A4 (en) * | 2016-06-29 | 2020-07-29 | Checkpoint Therapeutics, Inc. | Pd-l1-specific antibodies and methods of using the same |
EP3689910A2 (en) | 2014-09-23 | 2020-08-05 | F. Hoffmann-La Roche AG | Method of using anti-cd79b immunoconjugates |
WO2020157131A1 (en) | 2019-01-30 | 2020-08-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor |
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 |
WO2020163589A1 (en) | 2019-02-08 | 2020-08-13 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2020165370A1 (en) | 2019-02-13 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for selecting a cancer treatment in a subject suffering from cancer |
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 |
WO2020186176A1 (en) | 2019-03-14 | 2020-09-17 | Genentech, Inc. | Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab |
WO2020198672A1 (en) | 2019-03-28 | 2020-10-01 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2020198676A1 (en) | 2019-03-28 | 2020-10-01 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2020201568A1 (en) | 2019-04-03 | 2020-10-08 | Targimmune Therapeutics Ag | Immunotherapy for the treatment of cancer |
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 |
WO2020205626A1 (en) | 2019-03-29 | 2020-10-08 | Genentech, Inc. | Modulators of cell surface protein interactions and methods and compositions related to same |
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 |
WO2020214995A1 (en) | 2019-04-19 | 2020-10-22 | Genentech, Inc. | Anti-mertk antibodies and their methods of use |
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 |
WO2020216697A1 (en) | 2019-04-23 | 2020-10-29 | Innate Pharma | Cd73 blocking antibodies |
WO2020221796A1 (en) | 2019-04-30 | 2020-11-05 | 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 |
EP3736294A2 (en) | 2014-10-10 | 2020-11-11 | Innate Pharma | Cd73 blockade |
WO2020226986A2 (en) | 2019-05-03 | 2020-11-12 | 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 |
WO2020232375A1 (en) | 2019-05-16 | 2020-11-19 | Silicon Swat, Inc. | Oxoacridinyl acetic acid derivatives and methods of use |
WO2020232378A1 (en) | 2019-05-16 | 2020-11-19 | Silicon Swat, Inc. | Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use |
WO2020234875A2 (en) | 2019-05-19 | 2020-11-26 | Yeda Research And Development Co. Ltd. | Identification of recurrent mutated neopeptides |
WO2020243568A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy |
WO2020243570A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Cell localization signature and combination therapy |
WO2020243563A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Multi-tumor gene signatures for suitability to immuno-oncology therapy |
WO2020239558A1 (en) | 2019-05-24 | 2020-12-03 | Pfizer Inc. | Combination therapies using cdk inhibitors |
US10858432B2 (en) | 2015-12-02 | 2020-12-08 | Stcube, Inc. | Antibodies specific to glycosylated PD-1 and methods of use thereof |
CN112105644A (en) * | 2018-03-23 | 2020-12-18 | 得克萨斯州大学系统董事会 | Dual specific antibodies to human PD-L1 and PD-L2 and methods of use thereof |
EP3763742A1 (en) | 2014-09-01 | 2021-01-13 | Birdie Biopharmaceuticals Inc. | Anti-pd-l1 conjugates for treating tumors |
WO2021009365A1 (en) | 2019-07-18 | 2021-01-21 | Ctxt Pty Limited | Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting |
WO2021009362A1 (en) | 2019-07-18 | 2021-01-21 | Ctxt Pty Limited | Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting |
WO2021009267A1 (en) | 2019-07-15 | 2021-01-21 | Capella Bioscience Ltd | Anti-pd-l1 antibodies |
WO2021019526A1 (en) | 2019-07-29 | 2021-02-04 | Yeda Research And Development Co. Ltd. | Methods of treating and diagnosing lung cancer |
US10912748B2 (en) | 2016-02-08 | 2021-02-09 | Beyondspring Pharmaceuticals, Inc. | Compositions containing tucaresol or its analogs |
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 |
US10927158B2 (en) | 2016-12-22 | 2021-02-23 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
EP3783029A1 (en) | 2015-05-12 | 2021-02-24 | F. Hoffmann-La Roche AG | Therapeutic and diagnostic methods for cancer |
EP3789402A1 (en) | 2014-11-20 | 2021-03-10 | F. Hoffmann-La Roche AG | Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists |
EP3789399A1 (en) | 2014-11-21 | 2021-03-10 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
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 |
WO2021055994A1 (en) | 2019-09-22 | 2021-03-25 | Bristol-Myers Squibb Company | Quantitative spatial profiling for lag-3 antagonist therapy |
WO2021055698A1 (en) | 2019-09-19 | 2021-03-25 | Bristol-Myers Squibb Company | Antibodies binding to vista at acidic ph |
WO2021062018A1 (en) | 2019-09-25 | 2021-04-01 | Bristol-Myers Squibb Company | Composite biomarker for cancer therapy |
WO2021062085A1 (en) | 2019-09-27 | 2021-04-01 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
EP3799885A1 (en) | 2014-09-16 | 2021-04-07 | Innate Pharma | Neutralization of inhibitory pathways in lymphocytes |
EP3626266A4 (en) * | 2017-05-16 | 2021-04-07 | Jiangsu Hengrui Medicine Co., Ltd. | Pd-l1 antibody pharmaceutical composition and use thereof |
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 |
WO2021064180A1 (en) | 2019-10-03 | 2021-04-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating macrophages polarization |
WO2021064184A1 (en) | 2019-10-04 | 2021-04-08 | 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 |
WO2021064567A1 (en) | 2019-09-30 | 2021-04-08 | Astrazeneca Ab | Combination treatment for cancer |
EP3804620A1 (en) | 2016-03-01 | 2021-04-14 | North Carolina State University | Enhanced cancer immunotherapy by microneedle patch-assisted delivery |
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 |
WO2021079958A1 (en) | 2019-10-25 | 2021-04-29 | 第一三共株式会社 | Combination of anti-garp antibody and immunoregulator |
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 |
CN112805297A (en) * | 2018-07-14 | 2021-05-14 | 财团法人生物技术开发中心 | Anti-human PD-L1 antibodies and uses thereof |
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 |
WO2021090146A1 (en) | 2019-11-04 | 2021-05-14 | Astrazeneca Ab | Combination therapy for treating cancer |
WO2021092171A1 (en) | 2019-11-06 | 2021-05-14 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
WO2021091964A1 (en) | 2019-11-04 | 2021-05-14 | Duke University | Treatment for primary and metastatic cancer |
WO2021092380A1 (en) | 2019-11-08 | 2021-05-14 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for melanoma |
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 |
WO2021097110A1 (en) | 2019-11-13 | 2021-05-20 | Genentech, Inc. | Therapeutic compounds and methods of use |
WO2021097256A1 (en) | 2019-11-14 | 2021-05-20 | Cohbar, Inc. | Cxcr4 antagonist peptides |
WO2021106978A1 (en) | 2019-11-27 | 2021-06-03 | サイトリミック株式会社 | Pharmaceutical composition |
US11040948B2 (en) | 2017-09-29 | 2021-06-22 | Curis, Inc. | Crystal forms of immunomodulators |
WO2021123243A1 (en) | 2019-12-19 | 2021-06-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and vaccine compositions to treat cancers |
WO2021127217A1 (en) | 2019-12-17 | 2021-06-24 | Flagship Pioneering Innovations V, Inc. | Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly |
WO2021127554A1 (en) | 2019-12-19 | 2021-06-24 | Bristol-Myers Squibb Company | Combinations of dgk inhibitors and checkpoint antagonists |
US11046781B2 (en) | 2016-01-07 | 2021-06-29 | Birdie Biopharmaceuticals, Inc. | Anti-HER2 combinations for treating tumors |
US11053240B2 (en) | 2017-04-27 | 2021-07-06 | Birdie Biopharmaceuticals, Inc. | 2-amino-quinoline derivatives |
WO2021142203A1 (en) | 2020-01-10 | 2021-07-15 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2021144426A1 (en) | 2020-01-17 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2021155149A1 (en) | 2020-01-31 | 2021-08-05 | Genentech, Inc. | Methods of inducing neoepitope-specific t cells with a pd-1 axis binding antagonist and an rna vaccine |
WO2021154073A1 (en) | 2020-01-29 | 2021-08-05 | Merus N.V. | Means and method for modulating immune cell engaging effects. |
WO2021152548A1 (en) | 2020-01-30 | 2021-08-05 | Benitah Salvador Aznar | Combination therapy for treatment of cancer and cancer metastasis |
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) |
WO2021158938A1 (en) | 2020-02-06 | 2021-08-12 | Bristol-Myers Squibb Company | Il-10 and uses thereof |
WO2021158635A1 (en) | 2020-02-07 | 2021-08-12 | Al Therapeutics, Inc. | Anti-viral compositions and methods of use |
WO2021174045A1 (en) | 2020-02-28 | 2021-09-02 | Bristol-Myers Squibb Company | Radiolabeled fibronectin based scaffolds and antibodies and theranostic uses thereof |
WO2021170777A1 (en) | 2020-02-28 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing, prognosing and managing treatment of breast cancer |
US11110168B2 (en) | 2016-03-15 | 2021-09-07 | North Carolina State University | Nanoparticles, controlled-release dosage forms, and methods for delivering an immunotherapeutic agent |
US11110157B2 (en) | 2014-03-12 | 2021-09-07 | Curevac Ag | Combination of vaccination and OX40 agonists |
WO2021177980A1 (en) | 2020-03-06 | 2021-09-10 | Genentech, Inc. | Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist |
WO2021176424A1 (en) | 2020-03-06 | 2021-09-10 | Ona Therapeutics, S.L. | Anti-cd36 antibodies and their use to treat cancer |
WO2021178807A1 (en) | 2020-03-06 | 2021-09-10 | Celgene Quanticel Research, Inc. | Combination of an lsd-1 inhibitor and nivolumab for use in treating sclc or sqnsclc |
EP3878446A1 (en) | 2020-03-09 | 2021-09-15 | Universite De Geneve | Hsd11b1 inhibitors for use in immunotherapy and uses thereof |
WO2021183428A1 (en) | 2020-03-09 | 2021-09-16 | Bristol-Myers Squibb Company | Antibodies to cd40 with enhanced agonist activity |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021195485A1 (en) * | 2020-03-27 | 2021-09-30 | Vanderbilt University | Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) |
US11136300B2 (en) | 2017-10-11 | 2021-10-05 | Aurigene Discovery Technologies Limited | Crystalline forms of 3-substituted 1,2,4-oxadiazole |
US11136397B2 (en) | 2016-01-07 | 2021-10-05 | Birdie Pharmaceuticals, Inc. | Anti-EGFR combinations for treating tumors |
WO2021202959A1 (en) | 2020-04-03 | 2021-10-07 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2021207449A1 (en) | 2020-04-09 | 2021-10-14 | Merck Sharp & Dohme Corp. | Affinity matured anti-lap antibodies and uses thereof |
WO2021205444A1 (en) | 2020-04-06 | 2021-10-14 | Yeda Research And Development Co. Ltd. | Methods of diagnosing cancer and predicting responsiveness to therapy |
WO2021222167A1 (en) | 2020-04-28 | 2021-11-04 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
US11168144B2 (en) | 2017-06-01 | 2021-11-09 | Cytomx Therapeutics, Inc. | Activatable anti-PDL1 antibodies, and methods of use thereof |
WO2021224215A1 (en) | 2020-05-05 | 2021-11-11 | F. Hoffmann-La Roche Ag | Predicting response to pd-1 axis inhibitors |
WO2021231732A1 (en) | 2020-05-15 | 2021-11-18 | 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 |
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 |
WO2021252977A1 (en) | 2020-06-12 | 2021-12-16 | Genentech, Inc. | Methods and compositions for cancer immunotherapy |
WO2021249969A1 (en) | 2020-06-10 | 2021-12-16 | Merck Patent Gmbh | Combination product for the treatment of cancer diseases |
WO2021257503A1 (en) | 2020-06-16 | 2021-12-23 | Genentech, Inc. | Methods and compositions for treating triple-negative breast cancer |
WO2021257124A1 (en) | 2020-06-18 | 2021-12-23 | Genentech, Inc. | Treatment with anti-tigit antibodies and pd-1 axis binding antagonists |
US11214619B2 (en) | 2018-07-20 | 2022-01-04 | Surface Oncology, Inc. | Anti-CD112R compositions and methods |
WO2022006179A1 (en) | 2020-06-29 | 2022-01-06 | Flagship Pioneering Innovations V, Inc. | Viruses engineered to promote thanotransmission and their use in treating cancer |
US11220552B2 (en) | 2016-01-07 | 2022-01-11 | Birdie Biopharmaceuticals, Inc. | Anti-CD20 combinations for treating tumors |
WO2022008519A1 (en) | 2020-07-07 | 2022-01-13 | BioNTech SE | Therapeutic rna for hpv-positive cancer |
US11229642B2 (en) | 2016-06-06 | 2022-01-25 | Beyondspring Pharmaceuticals, Inc. | Composition and method for reducing neutropenia |
WO2022020716A1 (en) | 2020-07-24 | 2022-01-27 | Genentech, Inc. | Heterocyclic inhibitors of tead for treating cancer |
WO2022023379A1 (en) | 2020-07-28 | 2022-02-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for preventing and treating a cancer |
US11242393B2 (en) | 2018-03-23 | 2022-02-08 | Bristol-Myers Squibb Company | Antibodies against MICA and/or MICB and uses thereof |
WO2022036079A1 (en) | 2020-08-13 | 2022-02-17 | Bristol-Myers Squibb Company | Methods of redirecting of il-2 to target cells of interest |
WO2022036146A1 (en) | 2020-08-12 | 2022-02-17 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2022047189A1 (en) | 2020-08-28 | 2022-03-03 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for hepatocellular carcinoma |
WO2022047412A1 (en) | 2020-08-31 | 2022-03-03 | Bristol-Myers Squibb Company | Cell localization signature and immunotherapy |
EA039736B1 (en) * | 2015-09-15 | 2022-03-04 | Сайтомкс Терапьютикс, Инк. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2022053703A1 (en) | 2020-09-14 | 2022-03-17 | Boehringer Ingelheim International Gmbh | Heterologous prime boost vaccine |
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 |
US11291718B2 (en) | 2016-10-11 | 2022-04-05 | Cytlimic Inc. | Method for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein |
US11292842B2 (en) | 2017-02-21 | 2022-04-05 | Regeneron Pharmaceuticals, Inc. | Anti-PD-1 antibodies for treatment of lung cancer |
US11299544B2 (en) | 2013-03-15 | 2022-04-12 | Genentech, Inc. | Biomarkers and methods of treating PD-1 and PD-L1 related conditions |
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 |
WO2022076318A1 (en) | 2020-10-05 | 2022-04-14 | Bristol-Myers Squibb Company | Methods for concentrating proteins |
WO2022087402A1 (en) | 2020-10-23 | 2022-04-28 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for lung cancer |
WO2022084210A1 (en) | 2020-10-20 | 2022-04-28 | F. Hoffmann-La Roche Ag | Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors |
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 |
US11326170B2 (en) | 2017-04-18 | 2022-05-10 | Changchun Huapu Biotechnology Co. Ltd. | Immunomodulatory polynucleotides and uses thereof |
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 |
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 |
WO2022101484A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022101302A1 (en) | 2020-11-12 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes |
WO2022101481A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
US11339201B2 (en) | 2016-05-18 | 2022-05-24 | Albert Einstein College Of Medicine | Variant PD-L1 polypeptides, T-cell modulatory multimeric polypeptides, and methods of use thereof |
US11344620B2 (en) | 2014-09-13 | 2022-05-31 | Novartis Ag | Combination therapies |
WO2022119830A1 (en) | 2020-12-02 | 2022-06-09 | Genentech, Inc. | Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy |
WO2022120179A1 (en) | 2020-12-03 | 2022-06-09 | Bristol-Myers Squibb Company | Multi-tumor gene signatures and uses thereof |
EP3929215A4 (en) * | 2019-06-10 | 2022-06-22 | Shandong Boan Biotechnology Co., Ltd. | Bifunctional fusion protein against pdl1 and tgf? and use thereof |
US11370819B2 (en) | 2014-02-10 | 2022-06-28 | Merck Patent Gmbh | Targeted TGFβ inhibition |
WO2022136266A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022136257A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022136255A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
WO2022146947A1 (en) | 2020-12-28 | 2022-07-07 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
WO2022146948A1 (en) | 2020-12-28 | 2022-07-07 | Bristol-Myers Squibb Company | Subcutaneous administration of pd1/pd-l1 antibodies |
EP4026848A1 (en) | 2015-12-09 | 2022-07-13 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody for reducing the cytokine release syndrome |
WO2022148736A1 (en) | 2021-01-05 | 2022-07-14 | Transgene | Vectorization of muc1 t cell engager |
US11400086B2 (en) | 2017-02-01 | 2022-08-02 | Beyondspring Pharmaceuticals, Inc. | Method of reducing chemotherapy-induced neutropenia |
EP3841126A4 (en) * | 2018-08-20 | 2022-08-10 | 1Globe Biomedical Co., Ltd. | Novel cancer immunotherapy antibody compositions |
WO2022183018A1 (en) * | 2021-02-26 | 2022-09-01 | Fred Hutchinson Cancer Research Center | Protective antibodies against respiratory viral infections |
US11440960B2 (en) | 2017-06-20 | 2022-09-13 | Kymab Limited | TIGIT antibodies, encoding nucleic acids and methods of using said antibodies in vivo |
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 |
WO2022203090A1 (en) | 2021-03-25 | 2022-09-29 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
US11458195B2 (en) | 2013-02-22 | 2022-10-04 | Curevac Ag | Combination of vaccination and inhibition of the PD-1 pathway |
WO2022212876A1 (en) | 2021-04-02 | 2022-10-06 | The Regents Of The University Of California | Antibodies against cleaved cdcp1 and uses thereof |
WO2022212784A1 (en) | 2021-03-31 | 2022-10-06 | Flagship Pioneering Innovations V, Inc. | Thanotransmission polypeptides and their use in treating cancer |
WO2022212400A1 (en) | 2021-03-29 | 2022-10-06 | Juno Therapeutics, Inc. | Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy |
WO2022216898A1 (en) | 2021-04-09 | 2022-10-13 | Genentech, Inc. | Combination therapy with a raf inhibitor and a pd-1 axis inhibitor |
WO2022217123A2 (en) | 2021-04-08 | 2022-10-13 | Nurix Therapeutics, Inc. | Combination therapies with cbl-b inhibitor compounds |
WO2022219080A1 (en) | 2021-04-14 | 2022-10-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | New method to improve nk cells cytotoxicity |
WO2022223791A1 (en) | 2021-04-23 | 2022-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | 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 |
WO2022232503A1 (en) | 2021-04-30 | 2022-11-03 | Genentech, Inc. | Therapeutic and diagnostic methods and compositions for cancer |
US11491204B2 (en) | 2015-04-07 | 2022-11-08 | Cytlimic Inc. | Composition comprising poly I:C and LAG-3-IGG fusion protein |
US11492383B2 (en) | 2011-06-24 | 2022-11-08 | Stephen D. Gillies | Light chain immunoglobulin fusion proteins and methods of use thereof |
US11498968B2 (en) | 2016-12-22 | 2022-11-15 | Hoffmann-La Roche Inc. | Treatment of tumors with an anti-CSF-1R antibody in combination with an anti-PD-L1 antibody after failure of anti-PD-L1/PD1 treatment |
US11497734B2 (en) | 2017-11-03 | 2022-11-15 | Aurigene Discovery Technologies Limited | Dual inhibitors of TIM-3 and PD-1 pathways |
US11497735B2 (en) | 2017-11-06 | 2022-11-15 | Aurigene Discovery Technologies Limited | Conjoint therapies for immunomodulation |
US11505591B2 (en) | 2016-05-18 | 2022-11-22 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
WO2022243378A1 (en) | 2021-05-18 | 2022-11-24 | Kymab Limited | Uses of anti-icos antibodies |
US11517567B2 (en) | 2017-06-23 | 2022-12-06 | Birdie Biopharmaceuticals, Inc. | Pharmaceutical compositions |
WO2022254227A1 (en) | 2021-06-04 | 2022-12-08 | Kymab Limited | Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies |
US11525002B2 (en) | 2017-10-11 | 2022-12-13 | Board Of Regents, The University Of Texas System | Human PD-L1 antibodies and methods of use therefor |
EP3902563A4 (en) * | 2018-12-27 | 2022-12-28 | Gigagen, Inc. | Anti-pd-l1 binding proteins and methods of use thereof |
US11542335B2 (en) | 2016-08-25 | 2023-01-03 | Hoffmann-La Roche Inc. | Method of treating cancer in a patient by administering an antibody which binds colony stimulating factor-1 receptor (CSF-1R) |
WO2023278641A1 (en) | 2021-06-29 | 2023-01-05 | Flagship Pioneering Innovations V, Inc. | Immune cells engineered to promote thanotransmission and uses thereof |
WO2023279092A2 (en) | 2021-07-02 | 2023-01-05 | Genentech, Inc. | Methods and compositions for treating cancer |
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 |
WO2023285552A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
US11560425B2 (en) | 2017-06-27 | 2023-01-24 | Neuracle Science Co., Ltd. | Use of anti-FAM19A5 antibodies for treating cancers |
US11564995B2 (en) | 2018-10-29 | 2023-01-31 | Wisconsin Alumni Research Foundation | Peptide-nanoparticle conjugates |
WO2023007472A1 (en) | 2021-07-30 | 2023-02-02 | ONA Therapeutics S.L. | Anti-cd36 antibodies and their use to treat cancer |
WO2023010094A2 (en) | 2021-07-28 | 2023-02-02 | Genentech, Inc. | Methods and compositions for treating cancer |
WO2023010095A1 (en) | 2021-07-28 | 2023-02-02 | F. Hoffmann-La Roche Ag | Methods and compositions for treating cancer |
US11578372B2 (en) | 2012-11-05 | 2023-02-14 | Foundation Medicine, Inc. | NTRK1 fusion molecules and uses thereof |
EP3929213A4 (en) * | 2019-02-21 | 2023-03-08 | Eucure (Beijing) Biopharma Co., Ltd | Anti-pd-l1 antibody and use thereof |
US11603407B2 (en) | 2017-04-06 | 2023-03-14 | Regeneron Pharmaceuticals, Inc. | Stable antibody formulation |
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 |
WO2023052531A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
WO2023057882A1 (en) | 2021-10-05 | 2023-04-13 | Pfizer Inc. | Combinations of azalactam compounds with a pd-1 axis binding antagonist for the treatment of cancer |
US11629189B2 (en) | 2017-12-19 | 2023-04-18 | Kymab Limited | Bispecific antibody for ICOS and PD-L1 |
WO2023061930A1 (en) | 2021-10-11 | 2023-04-20 | BioNTech SE | Therapeutic rna for lung cancer |
US11633393B2 (en) | 2017-01-06 | 2023-04-25 | Beyondspring Pharmaceuticals, Inc. | Tubulin binding compounds and therapeutic use thereof |
WO2023077034A1 (en) | 2021-10-28 | 2023-05-04 | Lyell Immunopharma, Inc. | Methods for culturing immune cells |
WO2023077090A1 (en) | 2021-10-29 | 2023-05-04 | 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) |
WO2023080900A1 (en) | 2021-11-05 | 2023-05-11 | Genentech, Inc. | Methods and compositions for classifying and treating kidney cancer |
WO2023079428A1 (en) | 2021-11-03 | 2023-05-11 | Pfizer Inc. | Combination therapies using tlr7/8 agonist |
WO2023083868A1 (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 |
US11660352B2 (en) | 2016-03-29 | 2023-05-30 | Stcube, Inc. | Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof |
WO2023097195A1 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic indazole compounds and methods of use in the treatment of cancer |
WO2023097194A2 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic compounds and methods of use |
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 |
WO2023129438A1 (en) | 2021-12-28 | 2023-07-06 | Wisconsin Alumni Research Foundation | Hydrogel compositions for use for depletion of tumor associated macrophages |
US11702461B2 (en) | 2018-01-09 | 2023-07-18 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides comprising reduced-affinity immunomodulatory polypeptides |
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 |
US11732044B2 (en) | 2017-12-27 | 2023-08-22 | Innovent Biologics (Suzhou) Co., Ltd. | Anti-LAG-3 antibody and use thereof |
WO2023164638A1 (en) | 2022-02-25 | 2023-08-31 | Bristol-Myers Squibb Company | Combination therapy for colorectal carcinoma |
US11746152B2 (en) | 2016-07-20 | 2023-09-05 | Stcube, Inc. | Methods of cancer treatment and therapy using a combination of antibodies that bind glycosylated PD-L1 |
WO2023168404A1 (en) | 2022-03-04 | 2023-09-07 | Bristol-Myers Squibb Company | Methods of treating a tumor |
US11753479B2 (en) | 2014-03-04 | 2023-09-12 | Kymab Limited | Nucleic acids encoding anti-OX40L antibodies |
WO2023170606A1 (en) | 2022-03-08 | 2023-09-14 | Alentis Therapeutics Ag | Use of anti-claudin-1 antibodies to increase t cell availability |
WO2023178329A1 (en) | 2022-03-18 | 2023-09-21 | Bristol-Myers Squibb Company | Methods of isolating polypeptides |
EP4249066A2 (en) | 2014-12-23 | 2023-09-27 | Bristol-Myers Squibb Company | Antibodies to tigit |
US11771698B2 (en) | 2013-01-18 | 2023-10-03 | Foundation Medicine, Inc. | Methods of treating cholangiocarcinoma |
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 |
US11779604B2 (en) | 2016-11-03 | 2023-10-10 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses and methods |
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 |
US11786523B2 (en) | 2018-01-24 | 2023-10-17 | Beyondspring Pharmaceuticals, Inc. | Composition and method for reducing thrombocytopenia |
WO2023201291A1 (en) | 2022-04-13 | 2023-10-19 | Genentech, Inc. | Pharmaceutical compositions of mosunetuzumab and methods of use |
WO2023201299A1 (en) | 2022-04-13 | 2023-10-19 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
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 |
WO2023235415A1 (en) | 2022-06-01 | 2023-12-07 | Genentech, Inc. | Method to identify a patient with an increased likelihood of chemotherapy-induced peripheral neuropathy |
WO2023235847A1 (en) | 2022-06-02 | 2023-12-07 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
US11840567B2 (en) | 2017-10-03 | 2023-12-12 | Joint Stock Company “Biocad” | Bispecific antibodies with specific binding to CD47 and PD-L1 |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
US11851471B2 (en) | 2017-01-09 | 2023-12-26 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11858996B2 (en) | 2016-08-09 | 2024-01-02 | Kymab Limited | Anti-ICOS antibodies |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
US11878062B2 (en) | 2020-05-12 | 2024-01-23 | Cue Biopharma, Inc. | Multimeric T-cell modulatory polypeptides and methods of use thereof |
WO2024020432A1 (en) | 2022-07-19 | 2024-01-25 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024023750A1 (en) | 2022-07-28 | 2024-02-01 | Astrazeneca Uk Limited | Combination of antibody-drug conjugate and bispecific checkpoint inhibitor |
WO2024023740A1 (en) | 2022-07-27 | 2024-02-01 | Astrazeneca Ab | Combinations of recombinant virus expressing interleukin-12 with pd-1/pd-l1 inhibitors |
US11896643B2 (en) | 2018-02-05 | 2024-02-13 | Orionis Biosciences, Inc. | Fibroblast binding agents and use thereof |
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 |
WO2024049949A1 (en) | 2022-09-01 | 2024-03-07 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2024054992A1 (en) | 2022-09-09 | 2024-03-14 | Bristol-Myers Squibb Company | Methods of separating chelator |
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 |
US11933786B2 (en) | 2015-03-30 | 2024-03-19 | Stcube, Inc. | Antibodies specific to glycosylated PD-L1 and methods of use thereof |
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 |
WO2024077095A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating bladder 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 |
WO2024077166A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating lung cancer |
RU2817281C2 (en) * | 2014-09-11 | 2024-04-12 | Медиммьюн Лимитед | Antibodies to b7-h1 for treating tumours |
WO2024084034A1 (en) | 2022-10-21 | 2024-04-25 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of osteoarthritis |
WO2024089417A1 (en) | 2022-10-24 | 2024-05-02 | Memorial Sloan-Kettering Cancer Center | Tumour stratification for responsiveness to an immune checkpoint inhibitor |
WO2024091991A1 (en) | 2022-10-25 | 2024-05-02 | Genentech, Inc. | Therapeutic and diagnostic methods for multiple myeloma |
WO2024089418A1 (en) | 2022-10-24 | 2024-05-02 | Cancer Research Technology Limited | Tumour sensitisation to checkpoint inhibitors with redox status modifier |
US11976128B2 (en) | 2018-03-23 | 2024-05-07 | Board Of Regents, The University Of Texas System | Human PD-L2 antibodies and methods of use therefor |
WO2024094688A1 (en) | 2022-11-01 | 2024-05-10 | Heidelberg Pharma Research Gmbh | Anti-gucy2c antibody and uses thereof |
EP4378957A2 (en) | 2015-07-29 | 2024-06-05 | Novartis AG | Combination therapies comprising antibody molecules to pd-1 |
WO2024115725A1 (en) | 2022-12-01 | 2024-06-06 | BioNTech SE | Multispecific antibody against cd40 and cd137 in combination therapy with anti-pd1 ab and chemotherapy |
WO2024116140A1 (en) | 2022-12-01 | 2024-06-06 | Medimmune Limited | Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies |
WO2024126457A1 (en) | 2022-12-14 | 2024-06-20 | Astellas Pharma Europe Bv | Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and immune checkpoint inhibitors |
US12018065B2 (en) | 2020-04-27 | 2024-06-25 | Twist Bioscience Corporation | Variant nucleic acid libraries for coronavirus |
WO2024137776A1 (en) | 2022-12-21 | 2024-06-27 | Bristol-Myers Squibb Company | Combination therapy for lung cancer |
WO2024137589A2 (en) | 2022-12-20 | 2024-06-27 | Genentech, Inc. | Methods of treating pancreatic cancer with a pd-1 axis binding antagonist and an rna vaccine |
US12029782B2 (en) | 2020-09-09 | 2024-07-09 | Cue Biopharma, Inc. | MHC class II T-cell modulatory multimeric polypeptides for treating type 1 diabetes mellitus (T1D) and methods of use thereof |
WO2024150017A1 (en) | 2023-01-13 | 2024-07-18 | Akrivia Biomedics Limited | Method of profiling diseases |
WO2024151687A1 (en) | 2023-01-09 | 2024-07-18 | Flagship Pioneering Innovations V, Inc. | Genetic switches and their use in treating cancer |
WO2024150177A1 (en) | 2023-01-11 | 2024-07-18 | Advesya | Treatment methods for solid tumors |
US12054557B2 (en) | 2015-12-22 | 2024-08-06 | Regeneron Pharmaceuticals, Inc. | Combination of anti-PD-1 antibodies and bispecific anti-CD20/anti-CD3 antibodies to treat cancer |
WO2024160721A1 (en) | 2023-01-30 | 2024-08-08 | Kymab Limited | Antibodies |
US12059474B2 (en) | 2016-03-29 | 2024-08-13 | Stcube & Co., Inc. | Methods for selecting antibodies that specifically bind glycosylated immune checkpoint proteins |
US12077588B2 (en) | 2017-10-10 | 2024-09-03 | Numab Therapeutics AG | Antibodies targeting PDL1 and methods of use thereof |
US12090142B2 (en) | 2018-02-22 | 2024-09-17 | Board Of Regents, The University Of Texas System | Combination therapy for the treatment of cancer |
WO2024196952A1 (en) | 2023-03-20 | 2024-09-26 | Bristol-Myers Squibb Company | Tumor subtype assessment for cancer therapy |
WO2024200571A1 (en) | 2023-03-28 | 2024-10-03 | Institut National de la Santé et de la Recherche Médicale | Method for discriminating mono-immunotherapy from combined immunotherapy in cancers |
Families Citing this family (278)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108997498A (en) | 2008-12-09 | 2018-12-14 | 霍夫曼-拉罗奇有限公司 | Anti- PD-L1 antibody and they be used to enhance the purposes of T cell function |
DK3279215T3 (en) | 2009-11-24 | 2020-04-27 | Medimmune Ltd | TARGETED BINDING AGENTS B7-H1 |
WO2013013188A1 (en) | 2011-07-21 | 2013-01-24 | Tolero Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors |
MX362247B (en) | 2013-03-06 | 2019-01-09 | Astrazeneca Ab | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor. |
WO2014165082A2 (en) * | 2013-03-13 | 2014-10-09 | Medimmune, Llc | Antibodies and methods of detection |
US20150071910A1 (en) * | 2013-03-15 | 2015-03-12 | Genentech, Inc. | Biomarkers and methods of treating pd-1 and pd-l1 related conditions |
WO2014169078A2 (en) | 2013-04-09 | 2014-10-16 | Boston Biomedical, Inc. | Methods for treating cancer |
AP2016009088A0 (en) | 2013-09-16 | 2016-03-31 | Astrazeneca Ab | Therapeutic polymeric nanoparticles and methods of making and using same |
US10202454B2 (en) * | 2013-10-25 | 2019-02-12 | Dana-Farber Cancer Institute, Inc. | Anti-PD-L1 monoclonal antibodies and fragments thereof |
AU2015203904B2 (en) * | 2014-01-06 | 2018-07-19 | Expression Pathology, Inc. | SRM assay for PD-L1 |
EP3107538B1 (en) * | 2014-02-18 | 2020-05-27 | Health Research, Inc. | Combination therapy for hepatocellular carcinoma |
RU2702332C2 (en) | 2014-05-13 | 2019-10-08 | Медиммьюн Лимитед | Antibodies to b7-h1 and to ctla-4 for treating non-small-cell lung cancer |
KR20230144099A (en) | 2014-05-15 | 2023-10-13 | 브리스톨-마이어스 스큅 컴퍼니 | Treatment of lung cancer using a combination of an anti-pd-1 antibody and another anti-cancer agent |
AU2015265870B2 (en) | 2014-05-29 | 2020-07-09 | Ventana Medical Systems, Inc. | PD-L1 antibodies and uses thereof |
TW201618775A (en) | 2014-08-11 | 2016-06-01 | 艾森塔製藥公司 | Therapeutic combinations of a BTK inhibitor, a PI3K inhibitor, a JAK-2 inhibitor, a PD-1 inhibitor and/or a PD-L1 inhibitor |
ES2727137T3 (en) | 2014-08-28 | 2019-10-14 | Halozyme Inc | Therapy combined with a hyaluronan degradation enzyme and an immune control point inhibitor |
CA3203273A1 (en) | 2014-10-14 | 2016-04-21 | Halozyme, Inc. | Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same |
SG11201703332SA (en) | 2014-11-10 | 2017-05-30 | Medimmune Ltd | Binding molecules specific for cd73 and uses thereof |
MA41414A (en) | 2015-01-28 | 2017-12-05 | Centre Nat Rech Scient | ICOS AGONIST BINDING PROTEINS |
MA41460A (en) | 2015-02-03 | 2017-12-12 | Oncomed Pharm Inc | TNFRSF LIAISON AGENTS AND THEIR USES |
EP3254110B1 (en) | 2015-02-03 | 2020-03-18 | Ventana Medical Systems, Inc. | Histochemical assay for evaluating expression of programmed death ligand 1 (pd-l1) |
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 |
AU2016222928B2 (en) | 2015-02-26 | 2021-05-13 | Merck Patent Gmbh | PD-1 / PD-L1 inhibitors for the treatment of cancer |
WO2016150899A2 (en) | 2015-03-23 | 2016-09-29 | Bayer Pharma Aktiengesellschaft | Anti-ceacam6 antibodies and uses thereof |
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 |
US20160347848A1 (en) | 2015-05-28 | 2016-12-01 | Medimmune Limited | Therapeutic combinations and methods for treating neoplasia |
MA53355A (en) | 2015-05-29 | 2022-03-16 | Agenus Inc | ANTI-CTLA-4 ANTIBODIES AND METHODS OF USE THEREOF |
US11078278B2 (en) | 2015-05-29 | 2021-08-03 | Bristol-Myers Squibb Company | Treatment of renal cell carcinoma |
EA201792623A1 (en) | 2015-06-03 | 2018-04-30 | Бостон Биомедикал, Инк. | COMPOSITIONS CONTAINING CANCER STEM BONE INHIBITOR AND IMMUNOTHERAPEUTIC AGENT TO BE USED IN CANCER TREATMENT |
WO2016197367A1 (en) | 2015-06-11 | 2016-12-15 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
MY193229A (en) | 2015-06-16 | 2022-09-26 | Merck Patent Gmbh | Pd-l1 antagonist combination treatments |
FI3313441T3 (en) | 2015-06-24 | 2024-03-28 | Janssen Biotech Inc | Immune modulation and treatment of solid tumors with antibodies that specifically bind cd38 |
EP3858859A1 (en) | 2015-07-14 | 2021-08-04 | 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) |
CN108136025B (en) | 2015-07-16 | 2022-09-06 | 比奥克斯塞尔医疗股份有限公司 | A novel method of treating cancer using immunomodulation |
US20180230431A1 (en) | 2015-08-07 | 2018-08-16 | Glaxosmithkline Intellectual Property Development Limited | Combination Therapy |
MA44909A (en) | 2015-09-15 | 2018-07-25 | Acerta Pharma Bv | THERAPEUTIC ASSOCIATION OF A CD19 INHIBITOR AND A BTK INHIBITOR |
SG11201803520PA (en) | 2015-11-03 | 2018-05-30 | Janssen Biotech Inc | Antibodies specifically binding pd-1 and their uses |
TWI795347B (en) | 2015-11-18 | 2023-03-11 | 美商必治妥施貴寶公司 | Treatment of lung cancer using a combination of an anti-pd-1 antibody and an anti-ctla-4 antibody |
EP4015537A1 (en) | 2015-12-01 | 2022-06-22 | GlaxoSmithKline Intellectual Property Development Limited | Combination treatments and uses and methods thereof |
EP3366691A1 (en) | 2015-12-03 | 2018-08-29 | GlaxoSmithKline Intellectual Property Development Limited | Cyclic purine dinucleotides as modulators of sting |
WO2017098421A1 (en) | 2015-12-08 | 2017-06-15 | Glaxosmithkline Intellectual Property Development Limited | Benzothiadiazine compounds |
US20180364240A1 (en) * | 2015-12-10 | 2018-12-20 | Medimmune, Llc | Methods for treatment and selection of patients responsive to immune mediated cancer therapy |
KR102424513B1 (en) | 2015-12-14 | 2022-07-25 | 마크로제닉스, 인크. | Bispecific molecules with immunoreactivity with PD-1 and CTLA-4, and methods of use thereof |
CN106939047B (en) | 2016-01-04 | 2021-08-31 | 江苏怀瑜药业有限公司 | PD-L1 antibody and preparation method thereof |
EP3402503B1 (en) | 2016-01-13 | 2020-10-21 | Acerta Pharma B.V. | Therapeutic combinations of an antifolate and a btk inhibitor |
EP3417294B8 (en) | 2016-02-15 | 2022-05-04 | Astrazeneca AB | Methods comprising fixed intermittent dosing of cediranib |
WO2017153952A1 (en) | 2016-03-10 | 2017-09-14 | Glaxosmithkline Intellectual Property Development Limited | 5-sulfamoyl-2-hydroxybenzamide derivatives |
WO2017176925A1 (en) | 2016-04-05 | 2017-10-12 | Bristol-Myers Squibb Company | Cytokine profiling analysis for predicting prognosis of a patient in need of an anti-cancer treatment |
WO2017176565A1 (en) | 2016-04-07 | 2017-10-12 | Eli Lilly And Company | Combinations of an anti-b7-h1 antibody and a cxcr4 peptide antagonist for treating a solid tumor |
SG11201807474SA (en) * | 2016-04-25 | 2018-11-29 | Medimmune Llc | Compositions comprising coformulation of anti-pd-l1 and anti-ctla-4 antibodies |
JP2019516685A (en) | 2016-05-05 | 2019-06-20 | 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、(ナンバー2)、リミテッドGlaxosmithkline Intellectual Property (No.2) Limited | Enhancer of ZESTE Homolog 2 Inhibitor |
WO2017205875A1 (en) | 2016-05-27 | 2017-11-30 | Dnatrix, Inc. | Adenovirus and immunomodulator combination therapy |
CN109476751B (en) | 2016-05-27 | 2024-04-19 | 艾吉纳斯公司 | Anti-TIM-3 antibodies and methods of use thereof |
WO2017210453A1 (en) | 2016-06-02 | 2017-12-07 | Bristol-Myers Squibb Company | Pd-1 blockade with nivolumab in refractory hodgkin's lymphoma |
HUE063911T2 (en) | 2016-06-02 | 2024-02-28 | Bristol Myers Squibb Co | Use of an anti-pd-1 antibody in combination with an anti-cd30 antibody in lymphoma treatment |
KR102515509B1 (en) | 2016-06-03 | 2023-03-28 | 브리스톨-마이어스 스큅 컴퍼니 | Use of Anti-PD-1 Antibodies in the Treatment of Patients with Colorectal Cancer |
WO2017210631A1 (en) | 2016-06-03 | 2017-12-07 | Bristol-Myers Squibb Company | Anti-pd-1 antibody for use in a method of treatment of recurrent small cell lung cancer |
CN109476753A (en) | 2016-06-03 | 2019-03-15 | 百时美施贵宝公司 | For treating the anti-PD-1 antibody of the method for tumour |
CA3027045A1 (en) * | 2016-06-08 | 2017-12-14 | Abbvie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
EP3468960B1 (en) | 2016-06-08 | 2022-03-23 | GlaxoSmithKline Intellectual Property Development Limited | Chemical compounds as atf4 pathway inhibitors |
WO2017212423A1 (en) | 2016-06-08 | 2017-12-14 | Glaxosmithkline Intellectual Property Development Limited | Chemcical compounds |
JP7185530B2 (en) | 2016-06-13 | 2022-12-07 | トルク セラピューティクス, インコーポレイテッド | Methods and compositions for promoting immune cell function |
RU2656181C1 (en) * | 2016-07-13 | 2018-05-31 | Закрытое Акционерное Общество "Биокад" | Anti-pd-1 antibodies, method for their production, and method of application |
GB201612520D0 (en) | 2016-07-19 | 2016-08-31 | F-Star Beta Ltd | Binding molecules |
US20190241573A1 (en) | 2016-07-20 | 2019-08-08 | Glaxosmithkline Intellectual Property Development Limited | Isoquinoline derivatives as perk inhibitors |
CN106243223B (en) * | 2016-07-28 | 2019-03-05 | 北京百特美博生物科技有限公司 | Anti-human PDL1 antibody and application thereof |
US11312773B2 (en) * | 2016-08-15 | 2022-04-26 | Fuso Pharmaceutical Industries, Ltd. | Anti-PD-L1 antibody |
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 |
AU2017322501A1 (en) | 2016-09-09 | 2019-03-28 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Combination of an anti-CD20 antibody, PI3 kinase-delta inhibitor, and anti-PD-1 or anti-PD-L1 antibody for treating hematological cancers |
CA3037008A1 (en) | 2016-09-27 | 2018-04-05 | Oncologie, Inc. | Methods for treating cancer with bavituximab based on levels of .beta.2-glycoprotein 1, and assays therefor |
CA3039451A1 (en) | 2016-10-06 | 2018-04-12 | Pfizer Inc. | Dosing regimen of avelumab for the treatment of cancer |
AU2017343621B2 (en) | 2016-10-11 | 2021-12-02 | Agenus Inc. | Anti-LAG-3 antibodies and methods of use thereof |
TWI788307B (en) | 2016-10-31 | 2023-01-01 | 美商艾歐凡斯生物治療公司 | Engineered artificial antigen presenting cells for tumor infiltrating lymphocyte expansion |
WO2018094275A1 (en) | 2016-11-18 | 2018-05-24 | Tolero Pharmaceuticals, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
WO2018098352A2 (en) | 2016-11-22 | 2018-05-31 | Jun Oishi | Targeting kras induced immune checkpoint expression |
US11299469B2 (en) | 2016-11-29 | 2022-04-12 | Sumitomo Dainippon Pharma Oncology, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
KR20190090822A (en) | 2016-12-01 | 2019-08-02 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | Combination therapy |
AU2017369994A1 (en) | 2016-12-01 | 2019-06-13 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy |
CA3045508A1 (en) | 2016-12-03 | 2018-06-07 | Juno Therapeutics, Inc. | Methods for modulation of car-t cells |
MA50948A (en) | 2016-12-07 | 2020-10-14 | Agenus Inc | ANTIBODIES AND METHODS OF USING THE SAME |
PT3551660T (en) | 2016-12-07 | 2023-11-30 | Ludwig Inst For Cancer Res Ltd | Anti-ctla-4 antibodies and methods of use thereof |
CA3046963A1 (en) | 2016-12-14 | 2018-06-21 | Janssen Biotech, Inc. | Cd8a-binding fibronectin type iii domains |
WO2018111978A1 (en) | 2016-12-14 | 2018-06-21 | Janssen Biotech, Inc. | Cd137 binding fibronectin type iii domains |
US10597438B2 (en) | 2016-12-14 | 2020-03-24 | Janssen Biotech, Inc. | PD-L1 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 |
US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US11034667B2 (en) | 2017-01-09 | 2021-06-15 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
MX2019008346A (en) | 2017-01-13 | 2019-09-09 | Agenus Inc | T cell receptors that bind to ny-eso-1 and methods of use thereof. |
CN110325209A (en) | 2017-02-24 | 2019-10-11 | 宏观基因有限公司 | CD137 and the bi-specific binding molecule of tumour antigen and application thereof can be combined |
WO2018161872A1 (en) * | 2017-03-06 | 2018-09-13 | 江苏恒瑞医药股份有限公司 | Anti-b7-h3 antibody, antigen-binding fragment thereof, and pharmaceutical use thereof |
CA3055127A1 (en) * | 2017-03-09 | 2018-09-13 | Genmab A/S | Antibodies against pd-l1 |
CA3058276A1 (en) | 2017-03-30 | 2018-10-04 | Merck Patent Gmbh | Combination of an anti-pd-l1 antibody and a dna-pk inhibitor for the treatment of cancer |
US11571459B2 (en) | 2017-04-03 | 2023-02-07 | Oncxerna Therapeutics, Inc. | Methods for treating cancer using PS-targeting antibodies with immuno-oncology agents |
MX2019012223A (en) | 2017-04-13 | 2019-12-09 | Agenus Inc | Anti-cd137 antibodies and methods of use thereof. |
KR20190137911A (en) | 2017-04-21 | 2019-12-11 | 신라젠(주) | Anticancer Vaccinia Virus and Gateway Inhibitor Combination Therapy |
AR111651A1 (en) | 2017-04-28 | 2019-08-07 | Novartis Ag | CONJUGATES OF ANTIBODIES THAT INCLUDE TOLL TYPE RECEIVER AGONISTS AND COMBINATION THERAPIES |
TWI805582B (en) | 2017-05-01 | 2023-06-21 | 美商艾吉納斯公司 | Anti-tigit antibodies and methods of use thereof |
CN110050000B (en) | 2017-05-12 | 2022-07-26 | 苏州盛迪亚生物医药有限公司 | Fusion protein containing TGF-beta receptor and medical application thereof |
CA3062656A1 (en) | 2017-05-17 | 2018-11-22 | Boston Biomedical, Inc. | Methods for treating cancer |
CN110913911A (en) | 2017-05-18 | 2020-03-24 | 特沙诺有限公司 | Combination therapy for the treatment of cancer |
WO2018225093A1 (en) | 2017-06-07 | 2018-12-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds as atf4 pathway inhibitors |
JP2020522555A (en) | 2017-06-09 | 2020-07-30 | 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 | Combination therapy |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
SG11201912473PA (en) | 2017-06-22 | 2020-01-30 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
WO2018235056A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | Il-1beta binding antibodies for use in treating cancer |
WO2018237173A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
US20190048072A1 (en) | 2017-06-22 | 2019-02-14 | Novartis Ag | USE OF IL-1beta BINDING ANTIBODIES |
WO2019006007A1 (en) | 2017-06-27 | 2019-01-03 | Novartis Ag | Dosage regimens for anti-tim-3 antibodies and uses thereof |
US20200140383A1 (en) | 2017-07-03 | 2020-05-07 | 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 |
US20210145771A1 (en) | 2017-07-03 | 2021-05-20 | Glaxosmithkline Intellectual Property Development Limited | N-(3-(2-(4-chlorophenoxy)acetamido)bicyclo[1.1.1] pentan-1-yl)-2-cyclobutane-1- carboxamide derivatives and related compounds as atf4 inhibitors for treating cancer and other diseases |
US20200172617A1 (en) | 2017-07-20 | 2020-06-04 | Novartis Ag | Dosage regimens of anti-lag-3 antibodies and uses thereof |
WO2019021208A1 (en) | 2017-07-27 | 2019-01-31 | Glaxosmithkline Intellectual Property Development Limited | Indazole derivatives useful as perk inhibitors |
US11899017B2 (en) | 2017-07-28 | 2024-02-13 | Bristol-Myers Squibb Company | Predictive peripheral blood biomarker for checkpoint inhibitors |
WO2019025545A1 (en) | 2017-08-04 | 2019-02-07 | Genmab A/S | Binding agents binding to pd-l1 and cd137 and use thereof |
MX2020001980A (en) | 2017-08-28 | 2020-03-24 | Bristol Myers Squibb Co | Tim-3 antagonists for the treatment and diagnosis of cancers. |
CA3073055A1 (en) | 2017-09-04 | 2019-03-07 | Agenus Inc. | T cell receptors that bind to mixed lineage leukemia (mll)-specific phosphopeptides and methods of use thereof |
TW201922721A (en) | 2017-09-07 | 2019-06-16 | 英商葛蘭素史克智慧財產發展有限公司 | Chemical compounds |
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 |
EP3697442A4 (en) | 2017-09-30 | 2021-07-07 | Tesaro, Inc. | Combination therapies for treating cancer |
CA3076859A1 (en) | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | Combination therapies and uses thereof |
AU2018353432A1 (en) | 2017-10-19 | 2020-04-23 | Debiopharm International S.A. | Combination product for the treatment of cancer |
US20210040205A1 (en) | 2017-10-25 | 2021-02-11 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
WO2019094265A1 (en) * | 2017-11-10 | 2019-05-16 | Armo Biosciences, Inc. | Pd1 polypeptide binding molecules |
WO2019108900A1 (en) | 2017-11-30 | 2019-06-06 | Novartis Ag | Bcma-targeting chimeric antigen receptor, and uses thereof |
CN108144745B (en) * | 2017-12-20 | 2020-06-16 | 天康生物股份有限公司 | Separation device and method for reducing endotoxin content of live brucellosis vaccine |
US20200368268A1 (en) | 2018-01-08 | 2020-11-26 | Novartis Ag | Immune-enhancing rnas for combination with chimeric antigen receptor therapy |
CN112004537A (en) | 2018-01-09 | 2020-11-27 | 穿梭药业公司 | Selective histone deacetylase inhibitors for the treatment of human diseases |
JP2021510078A (en) * | 2018-01-10 | 2021-04-15 | 江▲蘇▼恒瑞医▲薬▼股▲フン▼有限公司Jiangsu Hengrui Medicine Co., Ltd. | PD-L1 antibody, its antigen-binding fragment, and its pharmaceutical use |
AU2019215031A1 (en) | 2018-01-31 | 2020-08-20 | Novartis Ag | Combination therapy using a chimeric antigen receptor |
WO2019152743A1 (en) | 2018-01-31 | 2019-08-08 | Celgene Corporation | Combination therapy using adoptive cell therapy and checkpoint inhibitor |
US20200399383A1 (en) | 2018-02-13 | 2020-12-24 | Novartis Ag | Chimeric antigen receptor therapy in combination with il-15r and il15 |
AU2019233596A1 (en) | 2018-03-14 | 2020-10-08 | Merck Patent Gmbh | Compounds and uses thereof to treat tumors in a subject |
US12110337B2 (en) | 2018-04-04 | 2024-10-08 | Bristol-Myers Squibb Company | Anti-CD27 antibodies and uses thereof |
WO2019193541A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic aromatic ring derivatives of formula (i) as atf4 inhibitors |
WO2019193540A1 (en) | 2018-04-06 | 2019-10-10 | Glaxosmithkline Intellectual Property Development Limited | Heteroaryl derivatives of formula (i) as atf4 inhibitors |
US20210147547A1 (en) | 2018-04-13 | 2021-05-20 | Novartis Ag | Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof |
BR112020021271A2 (en) | 2018-04-17 | 2021-01-26 | Celldex Therapeutics, Inc. | bispecific constructs and anti-cd27 and anti-pd-l1 antibodies |
JP7516254B2 (en) | 2018-04-18 | 2024-07-16 | ゼンコア インコーポレイテッド | IL-15/IL-15RA HETERODIMERIC FC FUSION PROTEINS AND USES THEREOF |
US11524991B2 (en) | 2018-04-18 | 2022-12-13 | Xencor, Inc. | PD-1 targeted heterodimeric fusion proteins containing IL-15/IL-15Ra Fc-fusion proteins and PD-1 antigen binding domains and uses thereof |
KR20210005096A (en) * | 2018-04-25 | 2021-01-13 | 메디뮨 리미티드 | Formulation of human anti-PD-L1 antibody |
JP2021522239A (en) | 2018-04-26 | 2021-08-30 | アジェナス インコーポレイテッド | Heat shock protein-binding peptide composition and how to use it |
WO2019219658A1 (en) | 2018-05-15 | 2019-11-21 | Medimmune Limited | Treatment of cancer |
AR126019A1 (en) | 2018-05-30 | 2023-09-06 | Novartis Ag | ANTIBODIES AGAINST ENTPD2, COMBINATION THERAPIES AND METHODS OF USE OF ANTIBODIES AND COMBINATION THERAPIES |
US20210214459A1 (en) | 2018-05-31 | 2021-07-15 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
US11492409B2 (en) | 2018-06-01 | 2022-11-08 | Novartis Ag | Binding molecules against BCMA and uses thereof |
CN112424167A (en) | 2018-07-09 | 2021-02-26 | 葛兰素史密斯克莱知识产权发展有限公司 | Chemical compound |
JOP20210001A1 (en) | 2018-07-10 | 2021-01-05 | 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 |
AR116109A1 (en) | 2018-07-10 | 2021-03-31 | Novartis Ag | DERIVATIVES OF 3- (5-AMINO-1-OXOISOINDOLIN-2-IL) PIPERIDINE-2,6-DIONA AND USES OF THE SAME |
WO2020014543A2 (en) | 2018-07-11 | 2020-01-16 | Actym Therapeutics, Inc. | Engineered immunostimulatory bacterial strains and uses thereof |
GB201811408D0 (en) | 2018-07-12 | 2018-08-29 | F Star Beta Ltd | CD137 Binding Molecules |
WO2020031107A1 (en) | 2018-08-08 | 2020-02-13 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
TW202031273A (en) | 2018-08-31 | 2020-09-01 | 美商艾歐凡斯生物治療公司 | Treatment of nsclc patients refractory for anti-pd-1 antibody |
WO2020060771A1 (en) * | 2018-09-18 | 2020-03-26 | Vanderbilt University | Human monoclonal antibodies to staphylococcal aureus isd proteins and uses thereof |
WO2020061429A1 (en) | 2018-09-20 | 2020-03-26 | Iovance Biotherapeutics, Inc. | Expansion of tils from cryopreserved tumor samples |
WO2020064971A1 (en) | 2018-09-26 | 2020-04-02 | Merck Patent Gmbh | Combination of a pd-1 antagonist, an atr inhibitor and a platinating agent for the treatment of cancer |
SG11202103192RA (en) | 2018-10-03 | 2021-04-29 | Xencor Inc | Il-12 heterodimeric fc-fusion proteins |
JP2022512642A (en) | 2018-10-09 | 2022-02-07 | ブリストル-マイヤーズ スクイブ カンパニー | Anti-MerTK antibody to treat cancer |
MA53862A (en) | 2018-10-12 | 2022-01-19 | Xencor Inc | FC FUSION PROTEINS OF IL-15/IL-15RALPHA TARGETTING PD-1 AND USES IN COMBINATION THERAPIES INVOLVING THE SAME |
JP2022504905A (en) | 2018-10-16 | 2022-01-13 | ノバルティス アーゲー | Tumor mutation loading alone or in combination with immune markers as a biomarker to predict response to targeted therapy |
WO2020081493A1 (en) | 2018-10-16 | 2020-04-23 | Molecular Templates, Inc. | Pd-l1 binding proteins |
US11798653B2 (en) | 2018-10-18 | 2023-10-24 | Medimmune, Llc | Methods for determining treatment for cancer patients |
BR112021007517A2 (en) | 2018-10-22 | 2021-10-26 | Glaxosmithkline Intellectual Property Development Limited | DOSAGE |
EP3873532A1 (en) | 2018-10-31 | 2021-09-08 | Novartis AG | Dc-sign antibody drug conjugates |
MX2021005018A (en) | 2018-11-09 | 2021-06-15 | Jiangsu Hengrui Medicine Co | Tgf-î² receptor fusion protein pharmaceutical composition and use thereof. |
CA3119563A1 (en) | 2018-11-14 | 2020-05-22 | Bayer Aktiengesellschaft | Pharmaceutical combination of anti-ceacam6 and either anti-pd-1 or anti-pd-l1 antibodies for the treatment of cancer |
TW202028222A (en) | 2018-11-14 | 2020-08-01 | 美商Ionis製藥公司 | Modulators of foxp3 expression |
MX2021005808A (en) | 2018-11-20 | 2021-07-02 | Univ Cornell | Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer. |
CN113453678A (en) | 2018-11-26 | 2021-09-28 | 德彪药业国际股份公司 | Combination therapy for HIV infection |
AR117206A1 (en) | 2018-11-30 | 2021-07-21 | Glaxosmithkline Ip Dev Ltd | OCTAHYDROPIRROLO [2,1-B] [1,3] THIAZEPIN-7-CARBOXAMIDE DERIVATIVES USEFUL IN HIV THERAPY AND FOR THE TREATMENT OF CANCER |
US11034710B2 (en) | 2018-12-04 | 2021-06-15 | Sumitomo Dainippon Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
CN113438961A (en) | 2018-12-20 | 2021-09-24 | Xencor股份有限公司 | Targeting heterodimeric Fc fusion proteins containing IL-15/IL-15R α and NKG2D antigen binding domains |
KR20210106437A (en) | 2018-12-20 | 2021-08-30 | 노파르티스 아게 | Dosage regimens and pharmaceutical combinations 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 |
US20220370606A1 (en) | 2018-12-21 | 2022-11-24 | Pfizer Inc. | Combination Treatments Of Cancer Comprising A TLR Agonist |
KR20210107730A (en) | 2018-12-21 | 2021-09-01 | 노파르티스 아게 | Use of IL-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome |
WO2020128613A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1beta binding antibodies |
US20220056123A1 (en) | 2018-12-21 | 2022-02-24 | Novartis Ag | Use of il-1beta binding antibodies |
AU2019408408A1 (en) | 2018-12-21 | 2021-06-03 | Valerio Therapeutics | New conjugated nucleic acid molecules and their uses |
CN113227135A (en) | 2018-12-28 | 2021-08-06 | 斯帕克斯治疗公司 | Binding molecules specific for claudin 18.2, compositions and methods thereof for the treatment of cancer and other diseases |
WO2020160375A1 (en) | 2019-02-01 | 2020-08-06 | Glaxosmithkline Intellectual Property Development Limited | Combination treatments for cancer comprising belantamab mafodotin and an anti ox40 antibody and uses and methods thereof |
MX2021009371A (en) | 2019-02-12 | 2021-09-10 | Sumitomo Pharma Oncology Inc | Formulations comprising heterocyclic protein kinase inhibitors. |
EP3924521A4 (en) | 2019-02-15 | 2023-03-29 | IncellDx, Inc. | Assaying bladder-associated samples, identifying and treating bladder-associated neoplasia, and kits for use therein |
CN113490528A (en) | 2019-02-15 | 2021-10-08 | 诺华股份有限公司 | 3- (1-oxo-5- (piperidine-4-yl) isoindoline-2-yl) piperidine-2, 6-dione derivatives and uses thereof |
EP3924055B1 (en) | 2019-02-15 | 2024-04-03 | Novartis AG | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
PT3927370T (en) | 2019-02-19 | 2024-06-03 | Turnstone Biologics Corp | Methods for producing autologous t cells useful to treat cancers and compositions thereof |
US11793802B2 (en) | 2019-03-20 | 2023-10-24 | Sumitomo Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (AML) with venetoclax failure |
MX2021011289A (en) | 2019-03-22 | 2021-11-03 | Sumitomo Pharma Oncology Inc | Compositions comprising pkm2 modulators and methods of treatment using the same. |
EP3946437A1 (en) | 2019-03-29 | 2022-02-09 | Myst Therapeutics, LLC | Ex vivo methods for producing a t cell therapeutic and related compositions and methods |
SG11202109441UA (en) | 2019-04-12 | 2021-09-29 | Vascular Biogenics Ltd | Methods of anti-tumor therapy |
US20220211847A1 (en) | 2019-05-06 | 2022-07-07 | Medimmune Limited | Combination of monalizumab, durvalumab, chemotherapy and bevacizumab or cetuximab for the treatment of colorectal cancer |
KR20220026585A (en) | 2019-06-26 | 2022-03-04 | 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 | IL1RAP binding protein |
CA3145864A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
CA3152027A1 (en) | 2019-08-30 | 2021-03-04 | Agenus Inc. | Anti-cd96 antibodies and methods of use thereof |
KR20220058601A (en) | 2019-09-05 | 2022-05-09 | 아스트라제네카 아베 | Compositions and methods for treating expanded stage small cell lung cancer (ES-SCLC) |
WO2021043961A1 (en) | 2019-09-06 | 2021-03-11 | Glaxosmithkline Intellectual Property Development Limited | Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy |
TW202124446A (en) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | Combination therapies with entpd2 antibodies |
JP2022548078A (en) | 2019-09-18 | 2022-11-16 | モレキュラー テンプレーツ,インク. | PD-L1 binding molecules containing Shiga toxin A subunit scaffolds |
WO2021055816A1 (en) | 2019-09-18 | 2021-03-25 | Molecular Templates, Inc. | Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds |
EP4031578A1 (en) | 2019-09-18 | 2022-07-27 | Novartis AG | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
US20230405105A1 (en) | 2019-09-20 | 2023-12-21 | Transgene Sa | Combination of a poxvirus encoding hpv polypeptides with an anti-pd-l1 antibody |
EP4034562A2 (en) | 2019-09-27 | 2022-08-03 | GlaxoSmithKline Intellectual Property Development Limited | Antigen binding proteins |
EP4023672A1 (en) * | 2019-09-30 | 2022-07-06 | Harbour Biomed (Shanghai) Co., Ltd | Anti-pd-l1 antigen binding protein, and application thereof |
CA3157024A1 (en) | 2019-10-03 | 2021-04-08 | Xencor, Inc. | Targeted il-12 heterodimeric fc-fusion proteins |
TW202128757A (en) | 2019-10-11 | 2021-08-01 | 美商建南德克公司 | Pd-1 targeted il-15/il-15ralpha fc fusion proteins with improved properties |
US11781138B2 (en) | 2019-10-14 | 2023-10-10 | Aro Biotherapeutics Company | FN3 domain-siRNA conjugates and uses thereof |
WO2021076546A1 (en) | 2019-10-14 | 2021-04-22 | Aro Biotherapeutics Company | Cd71 binding fibronectin type iii domains |
KR20220103947A (en) | 2019-10-21 | 2022-07-25 | 노파르티스 아게 | Combination Therapy with Venetoclax and TIM-3 Inhibitors |
AU2020370832A1 (en) | 2019-10-21 | 2022-05-19 | Novartis Ag | TIM-3 inhibitors and uses thereof |
CA3151629A1 (en) | 2019-11-07 | 2021-05-14 | Laura E. BENJAMIN | Classification of tumor microenvironments |
US20230000864A1 (en) | 2019-11-22 | 2023-01-05 | Sumitomo Pharma Oncology, Inc. | Solid dose pharmaceutical composition |
WO2021108727A1 (en) | 2019-11-27 | 2021-06-03 | Myst Therapeutics, Inc. | Method of producing tumor-reactive t cell composition using modulatory agents |
MX2022007759A (en) | 2019-12-20 | 2022-07-19 | Novartis Ag | Combination of anti tim-3 antibody mbg453 and anti tgf-beta antibody nis793, with or without decitabine or the anti pd-1 antibody spartalizumab, for treating myelofibrosis and myelodysplastic syndrome. |
KR20220128389A (en) | 2020-01-17 | 2022-09-20 | 노파르티스 아게 | A combination comprising a TIM-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia |
CA3167689A1 (en) | 2020-01-28 | 2021-08-05 | Glaxosmithkline Intellectual Property Development Limited | Combination treatments and uses and methods thereof |
AU2021227687B2 (en) | 2020-02-26 | 2023-02-23 | Vir Biotechnology, Inc. | Antibodies against SARS-CoV-2 and methods of using the same |
CA3172902A1 (en) | 2020-02-27 | 2021-09-02 | Myst Therapeutics, Llc | Methods for ex vivo enrichment and expansion of tumor reactive t cells and related compositions thereof |
WO2021194942A1 (en) | 2020-03-23 | 2021-09-30 | Bristol-Myers Squibb Company | Anti-ccr8 antibodies for treating cancer |
CN115461362A (en) | 2020-04-14 | 2022-12-09 | 葛兰素史密斯克莱知识产权发展有限公司 | Cancer combination therapy based on ICOS antibody and PD-L1 antibody TGF-beta receptor fusion protein |
CA3176356A1 (en) | 2020-04-22 | 2021-10-28 | Anne BROOKS | Systems and methods for coordinating manufacturing of cells for patient-specific immunotherapy |
US20210332105A1 (en) | 2020-04-24 | 2021-10-28 | Astrazeneca Ab | Compositions and methods of treating cancer with chimeric antigen receptors |
AU2021269832B2 (en) | 2020-05-12 | 2024-09-19 | Astrazeneca Ab | Methods and combinations for the treatment of cancer using immune checkpoint inhibitor antibodies |
US20230374597A1 (en) | 2020-05-12 | 2023-11-23 | Astrazeneca Ab | Biomarkers for predicting overall survival in recorrent/metastatic head and neck squamous cell carcinoma |
JP2023526400A (en) | 2020-05-21 | 2023-06-21 | アストラゼネカ・アクチエボラーグ | Mutational Burden Associated with Immunotherapy Susceptibility in Locally Advanced or Metastatic Urothelial Cancer |
TW202214857A (en) | 2020-06-19 | 2022-04-16 | 法商昂席歐公司 | New conjugated nucleic acid molecules and their uses |
CN115916199A (en) | 2020-06-23 | 2023-04-04 | 诺华股份有限公司 | Dosing regimens comprising 3- (1-oxoisoindolin-2-yl) piperidine-2, 6-dione derivatives |
US20230250173A1 (en) | 2020-07-01 | 2023-08-10 | Pfizer Inc. | Biomarkers for pd-1 axis binding antagonist therapy |
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 |
JP2023544635A (en) | 2020-10-12 | 2023-10-24 | アストラゼネカ・アクチエボラーグ | Adjuvant durvalumab in combination with chemotherapy for the treatment of cancer |
WO2022086957A1 (en) | 2020-10-20 | 2022-04-28 | Genentech, Inc. | Peg-conjugated anti-mertk antibodies and methods of use |
WO2022097060A1 (en) | 2020-11-06 | 2022-05-12 | Novartis Ag | Cd19 binding molecules and uses thereof |
TW202237119A (en) | 2020-12-10 | 2022-10-01 | 美商住友製藥腫瘤公司 | Alk-5 inhibitors and uses thereof |
EP4263600A1 (en) | 2020-12-18 | 2023-10-25 | Century Therapeutics, Inc. | Chimeric antigen receptor systems with adaptable receptor specificity |
CN116744971A (en) * | 2021-01-04 | 2023-09-12 | 上海翰森生物医药科技有限公司 | anti-ERBB 3 receptor antibody or antigen binding fragment thereof and medical application thereof |
EP4284510A1 (en) | 2021-01-29 | 2023-12-06 | Novartis AG | Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof |
TW202241508A (en) | 2021-01-29 | 2022-11-01 | 美商艾歐凡斯生物治療公司 | Cytokine associated tumor infiltrating lymphocytes compositions and methods |
US20240139198A1 (en) | 2021-02-10 | 2024-05-02 | Curon Biopharmaceutical (Shanghai) Co., Limited | Method and combination for treating tumors |
BR112023017296A2 (en) | 2021-03-02 | 2023-11-14 | Glaxosmithkline Ip Dev Ltd | SUBSTITUTED PYRIDIINES AS DNMT1 INHIBITORS |
WO2022195551A1 (en) | 2021-03-18 | 2022-09-22 | Novartis Ag | Biomarkers for cancer and methods of use thereof |
IL306090A (en) | 2021-03-25 | 2023-11-01 | Oncxerna Therapeutics Inc | Targeted therapies in cancer |
MX2023011332A (en) | 2021-03-26 | 2023-10-03 | Astrazeneca Ab | Combination treatments for melanoma. |
EP4314060A1 (en) | 2021-03-31 | 2024-02-07 | GlaxoSmithKline Intellectual Property Development Limited | Antigen binding proteins and combinations thereof |
TW202304979A (en) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
AU2022253351A1 (en) | 2021-04-09 | 2023-10-12 | Ose Immunotherapeutics | New scaffold for bifunctional molecules with improved properties |
WO2022214652A1 (en) | 2021-04-09 | 2022-10-13 | Ose Immunotherapeutics | Scaffold for bifunctioanl molecules comprising pd-1 or cd28 and sirp binding domains |
PE20240327A1 (en) | 2021-04-13 | 2024-02-22 | Nuvalent Inc | HETEROCYCLES WITH AMINO SUBSTITUTION TO TREAT CANCERS WITH EGFR MUTATIONS |
BR112023021325A2 (en) | 2021-04-14 | 2023-12-19 | Aro Biotherapeutics Company | CD71-BINDING TYPE III FIBRONECTIN DOMAINS |
WO2022226539A1 (en) * | 2021-04-23 | 2022-10-27 | Immunome, Inc. | Methods of administering antibodies against sars-cov-2 spike protein |
AR125874A1 (en) | 2021-05-18 | 2023-08-23 | Novartis Ag | COMBINATION THERAPIES |
CN117396222A (en) | 2021-05-21 | 2024-01-12 | 天津立博美华基因科技有限责任公司 | Pharmaceutical combination and use thereof |
BR112023023833A2 (en) | 2021-05-24 | 2024-01-30 | Astrazeneca Ab | COMPOSITIONS AND METHODS FOR TREATMENT OF LUNG CANCER |
CN117412767A (en) | 2021-05-25 | 2024-01-16 | 雪绒花免疫公司 | C-X-C motif chemokine receptor 6 (CXCR 6) binding molecules and methods of use thereof |
WO2022247972A2 (en) | 2021-05-26 | 2022-12-01 | Centro De Inmunologia Molecular | Use of therapeutic compositions for the treatment of patients with tumours of epithelial origin |
IL309662A (en) | 2021-07-02 | 2024-02-01 | Univ Yale | Compositions and methods for treating cancers |
EP4395832A1 (en) | 2021-08-31 | 2024-07-10 | Yale University | Compositions and methods for treating cancers |
KR20240051162A (en) | 2021-09-02 | 2024-04-19 | 도이체스크레브스포르슝스젠트룸스티프퉁데스외펜트리헨레크츠 | Anti-CECAM6 antibody with reduced side effects |
CN118159568A (en) | 2021-10-21 | 2024-06-07 | 杭州阿诺生物医药科技有限公司 | Fusion polypeptide and application thereof |
IL313439A (en) | 2021-12-16 | 2024-08-01 | Valerio Therapeutics | New conjugated nucleic acid molecules and their uses |
WO2023147488A1 (en) | 2022-01-28 | 2023-08-03 | Iovance Biotherapeutics, Inc. | Cytokine associated tumor infiltrating lymphocytes compositions and methods |
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 |
IL315265A (en) | 2022-03-03 | 2024-10-01 | Pfizer Inc | Multispecific antibodies and uses thereof |
WO2023170008A1 (en) | 2022-03-07 | 2023-09-14 | Astrazeneca Ab | Method for predicting patient response to immunotherapy |
WO2023174210A1 (en) | 2022-03-14 | 2023-09-21 | Laekna Limited | Combination treatment for cancer |
AU2022447580A1 (en) | 2022-03-18 | 2024-10-17 | Astrazeneca Ab | Methods of treating biliary tract cancer using anti-pd-l1 antibody in combination with chemotherapy |
WO2023201369A1 (en) | 2022-04-15 | 2023-10-19 | Iovance Biotherapeutics, Inc. | Til expansion processes using specific cytokine combinations and/or akti treatment |
WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
AR129423A1 (en) | 2022-05-27 | 2024-08-21 | Viiv Healthcare Co | USEFUL COMPOUNDS IN HIV THERAPY |
WO2024003241A1 (en) | 2022-06-30 | 2024-01-04 | Astrazeneca Ab | Treatment for immuno-oncology resistant subjects with an anti pd-l1 antibody an antisense targeted to stat3 and an inhibitor of ctla-4 |
WO2024030906A2 (en) * | 2022-08-05 | 2024-02-08 | Hbm Alpha Therapeutics, Inc. | Anti-corticotropin-releasing hormone antibodies and polycystic ovary syndrome |
WO2024040175A1 (en) | 2022-08-18 | 2024-02-22 | Pulmatrix Operating Company, Inc. | Methods for treating cancer using inhaled angiogenesis inhibitor |
TW202428254A (en) | 2022-09-09 | 2024-07-16 | 瑞典商阿斯特捷利康公司 | Compositions and methods for treating advanced solid tumors |
US20240190982A1 (en) | 2022-11-03 | 2024-06-13 | Incyte Corporation | Combination therapies comprising an anti-gitr antibody for treating cancers |
WO2024112571A2 (en) | 2022-11-21 | 2024-05-30 | Iovance Biotherapeutics, Inc. | Two-dimensional processes for the expansion of tumor infiltrating lymphocytes and therapies therefrom |
WO2024115966A2 (en) | 2022-12-01 | 2024-06-06 | Innate Pharma | Compositions and methods for neoadjuvant treatment in cancer |
WO2024151885A1 (en) | 2023-01-13 | 2024-07-18 | Iovance Biotherapeutics, Inc. | Use of til as maintenance therapy for nsclc patients who achieved pr/cr after prior therapy |
WO2024163477A1 (en) | 2023-01-31 | 2024-08-08 | University Of Rochester | Immune checkpoint blockade therapy for treating staphylococcus aureus infections |
WO2024192051A1 (en) | 2023-03-13 | 2024-09-19 | Turnstone Biologics Corp. | Composition of selected tumor infiltrating lymphocytes and related methods of producing and using the same |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050226883A1 (en) * | 2004-02-06 | 2005-10-13 | Paul Averback | Humanized antibody |
US20090055944A1 (en) * | 2005-07-01 | 2009-02-26 | Medarex, Inc. | Human monoclonal antibodies to be programmed death ligand 1 (pd-l1) |
Family Cites Families (142)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3180193A (en) | 1963-02-25 | 1965-04-27 | Benedict David | Machines for cutting lengths of strip material |
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
FR2413974A1 (en) | 1978-01-06 | 1979-08-03 | David Bernard | DRYER FOR SCREEN-PRINTED SHEETS |
US4263428A (en) | 1978-03-24 | 1981-04-21 | The Regents Of The University Of California | Bis-anthracycline nucleic acid function inhibitors and improved method for administering the same |
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
EP0052322B1 (en) | 1980-11-10 | 1985-03-27 | Gersonde, Klaus, Prof. Dr. | Method of preparing lipid vesicles by ultrasonic treatment, the use of this method and apparatus for its application |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
US4474893A (en) | 1981-07-01 | 1984-10-02 | The University of Texas System Cancer Center | Recombinant monoclonal antibodies |
US4714681A (en) | 1981-07-01 | 1987-12-22 | The Board Of Reagents, The University Of Texas System Cancer Center | Quadroma cells and trioma cells and methods for the production of same |
US4485045A (en) | 1981-07-06 | 1984-11-27 | Research Corporation | Synthetic phosphatidyl cholines useful in forming liposomes |
EP0088046B1 (en) | 1982-02-17 | 1987-12-09 | Ciba-Geigy Ag | Lipids in the aqueous phase |
DE3218121A1 (en) | 1982-05-14 | 1983-11-17 | Leskovar, Peter, Dr.-Ing., 8000 München | Pharmaceutical compositions for tumour treatment |
EP0102324A3 (en) | 1982-07-29 | 1984-11-07 | Ciba-Geigy Ag | Lipids and surfactants in an aqueous medium |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4675187A (en) | 1983-05-16 | 1987-06-23 | Bristol-Myers Company | BBM-1675, a new antibiotic complex |
US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
HUT35524A (en) | 1983-08-02 | 1985-07-29 | Hoechst Ag | Process for preparing pharmaceutical compositions containing regulatory /regulative/ peptides providing for the retarded release of the active substance |
ATE59966T1 (en) | 1983-09-26 | 1991-02-15 | Ehrenfeld Udo | MEDICATION AND PRODUCT FOR THE DIAGNOSIS AND THERAPY OF TUMORS AND FOR THE TREATMENT OF WEAKNESSES IN THE CELLULAR AND HUMORAL IMMUNE DEFENSE. |
US4615885A (en) | 1983-11-01 | 1986-10-07 | Terumo Kabushiki Kaisha | Pharmaceutical composition containing urokinase |
US4681581A (en) | 1983-12-05 | 1987-07-21 | Coates Fredrica V | Adjustable size diaper and folding method therefor |
US4740461A (en) | 1983-12-27 | 1988-04-26 | Genetics Institute, Inc. | Vectors and methods for transformation of eucaryotic cells |
US4735210A (en) | 1985-07-05 | 1988-04-05 | Immunomedics, Inc. | Lymphographic and organ imaging method and kit |
US5776093A (en) | 1985-07-05 | 1998-07-07 | Immunomedics, Inc. | Method for imaging and treating organs and tissues |
US5101827A (en) | 1985-07-05 | 1992-04-07 | Immunomedics, Inc. | Lymphographic and organ imaging method and kit |
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 |
WO1987006265A1 (en) | 1986-04-17 | 1987-10-22 | Kyowa Hakko Kogyo Co., Ltd. | Novel compounds dc-88a and dc-89a1 and process for their preparation |
US4959455A (en) | 1986-07-14 | 1990-09-25 | Genetics Institute, Inc. | Primate hematopoietic growth factors IL-3 and pharmaceutical compositions |
US4912040A (en) | 1986-11-14 | 1990-03-27 | Genetics Institute, Inc. | Eucaryotic expression system |
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 |
WO1988007089A1 (en) | 1987-03-18 | 1988-09-22 | Medical Research Council | Altered antibodies |
US5677425A (en) | 1987-09-04 | 1997-10-14 | Celltech Therapeutics Limited | Recombinant antibody |
US5648471A (en) | 1987-12-03 | 1997-07-15 | Centocor, Inc. | One vial method for labeling antibodies with Technetium-99m |
US4925648A (en) | 1988-07-29 | 1990-05-15 | Immunomedics, Inc. | Detection and treatment of infectious and inflammatory lesions |
US5601819A (en) | 1988-08-11 | 1997-02-11 | The General Hospital Corporation | Bispecific antibodies for selective immune regulation and for selective immune cell binding |
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 |
DE3920358A1 (en) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE |
DE69029036T2 (en) | 1989-06-29 | 1997-05-22 | Medarex Inc | SPECIFIC REAGENTS FOR AIDS THERAPY |
ATE172879T1 (en) | 1989-08-09 | 1998-11-15 | Rhomed Inc | DIRECT RADIO LABELING OF ANTIBODIES AND OTHER PROTEINS USING TECHNETIUM OR RHENIUM |
JP2840866B2 (en) | 1989-11-28 | 1998-12-24 | 日本ゼオン株式会社 | Adhesive composition of nitrile group-containing highly saturated copolymer rubber and organic synthetic fiber |
JP3068180B2 (en) | 1990-01-12 | 2000-07-24 | アブジェニックス インコーポレイテッド | Generation of heterologous antibodies |
US6673986B1 (en) | 1990-01-12 | 2004-01-06 | Abgenix, Inc. | Generation of xenogeneic 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 |
US5151510A (en) | 1990-04-20 | 1992-09-29 | Applied Biosystems, Inc. | Method of synethesizing sulfurized oligonucleotide analogs |
FR2664073A1 (en) | 1990-06-29 | 1992-01-03 | Thomson Csf | MEANS FOR MARKING OBJECTS, METHOD FOR PRODUCING THE SAME, AND DEVICE FOR READING. |
CA2086417C (en) | 1990-06-29 | 1999-07-06 | Biosource Technologies, Inc. | Melanin production by transformed organisms |
US6300129B1 (en) | 1990-08-29 | 2001-10-09 | Genpharm International | Transgenic non-human animals for producing heterologous antibodies |
ATE352612T1 (en) | 1990-08-29 | 2007-02-15 | Pharming Intellectual Pty Bv | HOMOLOGOUS RECOMBINATION IN MAMMAL CELLS |
US5874299A (en) | 1990-08-29 | 1999-02-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5789650A (en) | 1990-08-29 | 1998-08-04 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
ATE158021T1 (en) | 1990-08-29 | 1997-09-15 | Genpharm Int | PRODUCTION AND USE OF NON-HUMAN TRANSGENT ANIMALS FOR THE PRODUCTION OF HETEROLOGUE ANTIBODIES |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US6255458B1 (en) | 1990-08-29 | 2001-07-03 | Genpharm International | High affinity human antibodies and human antibodies against digoxin |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5194594A (en) | 1990-09-07 | 1993-03-16 | Techniclone, Inc. | Modified antibodies |
ATE160379T1 (en) | 1990-10-29 | 1997-12-15 | Chiron Corp | BISPECIFIC ANTIBODIES, METHOD FOR THE PRODUCTION THEREOF AND USES THEREOF |
WO1992019973A1 (en) | 1991-04-26 | 1992-11-12 | Surface Active Limited | Novel antibodies, and methods for their use |
WO1992022670A1 (en) | 1991-06-12 | 1992-12-23 | Genpharm International, Inc. | Early detection of transgenic embryos |
WO1992022653A1 (en) | 1991-06-14 | 1992-12-23 | Genentech, Inc. | Method for making humanized antibodies |
AU2235992A (en) | 1991-06-14 | 1993-01-12 | Genpharm International, Inc. | Transgenic immunodeficient non-human animals |
AU2515992A (en) | 1991-08-20 | 1993-03-16 | Genpharm International, Inc. | Gene targeting in animal cells using isogenic dna constructs |
EP0617706B1 (en) | 1991-11-25 | 2001-10-17 | Enzon, Inc. | Multivalent antigen-binding proteins |
JPH07503132A (en) | 1991-12-17 | 1995-04-06 | ジェンファーム インターナショナル,インコーポレイティド | Transgenic non-human animals capable of producing xenoantibodies |
CA2452130A1 (en) | 1992-03-05 | 1993-09-16 | Francis J. Burrows | Methods and compositions for targeting the vasculature of solid tumors |
AU4116793A (en) | 1992-04-24 | 1993-11-29 | Board Of Regents, The University Of Texas System | Recombinant production of immunoglobulin-like domains in prokaryotic cells |
CA2135313A1 (en) | 1992-06-18 | 1994-01-06 | Theodore Choi | Methods for producing transgenic non-human animals harboring a yeast artificial chromosome |
ES2301158T3 (en) | 1992-07-24 | 2008-06-16 | Amgen Fremont Inc. | XENOGENIC ANTIBODY PRODUCTION. |
WO1994004690A1 (en) | 1992-08-17 | 1994-03-03 | Genentech, Inc. | Bispecific immunoadhesins |
WO1994013804A1 (en) | 1992-12-04 | 1994-06-23 | Medical Research Council | Multivalent and multispecific binding proteins, their manufacture and use |
US5981175A (en) | 1993-01-07 | 1999-11-09 | Genpharm Internation, Inc. | Methods for producing recombinant mammalian cells harboring a yeast artificial chromosome |
JPH08509612A (en) | 1993-04-26 | 1996-10-15 | ジェンファーム インターナショナル インコーポレイテッド | Transgenic non-human animal capable of producing heterologous antibody |
US5885573A (en) | 1993-06-01 | 1999-03-23 | Arch Development Corporation | Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies |
CA2163345A1 (en) | 1993-06-16 | 1994-12-22 | Susan Adrienne Morgan | Antibodies |
US5625825A (en) | 1993-10-21 | 1997-04-29 | Lsi Logic Corporation | Random number generating apparatus for an interface unit of a carrier sense with multiple access and collision detect (CSMA/CD) ethernet data network |
JPH07309761A (en) | 1994-05-20 | 1995-11-28 | Kyowa Hakko Kogyo Co Ltd | Method for stabilizing duocamycin derivative |
US5643763A (en) | 1994-11-04 | 1997-07-01 | Genpharm International, Inc. | Method for making recombinant yeast artificial chromosomes by minimizing diploid doubling during mating |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
US6121022A (en) | 1995-04-14 | 2000-09-19 | Genentech, Inc. | Altered polypeptides with increased half-life |
US5869046A (en) | 1995-04-14 | 1999-02-09 | Genentech, Inc. | Altered polypeptides with increased half-life |
AU2466895A (en) | 1995-04-28 | 1996-11-18 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
TW311927B (en) | 1995-07-11 | 1997-08-01 | Minnesota Mining & Mfg | |
DE69636868T2 (en) | 1995-08-29 | 2007-10-25 | Kirin Beer Kabushiki Kaisha | CHIMERIC ANIMAL AND METHOD FOR THE PRODUCTION THEREOF |
GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
KR19990082463A (en) | 1996-02-13 | 1999-11-25 | 돈 리사 로얄 | Quinazolin derivatives as vascular endothelial growth factor inhibitors |
CN1116286C (en) | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
EP0904107B1 (en) | 1996-03-18 | 2004-10-20 | Board Of Regents, The University Of Texas System | Immunoglobin-like domains with increased half lives |
GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
WO1998023289A1 (en) | 1996-11-27 | 1998-06-04 | The General Hospital Corporation | MODULATION OF IgG BINDING TO FcRn |
KR20080059467A (en) | 1996-12-03 | 2008-06-27 | 아브게닉스, 인크. | Transgenic mammals having human ig loci including plural vh and vk regions and antibodies produced therefrom |
WO1998035985A1 (en) | 1997-02-12 | 1998-08-20 | The Regents Of The University Of Michigan | Protein markers for lung cancer and use thereof |
US6277375B1 (en) | 1997-03-03 | 2001-08-21 | Board Of Regents, The University Of Texas System | Immunoglobulin-like domains with increased half-lives |
GB9714249D0 (en) | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
DK2180007T4 (en) | 1998-04-20 | 2017-11-27 | Roche Glycart Ag | Glycosylation technique for antibodies to enhance antibody-dependent cell cytotoxicity |
GB9809951D0 (en) | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
WO2000034784A1 (en) | 1998-12-10 | 2000-06-15 | Phylos, Inc. | Protein scaffolds for antibody mimics and other binding proteins |
GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
GB9900752D0 (en) | 1999-01-15 | 1999-03-03 | Angiogene Pharm Ltd | Benzimidazole vascular damaging agents |
KR20060067983A (en) | 1999-01-15 | 2006-06-20 | 제넨테크, 인크. | Polypeptide variants with altered effector function |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
KR100838617B1 (en) | 1999-02-10 | 2008-06-16 | 아스트라제네카 아베 | Quinazoline derivatives as angiogenesis inhibitors |
EP2275541B1 (en) | 1999-04-09 | 2016-03-23 | Kyowa Hakko Kirin Co., Ltd. | Method for controlling the activity of immunologically functional molecule |
US6833268B1 (en) | 1999-06-10 | 2004-12-21 | Abgenix, Inc. | Transgenic animals for producing specific isotypes of human antibodies via non-cognate switch regions |
US7504256B1 (en) | 1999-10-19 | 2009-03-17 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing polypeptide |
PT1244647E (en) | 1999-11-05 | 2006-10-31 | Astrazeneca Ab | QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS |
ME00415B (en) | 2000-02-15 | 2011-10-10 | Pharmacia & Upjohn Co Llc | Pyrrole substituted 2-indolinone protein kinase inhibitors |
IL152682A0 (en) | 2000-05-31 | 2003-06-24 | Astrazeneca Ab | Indole derivatives with vascular damaging activity |
UA73993C2 (en) | 2000-06-06 | 2005-10-17 | Астразенека Аб | Quinazoline derivatives for the treatment of tumours and a pharmaceutical composition |
CN1255391C (en) | 2000-07-07 | 2006-05-10 | 安吉奥金尼药品有限公司 | COLCHINOL derivatives as vascular damaging agents |
PL359181A1 (en) | 2000-07-07 | 2004-08-23 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as angiogenesis inhibitors |
EA013224B1 (en) | 2000-10-06 | 2010-04-30 | Киова Хакко Кирин Ко., Лтд. | Cells producing antibody compositions |
US6946292B2 (en) | 2000-10-06 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Cells producing antibody compositions with increased antibody dependent cytotoxic activity |
EP1333032A4 (en) | 2000-10-06 | 2005-03-16 | Kyowa Hakko Kogyo Kk | Method of purifying antibody |
ATE489395T1 (en) | 2000-12-12 | 2010-12-15 | Medimmune Llc | MOLECULES WITH LONGER HALF-LIFE, COMPOSITIONS AND THEIR USE |
US20040002587A1 (en) | 2002-02-20 | 2004-01-01 | Watkins Jeffry D. | Fc region variants |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
DE10161767T1 (en) * | 2002-07-03 | 2018-06-07 | Honjo Tasuku | Immunopotentiating compositions containing an anti-PD-L1 antibody |
EP3502133A1 (en) | 2002-09-27 | 2019-06-26 | Xencor, Inc. | Optimized fc variants and methods for their generation |
EP2368578A1 (en) | 2003-01-09 | 2011-09-28 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
US20050226867A1 (en) | 2003-10-08 | 2005-10-13 | Kyowa Hakko Kogyo Co., Ltd. | IL-5R-specific antibody composition |
RS52036B (en) * | 2004-12-21 | 2012-04-30 | Medimmune Limited | Antibodies directed to angiopoietin-2 and uses thereof |
PT2397156T (en) * | 2005-06-08 | 2016-12-23 | The President And Fellows Of Harvard College | Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (pd-1)pathway |
TW200815469A (en) * | 2006-06-23 | 2008-04-01 | Astrazeneca Ab | Compounds |
EP2061504A4 (en) * | 2006-09-20 | 2010-01-27 | Univ Johns Hopkins | Combinatorieal therapy of cancer and infectious diseases with anti-b7-h1 antibodies |
CN101663323A (en) * | 2006-12-27 | 2010-03-03 | 埃默里大学 | The composition and the method that are used for the treatment of transmissible disease and tumour |
EP2170959B1 (en) * | 2007-06-18 | 2013-10-02 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
WO2009089149A1 (en) * | 2008-01-03 | 2009-07-16 | The Johns Hopkins University | B7-h1 (cd274) antagonists induce apoptosis of tumor cells |
KR101050829B1 (en) * | 2008-10-02 | 2011-07-20 | 서울대학교산학협력단 | Anticancer agents comprising an anti-PD-1 antibody or an anti-PD-L1 antibody |
CN108997498A (en) * | 2008-12-09 | 2018-12-14 | 霍夫曼-拉罗奇有限公司 | Anti- PD-L1 antibody and they be used to enhance the purposes of T cell function |
DK3279215T3 (en) * | 2009-11-24 | 2020-04-27 | Medimmune Ltd | TARGETED BINDING AGENTS B7-H1 |
JP6071725B2 (en) | 2013-04-23 | 2017-02-01 | カルソニックカンセイ株式会社 | Driving force control device for electric vehicles |
US9209965B2 (en) | 2014-01-14 | 2015-12-08 | Microsemi Semiconductor Ulc | Network interface with clock recovery module on line card |
US11392902B2 (en) | 2017-06-06 | 2022-07-19 | United Parcel Service Of America, Inc. | Systems, methods, apparatuses and computer program products for providing notification of items for pickup and delivery |
US11284893B2 (en) | 2019-04-02 | 2022-03-29 | Covidien Lp | Stapling device with articulating tool assembly |
-
2010
- 2010-11-24 DK DK17179204.7T patent/DK3279215T3/en active
- 2010-11-24 MX MX2012005809A patent/MX2012005809A/en active IP Right Grant
- 2010-11-24 KR KR1020127016372A patent/KR101573109B1/en active IP Right Review Request
- 2010-11-24 RS RS20171053A patent/RS56469B1/en unknown
- 2010-11-24 RS RS20200271A patent/RS60033B1/en unknown
- 2010-11-24 ES ES10833923.5T patent/ES2646863T3/en active Active
- 2010-11-24 NZ NZ599405A patent/NZ599405A/en unknown
- 2010-11-24 WO PCT/US2010/058007 patent/WO2011066389A1/en active Application Filing
- 2010-11-24 KR KR1020177011850A patent/KR101790767B1/en active IP Right Grant
- 2010-11-24 EP EP17179204.7A patent/EP3279215B1/en active Active
- 2010-11-24 LT LTEP17179204.7T patent/LT3279215T/en unknown
- 2010-11-24 HU HUE10833923A patent/HUE037159T2/en unknown
- 2010-11-24 LT LTEP10833923.5T patent/LT2504364T/en unknown
- 2010-11-24 KR KR1020157031862A patent/KR101740171B1/en active IP Right Grant
- 2010-11-24 DK DK10833923.5T patent/DK2504364T3/en active
- 2010-11-24 JP JP2012540171A patent/JP5837504B2/en active Active
- 2010-11-24 HU HUE17179204A patent/HUE049647T2/en unknown
- 2010-11-24 US US13/511,538 patent/US8779108B2/en active Active
- 2010-11-24 NO NO10833923A patent/NO2504364T3/no unknown
- 2010-11-24 EP EP10833923.5A patent/EP2504364B1/en active Active
- 2010-11-24 BR BR122021025338-2A patent/BR122021025338B1/en active IP Right Grant
- 2010-11-24 AU AU2010324757A patent/AU2010324757C1/en active Active
- 2010-11-24 KR KR1020177030381A patent/KR101934071B1/en active IP Right Grant
- 2010-11-24 RU RU2012126138A patent/RU2571204C3/en active Protection Beyond IP Right Term
- 2010-11-24 PT PT171792047T patent/PT3279215T/en unknown
- 2010-11-24 MX MX2015000738A patent/MX343747B/en unknown
- 2010-11-24 PL PL10833923T patent/PL2504364T3/en unknown
- 2010-11-24 CA CA2992770A patent/CA2992770A1/en not_active Abandoned
- 2010-11-24 SI SI201031562T patent/SI2504364T1/en unknown
- 2010-11-24 PT PT108339235T patent/PT2504364T/en unknown
- 2010-11-24 ES ES17179204T patent/ES2793330T3/en active Active
- 2010-11-24 BR BR112012012465-0A patent/BR112012012465B1/en active IP Right Grant
- 2010-11-24 MX MX2016015254A patent/MX359551B/en unknown
- 2010-11-24 NZ NZ628923A patent/NZ628923A/en unknown
- 2010-11-24 CN CN201080053042.1A patent/CN102918058B/en active Active
- 2010-11-24 PL PL17179204T patent/PL3279215T3/en unknown
- 2010-11-24 CA CA2778714A patent/CA2778714C/en active Active
- 2010-11-24 SI SI201031998T patent/SI3279215T1/en unknown
- 2010-11-24 CN CN201510112039.7A patent/CN104961829B/en active Active
- 2010-11-24 RU RU2015147286A patent/RU2706200C2/en active
-
2012
- 2012-05-17 IL IL219876A patent/IL219876A/en active Protection Beyond IP Right Term
-
2013
- 2013-03-15 HK HK18105585.0A patent/HK1246310A1/en unknown
-
2014
- 2014-05-06 US US14/271,108 patent/US9493565B2/en active Active
-
2015
- 2015-11-05 JP JP2015217170A patent/JP6047646B2/en active Active
-
2016
- 2016-01-28 IL IL243813A patent/IL243813A/en active IP Right Grant
- 2016-06-06 AU AU2016203758A patent/AU2016203758C1/en active Active
- 2016-10-25 US US15/333,683 patent/US10400039B2/en active Active
- 2016-11-21 JP JP2016225703A patent/JP6271684B2/en active Active
-
2017
- 2017-10-30 CY CY20171101127T patent/CY1119743T1/en unknown
- 2017-10-30 HR HRP20171653TT patent/HRP20171653T1/en unknown
- 2017-12-27 JP JP2017250880A patent/JP6480561B2/en active Active
-
2019
- 2019-01-09 FR FR19C1001C patent/FR19C1001I2/en active Active
- 2019-01-09 LT LTPA2019002C patent/LTC2504364I2/en unknown
- 2019-01-14 CY CY2019003C patent/CY2019003I2/en unknown
- 2019-01-14 LU LU00097C patent/LUC00097I2/en unknown
- 2019-01-14 NL NL300964C patent/NL300964I2/en unknown
- 2019-01-14 NO NO2019002C patent/NO2019002I1/no unknown
- 2019-01-14 HU HUS1900002C patent/HUS1900002I1/en unknown
- 2019-02-07 JP JP2019020325A patent/JP6700447B2/en active Active
- 2019-07-23 US US16/519,614 patent/US11518809B2/en active Active
-
2020
- 2020-03-09 HR HRP20200383TT patent/HRP20200383T1/en unknown
- 2020-04-22 CY CY20201100370T patent/CY1122816T1/en unknown
-
2022
- 2022-11-01 US US18/051,773 patent/US20230235062A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050226883A1 (en) * | 2004-02-06 | 2005-10-13 | Paul Averback | Humanized antibody |
US20090055944A1 (en) * | 2005-07-01 | 2009-02-26 | Medarex, Inc. | Human monoclonal antibodies to be programmed death ligand 1 (pd-l1) |
Non-Patent Citations (5)
Title |
---|
LI ET AL.: "Anti-Programmed Death-1 Synergized with Granulocyte Macrophage Colony- Stimulating Factor-Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors", CLINICAL CANCER RESEARCH, vol. 15, no. 5, March 2009 (2009-03-01), pages 1623 - 1634, XP055166457, DOI: doi:10.1158/1078-0432.CCR-08-1825 * |
LIN ET AL.: "The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors", PNAS, vol. 105, no. 8, 26 February 2008 (2008-02-26), USA, pages 3011 - 3016, XP002683218, DOI: doi:10.1073/PNAS.0712278105 * |
LIN, D ET AL., PROC. NATL. ACAD. SCI. USA, vol. 105, 2008, pages 3011 - 3016 |
NOMI ET AL.: "Clinical Significance and Therapeutic Potential of the Programmed Death-1 Pathway in Human Pancreatic Cancer", CLINICAL CANCER RESEARCH, vol. 13, 2007, pages 2151 - 2157, XP002533527, DOI: doi:10.1158/1078-0432.CCR-06-2746 * |
STROME ET AL.: "B7-H1 Blockade Augments Adoptive t-Cell Immunotherapy for Squamous Cell Carcinoma", CANCER RESEARCH, vol. 63, 2003, pages 6501 - 6505, XP002487684 * |
Cited By (826)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11685792B2 (en) | 2008-01-31 | 2023-06-27 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Antibodies against human CD39 and use thereof for inhibiting T regulatory cells activity |
US10662253B2 (en) | 2008-01-31 | 2020-05-26 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Antibodies against human CD39 and use thereof for inhibiting T regulatory cells activity |
US10072087B2 (en) | 2009-12-10 | 2018-09-11 | Hoffmann-La Roche Inc. | Antibodies against human CSF-1R and uses thereof |
US11492383B2 (en) | 2011-06-24 | 2022-11-08 | Stephen D. Gillies | Light chain immunoglobulin fusion proteins and methods of use thereof |
US10646567B2 (en) | 2011-08-01 | 2020-05-12 | Genentech, Inc. | Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors |
US11884724B2 (en) | 2011-11-28 | 2024-01-30 | Merck Patent Gmbh | Anti-PD-L1 antibodies and uses thereof |
US9624298B2 (en) | 2011-11-28 | 2017-04-18 | Merck Patent Gmbh | Anti-PD-L1 antibodies and uses thereof |
US10759856B2 (en) | 2011-11-28 | 2020-09-01 | Merck Patent Gmbh | Anti-PD-L1 antibodies and uses thereof |
EP3763741A1 (en) | 2011-11-28 | 2021-01-13 | Merck Patent GmbH | Anti-pd-l1 antibodies and uses thereof |
US10487147B2 (en) | 2011-11-28 | 2019-11-26 | Merck Patent Gmbh | Anti-PD-L1 antibodies and uses thereof |
WO2013079174A1 (en) | 2011-11-28 | 2013-06-06 | Merck Patent Gmbh | Anti-pd-l1 antibodies and uses thereof |
US10266594B1 (en) | 2012-05-15 | 2019-04-23 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10577423B2 (en) | 2012-05-15 | 2020-03-03 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US9856320B2 (en) | 2012-05-15 | 2018-01-02 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10323093B2 (en) | 2012-05-15 | 2019-06-18 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
EP3309175A1 (en) | 2012-05-15 | 2018-04-18 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting pd-1/pd-l1 signaling |
US10266595B2 (en) | 2012-05-15 | 2019-04-23 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10266596B1 (en) | 2012-05-15 | 2019-04-23 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10323092B2 (en) | 2012-05-15 | 2019-06-18 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10138299B2 (en) | 2012-05-15 | 2018-11-27 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10316090B2 (en) | 2012-05-15 | 2019-06-11 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10584170B2 (en) | 2012-05-15 | 2020-03-10 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US9212224B2 (en) | 2012-05-15 | 2015-12-15 | Bristol-Myers Squibb Company | Antibodies that bind PD-L1 and uses thereof |
US10604575B2 (en) | 2012-05-15 | 2020-03-31 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10072082B2 (en) | 2012-05-15 | 2018-09-11 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10316091B2 (en) | 2012-05-15 | 2019-06-11 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
US10308714B2 (en) | 2012-05-15 | 2019-06-04 | Bristol-Myers Squibb Company | Cancer immunotherapy by disrupting PD-1/PD-L1 signaling |
JP2020073571A (en) * | 2012-05-31 | 2020-05-14 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | Antigen binding protein that binds pd-l1 |
JP2015519375A (en) * | 2012-05-31 | 2015-07-09 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | Antigen binding protein that binds to PD-L1 |
US11878058B2 (en) | 2012-05-31 | 2024-01-23 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind PD-L1 |
US10058609B2 (en) | 2012-05-31 | 2018-08-28 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind PD-L1 |
CN109467601A (en) * | 2012-05-31 | 2019-03-15 | 索伦托治疗有限公司 | Antigen-binding proteins in conjunction with PD-L1 |
EP2854843A4 (en) * | 2012-05-31 | 2016-06-01 | Sorrento Therapeutics Inc | Antigen binding proteins that bind pd-l1 |
EP3553086A1 (en) * | 2012-05-31 | 2019-10-16 | Sorrento Therapeutics Inc. | Antigen binding proteins that bind pd-l1 |
CN109467601B (en) * | 2012-05-31 | 2022-07-08 | 索伦托药业有限公司 | Antigen binding proteins that bind to PD-L1 |
JP2017197586A (en) * | 2012-05-31 | 2017-11-02 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | Antigen binding protein that binds pd-l1 |
US11027012B2 (en) | 2012-05-31 | 2021-06-08 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind PD-L1 |
WO2014008218A1 (en) | 2012-07-02 | 2014-01-09 | Bristol-Myers Squibb Company | Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof |
EP3795592A1 (en) | 2012-07-02 | 2021-03-24 | Bristol-Myers Squibb Company | Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof |
EP3275899A1 (en) | 2012-07-02 | 2018-01-31 | Bristol-Myers Squibb Company | Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof |
US10548988B2 (en) | 2012-07-18 | 2020-02-04 | Birdie Biopharmaceuticals, Inc. | Compounds for targeted immunotherapy |
US10660971B2 (en) | 2012-07-18 | 2020-05-26 | Birdie Biopharmaceuticals, Inc. | Compounds for targeted immunotherapy |
EP3263601A1 (en) | 2012-10-02 | 2018-01-03 | Bristol-Myers Squibb Company | Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer |
WO2014055648A1 (en) | 2012-10-02 | 2014-04-10 | Bristol-Myers Squibb Company | Combination of anti-kir antibodies and anti-pd-1 antibodies to treat cancer |
US9828434B2 (en) | 2012-10-04 | 2017-11-28 | Dana-Farber Cancer Institute, Inc. | Human monoclonal anti-PD-L1 antibodies and methods of use |
EP2903641A2 (en) * | 2012-10-04 | 2015-08-12 | Dana-Farber Cancer Institute, Inc. | Human monoclonal anti-pd-l1 antibodies and methods of use |
US10604581B2 (en) | 2012-10-04 | 2020-03-31 | Dana-Farber Cancer Institute, Inc. | Human monoclonal anti-PD-L1 antibodies and methods of use |
US11578372B2 (en) | 2012-11-05 | 2023-02-14 | Foundation Medicine, Inc. | NTRK1 fusion molecules and uses thereof |
EP2926142B1 (en) | 2012-11-30 | 2018-11-07 | F.Hoffmann-La Roche Ag | Identification of patients in need of pd-l1 inhibitor cotherapy |
US11226339B2 (en) | 2012-12-11 | 2022-01-18 | Albert Einstein College Of Medicine | Methods for high throughput receptor:ligand identification |
KR102208505B1 (en) * | 2012-12-11 | 2021-01-27 | 앨버트 아인슈타인 컬리지 오브 메디신 | Methods for high throughput receptor:ligand identification |
KR20150094674A (en) * | 2012-12-11 | 2015-08-19 | 알버트 아인슈타인 컬리지 오브 메디신 오브 예쉬바 유니버시티 | Methods for high throughput receptor:ligand identification |
CN113321731A (en) * | 2012-12-21 | 2021-08-31 | 默沙东公司 | Antibodies that bind human programmed death ligand 1(PD-L1) |
JP2019193665A (en) * | 2012-12-21 | 2019-11-07 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Antibodies that bind to human programmed death ligand 1 (pd-l1) |
JP2021097705A (en) * | 2012-12-21 | 2021-07-01 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Antibodies that bind to human programmed death ligand 1 (PD-L1) |
JP2016504336A (en) * | 2012-12-21 | 2016-02-12 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Antibody binding to human programmed death ligand 1 (PD-L1) |
EP2943507B1 (en) | 2013-01-10 | 2020-02-26 | Genmab A/S | Inert format |
US20150344577A1 (en) * | 2013-01-11 | 2015-12-03 | Dingfu Biotarget Co., Ltd | Agents for treating tumors, use and method thereof |
US11771698B2 (en) | 2013-01-18 | 2023-10-03 | Foundation Medicine, Inc. | Methods of treating cholangiocarcinoma |
US11458195B2 (en) | 2013-02-22 | 2022-10-04 | Curevac Ag | Combination of vaccination and inhibition of the PD-1 pathway |
EP3292873B1 (en) | 2013-02-22 | 2019-05-01 | CureVac AG | Combination of vaccination and inhibition of the pd-1 pathway |
US10167336B2 (en) | 2013-03-14 | 2019-01-01 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
US11299544B2 (en) | 2013-03-15 | 2022-04-12 | Genentech, Inc. | Biomarkers and methods of treating PD-1 and PD-L1 related conditions |
US9192667B2 (en) | 2013-04-22 | 2015-11-24 | Hoffmann-La Roche Inc. | Method of treating cancer by administering CSF-1R antibodies and a TLR9 agonist |
WO2015016718A1 (en) | 2013-08-02 | 2015-02-05 | Bionovion Holding B.V. | Combining cd27 agonists and immune checkpoint inhibition for immune stimulation |
EP3366289A1 (en) | 2013-09-06 | 2018-08-29 | Aurigene Discovery Technologies Limited | Cyclic peptidomimetic compounds as immunomodulators |
US11512060B2 (en) | 2013-09-06 | 2022-11-29 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
WO2015033303A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | Cyclic peptidomimetic compounds as immunomodulators |
EP3363790A1 (en) | 2013-09-06 | 2018-08-22 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US10173989B2 (en) | 2013-09-06 | 2019-01-08 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
WO2015033299A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US9771338B2 (en) | 2013-09-06 | 2017-09-26 | Auirgene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US10160736B2 (en) | 2013-09-06 | 2018-12-25 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
US10961205B2 (en) | 2013-09-06 | 2021-03-30 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US10590093B2 (en) | 2013-09-06 | 2020-03-17 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US12037321B2 (en) | 2013-09-06 | 2024-07-16 | Aurigene Oncology Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US10106581B2 (en) | 2013-09-06 | 2018-10-23 | Aurigene Discovery Technologies Limited | Cyclic peptidomimetic compounds as immunomodulators |
WO2015033301A1 (en) | 2013-09-06 | 2015-03-12 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
EP3385257A1 (en) | 2013-09-06 | 2018-10-10 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
US9776978B2 (en) | 2013-09-06 | 2017-10-03 | Aurigene Discovery Technologies Limited | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators |
CN105873606A (en) * | 2013-09-11 | 2016-08-17 | 米迪缪尼有限公司 | Anti-b7-h1 antibodies for treating tumors |
IL274462A (en) * | 2013-09-11 | 2020-06-30 | Medimmune Ltd | Anti-b7-h1 antibodies for treating tumors |
WO2015036499A1 (en) * | 2013-09-11 | 2015-03-19 | Medimmune Limited | Anti-b7-h1 antibodies for treating tumors |
CN105873606B (en) * | 2013-09-11 | 2020-12-29 | 米迪缪尼有限公司 | anti-B7-H1 antibodies for the treatment of tumors |
US10336823B2 (en) | 2013-09-11 | 2019-07-02 | Medimmune Limited | Anti-B7-H1 antibodies for treating tumors |
US11827706B2 (en) | 2013-09-11 | 2023-11-28 | Medimmune Limited | Anti-B7-H1 antibodies for treating tumors |
EP3656398A1 (en) | 2013-09-11 | 2020-05-27 | MedImmune Limited | Anti-b7-h1 antibodies for treating tumors |
AU2020223728B2 (en) * | 2013-09-11 | 2024-03-07 | Medimmune Limited | Anti-b7-h1 antibodies for treating tumors |
US10829557B2 (en) | 2013-09-11 | 2020-11-10 | Medimmune Limited | Anti-B7-H1 antibodies for treating tumors |
RU2701327C2 (en) * | 2013-09-11 | 2019-09-25 | Медиммьюн Лимитед | Antibodies to b7-h1 for treating tumours |
US11512133B2 (en) | 2013-09-12 | 2022-11-29 | Hoffmann-La Roche Inc. | Methods for treating colon cancer or inhibiting cell proliferation by administering a combination of antibodies against human CSF-1R and antibodies against human PD-L1 |
WO2015036511A1 (en) * | 2013-09-12 | 2015-03-19 | F. Hoffmann-La Roche Ag | Combination therapy of antibodies against human csf-1r and antibodies against human pd-l1 |
EP3508502A1 (en) | 2013-09-20 | 2019-07-10 | Bristol-Myers Squibb Company | Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors |
US11274152B2 (en) | 2013-09-20 | 2022-03-15 | Bristol-Myers Squibb Company | Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors |
US10081681B2 (en) | 2013-09-20 | 2018-09-25 | Bristol-Myers Squibb Company | Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors |
EP4249065A2 (en) | 2013-09-20 | 2023-09-27 | Bristol-Myers Squibb Company | Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors |
WO2015042246A1 (en) | 2013-09-20 | 2015-03-26 | Bristol-Myers Squibb Company | Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors |
US10570204B2 (en) | 2013-09-26 | 2020-02-25 | The Medical College Of Wisconsin, Inc. | Methods for treating hematologic cancers |
US11708412B2 (en) | 2013-09-26 | 2023-07-25 | Novartis Ag | Methods for treating hematologic cancers |
US10259875B2 (en) | 2013-10-01 | 2019-04-16 | Mayo Foundation For Medical Education And Research | Methods for treating cancer in patients with elevated levels of BIM |
US11136393B2 (en) | 2013-10-01 | 2021-10-05 | Mayo Foundation For Medical Education And Research | Methods for treating cancer in patients with elevated levels of Bim |
EP3647324A1 (en) | 2013-12-17 | 2020-05-06 | F. Hoffmann-La Roche AG | Methods of treating cancers using pd-1 axis binding antagonists and taxanes |
US20170008971A1 (en) * | 2013-12-17 | 2017-01-12 | Genentech, Inc. | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
EP3680254A1 (en) | 2013-12-17 | 2020-07-15 | F. Hoffmann-La Roche AG | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
WO2015095410A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody |
EP3527587A1 (en) | 2013-12-17 | 2019-08-21 | F. Hoffmann-La Roche AG | Combination therapy comprising ox40 binding agonists and pd-l1 binding antagonists |
DE202014010421U1 (en) | 2013-12-17 | 2015-11-12 | Kymab Limited | Human goals |
WO2015095418A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
WO2015095423A2 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
US10548985B2 (en) | 2014-01-10 | 2020-02-04 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for treating EGFR expressing tumors |
US10328158B2 (en) | 2014-01-10 | 2019-06-25 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for immunotherapy |
US10744206B2 (en) | 2014-01-10 | 2020-08-18 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for immunotherapy |
US11633495B2 (en) | 2014-01-10 | 2023-04-25 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for immunotherapy |
US11786604B2 (en) | 2014-01-10 | 2023-10-17 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for treating HER2 positive tumors |
US11633494B2 (en) | 2014-01-10 | 2023-04-25 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for immunotherapy |
US10780180B2 (en) | 2014-01-10 | 2020-09-22 | Birdie Biopharmaceuticals, Inc. | Compounds and compositions for immunotherapy |
US10737113B2 (en) | 2014-01-23 | 2020-08-11 | Regeneron Pharmaceuticals, Inc. | Human antibodies to PD-1 |
EA034695B1 (en) * | 2014-01-23 | 2020-03-06 | Регенерон Фармасьютикалс, Инк. | Human antibodies to pd-l1 |
US9938345B2 (en) | 2014-01-23 | 2018-04-10 | Regeneron Pharmaceuticals, Inc. | Human antibodies to PD-L1 |
EP3473648A1 (en) | 2014-01-23 | 2019-04-24 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-l1 |
US11117970B2 (en) | 2014-01-23 | 2021-09-14 | Regeneron Pharmaceuticals, Inc. | Human antibodies to PD-L1 |
AU2015209238B2 (en) * | 2014-01-23 | 2019-09-12 | Regeneron Pharmaceuticals, Inc. | Human antibodies to PD-L1 |
US9987500B2 (en) | 2014-01-23 | 2018-06-05 | Regeneron Pharmaceuticals, Inc. | Human antibodies to PD-1 |
WO2015112805A1 (en) | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-l1 |
TWI680138B (en) * | 2014-01-23 | 2019-12-21 | 美商再生元醫藥公司 | Human antibodies to pd-l1 |
US9683048B2 (en) | 2014-01-24 | 2017-06-20 | Novartis Ag | Antibody molecules to PD-1 and uses thereof |
US9815898B2 (en) | 2014-01-24 | 2017-11-14 | Novartis Ag | Antibody molecules to PD-1 and uses thereof |
US11827704B2 (en) | 2014-01-24 | 2023-11-28 | Novartis Ag | Antibody molecules to PD-1 and uses thereof |
US10752687B2 (en) | 2014-01-24 | 2020-08-25 | Novartis Ag | Antibody molecules to PD-1 and uses thereof |
US9605070B2 (en) | 2014-01-31 | 2017-03-28 | Novartis Ag | Antibody molecules to TIM-3 and uses thereof |
US10981990B2 (en) | 2014-01-31 | 2021-04-20 | Novartis Ag | Antibody molecules to TIM-3 and uses thereof |
US9884913B2 (en) | 2014-01-31 | 2018-02-06 | Novartis Ag | Antibody molecules to TIM-3 and uses thereof |
US10472419B2 (en) | 2014-01-31 | 2019-11-12 | Novartis Ag | Antibody molecules to TIM-3 and uses thereof |
US11155620B2 (en) | 2014-01-31 | 2021-10-26 | Novartis Ag | Method of detecting TIM-3 using antibody molecules to TIM-3 |
US11370819B2 (en) | 2014-02-10 | 2022-06-28 | Merck Patent Gmbh | Targeted TGFβ inhibition |
US11773175B2 (en) | 2014-03-04 | 2023-10-03 | Kymab Limited | Antibodies, uses and methods |
US11753479B2 (en) | 2014-03-04 | 2023-09-12 | Kymab Limited | Nucleic acids encoding anti-OX40L antibodies |
US11110157B2 (en) | 2014-03-12 | 2021-09-07 | Curevac Ag | Combination of vaccination and OX40 agonists |
US10730951B2 (en) | 2014-03-31 | 2020-08-04 | Genentech, Inc. | Anti-OX40 antibodies and methods of use |
US9975957B2 (en) | 2014-03-31 | 2018-05-22 | Genentech, Inc. | Anti-OX40 antibodies and methods of use |
US10302653B2 (en) | 2014-05-22 | 2019-05-28 | Mayo Foundation For Medical Education And Research | Distinguishing antagonistic and agonistic anti B7-H1 antibodies |
US20160031990A1 (en) * | 2014-05-29 | 2016-02-04 | Medlmmune, Llc | Antagonists of pdl-1 and pd-1 for the treatment of hpv-negative cancers |
EP3610924A1 (en) | 2014-06-06 | 2020-02-19 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
WO2015187835A2 (en) | 2014-06-06 | 2015-12-10 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
EP3998079A1 (en) | 2014-06-06 | 2022-05-18 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
WO2015195163A1 (en) * | 2014-06-20 | 2015-12-23 | R-Pharm Overseas, Inc. | Pd-l1 antagonist fully human antibody |
US11279761B2 (en) | 2014-07-09 | 2022-03-22 | Birdie Biopharmaceuticals, Inc. | Anti-PD-L1 combinations for treating tumors |
WO2016004876A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
EP4001311A1 (en) | 2014-07-09 | 2022-05-25 | Birdie Biopharmaceuticals Inc. | Anti-pd-l1 combinations for treating tumors |
US10689445B2 (en) | 2014-07-11 | 2020-06-23 | Ventana Medical Systems, Inc. | Anti-PD-L1 antibodies and diagnostic uses thereof |
WO2016007235A1 (en) | 2014-07-11 | 2016-01-14 | Genentech, Inc. | Anti-pd-l1 antibodies and diagnostic uses thereof |
EP3309174A1 (en) | 2014-07-11 | 2018-04-18 | Genentech, Inc. | Anti-pd-l1 antibodies and diagnostic uses thereof |
US11530269B2 (en) | 2014-07-11 | 2022-12-20 | Ventana Medical Systems, Inc. | Anti-PD-L1 antibodies and diagnostic uses thereof |
EP3563870A1 (en) | 2014-07-15 | 2019-11-06 | F. Hoffmann-La Roche AG | Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors |
US10946093B2 (en) | 2014-07-15 | 2021-03-16 | Genentech, Inc. | Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors |
WO2016011160A1 (en) | 2014-07-15 | 2016-01-21 | Genentech, Inc. | Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors |
US10517875B2 (en) | 2014-07-23 | 2019-12-31 | Mayo Foundation for Medical Engineering and Research | Targeting DNA-PKcs and B7-H1 to treat cancer |
US11504376B2 (en) | 2014-07-23 | 2022-11-22 | Mayo Foundation For Medical Education And Research | Targeting DNA-PKCS and B7-H1 to treat cancer |
WO2016030455A1 (en) | 2014-08-28 | 2016-03-03 | Medimmune Limited | Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small lung cancer |
EP3763742A1 (en) | 2014-09-01 | 2021-01-13 | Birdie Biopharmaceuticals Inc. | Anti-pd-l1 conjugates for treating tumors |
EP4148069A1 (en) | 2014-09-01 | 2023-03-15 | Birdie Biopharmaceuticals Inc. | Anti-pd-l1 conjugates for treating tumors |
US11130812B2 (en) | 2014-09-01 | 2021-09-28 | Birdie Biopharmaceuticals, Inc. | Anti PD-L1 conjugates for treating tumors |
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) |
RU2817281C2 (en) * | 2014-09-11 | 2024-04-12 | Медиммьюн Лимитед | Antibodies to b7-h1 for treating tumours |
US11344620B2 (en) | 2014-09-13 | 2022-05-31 | Novartis Ag | Combination therapies |
EP4368205A1 (en) | 2014-09-16 | 2024-05-15 | Innate Pharma | Neutralization of inhibitory pathways in lymphocytes |
EP3799885A1 (en) | 2014-09-16 | 2021-04-07 | Innate Pharma | Neutralization of inhibitory pathways in lymphocytes |
EP3689910A2 (en) | 2014-09-23 | 2020-08-05 | F. Hoffmann-La Roche AG | Method of using anti-cd79b immunoconjugates |
EP3736294A2 (en) | 2014-10-10 | 2020-11-11 | Innate Pharma | Cd73 blockade |
US10851165B2 (en) | 2014-10-14 | 2020-12-01 | Novartis Ag | Antibody molecules to PD-L1 and methods of treating cancer |
US9988452B2 (en) | 2014-10-14 | 2018-06-05 | Novartis Ag | Antibody molecules to PD-L1 and uses thereof |
EP3550019A1 (en) | 2014-10-24 | 2019-10-09 | Astrazeneca AB | Combination |
WO2016081384A1 (en) | 2014-11-17 | 2016-05-26 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
EP4141032A1 (en) | 2014-11-20 | 2023-03-01 | F. Hoffmann-La Roche AG | Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists |
EP3789402A1 (en) | 2014-11-20 | 2021-03-10 | F. Hoffmann-La Roche AG | Combination therapy of t cell activating bispecific antigen binding molecules and pd-1 axis binding antagonists |
EP3725808A1 (en) | 2014-11-21 | 2020-10-21 | Bristol-Myers Squibb Company | Antibodies against cd73 and uses thereof |
EP3789399A1 (en) | 2014-11-21 | 2021-03-10 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
WO2016081748A2 (en) | 2014-11-21 | 2016-05-26 | Bristol-Myers Squibb Company | Antibodies against cd73 and uses thereof |
WO2016090300A1 (en) | 2014-12-05 | 2016-06-09 | Genentech, Inc. | Methods and compositions for treating cancer using pd-1 axis antagonists and hpk1 antagonists |
EP3808775A1 (en) * | 2014-12-09 | 2021-04-21 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized cluster of differentiation 274 gene |
US9913461B2 (en) | 2014-12-09 | 2018-03-13 | Regeneron Pharmaceuticals, Inc. | Genetically modified mouse whose genome comprises a humanized CD274 gene |
US12089575B2 (en) | 2014-12-09 | 2024-09-17 | Regeneron Pharmaceuticals, Inc. | Genetically modified mouse that expresses humanized PD1 and PD-L1 proteins |
US10881086B2 (en) | 2014-12-09 | 2021-01-05 | Regeneron Pharmaceuticals, Inc. | Genetically modified mouse whose genome comprises a humanized CD274 gene |
WO2016094481A1 (en) * | 2014-12-09 | 2016-06-16 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a humanized cluster of differentiation 274 gene |
CN113412818A (en) * | 2014-12-09 | 2021-09-21 | 瑞泽恩制药公司 | Non-human animal having humanized cluster of differentiation 274 gene |
EP4249066A2 (en) | 2014-12-23 | 2023-09-27 | Bristol-Myers Squibb Company | Antibodies to tigit |
US11534489B2 (en) | 2015-01-09 | 2022-12-27 | Agency For Science, Technology And Research | Anti-PD-L1 antibodies |
US9789183B1 (en) | 2015-01-09 | 2017-10-17 | Agency For Science, Technology And Research | Anti-PD-L1 antibodies |
WO2016111645A1 (en) * | 2015-01-09 | 2016-07-14 | Agency For Science, Technology And Research | Anti-pd-l1 antibodies |
US10517949B2 (en) | 2015-01-09 | 2019-12-31 | Agency For Science, Technology And Research | Anti-PD-L1 antibodies |
WO2016127052A1 (en) | 2015-02-05 | 2016-08-11 | Bristol-Myers Squibb Company | Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy |
US10357491B2 (en) | 2015-03-06 | 2019-07-23 | Beyondspring Pharmaceuticals, Inc. | Method of treating a brain tumor |
US10238650B2 (en) | 2015-03-06 | 2019-03-26 | Beyondspring Pharmaceuticals, Inc. | Method of treating cancer associated with a RAS mutation |
US11045467B2 (en) | 2015-03-06 | 2021-06-29 | Beyondspring Pharmaceuticals, Inc. | Method of treating cancer associated with a RAS mutation |
US10668063B2 (en) | 2015-03-06 | 2020-06-02 | Beyondspring Pharmaceuticals, Inc. | Method of treating cancer associated with a RAS mutation |
US10076518B2 (en) | 2015-03-06 | 2018-09-18 | Beyondspring Pharmaceuticals, Inc. | Method of treating a brain tumor |
US11918574B2 (en) | 2015-03-06 | 2024-03-05 | Beyondspring Pharmaceuticals, Inc. | Method of treating cancer associated with a RAS mutation |
US10781189B2 (en) | 2015-03-10 | 2020-09-22 | Aurigene Discovery Technologies Limited | 1,2,4-Oxadiazole and thiadiazole compounds as immunomodulators |
WO2016142833A1 (en) | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
US11465976B2 (en) | 2015-03-10 | 2022-10-11 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
EP4023645A1 (en) | 2015-03-10 | 2022-07-06 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
US10669339B2 (en) | 2015-03-13 | 2020-06-02 | Cytomx Therapeutics, Inc. | Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof |
AU2016233495B2 (en) * | 2015-03-13 | 2022-02-24 | Cytomx Therapeutics, Inc | Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof |
WO2016149201A3 (en) * | 2015-03-13 | 2016-11-24 | Cytomx Therapeutics, Inc. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
US11174316B2 (en) | 2015-03-13 | 2021-11-16 | Cytomx Therapeutics, Inc. | Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of use thereof |
US10336824B2 (en) | 2015-03-13 | 2019-07-02 | Cytomx Therapeutics, Inc. | Anti-PDL1 antibodies, activatable anti-PDL1 antibodies, and methods of thereof |
WO2016146259A1 (en) | 2015-03-16 | 2016-09-22 | Amal Therapeutics Sa | A novel complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for treatment of glioblastoma |
EP3693009A1 (en) | 2015-03-16 | 2020-08-12 | Amal Therapeutics SA | A novel complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for treatment of colorectal cancer |
WO2016146261A1 (en) | 2015-03-16 | 2016-09-22 | Amal Therapeutics Sa | Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine |
US11933786B2 (en) | 2015-03-30 | 2024-03-19 | Stcube, Inc. | Antibodies specific to glycosylated PD-L1 and methods of use thereof |
EP3277320A4 (en) * | 2015-03-30 | 2018-08-01 | Stcube, Inc. | Antibodies specific to glycosylated pd-l1 and methods of use thereof |
US10836827B2 (en) | 2015-03-30 | 2020-11-17 | Stcube, Inc. | Antibodies specific to glycosylated PD-L1 and methods of use thereof |
US11491204B2 (en) | 2015-04-07 | 2022-11-08 | Cytlimic Inc. | Composition comprising poly I:C and LAG-3-IGG fusion protein |
WO2016166348A1 (en) * | 2015-04-17 | 2016-10-20 | Elsalys Biotech | Anti-tyro3 antibodies and uses thereof |
CN108064245A (en) * | 2015-04-17 | 2018-05-22 | 埃尔萨里斯生物技术公司 | Anti- Tyro3 antibody and application thereof |
CN104830788A (en) * | 2015-05-05 | 2015-08-12 | 杨光华 | DC cell based on HBV-HCV antigen, targeting immune cell population, preparation method and applications thereof |
EP3783029A1 (en) | 2015-05-12 | 2021-02-24 | F. Hoffmann-La Roche AG | Therapeutic and diagnostic methods for cancer |
WO2016181349A1 (en) | 2015-05-14 | 2016-11-17 | Pfizer Inc. | Combinations comprising a pyrrolidine-2,5-dione ido1 inhibitor and an anti-body |
US10945994B2 (en) | 2015-05-14 | 2021-03-16 | Pfizer Inc. | Combinations comprising a pyrrolidine-2,5-dione IDO1 inhibitor and an anti-body |
WO2016196381A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Pd-l1 promoter methylation in cancer |
EP3763827A1 (en) | 2015-05-29 | 2021-01-13 | F. Hoffmann-La Roche AG | Pd-l1 promoter methylation in cancer |
WO2016196228A1 (en) | 2015-05-29 | 2016-12-08 | Bristol-Myers Squibb Company | Antibodies against ox40 and uses thereof |
EP4335931A2 (en) | 2015-05-29 | 2024-03-13 | F. Hoffmann-La Roche AG | Therapeutic and diagnostic methods for cancer |
US11254987B2 (en) | 2015-05-29 | 2022-02-22 | Genentech, Inc. | PD-L1 promoter methylation in cancer |
WO2016196298A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Therapeutic and diagnolstic methods for cancer |
EP3708681A1 (en) | 2015-05-29 | 2020-09-16 | F. Hoffmann-La Roche AG | Therapeutic and diagnostic methods for cancer |
WO2016196218A1 (en) | 2015-05-31 | 2016-12-08 | Curegenix Corporation | Combination compositions for immunotherapy |
WO2016200835A1 (en) | 2015-06-08 | 2016-12-15 | Genentech, Inc. | Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists |
WO2016197204A1 (en) | 2015-06-11 | 2016-12-15 | Bionomics Limited | Pharmaceutical combination and uses thereof |
WO2016201425A1 (en) | 2015-06-12 | 2016-12-15 | Bristol-Myers Squibb Company | Treatment of cancer by combined blockade of the pd-1 and cxcr4 signaling pathways |
WO2016205320A1 (en) | 2015-06-17 | 2016-12-22 | Genentech, Inc. | Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes |
WO2017004016A1 (en) | 2015-06-29 | 2017-01-05 | The Rockefeller University | Antibodies to cd40 with enhanced agonist activity |
US10155748B2 (en) | 2015-07-13 | 2018-12-18 | Beyondspring Pharmaceuticals, Inc. | Plinabulin compositions |
US11254657B2 (en) | 2015-07-13 | 2022-02-22 | Beyondspring Pharmaceuticals, Inc. | Plinabulin compositions |
US12024501B2 (en) | 2015-07-13 | 2024-07-02 | Beyondspring Pharmaceuticals, Inc. | Plinabulin compositions |
US10550104B2 (en) | 2015-07-13 | 2020-02-04 | Beyondspring Pharmaceuticals, Inc. | Plinabulin compositions |
EP3878465A1 (en) | 2015-07-29 | 2021-09-15 | Novartis AG | Combination therapies comprising antibody molecules to tim-3 |
WO2017019894A1 (en) | 2015-07-29 | 2017-02-02 | Novartis Ag | Combination therapies comprising antibody molecules to lag-3 |
EP3964528A1 (en) | 2015-07-29 | 2022-03-09 | Novartis AG | Combination therapies comprising antibody molecules to lag-3 |
EP4378957A2 (en) | 2015-07-29 | 2024-06-05 | Novartis AG | Combination therapies comprising antibody molecules to pd-1 |
WO2017019897A1 (en) | 2015-07-29 | 2017-02-02 | Novartis Ag | Combination therapies comprising antibody molecules to tim-3 |
US11225522B2 (en) | 2015-07-31 | 2022-01-18 | Suzhou Alphamab Co., Ltd. | Single domain antibody and derivative proteins thereof against programmed death-ligand (PDL1) |
EP3330290A4 (en) * | 2015-07-31 | 2019-08-28 | Suzhou Alphamab Co., Ltd | Single domain antibody for programmed death-ligand (pd-l1) and derived protein thereof |
RU2715595C2 (en) * | 2015-07-31 | 2020-03-02 | 3Д Медисинес (Бейджинг) Ко., Лтд. | Single-domain antibody and derivatives thereof to ligand-1 protein of programmed cell death (pdli) |
EP3348571A4 (en) * | 2015-07-31 | 2019-04-10 | Jiangsu Alphamab Biopharmaceuticals Co., Ltd. | Single domain antibody for programmed death-ligand (pd-l1) and derived protein thereof |
AU2016302951B2 (en) * | 2015-07-31 | 2019-10-10 | 3D Medicines (Beijing) Co., Ltd. | Single domain antibody for programmed death-ligand (PD-L1) and derived protein thereof |
EP3332006B1 (en) * | 2015-08-06 | 2023-10-11 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
WO2017020858A1 (en) | 2015-08-06 | 2017-02-09 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-pd-l1 antibodies |
US10981995B2 (en) | 2015-08-06 | 2021-04-20 | Wuxi Biologies Ireland Limited | Anti-PD-L1 antibodies |
US10214586B2 (en) | 2015-08-24 | 2019-02-26 | Eli Lilly And Company | PD-L1 antibodies |
EA039736B1 (en) * | 2015-09-15 | 2022-03-04 | Сайтомкс Терапьютикс, Инк. | Anti-pdl1 antibodies, activatable anti-pdl1 antibodies, and methods of use thereof |
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 |
WO2017058780A1 (en) | 2015-09-30 | 2017-04-06 | Merck Patent Gmbh | Combination of a pd-1 axis binding antagonist and an alk inhibitor for treating alk-negative cancer |
EP3360893A4 (en) * | 2015-10-10 | 2019-01-23 | Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences | High-affinity and soluble pdl-1 molecule |
WO2017064043A1 (en) | 2015-10-12 | 2017-04-20 | Innate Pharma | Cd73 blocking agents |
US10875923B2 (en) | 2015-10-30 | 2020-12-29 | Mayo Foundation For Medical Education And Research | Antibodies to B7-H1 |
WO2017075045A3 (en) * | 2015-10-30 | 2017-06-08 | Mayo Foundation For Medical Education And Research | Antibodies to b7-h1 |
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 |
AU2016357901B2 (en) * | 2015-11-17 | 2023-05-25 | Jiangsu Hengrui Medicine Co., Ltd. | Pd-l1 antibody, antigen-binding fragment thereof and medical application thereof |
TWI718206B (en) * | 2015-11-17 | 2021-02-11 | 大陸商江蘇恆瑞醫藥股份有限公司 | Pd-l1 antibody, antigen-binding fragments and pharmaceutical use thereof |
EP3378871A4 (en) * | 2015-11-17 | 2019-08-07 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Pd-l1 antibody, antigen fragment binding thereof and pharmaceutical use thereof |
US11780923B2 (en) | 2015-11-17 | 2023-10-10 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | PD-L1 antibody, antigen-binding fragment thereof and medical application thereof |
WO2017087678A2 (en) | 2015-11-19 | 2017-05-26 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
WO2017087851A1 (en) | 2015-11-19 | 2017-05-26 | Genentech, Inc. | Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors |
US11981736B2 (en) | 2015-12-02 | 2024-05-14 | St Cube Inc. | Antibodies specific to glycosylated PD-1 and methods of use thereof |
US10858432B2 (en) | 2015-12-02 | 2020-12-08 | Stcube, Inc. | Antibodies specific to glycosylated PD-1 and methods of use thereof |
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 |
EP4026848A1 (en) | 2015-12-09 | 2022-07-13 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody for reducing the cytokine release syndrome |
WO2017106656A1 (en) | 2015-12-17 | 2017-06-22 | Novartis Ag | Antibody molecules to pd-1 and uses thereof |
EP4424322A2 (en) | 2015-12-17 | 2024-09-04 | Novartis AG | Antibody molecules to pd-1 and uses thereof |
US12054557B2 (en) | 2015-12-22 | 2024-08-06 | Regeneron Pharmaceuticals, Inc. | Combination of anti-PD-1 antibodies and bispecific anti-CD20/anti-CD3 antibodies to treat cancer |
WO2017112741A1 (en) | 2015-12-22 | 2017-06-29 | Novartis Ag | Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy |
WO2017118634A1 (en) | 2016-01-04 | 2017-07-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
US11220552B2 (en) | 2016-01-07 | 2022-01-11 | Birdie Biopharmaceuticals, Inc. | Anti-CD20 combinations for treating tumors |
US11136397B2 (en) | 2016-01-07 | 2021-10-05 | Birdie Pharmaceuticals, Inc. | Anti-EGFR combinations for treating tumors |
US11046781B2 (en) | 2016-01-07 | 2021-06-29 | Birdie Biopharmaceuticals, Inc. | Anti-HER2 combinations for treating tumors |
US11702476B2 (en) | 2016-01-07 | 2023-07-18 | Birdie Biopharmaceuticals, Inc. | Anti-EGFR combinations for treating tumors |
EP3862365A1 (en) | 2016-01-08 | 2021-08-11 | F. Hoffmann-La Roche AG | Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies |
US10596257B2 (en) | 2016-01-08 | 2020-03-24 | Hoffmann-La Roche Inc. | Methods of treating CEA-positive cancers using PD-1 axis binding antagonists and anti-CEA/anti-CD3 bispecific antibodies |
WO2017125532A1 (en) | 2016-01-21 | 2017-07-27 | Innate Pharma | Neutralization of inhibitory pathways in lymphocytes |
EP3868787A1 (en) | 2016-01-21 | 2021-08-25 | Innate Pharma | Neutralization of inhibitory pathways in lymphocytes |
EP4421094A2 (en) | 2016-02-05 | 2024-08-28 | Orionis Biosciences BV | Targeted therapeutic agents and uses thereof |
WO2017134302A2 (en) | 2016-02-05 | 2017-08-10 | Orionis Biosciences Nv | Targeted therapeutic agents and uses thereof |
EP4059957A1 (en) | 2016-02-05 | 2022-09-21 | Orionis Biosciences BV | Bispecific signaling agents and uses thereof |
EP3998281A1 (en) | 2016-02-05 | 2022-05-18 | Orionis Biosciences BV | Cd8 binding agents |
WO2017134305A1 (en) | 2016-02-05 | 2017-08-10 | Orionis Biosciences Nv | Bispecific signaling agents and uses thereof |
EP3909978A1 (en) | 2016-02-05 | 2021-11-17 | Orionis Biosciences BV | Clec9a binding agents and use thereof |
US10912748B2 (en) | 2016-02-08 | 2021-02-09 | Beyondspring Pharmaceuticals, Inc. | Compositions containing tucaresol or its analogs |
US11857522B2 (en) | 2016-02-08 | 2024-01-02 | Beyondspring Pharmaceuticals, Inc. | Compositions containing tucaresol or its analogs |
CN108699153A (en) * | 2016-02-25 | 2018-10-23 | 细胞医学瑞士公司 | The binding members of PD-L1 |
US11434294B2 (en) | 2016-02-25 | 2022-09-06 | Cell Medica, Inc. | Binding members to PD-L1 |
WO2017144681A1 (en) | 2016-02-25 | 2017-08-31 | Cell Medica Switzerland Ag | Binding members to pd-l1 |
EP4086285A1 (en) | 2016-02-25 | 2022-11-09 | Cell Medica Switzerland AG | Binding members to pd-l1 |
WO2017151502A1 (en) | 2016-02-29 | 2017-09-08 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
EP4155415A1 (en) | 2016-02-29 | 2023-03-29 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
EP3804620A1 (en) | 2016-03-01 | 2021-04-14 | North Carolina State University | Enhanced cancer immunotherapy by microneedle patch-assisted delivery |
US11896800B2 (en) | 2016-03-01 | 2024-02-13 | North Carolina State University | Enhanced cancer immunotherapy by microneedle patch-assisted delivery |
EP3309177A4 (en) * | 2016-03-04 | 2018-10-10 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Pdl-1 antibody, pharmaceutical composition thereof, and uses thereof |
US10465014B2 (en) | 2016-03-04 | 2019-11-05 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | PDL-1 antibody, pharmaceutical composition thereof, and uses thereof |
US11136413B2 (en) | 2016-03-04 | 2021-10-05 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | PDL-1 antibody, pharmaceutical composition thereof, and uses thereof |
WO2017152085A1 (en) | 2016-03-04 | 2017-09-08 | Bristol-Myers Squibb Company | Combination therapy with anti-cd73 antibodies |
WO2017153433A1 (en) | 2016-03-08 | 2017-09-14 | Innate Pharma | Siglec neutralizing antibodies |
US11110168B2 (en) | 2016-03-15 | 2021-09-07 | North Carolina State University | Nanoparticles, controlled-release dosage forms, and methods for delivering an immunotherapeutic agent |
WO2017159699A1 (en) | 2016-03-15 | 2017-09-21 | Chugai Seiyaku Kabushiki Kaisha | Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies |
EP4112641A1 (en) | 2016-03-15 | 2023-01-04 | Chugai Seiyaku Kabushiki Kaisha | Methods of treating cancers using pd-1 axis binding antagonists and anti-gpc3 antibodies |
WO2017157964A1 (en) | 2016-03-16 | 2017-09-21 | Amal Therapeutics Sa | Combination of an immune checkpoint modulator and a complex comprising a cell penetrating peptide, a cargo and a tlr peptide agonist for use in medicine |
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 |
US11753473B2 (en) | 2016-03-23 | 2023-09-12 | Suzhou Transcenta Therapeutics Co., Ltd. | Anti-PD-L1 antibodies |
EP3433277A4 (en) * | 2016-03-23 | 2020-06-17 | Mabspace Biosciences (Suzhou) Co., Ltd | Novel anti-pd-l1 antibodies |
US10822416B2 (en) | 2016-03-23 | 2020-11-03 | Mabspace Biosciences (Suzhou) Co., Ltd | Anti-PD-L1 antibodies |
US11660352B2 (en) | 2016-03-29 | 2023-05-30 | Stcube, Inc. | Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof |
US12059474B2 (en) | 2016-03-29 | 2024-08-13 | Stcube & Co., Inc. | Methods for selecting antibodies that specifically bind glycosylated immune checkpoint proteins |
WO2017167921A1 (en) | 2016-03-30 | 2017-10-05 | Centre Léon-Bérard | Lymphocytes expressing cd73 in cancerous patient dictates therapy |
WO2017175156A1 (en) | 2016-04-07 | 2017-10-12 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
EP4032885A1 (en) | 2016-04-07 | 2022-07-27 | GlaxoSmithKline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
WO2017175147A1 (en) | 2016-04-07 | 2017-10-12 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides useful as protein modulators |
WO2017181111A2 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
WO2017181079A2 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
WO2017184619A2 (en) | 2016-04-18 | 2017-10-26 | Celldex Therapeutics, Inc. | Agonistic antibodies that bind human cd40 and uses thereof |
US11505600B2 (en) | 2016-05-13 | 2022-11-22 | Regeneron Pharmaceuticals, Inc. | Methods of treating skin cancer by administering a PD-1 inhibitor |
WO2017194783A1 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Targeted mutant interferon-beta and uses thereof |
WO2017194782A2 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Therapeutic targeting of non-cellular structures |
US10457725B2 (en) | 2016-05-13 | 2019-10-29 | Regeneron Pharmaceuticals, Inc. | Methods of treating skin cancer by administering a PD-1 inhibitor |
US11339201B2 (en) | 2016-05-18 | 2022-05-24 | Albert Einstein College Of Medicine | Variant PD-L1 polypeptides, T-cell modulatory multimeric polypeptides, and methods of use thereof |
US11505591B2 (en) | 2016-05-18 | 2022-11-22 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
WO2017200969A1 (en) | 2016-05-20 | 2017-11-23 | Eli Lilly And Company | Combination therapy with notch and pd-1 or pd-l1 inhibitors |
US10688104B2 (en) | 2016-05-20 | 2020-06-23 | Eli Lilly And Company | Combination therapy with Notch and PD-1 or PD-L1 inhibitors |
US11826317B2 (en) | 2016-05-20 | 2023-11-28 | Eli Lilly And Company | Combination therapy with notch and PD-1 or PD-L1 inhibitors |
WO2017210335A1 (en) | 2016-06-01 | 2017-12-07 | Bristol-Myers Squibb Company | Imaging methods using 18f-radiolabeled biologics |
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 |
US11229642B2 (en) | 2016-06-06 | 2022-01-25 | Beyondspring Pharmaceuticals, Inc. | Composition and method for reducing neutropenia |
WO2017220990A1 (en) | 2016-06-20 | 2017-12-28 | Kymab Limited | Anti-pd-l1 antibodies |
US10604576B2 (en) | 2016-06-20 | 2020-03-31 | Kymab Limited | Antibodies and immunocytokines |
WO2017220989A1 (en) | 2016-06-20 | 2017-12-28 | Kymab Limited | Anti-pd-l1 and il-2 cytokines |
WO2017220988A1 (en) | 2016-06-20 | 2017-12-28 | Kymab Limited | Multispecific antibodies for immuno-oncology |
US11965026B2 (en) | 2016-06-20 | 2024-04-23 | Kymab Limited | Anti-PD-L1 and IL-2 cytokines |
US9957323B2 (en) | 2016-06-20 | 2018-05-01 | Kymab Limited | Anti-ICOS antibodies |
US11834505B2 (en) | 2016-06-29 | 2023-12-05 | Checkpoint Therapeutics, Inc. | PD-L1-specific antibodies and methods of using the same |
EP3478723A4 (en) * | 2016-06-29 | 2020-07-29 | Checkpoint Therapeutics, Inc. | Pd-l1-specific antibodies and methods of using the same |
WO2018013818A2 (en) | 2016-07-14 | 2018-01-18 | Bristol-Myers Squibb Company | Antibodies against tim3 and uses thereof |
US11591392B2 (en) | 2016-07-14 | 2023-02-28 | Bristol-Myers Squibb Company | Antibodies against TIM3 and uses thereof |
US10077306B2 (en) | 2016-07-14 | 2018-09-18 | Bristol-Myers Squibb Company | Antibodies against TIM3 and uses thereof |
US10533052B2 (en) | 2016-07-14 | 2020-01-14 | Bristol-Myers Squibb Company | Antibodies against TIM3 and uses thereof |
US11746152B2 (en) | 2016-07-20 | 2023-09-05 | Stcube, Inc. | Methods of cancer treatment and therapy using a combination of antibodies that bind glycosylated PD-L1 |
US12030946B2 (en) | 2016-08-08 | 2024-07-09 | Hoffmann-La Roche Inc. | Therapeutic and diagnostic methods for cancer |
WO2018029124A1 (en) | 2016-08-08 | 2018-02-15 | F. Hoffmann-La Roche Ag | Therapeutic and diagnostic methods for cancer |
US11858996B2 (en) | 2016-08-09 | 2024-01-02 | Kymab Limited | Anti-ICOS antibodies |
WO2018029474A2 (en) | 2016-08-09 | 2018-02-15 | Kymab Limited | Anti-icos antibodies |
WO2018031865A1 (en) | 2016-08-12 | 2018-02-15 | Genentech, Inc. | Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a vegf inhibitor |
US11542335B2 (en) | 2016-08-25 | 2023-01-03 | Hoffmann-La Roche Inc. | Method of treating cancer in a patient by administering an antibody which binds colony stimulating factor-1 receptor (CSF-1R) |
WO2018049474A1 (en) | 2016-09-16 | 2018-03-22 | Bionomics Limited | Antibody and checkpoint inhibitor combination therapy |
WO2018055060A1 (en) | 2016-09-21 | 2018-03-29 | Amal Therapeutics Sa | Fusion comprising a cell penetrating peptide, a multi epitope and a tlr peptide agonist for treatment of cancer |
US11338027B2 (en) | 2016-09-21 | 2022-05-24 | Amal Therapeutics Sa | Fusion comprising a cell penetrating peptide, a multi epitope and a TLR peptide agonist for treatment of cancer |
US11513122B2 (en) | 2016-09-26 | 2022-11-29 | Hoffmann-La Roche Inc. | Predicting response to PD-1 axis inhibitors |
WO2018055145A1 (en) | 2016-09-26 | 2018-03-29 | F. Hoffmann-La Roche Ag | Predicting response to pd-1 axis inhibitors |
WO2018064299A1 (en) | 2016-09-29 | 2018-04-05 | Genentech, Inc. | Combination therapy with a mek inhibitor, a pd-1 axis inhibitor, and a taxane |
WO2018068028A1 (en) | 2016-10-06 | 2018-04-12 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2018065623A2 (en) | 2016-10-07 | 2018-04-12 | Enterome | Immunogenic compounds for cancer therapy |
WO2018065628A2 (en) | 2016-10-07 | 2018-04-12 | Enterome | Microbiota sequence variants of tumor-related antigenic epitopes |
WO2018065625A2 (en) | 2016-10-07 | 2018-04-12 | Enterome | Immunogenic compounds for cancer therapy |
US11759518B2 (en) | 2016-10-11 | 2023-09-19 | Nec Corporation | Medicine for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein |
US11291718B2 (en) | 2016-10-11 | 2022-04-05 | Cytlimic Inc. | Method for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein |
WO2018077893A1 (en) | 2016-10-24 | 2018-05-03 | Orionis Biosciences Nv | Targeted mutant interferon-gamma and uses thereof |
WO2018081621A1 (en) | 2016-10-28 | 2018-05-03 | Bristol-Myers Squibb Company | Methods of treating urothelial carcinoma using an anti-pd-1 antibody |
US11618786B2 (en) | 2016-10-30 | 2023-04-04 | Shanghai Henlius Biotech Inc. | Anti-PD-L1 antibodies and variants |
CN109963589B (en) * | 2016-10-30 | 2023-05-05 | 上海复宏汉霖生物技术股份有限公司 | anti-PD-L1 antibodies and variants |
US11274155B2 (en) | 2016-10-30 | 2022-03-15 | Shanghai Henlius Biotech Inc. | Anti-PD-L1 antibodies and variants |
EP3532100A4 (en) * | 2016-10-30 | 2020-11-25 | Shanghai Henlius Biotech, Inc. | Anti-pd-l1 antibodies and variants |
AU2017348475B2 (en) * | 2016-10-30 | 2024-02-08 | Shanghai Henlius Biotech, Inc. | Anti-PD-L1 antibodies and variants |
CN109963589A (en) * | 2016-10-30 | 2019-07-02 | 上海复宏汉霖生物技术股份有限公司 | Anti- PD-L1 antibody and variant |
WO2018085555A1 (en) | 2016-11-03 | 2018-05-11 | Bristol-Myers Squibb Company | Activatable anti-ctla-4 antibodies and uses thereof |
US11117968B2 (en) | 2016-11-03 | 2021-09-14 | Bristol-Myers Squibb Company | Activatable anti-CTLA-4 antibodies and uses thereof |
US11779604B2 (en) | 2016-11-03 | 2023-10-10 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses and methods |
WO2018093821A1 (en) | 2016-11-15 | 2018-05-24 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies |
WO2018099978A1 (en) | 2016-11-29 | 2018-06-07 | Horst Lindhofer | Combination of t-cell redirecting multifunctional antibodies with immune checkpoint modulators and uses 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 |
WO2018110515A1 (en) | 2016-12-12 | 2018-06-21 | 第一三共株式会社 | Combination of antibody-drug conjugate and immune checkpoint inhibitor |
US11273155B2 (en) | 2016-12-12 | 2022-03-15 | Daiichi Sankyo Company, Limited | Combination of antibody-drug conjugate and immune checkpoint inhibitor |
KR20190095280A (en) | 2016-12-12 | 2019-08-14 | 다이이찌 산쿄 가부시키가이샤 | Combination of Antibody-Drug Conjugates and Immune Checkpoint Inhibitors |
WO2018111890A1 (en) | 2016-12-12 | 2018-06-21 | Genentech, Inc. | Methods of treating cancer using anti-pd-l1 antibodies and antiandrogens |
US11987610B2 (en) | 2016-12-22 | 2024-05-21 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11739133B2 (en) | 2016-12-22 | 2023-08-29 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11377478B2 (en) | 2016-12-22 | 2022-07-05 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11401314B2 (en) | 2016-12-22 | 2022-08-02 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11905320B2 (en) | 2016-12-22 | 2024-02-20 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11851467B2 (en) | 2016-12-22 | 2023-12-26 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11498968B2 (en) | 2016-12-22 | 2022-11-15 | Hoffmann-La Roche Inc. | Treatment of tumors with an anti-CSF-1R antibody in combination with an anti-PD-L1 antibody after failure of anti-PD-L1/PD1 treatment |
US11530248B2 (en) | 2016-12-22 | 2022-12-20 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11117945B2 (en) | 2016-12-22 | 2021-09-14 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11505588B2 (en) | 2016-12-22 | 2022-11-22 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US10927158B2 (en) | 2016-12-22 | 2021-02-23 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11708400B2 (en) | 2016-12-22 | 2023-07-25 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
US11370821B2 (en) | 2016-12-22 | 2022-06-28 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
WO2018127570A1 (en) | 2017-01-05 | 2018-07-12 | Netris Pharma | Combined treatment with netrin-1 interfering drug and immune checkpoint inhibitors drugs |
US11633393B2 (en) | 2017-01-06 | 2023-04-25 | Beyondspring Pharmaceuticals, Inc. | Tubulin binding compounds and therapeutic use thereof |
US11851471B2 (en) | 2017-01-09 | 2023-12-26 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides and methods of use thereof |
WO2018129497A1 (en) | 2017-01-09 | 2018-07-12 | Bioxcel Therapeutics, Inc. | Predictive and diagnostic methods for prostate cancer |
WO2018138591A1 (en) | 2017-01-24 | 2018-08-02 | Pfizer Inc. | Calicheamicin derivatives and antibody drug conjugates thereof |
US11993625B2 (en) | 2017-01-24 | 2024-05-28 | Pfizer, Inc. | Calicheamicin derivatives and antibody drug conjugates thereof |
US11400086B2 (en) | 2017-02-01 | 2022-08-02 | Beyondspring Pharmaceuticals, Inc. | Method of reducing chemotherapy-induced neutropenia |
WO2018141964A1 (en) | 2017-02-06 | 2018-08-09 | Orionis Biosciences Nv | Targeted chimeric proteins and uses thereof |
WO2018141959A1 (en) | 2017-02-06 | 2018-08-09 | Innate Pharma | Immunomodulatory antibody drug conjugates binding to a human mica polypeptide |
WO2018144999A1 (en) | 2017-02-06 | 2018-08-09 | Orionis Biosciences, Inc. | Targeted engineered interferon and uses thereof |
US11325976B2 (en) | 2017-02-16 | 2022-05-10 | Ying Zhang | Anti-programmed death-ligand 1 (PD-L1) antibodies and therapeutic uses thereof |
WO2018150224A1 (en) | 2017-02-16 | 2018-08-23 | Shenzhen Runshin Bioscience | Anti-programmed death-ligand 1 (pd-l1) antibodies and therapeutic uses thereof |
WO2018152396A1 (en) | 2017-02-17 | 2018-08-23 | Innate Tumor Immunity, Inc. | Substituted imidazo-quinolines as nlrp3 modulators |
EP3753938A1 (en) | 2017-02-17 | 2020-12-23 | Innate Tumor Immunity, Inc. | Substituted imidazo-quinolines as nlrp3 modulators |
CN110337449B (en) * | 2017-02-21 | 2023-08-15 | 上海君实生物医药科技股份有限公司 | anti-PD-L1 antibodies and uses thereof |
US11926668B2 (en) | 2017-02-21 | 2024-03-12 | Regeneron Pharmaceuticals Inc. | Anti-PD-1 antibodies for treatment of lung cancer |
US11292842B2 (en) | 2017-02-21 | 2022-04-05 | Regeneron Pharmaceuticals, Inc. | Anti-PD-1 antibodies for treatment of lung cancer |
US11267890B2 (en) | 2017-02-21 | 2022-03-08 | Shanghai Junshi Biosciences Inc. | Anti-PD-L1 antibody and application thereof |
EP3587453A4 (en) * | 2017-02-21 | 2021-07-07 | Shanghai Junshi Bioscience Co., Ltd. | Anti-pd-l1 antibody and application thereof |
CN110337449A (en) * | 2017-02-21 | 2019-10-15 | 上海君实生物医药科技股份有限公司 | Anti- PD-L1 antibody and its application |
WO2018154520A1 (en) | 2017-02-27 | 2018-08-30 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors |
WO2018160841A1 (en) | 2017-03-01 | 2018-09-07 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
EP4431109A2 (en) | 2017-03-15 | 2024-09-18 | Cue Biopharma, Inc. | Combination of multimeric fusion polypeptides and immune checkpoint inhibitor for treating hpv-associated cancer |
US11767355B2 (en) | 2017-03-15 | 2023-09-26 | Cue Biopharma, Inc. | Methods for modulating an immune response |
US11958893B2 (en) | 2017-03-15 | 2024-04-16 | Cue Biopharma, Inc. | Methods for modulating an immune response |
US10927161B2 (en) | 2017-03-15 | 2021-02-23 | Cue Biopharma, Inc. | Methods for modulating an immune response |
US11479595B2 (en) | 2017-03-15 | 2022-10-25 | Cue Biopharma, Inc. | Methods for modulating an immune response |
US11993641B2 (en) | 2017-03-15 | 2024-05-28 | Cue Biopharma, Inc. | Methods for modulating an immune response |
WO2018170168A1 (en) | 2017-03-15 | 2018-09-20 | Cue Biopharma, Inc. | Methods for modulating an immune response |
WO2018167147A1 (en) | 2017-03-15 | 2018-09-20 | F. Hoffmann-La Roche Ag | Azaindoles as inhibitors of hpk1 |
US11104712B2 (en) | 2017-03-15 | 2021-08-31 | Cue Biopharma, Inc. | Methods for modulating an immune response |
WO2018167267A1 (en) | 2017-03-16 | 2018-09-20 | Innate Pharma | Compositions and methods for treating cancer |
US11578136B2 (en) | 2017-03-16 | 2023-02-14 | Innate Pharma | Compositions and methods for treating cancer |
WO2018172508A1 (en) | 2017-03-24 | 2018-09-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2018183956A1 (en) | 2017-03-30 | 2018-10-04 | Genentech, Inc. | Naphthyridines as inhibitors of hpk1 |
WO2018183964A1 (en) | 2017-03-30 | 2018-10-04 | Genentech, Inc. | Isoquinolines as inhibitors of hpk1 |
WO2018183928A1 (en) | 2017-03-31 | 2018-10-04 | Bristol-Myers Squibb Company | Methods of treating tumor |
US11603407B2 (en) | 2017-04-06 | 2023-03-14 | Regeneron Pharmaceuticals, Inc. | Stable antibody formulation |
WO2018187613A2 (en) | 2017-04-07 | 2018-10-11 | Bristol-Myers Squibb Company | Anti-icos agonist antibodies and uses thereof |
WO2018189220A1 (en) | 2017-04-13 | 2018-10-18 | F. Hoffmann-La Roche Ag | An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer |
WO2018191660A1 (en) | 2017-04-14 | 2018-10-18 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2018194496A2 (en) | 2017-04-17 | 2018-10-25 | Закрытое Акционерное Общество "Биокад" | Monoclonal antibody to pd-l1 |
EP3613770A4 (en) * | 2017-04-17 | 2021-01-27 | Joint Stock Company "Biocad" | Monoclonal antibody to pd-l1 |
US11236167B2 (en) | 2017-04-17 | 2022-02-01 | Joint Stock Company “Biocad” | Monoclonal antibody to PD-L1 |
KR102679554B1 (en) | 2017-04-17 | 2024-07-01 | 조인트 스탁 컴퍼니 “바이오케드” | Monoclonal antibodies against PD-L1 |
KR20190140979A (en) * | 2017-04-17 | 2019-12-20 | 조인트 스탁 컴퍼니 "바이오케드" | Monoclonal antibody against PD-L1 |
US11326170B2 (en) | 2017-04-18 | 2022-05-10 | Changchun Huapu Biotechnology Co. Ltd. | Immunomodulatory polynucleotides and uses thereof |
WO2018200430A1 (en) | 2017-04-26 | 2018-11-01 | Bristol-Myers Squibb Company | Methods of antibody production that minimize disulfide bond reduction |
US11834448B2 (en) | 2017-04-27 | 2023-12-05 | Birdie Biopharmaceuticals, Inc. | 2-amino-quinoline derivatives |
US11053240B2 (en) | 2017-04-27 | 2021-07-06 | Birdie Biopharmaceuticals, Inc. | 2-amino-quinoline derivatives |
US11654194B2 (en) | 2017-05-16 | 2023-05-23 | Jiangsu Hengrui Medicine Co., Ltd. | PD-L1 antibody pharmaceutical composition and use thereof |
WO2018213297A1 (en) | 2017-05-16 | 2018-11-22 | Bristol-Myers Squibb Company | Treatment of cancer with anti-gitr agonist antibodies |
EP3626266A4 (en) * | 2017-05-16 | 2021-04-07 | Jiangsu Hengrui Medicine Co., Ltd. | Pd-l1 antibody pharmaceutical composition and use thereof |
RU2766590C2 (en) * | 2017-05-16 | 2022-03-15 | Цзянсу Хэнжуй Медисин Ко., Лтд. | Pharmaceutical composition based on antibody to pd-l1 and its application |
WO2018218056A1 (en) | 2017-05-25 | 2018-11-29 | Birstol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
EP4098662A1 (en) | 2017-05-25 | 2022-12-07 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
WO2018219956A1 (en) | 2017-05-29 | 2018-12-06 | Gamamabs Pharma | Cancer-associated immunosuppression inhibitor |
US11807686B2 (en) | 2017-05-30 | 2023-11-07 | Bristol-Myers Squibb Company | Treatment of LAG-3 positive tumors |
EP4306542A2 (en) | 2017-05-30 | 2024-01-17 | Bristol-Myers Squibb Company | Treatment of lag-3 positive tumors |
US11723975B2 (en) | 2017-05-30 | 2023-08-15 | 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 |
US12049503B2 (en) | 2017-05-30 | 2024-07-30 | Bristol-Myers Squibb Company | Treatment of LAG-3 positive tumors |
WO2018222718A1 (en) | 2017-05-30 | 2018-12-06 | Bristol-Myers Squibb Company | Treatment of lag-3 positive tumors |
EP4245375A2 (en) | 2017-05-30 | 2023-09-20 | Bristol-Myers Squibb Company | Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent |
WO2018222711A2 (en) | 2017-05-30 | 2018-12-06 | Bristol-Myers Squibb Company | Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent |
WO2018222722A2 (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 |
WO2018223040A1 (en) | 2017-06-01 | 2018-12-06 | Bristol-Myers Squibb Company | Methods of treating a tumor using an anti-pd-1 antibody |
US11566073B2 (en) | 2017-06-01 | 2023-01-31 | Bristol-Myers Squibb Company | Methods of treating a tumor using an anti-PD-1 antibody |
US11168144B2 (en) | 2017-06-01 | 2021-11-09 | Cytomx Therapeutics, Inc. | Activatable anti-PDL1 antibodies, and methods of use thereof |
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 |
US11440960B2 (en) | 2017-06-20 | 2022-09-13 | Kymab Limited | TIGIT antibodies, encoding nucleic acids and methods of using said antibodies in vivo |
US11517567B2 (en) | 2017-06-23 | 2022-12-06 | Birdie Biopharmaceuticals, Inc. | Pharmaceutical compositions |
US11560425B2 (en) | 2017-06-27 | 2023-01-24 | Neuracle Science Co., Ltd. | Use of anti-FAM19A5 antibodies for treating cancers |
WO2019011855A1 (en) | 2017-07-10 | 2019-01-17 | Innate Pharma | Siglec-9-neutralizing antibodies |
WO2019014402A1 (en) | 2017-07-14 | 2019-01-17 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2019018757A1 (en) | 2017-07-21 | 2019-01-24 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2019032431A1 (en) | 2017-08-07 | 2019-02-14 | Amgen Inc. | Treatment of triple negative breast cancer or colorectal cancer with liver metastases with an anti pd-l1 antibody and an oncolytic virus |
WO2019059411A1 (en) | 2017-09-20 | 2019-03-28 | Chugai Seiyaku Kabushiki Kaisha | Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent |
US11939306B2 (en) | 2017-09-29 | 2024-03-26 | Curis, Inc. | Crystal forms of immunomodulators |
US11040948B2 (en) | 2017-09-29 | 2021-06-22 | Curis, Inc. | Crystal forms of immunomodulators |
US11643401B2 (en) | 2017-09-29 | 2023-05-09 | Curis, Inc. | Crystal forms of immunomodulators |
US11840567B2 (en) | 2017-10-03 | 2023-12-12 | Joint Stock Company “Biocad” | Bispecific antibodies with specific binding to CD47 and PD-L1 |
WO2019069269A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | Modulators of stimulator of interferon genes (sting) useful in treating hiv |
WO2019069270A1 (en) | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | Modulators of stimulator of interferon genes (sting) |
WO2019068907A1 (en) | 2017-10-06 | 2019-04-11 | Innate Pharma | Restoration of t cell activity via the cd39/cd73 axis |
WO2019072871A2 (en) | 2017-10-09 | 2019-04-18 | Enterome S.A. | Microbiota sequence variants of tumor-related antigenic epitopes |
WO2019072868A1 (en) | 2017-10-10 | 2019-04-18 | Numab Therapeutics AG | Multispecific antibody |
WO2019072870A1 (en) | 2017-10-10 | 2019-04-18 | Numab Innovation Ag | Antibodies targeting cd137 and methods of use thereof |
US12077588B2 (en) | 2017-10-10 | 2024-09-03 | Numab Therapeutics AG | Antibodies targeting PDL1 and methods of use thereof |
EP3470426A1 (en) | 2017-10-10 | 2019-04-17 | Numab Therapeutics AG | Multispecific antibody |
WO2019075090A1 (en) | 2017-10-10 | 2019-04-18 | Tilos Therapeutics, Inc. | Anti-lap antibodies and uses thereof |
US11230601B2 (en) | 2017-10-10 | 2022-01-25 | Tilos Therapeutics, Inc. | Methods of using anti-lap antibodies |
US11680051B2 (en) | 2017-10-11 | 2023-06-20 | Aurigene Discovery Technologies Limited | Crystalline forms of 3-substituted 1,2,4-oxadiazole |
US11136300B2 (en) | 2017-10-11 | 2021-10-05 | Aurigene Discovery Technologies Limited | Crystalline forms of 3-substituted 1,2,4-oxadiazole |
US11525002B2 (en) | 2017-10-11 | 2022-12-13 | Board Of Regents, The University Of Texas System | Human PD-L1 antibodies and methods of use therefor |
WO2019075468A1 (en) | 2017-10-15 | 2019-04-18 | Bristol-Myers Squibb Company | Methods of treating tumor |
US11919957B2 (en) | 2017-10-15 | 2024-03-05 | Bristol-Myers Squibb Company | Methods of treating tumor |
US11613566B2 (en) | 2017-10-18 | 2023-03-28 | Alpine Immune Sciences, Inc. | Variant ICOS ligand immunomodulatory proteins and related compositions and methods |
WO2019079520A2 (en) | 2017-10-18 | 2019-04-25 | Alpine Immune Sciences, Inc. | Variant icos ligand immunomodulatory proteins and related compositions and methods |
WO2019089921A1 (en) | 2017-11-01 | 2019-05-09 | Bristol-Myers Squibb Company | Immunostimulatory agonistic antibodies for use in treating cancer |
US11497734B2 (en) | 2017-11-03 | 2022-11-15 | Aurigene Discovery Technologies Limited | Dual inhibitors of TIM-3 and PD-1 pathways |
US11497735B2 (en) | 2017-11-06 | 2022-11-15 | Aurigene Discovery Technologies Limited | Conjoint therapies for immunomodulation |
WO2019090330A1 (en) | 2017-11-06 | 2019-05-09 | Bristol-Myers Squibb Company | Methods of treating a tumor |
WO2019090263A1 (en) | 2017-11-06 | 2019-05-09 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
US12064418B2 (en) | 2017-11-06 | 2024-08-20 | Curis, Inc. | Conjoint therapies for immunomodulation |
WO2019097369A1 (en) | 2017-11-14 | 2019-05-23 | Pfizer Inc. | Ezh2 inhibitor combination therapies |
WO2019122884A1 (en) | 2017-12-19 | 2019-06-27 | Kymab Limited | Antibodies to icos |
US11629189B2 (en) | 2017-12-19 | 2023-04-18 | Kymab Limited | Bispecific antibody for ICOS and PD-L1 |
US11952427B2 (en) | 2017-12-27 | 2024-04-09 | Bristol-Myers Squibb Company | Anti-CD40 antibodies and uses thereof |
WO2019133747A1 (en) | 2017-12-27 | 2019-07-04 | Bristol-Myers Squibb Company | Anti-cd40 antibodies and uses thereof |
US11306149B2 (en) | 2017-12-27 | 2022-04-19 | Bristol-Myers Squibb Company | Anti-CD40 antibodies and uses thereof |
US11732044B2 (en) | 2017-12-27 | 2023-08-22 | Innovent Biologics (Suzhou) Co., Ltd. | Anti-LAG-3 antibody and use thereof |
WO2019134946A1 (en) | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
US11702461B2 (en) | 2018-01-09 | 2023-07-18 | Cue Biopharma, Inc. | T-cell modulatory multimeric polypeptides comprising reduced-affinity immunomodulatory polypeptides |
WO2019140150A1 (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 |
WO2019140229A1 (en) | 2018-01-12 | 2019-07-18 | Bristol-Myers Squibb Company | Antibodies against tim3 and uses thereof |
WO2019143607A1 (en) | 2018-01-16 | 2019-07-25 | Bristol-Myers Squibb Company | Methods of treating cancer with antibodies against tim3 |
WO2019144126A1 (en) | 2018-01-22 | 2019-07-25 | Pascal Biosciences Inc. | Cannabinoids and derivatives for promoting immunogenicity of tumor and infected cells |
WO2019144098A1 (en) | 2018-01-22 | 2019-07-25 | Bristol-Myers Squibb Company | Compositions and methods of treating cancer |
US11786523B2 (en) | 2018-01-24 | 2023-10-17 | Beyondspring Pharmaceuticals, Inc. | Composition and method for reducing thrombocytopenia |
US11896643B2 (en) | 2018-02-05 | 2024-02-13 | 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 |
WO2019162325A1 (en) | 2018-02-21 | 2019-08-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
US12090142B2 (en) | 2018-02-22 | 2024-09-17 | Board Of Regents, The University Of Texas System | Combination therapy for the treatment of cancer |
WO2019165434A1 (en) | 2018-02-26 | 2019-08-29 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2019175113A1 (en) | 2018-03-12 | 2019-09-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers |
WO2019183040A1 (en) | 2018-03-21 | 2019-09-26 | Five Prime Therapeutics, Inc. | ANTIBODIES BINDING TO VISTA AT ACIDIC pH |
US11242393B2 (en) | 2018-03-23 | 2022-02-08 | Bristol-Myers Squibb Company | Antibodies against MICA and/or MICB and uses thereof |
EP3768723A4 (en) * | 2018-03-23 | 2021-12-29 | Board of Regents, The University of Texas System | Dual specificity antibodies to human pd-l1 and pd-l2 and methods of use therefor |
CN112105644B (en) * | 2018-03-23 | 2023-12-05 | 得克萨斯州大学系统董事会 | Dual specific antibodies against human PD-L1 and PD-L2 and methods of use thereof |
US11976128B2 (en) | 2018-03-23 | 2024-05-07 | Board Of Regents, The University Of Texas System | Human PD-L2 antibodies and methods of use therefor |
CN112105644A (en) * | 2018-03-23 | 2020-12-18 | 得克萨斯州大学系统董事会 | Dual specific antibodies to human PD-L1 and PD-L2 and methods of use thereof |
WO2019190327A2 (en) | 2018-03-30 | 2019-10-03 | Merus N.V. | Multivalent antibody |
WO2019191676A1 (en) | 2018-03-30 | 2019-10-03 | Bristol-Myers Squibb Company | Methods of treating tumor |
US11952424B2 (en) | 2018-03-30 | 2024-04-09 | Merus N.V. | Multivalent antibody |
WO2019200256A1 (en) | 2018-04-12 | 2019-10-17 | Bristol-Myers Squibb Company | Anticancer combination therapy with cd73 antagonist antibody and pd-1/pd-l1 axis antagonist antibody |
WO2019209896A1 (en) | 2018-04-25 | 2019-10-31 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
EP4353235A2 (en) | 2018-04-25 | 2024-04-17 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2021089765A1 (en) | 2018-05-04 | 2021-05-14 | Tollys | Tlr3 ligands that activate both epithelial and myeloid cells |
WO2019211492A1 (en) | 2018-05-04 | 2019-11-07 | Tollys | Tlr3 ligands that activate both epithelial and myeloid cells |
WO2019211489A1 (en) | 2018-05-04 | 2019-11-07 | Merck Patent Gmbh | COMBINED INHIBITION OF PD-1/PD-L1, TGFβ AND DNA-PK FOR THE TREATMENT OF CANCER |
WO2019219820A1 (en) | 2018-05-16 | 2019-11-21 | Ctxt Pty Limited | Substituted condensed thiophenes as modulators of sting |
US11613525B2 (en) | 2018-05-16 | 2023-03-28 | Ctxt Pty Limited | Substituted condensed thiophenes as modulators of sting |
WO2019229699A1 (en) | 2018-05-31 | 2019-12-05 | Novartis Ag | Hepatitis b antibodies |
US11932681B2 (en) | 2018-05-31 | 2024-03-19 | Novartis Ag | Hepatitis B antibodies |
WO2019241730A2 (en) | 2018-06-15 | 2019-12-19 | Flagship Pioneering Innovations V, Inc. | Increasing immune activity through modulation of postcellular signaling factors |
WO2019243252A1 (en) | 2018-06-18 | 2019-12-26 | Innate Pharma | Compositions and methods for treating cancer |
US11377503B2 (en) | 2018-06-18 | 2022-07-05 | Innate Pharma | Antibodies that bind human CD39 and inhibit ATPase activity of a soluble extracellular domain human CD39 polypeptide |
WO2019246557A1 (en) | 2018-06-23 | 2019-12-26 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor |
WO2020014132A2 (en) | 2018-07-09 | 2020-01-16 | Five Prime Therapeutics, Inc. | Antibodies binding to ilt4 |
WO2020014327A2 (en) | 2018-07-11 | 2020-01-16 | Five Prime Therapeutics, Inc. | Antibodies binding to vista at acidic ph |
WO2020011964A1 (en) | 2018-07-12 | 2020-01-16 | F-Star Beta Limited | Antibody molecules that bind pd-l1 and 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 |
EP3802577A4 (en) * | 2018-07-14 | 2022-05-18 | Development Center for Biotechnology | Anti-human pd-l1 antibodies and their uses |
CN112805297A (en) * | 2018-07-14 | 2021-05-14 | 财团法人生物技术开发中心 | Anti-human PD-L1 antibodies and uses thereof |
CN112805297B (en) * | 2018-07-14 | 2024-08-30 | 财团法人生物技术开发中心 | Anti-human PD-L1 antibodies and uses thereof |
WO2020018789A1 (en) | 2018-07-18 | 2020-01-23 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent |
US11214619B2 (en) | 2018-07-20 | 2022-01-04 | Surface Oncology, Inc. | Anti-CD112R compositions and methods |
US11279758B2 (en) | 2018-07-20 | 2022-03-22 | Surface Oncology, Inc. | Anti-CD112R compositions and methods |
WO2020023551A1 (en) | 2018-07-24 | 2020-01-30 | Genentech, Inc. | Naphthyridine compounds and uses thereof |
WO2020023560A1 (en) | 2018-07-24 | 2020-01-30 | F. Hoffmann-La Roche Ag | Isoquinoline compounds and uses thereof |
WO2020023707A1 (en) | 2018-07-26 | 2020-01-30 | Bristol-Myers Squibb Company | Lag-3 combination therapy for the treatment of cancer |
WO2020037094A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Substitued 4-amino-1h-imidazo[4,5-c]quinoline compounds and improved methods for their preparation |
WO2020037091A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Imidazo[4,5-c]quinoline derived nlrp3-modulators |
WO2020037092A1 (en) | 2018-08-16 | 2020-02-20 | Innate Tumor Immunity, Inc. | Imidazo[4,5-c]quinoline derived nlrp3-modulators |
EP3841126A4 (en) * | 2018-08-20 | 2022-08-10 | 1Globe Biomedical Co., Ltd. | Novel cancer immunotherapy antibody compositions |
WO2020043683A1 (en) | 2018-08-27 | 2020-03-05 | Pieris Pharmaceuticals Gmbh | Combination therapies comprising cd137/her2 bispecific agents and pd-1 axis inhibitors and uses thereof |
WO2020044206A1 (en) | 2018-08-29 | 2020-03-05 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as kinase inhibitors for use in the treatment cancer |
WO2020051099A1 (en) | 2018-09-03 | 2020-03-12 | Genentech, Inc. | Carboxamide and sulfonamide derivatives useful as tead modulators |
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 |
WO2020053742A2 (en) | 2018-09-10 | 2020-03-19 | Novartis Ag | Anti-hla-hbv peptide antibodies |
WO2020061060A1 (en) | 2018-09-19 | 2020-03-26 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2020058372A1 (en) | 2018-09-19 | 2020-03-26 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of cancers resistant to immune checkpoint therapy |
WO2020061377A1 (en) | 2018-09-19 | 2020-03-26 | Genentech, Inc. | Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof |
WO2020061349A1 (en) | 2018-09-21 | 2020-03-26 | Genentech, Inc. | Diagnostic methods for triple-negative breast cancer |
EP4249917A2 (en) | 2018-09-21 | 2023-09-27 | F. Hoffmann-La Roche AG | Diagnostic methods for triple-negative breast cancer |
WO2020069402A1 (en) | 2018-09-30 | 2020-04-02 | Genentech, Inc. | Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer |
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 |
WO2020072627A1 (en) | 2018-10-02 | 2020-04-09 | Genentech, Inc. | Isoquinoline compounds for the treatment of cancer |
WO2020072695A1 (en) | 2018-10-03 | 2020-04-09 | Genentech, Inc. | 8-aminoisoquinoline compounds and uses thereof |
WO2020076969A2 (en) | 2018-10-10 | 2020-04-16 | Tilos Therapeutics, Inc. | Anti-lap antibody variants and uses thereof |
US11130802B2 (en) | 2018-10-10 | 2021-09-28 | Tilos Therapeutics, Inc. | Anti-lap antibody variants |
WO2020081767A1 (en) | 2018-10-18 | 2020-04-23 | Genentech, Inc. | Diagnostic and therapeutic methods for sarcomatoid kidney cancer |
WO2020081928A1 (en) | 2018-10-19 | 2020-04-23 | Bristol-Myers Squibb Company | Combination therapy for melanoma |
EP4445958A2 (en) | 2018-10-19 | 2024-10-16 | Bristol-Myers Squibb Company | Combination therapy for melanoma |
WO2020086724A1 (en) | 2018-10-23 | 2020-04-30 | Bristol-Myers Squibb Company | Methods of treating tumor |
US11564995B2 (en) | 2018-10-29 | 2023-01-31 | Wisconsin Alumni Research Foundation | Peptide-nanoparticle conjugates |
WO2020092304A1 (en) | 2018-10-29 | 2020-05-07 | Wisconsin Alumni Research Foundation | Dendritic polymers complexed with immune checkpoint inhibitors for enhanced cancer immunotherapy |
WO2020102501A1 (en) | 2018-11-16 | 2020-05-22 | Bristol-Myers Squibb Company | Anti-nkg2a antibodies and uses thereof |
WO2020102728A1 (en) | 2018-11-16 | 2020-05-22 | Neoimmunetech, Inc. | Method of treating a tumor with a combination of il-7 protein and an immune checkpoint inhibitor |
WO2020102804A2 (en) | 2018-11-16 | 2020-05-22 | Arqule, Inc. | Pharmaceutical combination for treatment of cancer |
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 |
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 |
WO2020109355A1 (en) | 2018-11-28 | 2020-06-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and kit for assaying lytic potential of immune effector cells |
WO2020112781A1 (en) | 2018-11-28 | 2020-06-04 | Bristol-Myers Squibb Company | Antibodies comprising modified heavy constant regions |
WO2020109570A1 (en) | 2018-11-30 | 2020-06-04 | Gbg Forschungs Gmbh | Method for predicting the response to cancer immunotherapy in cancer patients |
WO2020117849A1 (en) | 2018-12-04 | 2020-06-11 | Bristol-Myers Squibb Company | Methods of analysis using in-sample calibration curve by multiple isotopologue reaction monitoring |
EP4198057A1 (en) | 2018-12-05 | 2023-06-21 | F. Hoffmann-La Roche AG | Diagnostic methods and compositions for cancer immunotherapy |
WO2020117952A2 (en) | 2018-12-05 | 2020-06-11 | Genentech, Inc. | Diagnostic methods and compositions for cancer immunotherapy |
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 |
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 |
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 |
WO2020127059A1 (en) | 2018-12-17 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sulconazole as a furin inhibitor |
WO2020132297A1 (en) | 2018-12-19 | 2020-06-25 | Cue Biopharma, Inc. | Multimeric t-cell modulatory polypeptides and methods of use thereof |
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 |
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 |
WO2020132560A2 (en) | 2018-12-21 | 2020-06-25 | Aim Immunotech Inc. | Compositions and methods for cancer therapy |
WO2020136145A2 (en) | 2018-12-26 | 2020-07-02 | Innate Pharma | Leucocyte immunoglobulin-like receptor neutralizing antibodies |
WO2020136147A1 (en) | 2018-12-26 | 2020-07-02 | Innate Pharma | Compounds and methods for treatment of head and neck cancer |
EP3902563A4 (en) * | 2018-12-27 | 2022-12-28 | Gigagen, Inc. | Anti-pd-l1 binding proteins and methods of use thereof |
WO2020136235A1 (en) | 2018-12-28 | 2020-07-02 | Transgene Sa | M2-defective poxvirus |
KR20210110838A (en) | 2018-12-28 | 2021-09-09 | 트랜스진 에스.에이. | M2 defective poxvirus |
WO2020150114A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Heterocyclic nlrp3 modulators, for use in the treatment of cancer |
WO2020150113A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Substituted quinazolines as nlrp3 modulators, for use in the treatment of cancer |
WO2020150152A1 (en) | 2019-01-14 | 2020-07-23 | Genentech, Inc. | Methods of treating cancer with a pd-1 axis binding antagonist and an rna vaccine |
WO2020150116A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2020150115A1 (en) | 2019-01-14 | 2020-07-23 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2020148338A1 (en) | 2019-01-15 | 2020-07-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Mutated interleukin-34 (il-34) polypeptides and uses thereof in therapy |
WO2020157131A1 (en) | 2019-01-30 | 2020-08-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor |
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 |
WO2020163589A1 (en) | 2019-02-08 | 2020-08-13 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2020165370A1 (en) | 2019-02-13 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for selecting a cancer treatment in a subject suffering from cancer |
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 |
EP3929213A4 (en) * | 2019-02-21 | 2023-03-08 | Eucure (Beijing) Biopharma Co., Ltd | Anti-pd-l1 antibody and use thereof |
WO2020186176A1 (en) | 2019-03-14 | 2020-09-17 | Genentech, Inc. | Treatment of cancer with her2xcd3 bispecific antibodies in combination with anti-her2 mab |
WO2020198672A1 (en) | 2019-03-28 | 2020-10-01 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2020198676A1 (en) | 2019-03-28 | 2020-10-01 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2020205626A1 (en) | 2019-03-29 | 2020-10-08 | Genentech, Inc. | Modulators of cell surface protein interactions and methods and compositions related to same |
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 |
WO2020201568A1 (en) | 2019-04-03 | 2020-10-08 | Targimmune Therapeutics Ag | Immunotherapy for the treatment of cancer |
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 |
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 |
WO2020214995A1 (en) | 2019-04-19 | 2020-10-22 | Genentech, Inc. | Anti-mertk antibodies and their methods of use |
WO2020216697A1 (en) | 2019-04-23 | 2020-10-29 | Innate Pharma | Cd73 blocking antibodies |
WO2020221796A1 (en) | 2019-04-30 | 2020-11-05 | 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 |
WO2020226986A2 (en) | 2019-05-03 | 2020-11-12 | 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 |
WO2020232378A1 (en) | 2019-05-16 | 2020-11-19 | Silicon Swat, Inc. | Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use |
WO2020232375A1 (en) | 2019-05-16 | 2020-11-19 | Silicon Swat, Inc. | Oxoacridinyl acetic acid derivatives and methods of use |
WO2020234875A2 (en) | 2019-05-19 | 2020-11-26 | Yeda Research And Development Co. Ltd. | Identification of recurrent mutated neopeptides |
WO2020239558A1 (en) | 2019-05-24 | 2020-12-03 | Pfizer Inc. | Combination therapies using cdk inhibitors |
WO2020243570A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Cell localization signature and combination therapy |
WO2020243563A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Multi-tumor gene signatures for suitability to immuno-oncology therapy |
WO2020243568A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy |
EP3929215A4 (en) * | 2019-06-10 | 2022-06-22 | Shandong Boan Biotechnology Co., Ltd. | Bifunctional fusion protein against pdl1 and tgf? and use thereof |
WO2021009267A1 (en) | 2019-07-15 | 2021-01-21 | Capella Bioscience Ltd | Anti-pd-l1 antibodies |
WO2021009365A1 (en) | 2019-07-18 | 2021-01-21 | Ctxt Pty Limited | Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting |
WO2021009362A1 (en) | 2019-07-18 | 2021-01-21 | Ctxt Pty Limited | Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting |
WO2021019526A1 (en) | 2019-07-29 | 2021-02-04 | Yeda Research And Development Co. Ltd. | Methods of treating and diagnosing lung 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 |
WO2021025177A1 (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 |
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 |
WO2021055698A1 (en) | 2019-09-19 | 2021-03-25 | Bristol-Myers Squibb Company | Antibodies binding to vista at acidic ph |
WO2021055994A1 (en) | 2019-09-22 | 2021-03-25 | Bristol-Myers Squibb Company | Quantitative spatial profiling for lag-3 antagonist therapy |
WO2021062018A1 (en) | 2019-09-25 | 2021-04-01 | Bristol-Myers Squibb Company | Composite biomarker for cancer therapy |
EP4424321A2 (en) | 2019-09-27 | 2024-09-04 | F. Hoffmann-La Roche AG | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021062085A1 (en) | 2019-09-27 | 2021-04-01 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021064567A1 (en) | 2019-09-30 | 2021-04-08 | 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 |
WO2021064180A1 (en) | 2019-10-03 | 2021-04-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating macrophages polarization |
WO2021064184A1 (en) | 2019-10-04 | 2021-04-08 | 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 |
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 |
KR20220088425A (en) | 2019-10-25 | 2022-06-27 | 다이이찌 산쿄 가부시키가이샤 | Combination of anti-GARP antibodies and immunomodulators |
WO2021079958A1 (en) | 2019-10-25 | 2021-04-29 | 第一三共株式会社 | Combination of anti-garp antibody and immunoregulator |
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 |
WO2021090146A1 (en) | 2019-11-04 | 2021-05-14 | Astrazeneca Ab | Combination therapy for treating cancer |
WO2021091964A1 (en) | 2019-11-04 | 2021-05-14 | Duke University | Treatment for primary and metastatic 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 |
WO2021092171A1 (en) | 2019-11-06 | 2021-05-14 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
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 |
WO2021092380A1 (en) | 2019-11-08 | 2021-05-14 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for melanoma |
WO2021097110A1 (en) | 2019-11-13 | 2021-05-20 | Genentech, Inc. | Therapeutic compounds and methods of use |
WO2021097256A1 (en) | 2019-11-14 | 2021-05-20 | Cohbar, Inc. | Cxcr4 antagonist peptides |
WO2021106978A1 (en) | 2019-11-27 | 2021-06-03 | サイトリミック株式会社 | Pharmaceutical composition |
WO2021127217A1 (en) | 2019-12-17 | 2021-06-24 | Flagship Pioneering Innovations V, Inc. | Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly |
WO2021123243A1 (en) | 2019-12-19 | 2021-06-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and vaccine compositions to treat cancers |
WO2021127554A1 (en) | 2019-12-19 | 2021-06-24 | Bristol-Myers Squibb Company | Combinations of dgk inhibitors and checkpoint antagonists |
WO2021142203A1 (en) | 2020-01-10 | 2021-07-15 | Innate Tumor Immunity, Inc. | Nlrp3 modulators |
WO2021144426A1 (en) | 2020-01-17 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2021154073A1 (en) | 2020-01-29 | 2021-08-05 | Merus N.V. | Means and method for modulating immune cell engaging effects. |
WO2021152548A1 (en) | 2020-01-30 | 2021-08-05 | Benitah Salvador Aznar | Combination therapy for treatment of cancer and cancer metastasis |
WO2021155149A1 (en) | 2020-01-31 | 2021-08-05 | Genentech, Inc. | 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) |
WO2021158938A1 (en) | 2020-02-06 | 2021-08-12 | Bristol-Myers Squibb Company | Il-10 and uses thereof |
WO2021158635A1 (en) | 2020-02-07 | 2021-08-12 | Al Therapeutics, Inc. | Anti-viral compositions and methods of use |
WO2021174045A1 (en) | 2020-02-28 | 2021-09-02 | Bristol-Myers Squibb Company | Radiolabeled fibronectin based scaffolds and antibodies and theranostic uses thereof |
WO2021170777A1 (en) | 2020-02-28 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing, prognosing and managing treatment of breast cancer |
WO2021177980A1 (en) | 2020-03-06 | 2021-09-10 | Genentech, Inc. | Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist |
WO2021178807A1 (en) | 2020-03-06 | 2021-09-10 | Celgene Quanticel Research, Inc. | Combination of an lsd-1 inhibitor and nivolumab for use in treating sclc or sqnsclc |
WO2021176424A1 (en) | 2020-03-06 | 2021-09-10 | Ona Therapeutics, S.L. | Anti-cd36 antibodies and their use to treat cancer |
EP3878446A1 (en) | 2020-03-09 | 2021-09-15 | Universite De Geneve | Hsd11b1 inhibitors for use in immunotherapy and uses thereof |
WO2021183428A1 (en) | 2020-03-09 | 2021-09-16 | Bristol-Myers Squibb Company | Antibodies to cd40 with enhanced agonist activity |
WO2021180643A1 (en) | 2020-03-09 | 2021-09-16 | Universite De Geneve | Hsd11b1 inhibitors for use in immunotherapy and uses thereof |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2021195485A1 (en) * | 2020-03-27 | 2021-09-30 | Vanderbilt University | Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (sars-cov-2) |
WO2021202959A1 (en) | 2020-04-03 | 2021-10-07 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2021205444A1 (en) | 2020-04-06 | 2021-10-14 | Yeda Research And Development Co. Ltd. | Methods of diagnosing cancer and predicting responsiveness to therapy |
WO2021207449A1 (en) | 2020-04-09 | 2021-10-14 | Merck Sharp & Dohme Corp. | Affinity matured anti-lap antibodies and uses thereof |
US12018065B2 (en) | 2020-04-27 | 2024-06-25 | Twist Bioscience Corporation | Variant nucleic acid libraries for coronavirus |
WO2021222167A1 (en) | 2020-04-28 | 2021-11-04 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
WO2021224215A1 (en) | 2020-05-05 | 2021-11-11 | F. Hoffmann-La Roche Ag | Predicting response to pd-1 axis inhibitors |
US11878062B2 (en) | 2020-05-12 | 2024-01-23 | Cue Biopharma, Inc. | Multimeric T-cell modulatory polypeptides and methods of use thereof |
WO2021231732A1 (en) | 2020-05-15 | 2021-11-18 | 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 |
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 |
WO2021252977A1 (en) | 2020-06-12 | 2021-12-16 | Genentech, Inc. | Methods and compositions for cancer immunotherapy |
WO2021257503A1 (en) | 2020-06-16 | 2021-12-23 | Genentech, Inc. | Methods and compositions for treating triple-negative breast cancer |
WO2021257124A1 (en) | 2020-06-18 | 2021-12-23 | Genentech, Inc. | Treatment with anti-tigit antibodies and pd-1 axis binding antagonists |
WO2022006179A1 (en) | 2020-06-29 | 2022-01-06 | Flagship Pioneering Innovations V, Inc. | Viruses engineered to promote thanotransmission and their use in treating cancer |
WO2022008519A1 (en) | 2020-07-07 | 2022-01-13 | BioNTech SE | Therapeutic rna for hpv-positive cancer |
WO2022020716A1 (en) | 2020-07-24 | 2022-01-27 | Genentech, Inc. | Heterocyclic inhibitors of tead for treating cancer |
WO2022023379A1 (en) | 2020-07-28 | 2022-02-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for preventing and treating a cancer |
WO2022036146A1 (en) | 2020-08-12 | 2022-02-17 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
WO2022036079A1 (en) | 2020-08-13 | 2022-02-17 | Bristol-Myers Squibb Company | Methods of redirecting of il-2 to target cells of interest |
WO2022047189A1 (en) | 2020-08-28 | 2022-03-03 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for hepatocellular carcinoma |
WO2022047412A1 (en) | 2020-08-31 | 2022-03-03 | Bristol-Myers Squibb Company | Cell localization signature and immunotherapy |
WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
US12029782B2 (en) | 2020-09-09 | 2024-07-09 | Cue Biopharma, Inc. | MHC class II T-cell modulatory multimeric polypeptides for treating type 1 diabetes mellitus (T1D) and methods of use thereof |
WO2022053703A1 (en) | 2020-09-14 | 2022-03-17 | Boehringer Ingelheim International Gmbh | Heterologous prime boost vaccine |
US12121565B2 (en) | 2020-09-14 | 2024-10-22 | Duke University | Methods of treatment of specific cancers with NLRP3 inhibitors and anti-PD1/PD-L1 antibodies |
WO2022076318A1 (en) | 2020-10-05 | 2022-04-14 | Bristol-Myers Squibb Company | Methods for concentrating proteins |
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 |
WO2022084210A1 (en) | 2020-10-20 | 2022-04-28 | F. Hoffmann-La Roche Ag | Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors |
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 |
WO2022087402A1 (en) | 2020-10-23 | 2022-04-28 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for lung cancer |
WO2022094567A1 (en) | 2020-10-28 | 2022-05-05 | Ikena Oncology, Inc. | Combination of an ahr inhibitor with a pdx inhibitor or doxorubicine |
WO2022093981A1 (en) | 2020-10-28 | 2022-05-05 | Genentech, Inc. | Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists |
WO2022101302A1 (en) | 2020-11-12 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies conjugated or fused to the receptor-binding domain of the sars-cov-2 spike protein and uses thereof for vaccine purposes |
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 |
WO2022101481A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022101484A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | 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 |
WO2022119830A1 (en) | 2020-12-02 | 2022-06-09 | Genentech, Inc. | Methods and compositions for neoadjuvant and adjuvant urothelial carcinoma therapy |
WO2022120179A1 (en) | 2020-12-03 | 2022-06-09 | Bristol-Myers Squibb Company | Multi-tumor gene signatures and uses thereof |
WO2022136257A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022136255A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022136266A1 (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 |
WO2022146948A1 (en) | 2020-12-28 | 2022-07-07 | Bristol-Myers Squibb Company | Subcutaneous administration of pd1/pd-l1 antibodies |
WO2022146947A1 (en) | 2020-12-28 | 2022-07-07 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
WO2022148736A1 (en) | 2021-01-05 | 2022-07-14 | Transgene | Vectorization of muc1 t cell engager |
WO2022183018A1 (en) * | 2021-02-26 | 2022-09-01 | Fred Hutchinson Cancer Research Center | Protective antibodies against respiratory viral infections |
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 |
WO2022203090A1 (en) | 2021-03-25 | 2022-09-29 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
WO2022212400A1 (en) | 2021-03-29 | 2022-10-06 | Juno Therapeutics, Inc. | Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy |
WO2022212784A1 (en) | 2021-03-31 | 2022-10-06 | Flagship Pioneering Innovations V, Inc. | Thanotransmission polypeptides and their use in treating cancer |
WO2022212876A1 (en) | 2021-04-02 | 2022-10-06 | The Regents Of The University Of California | Antibodies against cleaved cdcp1 and uses thereof |
WO2022217123A2 (en) | 2021-04-08 | 2022-10-13 | Nurix Therapeutics, Inc. | Combination therapies with cbl-b inhibitor compounds |
WO2022216898A1 (en) | 2021-04-09 | 2022-10-13 | Genentech, Inc. | Combination therapy with a raf inhibitor and a pd-1 axis inhibitor |
WO2022219080A1 (en) | 2021-04-14 | 2022-10-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | New method to improve nk cells cytotoxicity |
WO2022223791A1 (en) | 2021-04-23 | 2022-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | 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 |
WO2022232503A1 (en) | 2021-04-30 | 2022-11-03 | Genentech, Inc. | Therapeutic and diagnostic methods and compositions for cancer |
WO2022243378A1 (en) | 2021-05-18 | 2022-11-24 | Kymab Limited | Uses of anti-icos antibodies |
WO2022254227A1 (en) | 2021-06-04 | 2022-12-08 | Kymab Limited | Treatment of pd-l1 negative or low expressing cancer with anti-icos antibodies |
WO2023278641A1 (en) | 2021-06-29 | 2023-01-05 | Flagship Pioneering Innovations V, Inc. | Immune cells engineered to promote thanotransmission and uses thereof |
WO2023279092A2 (en) | 2021-07-02 | 2023-01-05 | Genentech, Inc. | Methods and compositions for treating cancer |
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 |
WO2023285552A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
WO2023010095A1 (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 |
WO2023007472A1 (en) | 2021-07-30 | 2023-02-02 | ONA Therapeutics S.L. | Anti-cd36 antibodies and their use to treat cancer |
WO2023051926A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
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 |
WO2023052531A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
WO2023057882A1 (en) | 2021-10-05 | 2023-04-13 | Pfizer Inc. | Combinations of azalactam compounds with a pd-1 axis binding antagonist for the treatment of cancer |
WO2023061930A1 (en) | 2021-10-11 | 2023-04-20 | BioNTech SE | Therapeutic rna for lung cancer |
WO2023077034A1 (en) | 2021-10-28 | 2023-05-04 | Lyell Immunopharma, Inc. | Methods for culturing immune cells |
WO2023077090A1 (en) | 2021-10-29 | 2023-05-04 | Bristol-Myers Squibb Company | Lag-3 antagonist therapy for hematological cancer |
WO2023079428A1 (en) | 2021-11-03 | 2023-05-11 | Pfizer Inc. | Combination therapies using tlr7/8 agonist |
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) |
WO2023080900A1 (en) | 2021-11-05 | 2023-05-11 | Genentech, Inc. | Methods and compositions for classifying and treating kidney cancer |
WO2023083868A1 (en) | 2021-11-09 | 2023-05-19 | BioNTech SE | Tlr7 agonist and combinations for cancer treatment |
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 |
WO2023097194A2 (en) | 2021-11-24 | 2023-06-01 | 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 |
US12110276B2 (en) | 2021-11-24 | 2024-10-08 | Genentech, Inc. | Pyrazolo compounds and methods of use 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 |
WO2023129438A1 (en) | 2021-12-28 | 2023-07-06 | Wisconsin Alumni Research Foundation | Hydrogel compositions for use for depletion of tumor associated macrophages |
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 |
WO2023164638A1 (en) | 2022-02-25 | 2023-08-31 | Bristol-Myers Squibb Company | Combination therapy for colorectal carcinoma |
WO2023168404A1 (en) | 2022-03-04 | 2023-09-07 | Bristol-Myers Squibb Company | Methods of treating a tumor |
WO2023170606A1 (en) | 2022-03-08 | 2023-09-14 | Alentis Therapeutics Ag | Use of anti-claudin-1 antibodies to increase t cell availability |
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 |
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 |
WO2023201299A1 (en) | 2022-04-13 | 2023-10-19 | 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 |
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 |
WO2023235415A1 (en) | 2022-06-01 | 2023-12-07 | Genentech, Inc. | Method to identify a patient with an increased likelihood of chemotherapy-induced peripheral neuropathy |
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 |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
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 |
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 |
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 |
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 |
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 |
WO2024077166A1 (en) | 2022-10-05 | 2024-04-11 | Genentech, Inc. | Methods and compositions for classifying and treating lung cancer |
WO2024084034A1 (en) | 2022-10-21 | 2024-04-25 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of osteoarthritis |
WO2024089418A1 (en) | 2022-10-24 | 2024-05-02 | Cancer Research Technology Limited | Tumour sensitisation to checkpoint inhibitors with redox status modifier |
WO2024089417A1 (en) | 2022-10-24 | 2024-05-02 | Memorial Sloan-Kettering Cancer Center | Tumour stratification for responsiveness to an immune checkpoint inhibitor |
WO2024091991A1 (en) | 2022-10-25 | 2024-05-02 | Genentech, Inc. | Therapeutic and diagnostic methods for multiple myeloma |
WO2024094688A1 (en) | 2022-11-01 | 2024-05-10 | Heidelberg Pharma Research Gmbh | Anti-gucy2c antibody and uses thereof |
WO2024116140A1 (en) | 2022-12-01 | 2024-06-06 | Medimmune Limited | Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies |
WO2024115725A1 (en) | 2022-12-01 | 2024-06-06 | BioNTech SE | Multispecific antibody against cd40 and cd137 in combination therapy with anti-pd1 ab and chemotherapy |
WO2024126457A1 (en) | 2022-12-14 | 2024-06-20 | Astellas Pharma Europe Bv | Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and immune checkpoint inhibitors |
WO2024137589A2 (en) | 2022-12-20 | 2024-06-27 | Genentech, Inc. | Methods of treating pancreatic cancer with a pd-1 axis binding antagonist and an rna vaccine |
WO2024137776A1 (en) | 2022-12-21 | 2024-06-27 | Bristol-Myers Squibb Company | Combination therapy for lung cancer |
WO2024151687A1 (en) | 2023-01-09 | 2024-07-18 | Flagship Pioneering Innovations V, Inc. | Genetic switches and their use in treating cancer |
WO2024150177A1 (en) | 2023-01-11 | 2024-07-18 | Advesya | Treatment methods for solid tumors |
WO2024150017A1 (en) | 2023-01-13 | 2024-07-18 | Akrivia Biomedics Limited | Method of profiling diseases |
WO2024160721A1 (en) | 2023-01-30 | 2024-08-08 | Kymab Limited | Antibodies |
WO2024196952A1 (en) | 2023-03-20 | 2024-09-26 | Bristol-Myers Squibb Company | Tumor subtype assessment for cancer therapy |
WO2024200571A1 (en) | 2023-03-28 | 2024-10-03 | Institut National de la Santé et de la Recherche Médicale | Method for discriminating mono-immunotherapy from combined immunotherapy in cancers |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11518809B2 (en) | Targeted binding agents against B7-H1 | |
MX2011002838A (en) | Antibodies against sonic hedgehog homolog and uses thereof. | |
QUEVA et al. | Patent 2778714 Summary |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080053042.1 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10833923 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2778714 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010324757 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 219876 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2012/005809 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012540171 Country of ref document: JP |
|
ENP | Entry into the national phase |
Ref document number: 2010324757 Country of ref document: AU Date of ref document: 20101124 Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 4769/DELNP/2012 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 20127016372 Country of ref document: KR Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2010833923 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010833923 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012126138 Country of ref document: RU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13511538 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112012012465 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 243813 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 112012012465 Country of ref document: BR Kind code of ref document: A2 Effective date: 20120524 |