TWI335821B - Immunoglobulin variants and uses thereof - Google Patents
Immunoglobulin variants and uses thereof Download PDFInfo
- Publication number
- TWI335821B TWI335821B TW092135563A TW92135563A TWI335821B TW I335821 B TWI335821 B TW I335821B TW 092135563 A TW092135563 A TW 092135563A TW 92135563 A TW92135563 A TW 92135563A TW I335821 B TWI335821 B TW I335821B
- Authority
- TW
- Taiwan
- Prior art keywords
- antibody
- cells
- cell
- antigen
- humanized antibody
- Prior art date
Links
- 108060003951 Immunoglobulin Proteins 0.000 title description 14
- 102000018358 immunoglobulin Human genes 0.000 title description 14
- 210000004027 cell Anatomy 0.000 claims description 236
- 230000027455 binding Effects 0.000 claims description 128
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 97
- 241000282414 Homo sapiens Species 0.000 claims description 97
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 96
- 238000011282 treatment Methods 0.000 claims description 91
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 66
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 65
- 201000010099 disease Diseases 0.000 claims description 59
- 239000000427 antigen Substances 0.000 claims description 56
- 108091007433 antigens Proteins 0.000 claims description 56
- 102000036639 antigens Human genes 0.000 claims description 56
- 206010028980 Neoplasm Diseases 0.000 claims description 55
- 230000000694 effects Effects 0.000 claims description 52
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 45
- 239000012634 fragment Substances 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 42
- 238000006467 substitution reaction Methods 0.000 claims description 41
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 32
- 230000004540 complement-dependent cytotoxicity Effects 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 32
- 239000013598 vector Substances 0.000 claims description 31
- 201000011510 cancer Diseases 0.000 claims description 30
- 150000007523 nucleic acids Chemical class 0.000 claims description 29
- 102000039446 nucleic acids Human genes 0.000 claims description 26
- 108020004707 nucleic acids Proteins 0.000 claims description 26
- 229940127089 cytotoxic agent Drugs 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 23
- 208000024891 symptom Diseases 0.000 claims description 22
- 208000023275 Autoimmune disease Diseases 0.000 claims description 21
- 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 claims description 17
- 238000001727 in vivo Methods 0.000 claims description 17
- 229960000485 methotrexate Drugs 0.000 claims description 17
- 101100495232 Homo sapiens MS4A1 gene Proteins 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 16
- 239000008280 blood Substances 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 208000011580 syndromic disease Diseases 0.000 claims description 15
- 239000002246 antineoplastic agent Substances 0.000 claims description 14
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 13
- 229960004397 cyclophosphamide Drugs 0.000 claims description 13
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 13
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 13
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 12
- 239000002254 cytotoxic agent Substances 0.000 claims description 12
- 210000004698 lymphocyte Anatomy 0.000 claims description 12
- 201000004681 Psoriasis Diseases 0.000 claims description 11
- 230000002285 radioactive effect Effects 0.000 claims description 11
- 239000013604 expression vector Substances 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
- 239000003053 toxin Substances 0.000 claims description 10
- 231100000765 toxin Toxicity 0.000 claims description 10
- 108700012359 toxins Proteins 0.000 claims description 10
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 230000001363 autoimmune Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 8
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 8
- 239000003018 immunosuppressive agent Substances 0.000 claims description 8
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 8
- 206010047115 Vasculitis Diseases 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 208000017604 Hodgkin disease Diseases 0.000 claims description 6
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 6
- 238000004113 cell culture Methods 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 5
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 5
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 5
- 208000010159 IgA glomerulonephritis Diseases 0.000 claims description 5
- 206010021263 IgA nephropathy Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 238000012258 culturing Methods 0.000 claims description 5
- 230000003013 cytotoxicity Effects 0.000 claims description 5
- 231100000135 cytotoxicity Toxicity 0.000 claims description 5
- 230000001419 dependent effect Effects 0.000 claims description 5
- 208000024908 graft versus host disease Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 206010028417 myasthenia gravis Diseases 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000003782 Raynaud disease Diseases 0.000 claims description 3
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 3
- 206010039710 Scleroderma Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 230000008439 repair process Effects 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-UHFFFAOYSA-N 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010036105 Polyneuropathy Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 230000007824 polyneuropathy Effects 0.000 claims description 2
- 206010043554 thrombocytopenia Diseases 0.000 claims description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims 2
- 208000005777 Lupus Nephritis Diseases 0.000 claims 2
- 208000019069 chronic childhood arthritis Diseases 0.000 claims 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims 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 claims 1
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 claims 1
- 206010021118 Hypotonia Diseases 0.000 claims 1
- 240000000233 Melia azedarach Species 0.000 claims 1
- 208000007379 Muscle Hypotonia Diseases 0.000 claims 1
- 206010009887 colitis Diseases 0.000 claims 1
- 238000001802 infusion Methods 0.000 claims 1
- 238000004064 recycling Methods 0.000 claims 1
- 208000017520 skin disease Diseases 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 description 53
- 229960004641 rituximab Drugs 0.000 description 44
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 39
- 102000004169 proteins and genes Human genes 0.000 description 37
- 241000699666 Mus <mouse, genus> Species 0.000 description 35
- 238000004458 analytical method Methods 0.000 description 33
- 235000018102 proteins Nutrition 0.000 description 33
- 239000000243 solution Substances 0.000 description 31
- -1 for example Chemical class 0.000 description 30
- 210000002706 plastid Anatomy 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 27
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 25
- 239000002609 medium Substances 0.000 description 25
- 108020004414 DNA Proteins 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 24
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 24
- 230000035772 mutation Effects 0.000 description 24
- 239000002953 phosphate buffered saline Substances 0.000 description 24
- 102220513849 Pecanex-like protein 1_D56N_mutation Human genes 0.000 description 20
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 20
- 239000000872 buffer Substances 0.000 description 20
- 241001465754 Metazoa Species 0.000 description 19
- 230000006870 function Effects 0.000 description 19
- 102220556084 Myeloid cell surface antigen CD33_N100A_mutation Human genes 0.000 description 18
- 102220517543 Calcium uniporter protein, mitochondrial_S92A_mutation Human genes 0.000 description 17
- 239000012636 effector Substances 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 150000001413 amino acids Chemical class 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 102220281543 rs1555509778 Human genes 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 206010025323 Lymphomas Diseases 0.000 description 13
- 206010036790 Productive cough Diseases 0.000 description 13
- 102220580962 Voltage-dependent T-type calcium channel subunit alpha-1H_M32V_mutation Human genes 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 208000024794 sputum Diseases 0.000 description 13
- 210000003802 sputum Anatomy 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 241000282567 Macaca fascicularis Species 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 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 10
- 241000288906 Primates Species 0.000 description 10
- 102220492217 Replication stress response regulator SDE2_N73K_mutation Human genes 0.000 description 10
- 241000700605 Viruses Species 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 210000000822 natural killer cell Anatomy 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 230000010076 replication Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 238000012216 screening Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 9
- 241000588724 Escherichia coli Species 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 210000001185 bone marrow Anatomy 0.000 description 9
- 229930195731 calicheamicin Natural products 0.000 description 9
- 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 9
- 210000004379 membrane Anatomy 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 8
- 108010087819 Fc receptors Proteins 0.000 description 8
- 102000009109 Fc receptors Human genes 0.000 description 8
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 8
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 125000005647 linker group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000003550 marker Substances 0.000 description 8
- 229920001542 oligosaccharide Polymers 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 230000004614 tumor growth Effects 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 7
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 7
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- 231100000433 cytotoxic Toxicity 0.000 description 7
- 230000001472 cytotoxic effect Effects 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 108020001096 dihydrofolate reductase Proteins 0.000 description 7
- 239000012091 fetal bovine serum Substances 0.000 description 7
- 230000036541 health Effects 0.000 description 7
- 230000002147 killing effect Effects 0.000 description 7
- 150000002482 oligosaccharides Chemical class 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- 208000003950 B-cell lymphoma Diseases 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 108091034117 Oligonucleotide Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 102220348035 c.218A>G Human genes 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 230000001086 cytosolic effect Effects 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 210000003527 eukaryotic cell Anatomy 0.000 description 6
- 230000033581 fucosylation Effects 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 229940127121 immunoconjugate Drugs 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 210000001503 joint Anatomy 0.000 description 6
- 210000003292 kidney cell Anatomy 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- 230000010412 perfusion Effects 0.000 description 6
- 238000003752 polymerase chain reaction Methods 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 6
- 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 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 5
- 241000282693 Cercopithecidae Species 0.000 description 5
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 description 5
- 108091035707 Consensus sequence Proteins 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000007995 HEPES buffer Substances 0.000 description 5
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 description 5
- 241000235649 Kluyveromyces Species 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 5
- 102220005331 rs281865555 Human genes 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- 108010092160 Dactinomycin Proteins 0.000 description 4
- 101710088194 Dehydrogenase Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 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
- 241000282553 Macaca Species 0.000 description 4
- 108090000157 Metallothionein Proteins 0.000 description 4
- 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 4
- 239000002033 PVDF binder Substances 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 102220580930 Voltage-dependent T-type calcium channel subunit alpha-1H_M32I_mutation Human genes 0.000 description 4
- 238000001994 activation Methods 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 4
- 230000001588 bifunctional effect Effects 0.000 description 4
- 150000001720 carbohydrates Chemical group 0.000 description 4
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000009266 disease activity Effects 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 206010025135 lupus erythematosus Diseases 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 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 4
- 229960001924 melphalan Drugs 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 4
- 238000002203 pretreatment Methods 0.000 description 4
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 102220322755 rs760716065 Human genes 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 3
- 102000000412 Annexin Human genes 0.000 description 3
- 108050008874 Annexin Proteins 0.000 description 3
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 102000036364 Cullin Ring E3 Ligases Human genes 0.000 description 3
- 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 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 108010008165 Etanercept Proteins 0.000 description 3
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 206010017711 Gangrene Diseases 0.000 description 3
- 102000006395 Globulins Human genes 0.000 description 3
- 108010044091 Globulins Proteins 0.000 description 3
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 102000004877 Insulin Human genes 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
- 102220553605 Lens fiber major intrinsic protein_S56A_mutation Human genes 0.000 description 3
- 108010000817 Leuprolide Proteins 0.000 description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 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
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 102000003792 Metallothionein Human genes 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 102220539293 Programmed cell death 1 ligand 2_F67A_mutation Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 3
- 102220509115 Sphingosine 1-phosphate receptor 1_Y97V_mutation Human genes 0.000 description 3
- 229930182558 Sterol Natural products 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 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
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 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 3
- 229930183665 actinomycin Natural products 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 3
- 229960002170 azathioprine Drugs 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class 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 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000000973 chemotherapeutic effect Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 229960001334 corticosteroids Drugs 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 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 3
- 230000002950 deficient Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 230000003325 follicular Effects 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 201000009277 hairy cell leukemia Diseases 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 201000008383 nephritis Diseases 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 210000004180 plasmocyte Anatomy 0.000 description 3
- 230000008488 polyadenylation Effects 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 229950008882 polysorbate Drugs 0.000 description 3
- 238000010188 recombinant method Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 102220036452 rs137882485 Human genes 0.000 description 3
- 102220462444 rs778785164 Human genes 0.000 description 3
- 102220214502 rs876658582 Human genes 0.000 description 3
- 238000013077 scoring method Methods 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 235000003702 sterols Nutrition 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 229960002317 succinimide Drugs 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000001732 thrombotic effect Effects 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- IZZIWIAOVZOBLF-UHFFFAOYSA-N 5-methoxysalicylic acid Chemical compound COC1=CC=C(O)C(C(O)=O)=C1 IZZIWIAOVZOBLF-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 108010051457 Acid Phosphatase Proteins 0.000 description 2
- 102000013563 Acid Phosphatase Human genes 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- BYXHQQCXAJARLQ-ZLUOBGJFSA-N Ala-Ala-Ala Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O BYXHQQCXAJARLQ-ZLUOBGJFSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 108090000672 Annexin A5 Proteins 0.000 description 2
- 102000004121 Annexin A5 Human genes 0.000 description 2
- 208000032467 Aplastic anaemia Diseases 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
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- 102220527021 Cytochrome b5 reductase 4_S99T_mutation Human genes 0.000 description 2
- 102220527020 Cytochrome b5 reductase 4_S99V_mutation Human genes 0.000 description 2
- 102220626122 DNA polymerase eta_Y52F_mutation Human genes 0.000 description 2
- 241000255925 Diptera Species 0.000 description 2
- 208000017701 Endocrine disease Diseases 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- 229930189413 Esperamicin Natural products 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 102000005731 Glucose-6-phosphate isomerase Human genes 0.000 description 2
- 108010070600 Glucose-6-phosphate isomerase Proteins 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 101000958041 Homo sapiens Musculin Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229920000877 Melamine resin Polymers 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 208000010428 Muscle Weakness Diseases 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102220619836 Pituitary-specific positive transcription factor 1_L78A_mutation Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- 102220607023 Ras-related protein Rap-1b_Y32A_mutation Human genes 0.000 description 2
- 102220495915 Serine-tRNA ligase, cytoplasmic_N54A_mutation Human genes 0.000 description 2
- 102220471545 Single-stranded DNA cytosine deaminase_S26A_mutation Human genes 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 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
- 239000004098 Tetracycline Substances 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 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 2
- 101710120037 Toxin CcdB Proteins 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- IXKSXJFAGXLQOQ-XISFHERQSA-N WHWLQLKPGQPMY Chemical compound C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CNC=N1 IXKSXJFAGXLQOQ-XISFHERQSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 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 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 230000004520 agglutination Effects 0.000 description 2
- 108010017893 alanyl-alanyl-alanine Proteins 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 229960003896 aminopterin Drugs 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000008228 bacteriostatic water for injection Substances 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960003669 carbenicillin Drugs 0.000 description 2
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 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
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 229960002842 clobetasol Drugs 0.000 description 2
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate 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)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 239000000430 cytokine receptor antagonist Substances 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 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 2
- 102000004419 dihydrofolate reductase Human genes 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000002228 disulfide group Chemical group 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 229940073621 enbrel Drugs 0.000 description 2
- 208000030172 endocrine system disease Diseases 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- 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 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
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 229960000304 folic acid Drugs 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 102000054767 gene variant Human genes 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000004727 humoral immunity Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 108091008042 inhibitory receptors Proteins 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- 201000002364 leukopenia Diseases 0.000 description 2
- 231100001022 leukopenia Toxicity 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound 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 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 208000005158 lymphoid interstitial pneumonia Diseases 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 description 2
- 210000001806 memory b lymphocyte Anatomy 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 2
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- 150000002923 oximes Chemical group 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000001126 phototherapy Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 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 2
- 239000003755 preservative agent Substances 0.000 description 2
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 2
- 239000013587 production medium Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 229950010131 puromycin Drugs 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- 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 2
- 206010037844 rash Diseases 0.000 description 2
- 229940116176 remicade Drugs 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 102200074783 rs144422014 Human genes 0.000 description 2
- 102220178356 rs769686237 Human genes 0.000 description 2
- 102220095972 rs876660949 Human genes 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 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 2
- 229940063683 taxotere Drugs 0.000 description 2
- 230000002381 testicular Effects 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 229940113082 thymine Drugs 0.000 description 2
- 238000000954 titration curve Methods 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000011573 trace mineral Substances 0.000 description 2
- 235000013619 trace mineral Nutrition 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- 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 2
- 229960004355 vindesine Drugs 0.000 description 2
- 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 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- OOIBFPKQHULHSQ-UHFFFAOYSA-N (3-hydroxy-1-adamantyl) 2-methylprop-2-enoate Chemical compound C1C(C2)CC3CC2(O)CC1(OC(=O)C(=C)C)C3 OOIBFPKQHULHSQ-UHFFFAOYSA-N 0.000 description 1
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- BQIMPGFMMOZASS-CLZZGJSISA-N (6r,7r)-7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CO)=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 BQIMPGFMMOZASS-CLZZGJSISA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- AESVUZLWRXEGEX-DKCAWCKPSA-N (7S,9R)-7-[(2S,4R,5R,6R)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione iron(3+) Chemical compound [Fe+3].COc1cccc2C(=O)c3c(O)c4C[C@@](O)(C[C@H](O[C@@H]5C[C@@H](N)[C@@H](O)[C@@H](C)O5)c4c(O)c3C(=O)c12)C(=O)CO AESVUZLWRXEGEX-DKCAWCKPSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- SXCIMUIAZXOVIR-PUCKCBAPSA-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 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(=O)CO)CCOCC1 SXCIMUIAZXOVIR-PUCKCBAPSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- VILFTWLXLYIEMV-UHFFFAOYSA-N 1,5-difluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(F)C=C1F VILFTWLXLYIEMV-UHFFFAOYSA-N 0.000 description 1
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 1
- BTFMCMVEUCGQDX-UHFFFAOYSA-N 1-[10-[3-[4-(2-hydroxyethyl)-1-piperidinyl]propyl]-2-phenothiazinyl]ethanone Chemical compound C12=CC(C(=O)C)=CC=C2SC2=CC=CC=C2N1CCCN1CCC(CCO)CC1 BTFMCMVEUCGQDX-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- XLEYFDVVXLMULC-UHFFFAOYSA-N 2',4',6'-trihydroxyacetophenone Chemical compound CC(=O)C1=C(O)C=C(O)C=C1O XLEYFDVVXLMULC-UHFFFAOYSA-N 0.000 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- FZDFGHZZPBUTGP-UHFFFAOYSA-N 2-[[2-[bis(carboxymethyl)amino]-3-(4-isothiocyanatophenyl)propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C(C)CN(CC(O)=O)CC(N(CC(O)=O)CC(O)=O)CC1=CC=C(N=C=S)C=C1 FZDFGHZZPBUTGP-UHFFFAOYSA-N 0.000 description 1
- JTXMVXSTHSMVQF-UHFFFAOYSA-N 2-acetyloxyethyl acetate Chemical compound CC(=O)OCCOC(C)=O JTXMVXSTHSMVQF-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- AAUQLHHARJUJEH-UHFFFAOYSA-N 2-hydroxy-5-methoxybenzoic acid Natural products COC1=CC=CC(O)=C1C(O)=O AAUQLHHARJUJEH-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- LBYVZRFDLNAPRC-UHFFFAOYSA-N 2-sulfanylguanidine Chemical compound NC(=N)NS LBYVZRFDLNAPRC-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- DJBRKGZFUXKLKO-UHFFFAOYSA-N 3-(pyridin-2-yldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSC1=CC=CC=N1 DJBRKGZFUXKLKO-UHFFFAOYSA-N 0.000 description 1
- OSJPPGNTCRNQQC-UWTATZPHSA-N 3-phospho-D-glyceric acid Chemical compound OC(=O)[C@H](O)COP(O)(O)=O OSJPPGNTCRNQQC-UWTATZPHSA-N 0.000 description 1
- 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 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- LDNQWFNUHJPIPO-UHFFFAOYSA-N 4-decoxy-2-(2-decoxy-2-oxoethyl)-2-hydroxy-4-oxobutanoic acid Chemical compound CCCCCCCCCCOC(=O)CC(O)(C(O)=O)CC(=O)OCCCCCCCCCC LDNQWFNUHJPIPO-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 102100033400 4F2 cell-surface antigen heavy chain Human genes 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 210000002925 A-like Anatomy 0.000 description 1
- 102220554192 APC membrane recruitment protein 1_H34A_mutation Human genes 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 102100036664 Adenosine deaminase Human genes 0.000 description 1
- 241000256118 Aedes aegypti Species 0.000 description 1
- 241000256173 Aedes albopictus Species 0.000 description 1
- QMGUSPDJTPDFSF-UHFFFAOYSA-N Aldophosphamide Chemical compound ClCCN(CCCl)P(=O)(N)OCCC=O QMGUSPDJTPDFSF-UHFFFAOYSA-N 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 102220495828 Alkaline ceramidase 1_F93A_mutation Human genes 0.000 description 1
- 102220486160 Alkaline ceramidase 1_R24A_mutation Human genes 0.000 description 1
- 102220495789 Alkaline ceramidase 1_S28A_mutation Human genes 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102100029361 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000351920 Aspergillus nidulans Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 206010064539 Autoimmune myocarditis Diseases 0.000 description 1
- 206010055128 Autoimmune neutropenia Diseases 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 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
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 1
- 102220477610 Bis(5'-nucleosyl)-tetraphosphatase [asymmetrical]_Y27A_mutation Human genes 0.000 description 1
- 241001674044 Blattodea Species 0.000 description 1
- 241000255789 Bombyx mori Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100033640 Bromodomain-containing protein 1 Human genes 0.000 description 1
- 102220562905 Bromodomain-containing protein 1_I51K_mutation Human genes 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102220588724 C2 domain-containing protein 5_P51A_mutation Human genes 0.000 description 1
- 229940124292 CD20 monoclonal antibody Drugs 0.000 description 1
- 108010084313 CD58 Antigens Proteins 0.000 description 1
- 102220479102 CD59 glycoprotein_N33Q_mutation Human genes 0.000 description 1
- 101100342815 Caenorhabditis elegans lec-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102220586197 Chemerin-like receptor 2_K62A_mutation Human genes 0.000 description 1
- 102220586190 Chemerin-like receptor 2_K62R_mutation Human genes 0.000 description 1
- 206010068051 Chimerism Diseases 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 102220604032 Clathrin heavy chain 1_Q89A_mutation Human genes 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 108091033380 Coding strand Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 210000004128 D cell Anatomy 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
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-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
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 102100033072 DNA replication ATP-dependent helicase DNA2 Human genes 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- 102220597351 DNA-directed RNA polymerases I, II, and III subunit RPABC2_N94A_mutation Human genes 0.000 description 1
- 101100422577 Danio rerio stil gene Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 208000001154 Dermoid Cyst Diseases 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
- 102220559699 Differentially expressed in FDCP 8 homolog_K73Q_mutation Human genes 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 1
- 101100377506 Drosophila melanogaster 14-3-3zeta gene Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 102220579904 E3 ubiquitin-protein ligase RING2_D56K_mutation Human genes 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 102220519462 Enoyl-CoA hydratase, mitochondrial_Q90A_mutation Human genes 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 244000004281 Eucalyptus maculata Species 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 108090000156 Fructokinases Proteins 0.000 description 1
- 102220605905 GTPase HRas_Y32F_mutation Human genes 0.000 description 1
- 102220486715 Gap junction beta-2 protein_M34A_mutation Human genes 0.000 description 1
- 108700023863 Gene Components Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 1
- 102100022624 Glucoamylase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 102100025591 Glycerate kinase Human genes 0.000 description 1
- 102000000587 Glycerolphosphate Dehydrogenase Human genes 0.000 description 1
- 108010041921 Glycerolphosphate Dehydrogenase Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 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
- 244000299507 Gossypium hirsutum Species 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 244000041633 Grewia tenax Species 0.000 description 1
- 235000005612 Grewia tenax Nutrition 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 102220511662 Heme oxygenase 1_S58A_mutation Human genes 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 101000800023 Homo sapiens 4F2 cell-surface antigen heavy chain Proteins 0.000 description 1
- 101100273713 Homo sapiens CD2 gene Proteins 0.000 description 1
- 101000927313 Homo sapiens DNA replication ATP-dependent helicase DNA2 Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000691459 Homo sapiens Serine/threonine-protein kinase N2 Proteins 0.000 description 1
- 101001115218 Homo sapiens Ubiquitin-40S ribosomal protein S27a Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 241000701109 Human adenovirus 2 Species 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010021067 Hypopituitarism Diseases 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 1
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 1
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 1
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102220492658 Integrin alpha-3_D56S_mutation Human genes 0.000 description 1
- 102220492704 Integrin alpha-3_H35A_mutation Human genes 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 102100025381 Keratin, type II cytoskeletal 73 Human genes 0.000 description 1
- 241001138401 Kluyveromyces lactis Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000160780 Lasiommata megera Species 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102220641311 Leukotriene C4 synthase_Y59F_mutation Human genes 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 206010025280 Lymphocytosis Diseases 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 101100273714 Macaca fascicularis CD2 gene Proteins 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 239000004907 Macro-emulsion Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 102220472556 Melanoregulin_Q61A_mutation Human genes 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 1
- 102220480557 Metabotropic glutamate receptor 3_Y98A_mutation Human genes 0.000 description 1
- 235000005135 Micromeria juliana Nutrition 0.000 description 1
- 102220601218 Microtubule-associated protein tau_T30A_mutation Human genes 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 102220612416 Mitogen-activated protein kinase kinase kinase 1_S92N_mutation Human genes 0.000 description 1
- HYFMSAFINFJTFH-UHFFFAOYSA-N Mitomycin-A Natural products O=C1C(OC)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)N2CC2NC21 HYFMSAFINFJTFH-UHFFFAOYSA-N 0.000 description 1
- 229940121849 Mitotic inhibitor Drugs 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101000935589 Mus musculus Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000822667 Mus musculus Something about silencing protein 10 Proteins 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 102220631334 NCK-interacting protein with SH3 domain_S92G_mutation Human genes 0.000 description 1
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 101100442582 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) spe-1 gene Proteins 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 102000003940 Occludin Human genes 0.000 description 1
- 108090000304 Occludin Proteins 0.000 description 1
- 102220576120 Oligodendrocyte transcription factor 1_Y27W_mutation Human genes 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 102220632791 Ornithine aminotransferase, mitochondrial_K64A_mutation Human genes 0.000 description 1
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 1
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 1
- 101100081884 Oryza sativa subsp. japonica OSA15 gene Proteins 0.000 description 1
- 101150082245 PSAG gene Proteins 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 241000282376 Panthera tigris Species 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 240000007377 Petunia x hybrida Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000233614 Phytophthora Species 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010036297 Postpartum hypopituitarism Diseases 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010052649 Primary hypogonadism Diseases 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 101710179016 Protein gamma Proteins 0.000 description 1
- 102220480127 Protein-tyrosine sulfotransferase 1_N60A_mutation Human genes 0.000 description 1
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 description 1
- 102220505583 Putative uncharacterized protein C1orf140_N33A_mutation Human genes 0.000 description 1
- 102220505587 Putative uncharacterized protein C1orf140_S30A_mutation Human genes 0.000 description 1
- 102220469433 Putative uncharacterized protein URB1-AS1_W91F_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
- 102220536023 Quinone oxidoreductase-like protein 1_Y59W_mutation Human genes 0.000 description 1
- 102000004879 Racemases and epimerases Human genes 0.000 description 1
- 108090001066 Racemases and epimerases Proteins 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 240000002114 Satureja hortensis Species 0.000 description 1
- 235000007315 Satureja hortensis Nutrition 0.000 description 1
- 241000235347 Schizosaccharomyces pombe Species 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- 102100023230 Serine/threonine-protein kinase MAK Human genes 0.000 description 1
- 102100026180 Serine/threonine-protein kinase N2 Human genes 0.000 description 1
- 102220482486 Serine/threonine-protein kinase Nek7_N33D_mutation Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 201000009895 Sheehan syndrome Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 102220509100 Sphingosine 1-phosphate receptor 1_Y97W_mutation Human genes 0.000 description 1
- 241000256247 Spodoptera exigua Species 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 102220617493 Syndecan-4_F63A_mutation Human genes 0.000 description 1
- 102220610549 Syndecan-4_Y59A_mutation Human genes 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102220522291 THAP domain-containing protein 1_S31A_mutation Human genes 0.000 description 1
- 102220536512 THAP domain-containing protein 1_S52A_mutation Human genes 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 102220608115 TYRO protein tyrosine kinase-binding protein_G49L_mutation Human genes 0.000 description 1
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 102220481238 Thymocyte selection-associated high mobility group box protein TOX_F29A_mutation Human genes 0.000 description 1
- 108010046075 Thymosin Proteins 0.000 description 1
- 102000007501 Thymosin Human genes 0.000 description 1
- 206010043781 Thyroiditis chronic Diseases 0.000 description 1
- 206010043784 Thyroiditis subacute Diseases 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 206010044223 Toxic epidermal necrolysis Diseases 0.000 description 1
- 231100000087 Toxic epidermal necrolysis Toxicity 0.000 description 1
- 102220535799 Transcription factor JunD_L54A_mutation Human genes 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 241000223259 Trichoderma Species 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100023341 Ubiquitin-40S ribosomal protein S27a Human genes 0.000 description 1
- 102220596171 Uncharacterized protein C1orf131_N53A_mutation Human genes 0.000 description 1
- 108091023045 Untranslated Region Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000016807 X-linked intellectual disability-macrocephaly-macroorchidism syndrome Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 1
- ZYVSOIYQKUDENJ-ASUJBHBQSA-N [(2R,3R,4R,6R)-6-[[(6S,7S)-6-[(2S,4R,5R,6R)-4-[(2R,4R,5R,6R)-4-[(2S,4S,5S,6S)-5-acetyloxy-4-hydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-7-[(3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-4,10-dihydroxy-3-methyl-5-oxo-7,8-dihydro-6H-anthracen-2-yl]oxy]-4-[(2R,4R,5R,6R)-4-hydroxy-5-methoxy-6-methyloxan-2-yl]oxy-2-methyloxan-3-yl] acetate Chemical class COC([C@@H]1Cc2cc3cc(O[C@@H]4C[C@@H](O[C@@H]5C[C@@H](O)[C@@H](OC)[C@@H](C)O5)[C@H](OC(C)=O)[C@@H](C)O4)c(C)c(O)c3c(O)c2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@@H]2C[C@@H](O[C@H]3C[C@](C)(O)[C@@H](OC(C)=O)[C@H](C)O3)[C@H](O)[C@@H](C)O2)[C@H](O)[C@@H](C)O1)C(=O)[C@@H](O)[C@@H](C)O ZYVSOIYQKUDENJ-ASUJBHBQSA-N 0.000 description 1
- GBXZONVFWYCRPT-JGWLITMVSA-N [(2r,3s,4r,5r)-3,4,5,6-tetrahydroxy-1-oxohexan-2-yl] dihydrogen phosphate Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)OP(O)(O)=O GBXZONVFWYCRPT-JGWLITMVSA-N 0.000 description 1
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- 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
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- 238000003916 acid precipitation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 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 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229940126574 aminoglycoside antibiotic Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000000781 anti-lymphocytic effect Effects 0.000 description 1
- 230000003460 anti-nuclear 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
- 208000037908 antibody-mediated disorder Diseases 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 229940059756 arava Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012911 assay medium Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 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 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 108010051210 beta-Fructofuranosidase 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
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- HUTDDBSSHVOYJR-UHFFFAOYSA-H bis[(2-oxo-1,3,2$l^{5},4$l^{2}-dioxaphosphaplumbetan-2-yl)oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O HUTDDBSSHVOYJR-UHFFFAOYSA-H 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-YCVQJEHTSA-N bryostatins Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)C([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-YCVQJEHTSA-N 0.000 description 1
- CJGYSWNGNKCJSB-YVLZZHOMSA-N bucladesine Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 CJGYSWNGNKCJSB-YVLZZHOMSA-N 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 102220362486 c.167A>G Human genes 0.000 description 1
- 102220354611 c.211G>A Human genes 0.000 description 1
- 102220351956 c.26G>A Human genes 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 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
- 238000004364 calculation method Methods 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 108010047060 carzinophilin Proteins 0.000 description 1
- 108010079058 casein hydrolysate Proteins 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 241000902900 cellular organisms Species 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229950008249 chlornaphazine Drugs 0.000 description 1
- 108010025790 chlorophyllase Proteins 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)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](OC(C)=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](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 210000001268 chyle Anatomy 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 210000000078 claw Anatomy 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 229940027008 deltasone Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229950003913 detorubicin Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- CELBUDBANIEXBV-UHFFFAOYSA-N dichloromethanamine Chemical compound NC(Cl)Cl CELBUDBANIEXBV-UHFFFAOYSA-N 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 102220500038 eIF5-mimic protein 2_M33A_mutation Human genes 0.000 description 1
- 102220481278 eIF5-mimic protein 2_Y27F_mutation Human genes 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 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
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- LKVXSBPPCRGKIF-UHFFFAOYSA-N ethyl n,n-bis(2-chloroethyl)carbamate Chemical compound CCOC(=O)N(CCCl)CCCl LKVXSBPPCRGKIF-UHFFFAOYSA-N 0.000 description 1
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 239000012530 fluid Substances 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
- 239000011888 foil Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 239000012537 formulation buffer Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 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 1
- 230000030414 genetic transfer Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 208000024693 gingival disease Diseases 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 108010086476 glycerate kinase Proteins 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 102000035122 glycosylated proteins Human genes 0.000 description 1
- 108091005608 glycosylated proteins Proteins 0.000 description 1
- 229940076085 gold Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960002706 gusperimus Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 231100000508 hormonal effect Toxicity 0.000 description 1
- 102000053350 human FCGR3B Human genes 0.000 description 1
- 102000046949 human MSC Human genes 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000014726 immortalization of host cell Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 1
- 229940055742 indium-111 Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) 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(=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@@H](C)O)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@@H](C)CC)[C@@H](C)O)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 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 230000008407 joint function Effects 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 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 1
- 239000004571 lime Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 229940087857 lupron Drugs 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 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
- 235000012054 meals Nutrition 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229950009246 mepitiostane Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000033600 microtubule polymerization or depolymerization Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- HYFMSAFINFJTFH-NGSRAFSJSA-N mitomycin A Chemical compound O=C1C(OC)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@]1(OC)N2C[C@@H]2N[C@@H]21 HYFMSAFINFJTFH-NGSRAFSJSA-N 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- IDINUJSAMVOPCM-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-INIZCTEOSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 230000007302 negative regulation of cytokine production Effects 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- YMVWGSQGCWCDGW-UHFFFAOYSA-N nitracrine Chemical compound C1=CC([N+]([O-])=O)=C2C(NCCCN(C)C)=C(C=CC=C3)C3=NC2=C1 YMVWGSQGCWCDGW-UHFFFAOYSA-N 0.000 description 1
- 229950008607 nitracrine Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000010529 odontogenesis of dentin-containing tooth Effects 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical class O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 210000004923 pancreatic tissue Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000008884 pinocytosis Effects 0.000 description 1
- 229960004265 piperacetazine Drugs 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000012342 propidium iodide staining Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 231100001028 renal lesion Toxicity 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- 102220196645 rs1057518868 Human genes 0.000 description 1
- 102200153431 rs1060501000 Human genes 0.000 description 1
- 102220222103 rs1060501223 Human genes 0.000 description 1
- 102200061297 rs121909233 Human genes 0.000 description 1
- 102200068095 rs121913658 Human genes 0.000 description 1
- 102200114091 rs121965048 Human genes 0.000 description 1
- 102200114092 rs121965060 Human genes 0.000 description 1
- 102220337694 rs1228819238 Human genes 0.000 description 1
- 102220289524 rs1250849257 Human genes 0.000 description 1
- 102200037741 rs137853960 Human genes 0.000 description 1
- 102220122463 rs142178073 Human genes 0.000 description 1
- 102220288775 rs1554193610 Human genes 0.000 description 1
- 102220282120 rs1555509758 Human genes 0.000 description 1
- 102200108018 rs199473052 Human genes 0.000 description 1
- 102220041065 rs200979664 Human genes 0.000 description 1
- 102200082911 rs33926764 Human genes 0.000 description 1
- 102220005404 rs33931314 Human genes 0.000 description 1
- 102220005485 rs33931314 Human genes 0.000 description 1
- 102220005394 rs33984621 Human genes 0.000 description 1
- 102220095210 rs370243092 Human genes 0.000 description 1
- 102220006678 rs41306027 Human genes 0.000 description 1
- 102220293486 rs575604496 Human genes 0.000 description 1
- 102220046415 rs587777600 Human genes 0.000 description 1
- 102220072209 rs727505205 Human genes 0.000 description 1
- 102220330862 rs748216749 Human genes 0.000 description 1
- 102220340177 rs782563826 Human genes 0.000 description 1
- 102220096727 rs876659692 Human genes 0.000 description 1
- 102220105250 rs879254386 Human genes 0.000 description 1
- 102220147472 rs886060981 Human genes 0.000 description 1
- 102200111189 rs906807 Human genes 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 1
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 1
- 235000005493 rutin Nutrition 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 101150108347 sdhB gene Proteins 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 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 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 201000007497 subacute thyroiditis Diseases 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940126703 systemic medication Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- RUELTTOHQODFPA-UHFFFAOYSA-N toluene 2,6-diisocyanate Chemical compound CC1=C(N=C=O)C=CC=C1N=C=O RUELTTOHQODFPA-UHFFFAOYSA-N 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 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
- 229960001670 trilostane Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000002485 urinary effect Effects 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
- 229940005605 valeric acid Drugs 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 208000037911 visceral disease Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-OUBTZVSYSA-N water-17o Chemical compound [17OH2] XLYOFNOQVPJJNP-OUBTZVSYSA-N 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229940070524 zinc protein complex Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
-
- 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
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/522—CH1 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/72—Increased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/734—Complement-dependent cytotoxicity [CDC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/75—Agonist effect on antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Pulmonology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Microbiology (AREA)
- Hematology (AREA)
- Plant Pathology (AREA)
- Communicable Diseases (AREA)
- Vascular Medicine (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
Description
1335821 玖、發明說明: 【發明所屬之技術領域】 本發明係關於抗-CD20抗體,及其在治療B_細胞相關疾病 上之用途。 【先前技術】 淋巴球是數群白丘球細胞中的一群;其可專一性辨識外 來的抗原,並產生反應。主要三類的淋巴球為B淋巴球(B 細胞)、τ淋巴球(τ細胞)及自然殺手(NK)細胞。B淋巴球是 負貝產生抗體的細胞,及提供體液免疫作用。B細胞在骨髓 中進行熟化,並使其細胞表面上留下骨髓表面抗原_鍵結抗 體’當天然B細胞首次遇到與其膜_鍵結抗體具有專一性的 抗原時,細胞便開始快速分裂,而其子細胞可分化成記憶B 細胞及.所謂漿細胞之效應子細胞。記憶B細胞具有較長的生 命週期’並且可以持續表現出與原來母細胞具有相同專一 性之膜-鍵結抗體,但漿細胞則不會產生膜_鍵結抗體,而是 產生分泌形式的抗體◊分泌型抗體是體液免疫的主要效應 子分子0 CD20抗原(亦稱為人類B-淋巴球_限制性分化抗原,Bp35) 是位於前-B細胞及成熟B淋巴球上之疏水性穿膜蛋白,分子 量約 35 kD(Valentine等人,《/· Βζ·ο/· 264(19):11282-11287 (1989);及Einfeld等人,X 7(3):711-717 (1988)),該 抗原亦表現於90%以上的非-何傑金氏淋巴瘤(NHl)b細胞 上(Anderson等人,63(6):1424-1433 (1984)),但造血 幹細胞、前-B細胞、正常漿細胞或其他正常組織均未發現 〇:V90\90156.DOC -6 - 1335821 該抗原(Tedder等人、’ 135(2):973-979(1985))0 CD20被認為可鈿節細胞週期啟動及分化作用之活化過程 的早期步驟(Tedder等人.,虎逑),並可能是作為鈣離子通道 的功能(Tedder等人,《/· Ce//· 5z’oc/zem. 14D:195 (1990))。 由於CD20在B細胞淋巴瘤上的表現,此抗原業已成為此 類淋巴瘤一個有用的治療標靶。在美國超過300,000人罹患 B-細胞NHL,且每年超過56,000診斷出為新病例。例如,利
特西馬(rituximab)(RITUXAN®)抗體(係以遺傳工程方式生 產之抗人類CD20抗原之老鼠/人類嵌合性單株抗體,購自 Genentech公司,南三蕃市,加州,美國)可用以治療罹患 CD20陽j生生或f或渡泡j生非-Mi桀|氏B細 胞淋巴瘤。利特西.馬係1 998年4月7日公佈之美國專利 5,736,1.37號(Anderson等人)中所指之” C2B8”抗體。活體外 作用研究機制已證明RITUXAN®可與人類補體鍵結,並經
由補體-依賴性細胞毒性(CDC)溶解淋巴B細胞株(Reff等 人83(2):435-445(1994)),除此之外,其在抗體-依賴 性細胞媒介細胞毒性(ADCC)分析上具有顯著的活性。活體 内臨床前研究已證明RITUXAN®可能會藉由補體及細胞 -媒介過程來減損食蟹猴週邊血液、淋巴結及骨髓中的B細 胞(Reff等人,83(2):435-445(1994))。其他用來治療 NHL的抗-CD20抗體包括老鼠抗體ZevalinTM(其鍵結放射性 同位素釔-90 ; IDEC藥廠、聖地牙哥,加州)、BexxarTM(另 一種共軛1-131的完全老鼠抗體(卡利西城,華盛頓州))。 在人類治療上使用老鼠抗體的主要限制是人類抗-老鼠
O:\90\90156.DOC 1335821 抗體(human anti-mOuse antibody ; HAMA)反應(參見,例 如,Miller,'R· A.等人,"七位罹患T-細胞淋巴瘤中進行的單 株抗體治療試驗 62:988-995,1983 ;及 Schroff,R.W.,
等人,'’病患接受單株抗體治療之人類抗-老鼠免疫球蛋白 反應”Cawcer及以.,45:879-885,1985)。即使是其中嚅齒動 物抗體之可變區域(V)融合至人類固定區域(C)之嵌合性分 子,其仍會引發明顯的免疫反應(人顏抗-嵌合性抗體 (HACA ; human anti-chimeric antibody))(Neuberger等人, 倫敦),314··268-270,(1985)。克服這些於臨床使用 單株抗體的限制性之有利方法是將老鼠抗體或源自非-人 類物種之抗體進行”人源化作用"(Jones等人,倫 敦),321:522-525,1986 ; Riechman等人,iVaiwM(倫敦), 332:323- 327 (1988)。
據此,製備當投與病患時(特別是慢性治療)會產生最低或 不具有抗原性之抗CD20抗原之治療性抗體是有益處的,本 發明即可滿足此一需求及其他的需求。本發明提供抗-CD20 抗體,其可克服近來治療用組合物之限制性,及具有後文 將詳述之其他額外優點。 【發明内容】 本發明提供CD20鍵結抗體或其具有功能性的片段,及其 在治療B_細胞相關疾病上的用途’這些抗體為单株抗體。 在特定的具體實例中,鍵結CD20的抗體是人源化或嵌合性 抗體。人源化2H7變異體包括在FR具有胺基酸取代作用的 變異體,及在移植CDRs上具有經改變親和力熟化變異體。
O:\90\90I56.DOC 1335821
CDR或FR中的取代胺基酸不侷限於本發明供體抗體或接受 抗體中所含'有者。在其他具體實例中,本發明抗-CD20抗體 另外包括改變Fc區域中的胺基酸殘基(其可增進效應子功 能,包括增強CDC及/或ADCC功能及殺死B-細胞(亦係本專 利說明所稱B-細胞減損))。本發明其他抗_Cd20抗體包括具 有能增進穩定性之特殊變化者。在一個特定具體實例中, 具有較高穩定性的人源化2H7變異體揭示於後文實例6中。 在一個具體實例中,嵌合性抗-CD20抗體係具有老鼠的V區 域及人類的C區域,此一種之特定嵌合性抗_cd20抗體為 Rituxan®(利特.西馬 ® ; Genentech公司)。 在本發明所用之所有抗體組合物及方法中一個較佳的具 體實例中,人源化CD20鍵結抗體2H7.V16,其具有分別示 於圖6(3£(^10^^0.21)及圖7(8£卩10]^0.22)之輕鏈及重鏈 胺基酸序列。除了本專利說明書所揭示之胺基酸取代作用 位置外’所有以16變異體為基礎之其他變異體均具有vl 6的
胺基酸序列。除非另有所指’ 2H7變異體具有與vi6相同的 L鏈。 本發明提供一可鍵結人類CD20的人源化抗體,或其抗原 -鍵結片段,其中該抗體可有效地減損靈長動物活體内的B 細胞’該抗體包括在Η鏈可變區域(VH)至少有一源自抗-人 類CD20抗體之CDR3序列(SEQ ID N0.12),及實質上人類亞 型III重鏈(VHIII)的人類一致性架構(FR)殘基。在一個具體 實例中,靈長動物B細胞係來自人類及食蟹猴。在一個具體 貫例中’該抗體另外包括重鏈CDR1序列(SEQ ID NO. 10)及
O:\90\90156.DOC 1335821 CDR2序列(SEQ ID N0.11)。在另一個具體實例中,前述抗 體包括輕鏈bDRl序列(SEQ ID N0.4)、CDR2序列(SEQ ID N0.5)、CDR3序列(SEQ ID N0.6),及實質地人類輕鏈/c亞 型I(V /c I)的人類一致性架構(FR)殘基。本專利說明書中” 實質地"係指包含某些胺基酸取代作用之序列,例如,每一 FR序列(FR1、FR2等)具有不同於原始序列的一或兩個胺基 酸取代作用。 前述具體實例之抗體包括示於圖1B中vl 6之VH序列(SEQ _ ID NO.8),在前述的另一個具體實例中,抗體另外包括示 -於圖 1A中 vl6之 VL序列(SEQ ID NO.2)。 在其他具體實例中,人源化抗體是具有分別示於圖6 (8£(^1〇1^0.2)及圖8(8£()1〇]^0.23)之輕鏈及重鏈胺基酸 序列之2Η7·ν31 ; 2H7.V31具有示於圖8中SEQ ID N0.23之胺 基酸序列的重鏈;2H7.V96則在vl6之Η鏈的D56A及N100A 及L鏈的S92A具有胺基酸取代作用。
在另一個具體實例中,任何前述具體實例之抗體另外包 括至少在Fc區域有一個胺基酸取代作用,其可使ADCC及/ 或CDC活性超越原衍生的原始或親本抗體者。ν·16是最常用 以比較之親本抗體例子。一種具有此改良活性之抗體係包 括在?0區域具有3298八/丑33 3八/;〇34八之三個丙胺酸取代作 用者。一種具有S298A/E333A/K334A取代作用之抗體為具 有SEQ ID Ν0.23重鏈胺基酸序列之2Η7·ν31。抗體2H7.V114 及2H7.V115與Rituxan相較顯示至少有10倍強的ADCC活 性0 O:\90\90156.DOC -10· 1335821 在另一個具體實例中,該抗體包括至少在Fc區域有一個 胺基酸取代作用’其較所源自的親本抗體之CDC活性低, v 16是最常用以比較之抗體例子。一種具有較v丨6低cdc活 性之此抗體包括至少在重鏈上包含K322A取代作用者。 ADCC及CDC活性的比較可以實例中所揭示者分析之。 在一較佳的具體實例中,本發明抗體為全長抗體,其中 VH區域接合至人類1§(}重鏈固定區域上,在一個較佳的具體 實例中,IgG為人類的igGl或IgG3。 在一個具體實例中,CD20鍵結抗體鍵結至一細胞毒性劑 上,在較佳的具體實例中,該細胞毒性劑為毒素或放射性 活性同位素。 在一個具體實例中,作為治療或診斷目的所用之本發明 抗體係.於CHO細胞中產生。 本發明亦提供一包括前述具體實例中之任一抗體及載劑 之組合物。在一個具體實例中,該載劑為醫藥學上可接受 之載劑。這些組合物可為產品中的一物品或套組。 本發明亦提供一編碼本專利說明書所揭示任一抗體之經 刀離核酸,包括用以表現該抗體之表現載體。 本發明另一方面係包括前述核酸之宿主細胞,及用以產 生該抗體之宿主細胞’後者較佳的具體實例中,該宿主細 胞為CHO細胞。本發明亦提供製備這些抗體的方法,該方 法包括培養可產生該抗體之宿主細胞,及自細胞培養中回 收該抗體。 本發明另-個方面係一製造產品,其包括容器及其内含
O:\90\90156.DOC 1335821 的組合物,其中該組合物包括前述具體實例中任一抗體。 以治療NHL用途而言,該製造產品另外包括用以說明該組 合物係為治療非-何傑金氏淋巴瘤用之包裝插頁。 本發明另一方面係誘發活體内B細胞凋零作用的方法,包 括將B細胞與前述任一抗體接觸反應,藉此殺死b細胞。 本發明亦提供治療本專利說明書中所揭示的疾病之方 -法其係藉投與患病哺乳動物(諸如人類病患)CD2〇鍵結抗 : 體或其功旎性片段。在任一治療自體免疫疾病或CD2〇陽性 癌症之方法中,在一個具體實例中,抗體為具有分別示於_ 圖6及圖7中SEQ ID N0.21及22之輕鏈及重鏈胺基酸序列之 2Η7·ν16。據此,一個具體實例係一治療cD2〇陽性癌症之 方法,其包括投與癌症病患一有效治療量之本發明人源化 CD20鍵結抗體。在較佳的具體實例中,CD2〇陽性癌症為b 細胞淋巴瘤或白血症,包括非_何傑金氏淋巴瘤(NHL)或淋 巴球優勢何傑金氏疾病(LPHD)、慢性淋巴球性白血病(clL) 或SLL。在一個治療b細胞淋巴瘤或白血症之具體實例方法 中’該抗體投與劑量範圍約275-375毫克/平方米。在另一具 體貫例中’治療方法另外包括投與病患至少一種化學治療 -劑’其中以非-何傑金氏淋巴瘤而言,該化學治療劑選自由 · 杜瑟陸賓辛(doxorubicin)、環磷醯胺(CyCi〇ph〇sphamide)、 威利司汀(vincristine)及去氫可體醇(prednis〇1〇ne)所組之 群。 本發明亦提供一種治療自體免疫疾病之方法,其包括投 與惟患自體免疫疾病病患一治療有效量之前述任一聲明之 O:\9O\90156.DOC -12· 1335821 *原:CD20鍵結抗體。自體免疫疾病係選自類風濕性關節 人月乂年i員風濕性關節炎、全身性紅斑性狼瘡(咖)、緯 。、”氏疾病發炎性腸疾病、特發性血小板低下紫斑症 (πτ)、血栓性血小板低下紫斑症(ττρ)'自體免疫血小板減 ^夕發性硬皮症、牛皮癣、IgA腎病變、IgM多發性神經 病艾、重症肌無力、血管炎、糖尿病、雷諾氏症候、修格 連氏症候及腎絲球腎炎所組之群。當自體免疫疾病為類風 性關節火時,該抗體可另一種治療劑合併投用,較佳者 為甲胺嗓吟。 在与些治療方法中,CD2〇鍵結抗體可單獨投用,或與另 I種治療劑(諸如另一種抗體)或化學治療劑或免疫抑制劑 合併投用。另一種抗體可以是為與CD2〇鍵結的抗體或與不 同B細胞抗原,或NK或T細胞抗原鍵結的抗體。在一個具體 實例中,另一種抗體為放射性標記的抗_CD2〇抗體。在另— 個具體實例中,該CD20鍵結抗體係共軛至一細胞毒性劑 上’包括毒素或放射性活性同位素。 另一方面,本發明提供一種治療自體免疫疾病的方法, 該自體免疫疾病選自由皮肌炎、瑋格納氏肉芽腫、ANca、 再生障礙性貧血症、自體免疫溶血貧血症(AIHA)、因子νπι 缺少、A型血友病、自體免疫嗜中性白血球缺乏症、卡斯特 萊曼氏症候、古德巴斯德氏症候、固形器官移植排斥作用、 移植物抗宿主疾病(GVHD)、IgM媒介之血栓性血小板低下 紫斑症(TTP)、橋本氏曱狀腺炎、自體免疫肝炎、淋巴細胞 間質性肺炎(HIV) '阻塞性支氣管炎(非移植)相對Nsip、居 O:\90\90156.DOC •13· 1335821 專一性抗體),及抗體片段,只要這些抗體呈現所要的生物 活性或功能k卩可。 本發明CD20鍵結抗體及人源化CD2〇鍵結抗體之生物活 性包括至少該抗體可鍵結至人類CD2〇上,更佳者係可鍵結 至人類及其他靈長動物之CD2〇(包括,食蟹猴、恆河猴、黑 獲獲)。s亥抗體鍵結CD20的1^值不高於1 x 1 〇·8,較佳地是κ」 . 值不高於lxl〇-9,且當與適當未經此一抗體處理之陰性控制 . 組比較時,較佳至少能夠殺死或減損活體内2〇%的B細胞, B細胞減損是-或多種ADCC、CDC、細胞〉周零,或其他機餐 制所造成的結果。在本專利說明書中某些疾病治療的具體 實例中’所要的特定效應子功能或機制需求高過其他者, 且人源化2H7的某些變異體較佳具有該等生物功能,諸如 ADCC。 ••抗體片段"包括全長抗體的一部分,通常係其抗原鍵結 區域或可受區域。抗體片段的實例包括Fab、Fab,、;p(ab , 及Fv片段;雙抗體;直線抗體;單鏈抗體分子;及由抗體 塌· 片段所形成之多專一性抗體。 "Fv”係包含一完整的抗原-辨識及抗原_鍵結位置之最小 . 抗體片段’此片I又係由一個重鍵及一個輕鍵的可變區域以 ^ 緊密、非-共價鍵方式所結合之雙體。此兩個區域的交疊產 生六個超變化曲環(每個Η及L鏈各有3個曲環),此曲環提供 抗原鍵結之胺基酸殘基及賦予與抗體之抗原鍵結專一性。 然而,即使是一個單一可變區域(或包括僅有對抗原有專一 性之二個CDRs之Fv的一半)仍具有辨識及鍵結抗原之能 O:\90\90156.DOC -15· 1335821 力’雖,然其較完整鍵結位置的親和力低。 本專利說明書中所用”留I _ 曰y所用早株抗體"係指自一 體所獲得之抗體,換言之, ^實質⑽抗 量突變作用外,抗體群中所勺括夕有自然發生之少 抗體且右一谇査 匕括之個別抗體均等同。單株 ,、“度專-性,其對抗單一抗原位置,除此之外, =)=抗不同抗原決定子(抗原子)之傳統抗體(多 =細目異之處是,每一軍株抗體係對抗抗原上翠一 =:1。修飾語”單株”係指實質上獲自均質抗體群之 f 何特定方法所需製備之抗 體例如,根據本發明所用的單株抗體可為以Kohler等人, 偏⑽編95 (1975)首次揭示的融合瘤方法製備者,或以 重組DNA方法(參考,例如,美國專利第MW567號)製備 者,例如,亦可利用Clackson等人,編_52派628 〇 及Marks等人,乂胸.咖222:581 597 (1991)所揭示之 技術從嗜菌體抗體庫中分離出"單株抗體"。 本發明CD20鍵結抗體之”功能片段”係指仍以與完整全長 抗體鏈分子實質性_親和力鍵結至CD20,絲生自全^ 抗體鏈分子之片段者,且其顯示包括具有以活體外或活體
内分析法(諸如本專利說明書中所揭示者)所測定之減損B 細胞的生物活性。 "可變區”一詞係指抗體間某些可變區域片段之序列普遍 不相同’V區域會媒介抗原鍵結,且界定了較抗體對其特 定抗原的專-性而’可變性並非平均地分布在可變區 域的U0胺基酸範圍中,取而代之的1,v區域係由數個
O:\90\90156.DOC •16- 1335821 15-30個胺基酸相'當恆定片段之架構區域 regions ; FRs)所‘組成,該等恆定片段則被稱為"超變化區域" 之9-12個胺基酸長度之極度變化性短區域區隔開,天然的 重鏈及輕鏈之可變區域各包括四個Frs(大部分係採疊板 架構),其被三個超變化區域連接起來(其形成曲環接合), 而在某些情況下會形成部分的β_疊板架構。每一蛋白鏈的 -超變化區域緊密的以FRs靠在一起,且與其他蛋白鏈的超變 化區域形成抗體之抗原-鍵結位置(參考,Rabat等人,_ 趣免疫蛋电_序列,第五版,公共衛生院,國家健康局,畢 _ 士大’馬里蘭州(1991))。固定區域並未直接參與抗體與抗 原的鍵結’但卻呈現各種的效應子功能,諸如抗體依賴性 細胞毒性(ADCC)中抗體的參與作用。 當本’專利說明書使用"超變化區域"一詞時,其係指抗體 上負責抗原鍵結之胺基酸殘基。超變化區域通常包括源自 π互補決定區”或"CDR”的胺基酸殘基(例如,在Vl中約 24-34(Ll)、50-56(L2)及 89-97(L3)之殘基及 VH 中約 31-35B __ (HI)、50-65(H2)及 95-102(H3)之殘基)(Kabat等人,感興趣 · 免i蛋白序列,第五版,公共健康院,國家健康局,畢士 · 大’馬里蘭州(1 99 1))’及/或源自"超變化曲環,,的殘基者(例 . 如’在VL 中約 26-32(Ll)、50-52(L2)及 91-96(L3)之殘基及 VH 中約 26-32(Η1)、52A-5 5(H2)及 96-101(H3)之殘基(Chothia 及 Lesk J. Mol. Biol. 196:901-9 1 7 (1987))。 當本專利說明書提及"一致性序列"或一致性V區域序列 時’係指源自已知人類免疫球蛋白可變區域序列之胺基酸 O:\90\90I56.DOC -17- 1335821 序列比較後之人工序列。根據這些比較結果,可製備編碼 源自人類K及人類Η鏈亞型III V區域上一致性序列之v區域 胺基酸之重組性核酸序列,該一致性v序列不具任何已知抗 體的鍵結專一性或親和力。 "嵌合性"抗體(免疫球蛋白)具有與源自特定物種或屬於 特定抗體群或亞型之抗體之對應序列相同或同質性的重鏈 及/或輕鏈之一部分,而所剩下的蛋白鏈則與源自另一物種 或屬於另一抗體群或亞型之對應序列相同或與其具有同質 性,以及該等抗體的片段,只要其仍具有所要的生物活性 即可(美國專利第4,816,567號及Morrison等人,/v〇c.
Ad· 81:6851-6855 (1984))。本專利說明書所用人 源化抗體係一群嵌合性抗體。 非-人類(例如,鼠類)抗體之"人源化,,形式係指所含源自 非-人類免疫球蛋白序列為最少之嵌合性抗體。大部分而 吕,人源化抗體為人類免疫球蛋白(接受抗體或受體抗體), 其中接受抗體的超變化區域之殘基經非_人類物種(諸如,具 有所要專一性、親和力及能力之老鼠、大鼠、兔子或非人 類靈長類)之供體抗體的超變化區域殘基取代。在某些情況 下’人類免疫球蛋白的Fv架構區域(FR)殘基經對應的非-人 類物種之殘基取代,除此之外,人源化抗體可包括未曾發 現於接受抗體或供體抗體的殘基,這些修飾作用可進一步 的界定抗體的效率表現(諸如鍵結的親和力)。一般而言,人 源化抗體包括實質上所有至少一種及典型地兩種可變區 域,其中所有或實質上所有的超變化曲環對應至非_人類免
O:\9O\90156.DOC •18- 1335821 疫球蛋白者,且所有或實質上所有的FR區域為人類免疫球 蛋白者雖:然,FR可包括一或多個可增進鍵結親和力之胺 基酸取代作用。這些在FR上胺基酸取代作用之數目典型地 在Η鏈不超過6個’而在匕鏈則不超過3個。人源化抗體亦可 選擇性地包括至少一免疫球蛋白固定區域(Fc)之部分,典型 地為人類免疫球蛋白。進一步詳細内容,參考J〇nes等人’ 伽脚 321.522-525 (1986) ; Reichmann等人,漏⑽ 332:323-329 (1988) ’ 及 Presta,Cwrr. 〇p· 5ζ·ο/. 2:593-596 (1992)。 抗體’’效應子功能”係指導因於抗體Fc區域(天然序列之Fe 區域或胺基酸序列變異體Fc區域)的生物活性者,且其會隨 著抗體同種型而有所不同。抗體效應子功能的實例包括: C1 q鍵結及補體依賴性細胞毒性;Fc受體鍵結;抗體-依賴 性細胞媒介細胞毒性(ADCC);吞嗤作用;細胞表面受體(例 如B細胞受體)的逆調控;及b細胞活化作用。 "抗體-依賴性細胞媒介細胞毒性"或"ADCC"係指一種細 胞毋性形式’其中鍵結至存於某些細胞毒性細胞(例如天然 殺手(NK)細胞、嗜中性細胞及巨嗜細胞)Fc受體(FcRs)上之 分泌的Ig能使細胞毒性效應子專一性鍵結至帶有抗原標乾 細胞’並隨後以細胞毒素殺死標靶細胞。抗體會"臂抱"細 胞毒性細胞’且是此獵殺作用絕對需要的《媒介ADCC的主 要細胞(NK細胞)只表現FcyRIII,而單核細胞則表現FcyRI、 FcyRII及FcyRIII。造企細胞上FcR的表現摘錄於Ravetcj^
Kinet,/mmwrto/ 9:457-92 (1991)第 464頁的表 3 中。為評估感興趣分子之ADCC活性,可以(諸如)揭示於美 O:\90\90156.DOC -19· 1335821 國專利第5,500,362號或第5,821,337號中之活體外ADCC分 析法進行評估。:此種分析法所用料效應子細胞包括周^ 血液單核細胞(PBMC)及天然殺手(NK)細胞,另一種方式 疋,或除此之外,可以(諸如)clynes等人,尸见^ 9乂 652-656 (1998)中所揭示的動物模式以活體内方法評估感 興趣分子的ADCC活性。 ”Fc受體”或"FcR"係指可鍵結至抗體Fc區域之受體,較佳 的FcR為天然序列之人類FcR。另外,較佳的FcR是一種可 鍵結至IgG抗體(咖瑪受體;)者,及包括FcyRI、FcyRn& FcyRIII亞型之受體,包括對偶基因變異體及這些受體另一 種的移接形式。FcyRII受體包括FCyRnA("活化受體")及 FqRIIB(”抑制受體”),其具有相似的胺基酸序列,主要差 異在其.細胞質區域。活化受體FcyRIIA在其細胞質區域中含 有一免疫受體酪胺酸-基礎活化位置(ITAM),而抑制受體 FqRIIB則在其細胞質區域中含有一免疫受體酪胺酸_基礎 抑制位置(ITIM)(參考 ’ M. in DaSron,J««w. //wwmwo/. 15: 203-234 (1997))。FcRs 於 Ravetch 及 Kinet,dn亂 /www?7〇/:457-92 (1991) ; Capel 等人,4: 25-34 (1994);及 de Haas 等人,X C//«_ Med 126:330-41 (1995)等文獻中有總評論。其他的FcRs(包括未來所鑑定者) 均包含於本專利說明書"FcR" —詞中。該術語亦包括新生兒 受體(FcRn),其負責將母體IgGs移轉至胎兒(Guyer等人,X /wwwwo/· 117:587 (1976)及 Kim 等人,J. iwwMrtoi. 24:249 (1994)) 〇 O:\90\90I56.DOC •20· 1335821 世界專利00/42072(Presta)揭示具有增強或消減與FcRs鍵 結之抗體變莫體,該專利申請案之内文具體地併入本專利 說明書參考,亦參考Shields等人J.仍〇/. 9(2):6591- 6604 (2001)。
”人類效應子細胞”係為可表現一或多種FcRs及扮演效應 子功能之白血球細胞,較佳地,該細胞表現至少FcyRIII, 並進行ADCC效應子功能。媒介ADCC之人類白血球細胞包 括週邊血液單核細胞(PBMC)、天然殺手(NK)細胞、單核細 胞、細胞毒性T細胞及嗜中性白血球;其中以PBMCs及NK 細胞較佳。效應子細胞可自天然來源(例如,血液)中分離出 來。
”補體依賴性細胞毒性”或"CDC”係指在補體存在下溶解 標靶細胞。傳統補體流程的活化作用係在補體系統中第一 個補體(Clq)鍵結至已鍵結同族抗原之(適當亞型)抗體上而 啟動的。例如,Gazzano-Santoro等人,/. /mmtmo/. Mei/zocls 202:163 (996)中所述之CDC方法進行評估補體活化作用。 具有變更Fc區域胺基酸序列及較強或較弱Clq鍵結能力 之聚肽變異體揭示於美國專利第6,194,551B1號及世界專利 99/5 1642中。這些專利發表案具體地併入本專利說明書參 考,亦可參考 Idusogie 等人 J. Immunol. 164:4178-4184 (2000) °
IgG的N-醣化作用係在CH2區域之Asn297處。本發明亦提 供可與CD20鍵結及具有Fc區域之人源化抗體之組合物,其 中組合物中有80-100%(較佳者約90-99%)之抗體包括接合 O:\9O\90156.DOC •21 · 1335821 至醣蛋白Fc區域之熟化中心碳水化合物結構(其不含岩藻 糖)。本專利說明書所揭示之彼等組合物與]7(^11111八^158) 的鍵結具有令人驚訝地改進效果,其與人類IgG的交互反應 上不如Fc^RIIIA(Vl58)有效,因此,本專利說明書組合物 預期優於先前所揭示之抗_CD2〇抗體組合物,特別是治療能 表現Fc^RIII(F158)之人類病患。在正常健康的非裔美國人 及高加索人中FdIiIA(F158)較Fc^RIIIA(vl58)更為普 遍,參考,Lehrnbecher等人,別⑽j 94:4220 (1999)。本申 請案另外證實FkRIII鍵結及/或ADCC功能之加乘性增加 係因本專利說明書醣化作用變異及在醣化蛋白以區域胺基 酸序列修飾作用的合併作用所造成的。 "經分離"抗體係指一經確認的抗體,且是從天然環境成 分中所·分離及/或回收出來的。其天然環境的致污成分係指 會干擾該抗體診斷或治療用途之物質,包括酵素、激素及 其他蛋白性或非蛋白性的溶質。在較佳的具體實例中,該 抗體所純化的條件需要(1)以路易士(L〇wry)方法測定該抗 體,純度高於95%重量比,而最佳者高於99%重量比’(2) 純化至足以以旋轉杯定序儀獲得至少丨5個N_端或内部胺基 酸序列之殘基的程度,或利用SDS_pAGE在還原或非還 原條件下,利用卡麻薩蘭,或較佳以銀染劑染色顯示為均 質性。經分離抗體包括重組細胞中原位抗體,因為至少一 種天然環境之成分不存在。然而,一般經分離抗體係以至 少一種純化步驟製備之。 經分離”核酸分子係為一經確認之核酸分子,並分離自
O:\90\90156.DOC '22- 1335821 至少一種正常下與抗體核酸自然來源有關之致污核酸分子 中。經分離核酸有別於自然界所發現的形式或背景。經分 離核酸分子因此可與天然細胞所存在的核酸分子區分,然 而,一經分離核酸分子包括通常可表現該抗體之細胞申所 含有之核酸,例如,核酸分子位在不同於天然細胞之染色 體位置。 表現控制序列”係指用以表現特定有機體中以人工方式 連接編碼序列所需之DNA序列。適合原核細胞之控制序 列,例如,包括啟動子、視情況操縱子序列,及核糖體鍵 結位置。真核細胞已知係使用啟動子、聚腺苷酸訊息及促 進子。 核&以人工方式連結"係指與其他核酸序列置放在具有 功能性.的關係。例如,假若DNA係以參與分泌的聚狀之前 蛋白方式表現,則該DNA係以前序列或分泌性前導序列以 人工方式連結至-聚肽的DNA上;假若啟動子或促進子係 影響續序㈣轉錄作用,财仙人u式結結至一編碼 序列上;或假若一核糖體鍵結位置所在位置可輔助轉譯作 用則其係以人工方式連結至-編碼序列上。-般而言," x人工方式連結’係指所連結的DNA序列係連續性的,且以 分泌性前導序列而言,其為連續性且順讀方式,然而,促 進^無須為連續性。在方便的限制酶切割位置進行接合作 °疋成連、,如果不存在此種位置,根據慣用實務可使 用合成性的寡核苷酸接頭子或連結子。 戴體包括牙梭裁體及表現載體。典型地,質體構築體
O:\90\90IS6.DOC -23· 1335821 亦包括細菌中質體之複製源(例如,複 性標誌(例如.,安皮西林或四環 原、)及師擇 好练,里,丨主 、抗性)’以便進行複製作用 及師選。I現載體"係指在細菌或真核細胞中含 現勒包括本發㈣體片狀抗體之必須控料列或調控元ί 之載體。適當的載體揭示如下。 ,、 產生本發明人源化CD20鍵結抗體之細胞包括編碼举已 Γ::體:酸之細菌性細胞及真核宿主細胞。適當之宿主 細胞揭不如下。 本專利說明書所用"標記物"係指直接或間接共扼至抗體 之可偵測之化合物或組合物。該標記物本身能被债測到(例 如’放射性同位素或螢光標記物)’以酵素性標記物的情況 而言,或該標記物可催化改變具有谓測性受質化合物或组 合物之化學作用。 本專利說明書所用”自體免疫疾病"係指源自並對抗㈣ 自己(本身)抗原及/或組織之非-惡性疾病或失調症。 本專利說明書所用”B細胞減損”係指動物或人類經過藥 劑或抗體治療後,其B細胞數量與治療前的B細胞數量比較 後減少。利用熟知的分析法(諸如實驗實例中所揭示者)可測 定B細胞數量。B細胞減損可為完全減損或部分減損,在一 個具體實例中,減損CD20表現細胞至少25%。 本專利說明書所用"細胞毒性劑"係指可抑制或預防細胞 功能或造成細胞壞死的物質。此名詞意欲包括放射線活性 同位素(例如,I⑴,1丨25, Y90及Re丨力、化療劑,及毒素, 諸如具有酵素活性之細菌性、真菌性、植物或動物來源之 O:\90\90IS6.DOC -24- 1335821 毒素,或其片段。
"化療劑"if系一可用於治療癌症之化學化合物,化療劑的 實例包括烷化分解劑或烷化劑(諸如,賽替派(thiotepa)及環 磷醯胺(細特森TM(CYTOXANtm));烷基磺酸酯類(諸如,白 血福恩(busulfan)、英丙舒凡(improsulfan)及派泊舒凡 (piposulfan));氮丙啶類(aziridines)(諸如,苯并多巴 (benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa) 及優利多巴(uredopa));次亞胺類及甲基拉胺類 (methylamelamines)(包括六甲蜜胺(altretamine)、曲他胺 (triethylenemelamine) 、 三伸 乙基 填醯胺
(trietylenephosphoramide)、三伸 乙基硫鱗酿胺 (triethylenethiophosphaor amide)及三 甲 基羅拉胺 (trimethylolomelamine));氮芥類(nitrogen mustards)(諸如, 苯丁 酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、克洛 碌醯胺(cholophosphamide);雌莫司汀(estramustine)、異環 碟醯胺(ifosfamide)、二氣甲基二乙酸(mechlorethamine)、 氧化二氯甲基二乙酸氫氣酸、美法侖(melphalan)、諾威拜 辛(novembichin)、酴斯特利(phenesterine)、潑尼莫司汀 (prednimustine)、曲磷胺(trofosfamide)、尿0^ 咬氮芥(uracil mustard));硝脲類(nitrosureas)(諸如,卡莫司汀(carmustine) 、氣唑特辛(chlorozotocin)、莫司汀(foteniustine)、洛莫司 汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)) ;抗生素(諸如,阿勒西諾黴素(aclacinomysins)、放線菌素、 歐若黴素(authramycin)、重氮乙醯絲氨酸(azaserine)、平陽 O:\90\90156.DOC -25- 1335821 黴素(bleomycins)、卡替諾黴素(cactinomycin)、卡奇黴素 (calicheamicin)、‘卡洛皮辛(carabicin)、洋紅黴素(carminomycin) 、卡井諾芬林(carzinophilin)、色黴素(chromomycins)、更 生黴素(dactinomycin)、柔紅黴素(daunorubicin)、迪特洛匹 辛(detorubicin)、6-二氮-5-氧-L-正白胺酸、阿黴素(Adriamycin)
、表柔比辛(epirubicin)、依索比辛(esorubicin)、伊達比辛 (idarubicin)、馬瑟洛黴素(marcellomycin)、絲裂黴素、麥 考粉酸(mycophenolic acid)、諾加黴素(nogalamycin)、奥利 佛黴素(olivomycins)、匹來黴素(peplomycin)、波福洛黴素 (potfiromycin)、嘌吟徽素(puromycin)、格勒黴素(quelamycin) 、羅德比辛(rodorubicin)、鏈黑菌素(streptonigrin)、鏈佐星 (streptozocin)、特伯西丁(tubercidin)、烏苯美司(ubenimex) 、淨司·汀(zinostatin)、佐柔比辛(zorubicin));抗-代謝物(諸 如,甲胺喋呤及5-氟尿嘧啶(5-FU));葉酸類似物(諸如,迪 諾特利(denopterin)、甲胺嗓吟、蝶囉呤(pteropterin)、三 甲曲沙(trimetrexate)) ; 11票吟類似物(諸如,氟達拉賓 (fludarabine)、6-疏基 °票吟 '塞米普林(thiamiprine)、硫鳥 口票吟(thioguanine));哺咬類似物(諸如’安西他濱(ancitabine) 、阿札胞苦(azacitidine)、6-氮尿普(azauridine)、卡莫氣 (carmofur)、阿糖胞苦(cytarabine)、二去氧尿D密β定、去氧氣 尿苷(doxifluridine)、依諾他濱(enocitabine)、氟展苷 (floxuridine)、5-FU);雄性激素類(諸如,卡路思酮 (calusterone)、德洛斯特酮丙酸(dromostanolone propionate) 、表替歐思酿I (epitiostanol)、美雄烧(mepitiostane)、睪内酷· O:\90\90I56.DOC -26- 1335821
(testolactone));抗腎臟腺皮質類固醇(諸如,胺魯米特 (aminoglutethinlide) ' 米托坦(mitotane)、環氧雄烧 (trilostane));葉酸補充劑(諸如,福洛尼酸(frolinic acid)); 阿熙樂酮(aceglatone);阿德構醯胺(aldophosphamide glycodie);胺基果糖酸(aminolevulinic acid);阿姆薩利 (amsacrine);貝斯洛布希(bestrabucil);比生群(bisantrene); 伊德洛特(edatraxate);迪福夫明(defofamine);秋水仙胺 (demecolcine);地 σ丫醒(diaziquone);依氣鳥氨酸(elfornithine) ;依利醋 I安(elliptinium acetate);依乾格魯(etoglucid);硝 酸鎵(gallium nitrate);經基尿(hydroxyurea);遵兹多糖 (lentinan);氣尼達明(lonidamine);米托胍腙(mitoguazone) 、米托蒽酉昆(mitoxantrone);模皮德莫(mopidamol);尼特利 (nitracrine);噴特司汀(pentostatin);芬納麥(phenamet);
皮柔比辛(pirarubicin);足葉草酸(podophyllinic acid) ; 2-乙 基肼;丙卡巴肼(procarbazine) ; PSK® ;雷佐生(razoxane); 西佐糖(sizofiran);鍺螺胺(spirogermanium);替諾°坐酸 (tenuazonic acid);三亞胺醒(triaziquone) ; 2,2',2”-三氯三 乙基胺;尿烧(urethan);長春地辛(vindesine);達卡巴。秦 (dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇 (mitobronitol);二溴衛矛醇(mitolactol);哌泊溴炫(pipobroman) ;格胞 ^(gacytosine);阿糖腺苦(arabinoside)("Ara-Cn);塞 替派(thiotepa);類毒素(例如,太平洋紫杉醇(paclitaxel) (TAXOL®,Bristol-Myers Squibb Oncology,普林斯頓城, 紐澤西州)及多西特爾(doxetaxel)(TAXOTERE®,Rhone- O:\9O\90IS6.DOC -27- 1335821
Poulenc Rorer,安東尼城,法國);苯丁酸氛芥(chlorambucil) ;健擇賓(gemcitabine); 6-硫鳥嗓吟;疏基嗓吟;曱胺嗓吟; 在白類似物(諸如,西斯I自(cisplatin)及碳翻(carboplatin)); 鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺;絲裂黴素C (mitomycin C);米托蒽醌(mitoxantrone),·_ 威利司、;丁;長春 花驗(vinblastine);長春瑞賓(vinorelbine);諾溫平 (navelbine);諾貝酮(novantrone);替尼泊苷(teniposide); 柔紅黴素(daunomycin);胺基喋啶(aminopterin);截瘤達 (xeloda);伊班膦酸鹽(ibandronate) ; CPT-11 ;托樸異構酶 (topoisomerase)抑制劑 RFS 2000 ;二氟曱基鳥氨酸(DMFO) ,·維 A酸;艾斯柏黴素(esperamicins);截瘤達(capecitabine) 及上述任一物質之醫藥學上可接受之鹽類;酸類或衍生 物。在-此定義亦包括可作用調控或抑制腫瘤上激素作用之 抗-激素藥劑’諸如抗雌激素類(諸如,包括他莫西芬 (tamoxifen);雷諾西芬(raloxifene)、芳香酶(ar〇matase)抑制 劑4(5)-咪唑、4-羥基他莫西芬、特例西芬(tri〇xifene)、奇 歐西芬(keoxifene)、LY117018、奥那司酮(onaprist〇ne)及特 利米芬(t〇remifene)(Fareston);抗雄激素類(諸如,氟他胺 (flutamide)、尼魯米特(nilutamide)、白卡羅他邁 、亮丙瑞林(leuprolide)及戈舍瑞林(g〇serelin));其他化學 治療劑(諸如,去氫可體醇八上述任一藥劑之醫藥學上可= 受鹽類、酸類或衍生物均包括在内。 醫治”或”治療π或"舒緩"係指治療及預防性或阻礙性措 施兩者,其中的目的係為避免或減緩(舒緩)標的病理疾病^
O:\90\90156.DOC -28- 1335821 失調症。假若當個體接受治療含量之根據本發明方法之 CD20鍵結抗體後,顯現出特定疾病的一或多種病徵及症狀 可觀察性及/或可測量性的減少或消失,則表示該個體係成 功地”治療”CD20陽性癌症或自體性免疫疾病。例如,以癌 症而言’癌症細胞數目的減少或癌症細胞的消失;減小腫 瘤的大小;抑制(換言之,減低至某種程度及較佳地是停止) 腫瘤的移轉;抑制腫瘤生長至某種程度;增加疾病舒緩期 ㈣間,及/或舒緩與特定癌症相關之一或多種症狀至某種 程又減低《病率及死亡率。病患亦會感受到疾病病徵或 症狀的舒緩。治療可以達到完全的反應(其界定為所有癌症 的病徵均消失)或部分反應(其中腫瘤大小減少較佳超過5〇 百分比’更佳者75%)。假若病患經歷感受到穩定狀態的疾 病,則病患純視為㈣療改善。在—難具體實例中,、 癌症病心在年後(較佳為15個月後)其癌症仍不具有前進 性。這些用以評估成功治療及改善疾病的參數可輕易地以 熟知技藝醫師所精通的例行性方法測定之。 ”具療效含量"係指可有效用以治療,,個體疾病或失調症 之抗體或藥劑含量。以癌症情況而言,具療效含量之藥劑 可減少癌症細胞的數目;減小腫瘤的大小;抑制(換十之, ^緩至某種程度及較佳地是停止)癌症細胞浸透至週邊器 吕,抑制(換言之’減緩至某種程度及較佳地是停止)腫瘤的 移轉;抑制腫瘤生長至某種程度;及/或舒緩-或多種與癌 症相關症狀。參考前述”治療"之定義。 k性"投藥係指與急性模式相反的持續性投用藥劑,以
O:\90\90156.DOC -29- 1335821 便維持初期治療效果(活性)一段長時間。"間歇性”投藥係指 非中斷性的非連貫性治療,但在特性上卻是具有週期性的。 本發明组合物及方法
本發明提供可鍵結至人類CD20及較佳為靈長動物CD20 之人源化抗體,其包括含有至少一個(較佳兩個)非人類物種 抗-人類CD20抗體(供體抗體)之CDRs的Η鏈,及實質上所有 人類一致性抗體(接受抗體)之架構殘基。在一個具體實例 中,供體抗體為老鼠2Η7抗體。包括每一 m2H7、人類Η鏈亞 型III及人類/C之Η及L鏈CDR及FR序列之V區域序列示於圖 1Α及1Β中。本發明人源化2Η7抗體具有至少老鼠供體抗體Η 鏈的CDRs。在一特定的具體實例中,在一個具體實例中, 鍵結人類CD20之人源化抗體包括供體抗體Η及L鏈兩者的 CDRs。·在一個具體實例中,人源化抗體包括供體Η及L鏈兩 者的CDRs。供體抗體可來自各種非-人類物種者,包括,老 鼠、大老鼠、天竺鼠、山羊、兔子、馬、靈長類動物,但 常為老鼠抗體。在一個特定的具體實例中,供體抗體為老 鼠抗體。 在一個具體實例中,人類Fab架構的殘基相當於人類V /c 亞型I及VH亞型III的一致性序列,這些一致性序列分別示於 圖1A及1B中。 在一個全長的抗體中,本發明人源化CD20鍵結抗體包括 鍵結至人類免疫球蛋白C區域之人源化V區域。在一個較佳 的具體實例中,Η鏈C區域係來自人類IgG,較佳者為IgGl 或IgG3。L鍵C區域較佳來自人類/c鍵。 O:\90\9O156.DOC -30- 1335821 除非另有所指’除了在後文實驗範例中所指的胺基酸取 代或改變位置外,本專利說明書所指的人源化2H7抗體變異 體具有 2H7.vl6 L鏈(圖 6,SEQ ID N〇.21)及Η鏈(圖 7,SEQ ID NO.22)的V及c區域序列。 人源化CD20鍵結抗體至少可與人類CD加鍵結,及較佳可 與其他靈長動物CD20鍵結,諸如猴子(包括,食蟹猴及獼猴) 及黑獲獲。食蟹猴CD20的序列揭示於實例丨5及圖丨9中。 CD20鍵結抗體及本發明人源化CD2〇鍵結抗體的生物活 性包括至少該抗體係以不高於1χ1〇·8之心值(較佳者不高於 約1><1〇-9之心值,更佳者不高於卜⑺-^之心值)鍵結至人類 CD20上,更佳者係可鍵結至人類及靈長動物cd2〇(包括食 蟹猴、摘狼、黑㈣),且可殺死或減損活體外或活體内的 B細胞,.較佳者係當與未經此—抗體處理之適當陰性控制組 比較時,減損的量為20%。 所要減損的B細胞程度端視疾病而定。以治療cm〇陽性 癌症而言’咸欲減損本發明抗{⑽抗體標乾之B細胞至最 ^程度。據此’以治療CD2〇陽性B細胞腫瘤而言,咸欲減 七的B細胞係足以至少避免該疾病的進展,熟識技藝醫事人 員例如可藉由監控腫瘤生長(大小)、癌症細胞種類的增生、 移轉、其他特定癌症的病徵及症狀來評估疾病的進展。較 佳地,B細胞減損係足以避免疾病的進展至少2個月,更佳 f則,更佳者4個月’更佳者5個月,更佳者6個月或更 Ϊ二。在更佳的具體實例中,B細胞減損係足以增加疾病 W期至少6個月,更佳者9個月,更佳者!年,更佳者2年, 〇:\W^〇,56.D〇c -31 · 1335821 更佳者3年,更佳者5年或更多年。在一最佳的具體實例中, B細胞減損4足’以治癒該疾病,在較佳的具體實例中,癌症 病患中之B細胞減損至少約75%,及更佳者為治療前治療水 平的 80%、85%、90%、95%、99%,甚至 1〇0%。 以治療一自體免疫疾病而言,咸欲調控B細胞減損端視個 體病患的疾病及/或病症嚴重性來調整CD2〇鍵結抗體的劑 里。據此,不一定要完全的B細胞減損,或者是,在最初的 冶療需要完全的B細胞減損,但在後續的治療則調整劑量至 可達部分減損即可。在一個具體實例中,當與治療前的基 礎水準相較,B細胞減損至少為2〇%(例如,8〇%)或更低 陽性B細胞殘留。在另一個具體實例中,B細胞減損為25%、 30%、4〇%、50%、60〇/〇、70〇/〇或更多。較佳地,B細胞減損 至足以·停止疾病的進展,更佳者係舒緩治療下特定疾病的 病徵及症狀,更佳者係治癒該疾病。 本發明亦提供雙專一性CD2〇鍵結抗體,其中該抗體的一 支#手具有本發明人源化CD20鍵結抗體之人源化η及L 鏈,而另一支臂手則具有與另一抗原具有鍵結專一性的ν 區域。在特定的具體實例中,另一抗原為選自CD3、cd64、 CD32A、CD16、NKG2D或ΝΚ活化配位體組成之群。 病患在第一次灌注治療抗體時會經歷灌注反應或與灌注 相關的症狀,這些症狀嚴重性各異,通常以醫藥干預性做 法可以恢復。這些症狀包括(但不侷限於)類似感冒的發燒、 發寒/發冷、反胃、出疹、頭痛、支氣管痙攣、血管性水腫。 本發明疾病治療方法咸欲將灌注反應減至最小。據此,本
O:\90\90156.DOC •32· !335821 發明另依方面係藉投用人源化CD20鍵結抗體來治療所揭 示疾病的方法,其中該抗體具有減弱或無補體依賴性細胞 毒性,且與以Rituxan®治療相較會產生較低的灌注相關症 狀。在一個具體實例中,人源化CD2〇鍵結抗體為2H7vU6。 載想、宿主細胞及重組方法 本發明亦提供一編碼人源化CD20鍵結抗體之經分離核 酸、包括該核酸之載體及宿主細胞,及製備該等抗體之重 組技術。 以重組方式製備該抗體而言,分離編碼該抗體之核酸, 並將其插入可複製之載體中,以進一步選殖(〇]^八增幅)或 表現。利用傳統的流程(例如,利用可專一性鍵結至編碼抗 體重鏈及輕鏈基因之寡核苷酸)可輕易地分離及定序出編 碼單株.抗體之DNA。許多的載體係可以利用的。載體構成 要素般包括(但不侷限於)下列一或多項:訊息序列、複製 源、一或多種標誌基因、促進子元素、啟動子,及轉錄作 用終止序列。 (Ό訊息序列構成要素 本發明CD20鍵結抗體不只可以直接以重組方式製備 之,亦可製備成帶有異質性聚肽之融合聚肽,其較佳係在 成熟的蛋白或聚肽的N_端處具有特異性切割處之訊息序列 或其他聚肽。所選的異f性訊息序列較佳地係可被宿主細 胞變識及處理(換言之,被訊息肽酶切割)。由於原核宿主細 胞不能辨識及處理天然的CD2〇鍵結抗體訊息序列,故訊息 序列需經選自’例驗性碌酸酶' 青徽素酶、lpp或熱- O:\90\90156.DOC •33- 1335821 穩定腸毒素11前導序列之群的原核性訊息序列取代。以酵母 菌分泌而言’該天然訊息序列可經,例如,酵母菌轉化酶 月J $序列、α_因子前導序列(包括及 少vero卿⑽α_因子前導序列),或酸磷酸酶前導序列、白 色念珠菌(C. a/Hca«_s)葡萄糖澱粉酶前導序列,或世界專利 90/13646中所揭示之訊息序列所取代。在哺乳細胞表現作 用中,則可利用哺乳動物訊息序列及病毒性分泌前導序 列’例如’單純泡疹病毒gD訊息序列。 該等先驅區域之DNA係以順讀架構方式連結至編碼 CD20鍵結抗體之dna上。 複製源 表現載體及選殖載體兩者均包括可使該載體於一或多種 所選定之宿主細胞中複製之核酸序列。一般而言,選殖載 體中的此種序列使載體的複製作用獨立於染色體DNA之 外,並包括複製源或獨立自主之複製序列。此種序列在許 夕、’'田菌、酵母菌及病毒是熟知的。質體PBR322複製源適合 大部分之革蘭氏陰性細菌,2μ質體源適合酵母菌,而各種 的病毒源(SV40、多瘤病毒、腺病毒、vsv或Βρν)可作為哺 礼動物細胞之選殖載體。一般而言,複製源構成要素並非 哺乳動物表現載體所需(典型地使用3乂4〇源僅係因為其含 有早期啟動子)。 (Ui)篩選基因構成要素 表現載體及選殖載體可含有篩選基因,其又稱為可篩選 標誌」典型地篩選基因所編碼的蛋白質⑷可提供對抗生素
〇A9〇\9〇i56x)〇C -34 - 1335821 或其他毒素(例如,安皮西林、新黴素、甲胺喋呤或四環素) 之抗性,(by互補缺乏營養性的缺失,或(c)提供不能獲自複 合性培養基中的重要營養素,例如,芽孢桿菌編碼 D-丙胺酸消旋酶的基因。
一個篩選流程的實例係利用藥物來抑制宿主細胞生長, 由於成功經異質性基因轉型的這些細胞會產生提供藥物抗 性的蛋白質,故在篩選流程中可以存活。此種優勢篩選的 實例係使用藥物新徽素、黴酌酸及潮黴素。 另一種適合哺乳動物細胞的可篩選標誌實例是能夠確認 細胞攝入CD20鍵結抗體核酸者,諸如DHFR、胸嘧啶激酶、 金屬硫蛋白-I及-II,較佳者為靈長動物金屬硫蛋白基因、 腺苷去胺酶、鳥胺酸去羧基酶等。
例如.,將所有的轉型細胞培養在含有甲胺喋呤(Mtx)(其為 DHFR的競爭性拮抗劑)培養基中,先鑑定出帶有DHFR篩選 基因的轉型細胞。當採用野生型DHFR時,適當的宿主細胞 為缺乏DHFR活性之中國倉鼠卵(CHO)細胞株(ATCC CRL-9096)。 另一種方式是,將經編碼CD20鍵結抗體、野生型DHFR 蛋白及另一可篩選標誌(諸如胺基配糖苷3'-磷酸移轉酶 (ΑΡΗ))之DNA序列轉型或共同轉型之宿主細胞(特別是包 括内因性DHFR之野生型宿主)培養在含有可篩選標誌之篩 選劑之培養基中(諸如,胺基配糖苷抗生素,例如,卡那黴 素、新黴素或G41 8),利用細胞生長來篩選之。參考美國專 利第 4,965,199號。 O:\90\90156.DOC -35- 1335821 適合酵母菌使用之篩選基因是酵母菌質體YRp7中存在 的 基因(Stirichcomb等人,iVaiwre,282:39 (1979))。
基因可提供缺乏可生長在色胺酸能力之酵母菌突變株之篩 選標諸,例如,ATCC No. 44076 或 PEP4-1。Jones, Gewei/cs, 85:12 (1977)。藉由可生長於不含有色胺酸下,酵母菌宿主 細胞基因體中斤p 1損傷的存在可提供有效偵測轉型作用的 環境。相似性地,缺乏性酵母菌株(ATCC 20,622或 3 8,626)可以帶有基因的已知質體互補之。 除此之外,源自1 _6微米環狀質體pKDl之載體可用以進行 足/w少veromyce·?酵母菌的轉型作用。另一種方式是所報導的 大量製備乳酸克魯維酵母(尺· /acib)重組性牛凝酪酵素之雀 應名.親,Van den Berg,幻/,8:135 (1990)。亦 已揭示.利用尺/¾少verowyces的工業株以穩定性多倍數表現載 體分泌出成熟重組性人類血清白蛋白。Fleer等人 价,9:968-975 (1991)。
(iv)啟動子構成要素 表現載體及選殖載體通常包含一宿主有機體可辨識之啟 動子,且係以人工方式連接至編碼CD20鍵結抗體的核酸 上。適合原核宿主使用的啟動子包括p/zoA啟動子、β-内醯 胺酶及乳酸啟動子系統、驗性填酸酶啟動子、色胺酸(trp) 啟動子系統,及雜合啟動子(諸如tac啟動子)。然而,其他 已知細菌性啟動子亦適合。細菌系統所使用之啟動子亦含 有Shine-Dalgarno(S.D·)序列,其係以人工方式連接至編碼 CD20鍵結抗體之DNA上。 O:\90\9OJ56.DOC -36- 1335821 真核細胞的啟動子序列係已知的,事實上所有的真核細 胞基因具有-富含AT的區域,其位於轉錄作^起始位置约 25至30鹼基上游處,在許多基因轉錄作用起始處川至肋驗 基上游處發現的另-序列為CNCAAT區域,其中⑽指任何 的核苦酸。大部分真核細胞基因的3,端為aataaa序列,其 為將聚A尾部加成至編碼序列3,端的訊息。將所有的這些序 列適當地插入至真核細胞表現載體申。 適合使用在酵母菌宿主的啟動子序列之實例包括3_填酸 甘油酸激酶或其他糖解酵素的啟動子,諸如,稀醇酶、甘 油路-3-磷酸去氫酶、六碳醣激酶、丙酮酸去幾基酶、碌酸 果糖激酶、葡萄糖-6_磷酸異構物酶、3_磷酸甘油酸變位酶、 丙嗣I激酶、二碳醣碟酸異構酶、磷酸葡萄糖異構物酶, 及葡萄糖激酶。 其他酵母@啟動子(具有藉由生長條件控㈣錄作用之 額外優點之誘導性啟動子)為乙醇去氫酶2、異細胞色素c、 酸磷酸酶、氮代謝相關的分解酵素、金屬硫蛋白、甘㈣馨 ''酸去氫酶’及負責利用麥芽糖及半乳糖之酵素之啟動· 子區域1於酵母g表現之適合載體及啟動子進—步揭# 中。酵母菌促進子與酵母菌啟動子一起使用亦. 在哺礼動物宿主細胞中載體的CD20鍵結抗體之轉錄作 :係文到,例如,源自病毒基因體的啟動子之控制,諸如,
St:底病毒、腺病毒(諸如,腺病毒2)、牛肉瘤病 母、、…田病毒、細胞巨病毒、反轉錄病毒、β型肝炎病毒
0:\9<Λ90156.DOC •37- 1335821 及最佳是猴病毒40(SV4〇)的啟動子、源自異質性哺乳動物 啟動子(例如,㈣蛋白啟動子或免疫球蛋白啟動子)、源自 熱激蛋白啟動子,假若這些啟動子是與宿主細胞系統相容 的條件下。 SV40病毒之早期及晚期啟動子可方便地以sv4〇限制酶 片段形式取得,該片段中亦含有SV4〇病毒之複製源。人類 '田胞巨病毋之極早期啟動子則係以方便地以E限制 酶獲知之。利用牛肉瘤病毒為載體於哺乳動物中表現⑽A 之系統揭示於美國專利第4,419,446號中,此系統的變更型 式揭示於美國專利第4,6〇1,978號中,亦可參考尺叮以等人, 297:598-6Gl (1982)所著人類β_干擾素eDNA在老鼠 細胞中於單純泡療病毒之胸Μ激酶啟動子控制下的表現 作用。·另一種方式是,以羅斯(R〇us)肉瘤病毒長端重複序 列作為啟動子。 (y)促進子元素構成要素 將促進子序列插人至载體中常可增強高等真核細胞進行 編碼本發明CD2〇鍵結抗體DNA之轉錄作用。現在已經知道 許多哺乳動物基因的促進子序列(球蛋白、彈性酵素、白蛋 白、α-胎兒蛋白及胰島素然而,典型地的是,吾人可使 用真核細胞病毒之促進子,實例包括SV4〇促進子(位於複製 源的遠邊處(bp 100-270))、細胞巨病毒早期啟動子促進子、 多瘤病毒促進子(位於複製源的遠端邊)及腺病毒促進子), 參考Yaniv,爪297:17-18 (1982)所著活化真核細胞啟 動子之促進元素。促進子可移接至位於編碼(:〇2〇鍵結抗體
O:\90\90I56.DOC -38 - 1335821 序列之5’或3’端之載體上,但是較佳是位於啟動子的5,端處。 (W)轉錄祚用‘終止構成要素 真核宿主細胞(酵母菌、真菌、昆蟲、植物、動物、人類 或其他多細胞有機體的有核細胞)所用的表現載體亦含有 終止轉錄作用及穩定mRNA時所需之序列,該等序列通常係 利用來自真核細胞或病毒DNA或cDNA之未轉譯區域的5, 端序列,及有時候是3,端序列。這些區域含有轉譯成編碼 CD20鍵結抗轉譯部分之經聚腺苷化片段之核苷 酸片段。其中一種有用的轉錄作用終止構成要素是牛生長 激素聚腺苷作用區域,參考世界專利94/11〇26及本專利說 明書所揭示之表現載體。 (vii)篩選及轉型宿主細胞 革蘭氏陽性細菌,例如,腸道菌科,諸 如,大腸桿菌)、腸菌屬、伊文氏菌屬、 开/菌屬、沙門氏菌屬(例如,副傷寒桿| 適合·選殖或表現本發明專利說明書載體中DNA2適當宿 主細胞為原核細胞、酵母菌’或上述較高等的真核細胞。 本目的之適當原核生物包括真細菌,諸如,革蘭氏陰性或 腸道菌科,諸如,埃希氏菌屬(例
O:\90\90156.DOC •39- 1335821 27,325))料制。這些實例細㈣明,非作限制 全長的抗體、抗體片段及抗體融合蛋白可以在細菌中生 產,特別是當該等抗體無須進行醋化作用及&效應子功能 時,諸如’當治療用的抗體共親至細胞毒性劑(例如,毒素) 上,而該免疫共扼物本身即具有腫瘤細胞破壞性效果的時 候。全長的抗體在循環時具有純的半衰^在大腸桿菌 中製備較快,a更具有經濟效能。在細菌中表現抗體片段 及聚肽而言,可參考美國專利第5,648,237號(〜如等人卜 美國專利第5,789,199號㈤y等人)及美國專利第5,84〇,523 號(Simmon等人)’其揭示轉譯作用起始區域(tir)及最大化 表現及分泌之訊息序列,這些專利案一併併入本專利說明 書參考。表現之後,從大腸桿菌細胞糊狀物之可溶分液中 分離出·抗體,並經根據同種型的(例如)蛋白八或〇管柱純 化,所進行的最終純化作用與純化表現於(例如)c H 〇細胞中 的抗體之流程相似。 除了原核生物外,真核微生物(諸如,絲狀真菌或酵母菌)φ 適&作為選殖或表現編碼CD20鍵結抗體載體之宿主。在較 低等的真核宿主微生物中,單釀酒酵母(心* cereWhae)或一般的烘焙酵母菌是最常使用者,然而,一些 . 其他科、種及株亦可並可使用於本專利說明書中,諸如裂 ^ ^ # (Schizosaccharomyces pombe) \ 克魯維酵母屬 宿主’諸如,乳酸克魯維酵母(尺./flc…)、 脆壁克魯維酵母([/W^_/b)(ATCC 12,424)、保加利亞克魯 維酵母(尺.16,045)、威克洛米埃克魯維酵 O:\90\90156.DOC -40- 1335821 母([wic^erami〇(ATCC 24,178)、瓦替克魯維酵母(尺·㈣/"·〇 (ATCC 56,5〇0).、付洛非樂克魯維酵母(尺.办謂) (ATCC 36,906)、而ί 熱克魯維酵母(k. i/zermoio/eraws)及馬勒 那斯克魯維酵母(尤廳«奶);優洛瓦亞酵母(少wrowk) (歐洲專利第402,226號)’畢赤巴斯德酵母 (歐洲專利第183,070號);念珠菌屬(c⑽心而);利希亞木黴 菌(TWc/zoArmflt reesk)(歐洲專利第244,234號);頭孢真菌
;許瓦諾黴菌屬(以/^⑽,諸 如’ <Sc/wa謂’⑽火⑽t?cc法?ua/k ;及絲狀真菌,諸如,鏈 孢黴菌(A^wrojpora)、青黴菌(户6«〜7/〜所)、彎頸孢霉 (Tb/_y/?oc/i^/MW),及曲黴宿主,諸如,構巢曲 黴(儿⑴及黑曲黴(儿wz'ger)。 適合.表現經醣化CD20鍵結抗體之宿主細胞係源自多細
胞有機體,無脊椎動物細胞的實例包括植物及昆蟲。多種 桿病毒株及變異體及對應允許的昆蟲宿主細胞’諸如,草 地夜蛾/rwgz>erc/a)(毛毛蟲)、埃及斑蚊(jedes aeg少;?")(蚊子)、白線斑蚊(Aedes albopictus)(蚊子)、黃果 繩办"β we/anogasia)(果織)及豕邊(五0wo”_)業 已鑑定出來了。轉染作用的各式的病毒株是公開可利用 的,例如,加州苜蓿夜蛾(iwWgrap/ζα ca/(/br«i_ca) NPV的 L-1 變異株及家蠶NPV的Bm-5株’而該等病毒株可作為根據本 發明專利說明書之病毒,特別是轉染草地夜蛾細胞。 棉花、玉米、馬鈴薯、大豆、矮牽牛、番茄及菸草之植 物細胞培養亦可作為宿主。
O:\9Cft90156.DOC .41 - 1335821
然而,脊椎動物細胞係令人感到最大的興趣,而以培養 方式製備脊椎動物細胞(組織培養)儼已成為例行性的方 法。有用的哺乳動物宿主細胞之實例為經SV40轉型之猴子 腎臟CV1細胞株(COS-7、ATCC CRL 1651);人類胚胎腎臟 細胞株(293或生長於懸浮培養液經轉代之293細胞細胞, Graham等人,J· Gm. Kz>o/· 36:59 (1977));小倉鼠腎臟細 胞(ΒΗΚ,ATCC CCL 10);中國倉鼠卵巢細胞/-DHFR(CHO, Urlaub等人,iVoc. iVa". 5W. C/M 77:4210 (1980));
老鼠賽托利(Sertoli)細胞(TM4, Mather,5ζ·ο/.及印⑺汶 23:243-251 (1980));猴腎臟細胞(CV1 ATCC CCL 70);非洲綠猴腎臟 細胞(VERO-76、ATCC CRL-1587);人類子宮頸癌細胞 (HELA,ATCC CCL 2);狗腎臟細胞(MDCK,ATCC CCL
34) ; buffalo rat 肝細胞(BRL 3A,ATCC CRL 1442);人類 肺細胞(W138,ATCC CCL 75);人類肝細胞(Hep G2,HB 8065);老鼠乳房腫瘤(MMT 060562,ATCC CCL 51) ; TRI 細胞(Mather,等人,N.Y. Acad. Sci. 383:44-68 (1982)) ; MRC 5細胞;FS4細胞;及人類肝癌細胞株(Hep G2)。„ 宿主細胞經上述用以產生CD20鍵結抗體的表現載體或 選殖載體轉型,並培養在經修飾成適合誘發性啟動子、篩 選轉型體,或增幅編碼所要序列之基因之慣用營養培養基 中。 (viii)培養宿主細胞 用以製備本發明CD20鍵結抗體之宿主細胞可培養於多 O:\9O\90l56.DOC •42· 1335821 種的培養基中,市售可用的培養基(諸如Hamis
FlO(Sigma)、最低必須培養基(MEM)(Sigma)、RPMI-1640 (Sigma)及Dulbecco's改質培養基(DMEM,Sigma))適合培養 宿主細胞,除此之外,揭示於Ham等人,MeA.hz· 58:44 (1979),Barnes等人 ’ dna/· Aoc/zem. 102:255 (1980)、美國 專利第 4,767,704號、第 4,657,866號、第 4,927,762號、第 4,56〇,655號或第號;世界專利90/03430 ;世界專
利87/00195或美國專利修正第3〇,985號中任一培養基均可 作為宿主細胞之培養基。這些任一培養基可依需要補充激 素及/或其他生.長因子(諸如,胰島素、運鐵蛋白或表皮生長 因子)、鹽類(諸如,氯化鈉、鈣、鎂及磷酸)、緩衝物 (HEPES)、核苷酸(諸如,腺苷及胸苷)、抗生素(諸如,見 大黴素tm(GENTAMYCINtm))、微量元素(其定義係指存在最 終濃度為微莫耳範圍的無機化合物),及葡萄糖或等同能量 來源者。亦可包含熟識技藝者所熟知之任一其他需要的補 充物。培養條件(諸如,溫度、pH及類似的條件)則是前所 選以作為表現用之宿主細胞的培養條件,其是一般熟識技 藝者所知者。 (ix)純化CD20鍵結抗體 當利用重組技術時,抗體可以產生在細胞内、胞質間隙 間,或直接分泌至培養基中。假若抗體係產生在細胞内, 則第一步驟係(例如)藉離心作用或超過濾作用去除顆粒狀 的殘渣、宿主細胞或所分解的片段。Carter等人,別 7^^〇/〇抄10:163_167 (1992)中揭示分離分泌至大腸桿菌
O:\9O\90156.DOC -43- 1335821 胞質間隙間之抗體之步驟,簡而言之,將細胞糊狀物於醋 酸鈉(pH3.5:i、EDTA及苯基甲基磺醯基氟(PMSF)存在下解 柬約3 0分鐘,以離心作用去除細胞殘渣。當抗體係分泌至 培養基時’則先利用市售可用的蛋白質濃縮膜(例如, Amicon或Millipore Pellicon超過濾單位)濃縮此表現系統的 澄清液。任一前述的步驟中均包含以抑制蛋白分解作用之 蛋白酶抑制劑(諸如’ PMSF),及避免外來污染物滋長的抗 生素。 從細胞所製備之抗體組合物可利用,諸如,經基麟灰石 層析法、膠片電泳法、透析法及親和力層析法純化之,其 中以親和力層析法為較佳的純化技術。作為親和力配位體 的合適蛋白質A端視物種及存於抗體上任一免疫球蛋白Fc 區域之.同種型而定。蛋白質A可用以純化以人類"、…或“ 重鏈為基礎之抗體(Lindmark等人,《/. 62:1_13 (1983)) ’蛋白質G則建議用於所有老鼠同種型及人類 Y3(GUSS等人,五細〇丄5:1567_1575 (1986))。連結至親和 力配位體上的基質最常者為洋菜膠,但其他基質亦可使 用。機械式穩定基質(諸如,孔徑經控制的玻璃或聚(苯乙烯 二乙烯基)苯可使流速較快,而使得所需的處料間較使用 洋菜膠短。當抗體包括Ch3區域時,係使用Bake知d ΑΒχΤΜ 樹脂(J.T.Baker 1力匹茲堡城,每澤西州)進行純化。其他 蛋白純化作用之技術(諸如,離子交換管柱之分顧作用、乙 醇沉澱作用、逆相HPLC、矽瑕®把、+ , 矽膠層析法、以陰離子或陽離子 交換樹脂(諸如聚天門冬胺酸管柱)進行之層 析法或肝素赛
O:\9O\9015e.DOC •44- 1335821 法洛斯TM声彳 曰 、色層焦集法、SDS-PAGE及硫酸錢沉澱法) '、可使用^视所要回收的抗體而定。 人 先期純化步驟、包括感興趣抗體及致污物之混 物均係和用'中堤緩衝液(pH值介於約2.5-4.5之間)較佳於 低黑濃度下(例如,約〇_〇·25 M鹽)進行低口1^疏水性交互作用 層析法。 抗體共軛物 ^體可八輕至細胞毒性劑(諸如,毒素或放射性活性同位 ) 該骨素為卡奇黴素、類美坦生(maytansinoid)、多樂 5 T (dolastatiij)及其類似物或衍生物之某具體實例為較佳 者。 較佳的藥劑/毒素包括DNA破壞劑、微管聚合作用或去聚 —乍用的抑制劑及抗代謝物。較佳的細胞毒素劑種類包 括,例如,酵素抑制劑,諸如二氫葉酸還原酶抑制劑及胸 腺化合成酶抑制劑、1)1^八插入劑、DNA切割劑、拓樸酶抑 制劑、恩環素族藥劑、長春花藥劑、絲裂黴素、平陽黴素 (bleomycins)、細胞毒素核普、蝶^(pteridine)族藥劑、代 心(diynenes)、鬼臼毒素(podophyllotoxins)及分化誘發劑。 這類藥劑中特別有用者,例如,甲胺喋呤、甲胺喋呤、二 氯甲胺喋呤、5-氟尿嘧啶、6-巯基嘌呤、胞嘧啶阿拉伯糖苷 (cytosine arabinoside)、美法侖(meiphalan)、環氧長春驗 (leUr〇Slne)、長春鹼丁(leur〇sideine)、放線菌素(actinomycin) 、柔紅黴素(daunorubicin)、阿黴素、N-(5,5-二乙醯氧戊基) 阿黴素、嗎啉基-阿黴素、丨—^-氯乙基基)_i,2_二甲烷磺醯
O:\90\90156.DOC •45· 1335821 基肼、N8-乙醯基精脒、胺基喋啶甲胺喋呤(amin〇pterin methopterin)' 伊斯洛米辛(eSperamicin)、絲裂黴素 c(mit〇myCin C)、絲裂徽素 A(mitomycin A)、放射菌素(actinomycin)、平 陽黴素(bleomycin)、洋紅黴素(carminomycin)、胺基°業口定 (aminopterin)、把利索黴素(taiiySOmyCin)、鬼臼毒素 (podophyllotoxin)及鬼臼毒素衍生物(諸如,伊托普西 (etoposide)或伊托普苦磷酸、長春新驗(vinbiastjne)、威利 司>丁、長春地辛(vindesine)、紫杉醇(taxol)、特西替爾 (taxotere)、維 A酸(retinoic acid)、丁酸、N8-乙醯基精脒、 吾樹驗(camptothecin)、卡奇黴素(calicheamicin)、草苔蟲素 (bryostatins)、西法斯坦丁(cephalostatins)、安絲菌素 (ansamitocin)、阿特辛(actosin)、類美坦生(maytansin〇ids) (諸如 DM-1、美坦生(maytansine)、美坦西醇(maytansin〇1)、 N-去曱基-4,5-去環氧基美坦西醇、c-19-去氯美坦西醇、 C-20-|^基美坦西醇、c-20-去曱氧基美坦西醇、C-9-SH美 坦西醇、C-14-烷氧基曱基美坦西醇、C14-羥基或乙醯基氧 基美坦西醇、C15-經基/乙龜基氧基美坦西醇、C15-甲氧基 美坦西醇、C-18-N-去甲基美坦西醇及4,5 -去氧基美坦西 醇、奥力斯汀類(auristatins)(諸如奥力斯汀E、Μ、PHE及 ΡΕ),多樂司、汀類(dolostatins)(諸如,多樂司、;丁 Α、多樂司 汀B、多樂司汀c、多樂司汀D、多樂司汀E(20-表及11-表)、 多樂司汀G、多樂司汀Η、多樂司汀I、多樂司汀1、多樂司 >丁 2、多樂司汀3、多樂司·;丁 4、多樂司汀5、多樂司汀6、多 樂司汀7、多樂司汀8、多樂司汀9、多樂司汀1 〇、多樂司汀 O:\90\90156.DOC -46- 1335821 11、多樂司’/丁 12、多樂司汀13、多樂司汀14、多樂司汀15、
多樂司> 丁 16、多樂司丨丁 17、多樂司彡丁 18 ;西法司、;丁類 (cephalostatins)(諸如,西法司汀】、西法司汀2、西法司汀3、 西法司汀4、西法司汀5、西法司汀6、西法司汀7、25,_表_ 西法司汀7、20-表-西法司汀7、西法司汀8、西法司汀9、西 法司汀10、西法司汀11、西法司汀12、西法司汀13、西法 司汀14、西法司汀15、西法司汀16、西法司汀17、西法司 汀18及西法司汀19。 類美坦生係藉抑制微管蛋白聚合作用之有絲分裂抑制 _ 劑。美坦生首次係從東非灌木少(美國專利第 3,896,111號)中分離出來的’而後’咸已發現某些微生物亦 產生類美坦生(諸如’美坦生西醇及C-3美坦生西醇醋(美國 專利第4,151,042號)。在,例如,美國專利第4,137,230號; 第 4,248,870號’第 4,256,746號;第 4,260,608號;第 4,265,814 號;第 4,294,757號;第 4,307,016號;4,308,268號;4,308,269 號;4,309,428號;4,313,946號;第 4,315,929號;第 4,317,821 孀^ 號;第 4,322,348號;第 4,331,598號;第 4,361,650號;第 · 4,364,866號;第 4,424,219號;第 4,450,254號;第 4,362,663 · 號及第4,371,533號中揭示合成性美坦生西醇及其衍生物與 · 類似物,該等揭示專利案一併併入本專利說明書參考。 美坦生及類美坦生可與能專一性鍵結至腫瘤細胞抗原之 抗體共輛。含有類美坦生之免疫共輛物及其治療上的用途 業已揭示於,例如,美國專利第5,208,020號、第5,416,064 號及歐洲專利案0 425 235 Β 1中,該等揭示專利案一併併入 O:\90\90156.DOC -47- 1335821 本專利說明書參考。Liu等人,Proc. Natl. Acad. Sci. USA 8618-8623 (1996)中說明包括將名為DM1之類美坦生連 結至可對抗人類結直腸癌之單株抗體C242上之免疫共軛 物’咸發現該共扼物對經培養的結腸癌細胞具有高度的細 胞毒性,且其在活體内腫瘤生長分析上具有抗腫瘤的活 性。Chari等人’ Cancer Research 5?,· 197-1^1 (1992)說明在 免疫共軛物中的類美坦生係經雙硫連結子共軛至老鼠抗體 A7(其可鍵結至人類結腸癌細胞株的抗原上)或其他老鼠單 株抗體ΤΑ· 1 (其可與HER-2/wew致癌基因鍵結)》 技藝中有許多已知的連結基團可用以製造抗體-類美坦 生共軛物,包括於,例如,美國專利第5,2〇8,〇2〇號或歐洲 專利案 0 425 235 Β1 及 Chari 等人,Cancer Re.e.r.h (1992)中所揭示者。連結基團包括於上述經確認專利案中所 揭示之雙硫基團、硫醚基團、酸不安定基團、光不安定基 團、肽酶不安定基團或酯酶不安定基團,其中以雙硫及硫 鱗者較佳。 抗體及類美坦生之共軛物可利用各式具有雙功能蛋白偶 合劑(諸如,N-琥珀醯亞胺基_3_(2_吡啶基二硫)丙酸 (SPDP)、琥ί6醯亞胺基-4-(N-馬來醯亞胺甲基)環己烷 羧、毓醇亞胺(IT))、亞胺酯類雙功能衍生物(諸如阿迪皮酸 二甲酯HCL)、活化酯(辛二酸二琥珀醯亞胺酯)、醛類(諸 如,戊二醛)' 雙-重氮基化合物(諸如,雙(對-重氮苯甲醯 基)己烷二胺)、雙-二重氮鹽衍生物(諸如,雙_(對_二重氮笨 甲醯基)-伸乙基二胺)、雙異氰酸(甲苯2,6-二異氰酸)及雙- O:\90\90156.DOC .48- 1335821 活性氟化合物(諸如,i,5_雙氟_2,4_二硝基笨)。提供一雙硫 鏈結者之特佳偶合劑包括N_琥珀醯亞胺基_3_(2•吡啶基二 硫)丙酸(SPDP) (Carlsson 等人 J. 173:723-737 [1978])及N-號功g藍亞胺—‘(^比咬基硫)戊酸(spp),
連結子可連結至類美坦生分子不同位置處,端視連結的 種類而定。例如,利用慣用偶合技術與羥基反應可以形成 醋連結,該反應可發生在具有羥基的C_3位置、經羥基甲基 修飾之C-14位置、經羥基修飾之c_15位置及具有羥基的 C-20位置。在一較佳的具體實例,該連結發生在美坦生西 醇或美坦生西醇類似物的C-3位置處。 卡奇黴素 另一種令人感興趣的免疫共軛物包括共軛至一或多個卡 奇黴素分子之CD20鍵結抗體。抗生素卡奇黴素族在低於微 微克濃度下能夠使雙股DNA產生壞損。以製備卡奇黴素族 的共軛物而言’參見美國專利第5,712,374號、第5,714,586 號、第 5,739,116號、第 5,767,285 號、第 5,770,701 號、第 鲁 5,770,710號、第5,773,001號、第5,877,296號(所有的專利案 .
I 皆屬美國Cyanamid公司)。可使用的卡奇黴素結構類似物包 \ 括(但不侷限於)γ/、CX21、以、N-乙醯基-γ/、PSAG及 · 〇I1(Hinman# K , Cancer Research 53 : 3336-3342(1993)、
Lode等人 ’ Cancer Research 58:2925-2928 (1998)及前述屬 於美國Cyanamid公司的美國專利其他可與抗體共軛的抗 腫瘤藥劑為抗葉酸之QFA。由於卡奇黴素及QFA作用的位置 係在細胞内,且不能輕易地穿越細胞膜,因此,細胞經由 O:\90\90I56.DOC •49· 1335821 抗體媒介的胞飲作用吸收這些藥劑可大大增加其細胞毒性 效果。 放射性活性同位素 為了選擇性破壞腫瘤,抗體可以包括一具有高度放射性 活性原子。各種的放射性活性同位素可用以製備放射性共 軛之抗_CD20抗體,實例包括At2丨丨、I丨31、I丨25、γ9。、Rel86、 -
Sm 、Bl212、P32、Pb212及Lu的放射性活性同位素。當共 軛物係作為診斷之用時,其可包括閃爍描繪研究用之放射 | 性活性原子(例如,,或核磁共振(nmr)顯影(亦_ 為磁共振影像,mri)之旋轉標記時,可使用碘123、碘·131、 銦-111、氟-19、碳-13、氮-15、氧·17、釓、鎂或鐵。 放射性-或其他標記可以已知的方法併入共軛物中,例 如,利用適當的胺基酸先驅物以化學性胺基酸合成作用(涉 及’例如以氟-19取代氫)進行生物合成或合成肽,標記物(例 如,tc心或Π Rem、Rem及Ιη111可經由肽上的半胱胺酸 殘基連接上去。釔-90可經由離胺酸進行連接。i〇d〇gen ^ 方法(Fraker 等人(1978) Biochem. Biophys. Res. Commun. · 80:49-57可用以併入填-123。"免疫科學中之單株抗體" . (Chatal,CRC印行1989)詳細說明了其他方法。 . 可利用各式的具有雙功能蛋白偶合劑製造抗體及細胞毒 性劑之共軛物(諸如,N-琥珀醯亞胺基_3_(2-吡啶基二硫)丙 酸(SPDP)、琥珀醯亞胺基-4-(N-馬來醯亞胺甲基)環己烷」 -羧酸、毓醇亞胺(IT))、亞胺酯類雙功能衍生物(諸如阿迪 皮酸二曱酯HCL)、活化酯(辛二酸二琥珀醯亞胺酯)、醛類 O:\90\90156.DOC -50- 1335821 (諸如,戊二醛)、雙-重氮化合物(諸如,雙(對-重氮苯甲醯 基)己炫》—'胺)、雙一重氛鹽衍生物(諸如,雙-(對-二重氮苯 甲基)-伸乙基二胺)、雙異氰酸(甲笨2,6-二異氰酸)及雙-活 性氟化合物(諸如’ 1,5-雙氟-2,4-二硝基苯)。例如,可用 Vitetta等人’ ⑼ce 238:1098 (1987)所揭示者製備蓖麻毒
蛋白免疫毒素。經碳-14-標記之1_異硫氰基苄基_3_甲基二 伸乙基三胺戊乙酸(MX-DTPA)係一個將放射性核苷酸共輛 至抗體之螯合劑實例,參見世界專利94/11 〇26。連接子可 以是幫助細胞毒性劑於細胞中釋放之"可切除之連結子", 例如,可以使用酸不安定連接子(Chari等人,心加以 i^earc/2 52:127-131 (1992);美國專利第 5,208,020號)。 CD20鍵結抗體的治療用途 本發明鍵結抗體可用以治療許多惡性及非惡性疾病(包 括自體滿意疾病及相關的病症),及CD20陽性癌症(包括B 細胞淋巴瘤及白血症)。骨髓中的幹細胞(B_細胞親本細胞) 缺少CD20抗原,因此,治療後健康的B_細胞可以再生,並 0 在數個月之内恢復到正常的數量。 . 自體免疫疾病或自體免疫相關病症包括關節炎(類風濕 ·, 性關卽义、月少年類風濕性關節炎、骨關節炎、乾癖性關 - 節炎)、牛皮癖、皮膚炎(包括異位性皮膚炎);慢性自體免 疫麻疹、多發性肌炎/皮膚肌炎、毒性表皮壞死松解癥、全 身性硬皮症及硬化症、與發炎性腸疾病相關之反應(庫氏疾 病、潰瘍性大腸炎)、呼吸窘迫症候群、成人呼吸窘迫症候 群(ARDS)、腦膜炎、過敏性鼻炎、腦炎、葡萄膜炎、大腸 O:\90\90I56.DOC •51· 1335821 尺、腎絲球腎炎、過敏病、渔疹、氣喘、與τ細胞;心漏有關 之疾病及忮k發炎疾病、動脈硬化、自體免疫心肌炎、白 血球細胞吸附缺陷、全身性紅斑性狼瘡(SLE)、狼瘡(包括 腎臟炎、非-腎臟、盤狀紅斑狼瘡、禿髮)、青少年發生之糖 尿病、多發性硬化症、過敏性腦脊髓炎、由細胞素及τ_ 淋巴細胞媒介與急性或延遲過敏性有關之免疫反應、肺結 核、結節病、肉牙腫病(包括瑋格納氏肉牙腫病、顆粒性白 血球減少症、血管炎(包括ANCA)、再生障礙性貧血、庫姆 斯陽性貧血、戴莫·布來芬氏貧血、免疫溶血性貧血(包括自 體免疫溶血貧血(AIHA)、惡性貧血、純紅血球不全 (PRCA)因子VIII缺乏、&友病A、自體免疫中性粒細胞減 少症、全血球減少症、白血球減少症、與白血球滲出血管 壁有關之疾病、CNS發炎疾病、多重器官受損症候群、重 症肌無力、抗原-抗體媒介之疾病、抗-腎小球基礎膜疾病、 抗-磷脂質抗體症候群、過敏性神經炎、貝雪疾病、卡斯曼 氏症狀、SM寺巴斯德氏症候群、拉姆伯特_伊頓肌無力症候 群、雷諾氏症候群、修格連氏症候群、史蒂芬_強生症候群、 固體器官移植排斥(包括高反應抗體校價之事先處理, 沉積在組織等)、移植物對抗宿主疾病(GVHD)、大皰性類 天皰瘡、天皰瘡(所有的均包括痤瘡、面皰)、自體免疫多重 内分泌疾病、萊特氏疾病、僵硬人症候群、巨細胞動脈炎、 免疫複合物腎臟炎、IgA腎病變、IgM多重腎病變或⑽媒 介神經病變、特發性血小板低下紫斑症(ITp)、自體免疫血 小板減少、睪丸及卵巢自體免疫疾病(包括自體免疫睪丸产
O:\90\90I56.DOC -52- 1335821 及印巢炎)、原發性初級甲腺低能症;自體免疫内分泌疾病 (包括自體免疫甲狀腺炎、慢性甲狀腺炎(橋本氏甲狀腺 炎)、次急性甲狀腺炎、特發性甲腺低能症)、艾迪生氏疾病 、格雷夫氏疾病、自體免疫多發性腺體症候群(或多發性腺 體内分泌病症候群)、第丨型糖尿病(亦稱為胰島素依賴性糖 尿病(IDDM))及席漢氏症候群;自體免疫肝炎、淋巴樣間質 性肺炎(HIV)、阻塞性細支氣管炎(非-移植)對抗Nsip)、格 萊恩-巴爾氏症候群、大血管血管炎(包括風濕性多肌痛病症 及巨細胞(面:it氏)動脈炎)、中血管血管炎(包括川崎氏病及 結節性多動脈炎)、僵直性脊髓炎、伯格氏疾病(IgA腎病 變)、快速進展腎絲球腎炎、原發性膽汁性肝硬化、乳糜濕 (麩質腸病變)、冷凝球蛋白血症、ALS、冠狀動脈疾病。 CD20陽性癌症為包括在細胞表面上表現cd2〇之細胞異 常增生者。CD20陽性B細胞腫瘤包括CD20陽性何傑金氏疾 病(包括淋巴細胞優勢何傑金氏疾病(LPHD));非-何傑金氏 淋巴瘤(NHL);濾泡性中心細胞(FCC)淋巴瘤;急性淋巴細 胞性白血病(ALL);慢性淋巴細胞性白血病(CLL);毛細胞 細胞白血病。非-何傑金氏淋巴瘤包括低度/濾泡性非_何傑 金氏淋巴瘤(NHL)、小淋巴細胞性淋巴瘤(Sll)、中度/濾泡 NHL· '中度擴散性NHL、高度免疫母細胞性NHL、高度免 疫母細胞性NHL、高度小非凹陷細胞淋巴瘤及瓦爾登斯特 倫氏巨球蛋白血病。治療這些癌症的復發亦包括在内。 LPHD是一種類型的何傑金氏疾病,雖然經過放射線或化學 治療’其常常會有復發的傾向,且其特徵是CD2-陽性惡性 O:\90\90156.DOC -53- 1335821 細胞小琳巴細胞性淋巴瘤(SLL)。CLL是四種主要白血病中 的一種,稱之為淋巴細胞之成熟心細癌症之癌症,CLl的 特徵是細胞會在血液 '骨髓及淋巴性組織中進行性累積。 在特定性具體實例中,CD20鍵結抗體及其功能性片段可 用以治療非-何傑金氏淋巴瘤(NHL)、淋巴細胞優勢何傑金 氏疾病(LPHD)、小淋巴細胞性淋巴瘤(SLL)、慢性淋巴細胞 性白血病、類風濕性關節炎及青少年類風濕性關節炎、全 身性紅斑性狼瘡(SLE)(包括紅斑性狼瘡腎炎)、瑋格納氏疾 病、發炎性腸疾病、特發性血小板低下紫斑症(ιτρ)、血栓 性血小板低下紫斑症(ΤΤΡ)、自體免疫血小板減少、多發性 硬皮症牛皮癬' βΑ腎病變、IgM多發性神經病變、曹 肌無力、血管炎、糖尿病、㈣氏症候群、修^氏^ 群及腎.絲球腎炎。 人源化CD20鍵結抗is或其功能性片段可作為單一藥劑 治療,例如用於治療復發性或低頑固度或濾泡、cd2〇、_陽 性、B·細胞NHL上,或可與其他藥劑合併以多重藥劑療程 投與病患。 … 頑固淋巴瘤係-生長速度慢、無法治癒的疾病,其中平 均病患經過多次舒緩期及復發期&之存活期介於6至^年 之間。在-個具體實例中,人源化⑽晴結抗體或其功能 性片段可用以治療頑固淋巴瘤。 否之參數係熟識適當疾病 ,熟練的醫事人員會檢視 況,參數包括疾病進行的 評估治療腫瘤的效果或成功與 之醫事人員所熟知的。通常而言 特定疾病的病徵及症狀的減少狀
O:\90\90156.DOC •54- 1335821 中段時間、疾病穩定舒緩期的時間。 下列參考文獻說明淋巴瘤及CLL、其診斷、治療及其測 量治療效果之標準醫事步驟。 下列參考文獻說明淋巴瘤及CLL、其診斷、治療及其測 量治療效果之標準醫事步驟。Canellos GP,Lister,TA,Sklar JL: 77ze W.B· Saunders公司,費城,1998 ; van •’
Besien K及Cabanillas,F :臨床表現,非傑金氏淋巴瘤之病 ·· 程期與治療,第七章’ 1293_1338頁,in :价所釘〇/〇以,基鲁 本原理及實務,第三版Hoffman等人(出版者),Churchill , Livingstone,費城,2000 ;及Rai,κ及patei,d :慢性淋巴 細胞性白血病’第 72 章,1350-1362 頁,in : , 基本原理及實務’第三版Hoffman等人(出版者),Churchill
Livingstone,費城,2000 〇 評估治療自體免疫或自體免疫疾病相關疾病的效果或成 功與否之參數係熟識適當疾病之醫事人員所熟知的。通常 而言’熟練的醫事人員會檢視特定疾病的病徵及症狀之減 φ 少狀況。下列係以實例說明之。 · 在一個具體實例中,本發明抗體可用以治療類風濕性關 ·. 節炎。RA的特徵是多處關節處發炎、軟骨流失及骨骼侵 - 触’導致關節破壞,最終降低關節的功能。除此之外,由 於RA為全身性疾病,所以其會影響其他的組織,諸如肺 臟、眼睛及骨髓。罹患RA十年以上病患中,低於50%者在 每曰基礎生活上可持續工作或功能仍正常。 抗體可作為罹患早期RA病患的第一線治療(例如,未接受
O:\90\90156.DOC -55- 1335821 甲胺喋呤(MTX)者),並可為單一藥劑治療,或與(例如)Μτχ 或%墻酿胺合併投用,或者疋’該抗體可作為無法以 DMARD及/或ΜΤΧ治療之病患之第二線治療,並可為單一 藥劑治療或與(例如)ΜΤΧ合併投用。人源化CD20鍵結抗體 可用以預防或控制關節損壞、延遲結構的破壞、減少與尺八 _ 發炎相關的疼痛’並通常可減少中度至重度r Α的病徵及症 ·' 狀。RA病患可於以其他治療RA藥劑之前、之後或一起使用 - 人源化CD20抗1體治療(參見下列組合治療)。在一個且體實 例中,前已以疾病修飾抗風濕性藥劑治療而失敗之病患及/ _ 或無法對單以甲胺嗓吟治療有充分反應之病患可以本發明 人源化CD20鍵結抗體治療之。在此治療的一個具體實例 中’該病患於1 7-天的治療療程中只接受人源化CD20鍵結抗 體(在第1天及第15天靜脈灌注1公克);接受cd20鍵結抗體 加上環磷醯胺(在第3天及17天靜脈灌注75〇毫克);或接受 CD20鍵結抗體加上甲胺κ業吟。 s平估RA治療效果的一個方法係根據美國風濕學學院 # (ACR)標準’其在許多事宜中,測量脆弱及腫脹關節改良的 . » 百分比。RA病患可與未經抗體處理(例如,治療前的基礎線) ·. Λ 或以安慰劑治療後比較計以例如ACR 20(20%的改善),其他 評估抗體治療的效果包括用以評分結構破壞(諸如骨骼侵 姓及關節空間窄化)之X-光評分法(諸如Sharp X-光計分 法)。亦可根據健康評估問卷[HAq;j計分法、AIMS計分法、 SF-36等於治療期間或治療之後,來評估病患不良於行的預 防或改善。ACR 20標準包括於脆弱(疼痛)關節數目及腫脹
O-.V90\90l56.DOC -56- 奇節數目兩者上有20〇/〇的改善及至少於5項測量上有至少 有3項為20%—改善: 1.藉由視覺類比表(Vlsual anal()g ; vas)評估病患疼 痛, 2·病患對疾病活性之整體評估(VAS), 3.醫事人員對疾病活性之整體評估(VAs), (病患藉由健康評估問卷自行評估失能狀況,及 5 ·急性期反應物、CRP或ESR。 ACR50及7G係以相似的方式定義之。較佳地,病患係投 與可連至少八(^2()計分劑量之本發明CD2Q鍵結抗體,較佳 者至少為ACR30之劑量,更佳者至少為八〇115〇之劑量,甚 至至少為ACR70之劑量,最佳者至少為ACR75劑量及更高 的劑量·。 、乾癬I·生關節火具有獨特及不同的顯影圖。以乾癖性關節 炎而言,關節侵姓及關節空間窄化亦可以处叫計分法評估 之。本發明人源化CD2G鍵結抗體可用以預防關節壞損,及 減少疾病病徵及失調症之症狀。 本發明另一方面係治療狼瘡或SLE之方法,其係投與罹患 SLE病患一有效治療量之本發明人源化CD2〇鍵結抗體。 SLEDM計分法提供可提供疾病活性之數值定量法。 SLEDAI是將24個已知與疾病活性㈣,而數值範圍介於 0-130之臨床及實驗室參數經加權後所得之指數,參見 Bryan Gescuk & John Davis,現今風濕學觀念”全身性紅斑 性狼瘡之新穎治療藥劑”2002,14:5 i 5·52 i。咸信對抗雙股 O:\90\90156.DOC •57· 1335821 DNA的抗體會造成腎臟病灶惡化及狼瘡其他的症狀顯現。 進行抗體治療的病患要監控腎臟病灶擴展狀況(其定義為 明顯、重複性的增加血清肌酸、尿蛋白或血尿)。另一種方 式:除此之外’病患可監控抗核抗體及抗雙股⑽A抗體的 3里SLE的/。療包括兩劑量皮質類固醇及,或環磷醯胺 (HDCC)。 脊柱關畴病疋-群關節的失調症,包括僵直性脊椎炎、 乾癖性關節炎及座&、左、戌。m > 準氏疾病利用有效的病患及醫事人員整 體評估測量工具可決定治療成功與否。 各種的醫藥可用以治療牛皮癣;治療方式的不同直接地 與疾病嚴重性有關。罹患比輕度稍重型式牛皮癬的病患典 型也係利用局部治療法(諸如,局部類固醇、蒽林 (anthralin)、巧泊二醇(ealcip〇trene)、氯倍他索㈣bMas〇1) 及他佐羅汀(taZarotene)),以調控該疾病,然❿,罹患中度 及重度牛皮癖病患則更可能採用全身性的治療法(甲胺嗓 7類AI、%孢素、PUVA及UVB),亦可使用煙油,這些 治f法綜合了安全性、所需療程時間,或治療不便流程等 考里除此之外,某些治療在工作場所背景方面需要昂貴 的•又備及專用的空間。全身性用藥會產生嚴重的副作用, 包括问血壓、向脂血症、骨髓無法正常生長、肝臟疾病、 月臟疾病及腸月不適。另外,光治療的用途會增加皮膚癌 的發生率除了有局部治療有關的不便性及不舒適外,光 療及王身性治療需要病患進行治療及不治療的週期循 環,並因為其副作用而需要终身監控暴露。
O:\90\90156.DOC -58 - 1335821 化= 徵及疾病症狀相較與基礎線狀況下的變 變===療·Γ包括*事人員整趙評_ ㈣二 數(PASI)計分法、牛皮癣症 覺類比表錢測量整個治療過料程度之視 劑量 根據欲治療的疾病及與劑量有關之因素(此事熟識㈣ 域之醫事人員所熟悉者)’本發明投與的劑量對治療疾病是 有效果的,然而具有最低的毒性及副作用。以治療⑽㈣ 性癌症或自體免疫疾病而言,治療有效劑量範圍為約25〇毫 克/平方米至約400毫克/平方米,較佳者約25〇_375毫克/平 方米。在一個具體實例中,劑量範圍為275_375毫克/平方 米。在·一個治療CD20陽性B細胞腫瘤的具體實例中,抗體 投用範圍·-375毫克/平方米,以治療罹患B_細胞淋巴瘤 (諸如非-何傑金氏淋巴瘤)而言,在—特定的具體實例中, 本發明抗-CD20抗體及人源化抗_CD2〇抗體投與人類病患 的劑量為1〇毫克/公斤或375毫克/平方米。以治療nhl而 言,一個劑量療程係在治療首週投與1〇毫克/公斤劑量之抗 體組合物,而後經過兩週間隔再投與第二劑相同劑量的抗 體。一般而言,NHL於一年期間接受一次的此種治療,但 淋巴瘤復發後’此種治療可以重複。在另一種劑量療程中, 羅患低度NHL之病患接受四週的人源化2H7變異體,較佳者 為vl6變異體(每週為375毫克/平方米),而後在第五週,接 受額外二次抗體加上標準CHOP療程(環磷酿胺、阿黴素、 O:\90\90156.DOC 59· 1335821 减利斯丁及腎上皮質素)或CVP(環磷醯胺、戚利司汀、腎上 皮質素)化學-療法,每三週投與一次,共三個循環。 ,治療疾病,本發明CD20鍵結抗體可根據熟識疾病醫事 人員以慢性方式或間歇性方式投與病患。 病患以靜脈灌注法或皮下方式投與藥劑時可能會有不良 反應出現,諸% ’發燒、畏寒、灼熱感、虛弱及頭痛。: 了舒緩或減少此種不良反應,病患可接受初始調整劑量抗 體’而後再接受治療劑量。調製劑量比治療劑量低,以便 將病患調整至可以耐受較高的劑量。 投藥途徑 CD20鍵結抗體係根據已知的方法投與人類病患,諸如靜 脈投藥法(例如,全劑)或持續一段時間的灌注法 '皮下、肌 肉内、腹膜内、腦脊髓内、滑液體内、脊椎内或吸入途徑, 通常係以靜脈或皮下方式投藥法。 在治療上述之B-細胞腫瘤中,病患可以本發明CD2〇鍵結 杬體併與一或多種治療藥劑治療之,諸如,多重藥劑療法 中之化學治療劑。CD20鍵結抗體可與化學治療劑同時、依 序或交互投用,或經其他治療法未有反應後投用。淋巴瘤 治療的標準化學治療包括環磷醯胺、阿糖胞苷、美法侖及 曱胺喋呤加上美法侖。CH〇p是一種最常用以治療非-何傑 金氏淋巴瘤之化學治療療程。下列為用於CH〇p療程之藥 劑:環磷醯胺(商品名細特森,尼薩(Ne〇sar));阿黴素(杜瑟 陸賓辛/羥基杜瑟陸賓辛);威利司汀(〇nc〇vin);及去氫可
O:\90\90156.DOC -60- 1335821 體醇(有時候稱之為迪特松(Deltasone)或歐洛松 (Orasone))。在特定的具體實例中,cd2〇鍵結抗體係與下 列一或多種化學治療藥劑:杜瑟陸賓辛、環磷醯胺、威利 司、;丁及去氫可體醇合併投與有需要之病患。在一特定具體 貫例中,罹患淋巴瘤(諸如,非_何傑金氏淋巴瘤)病患係以 本發明抗-CD20抗體併與CHOP(環磷醯胺、杜瑟陸賓辛、威 利司汀及腎上皮質素)治療。在另一個具體實例中,癌症病 患可用本發明人源化CD20鍵結抗體併與CVP(環磷醯胺、威 利司:T及腎上皮質素)治療。在一特定具體實例中,罹患 CD20-陽性NHL病患係以人源化2H7.V16抗體併與CVP治 療。在一特定治療CLL的具體實例中,CD20鍵結抗體係與 化學治療藥劑氟達拉賓及細特森之一或兩者合併投藥。 在治.療上述自體免疫疾病或自體免疫相關疾病時,病患 係以本發明CD20鍵結抗體併與多重藥劑治療療程之另一 種治療藥劑(諸如,免疫抑制劑)治療之。CD2〇鍵結抗體可 與免疫抑制劑同時、依序或交互投用,或於以其他治療時 未發生反應時投用。所投用的免疫抑制劑可與技藝中所訂 之劑畺相同或較低。較佳的輔助性免疫抑制劑端視許多因 子而定,包括欲治療的疾病及病患病史。 本專利說明書中所用輔助治療用"免疫抑制劑"係指作用 為抑制或遮蔽病患免疫系統之物質,此種藥劑包括可抑制 細胞素產生、逆調節或抑制自體抗原表現,或遮蔽抗 原之物質。此種藥劑的實例包括類固醇(諸如,腎上腺糖皮 質類固醇,例如:腎上皮質素、甲基去氫可體醇及迪瑟美
O:\90V90I56.DOC 1335821 沙松(dexamethasone) ; 2-胺基-6-芳基-5-經取代嘧啶(參見, 美國專利第4,665,077號)、硫唑嘌呤(azathioprine)(或假若對 硫唑嘌呤有不良反應者,則為環磷醯胺);溴隱汀 (bromocriptine);戊二醛(其可遮蔽MHC抗原,如美國專利 第4,120,649號中所述);抗]^11(:抗原及1411(:片段之抗-獨特 型抗體;環孢素A ;細胞素或細胞素受體拮抗劑(包括抗-干 擾素-γ、-β或-α抗體;抗-腫瘤壞疽因子-α抗體;抗-腫瘤壞 疽因子-β抗體;抗-白介素-2-抗體及抗-IL-2受體抗體;抗 -L3T4抗體;異質性抗-淋巴細胞球蛋白;泛_τ抗體(較佳者 為抗-CD3或抗-CD4/CD4a抗體);含有LFA-3鍵結區域之可 溶性肽(7/26/90發表之世界專利案90/08187),鏈激酶; TGF-β;鏈道酶;宿主得來之RNA或DNA; FK506; RS-61443 ;脫氧司加林(deoxyspergualin);納巴黴素(rapamycin) ; T-細胞受體(美國專利第5,114,721號);T-細胞受體片段 (Offner 等人,,Science 251 : 430-432(1991);世界專利案 90/1 1294及世界專利案91/01133);及丁-細胞受體(歐洲專利 第 340,109)(諸如,T10B9)。 以治療類風濕性關節炎而言,病患可以本發明CD20抗體 併與一或多種下列藥劑治療之:DMARDS(疾病修飾抗風濕 性藥劑(例如,甲胺喋呤)、NSAI或NSAID(非-類固醇性抗-發炎性藥劑)、HUMIRAtm(阿達利馬(adalimumab) ; Abbott 實驗室)、ARAVA®(利氟諾胺(leflunomide))、REMICADE®(伊 氣西馬(infliximab) ; Centocor公司,莫爾文城,賓夕法尼 亞州)、ENBREL® (伊特諾特(etanercept) ; Immunex,華盛 O:\90i\9O156.DOC -62- 1335821 頓)、C0X-2抑制劑。RA常用的DMARDs為羥基氯奎寧、硫 氮項°比咬(sulfasalazine)、甲胺喋呤、利氟諾胺、伊特諾特、 伊氟西馬、硫唑嘌呤、D-青黴素胺、金(口服)、金(肌肉内)、 美滿徽素(minocycline)、環孢素、葡萄球菌蛋白A免疫吸 附。阿達利馬為人類的單株抗體,其可鍵結至TNFa上。伊 特諾特為”免疫吸附"融合蛋白,其係由人類75kD(p75)腫瘤 壞疽因子受體(TNFR)胞外配位體鍵結部份連結至人類IgGl 的Fc部分所組成的。以傳統治療RA而言,參見,例如,”管 理類風濕性關節炎的準則ii/zewwfiribw 46(2): 328-346 (2002年2月)。在一個特定具體實例中,RA病患係 以本發明CD20抗體併與曱胺喋呤(MTX)治療之,MTX例示 性劑量約7.5-25毫克/公斤/週。可以口服方式或皮下方式投 用 MTX.。 以治療僵直性脊椎炎、乾癬性關節炎及庫氏疾病而言, 病患可以本發明CD20鍵結抗體併與(例如)Remicade®(伊氟 西馬;Centocor公司,莫爾文城,賓夕法尼亞州)、ENBREL (伊特諾特,Immunex,華盛頓州)治療之。 SLE治療包括高劑量的皮質類固醇及/或環磷醯胺 (HDCC)。 以治療牛皮癬而言,病患投用CD20鍵結抗體併與局部治 療,諸如,局部類固醇、蒽林、鈣泊三醇、氯倍他索及他 佐羅汀,或併與曱胺喋呤、類A酸、環孢素、PUVA及PUVB 療法。在一個具體實例中,牛皮癖病患係以CD20鍵結抗體 以依序方式或同時併以環孢素治療之。 O:\9Q\90156.DOC -63· 1335821 醫藥調配物 製備保存用之根據本發明所用的CD2〇_鍵結抗體之治療 調配物係將具有所要純度知抗體與選擇性醫藥學上可接受 載劑賦形劑或安疋劑混合在—起,以形成冷凍乾燥調配 物或水溶液。可接受的載劑、賦形劑,或穩定劑於採用的 4里及辰度%對艾體是不具毒性的,且包括緩衝劑(諸如, 磷酸、擰檬酸及其他有機酸);抗氧化劑包括抗壞血酸及甲 硫胺酸;保存劑(諸如十八基二甲基节基氣化銨;氣化己甲 銨(hexamethonium chloride);氣化苯二甲羥銨 (benzalkonium chloride) . ^ t ^ (benzethonium chloride);酚、丁基或苄醇;對羥基苯甲酸烷酯類(諸如, 對經基苯甲酸甲酯或丙酯);鄰苯二酚;間苯二酚;環己醇; 3-戊醇及間-甲酚);低分子量(少於約1〇個殘基)聚肽;蛋白 質(諸如,血清白蛋白、動物膠,或免疫球蛋白);親水性聚 合物(諸如聚己烯基咯烷醐);胺基酸(諸如,甘胺酸、麵胺 醯胺、天門冬醯胺、組胺酸、精胺酸或離胺酸);單醣、雙 醣及其他碳水化合物(包括,葡萄糖、甘露糖、糊精);螯合 鈉(諸如,EDTA),醣類(蔗糖、甘露醇、海藻糖或山梨糖醇); 形成鹽類的反向離子(諸如,鈉);金屬複合物(例如,鋅_ 蛋白複合物);及/或非-離子性表面活性劑(諸如, TWEENtm、PLURONICSTM或聚乙烯丙二醇(PEG)。
例示性抗-CD20抗體調配物揭示於世界專利98/56418 中,該申請案明確地併入本專利說明書參考。另一調配物 係液態複劑量調配物,其包括40毫克/毫升抗_CD2〇、25 mM O:\90\90156.DOC •64- 1335821 醋酸、15〇福海藻糖、〇_9%节醇、〇鄕山梨醇醋2〇,扑 5.0,其保存在2听下最少有兩年的上架期。另_感興趣的 杬-CD20調配物係包括溶於9 〇毫克/毫升氯化鈉、'Μ毫克/ 毫升檸檬酸鈉二水合、0.7毫克/毫升聚山梨醇酉旨8〇及無菌注 射用水(pH 6.5)之10毫克/毫升抗體。另一種水溶液醫藥調 配物包括10-30 mM醋酸鈉(約pH 4.8至約pH 5 5,較佳者為 pH 5_5)、作為表面活性劑之聚山梨醇酯(含量約 重量比)、海藻糖(含量約孓1〇%重量體積比)及作為防腐劑之 苄醇(美國專利第6,171,586號)。適合皮下投藥之冷凍乾燥 調配物揭示於世界專利世界專利97/〇48〇1中,此等冷凍乾 燥調配物可以適當之稀釋劑復水成具有高蛋白濃度,而復 水之調配物可以皮下方式投與本專利說明書欲治療之哺乳 動物。. 一種人源化2H7變異體之調配物係含有溶於1〇 mM組胺 酉夂,6/ί>嚴糖、〇·〇2%聚山梨醇醋2〇,pH 5.8之12-14毫克/毫 升抗體。 本專利說明書調配物為了所欲治療的特定適應症亦可如 需要含有超過一種之活性化合物,較佳係具有互補活性而 不會彼此有不良影響者。例如,咸意欲另外提供一細胞毒 性劑、化療劑、細胞素或免疫抑制劑(例如,一種作用在T 細胞上者’諸如環抱素,或一可鍵結τ細胞之抗體,例如一 種鍵結LFA-1者)。該等其他藥劑之有效含量端視調配物中 所含有的抗體含量、所欲治療的疾病及失調症,及前所討 論的因子而定。這些通常使用相同的劑量,並使用本專利 O:\90\90156.DOC -65· "兄明書所揭示相同的投藥、太,々α J仅樂去,或使用前所採用劑量之約1至 99% 〇 -. /舌!·生成分亦可置入於’例如,#由凝聚作用或藉由界面 聚《作用所製備之微膠囊中,例如分別在膠體藥物傳送系 統中之經基甲基纖維素或動物膠.微㈣及聚_(甲基甲基丙 基酸)微膠囊(例如,脂小體、白蛋白微球、微乳液、奈-顆 粒及不膠囊)或巨乳液中。該種技術係揭示於Remington^ Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) 〇 可製備持續性-釋放製劑。適當的持續性_釋放製劑之實例 包括含有拮抗劑之固態疏水性聚合物半滲透基質,該基質 係為成形物體,例如,濾膜,或微膠囊。持續性_釋放基質 包括聚酯類、水凝膠(例如,聚(2_羥基乙基-曱基丙基酸)、 或聚(乙埽基醇))、聚交酯類(美國專利第3,773,919號)、L-麵胺酸及乙基-L-麵胺酸之共聚物、非生解性乙烯_醋酸乙稀 酉旨、分解性乳酸-甘醇酸共聚物,諸如LUPRON DEPOTtm(注 射性微球’係由乳酸-甘醇酸共聚物及醋酸亮丙瑞來 (leuprolide acetate),及聚-D-(-)-3-羥基丁酸。 作為活體内投藥用之調配物必須為無菌狀態,此藉由無 菌濾膜之過濾作用可輕易完成。 製造產品及套组 本發明另一個具體實例係包含用以治療自體免疫疾病及 相關病症及CD20陽性癌症(諸如非-何傑金氏淋巴瘤)物質 之製造產品,該製造產品包括一容器及在容器上之標籤或 伴隨容器所附之包裝插頁。適當的容器包括(但不侷限於) 〇:\9〇W156.D〇C -66- 1335821 瓶子、小叛、針筒等,容器可以各種不同的材料形成,諸 如玻璃或歸。·容n内含能有效治療病徵之組合物,並具 有無菌的進入口 (例如’容器為—具有可以皮下注射針筒穿 刺而過之栓塞之靜脈用溶液袋或小瓶子)。組合物中至少一 種活性劑為本發明CD20鍵結抗體。標籤或包裝插頁說明該 組合物係用以治療特定的病/症,標籤或包裝插頁另外包括 將該抗體組合物投與病患之說明t,包裝插頁通常係指市 =治療產品包裝中所包含之說明書,《包含關於使用該等 治療產品在適應症、用途、劑量、投藥、禁忌及/或警語有 關之資訊。在—個具體實例中,包裝插頁說明該組合物係 用以治療非-何傑金氏淋巴瘤。 除此之外,本發明製造產品可另外包括第二個容器,其 包括-’醫藥學上可接受之緩衝劑,諸如抑菌性注射用水 (bwFI)、錢鹽'緩衝性食鹽水、雷氏溶液及葡萄糖溶液。 °另卜匕括商業上及使用者觀點所想要之其他物質,包 括其他緩衝劑、稀釋劑、濾膜、注射針、針筒。 本發明亦提供用於各種目的之套組,例如,殺死B_細胞 之分析法、作為細胞料分析法之陽性控制組、從細胞中 純化或免疫《出CD2G。以分離及純化CD2Q而言,該套組 可含有偶合至小珠(例如,赛法洛斯…加叫小珠)之抗 抗體’所提供之套組中含有,例如,阳从或西方墨 f法中用以偵測及定量活體外CD2〇之抗體。一如製造產 品,該套組包括—容器及在容器上之—標籤或伴隨容器所 附之包3插頁。容器中内裝有包括至少—種本發明抗_哪〇
O:\90\90I56.DOC •67· 1335821 士大’馬里蘭州(1991))比較後,確認出2H7的CDR殘基。根 據序列的超變化區域界定出輕鏈及重鏈的CDR區域(Kabat 等人’同上),並分別示於圖1A及圖1B中。利用合成性寡核 音 ’ 以位置引導犬變作用(Kunkel,Pr〇c. Αύτίΐ <SW. 82:488-492 (1985))可將所有六個老鼠2H7 CDR區域引入至 對應於包含於質體pVX4(圖2)上之一致性序列V « I、 ·· VHIII(VL卡巴亞型I、νΗφ型m)之完整人類Fab架構上。 - 嗜菌質體pVX4(圖2)係在大腸桿菌中進行突變及作為表 % 現F(ab)s之用。以嗜菌質體pb〇72〇(pB〇475衍生物)為基礎 -(Cunningham等.人,243:1330-1336 (1989)),pVX4 含有編碼人源化一致性/c -亞型I輕鏈(VL /c I-CL)及人源化 一致性亞型III重鏈(VHIli_cHl)抗-IFN-a(干擾素α)抗體之 DNA片段。pVX4亦具有鹼性磷酸酶的啟動子及 Shine-Dalgamo序列(此兩者均是衍生自另一前所揭示以 pUC119為基礎之質體,pAK2(Carter等人,广〇<7.7\^3".^4£^6?· 5W. USA 89:4285 (1992))。在編碼 F(ab)輕鏈及重鏈的 DNA % 間引入了一個獨特的Spe 1限制酶切割位置。在抗-IFN-α重 ' 鏈及輕鏈兩者的前23個胺基酸為Sill分泌訊號序列(Chang 亀 等人,Ge似 55:189-196 (1987))。 ·
為了構築2H7的CDR-交換變異體(2H7.V2),在含有去氧尿 嘧啶的pVX4模板上進行位置引導突變作用;將抗-IFN-α上 所有的六個CDRs改變成老鼠2H7 CDRs。所產生的分子稱為 人源化2H7 2變異體(2H7.V2),或稱為2H7的"CDR-交換變異 體”,其具有一致性人類FR殘基之m2H7 CDR殘基(如圖1A O:\90\90156.DOC 69- 1335821 為與人源化構築體比較,利用位置引導突變作用 (Kunke卜同上)’以合成性寡核苷酸構築可表現嵌合性2H7 Fab(含有老鼠VL及Vh區域,及人類Cl及CHi區域)之質體, 以便將老鼠架構殘基引入至2H7.V2中。所得可表現敌合性 Fab(已知為2Η7·ν6_8)之質體構築體序列示於圖3中。每一 Fab編碼鏈具有如前pVX4(圖2)所述之23個胺基酸Sill分泌 訊號序列。
以老鼠2H7架構殘基與人類\^1、VHIII—致性架構區域 (圖1A及圖1B)及先前的人源化抗體的序列(Carter等人, Proc. Natl. Acad. Sci. USA 89:4285-4289 (1992)) tb ^ 為基礎,利用位置引導突變作用將數個架構突變引入至 2H7.v2 Fab構築體中,這些突變作用會將某些人類一致性 架構區域殘基改變成老鼠2H7架構區域上所發現者,這些位 置可能會影響CDR結構或抗原的接觸。3變異體含有 VH(R71V、N73K)、4變異體含有VH(R71V)、5變異體含有 VH(R71V、N73K)及 Vl(L46P),而 6變異體含有 Vh(R71V、 N73K)及 Vl(L46P、L47W)。 m2H7抗體之人源化及欲合性Fab版變異體可以在大腸桿 菌中表現,並可以下列方式純化。將質體轉型至大腸桿菌 株XL-1藍(Stratagene,聖地牙哥,加州),以製備雙股及單 股DNA。對每個變異體而言,利用二去氧核苷酸方法可完 全將輕鏈及重鏈兩者定序(定序酶,美國生化公司)。將質體 轉型至大腸桿菌株16C9(MM294的衍生物),平盤培養在含 有5微克/毫升叛苄青黴素(carbenicilliii)之LB培養盤上,並 O:\90\90156.DOC -71· 1335821 且篩選出單一菌落進行蛋白表現之用。將單一菌落生長在5 毫升LB_100微克/毫升羧苄青黴素中,在37 °C培養5-8小 時。將5毫升的培養液加至含有1〇〇微克/毫升羧苄青黴素之 5 00毫升AP5中,並讓其在4公升長頸振盪燒瓶中於37。〇生長 16小時。AP5培養基係將1.5克葡萄糖、11〇酪蛋白水解物 ' SF、0.6克酵母萃取物(認證過)、〇 19克無水硫酸鎂、ίο? ·. 克NH4C卜3.73 Κα、1.2克NaCM、120毫升1M的三乙醇胺 (ρΗ7·4)加水至1公升,而後通過〇1微米Sealkeen濾膜進行無 _ 菌化。 將細胞置於1公升離心瓶中以3〇〇〇 xg速度離心並丟棄澄 清液,以回收細胞,冷凍i小時後,將沉澱物重新懸浮於25 毫升冷的 10 mM MES-10 mM EDTA,pH 5.0(緩衝液 A)中, 加入25.0微升〇·ι M PMSF(以抑制蛋白分解作用),及35毫升 10毫克/¾升母雞蛋白溶解酶(以助細菌細胞壁的溶解),在 冰上溫和地振盪後’將樣品以4〇,〇〇〇 xg的速度離心丨5分 鐘。將澄清液以緩衝液A稀釋至5〇毫升,並加至業經緩衝液 | A平衡之2毫升DEAE管柱中,而後將所流出的液體加至業經 . 緩衝液A平衡之蛋白質G_賽法洛斯CL_4B(pharmacia)管柱 · · (0.5毫升基床體積)中,用1〇毫升的緩衝液八清洗管柱,並以 . 3毫升0.3 Μ甘胺酸(pH 3.0)於1.25毫升1 M Tris pH 8.0之液 體沖堤。利用濃縮器Centricon-30(Amicon)將F(ab)的緩衝液 換成PBS,並將最終體積濃縮成〇 5毫升。所有的F(ab)s進行 SDS-PAGE膠片電泳作用以確認純度,並以電灑式質譜術確 認每一變異體的分子量。
O:\90\90156.DOC -72· 1335821 在以細胞為基礎的ELISA鍵結分析法(如下所述)中,
Fabs(包括2H7 Fab)與CD20的鍵結難以偵測,因此,2H7 Fab 變異體需再次轉型為全長的IgG1抗體,以利分析及進一步 的突變作用。 將嵌合性2H7(v6.8)Fab及人源化Fab變異體2至6的VL及 VH區域次選殖至前所述用以哺乳動物細胞表現作用之PRK · 载體(Gorman 等人,DAOi Proi•五wg. 2:3-10 (1990)) · 中’以構築能表現全長IgG's的質體。簡而言之,每個Fab ^ 構築體以£C0jRV及5化1消化,以切割VL片段,將其選殖至能 -表現完整輕鏈(VL-CL)的質體pDRl(圖4)之心的位 置上’除此之外,每個Fab構築體以PvwII及消化,以切 割Vh片段,將其選殖至能表現完整重鏈(Vh-CH^CH^CHs 區域)之殖體pDR2(圖5)之PvMlIA4paI位置上。以每個IgG變 異體而言,將輕鏈表現質體及重鏈表現質體共同轉染至經 腺病毒轉型之人類胚胎腎臟細胞株293(Graham等人,丄Ge«.
36:59-74 (1977))進行暫時性轉染作用,簡而言之, 在進行轉染作用的前一天,將293細胞分盤並種植培養在含 有血·清的培養基中。次日,加入以製備成磷酸鈣沉澱物的 雙股DNA,而後加入pAdV AntageTM DNA(Promega,麥迪 遜,威斯康辛州),將細胞置於37°C下隔夜培養,細胞培養 在不含有血清的培養基中,並在4天後回收細胞。利用蛋白 質A-赛法洛斯CL-4B自細胞培養澄清液中純化出抗體,而後 將緩衝液置換成10 mM NaCl, pH 6.0,並利用Centricon-10 (Amicon)濃縮之。利用定量性胺基酸分析法測定蛋白質濃 O:\90\90I56.DOC -73- 1335821 度0
為了測定與CD20抗原的相對鍵結親和力,需建立以細胞 為基礎之ELISA分析法。人類B_淋巴母細胞wlL2_s細胞 (ATCC CRL 8885,美國型細胞培養收集中心,洛克菲洛,馬 里蘭州)係以RPMI培養基(添加有2 mM L-麩胺醯胺、20 mM HEPES,pH 7.2及10%熱失活胎牛血清)生長培養於潮濕化 5% C〇2培養箱中。細胞用含有i% fBS(分析緩衝液)的pBS 清洗’並以250-300,000細胞/槽孔的密度種植在圓底%槽孔 盤(Nunc,羅斯奇城,丹麥)中,將溶於分析緩衝液中的兩 倍連績稀釋標準品(1 5.6-1000奈克/毫升之2H7 v6.8嵌合性
IgG)及3倍連續稀釋之樣品(2,7-2〇〇〇奈克/毫升)加至培養盤 中,將培養盤埋入冰中,並培養45分鐘。為了去除未鍵結 的抗體將0.1毫升的分析緩衝液加至槽孔中,將培養盤離 心並去除澄清液,再用兩次0.2毫升分析緩衝液清洗細胞, 將過氧化酶共軛山羊抗-人類Fc抗體(Jackson ImmunoResearch ’西格洛福城,賓夕法尼亞州)加至培養盤 中以偵測鍵結至培養盤的抗體。經過45分鐘的培養後,以 前述方法清洗細胞,將TMB受質(3,3',5,5'_四甲基聯苯胺; Kirkegaard & Perry Laboratories ’ 蓋士堡,馬里蘭州)加至 培養盤中,加入1 Μ的麟酸終止反應。滴定曲線符合四參數 非直線回歸曲線符合程式(KaleidaGraph,Synergy軟體,雷 丁城,賓州)。求出滴定曲線中點的吸收值(mid-OD)及其對 應標準品,而後求出每個變異體在此mid-OD的濃度,將標 準品濃度除以每個變異體的濃度’據此所得數值即為每個 O:W3\90\56.DOC -74- 2H7 變異體 重鏈(VH) 取代作用 輕鏈(VL) 取代作用 相對 鍵結 6.8 (嵌合性) (嵌合性) -1- 2 (CDR-交換) (CDR-交換) 0.01 3 R71V、N73K (CDR-交換) 0.21 4 R71V (CDR-交換) 0.21 5 R71V、N73K L46P 0.50 6 R71V、N73K L46P、L47W 0.58 7 R71V L46P 0.33 8 R71V、L78A L46P 0.19 9 R71V 、 F67A L46P 0.07 10 R71V、F67A、I69L L46P 0.12 11 R71V、F67A、L78A L46P 0.19 12 R71V L46P、M4L 0.32 13 R71V L46PM33I 0.31 14 R71V L46PF71Y 0.25 15 R71Y L46P、M4L、M33I 0.26 16 R71V、N73K、A49G L46P 0.65 17 R71V、N73K、A49G L46P、L47W 0.67 1335821 表3.用以構築人源化2H7變異體16(2H7,vl6)中突變 Vh(A49G 、R71V、N73K)及Vl(L46)之寡核苷酸序列。畫 底線者係編碼所示胺基酸之取代作用。以Vh(R71V、N73K) 及Vl(L46P)而言,所示的寡核苷酸為正向股,因為這些係 用以在Fab模板上的突變作用,而VH(A49G)所示之寡核苷酸 則為反向股,因為此係用於pRK(IgG重鏈)模板。變異體16 的蛋白質序列示於圖6及圖7中。 O:\90\90156.DOC •76· 1335821 2H7 CDR 重鏈 輕鏈 相對鍵結 變異體 位-置.. 取代作用 取代作用 16 - 两 - -1- 140 HI G26A - 0.63 141 HI Y27A - 0.47 34 HI T28A - 0.86 35 HI F29A - 0.07 36 HI T30A - 0.81 37 HI S31A - 0.97 142 HI Y32A - 0.63 143 HI N33A - NDB 144 HI M34A - 1.2 145 HI H35A - < 0.25 146 H2 A50G 0.31 147 H2 I51A - 0.65 38 H2 Y52A - 0.01 148 H2 P52Aa - 0.66 39 H2 G53A - 0.89 67 H2 N54A - 1.4 40 H2 G55A - 0.79 41 H2 D56A - 2.0 89 H2 T57A 0.61 90 H2 S58A 0.92 91 H2 Y59A - 0.74 92 H2 N60A - 0.80 93 H2 Q61A - 0.83 O:\9O\901S6.DOC -78- 1335821 94 H2 K62A - 0.44 95 H2- F63A - 0.51 83 H2 V71A - 0.96 149 H2 K64A - 0.82 150 H2 G65A - 1.2 153 H3 V95A - 0.89 42 H3 V96A 0.98 43 H3 Y97A - 0.63 44 H3 Y98A - 0.40 45 H3 S99A 0.84; 0.92 46 H3 N100A - 0.81 47 H3 SlOOaA 0.85 48 H3 YlOObA 0.78 49 H3 WlOOcA - 0.02 59 H3 YlOOdA - 0.98 60 H3 FlOOeA - NDB 61 H3 D101A - 0.31 151 H3 V102A - 1.1 117 LI R24A 0.85 118 LI A25G 0.86 119 LI - S26A 0.98 120 LI - S27A 0.98 121 LI - S28A 1.0 122 LI - V29A 0.41 50 LI - S30A 0.96 51 LI - Y32A 1.0 O:\90\90156.DOC -79- 123 L1 - M33A 1.0 124 L1. - H34A 0.21 125 L2 - A50G 0.92 126 L2 - P51A 0.88 52 L2 - S52A 0.80 53 L2 - N53A 0.76 54 L2 - L54A 0.60 127 L2 - A55G 1.1 128 L2 S56A 1.1 129 L3 - Q89A 0.46 130 L3 - Q90A <0.22 55 L3 W91A 0.88 56 L3 - S92A 1.1 57 L3 - F93A 0.36 58 L3 - N94A 0.61 131 L3 P95A NDB 132 L3 - P96A 0.18 133 L3 - T97A <0.22 1335821 實例3 2H7 CDR區域内額外的突變作用 亦測試CDR位置的其他另外殘基的取代作用及取代作用 的組合,這些取代作用經Ala-掃描確認相當重要。數種組 合變異體(特別是v.96)顯示比V. 16變異體鍵結的更為緊密。 表5.利用細胞-基礎ELISA(WIL2-S細胞)測定人源化 2H7.V16上CDR區域上突變作用及非-丙胺酸取代作用的組 O:\90\90156.DOC • 80 - 1335821 合效應。相對鍵結力係以2H7.v 16親本抗體濃度比上需要相 等鍵結力之迻異濃度來表示;因此,比例<1表示變異體具 有較弱的親和力;比例> 1表示變異體的親和力較高。相對 測定值的標準偏差平均為+/-10%。相對2H7.V 16可變區域的 架構區域取代作用係根據Kabat編碼系統(Kabat等人,廣· 述、。 2H7 變異體 重鏈 取代作用 輕鏈 取代作用 相對 鍵結 16 - - -1- 96 D56A、N100A S92A 3.5 97 S99T、N100G、YlOObI - 0.99 98 S99G、N100S、YlOObI - 1.6 99 N100G、YlOObI - 0.80 101 N54S > D56A - 1.7 102 N54K > D56A - 0.48 103 D56A、N100A - 2.1 104 S99T、N100G - 0.81 105 S99G、N100S - 1.1 106 N100G - 〜1 167 SlOOaG 、 YlOObS - 136 D56A、N100A S56A、S92A 2.6 137 D56A、N100A A55G ' S92A 2.1 156 D56A、N100A S26A、S56A、 S92A 2.1 O:\90\90156.DOC -81 - 1335821 107 D56A、N100A、YlOObI S92A 未表現 - 182 Y27W - 183 Y27F - 184 F29Y - 185 F29W - 186 Y32F - 187 Y32W - 188 N33Q 189 N33D - 190 N33Y - 191 N33S - 208 H35S - 209 A50S - 210 A50R - 211 A50V - 212 A50L - 168 Y52W - 169 Y52F 0.75 170 N54D - 0.25 171 N54S - 1.2 172 D56K - 1 173 D56R - 174 D56H - 1.5 175 D56E - 1.2 O:\90\90156.DOC -82- 1335821
213 D56S - 214 D56G 215 D56N - 216 D56Y _ 176 Y59W - 177 Y59F - 180 K62R - 181 K62D - 178 F63W - 179 F63Y - 157 Y97W - 0.64 158 Y97F - 1.2 159 Y98W - 0.64 160 Y97F - 0.88 106 N100G 161 WlOOcY - 0.05 162 WlOOcF - 0.27 163 FlOOeY - 0.59 164 FlOlEw - 0.71 165 D101N - 0.64 166 S99G、N100G、SlOOaD、 YlOOb刪除 - 0.99 217 V102Y - 1.0 207 - H34Y O:\90\90156.DOC -83 ·
192 - Q89E 193 - ' Q89N 194 - Q90E 195 - Q90N 196 - W91Y 197 - W91F 205 - S92N 206 - S92G 198 - F93Y 199 - F93W 204 F93S 、 N94Y 200 - P96L 201 - P96Y 202 - P96W 203 - P96R 1335821 實例4 人源化作用架構區域取代作用之突變 亦測試具有2H7.V16背景變異體架構位置上其他另外殘 基的取代作用(係在人源化作用期間改變的)。明確言之,係 於VL(P46)及VH(G49,V71及K73)位置上產生既未發現於老 鼠2H7親本抗體亦未發現於人類一致性架構區域上的另一 種架構區域取代作用。 這些取代作用在相對鍵結上通常會導致小量的改變(表 6),此表示這些位置上的架構區域殘基具有某些彈性。 表6.以細胞-基礎(WIL2-S細胞)分析架構區域取代作用之 O:\90\90156.DOC -84- 1335821 相對鍵結。IgG變異體顯示具有與2H7.V16相關背景的突變 作用,相對鍵結係以2H7.V6.8嵌合體濃度比上需要相等鍵 結力之變異體濃度表示;因此,比例<1表示變異體具有較 弱的親和力;比例>1表示變異體的親和力較高。相對測定 值的標準偏差平均為+/-10%。相對2H7.V 16可變區域的架構 區域取代作用係根據Kabat編碼系統(Kabat等人,前述)。(*) 變異體係以2H7.V1 6為標準比較者分析之;相對的數值經與 該嵌合體之數值標準化。 2H7 變異體 重鍵 取代作用 輕鏈 取代作用 相對 鍵結 6.8 (嵌合體) (嵌合體) -1- 16 _ - 0.64 78 K73R - 0.72 79 K73H - 0.49 80 K73Q - 0.58 81 V71I 0.42 82 V71T 0.58 83 V71A 84 G49S - 0.32 85 G49L - 86 - P46E 0.22 87 - P46V 0.51 88 - P46T 108 G49A、V71T、K73R S92A、M32L、P46T 0.026* 109 G49A、A49G、V71T、 K73R S92A、M32L、P46T 0.026* O:\90\90156.DOC -85 · 110 K73R、D56A、N100A S92A ' M32L 未表現 111 G49A ' V71T ' K73R - 0.46* 112 G49A、A50G、V71T、 K73R - 0.12* (*)變異體係以2H7.V16為標準比較體分析之; 1335821 相對的數值經與該嵌合體的數值標準化。 實例5 具有較強效應子功能之人源化2H7變異鱧 因為經由補體-依賴性細胞毒性(CDC)及抗體-依賴性細 胞媒介細胞毒性(ADCC)兩者均可媒介溶解B-細胞,因此, 吾人欲探索具有較高CDC及ADCC活性之人源化2H7.vl 6變 異體。發生在Fc區域中的某些殘基之突變作用已揭示 (Idusogie 等人,J· /mwwnc»/· 166:2571-2575 (2001))可藉增強 鍵結至輛體成分Clq上,而增強CDC。業已揭示經由增強IgG 鍵結至活化Fey受體及減低IgG鍵結至抑制性Fey受體,以增 強 ADCC 之突變作用(Shields 等人,/ .&·〇/· Chem. 276: 6591-6604 (2001) ; Presta等人 ’ rraws·. 30:487-490 (2002))。明確言之,已經確定有三個突變作用可增進CDC 及 ADCC 活性:如所述 S298A/E333A/K334A(Idusogie等人, #遂(2001) ; Shields等人,#迷·)(本專利說明書亦稱為三丙 胺酸突變體或變異體;Fc上的編號係根據EU編號系統; Kabat等人,廣"遂)。 為了增強2H7的CDC及ADCC活性,構築2H7 Fc的三丙胺 酸突變異體。已經製備出具有S298A/E333A/K334A突變之 抗-HER2抗體4d5之人源化變異體,亦稱為4D5FcllO(換言 O:\90\90156.DOC -86- 1335821 之,抗-p185HER2 IgGl(S298A/E333A/K334A) ; Shields 等 人,#逑)。_編碼抗體4D5FcllO(Shields等人.,#避·)之質體 p4D5FcllO經dpal及消化後,將Fc片段(含有突變 S298A/E333A/K334A)接合至 2H7 重鏈-載體 pDR2-vl6 的 dpal/eki/III位置上,以產生pDR2-v3 1。完整的31變異體之 Η鏈胺基酸序列示於圖8中,而L鏈則與vl6變異體者相同。
雖然IgGl抗體的Fc區域的固定區域在某特定物種中相當 的保守,但是仍存有對偶基因變異(Lefranc及Lefranc總論, 於人類IgG亞型:結構分子分析、功能及調節,43-78頁, F· Shakib(出版),Pergammon印行,牛津(1990))。 表7. Fc區域的取代作用對CD20鍵結的效應。與CD20相對 鍵結力係以細胞-基礎(WIL2-S細胞)分析法測定架構區域 取代作用。Fc突變(*)係以EU編碼系統(Kabat,#述)所示, 並相對於2H7.V16親本抗體。v.31變異體的Fc區域上三個丙
胺酸改變的組合係以"Fcl 10”表示,IgG變異體顯示具有與 2H7.V16相關背景的突變作用,相對鍵結力係以2H7.V6.8嵌 合體濃度比上需要相等鍵結力之變異體濃度表示;因此, 比例<1表示變異體具有較弱的親和力。相對測定值的標準 偏差平均為+/-10%。 2H7 變異體 Fc 取代作用* 相對 鍵結 6.8 - -1- 16 - 0.65 31 S298A、E333A、K334A 0.62 O:\90\90156.DOC -87- 1335821 實例6 真有較高穩定性的人源化2H7變異想 為了開發治療性蛋白質’咸欲在有關氧化作用、去醯胺 作用或其他可以影響產物品質的流程上,選擇出於適當調 配物緩衝液中仍保有穩定性的變異體。在2H7.vl6中,已鑑 定出數種的殘基(VL(M32)及VH(M34、N100))可能是不穩定 性的來源。因此’在這些位置處引入突變以便與v 1 6變異體 比較。 表8.以細胞-基礎(WIL2-S細胞)分析用以增強穩定性及/ 或效應子功能之2H7變異體對CD20之相對鍵結力。IgG變異 體顯示具有與2H7,v 16相關背景的突變作用,相對鍵結力係 以2H7_v6.8敢合體濃度比上需要相等鍵結力之變異體濃度 表示;.因此,比例<1表示變異體具有較弱的親和力;比例 >1表示變異體的親和力較高。相對測定值的標準偏差平均 為+Λ10%。相對2H7.V16可變區域的架構區域取代作用係根 據Kabat編碼系統,而Fc突變(*)則係以Eu編碼系統所示 (Kabat等人’ #逑變異體係以2h7.v16為標準比較者 分析之;相對的數值經與該嵌合體之數值標準化。 額外的Fc突變與穩定性或增強親和力突變組合,以改變 或增強根據前所報導突變作用效應子功能(Idus〇gie等人 (2000),Idusogie等人,(2001) ; Shields 等人(2001))。這些 改變包括貫例5中所述的S298A、E333A、K334A ;降低CDC 活性的K322A,降低ADCC活性的D265A;增強CDC活性的 K326A或K326W ;及試驗Fc區域上同種異型變化效應的 O:\90\90I56.DOC •88, 1335821 E3 5 6D/M3 58L。這些突變在CD20鍵結親和力上均未造成明 顯的差異。- 2H7 變異體 重鏈(vH) 變化 輕鏈(Vl) 變化 Fc變化* 相對 鍵結 6.8 (嵌合體) (嵌合體) - -1- 16 - - - 0.65 62 - M32I 0.46 63 M34I - - 0.49 64 N100A - - 65 N100A L47W - 0.74 66 S99A L47W 一 0.62 67 N54A - 68 - M32I - 0.48 69 - M32L - 0.52 70 N100A - S298A、E333A、 K334A 0.80 71 N100D - S298A、E333A、 K334A 0.44 72 N100A M32I - 0.58 73 N100A M32L - 0.53 74 N100A M32I S298A、E333A、 K334A 0.61 75 N100A M32L S298A、E333A、 K334A 0.60 113 - - E356D、M358L 0.60** 114 D56A、N100A M32L、S92A S298A、E333A、 K334A 1.2** 115 D56A、N100A M32L、S92A S298A、E333A、 K334A、E356D、 M358L 1.4** O:\90\90156.DOC •89- 1335821 116 D56A、Ν100Α M32L、S92A S298A、Κ334Α、 Κ322Α 1.2** 134 D56A、Ν100Α M32L、S92A E356D、M358L、 D265A 1.5" 135 D56A、Ν100Α M32L > S92A E356D、M358L、 D265A ' K326W 0.95** 138 D56A、Ν100Α M32L ' S92A S298A、Ε333Α、 Κ334Α、Κ326Α 1.2** 139 D56A、Ν100Α M32L、S92A S298A、Ε333Α、 Κ334Α、Κ326Α、 Ε356Ν ' M358L 1.1" 154 - D265A 0.70** 155 - • S298A、Κ322Α、 Κ334Α 0.70**
(**)變異體係以2H7.V16為比較者測定之; 相對鍵結數值經與嵌合體數值標準化。
為了試驗穩定性突變對蛋白質分解速率的效應,將 2H7.V16及2H7.V73以濃度12-14毫克/毫升調酉己於10 mM組 胺酸、6%蔗糖、0.02%聚山梨醇20,pH 5.8中,並在40°C下 培養16天,而後將經培養的樣品經離子交換層析、凝集及 藉由分子量大小排除層析之分片作用後,分析變異體的變 化,並以細胞-基礎(WIL2-S)分析相對鍵結。 結果(圖9)顯示在加速穩定性條件下,以離子交換層析流 失主峰分液後,2H7.V73的穩定性較2Η7·ν16大。有關凝集、 分片作用或鍵結親和力並無明顯差異。 實例7 抗體鍵結至WIL2-S細胞上CD20的史氏分析 O:\90\90156.DOC -90- 1335821 利用放射性標記的2H7 IgG來測定2H7 IgG變異體鍵結至 WILLS細胞的平衡解離常數(Kd)。IgG變異體係在CHO細胞 中產生,Rituxan®(所有實驗的來源為Genentech,南三蕃 市,加州),而老鼠2H7(BD PharMingen,聖地牙哥,加州) 則用來與人源化變異體做比較。老鼠2H7抗體亦獲自其他來 源,例如:eBioscience及Calbiochem(兩者均位於聖地牙哥, 加州)、Accurate Chemical & Scientific 公司(威斯特柏利 城,紐約州)、Ancell(培伯特城,明尼蘇達州)及 Vinci-Biochem(文西城,義大利)。所有的稀釋均在鍵結分 析緩衝液(含有1%牛血清白蛋白、25 111]^1^?丑8卩1'17.2及 0.01°/。疊氮鈉之DMEM培養基)中進行。將濃度為0.8 nM的 125I-2H7.vl6(用乳酸過氧化酶進行碘化作用)分液(0.025毫 升)分裝至96槽孔V底的微量分析盤中,並加入連續稀釋的 冷抗體(0.05毫升)及混合,而後加入WIL2-S細胞(0.025毫升 有60,000個細胞),將微量分析盤封起來,置於室溫下培養 24小時,而後以3,500 RPM速度離心15分鐘,吸掉澄清液, 並清洗細胞沉澱物並離心,再次抽掉澄清液,將沉澱物溶 解於IN NaOH中,並移至試管中進行珈瑪計數。將數據利 用程式Ligand(McPherson,Compwr 17: 107-1 14 (1983))作史氏分析(Munson 及 Rodbard, Χπα/. 价oc/zew. 107:220-239 (1980))。結果(如表9所示)顯示,人 源化2H7變異體與老鼠2H7比較,具有相似的CD20鍵結親和 力,與Rituxan®具有相似的鍵結親和力。根據上述表7所述 的鍵結,咸預期2H7.V31與vl6具有非常相似的Kd。 O:\90\901S6.DOC -91 - 1335821 表9.以史氏分析之2H7變異體平衡鍵結親和力 抗體變異體 Kd(nM) η Rituxan 0.99 ±0.49 3 2H7(老鼠) 1.23 ± 0.29 3 2H7.vl6 0.84 ± 0.37 4 2H7.v73 1.22 ± 0.39 4 2H7.V75 1.09 士 0.17 4 實例8
補體依賴性細胞毒性(CDC)分析 本質地如(Idusogie 等人,《/· /所则如/ 164:4178-4184 (2000) ; Isusogie等人,J. /w则《〇/· 166:2571-2575 (2001))
所述’來分析2H7 IgG變異體媒介補體依賴性溶解wil2-S 細胞(.種表現C D 2 0淋巴母細胞B -細胞株)的能力。將〇 1毫 克/毫升的抗體儲備溶液以1 : 3稀釋比例進行連續稀釋。將 0.05毫升各稀釋度分液加至96槽孔的組織培養盤(内含〇 〇5 毫升正常人類補體(Quide卜聖地牙哥城,加州)的溶液)中, 在此混合物中’加入〇·05毫升體積内含5〇,〇〇〇個WIL2 S細 胞’置於37 C下培養2小時後,加入〇.〇5毫升的Alamar藍溶 液(Accumed International,威斯雷克城,俄亥俄州),並於 37°C下再連續培養18小時,取下培養盤的蓋子,於室溫下, 將培養盤置於圓形旋轉器上振盪15分鐘’利用53〇奈米激發 濾片及590奈米發射濾片讀取相對螢光單位(RFU),利用
KaleidaGraph軟體,將RFU對應各抗體濃度做繪出函數圖形 求出EC50。 O:\90\90156.DOC -92· 1335821 結果(表10)顯示,人源化2H7抗體在CDC上具有令人驚訝 的增加,v.73變‘異體的相對效價與Rituxan®相似,v.75變異 體則比Rituxan®高3倍,而ν·16比Rituxan®低3倍。 表10. 2H7與Rituxan的CDC活性比較。數值>1表示比 Rituxan®的CDC活性效價低,而數值<1則表示比Rituxan®的 CDC活性效價高。抗體係從穩定的CHO細胞株所產生的, 而以(*)表示者除外,其係為暫時性轉染細胞產生的抗體。 抗體變異體 η EC5〇(變異體)/EC5〇(Rituxan) Rituxan® 4 -1- 2H7.V16 4 3.72 ; 4.08 2H7.V31* 4 2.21 2H7.V73 4 1.05 2H7.v75 4 0.33 2H7.v96* 4 0.956 2H7.vll4* 4 0.378 2H7.V115* 4 0.475 2H7.V116* 1 >100 2H7.V135* 2 0.42 實例9 抗體依賴性細胞毒性(ADCC)分析 本質地如(Shields等人,J. Biol.Chem. 276:6591-6604 (2001))所述,以乳酸去氫酶(LDH)解析來分析2H7IgG變異 體媒介天然殺手細胞(NK細胞)溶解WIL2-S細胞(一種表現 O:\90\90I56.DOC -93· 1335821 CD20淋巴母細胞B -細胞株)的能力。從取自正常人類供體 (其對FcyRIli(亦‘稱為CD16)具有同種型)(Koene等人,价
90:1109-1114 (1997)之100毫升經肝素處理之血液中製備出 ΝΚ細胞,以100毫升PBS(磷酸緩衝鹽液)稀釋之。在此實驗 中,得自人類供體的ΝΚ細胞為CD16的異合體 (F158/V158)。將稀釋的血液舖層在15毫升的淋巴細胞分離 培養基(ICN Biochemical,奥羅拉城,俄亥俄州)上,並以 2000 RPM轉速離心20分鐘。將介於液層間的白血球分裝注 入至4支乾淨的50-毫升試管中,該試管中裝有内含15%胎牛 血清之RPMI培養基。試管以1400 RPM轉速離心5分鐘,並 丟棄澄清液,將沉澱物重新懸浮於MACS缓衝液(0.5% BSA、2 mM EDTA)中,而NK細胞係根據製造商的步驟 (Milten.yi Biotech)以小珠(NK細胞分離套組,130-046-502) 純化之。NK細胞在MACS緩衝液中稀釋至2x106個細胞/毫 升。
在96槽孔的圓底組織培養盤中加入溶於分析培養基 (F12/DMEM 50:50,不含甘胺酸、1 mM HEPES緩衝液pH 7.2、青黴素/鏈黴素(1〇〇單位/毫升;Gibco)、麩胺醯胺及1% 熱失活胎牛血清)之連續稀釋抗體(0.05毫升)。用分析緩衝 液將WIL2-S細胞稀釋成4xl〇5個細胞/毫升,將WIL2-S細胞 (每個槽孔0.05毫升)與96槽孔培養盤中的抗體混合,並在室 溫下培養30分鐘,使抗體可以鍵結至CD20上(調理作用)。 在每個槽孔中加入0.1毫升的NK細胞開始啟動ADCC反 應,控制組的槽孔中則加入Triton X-100,而後將培養盤置 O:\90\9OI56.DOC -94- 1335821 於37°C下培養4小時,利用細胞毒性(LDH)偵測套組(套組 #1644793,iloche Diagnostics,印第安納波里,印第安納 州),根據製造商的說明測定所釋放的LDH含量。在每個 槽孔中加入0.1毫升的顯色劑,而後混合10秒鐘,用鋁箔將 培養盤蓋上,於室溫暗室下培養1 5分鐘,後讀取490奈米處 的讀值,除以控制組槽孔中所測定的LDH值,求出溶解的 百分比。將溶解作用對應抗體濃度繪出函數圖形,並以4-參數曲線圖(KaleidaGraph)求出EC50濃度。 結果顯示,人源化2H7抗體在ADCC上具有活性,v.31及 v.75變異體的相對效價比Rituxan®高20倍,v.16變異體的效 價比Rituxan®高5倍,而v.73變異體的效價幾乎是Rituxan®4 倍。 表11’.根據η次的實驗結果,2H7抗體相較2H7.V16變異體 對WIL2-S細胞的ADCC活性之結果(數值>1表示比2H7.V16 的效價低,而數值<1則表示具有較高的效價) 抗體變異體 N EC50(變異體)/EC5Q(2H7.v16) Rituxan® 4 5.3 2H7.V16 5 1 2H7.V31 1 0.24 2H7.V73 5 1.4 2H7.V75 4 0.25 進行另外的ADCC分析,以比較2Η7組合式變異體與 Rituxan®。這些分析結果顯示,2H7.V114及2H7.vl 15之ADCC 效價比Rituxan®增加10倍以上(表12)。 O:\90\90156.DOC -95- 表12.根據η次的實驗結果,2H7抗體相較Rituxan®對 WIL2-S細胞的ADCC活性之結果(數值 >;[表示比Rituxan®的 效價低,而數值< 1則表示具有較高的效價) 抗體變異體 EC5〇(變異體)/EC50(Rituxan) Rituxan® 2 -1 - 2H7. v 1 6 2 0.52 2H7.v96 2 0.58 2H7.V114 2 0.093 2H7.vll5 2 0.083 2H7.V116 2 0.30 1335821 實例10 2H7變異體在食餐猴活體内試驗性研究中的效應 為評估2H7變異體(暫時轉染CH0細胞所產生者)在活體 内的活性,將其於正常雄性食蟹猴(Macaca /ascz.cw/arb)中 試驗之。其他抗_CO20抗體(諸如C2B8(Rituxan®》業已證明 在正常靈長動物中具有減損B_細胞的能力(Reff等人, 83:435-445 (1994)) ° 在一個研究中,比較人源化2H7變異體。在平行對等的研 究中’ Rituxan®亦在食蟹猴中進行試驗。在五組投藥中每一 組用了四隻猴子:(1)媒劑,(2)0.05毫克/公斤hu2H7.vl6, (3)10 毫克/公斤 hu2H7.vl6,(4)0.05 毫克/公斤 hu2H7.v31, 及(5)10毫克/公斤hu2H7 ν3ι。以靜脈内方式投與濃度為〇、 0.2或20毫克/毫升的抗體,在研究的第1天及第8天各施與1 O:\90V9OI56.DOC -96- 1335821 劑,共施與兩劑。投藥的首日定為天1,而前一日則定為天 _1’恢復的昔曰(每組有兩隻動物)定為天11。在天-19、-12、 1(投藥前)及首劑後第6小時、24小時及72小時後,收集血液 樣品’另外在天8(投藥前)、天1〇(殺死每組2隻動物前)及天 36及67(恢復動物)取出樣品。 利用計數CD3-/CD40+細胞的FACS方法來測定週邊B_: 胞展度。猴子樣品中總淋巴細胞的CD3-CD40+B細胞的百,
匕係利用下列的限制參數獲得。淋巴細胞群標記在向前: 描/側光掃描,以界定區域1(R1),利用R1的結果,螢光: 度點圖係為CD.40及CD3的標記,經螢光標記同種型控制〗 係用以測定CD40及CD3為陽性反應之相對臨界值點。 結果顯示,2H7.V16及2Η7·ν31兩者在1〇毫克/公斤濃度【 均能產·生完全的週邊細胞減損,而為〇〇5毫克/公斤濃』 時則為部份的B-細胞減損(圖〗丨)。此兩種抗體在投藥後的$ 72小時間所測定的時間點及Β_細胞減損程度相似,從恢名
的動物續後的分析顯示,經2H7v31處理的動物相較舍 2H7.V16處理者,顯示具有較長的Β·細胞減損時間,明確1 之,經以毫克/公斤2Η7.ν16處理後之恢復動物顯示,負 質上B'細胞恢復的時間點介於天1G及天%的取樣時間。教 而,經以10毫克/公斤2H7.v31處理之恢復細胞而士,一直 到天36及天67天間,其B•細胞並未顯示恢復。此推私 2Η7·ν3"^Η7.ν16的完全減損期間長約】個月。 不論低或高劑量均未在動物中發現毒性現象,且 病理是正常的。 正體的
O:\90\90I56.DOC •97- 1335821 以2H7.vl6對Rituxan®處理食蟹猴的數據推論減少5倍的 CDC活性不i有負面的影響效果。關於首次的灌注反應而 言,具有ADCC活性但較低CDC活性的抗體與具有較高的 CDC之抗體比較,其更具有利的安全性效果, 實例11 缺乏岩藻糖2H7變異抗體具有較強的效應子功能 將岩藻糖加至正常的CHO及HEK293細胞的IgG寡醣上至 -相當高的程度(97-98%),血清中的IgG亦相當高度岩藻糖 | 化。 -
使用DP12(缺.乏二氫葉酸還原酶(DHFR_)的CHO細胞株, 該細胞係可以進行岩藻糖化作用)及Lecl3(無法進行蛋白質 岩藻糖化作用的細胞株)來生產本研究用抗體。CHO細胞株 Pro-LeGl3.6a(Lecl3)得自猶太大學愛因斯坦醫學院的 Pamela Stanley教授,親本細胞株為Pro-(脯胺酸營養缺陷型) 及Gat-(甘胺酸、腺苷及胸腺嘧啶營養缺陷型)。CHO-DP12 細胞株係為CH0-K1細胞株(ATCC#CCL-61)的衍生株,其缺 乏二氫葉酸還原酶,且對胰島素需求較低。利用Super.fect 方法(Qiagen,瓦倫西亞城,加州)用cDNA轉染細胞株。利 用含有10微克/毫升嘌呤黴素二氯化氫(Calbiochem,聖地牙 哥城,加州)之生長培養基篩選出可表現轉染抗體之Lec 13 細胞,該生長培養基為:具有麩胺醯胺、核醣核苷及去氧 核醣核苷之MEM阿爾法培養基(GIBCO-BRL,蓋士堡城, 馬里蘭州),並添加10%失活FBS(GIBCO)、10 mM HEPES 及IX青黴素/鏈黴素(GIBCO)。以相似的方式在含有Ham's O:\90\90156.DOC -98- 1335821 FA12(沒有GHT)之生長培養基(即沒有甘胺酸、含有 NaHC03、添加 5% FBS(GIBCO)、10 mM HEPES、2 mM L-麩胺醯胺、IX GHT(甘胺酸、次黃嘌呤、胸腺嘧啶)及IX青 黴素/鏈黴素之低葡萄糖DMEM)來篩選CHO細胞 細胞群落會在兩至三週内形成,將其混在一起以便進行 細胞增幅及蛋白質表現。開始時將3χ 1 06個細胞混合液種植 ’ 於10公分的培養盤中,以小批次進行蛋白質表現。一旦細 · 胞生長至90-95%的滿度,則將細胞轉換至不含血清的培養 | 基中,且於3-5天後,收集細胞澄清液,並以Fc IgG-及完整 -的IgG-ELISA測試蛋白質表現量。在轉換至PS24生產培養 基(添加10毫克/升重組人類胰島素及1毫克/升微量元素)的 前一天,將大約8xl06個細胞之Lecl3及CHO細胞種植在15 公分的培養盤中。
將Lec 1 3細胞及DP 12細胞保持在不含血清的生產培養基 中3-5天,收集澄清液,並置於150毫升的錐底管中,以離 心方式淨化去除細胞及細胞殘渣。加入蛋白酶抑制劑PMSF 及抑肽酵素(Sigma,聖路易士城,蒙大拿州),在以蛋白質 G層析法(Amersham Pharmacia Biotech,匹兹卡特威城,紐 澤西州)進行純化作用之前,先利用MWCO30濾膜(Amicon ,比佛利城,麻薩諸塞州)將澄清液於攪拌槽中濃縮5倍, 利用Centripriep-30濃縮器(Amicon)將所有蛋白質的缓衝液 置換成磷酸缓衝鹽液(PBS),並以SDS-聚丙烯醯胺膠片電泳 法分析之。利用A280測定蛋白質濃度,並利用胺基酸組成 分析確認之。 O:\9O\90156.DOC 99· 1335821
CHO細胞經可表現人源化2Η7ν.16、2Η7ν·31之載體轉 染,並以上迹方'式篩選之。2H7v. 16抗體保留野生型的Fc區 域,而ν·31(參見前述實例5,表7)所具有的Fc區域其中有3 個胺基酸改變(S298A、E333A、K334A),其會導致對Fc r Rllla受體具有較高的親和力(Shields等人,J. Biol. Chem. 276(9):6591-6604 (2001))。經過轉染作用及篩選作用後, 分離個別的細胞群落,並評估蛋白質表現量,並將最高產 生量的細胞群落經甲氨蝶呤篩選,以篩選出經增幅質體拷 貝數量的細胞,經此可以生產出高量的抗體。培養細胞, 將細胞轉換至不含有血清的培養基中7天,而後收集培養 基,加至蛋白質A管柱上,利用標準技術沖堤抗體。利用測 定完整抗體的Elisa方法測定抗體的最終濃度,利用 Centrip.riep-30濃縮器(Amicon)將所有蛋白質的緩衝液轉換 成磷酸緩衝鹽液(PBS),並以SDS-聚丙烯醯胺膠片電泳法分 析之。
天冬胺酸-連結寡醣之基質輔助雷射脫附/游離飛行時間 曾分务:利用 Papac 等人,G/少(:〇6,_〇/〇忌少 8, 445-454 (1998)中所述的步驟釋放出重組醣蛋白中的N-連 結寡醣。簡而言之,以100微升曱醇將襯有PVDF的96槽孔 之微量盤(Millipore,比德福城,麻薩諸塞州)調整至良好狀 態,藉由對Millipore Multiscreen真空歧管抽取真空,將甲 醇經PDVF膜抽掉。用3x250微升的水清洗經調整的PVDF 膜。在所有的清洗步驟之間,對歧管輕輕施與抽真空來完 全抽掉槽孔中的水分。以由6 Μ胍氫氯酸、360 mM Tris、2 O:\90\90156.DOC -100- 1335821
mM EDTA,pH 8.6所組成之還原及缓基曱基化作用緩衝液 (RCM)清洗該膜’。在每個個別槽孔中加入醣蛋白樣品(50微 克),輕輕的抽真空經PVDF膜將其抽乾,並用2x50微升的 RCM緩衝液清洗槽孔。每個槽孔中加入50微升的0.1 Μ二硫 蘇糖醇(DTT)溶液以還原固定樣品,將微量盤置於37°C下培 養1小時。真空抽氣去除DTT,用4x250微升水清洗槽孔, 加入50微升的0.1 Μ碘乙酸(IAA)溶液(新鮮配製於1 MNaOH 中,並以RCM稀釋至0.1 Μ)將半胱胺酸羧基曱基化,培養 在暗室室溫下30分鐘後,完成羧基甲基化作用,對培養盤 施與真空抽氣去除ΙΑΑ溶液,並以4x250微升純水清洗槽 孔,添加100微升的1% PVP360(聚乙烯吡咯烷酮360,000分 子量)(Sigma)溶液,並置於室溫下培養1小時阻斷PVDF膜, 輕輕地抽真空去除PVP-360溶液,並以4x250微升水清洗槽 孔,每個槽孔中加入PNGaseF(NewEnlgandBiolabs,比佛 利城,麻薩諸塞州)消化溶液(溶於10 mM Tris乙酸,25微升 之25單位/毫升溶液),並於37°C下進行3小時消化作用。消 化後,將樣品移至500微升的離心小管中,每個樣品中加入 2.5微升之1.5 Μ乙酸溶液,酸化的樣品置於室溫下培養3小 時,以便將寡糖從糖苷胺轉換成羥基形式。在進行 MALDI-TOF質譜分析之前,利用0.7毫升厚床的陽離子交換 樹脂(氫型態的AG5〇W-X8樹脂)(Bio-Rad,赫丘力士城,加 州)混水裝載至緊密反應管柱(US Biochemical,克利夫蘭 城,俄亥俄州)中,以便將所釋放的寡醣去鹽化。 以陽性模式樣品的MALDI-TOF質譜分析而言,去鹽化寡 O:\90\90156.DOC -101 - 1335821 醣(〇·5微升分液)加至具有〇5微升2,5二羥基苯甲酸基質 (sDHB)(其‘將2毫克2,5二羥基苯甲酸與毫克的5_甲氧 基水楊酸溶解於體積比為1:1之丨毫升甲醇/1〇 mM氯化鈉混 合洛液中而製備的)不鏽鋼標的上。以真空來乾燥樣品/基質 混合物。以陰性模式的分析作用而言,將去鹽化N_連結寡 醣(〇·5微升分液)混與〇 5微升2,,4,,61_三羥基苯乙酮基質 (THAP)(以體積比為1:3之乙/13.3 mM檸檬酸銨緩衝液製 備之)施與不鏽鋼標的上。樣品/基質混合物經真空乾燥,而 後於分析前吸收大氣中的溼氣,於PerSeptive Bi〇Systems v〇yager-DE質譜儀上,以MALDI_T〇F分析所釋放的寡醣。 質譜儀係在20 kV下,以直線架構的陽性或陰性模式,並利 用延遲萃取方式進行操作。數據需要使用13〇〇雷射力量及 數據合計模式(240掃描),以改善對雜訊的訊號。用標準寡 醣的混合物來校正儀器,在指定質量之前,利用19點 Savitsky-Golay計算法求出最佳數據,利用caesar 7 〇數據分 析軟體套組(SciBridge軟體)完成質譜數據的積分。 天然殺手(NK)細胞抗體依賴性細胞毒性分析 一如實例9中所述者進行ADCc的分析。NK與標的細胞 (WIL2-S)的比例為4比卜分析進行4小時,毒性係以前所利 用的乳糖去氫酶分析法測定之。在添加胞之前,標的 細胞以所指濃度之抗體調理3〇分鐘,所用的Rituxan<g)為 Genentech(南二蕃市,加州)者。圖12所示為代表性adcc 分析的結果。 結果顯不,岩藻糖化程度較低之抗體與完全岩藻糖化之
O:\90\90I56.DOC -102· 1335821
抗體相較,其所媒介殺死NK細胞標的細胞上更為有效率。 在媒介殺死'標的細胞上,岩藻糖化程度較低的抗體, 2H7.V31,是最有效率的,此抗體在較低的濃度就有效果, 且其在較高濃度下與其他的抗體相較,所媒介殺死標的細 胞之能力具有較高的百分比。抗體的活性如下:Lec 13-衍 生2117.¥3 1>1^〇13衍生2117.¥16>0?12衍生2117.\^31>0卩12衍 生2H7.vl6>或=Rituxan。蛋白質及碳水化合物的改變具有 加成的效果,比較Lecl3-所產生的天然IgG及CHO-產生的 IgG上所發現的碳水化合物,發現半乳糖化作用的程度上並 無明顯的差異,因此,此結果只能歸因於岩藻糖的存在/缺 乏有關。 實例12
缺乏岩藻糖2H7變異體抗體在活體内具較高的ADCC
本實例係說明比較以Lec 13產生之缺少岩藻糖人源化2H7 變異體(包括v. 16及ν·31)與以DP 12產生之具正常岩藻糖化 對應部分在可以表現人類CD16[FcRyIII]及人類CD20之老 鼠中的ADCC活性。 產生 huCD20Tg+huCD16Tg + mCD16-’-老鼠 從人類CD20 BAC DNA(Invitrogen,卡斯柏城,加州)產 生人類CD20轉基因老鼠。先根據FACS分析筛選出能表現人 類CD20的老鼠,而後將huCD20Tg+老鼠與huCD16Tg+mCD16"· 老鼠交配,以產生huCD20Tg+huCD16Tg+mCD16·/-老鼠。 活體内處理方式 經由腹腔内注射法,投與huCD20Tg+huCD16Tg+mCD16-/- O:\90\90156.DOC -103 - 1335821 老鼠10至100微克之2H7變異體或Rituxan®。等量的同種型 相符的抗體以相似的方法投與陰性控制組的動物。 老鼠淋巴細胞的製備 根據"免疫學現今步驟,John Coligan,Ada Jruisbeek, David Margulies 出版,Ethan Shevach及 Warren Strober 印 行,1994”中所述的標準步驟,自老鼠的全血、胰臟、淋巴 結及骨髓中製備老鼠的淋巴細胞。
FACS分析法 清洗五十萬個細胞,並重新懸浮於100微升(其含有5微升 著色抗體或控制抗體)之FACS緩衝液中,該緩衝液為含有 1 % BSA的磷酸緩衝鹽液。所有的著色抗體(包括同種型抗 體控制組)係得自PharMingen,聖地牙哥城,加州。藉由與 Rituxan®及FITC-共軛抗-人類IgGl第二種抗體的染色作用 來評估人類CD20的表現作用。FACS分析法係以FACScan及
Cell Quest(Becton Dickinson Immunocytometry Systems > 聖 約瑟城,加州)進行的。所有的淋巴細胞均界定在向前及側 光的掃描面,而所有的B淋巴細胞則係指細胞表面上表現 B220 者。 動物注射後首週及其後的每週,利用FACS每日分析胰 臟、淋巴結及骨髓中週邊B細胞數目及分析hCD20+B細胞, 以評估B細胞減損及回復量。 此活體内分析的結果證實活體外的發現,即缺乏岩藻糖 2H7變異體比經相對醣化的野生型(係指岩藻糖化作用)具 有較高的ADCC活性及較大的B細胞減損。 O:\90\9OI56.DOC -104- 1335821 實例13 細胞凋零活性 業已證明抗-CD20抗體(包括Rituxan®)經另一抗體或化學 方式交錯連結後,可誘發活體外的細胞凋零(Shan等人, Blood 9:1644-1652 (1998) ; Byrd等人,Blood 99:1038-43 (2002) ; Pederson等人,Blood 99:1314-19 (2002))。當以化 學方式交錯連結時,老鼠2H7雙體可誘發Daudi細胞的細胞 调零(Ghetie 等人,Proc Natl Acad Sci USA 94:7509-14 (1997))。老鼠2H7抗體與另一抗體交錯連結後亦可誘發細 胞凋零(Shan等人,1998)。咸信這些活性是與生理學上具有 關聯性的,因為許多的機制會導致活體内抗-CD20抗體鍵結 至細胞表面CD20上之交錯連結。 利用另一種交錯連結的抗體,在活體外以細胞凋零分析 法來比較rhuMAb 2H7.V16[人源化2H7.vl6 ; rhuMAb代表重 組性人類單株抗體]及Rituxan®。用一種可表現CD20的人類 B淋巴細胞株(Ramos細胞,CRL-1 596,ATCC,馬納薩斯城, 佛吉尼亞州)經由膜聯蛋白V及碘化丙啶染劑排放方法 (Vybrant®,細胞;周零分析套組,Molecular Probes,西雅圖 城,華盛頓州)來測量抗-CD20單株抗體rhuMAb 2Η7·ν16及 利特西馬(Rituximab)相較陰性控制組抗體-特茲如馬 (Trastuzumab)(Herceptin®,Genentech,南三蕃市,加州) 誘發細胞凋零的能力。將Ramos細胞培養在含有1 0%胎牛血 清(Biosource International ’卡馬利歐城,加州)及2 mM麵胺 酸胺(Gibco)之RMI-1 640培養基(Gibco,洛克菲洛,馬里蘭 O:\90\90156.DOC -105- 1335821 州)中,在進行分析之前,以新鮮的培養基清洗細胞兩次, 並將細胞濃度調整至每毫升為2><106個,將細胞(15〇微升) 加至含有150微升混有F(ab),2山羊抗_人類Fc抗體 Biotechnology ’羅克福德城,伊利諾州)之事先定量之控制 IgG1、rhuMAb 2H7.V16,或利特西馬之96槽孔的分析盤 (Becton Dickinson,帕洛阿爾托城,加州卜最終lgG濃度為 100、10、1.0、0.1、〇.01及〇 001 nM,而 F(ab),U 羊抗人 類Fc抗體的濃度則為個別樣品抗體濃度的兩倍。每個稀釋 度進行三重複。在37°C下培養24小時後,用PBS清洗細胞兩 次,而後根據製.造商的建議說明以膜聯蛋白v及碘化丙啶染 色,用FACscan流動細胞儀(Bect〇n Dickinson,聖約瑟城, 加州)以流動細胞學來分析Ram〇s細胞的染色型態,而收集 10秒段的數據,利用 CellqUest Pr〇軟體(Bect〇n Dickins〇n) 推導據數。計算(1)膜聯蛋白v染色、(2)膜聯蛋白v及碘化 丙咬雙重染色為陽性反應的Ranios細胞,及(3)未經染色之 /舌細胞數目’並以KaleidaGraph軟體(協同軟體,雷丁城, 賓夕法尼亞州)繪圖。 相較與不相關的IgGl控制抗體交錯連結,當rhuMAb 2H7.V16及利特西馬兩者與抗_人類以抗體交錯連結後均可 誘發Ramos細胞的細胞凋零(圖13_15)。rhuMAb 2H7的細胞 >周零活性稿微比利特西馬低。當交錯連結rhuMAb 2H7、利 特西馬及控制IgGl抗體濃度為1〇 nM時,經膜聯蛋白V染色 細胞部分分別為18.5、16.5、2.5%,經雙重標記的細胞部分 為29、38及16。/。,而每丨0秒鐘所計算的活細胞則為5200、
O.'SO'SOlSe.DOC -106- 1335821 3100及 8600 〇 這些活體 '外的數據證明細胞凋零係造成活體内Β細胞減 損的一種可能機制。活體内rhuMAb 2Η7或利特西馬交錯連 結鍵結至細胞表面CD20上可能係經由免疫效應子細胞表 面上的FcyR發生的。 實例14 活體内抑制腫瘤生長 在Balb/c裸鼠(無胸腺)中評估rhUMAb 2H7.V16抑制Raji人 類B-細胞(淋巴瘤細胞株(ATcc CCL 86))的生長能力。Raji 細胞能表現CD20,其經報導可在裸鼠中生長,產生轉移性 的疾病;且Rituxan®可抑制腫瘤生長(ciynes等人,jVaiwre 6’ 4M-446 (2000))。將 56 隻 8-10週大的 Balb/C裸 鼠分為.7組(A-G) ’每組由8隻老鼠組成。在第〇天時,每隻 老鼠以皮下注射方式於側腹接受5χ1〇6個Raji B_淋巴瘤細 胞。在第0天開始時,每隻老鼠分別接受1〇〇微升的陰性控 制組溶液(PBS ;磷酸緩衝液)、Rituxan®或2H7 vi6,劑量端 視體重而定,並經尾巴靜脈以靜脈内方式傳送藥劑。A組老 鼠接受PBS ’ B-D組老鼠分別接受5〇毫克/公斤、〇·5毫克/ =斤及〇.〇5毫克/公斤的Rituxa,,E_G組老鼠分別接受5 〇 宅以公斤、0.5毫克/公斤及〇〇5毫克/公斤的2H7 vi6,每週 重複注射共達6週。㈣期間於每週間隔時以觸診方式檢查 ^隻老^在注射位置處所存在之腫瘤,倘若有腫瘤的存 & :測減紀錄腫瘤的體積。最後的檢查是在第8週(未治 療後兩週間隔)。
O:\90\90I56.DOC -107- 1335821 此研究的結果顯示rhuMAb 2H7.v 16及Rituxan®在抑制裸 鼠皮下Raji-細胞腫瘤生長是有效果的(圖16-18)。PBS控制 組開始於第4週時發現腫瘤生長,然而,在研究8週期間經 以5亳克/公斤及0.5毫克/公斤的Rituxan®或2H7.vl6處理者 均未發現有腫瘤的生長,以低劑量0.05毫克/公斤處理組 中,在2H7組中有一隻動物及在Rituxan®組中有一隻動物發 現腫瘤(圖18)。
實例15 選殖食蟹猴CD2〇及抗體鍵結
從食蟹猴胰臟cDNA庫中分離出編碼CD20的cDNA,測定 食蟹狼(Macaca fascicularis)CD20 DNA之序列。將 cDNA合 成及質體選殖之SUPERSCRIPT™質體系統(目錄編號 # 1 8248-013,Invitrogen,卡斯柏城,加州)稍做改良來構築 核酸庫,利用限制酶切割位置Xho I-及Not I,將cDNA庫接 合至pRK5E載體上。從胰臟組織中分離出mRNA(加州區域 研究靈長動物中心,戴維斯,加州)。根據人類CD20的非編 碼序列設計出用以增幅編碼CD20的cDNA的引子,利用聚合 酶鏈反應(PCR),使用N-端區域引子5'-AGTTTTGAGAGCAAAATG-3' 及C-端區域引子5'-AAGCTATGAACACTAATG-3'選殖編碼 食蟹猴CD20的cDNA。根據製造商的建議(Gibco,洛克菲洛 城,馬里蘭州),使用鉑Taq DNA高忠誠度之聚合酶進行PCR 反應,將PCR產物次選殖至pCR®2_l-TOPO®載體(Invitrogen) 中,並轉型至XL-1藍色大腸桿菌(Stratagene,拉霍亞城, 加州)中,從個別選殖體中分離出含有經接合PCR產物之質 O:\90\90I56.DOC -108- 1335821 體DNA,並定序之。 食蟹猴CD—20胺基酸序列示於圖19中,圖20為食蟹猴與人 類CD20的比較,食蟹猴CD20中有97.3%與人類〇〇20相似, 而有8處不同’胞外區域含有一個變異(在vi 57A),而其餘7 個殘基係在細胞質或穿膜區域中發現。 分析對抗人類CD20之抗體於鍵結及取代可鍵結至能表 現CD20之食蟹狼之FITC-共輛老鼠2H7的能力。從2隻食蟹 猴(加州區域研究靈長動物中心’戴維斯,加州)抽取2〇毫升 的企液’混與肝素鈉’並直接運送至Genentech公司。同一 天,將血液樣品倒在一起,並添加4〇毫升的碌酸緩衝液(pBs) 以1:1稀釋之。將20毫升的稀釋血液分層累積於2〇毫升飛克 爾-沛克溶液襯墊(Ficoll-PaqueTM Plus)之50毫升錐底管(目 錄編號#352098,Falcon,福蘭克林湖城,新澤西州)中(共 進行了 4管)’並於室溫下’於s〇rvai 7離心機(杜邦,新城, 康乃迪格州)以1300 rpm的轉速離心3〇分鐘。分離pBMC 層,並於PBS中清洗。將紅血球細胞在〇 2q/。NaC1溶液中溶 解,用等體積的1.6% NaCl溶液使其恢復成等張性,並以 1 000 RPM的轉速離心1 〇分鐘。將pBMC沉澱物重新懸浮於 内含5%胎牛血清(FBS)之RPMI 1640(Gibco,洛克菲洛市, 馬里蘭州)中,並配散至直徑1〇公分的組織培養盤中丨小時 (37 C下)’以抽取方式去除未吸附的Β&τ細胞群,離心及 計异數目,共回收2.4x1 〇7個細胞。將重新懸浮的pBMC分 散在2〇支12><75毫米的培養試管(目錄編號#352〇53,Faic〇n) 中,每支試管於0.25毫升含有lxl〇6個細胞,將這些培養試
O:\90\90156.DOC •109- 1335821
管分成四組,每組5支試管,每一組分別加入培養基(RPMI 1640,5%胎丰血*清)、定量之控制人類]^〇1抗體、1^1;11乂311®、 2117^16或2117^31,每種抗體的最終濃度為30、10、3.3及 1.1 nM,除此之外,每支培養試管中另加20微升的經螢光 異硫氰酸(?1丁(:)共軛之抗-人類€〇20(目錄編號#5 55622,8〇 Bioscience,聖地牙哥,加州)。細胞經溫和地混合後,培 養在冰上1小時,而後用冷的PBS清洗兩次,於Epic XL-MCL(Coulter,邁阿密,佛羅里達州)分析細胞表面的染 色,推導出幾何平均值,針對抗體濃度畫出函數圖形 (KaleidaGraphTM,協同軟體,雷丁城,賓夕法尼亞州)。
圖21中的數據顯示2H7.V16及2H7.V31可以競爭性方式取 代FITC-老鼠2H7與食蟹猴細胞的鍵結,除此之外,Ritumax® 亦可取.代FITC-老鼠2H7鍵結,因此證明2H7及Ritumax®兩 者可鍵結至CD20上的重疊抗原決定子,另外,該數據顯示 2Η7.ν16、2Η7·ν31 及 Ritumax 的 IC5〇 數值相近,且落在 4-6nM
範圍内。 結論 上述數據證明製備人源化CD20鍵結抗體(特別是人源化 2H7抗體變異體)是成功的,該抗體仍保有其生物特性,甚 至是更為增強。可鍵結至CD20之本發明人源化2H7抗體在 親和力方面與老鼠供體抗體及嵌合性2H7抗體相似,且可有 效的殺死靈長動物中的B細胞,而導致B細胞的減損。某些 變異體顯示具有比現今用以治療NHL的嵌合性抗-CD20抗 體為高之ADCC,此有利病患使用較低劑量之治療抗體,除 O:\90\90156.DOC -110- 1335821 此之外’為了預防對抗具有老鼠FR.基之嵌合性抗體的抗 體反應,故所投用之嵌合性抗體必須達到完全B細胞減損的 劑量,而本發明人源化抗體則可投與達到部分或完全B細胞 減損之劑量,及根據特定疾病及病患所需在不同的時間投 藥,另外,這些抗體業經證明在溶液中係穩定的。這些人 源化2H7抗體的特性使得這些抗體成為治療CD2〇陽性癌症 及自體免疫疾病的理想免疫治療劑;這些抗體預期在人體 疋不具有免疫抗原特性的,或至少比全長的老鼠抗體或嵌 合性抗-CD20抗體之免疫抗原性低。 參考文獻 本申請案中所列舉的參考文獻,包括專利案、公開發表 申請案及其他出版刊物,一併併入本專利說明書參考。
除非另有所指’本發明實務係採用屬於技藝中技能之分 子生物學及類似科學之慣用技術,該等技術在文獻中均有 3羊盡的說明’參見’例如,分子選殖:實驗室手冊(J. Sambrook等人,冷泉灣實驗室,冷泉灣,紐約,1989);全 子生物學現今步驟(F.Ausuhel答人出版,1987再版); 分子生物學(T. Brown出版,IRX印行1991);基因袅規枯街 (Goeddel出版,學院印行1991);真核細胞篡因撰碚方法乃 基因分析(A.Bothwell算人出版,Bartlett印行1990);基且^ 轉及表現(M. Kriegler Stockton印行1990);重|且DNA方法學 II(R.Wu等人出版,學院印行1995) ; PCR :實務 # & (M.McPherson等人,IRL印行,牛津大學印行1991) ; % ^ 苷酸合成作用(M.Gait出版,1984);生物化學定之細晌接養 O:\90\90156.DOC -111 - 1335821
(R.Adam出版,Elsevier科學出版社1990);哺乳動物細胞之 基因移轉載it(7.Miller & M.Calos出版,1987);哺乳動物 細胞生物技術(M.Butler出版,1991);動物細胞培卷 (J.Pollard等人出版,人類出版社印行1990);培養動物細胞 第二版(R.Freshnev箄人出版,Alan R.Liss 1987);流動細胞 學及分類(M.Melamed算人出版,Wiley-Liss 1990);酵素學 叢刊(學院印行);Wirth Μ及Hauser H.(1993);實務免癌化 學,第三版,A·Johnstone & R. Thorpe, Blackwell科學,康 橋,麻塞諸塞州,1996 ;免疫細胞化學技術(G. Bullock & P.Petrusz 出版,學院印行 1982、1983、1985、1989);實驗 免疫學手冊(D. Weir & C.Blackwell出版);免疫學現今步驟 (J. Coligan等人出版 1991);免,痛分析法(E.P. Diamandis & T.K. Christopoulos 出版,學院印行 1996) ; Goding (1986)單 株抗體:原理及實務(第二版)學院印行,紐約;Ed Harlow 及David Lane,抗體A實驗窒手冊,冷泉灣實驗室,冷泉灣, 紐約,1988 ;抗體工程,第二版(C. Borrebaeck出版,牛津 大學印行,1995);及免疫年度評論叢刊;免疫學進階叢刊。 【圖示簡單說明】 圖1A為老鼠2H7(SEQ ID N0.1)、人源化2H7.V16變異體 (SEQ ID N0.2)及人類卡巴〇 )亞塑輕鏈I(SEQ ID N0.3)之 輕鏈可變區域(VL)的胺基酸排列比較。2H7及hu2H7_vl6的 VL之 CDRs如下:CDR1(SEQ ID N0.4)、CDR2(SEQ ID NO.5) 及 CDR3(SEQ ID ΝΟ·6)。 圖IB為老鼠2H7(SEQ ID N0.7)、人源化2H7.vl6變異體 O:\90\90156.DOC -112- 1335821 (SEQIDN0.8)及人類重鏈亞型III一致性序列(SEQIDN09) 之VH序列的'序列排列比較。2H7及hu2H7.vl6的VH之CDRs 如下:CDR1(SEQ ID NO.IO)、CDR2(SEQ ID N0.11)及 CDR3(SEQ ID N0.12)。 在圖1A及圖IB中,每個鏈中的CDIU、CDR2及CDR3係於 括弧中,兩旁為所示的FR1-FR4架構區域。2H7表示老鼠2H7 * 抗體。兩排序列間的星號是指兩個序列不同處。殘基的編 * 號係根據Kabat等人,免疫學感興趣之序列,第五版,公共 | 衛生院,國家健康局,畢士大,馬里蘭州,1991,插頁a、 -b、c、d及e戶斤示0 圖2所示為構築2H7 Fab質體(參見實例1)所用之嗜菌質體 pVX4之序列(SEQ ID N0.13),及CDR-移植抗-IFN-α人源化 抗體之ϊ?ab之L鏈(SEQIDN0.14)及H鏈(SEQIDN0.15)之胺 基酸序列。
圖3所示為編碼嵌合性2H7.v6.8 Fab之表現質體之序列 (SEQIDNO·16)。並顯示L鏈(SEQIDNO·17)及H鏈(SEQID N0.18)之胺基酸序列。 圖4所示為用以表現實例1所述之免疫球蛋白輕鏈之質體 pDRl之序列(SEQ ID N0.19 ; 5391鹼基對)。pDRl含有編碼 不相關抗體之序列(人源化抗-CD3抗體之輕鏈(Shalaby等 人,J. Exp. Med. 175:217-225 (1992)),其起始密碼及終止 密碼以粗體及底線表不之。 圖5所示為用以表現實例1所述之免疫球蛋白重鏈之質體 ?〇112之序列(8£(511)>1〇.20;6135鹼基對)。?〇尺2含有編碼 O:\9Cft90156.DOC -113- 1335821
不相關抗體之序列(人源化抗_CD3抗體之輕鏈(Shalaby等 人,必7廣")’其起始密碼及終止密碼以粗體及底線表不之。 圖6所示為2H7.V16完整L鏈的胺基酸序列(SEQ ID N0.21) 〇 圖7所示為2H7.V16完整Η鏈的胺基酸序列(SEQ ID N0.22)。將圖1B(SEQIDN0.8)的VH序列與完整的Η鏈序列 排列比較,人類γ 1固定區域係位於SEQ ID NO.22的胺基酸 位置 114-471。 圖8所示為2H7.v3 1完整Η鏈的胺基酸序列(SEQ ID N0.23) ’ L鏈與2H7.V16者相同(參見圖6)。 圖9所示為2Η7·ν16與2H7.v73 IgG變異體的相對穩定 性,分析結果經與培養前的數值標準化,且係以培養後所 剩餘之百分比報告。 圖10所示為從老鼠2H7胺基酸改變成一群人源化變異體 (至v75變異體)之流程綜合圖。 圖11如實例10中所述’所有實驗組(2H7研究組及Rituxan 研究)之平均絕對B-細胞數目總合[CD3-/CD40+]。 圖12係以實例丨丨所述,以缺乏岩藻糖2H7變異體進行之代 表性ADCC分析結果。 圖13為聯膜蛋白γ染色結果相對抗體濃度所做函數圖 形。Ramos細胞在有交錯連結的另一個抗體存在下,以不相 關IgGl控制組抗體(Hereeptin@;圓形)、利特西馬抗體(方 形)或rhuMAb 2H7.vl6(二角形)處理,並以FACS分析之。圖 13 -1 5於實例13中說明。
O:\90\90156.DOC -114-
Claims (1)
- 2135563號專利申請案 申請專利範圍替換本(99年8月) 拾、申請專利範圍:^年f月0曰修正本 1. 一種人源化抗體,其結合人類CD20且包含SEQ ID N0:8 之VH序列及SEQIDN0:2之VL序列。 2. 如請求項1之人源化抗體,其包含分別為SEQ ID NO:39及 40之重鏈及輕鏈胺基酸序列。 3. 如請求項1之人源化抗體,其包含分別為SEQ ID ΝΟ.·41及 40之重鏈及輕鏈胺基酸序列。 4. 如請求項1之人源化抗體,其包含分別為SEQ ID ΝΟ:39及 40之重鏈及輕鏈胺基酸序列,且另外包含在Fc區域之至 少一個可增進抗體-依賴性細胞媒介細胞毒性(ADCC)及/ 或補體-依賴性細胞毒性(CDC)活性之胺基酸取代。 5. 如請求項4之人源化抗體,其中該胺基酸取代為 S298A/E333A/K334A。 6. 如請求項4之人源化抗體,其中在Fc區域之胺基酸取代增 進CDC活性。 7. 如請求項6之人源化抗體,其中該胺基酸取代為K326A或 K326W。 8. 如請求項5之人源化抗體,其中在Fc另外包含K326A胺基 酸取代。 9. 如請求項1之人源化抗體,其包含分別為SEQ ID NO:39及 40之重鏈及輕鏈胺基酸序列,且另外包含在Fc區域之至 少一個可降低CDC活性之胺基酸取代。 10. 如請求項9之人源化抗體,其中該胺基酸取代為K322 A。 11. 如請求項1至1 〇中任一項之人源化抗體,其結合至細胞毒 90156-990823.doc 12. 如凊求項11之人源化抗體,其中細胞毒性劑為放射性活 性同位素或毒素。 13. 14. 15. 16. 17. 18. 19. —種如請求項1至1 〇中任一項之人源化抗體之抗原結合 片段。 如請求項13之抗原結合片段,其結合至細胞毒性劑上。 如請求項14之抗原結合片段,其中細胞毒性劑為放射性 活性同位素或毒素。 —種醫藥組合物,其包含如請求項1至12中任一項之抗體 或如請求項1 3至1 5中任一項之抗原結合片段以及醫藥學 上可接受之載劑。 種製造產品,其包括容器及其内含的組合物,其中該 組合物包含如請求項丨至12中任一項之抗體或如請求項 1 3至1 5中任一項之抗原結合片段。 T 4求項17之製造產σ口口,其另外包括以說明該組合物 可用於治療非-何傑金氏淋巴瘤及/或自體免疫疾病之包 裝仿單。 如晴求項18之製造產品,其中該自體免疫疾病係選自由 以下所組成之群:類風濕性關節炎、青少年類風濕性關 節炎、全身性紅斑性狼瘡(SLE)、狼瘡腎臟炎、潰癌性結 腸炎、瑋格納氏疾病、發炎性腸疾病、特發性▲小板低 下紫斑症(m>)、血检性血小板低下紫斑症(ττρ)、自體免 板減少、多發性硬皮症、牛皮癬、IgA腎病變、IgM 多毛性神經病變、重症肌無力、i管炎、繼A也管炎、 90156-990823.doc 1335821 固體器官移植排斥、移植物對抗宿主疾病、糖尿病、雷 諾氏症候、修格連氏症候及腎絲球腎炎。 20. —種核酸’其編碼如請求項1至丨〇中任一項之抗體或如請 求項13之抗原結合片段。 21. —種表現載體,其包含如請求項2〇之核酸。 22. —種宿主細胞’其包含編碼如請求項1至1〇中任一項之抗 體或如請求項13之抗原結合片段之核酸。 23. 如請求項22之宿主細胞,其為CHO細胞。 24. —種製造人源化抗體或抗原結合片段之方法,包含培養 產生如請求項1至1〇中任一項之抗體或如請求項13之抗 原結合片段之宿主細胞’及自細胞培養物中回收抗體或 抗原結合片段。 25. —種抗體,其係利用包含下述步驟之方法所製造:於宿 主細胞中表現編碼分別包含SEQ ID NO:39及40之重鏈及 輕鏈胺基酸序列之抗體之核酸,及回收該宿主細胞表現 之抗體。 26· —種如請求項1至12中任一項之抗體或如請求項13至15 中任一項之抗原結合片段之用途,其係用於製造誘發活 體内B細胞凋零作用之藥物,該藥物藉由使B細胞與抗體 或抗原結合片段接觸反應以殺死B細胞。 27. —種如請求項1至12中任一項之抗體或如請求項13至15 中任一項之抗原結合片段之用途,其係用於製造用於治 療CD20陽性癌症之藥物。 28·如請求項27之用途,其中該CD20陽性癌症為B細胞淋巴 90156-990823.doc 1^^5821 瘤或白血症。 29·如清求項28之用途’其中該CD20陽性癌症為非-何傑金氏 淋巴瘤(NHL)或淋巴球優勢何傑金氏疾 病(LPHD)。 3〇·如睛求項27之用途’其中該CD2〇陽性癌症為慢性淋巴細 月^ !·生白血病或小淋巴細胞性淋巴瘤(sll)。 .如句求項28之用途’其中該藥物係用於提供約25〇mg/m2 至約400 mg/m2之劑量範圍。 32. 如請求項28之用途,其中該藥物係用於提供約275mg/m2 至約375 mg/m2之劑量範圍。 33. 如清求項28之用途其中該藥物係供服用以提供至少兩 劑量’母劑量375 mg/m2之抗體。 34. 如咕求項33之用途’其中該藥物係用於提供間隔兩週服 用之兩劑量。 3 5.如6月求項28之用途,其中該藥物係用於與至少一種化療 劑一起服用。 36.如吻求項3 5之用途,其中該癌症為非-何傑金氏淋巴瘤 (NHL)且該化療劑係選自由杜瑟陸賓辛(d〇x〇rubicin)、環 % 胺(cyclophosphamide)、威利司汀(vincristine)、去氫 可體醇(prednisol〇ne)及CHOP所組成之群。 3 7· —種如請求項i至12中任一項之抗體或如請求項13至15 中任—項之抗原結合片段之用途,其係用於製造治療自 體免疫疾病之藥物。 38·如請求項37之用途’其中該自體免疫疾病係選自由以下 所組成之群:類風濕性關節炎、青少年類風濕性關節炎、 90156-990823.doc 1335821 全身性紅斑性狼瘡(SLE)、狼瘡腎臟炎、潰癌性結腸炎、 瑋格納氏疾病、發炎性腸疾病、特發性血小板低下紫斑 症(ITP)、錄性血小板低下紫斑症(ττρ)、自體免疫盘小 板減少、多發性硬皮症、牛皮癖、IgA腎病變、IgM多發 性神經病變、重症肌無力、血管炎、ANCA血管炎、固體 器官移植排斥、移植物對抗宿主疾病、糖尿病、雷諾氏 症候、修格連氏症候及腎絲球腎炎。 39. 如請求項38之用途’其中該自體免疫疾病為類風濕性關 即炎。 40. 如請求項38之用途’其中該自體免疫疾病為多發性硬化 症。 41·如請求項39之用途,其中該自體免疫疾病為輕度至重度 類風溼性關節炎,且對於至少一種疾病修飾抗風溼性藥 劑有抗性。 42. 如請求項39之用途,其中該藥物係用於與第二種治療劑 一起服用。 43. 如請求項42之用途,其中該第二種治療劑為免疫抑制劑。 44. 如請求項43之用途,其中免疫抑制劑為甲胺喋呤 (methotrexate)。 45. 如請求項37之用途’其中該藥物係經調配以供靜脈内輸 注。 46_如請求項37之用途,其中該藥物係經調配以供皮下施用。 47. —種人源化抗體,其結合人類cd2〇且包含分別為SEqID NO:42及43之重鏈及輕鏈胺基酸序列。 90156-990823.doc 1335821 48. —種人源化抗體,其結合人類CD20且包含SEQ ID N〇:51 之VH序列及SEQIDNO:52之VL序列。 49. 如請求項48之人源化抗體,其中該抗體包含分別為SEQ ID NO:44及45之重鏈及輕鏈胺基酸序列。 50. —種人源化抗體,其結合人類CD20且包含SEQ ID NO:51 之VH序列及SEQIDNO:53之VL序列。 51. 如請求項50之人源化抗體,其中該抗體包含分別為SEQ ID NO:46及47之重鏈及輕鏈胺基酸序列。5 2.如請求項50之人源化抗體,其中該抗體包含分別為SEQ ID NO:48及47之重鏈及輕鏈胺基酸序列。 53. 如請求項50之人源化抗體,其中該抗體包含分別為SEQ ID NO:49及47之重鏈及輕鏈胺基酸序列。 54. 如請求項50之人源化抗體,其中該抗體包含分別為SEQ ID NO:50及47之重鏈及輕鏈胺基酸序列。 5 5.如請求項50之人源化抗體,其中VH區域接合至人類IgG重 鏈固定區域上。 56. 如請求項55之人源化抗體,其中人類IgG為IgGl或IgG3。 57. 如請求項55之人源化抗體,其中人類IgG為IgGl。 58. 如請求項55之人源化抗體,其中人類IgG為IgGl,且IgGl Fc區域包括S298A/E333A/K334A之胺基酸取代。 59. —種如請求項47至58中任一項之人源化抗體之抗原結合 片段。 60. —種醫藥組合物,其包含如請求項47至58中任一項之人 源化抗體或如請求項59之抗原結合片段以及醫藥學上可 90156-990823.doc -6- 1335821 接受之载劑。 61. —種核酸,其編碼如請求項47至58中任一項之抗體或如 請求項59之抗原結合片段。 62. 種表現載體’其包含編碼如請求項1至1〇中任一項之抗 體或如清求項13之抗原結合片段之核酸。 63. —種宿主細胞,其包含編碼如請求項”至^中任一項之 抗體或如請求項59之抗原結合片段之核酸。 64·如請求項63之宿主細胞,其為CHO細胞。 65. —種製造抗體或抗原結合片段之方法,包含培養可產生 如請求項4 7至5 8中任一項之抗體或如請求項5 9之抗原結 合片段之宿主細胞,及自細胞培養物中回收抗體。 66_ —種抗體’其係利用包含下述步驟之方法所製造:於宿 主細胞中表現編碼如清求項3及4 7至5 8中任一項之抗體 之核酸’及回收該宿主細胞表現之抗體。 90156-990823.doc
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US43411502P | 2002-12-16 | 2002-12-16 | |
US52616303P | 2003-12-01 | 2003-12-01 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200501982A TW200501982A (en) | 2005-01-16 |
TWI335821B true TWI335821B (en) | 2011-01-11 |
Family
ID=32685285
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW092135563A TWI335821B (en) | 2002-12-16 | 2003-12-16 | Immunoglobulin variants and uses thereof |
TW098128310A TW201000132A (en) | 2002-12-16 | 2003-12-16 | Immunoglobulin variants and uses thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW098128310A TW201000132A (en) | 2002-12-16 | 2003-12-16 | Immunoglobulin variants and uses thereof |
Country Status (35)
Country | Link |
---|---|
US (7) | US7799900B2 (zh) |
EP (5) | EP1944320A1 (zh) |
JP (3) | JP4351674B2 (zh) |
KR (2) | KR20070055625A (zh) |
CN (1) | CN103833854B (zh) |
AR (3) | AR042485A1 (zh) |
AT (1) | ATE470675T1 (zh) |
AU (1) | AU2003301079C1 (zh) |
BE (1) | BE2018C021I2 (zh) |
BR (2) | BRPI0316779B1 (zh) |
CA (1) | CA2507898C (zh) |
CL (1) | CL2008003323A1 (zh) |
CR (2) | CR7875A (zh) |
CY (2) | CY1110759T1 (zh) |
DE (1) | DE60332957D1 (zh) |
DK (2) | DK1572744T3 (zh) |
ES (2) | ES2347241T3 (zh) |
FR (1) | FR18C1023I2 (zh) |
HK (2) | HK1074208A1 (zh) |
HR (1) | HRP20050649B1 (zh) |
HU (3) | HUE035898T2 (zh) |
IL (2) | IL168754A (zh) |
MA (1) | MA27704A1 (zh) |
MX (1) | MXPA05006511A (zh) |
NO (1) | NO338402B1 (zh) |
NZ (1) | NZ566907A (zh) |
PL (1) | PL212899B1 (zh) |
PT (1) | PT1572744E (zh) |
RS (2) | RS51318B (zh) |
RU (1) | RU2326127C2 (zh) |
SG (1) | SG2013036975A (zh) |
SI (2) | SI2289936T1 (zh) |
TW (2) | TWI335821B (zh) |
UA (1) | UA89350C2 (zh) |
WO (1) | WO2004056312A2 (zh) |
Families Citing this family (981)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ258392A (en) | 1992-11-13 | 1997-09-22 | Idec Pharma Corp | Chimeric and radiolabelled antibodies to the b lymphocyte cellsurface antigen bp35 (cd-20) and their use in the treatment of b cell lymphona |
US7744877B2 (en) | 1992-11-13 | 2010-06-29 | Biogen Idec Inc. | Expression and use of anti-CD20 Antibodies |
CN1320044A (zh) | 1998-08-11 | 2001-10-31 | Idec药物公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
ES2543819T3 (es) | 1998-11-09 | 2015-08-24 | Biogen Inc. | Tratamiento de neoplasias hematológicas asociadas con células tumorales circulantes utilizando anticuerpo quimérico dirigido contra CD20 |
MY155913A (en) * | 1998-11-09 | 2015-12-15 | Biogen Inc | Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transpants |
US7183387B1 (en) | 1999-01-15 | 2007-02-27 | Genentech, Inc. | Polypeptide variants with altered effector function |
EP1642596A3 (en) * | 1999-05-07 | 2006-04-12 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to B cell surface markers |
PL201086B1 (pl) * | 1999-07-12 | 2009-03-31 | Genentech Inc | Zastosowanie przeciwciał wiążących się z antygenem CD20 |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
KR20040023565A (ko) * | 2000-09-18 | 2004-03-18 | 아이덱 파마슈티칼즈 코포레이션 | B 세포 고갈/면역조절 항체 조합을 이용한 자가면역질환의 치료를 위한 조합 요법 |
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
MXPA04003798A (es) * | 2001-10-25 | 2004-07-30 | Genentech Inc | Composiciones de glicoproteina. |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
US7662925B2 (en) | 2002-03-01 | 2010-02-16 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US8188231B2 (en) | 2002-09-27 | 2012-05-29 | Xencor, Inc. | Optimized FC variants |
US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
JP2006512891A (ja) * | 2002-04-18 | 2006-04-20 | ジェネンコー・インターナショナル・インク | 糸状菌における機能性抗体の生産 |
BRPI0316779B1 (pt) | 2002-12-16 | 2020-04-28 | Genentech Inc | anticorpo humanizado que liga cd20 humano, composição, artigo manufaturado, método de indução da apoptose, método de tratamento de câncer cd20 positivo, métodos de tratamento de doenças autoimunes, ácidos nucléicos isolados, vetores de expressão, células hospedeiras, método para a produção de um anticorpo 2h7 humanizado, polipeptídeo isolado, formulação líquida, método de tratamento de artrite reumatóide (ra) e anticorpos de ligação de cd20 humanizados |
US8388955B2 (en) | 2003-03-03 | 2013-03-05 | Xencor, Inc. | Fc variants |
US20090010920A1 (en) | 2003-03-03 | 2009-01-08 | Xencor, Inc. | Fc Variants Having Decreased Affinity for FcyRIIb |
US8084582B2 (en) | 2003-03-03 | 2011-12-27 | Xencor, Inc. | Optimized anti-CD20 monoclonal antibodies having Fc variants |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
JP2006522811A (ja) * | 2003-04-09 | 2006-10-05 | ジェネンテック・インコーポレーテッド | TNFαインヒビターに対して不十分な反応を示す患者の自己免疫疾患治療法 |
US9051373B2 (en) | 2003-05-02 | 2015-06-09 | Xencor, Inc. | Optimized Fc variants |
ES2538469T3 (es) * | 2003-06-05 | 2015-06-22 | Genentech, Inc. | Terapia de combinación para trastornos de células B |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US8883147B2 (en) | 2004-10-21 | 2014-11-11 | Xencor, Inc. | Immunoglobulins insertions, deletions, and substitutions |
US8399618B2 (en) | 2004-10-21 | 2013-03-19 | Xencor, Inc. | Immunoglobulin insertions, deletions, and substitutions |
SI2380911T1 (en) | 2003-11-05 | 2018-07-31 | Roche Glycart Ag | ANTIGEN-RELATED PATIENTS WITH INCREASED ATTENTION ON THE RECEPTOR FC AND EFFECTORAL FUNCTION |
WO2005063815A2 (en) * | 2003-11-12 | 2005-07-14 | Biogen Idec Ma Inc. | Fcϝ receptor-binding polypeptide variants and methods related thereto |
SV2006002131A (es) * | 2004-06-04 | 2006-01-26 | Genentech Inc | Uso de un anticuerpo para el tratamiento de lupus |
EP3130349A1 (en) * | 2004-06-04 | 2017-02-15 | Genentech, Inc. | Method for treating multiple sclerosis |
JP2008504289A (ja) * | 2004-06-25 | 2008-02-14 | メディミューン,インコーポレーテッド | 部位特異的突然変異誘発による哺乳動物細胞における組換え抗体の産生の増加 |
WO2006085967A2 (en) * | 2004-07-09 | 2006-08-17 | Xencor, Inc. | OPTIMIZED ANTI-CD20 MONOCONAL ANTIBODIES HAVING Fc VARIANTS |
US20150010550A1 (en) | 2004-07-15 | 2015-01-08 | Xencor, Inc. | OPTIMIZED Fc VARIANTS |
WO2006012508A2 (en) * | 2004-07-22 | 2006-02-02 | Genentech, Inc. | Method of treating sjögren's syndrome |
EP1776384B1 (en) | 2004-08-04 | 2013-06-05 | Mentrik Biotech, LLC | Variant fc regions |
AU2005285347A1 (en) * | 2004-08-19 | 2006-03-23 | Genentech, Inc. | Polypeptide variants with altered effector function |
CN101087807A (zh) * | 2004-10-05 | 2007-12-12 | 健泰科生物技术公司 | 治疗血管炎的方法 |
TW200630106A (en) * | 2004-10-08 | 2006-09-01 | Wyeth Corp | Immunotherapy of autoimmune disorders |
JO3000B1 (ar) * | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
US8546543B2 (en) | 2004-11-12 | 2013-10-01 | Xencor, Inc. | Fc variants that extend antibody half-life |
US8367805B2 (en) | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
CN102746404B (zh) | 2004-11-12 | 2016-01-20 | 赞科股份有限公司 | 对FcRn的结合被改变的Fc变体 |
US8802820B2 (en) | 2004-11-12 | 2014-08-12 | Xencor, Inc. | Fc variants with altered binding to FcRn |
FR2879204B1 (fr) | 2004-12-15 | 2007-02-16 | Lab Francais Du Fractionnement | Anticorps cytotoxique dirige contre les proliferations hematopoietiques lymphoides de type b. |
EP1831258B2 (en) | 2004-12-28 | 2023-06-07 | Innate Pharma S.A. | Monoclonal antibodies against nkg2a |
ZA200705459B (en) * | 2005-01-13 | 2008-09-25 | Genentech Inc | Treatment method |
DOP2006000029A (es) * | 2005-02-07 | 2006-08-15 | Genentech Inc | Antibody variants and uses thereof. (variantes de un anticuerpo y usos de las mismas) |
TW200714289A (en) * | 2005-02-28 | 2007-04-16 | Genentech Inc | Treatment of bone disorders |
AR053579A1 (es) * | 2005-04-15 | 2007-05-09 | Genentech Inc | Tratamiento de la enfermedad inflamatoria intestinal (eii) |
WO2006114700A2 (en) * | 2005-04-26 | 2006-11-02 | Bioren, Inc. | Method of producing human igg antibodies with enhanced effector functions |
JP2008541758A (ja) * | 2005-06-02 | 2008-11-27 | アストラゼネカ エービー | Cd20に対する抗体およびその使用 |
EP1912675B1 (en) | 2005-07-25 | 2014-02-12 | Emergent Product Development Seattle, LLC | B-cell reduction using cd37-specific and cd20-specific binding molecules |
AU2006281978A1 (en) * | 2005-08-12 | 2007-02-22 | Garvan Institute Of Medical Research | Phrophylactic and/or therapeutic method for treatment of autoimmune disease |
US7612181B2 (en) | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP1931709B1 (en) | 2005-10-03 | 2016-12-07 | Xencor, Inc. | Fc variants with optimized fc receptor binding properties |
CA2625998C (en) | 2005-10-06 | 2015-12-01 | Xencor, Inc. | Optimized anti-cd30 antibodies |
EP1940881B1 (en) * | 2005-10-11 | 2016-11-30 | Amgen Research (Munich) GmbH | Compositions comprising cross-species-specific antibodies and uses thereof |
MY149159A (en) * | 2005-11-15 | 2013-07-31 | Hoffmann La Roche | Method for treating joint damage |
AU2006318539B2 (en) | 2005-11-23 | 2012-09-13 | Genentech, Inc. | Methods and compositions related to B cell assays |
CA2631961A1 (en) | 2005-12-02 | 2007-11-08 | Genentech, Inc. | Compositions and methods for the treatment of diseases and disorders associated with cytokine signaling relating to antibodies that bind to il-22 |
ES2526204T3 (es) | 2006-01-05 | 2015-01-08 | Genentech, Inc. | Anticuerpos anti-EphB4 y métodos para usar los mismos |
ZA200806187B (en) | 2006-01-20 | 2009-10-28 | Genentech Inc | Anti-EphrinB2 antibodies and methods using same |
AR059851A1 (es) | 2006-03-16 | 2008-04-30 | Genentech Inc | Anticuerpos de la egfl7 y metodos de uso |
TWI523864B (zh) | 2006-05-30 | 2016-03-01 | 建南德克公司 | 抗體及免疫接合物及其用途 |
JP2009539384A (ja) | 2006-06-06 | 2009-11-19 | ジェネンテック・インコーポレーテッド | 抗dll4抗体および抗dll4抗体使用の方法 |
FR2902799B1 (fr) | 2006-06-27 | 2012-10-26 | Millipore Corp | Procede et unite de preparation d'un echantillon pour l'analyse microbiologique d'un liquide |
EP2038306B1 (en) | 2006-06-30 | 2014-12-03 | Novo Nordisk A/S | Anti-nkg2a antibodies and uses thereof |
JP5605895B2 (ja) | 2006-07-04 | 2014-10-15 | ゲンマブ エー/エス | Copdを処置するためのcd20結合分子 |
EP1878747A1 (en) | 2006-07-11 | 2008-01-16 | greenovation Biotech GmbH | Glyco-engineered antibodies |
WO2008008482A2 (en) * | 2006-07-13 | 2008-01-17 | Genentech, Inc. | Altered br3-binding polypeptides |
CA2657934C (en) | 2006-07-19 | 2017-04-04 | The Trustees Of The University Of Pennsylvania | Wsx-1/p28 as a target for anti-inflammatory responses |
AU2007285976B2 (en) | 2006-08-14 | 2011-08-18 | Xencor, Inc | Optimized antibodies that target CD19 |
WO2008034076A2 (en) * | 2006-09-15 | 2008-03-20 | The Johns Hopkins University | Cyclophosphamide in combination with immune therapeutics |
CA2660795C (en) | 2006-09-18 | 2014-11-18 | Xencor, Inc. | Optimized antibodies that target hm1.24 |
KR20090078349A (ko) | 2006-10-12 | 2009-07-17 | 제넨테크, 인크. | 림포톡신-알파에 대한 항체 |
PT2061814E (pt) | 2006-10-27 | 2012-09-10 | Genentech Inc | Anticorpos e imunoconjugados e suas utilizações |
PT2662091T (pt) | 2006-12-01 | 2018-12-03 | Novartis Ag | Anticorpos anti-p-selectina e métodos para os utilizar no tratamento de doenças inflamatórias |
US8362217B2 (en) | 2006-12-21 | 2013-01-29 | Emd Millipore Corporation | Purification of proteins |
US8163886B2 (en) | 2006-12-21 | 2012-04-24 | Emd Millipore Corporation | Purification of proteins |
US8569464B2 (en) | 2006-12-21 | 2013-10-29 | Emd Millipore Corporation | Purification of proteins |
MX2009007632A (es) | 2007-01-22 | 2009-07-24 | Genentech Inc | Precipitacion de polielectrolito y purificacion de proteinas. |
RU2009133784A (ru) | 2007-02-09 | 2011-03-20 | Дженентек, Инк. (Us) | АНТИ-Robo4-АНТИТЕЛА И ИХ ПРИМЕНЕНИЯ |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
PE20090321A1 (es) | 2007-06-04 | 2009-04-20 | Genentech Inc | Anticuerpos anti-notch1 nrr, metodo de preparacion y composicion farmaceutica |
SI2158315T1 (sl) * | 2007-06-25 | 2016-05-31 | Esbatech, An Alcon Biomedical Research Unit Llc | Postopki za spreminjanje protiteles in spremenjena protitelesa z izboljšanimi funkcionalnimi lastnostmi |
JP5500730B2 (ja) * | 2007-09-13 | 2014-05-21 | デレネックス セラピューティクス アーゲー | β−アミロイドペプチドに対するヒト化抗体 |
GB0718684D0 (en) * | 2007-09-24 | 2007-10-31 | Roche Products Ltd | Treatment method |
ES2687808T3 (es) | 2007-09-26 | 2018-10-29 | Chugai Seiyaku Kabushiki Kaisha | Región constante de anticuerpo modificado |
US20090098118A1 (en) | 2007-10-15 | 2009-04-16 | Thomas Friess | Combination therapy of a type ii anti-cd20 antibody with an anti-bcl-2 active agent |
EP2211903A4 (en) | 2007-10-17 | 2011-07-06 | Nuvelo Inc | CLL-1 ANTIBODY |
HUE037409T2 (hu) | 2007-10-30 | 2018-08-28 | Genentech Inc | Antitest-tisztítás kationcserés kromatográfiával |
KR20160129099A (ko) | 2007-11-07 | 2016-11-08 | 제넨테크, 인크. | 미생물 질환의 치료를 위한 조성물 및 방법 |
TWI580694B (zh) | 2007-11-30 | 2017-05-01 | 建南德克公司 | 抗-vegf抗體 |
PL2235059T3 (pl) | 2007-12-26 | 2015-08-31 | Xencor Inc | Warianty FC o zmodyfikowanym wiązaniu do FCRN |
JP5774312B2 (ja) | 2008-01-24 | 2015-09-09 | ノボ・ノルデイスク・エー/エス | ヒト化抗ヒトnkg2aモノクローナル抗体 |
TWI489994B (zh) | 2008-03-17 | 2015-07-01 | Baxter Healthcare Sa | 供免疫球蛋白及玻尿酸酶之皮下投藥之用的組合及方法 |
AR072947A1 (es) * | 2008-03-25 | 2010-10-06 | Glycart Biotechnology Ag | Terapia de combinacion de un anticuerpo anti-cd20 de tipo ii con citotoxicidad, celular dependiente de anticuerpos (ccda) aumentada, composicion farmaceutica, anticuerpo anti-cd20 de tipo ii |
JP6013733B2 (ja) | 2008-04-11 | 2016-10-25 | エマージェント プロダクト デベロップメント シアトル, エルエルシー | Cd37免疫治療薬および二機能性化学療法薬とのその組合せ |
US20100260668A1 (en) * | 2008-04-29 | 2010-10-14 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
KR20110014607A (ko) * | 2008-04-29 | 2011-02-11 | 아보트 러보러터리즈 | 이원 가변 도메인 면역글로불린 및 이의 용도 |
UY31861A (es) * | 2008-06-03 | 2010-01-05 | Abbott Lab | Inmunoglobulina con dominio variable dual y usos de la misma |
MX2010013239A (es) * | 2008-06-03 | 2011-02-24 | Abbott Lab | Inmunoglobulinas de dominio variable doble y usos de las mismas. |
WO2009151514A1 (en) | 2008-06-11 | 2009-12-17 | Millipore Corporation | Stirred tank bioreactor |
MX2010014574A (es) * | 2008-07-08 | 2011-04-27 | Abbott Lab | Inmunoglobulinas de dominio variable dual para prostaglandina e2 y usos de las mismas. |
ES2442024T3 (es) | 2008-07-15 | 2014-02-07 | Academia Sinica | Matrices de glucano sobre portaobjetos de vidrio revestidos con aluminio de tipo PTFE y métodos relacionados |
WO2010019148A1 (en) | 2008-08-14 | 2010-02-18 | Genentech, Inc. | Methods for removing a contaminant using indigenous protein displacement ion exchange membrane chromatography |
CN103599541A (zh) | 2008-09-10 | 2014-02-26 | 弗·哈夫曼-拉罗切有限公司 | 用于防止蛋白质氧化降解的组合物和方法 |
TW201014605A (en) | 2008-09-16 | 2010-04-16 | Genentech Inc | Methods for treating progressive multiple sclerosis |
SG195558A1 (en) | 2008-10-14 | 2013-12-30 | Genentech Inc | Immunoglobulin variants and uses thereof |
RU2011124527A (ru) * | 2008-11-17 | 2012-12-27 | Дженентек, Инк. | Способ и композиция для уменьшения агрегации макромолекулы в физиологических условиях |
EA022752B1 (ru) | 2008-12-09 | 2016-02-29 | Галозим, Инк. | Длинные растворимые полипептиды рн20 и их использование |
EP2370561B1 (en) | 2008-12-16 | 2019-08-07 | EMD Millipore Corporation | Stirred tank reactor and method |
SG172219A1 (en) | 2008-12-17 | 2011-07-28 | Genentech Inc | Hepatitis c virus combination therapy |
WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
CN102264759B (zh) | 2008-12-23 | 2016-05-11 | 弗·哈夫曼-拉罗切有限公司 | 与蛋白a的结合改变的免疫球蛋白变体 |
MX2011008611A (es) * | 2009-02-16 | 2011-10-21 | Biolex Therapeutics Inc | Anticuerpos anti-cd20 humanizados y metodos de uso. |
US8435488B2 (en) | 2009-02-27 | 2013-05-07 | Genentech, Inc. | Methods and compositions for protein labelling |
MY152068A (en) | 2009-03-20 | 2014-08-15 | Genentech Inc | Bispecific anti-her antibodies |
BRPI1006448B1 (pt) | 2009-03-25 | 2021-08-17 | Genentech, Inc | Anticorpo antagonista anti-fgfr3, anticorpo monoclonal, polinucleotídeo, vetor, microorganismo transgênico, método para produção de um anticorpo anti-fgfr3, formulação farmacêutica e usos do anticorpo antagonista anti-fgfr3 |
PE20120770A1 (es) | 2009-03-25 | 2012-07-10 | Genentech Inc | ANTICUERPOS ANTI alfa5ß1 CON ACTIVIDAD SOBRE GLIOBLASTOMAS |
AR075982A1 (es) | 2009-03-31 | 2011-05-11 | Roche Glycart Ag | Terapia de combinacion de un anticuerpo afucosilado y una o mas de las citoquinas seleccionadas de gm- csf humano, m -csf humano y/o il-3 humano y composicion |
EP2417156B1 (en) | 2009-04-07 | 2015-02-11 | Roche Glycart AG | Trivalent, bispecific antibodies |
EP2427479B1 (en) * | 2009-05-07 | 2018-11-21 | The Regents of The University of California | Antibodies and methods of use thereof |
EP2430153A4 (en) * | 2009-05-13 | 2013-02-27 | Gliknik Inc | PROCESS FOR USE OF IMMOBILIZATION LOBULIN COMPLEXES |
WO2010138184A2 (en) * | 2009-05-27 | 2010-12-02 | Synageva Biopharma Corp. | Avian derived antibodies |
US9676845B2 (en) | 2009-06-16 | 2017-06-13 | Hoffmann-La Roche, Inc. | Bispecific antigen binding proteins |
US20100316639A1 (en) | 2009-06-16 | 2010-12-16 | Genentech, Inc. | Biomarkers for igf-1r inhibitor therapy |
AR077595A1 (es) | 2009-07-27 | 2011-09-07 | Genentech Inc | Tratamientos de combinacion |
UY32808A (es) * | 2009-07-29 | 2011-02-28 | Abbott Lab | Inmunoglobulinas como dominio variable dual y usos de las mismas |
ES2513292T3 (es) | 2009-07-31 | 2014-10-24 | Genentech, Inc. | Inhibición de metástasis tumoral usando anticuerpos anti-G-CSF |
SG178322A1 (en) | 2009-08-14 | 2012-03-29 | Roche Glycart Ag | Combination therapy of an afucosylated cd20 antibody with fludarabine and/or mitoxantrone |
TWI409079B (zh) | 2009-08-14 | 2013-09-21 | Roche Glycart Ag | 非典型岩藻醣化cd20抗體與苯達莫斯汀(bendamustine)之組合療法 |
UY32870A (es) * | 2009-09-01 | 2011-02-28 | Abbott Lab | Inmunoglobulinas con dominio variable dual y usos de las mismas |
US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
DK2473522T3 (en) | 2009-09-02 | 2016-11-28 | Genentech Inc | Smoothened MUTANT AND METHODS OF USING THE SAME |
CN107385034B (zh) | 2009-09-03 | 2021-08-17 | 弗·哈夫曼-拉罗切有限公司 | 用于治疗、诊断和监控类风湿性关节炎的方法 |
AR078161A1 (es) | 2009-09-11 | 2011-10-19 | Hoffmann La Roche | Formulaciones farmaceuticas muy concentradas de un anticuerpo anti cd20. uso de la formulacion. metodo de tratamiento. |
IN2012DN01663A (zh) | 2009-09-16 | 2015-06-05 | Immunomedics Inc | |
JP5734985B2 (ja) | 2009-09-17 | 2015-06-17 | バクスター・ヘルスケヤー・ソシエテ・アノニムBaxter Healthcare SA | ヒアルロニダーゼおよび免疫グロブリンの安定な共製剤およびそれらの使用方法 |
RU2012119756A (ru) * | 2009-10-15 | 2013-11-20 | Эбботт Лэборетриз | Иммуноглобулины с двумя вариабельными доменами и их применение |
EP2491059B1 (en) | 2009-10-22 | 2015-02-25 | F.Hoffmann-La Roche Ag | Anti-hepsin antibodies and methods using same |
WO2011056502A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Bone morphogenetic protein receptor type ii compositions and methods of use |
WO2011056494A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor-like kinase-1 antagonist and vegfr3 antagonist combinations |
WO2011056497A1 (en) | 2009-10-26 | 2011-05-12 | Genentech, Inc. | Activin receptor type iib compositions and methods of use |
UY32979A (es) | 2009-10-28 | 2011-02-28 | Abbott Lab | Inmunoglobulinas con dominio variable dual y usos de las mismas |
WO2011056997A1 (en) | 2009-11-04 | 2011-05-12 | Fabrus Llc | Methods for affinity maturation-based antibody optimization |
US8361744B2 (en) | 2009-11-05 | 2013-01-29 | Genentech, Inc. | Methods and composition for secretion of heterologous polypeptides |
CA2782004A1 (en) | 2009-11-30 | 2011-06-03 | Biotest Ag | Humanized anti-il-10 antibodies for the treatment of systemic lupus erythematosus (sle) |
BR112012013330A2 (pt) | 2009-12-02 | 2017-03-28 | Acceleron Pharma Inc | composições e métodos para aumentar meia vida do soro de proteínas de fusão fc |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
TWI505836B (zh) | 2009-12-11 | 2015-11-01 | Genentech Inc | 抗-vegf-c抗體及其使用方法 |
AR079704A1 (es) | 2009-12-23 | 2012-02-15 | Genentech Inc | Anticuerpos anti-bv8 y sus usos |
WO2011091078A2 (en) | 2010-01-19 | 2011-07-28 | Xencor, Inc. | Antibody fc variants with enhanced complement activity |
CN102933231B (zh) | 2010-02-10 | 2015-07-29 | 伊缪诺金公司 | Cd20抗体及其用途 |
WO2011101328A2 (en) | 2010-02-18 | 2011-08-25 | Roche Glycart Ag | Treatment with a humanized igg class anti egfr antibody and an antibody against insulin like growth factor 1 receptor |
CN102892779B (zh) | 2010-02-18 | 2016-12-21 | 基因泰克公司 | 神经调节蛋白拮抗剂及其在治疗癌症中的用途 |
CN106983862A (zh) | 2010-03-22 | 2017-07-28 | 弗·哈夫曼-拉罗切有限公司 | 对于稳定含有蛋白质的制剂有用的组合物和方法 |
KR101899835B1 (ko) | 2010-03-24 | 2018-09-19 | 제넨테크, 인크. | 항-lrp6 항체 |
WO2011123813A2 (en) | 2010-04-02 | 2011-10-06 | Amunix Operating Inc. | Binding fusion proteins, binding fusion protein-drug conjugates, xten-drug conjugates and methods of making and using same |
WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
MX342590B (es) | 2010-04-27 | 2016-10-05 | Roche Glycart Ag | Terapia de combinacion de un anticuerpo cd20 afucosilado con un inhibidor mtor. |
MX2012012743A (es) | 2010-05-03 | 2012-11-23 | Genentech Inc | Composiciones y metodos utiles para reducir la viscosidad de formulaciones que contienen proteina. |
KR101745386B1 (ko) | 2010-05-10 | 2017-06-09 | 아카데미아 시니카 | 항-인플루엔자 활성을 가진 자나미비르 포스포네이트 동족체 및 인플루엔자 바이러스의 오셀타미비르 감수성을 확인하는 방법 |
UY33386A (es) | 2010-05-14 | 2011-12-30 | Abbott Laboratoires | Proteínas de unión a il-1 |
US8691918B2 (en) | 2010-05-17 | 2014-04-08 | Emd Millipore Corporation | Stimulus responsive polymers for the purification of biomolecules |
WO2011147834A1 (en) | 2010-05-26 | 2011-12-01 | Roche Glycart Ag | Antibodies against cd19 and uses thereof |
NZ602840A (en) | 2010-06-03 | 2014-11-28 | Genentech Inc | Immuno-pet imaging of antibodies and immunoconjugates and uses therefor |
CA2794731C (en) | 2010-06-18 | 2019-03-19 | Genentech, Inc. | Anti-axl antibodies and methods of use |
WO2011161119A1 (en) | 2010-06-22 | 2011-12-29 | F. Hoffmann-La Roche Ag | Antibodies against insulin-like growth factor i receptor and uses thereof |
WO2011161189A1 (en) | 2010-06-24 | 2011-12-29 | F. Hoffmann-La Roche Ag | Anti-hepsin antibodies and methods of use |
KR101924653B1 (ko) | 2010-06-24 | 2018-12-03 | 제넨테크, 인크. | 단백질-함유 제제를 안정화시키기 위한 알킬글리코시드 함유 조성물 및 방법 |
WO2012006503A1 (en) | 2010-07-09 | 2012-01-12 | Genentech, Inc. | Anti-neuropilin antibodies and methods of use |
WO2012010582A1 (en) | 2010-07-21 | 2012-01-26 | Roche Glycart Ag | Anti-cxcr5 antibodies and methods of use |
CA2806252C (en) | 2010-07-29 | 2019-05-14 | Xencor, Inc. | Antibodies with modified isoelectric points |
TW201206473A (en) | 2010-08-03 | 2012-02-16 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
RU2013106216A (ru) | 2010-08-03 | 2014-09-10 | Ф. Хоффманн-Ля Рош Аг | Биомаркеры хронической лимфоцитарной лейкемии |
JP2013541937A (ja) | 2010-08-05 | 2013-11-21 | エフ.ホフマン−ラ ロシュ アーゲー | 抗mhc抗体−抗ウイルス性サイトカイン融合タンパク質 |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
RU2584597C2 (ru) | 2010-08-13 | 2016-05-20 | Рош Гликарт Аг | Антитела против а2 тенасцина с и способы их применения |
LT2603530T (lt) | 2010-08-13 | 2018-01-25 | Roche Glycart Ag | Anti-fap antikūnai ir jų naudojimo metodai |
TW201208703A (en) | 2010-08-17 | 2012-03-01 | Roche Glycart Ag | Combination therapy of an afucosylated CD20 antibody with an anti-VEGF antibody |
AR082518A1 (es) | 2010-08-25 | 2012-12-12 | Hoffmann La Roche | Anticuerpos contra il-18r1 y usos de los mismos |
JP2013539364A (ja) | 2010-08-26 | 2013-10-24 | アッヴィ・インコーポレイテッド | 二重可変ドメイン免疫グロブリンおよびその使用 |
DK2612151T3 (en) | 2010-08-31 | 2017-10-02 | Genentech Inc | BIOMARKETS AND METHODS OF TREATMENT |
WO2012045082A2 (en) | 2010-10-01 | 2012-04-05 | Jason Schrum | Engineered nucleic acids and methods of use thereof |
US8481680B2 (en) | 2010-10-05 | 2013-07-09 | Genentech, Inc. | Mutant smoothened and methods of using the same |
KR20200059320A (ko) | 2010-11-08 | 2020-05-28 | 제넨테크, 인크. | 피하 투여용 항―il―6 수용체 항체 |
ES2607086T3 (es) | 2010-11-10 | 2017-03-29 | F. Hoffmann-La Roche Ag | Métodos y composiciones para la inmunoterapia de enfermedades neuronales |
CN112168962A (zh) | 2010-12-16 | 2021-01-05 | 弗·哈夫曼-拉罗切有限公司 | 与th2抑制相关的诊断和治疗 |
EP2651976A1 (en) | 2010-12-16 | 2013-10-23 | Roche Glycart AG | Combination therapy of an afucosylated cd20 antibody with a mdm2 inhibitor |
KR20140014116A (ko) | 2010-12-20 | 2014-02-05 | 제넨테크, 인크. | 항-메소텔린 항체 및 면역접합체 |
AU2011348232A1 (en) | 2010-12-22 | 2013-07-18 | Genentech, Inc. | Anti-PCSK9 antibodies and methods of use |
WO2012092539A2 (en) | 2010-12-31 | 2012-07-05 | Takeda Pharmaceutical Company Limited | Antibodies to dll4 and uses thereof |
EP2482074A1 (en) * | 2011-01-27 | 2012-08-01 | Medizinische Hochschule Hannover | Methods and means for diagnosing vasculitis |
US10689447B2 (en) | 2011-02-04 | 2020-06-23 | Genentech, Inc. | Fc variants and methods for their production |
US20120258073A1 (en) | 2011-02-10 | 2012-10-11 | Christian Gerdes | Immunotherapy |
MX342034B (es) | 2011-02-28 | 2016-09-12 | Hoffmann La Roche | Proteinas monovalentes que se unen a antigenos. |
EP2680884B1 (en) | 2011-02-28 | 2018-01-17 | F. Hoffmann-La Roche AG | Biological markers and methods for predicting response to b-cell antagonists |
EP2681239B8 (en) | 2011-02-28 | 2015-09-09 | F. Hoffmann-La Roche AG | Antigen binding proteins |
US20120222851A1 (en) * | 2011-03-04 | 2012-09-06 | GM Global Technology Operations LLC | Hvac system damper |
RU2607014C2 (ru) | 2011-03-29 | 2017-01-10 | Рош Гликарт Аг | Fc варианты антитела |
AU2012236099A1 (en) | 2011-03-31 | 2013-10-03 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
KR20140021589A (ko) | 2011-04-07 | 2014-02-20 | 제넨테크, 인크. | 항-fgfr4 항체 및 사용 방법 |
EA201892619A1 (ru) | 2011-04-29 | 2019-04-30 | Роше Гликарт Аг | Иммуноконъюгаты, содержащие мутантные полипептиды интерлейкина-2 |
WO2012146630A1 (en) | 2011-04-29 | 2012-11-01 | F. Hoffmann-La Roche Ag | N-terminal acylated polypeptides, methods for their production and uses thereof |
WO2012155019A1 (en) | 2011-05-12 | 2012-11-15 | Genentech, Inc. | Multiple reaction monitoring lc-ms/ms method to detect therapeutic antibodies in animal samples using framework signature pepides |
EA030462B1 (ru) | 2011-05-16 | 2018-08-31 | Дженентек, Инк. | Агонисты fgfr1 и способы их применения |
SG10201509588TA (en) | 2011-05-21 | 2015-12-30 | Macrogenics Inc | CD3-Binding Molecules Capable Of Binding To Human And Non-Human CD3 |
CA2837914A1 (en) | 2011-06-15 | 2012-12-20 | F. Hoffmann-La Roche Ag | Anti-human epo receptor antibodies and methods of use |
BR112013032217B1 (pt) | 2011-06-17 | 2021-01-19 | Novo Nordisk A/S | uso de um anticorpo anti-nkg2a |
ES2667864T3 (es) | 2011-06-22 | 2018-05-14 | F. Hoffmann-La Roche Ag | Eliminación de células diana mediante linfocitos T citotóxicos específicos de virus en circulación usando complejos que comprenden MHC de clase I |
TW201306866A (zh) | 2011-06-30 | 2013-02-16 | Genentech Inc | 抗-c-met抗體調配物 |
MX2014001736A (es) | 2011-08-17 | 2014-03-31 | Genentech Inc | Inhibicion de angiogenesis en tumores refractarios. |
CN103890007A (zh) | 2011-08-17 | 2014-06-25 | 霍夫曼-拉罗奇有限公司 | 神经调节蛋白抗体及其用途 |
BR112014003598B1 (pt) | 2011-08-23 | 2022-05-31 | Roche Glycart Ag | Molécula de ligação de antígeno biespecífica, composição farmacêutica e uso da molécula de ligação de antígeno biespecífica |
RU2014109038A (ru) | 2011-08-23 | 2015-09-27 | Рош Гликарт Аг | Антитела к хондроитинсульфат протеогликану меланомы |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
CN103930781A (zh) | 2011-09-15 | 2014-07-16 | 霍夫曼-拉罗奇有限公司 | 促进分化的方法 |
US20130078252A1 (en) | 2011-09-19 | 2013-03-28 | Genentech, Inc. | Combination treatments comprising c-met antagonists and b-raf antagonists |
EP3682905B1 (en) | 2011-10-03 | 2021-12-01 | ModernaTX, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US9663573B2 (en) | 2011-10-05 | 2017-05-30 | Genentech, Inc. | Methods of treating liver conditions using Notch2 antagonists |
CN108373506A (zh) | 2011-10-14 | 2018-08-07 | 霍夫曼-拉罗奇有限公司 | 抗HtrA1抗体及使用方法 |
EP2766000A2 (en) | 2011-10-15 | 2014-08-20 | F.Hoffmann-La Roche Ag | Scd1 antagonists for treating cancer |
WO2013059531A1 (en) | 2011-10-20 | 2013-04-25 | Genentech, Inc. | Anti-gcgr antibodies and uses thereof |
CN104023743B (zh) | 2011-10-25 | 2017-05-03 | 普罗西纳治疗有限公司 | 抗体制剂和方法 |
AU2012328980A1 (en) | 2011-10-28 | 2014-04-24 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
EP2780372B1 (en) | 2011-11-17 | 2019-01-02 | Jung, Gundram | Bi-specific antibodies for medical use |
BR112014012005A2 (pt) | 2011-11-21 | 2017-12-19 | Genentech Inc | composições, métodos, formulação farmacêutica e artigo |
US20130302274A1 (en) | 2011-11-25 | 2013-11-14 | Roche Glycart Ag | Combination therapy |
WO2013083497A1 (en) | 2011-12-06 | 2013-06-13 | F. Hoffmann-La Roche Ag | Antibody formulation |
RU2685867C2 (ru) | 2011-12-15 | 2019-04-23 | Алтернатив Инновейтив Текнолоджиз Ллц | Гибридные белки и белковые конъюгаты на основе белка теплового шока-70 (БТШ70) и способы их применения (варианты) |
DK2791160T3 (da) | 2011-12-16 | 2022-05-30 | Modernatx Inc | Modificerede mrna-sammensætninger |
MX2014007262A (es) | 2011-12-22 | 2014-08-01 | Hoffmann La Roche | Sistema de exhibicion de anticuerpos de longitud completa para celulas eucarioticas y su uso. |
SG10201805622QA (en) | 2011-12-22 | 2018-08-30 | Hoffmann La Roche | Expression Vector Organization, Novel Production Cell Generation Methods And Their Use For The Recombinant Production Of Polypeptides |
MX355624B (es) | 2011-12-22 | 2018-04-25 | Hoffmann La Roche | Combinaciones de elementos de vector de expresion, metodos novedosos de generacion de celulas de produccion y su uso para la produccion recombinante de polipeptidos. |
MX360453B (es) | 2011-12-22 | 2018-11-01 | Genentech Inc | Cromatografia de membrana de intercambio ionico. |
AR089434A1 (es) | 2011-12-23 | 2014-08-20 | Genentech Inc | Procedimiento para preparar formulaciones con alta concentracion de proteinas |
DK3130347T3 (da) | 2011-12-30 | 2019-10-14 | Halozyme Inc | PH20-polypeptidvarianter, formuleringer og anvendelser deraf |
MX2014008101A (es) | 2011-12-30 | 2014-09-25 | Abbvie Inc | Proteinas de union especificas duales dirigidas contra il-13 y/o il-17. |
WO2013101771A2 (en) | 2011-12-30 | 2013-07-04 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
EP2802601B1 (en) | 2012-01-09 | 2019-11-13 | The Scripps Research Institute | Humanized antibodies with ultralong cdr3s |
CN104520321A (zh) | 2012-01-09 | 2015-04-15 | 斯克利普斯研究所 | 超长互补决定区及其用途 |
SG11201404198TA (en) | 2012-01-18 | 2014-08-28 | Genentech Inc | Anti-lrp5 antibodies and methods of use |
KR20140119114A (ko) | 2012-01-18 | 2014-10-08 | 제넨테크, 인크. | Fgf19 조절제의 사용 방법 |
WO2013109279A2 (en) * | 2012-01-19 | 2013-07-25 | Therapeutic Proteins Inc. | Stabilization of the anti-cd20 antibody rituximab |
SG11201404486QA (en) | 2012-01-31 | 2014-11-27 | Genentech Inc | Anti-ig-e m1' antibodies and methods using same |
US20130209473A1 (en) | 2012-02-11 | 2013-08-15 | Genentech, Inc. | R-spondin translocations and methods using the same |
CA2860600C (en) | 2012-02-15 | 2022-07-26 | F. Hoffmann-La Roche Ag | Fc-receptor based affinity chromatography |
JP2015514710A (ja) | 2012-03-27 | 2015-05-21 | ジェネンテック, インコーポレイテッド | Her3阻害剤に関する診断及び治療 |
AU2013240280A1 (en) | 2012-03-27 | 2014-10-16 | Genentech, Inc. | Improved harvest operations for recombinant proteins |
AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
DE18200782T1 (de) | 2012-04-02 | 2021-10-21 | Modernatx, Inc. | Modifizierte polynukleotide zur herstellung von proteinen im zusammenhang mit erkrankungen beim menschen |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
AU2013243861A1 (en) | 2012-04-05 | 2014-10-23 | Ac Immune S.A. | Humanized Tau antibody |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
EP2844300B1 (en) | 2012-05-01 | 2018-10-17 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
WO2013170191A1 (en) | 2012-05-11 | 2013-11-14 | Genentech, Inc. | Methods of using antagonists of nad biosynthesis from nicotinamide |
RU2625771C2 (ru) | 2012-05-23 | 2017-07-18 | Дженентек, Инк. | Способ отбора терапевтических средств |
US9266961B2 (en) | 2012-06-15 | 2016-02-23 | Genentech, Inc. | Anti-PCSK9 antibodies, formulations, dosing, and methods of use |
BR112014030843A2 (pt) | 2012-07-04 | 2019-10-15 | Hoffmann La Roche | anticorpo anti-teofilina, formulação farmacêutica e uso do anticorpo |
EP2870180B1 (en) | 2012-07-04 | 2024-08-28 | F. Hoffmann-La Roche AG | Anti-biotin antibodies and methods of use |
SI2869848T1 (sl) | 2012-07-04 | 2017-01-31 | F. Hoffmann-La Roche Ag | Kovalentno vezani konjugati antigen-protitelo |
KR102216606B1 (ko) | 2012-07-04 | 2021-02-17 | 리젠 파마슈티컬스 소시에떼 아노님 | 선택적 pi3k 델타 억제제 |
CN110042114B (zh) | 2012-07-05 | 2024-09-10 | 弗·哈夫曼-拉罗切有限公司 | 表达和分泌系统 |
TR201802376T4 (tr) | 2012-07-09 | 2018-03-21 | Genentech Inc | Anti-CD79b antikorları içeren immünokonjugatlar. |
WO2014011520A1 (en) | 2012-07-09 | 2014-01-16 | Genentech, Inc. | Immunoconjugates comprising anti-cd22 antibodies |
BR112015000437A2 (pt) | 2012-07-09 | 2017-06-27 | Genentech Inc | imunoconjugados, formulação farmacêutica, métodos de tratamento e de inbir a proliferação de uma célula |
TW201406785A (zh) | 2012-07-09 | 2014-02-16 | Genentech Inc | 抗cd22抗體及免疫結合物 |
AR091755A1 (es) | 2012-07-12 | 2015-02-25 | Abbvie Inc | Proteinas de union a il-1 |
AR092027A1 (es) | 2012-07-13 | 2015-03-18 | Roche Glycart Ag | Anticuerpos biespecificos anti-vegf/anti-ang-2 y su utilizacion en el tratamiento de enfermedades vasculares oculares |
JP6307077B2 (ja) | 2012-08-02 | 2018-04-04 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 不活性免疫グロブリンFc領域とのFc融合体としての可溶性FcRを生産するための方法およびその使用 |
ES2848732T3 (es) | 2012-08-07 | 2021-08-11 | Roche Glycart Ag | Inmunoterapia mejorada |
AU2013306098A1 (en) | 2012-08-18 | 2015-02-12 | Academia Sinica | Cell-permeable probes for identification and imaging of sialidases |
EP2888238A4 (en) | 2012-08-21 | 2016-01-27 | Academia Sinica | BENZOCYCLO-OCTYNE COMPOUNDS AND USES THEREOF |
WO2014052713A2 (en) | 2012-09-27 | 2014-04-03 | Massachusetts Institute Of Technology | Her2-and vegf-a-binding proteins with enhanced stability |
TW201811825A (zh) | 2012-11-01 | 2018-04-01 | 美商艾伯維有限公司 | 抗-vegf/dll4雙重可變區域免疫球蛋白及其用途 |
BR112015009879A8 (pt) | 2012-11-02 | 2019-09-17 | Lab Francais Du Fractionnement | método in vitro de inibição da proliferação de uma população de células, composto, kit e composição farmacêutica |
WO2014071358A2 (en) | 2012-11-05 | 2014-05-08 | Foundation Medicine, Inc. | Novel ntrk1 fusion molecules and uses thereof |
EP2917243B1 (en) | 2012-11-08 | 2018-03-14 | F.Hoffmann-La Roche Ag | Her3 antigen binding proteins binding to the beta-hairpin of her3 |
SG11201503734UA (en) | 2012-11-13 | 2015-06-29 | Genentech Inc | Anti-hemagglutinin antibodies and methods of use |
US10590202B2 (en) | 2012-11-19 | 2020-03-17 | Baliopharm Ag | Recombinant bispecific antibody binding to CD20 and CD95 |
HRP20220607T1 (hr) | 2012-11-26 | 2022-06-24 | Modernatx, Inc. | Terminalno modificirana rna |
US9393327B2 (en) | 2012-12-19 | 2016-07-19 | Genentech, Inc. | Methods and compositions for radiohalogen protein labeling |
MX361076B (es) | 2012-12-21 | 2018-11-27 | Hoffmann La Roche | Proteínas multifunción que comprenden complejo mayor de histocompatibilidad (cmh) de clase i multivalente unido mediante disulfuro. |
EP3939614A1 (en) | 2013-01-18 | 2022-01-19 | Foundation Medicine, Inc. | Methods of treating cholangiocarcinoma |
WO2014116749A1 (en) | 2013-01-23 | 2014-07-31 | Genentech, Inc. | Anti-hcv antibodies and methods of using thereof |
US9255155B2 (en) | 2013-01-31 | 2016-02-09 | The Regents Of The University Of California | Antibodies specific for urokinase-type plasminogen activator and methods of treating cancer |
KR20150118159A (ko) | 2013-02-22 | 2015-10-21 | 에프. 호프만-라 로슈 아게 | 암의 치료 방법 및 약물 내성의 예방 방법 |
JP2016512489A (ja) | 2013-02-26 | 2016-04-28 | ロシュ グリクアート アーゲー | 抗mcsp抗体 |
KR20150123250A (ko) | 2013-03-06 | 2015-11-03 | 제넨테크, 인크. | 암 약물 내성의 치료 및 예방 방법 |
MX2015012808A (es) * | 2013-03-12 | 2016-05-31 | Molecular Templates Inc | Inmunotoxinas de union a cd20 para inducir internalizacion celular y metodos que usan las mismas. |
SG10201913932VA (en) | 2013-03-13 | 2020-03-30 | Genentech Inc | Antibody formulations |
BR112015022019A2 (pt) | 2013-03-14 | 2017-08-29 | Genentech Inc | Anticorpos isolados, ácido nucleico, célula hospedeira, método de produção de anticorpos, imunoconjugado, formulação farmacêutica, métodos de tratamento de indivíduos, de inibição da proliferação de células, de detecção de b7-h4 humano e de detecção de câncer |
WO2014153030A2 (en) | 2013-03-14 | 2014-09-25 | Genentech, Inc. | Methods of treating cancer and preventing cancer drug resistance |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
US20140271634A1 (en) | 2013-03-14 | 2014-09-18 | The Regents Of The University Of California | Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use |
CA2902910A1 (en) | 2013-03-15 | 2014-09-25 | Ac Immune S.A. | Anti-tau antibodies and methods of use |
SG11201507427QA (en) | 2013-03-15 | 2015-10-29 | Genentech Inc | Compositions and methods for diagnosis and treatment of hepatic cancers |
BR112015021521A2 (pt) | 2013-03-15 | 2017-10-10 | Genentech Inc | anticorpos anti-crth2 e métodos para seu uso |
TW201512219A (zh) | 2013-03-15 | 2015-04-01 | Abbvie Inc | 針對IL-1β及/或IL-17之雙特異性結合蛋白 |
SG10201701380TA (en) | 2013-03-15 | 2017-04-27 | Genentech Inc | Biomarkers and methods of treating pd-1 and pd-l1 related conditions |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
CN105339001A (zh) | 2013-03-15 | 2016-02-17 | 基因泰克公司 | 治疗癌症和预防癌症耐药性的方法 |
ES2798307T3 (es) * | 2013-03-15 | 2020-12-10 | Hoffmann La Roche | Composiciones de cultivo de células con antioxidantes y procedimientos para la producción de polipéptidos |
ES2676023T3 (es) | 2013-03-15 | 2018-07-16 | F. Hoffmann-La Roche Ag | Polipéptidos de IL-22 y proteínas de fusión de IL-22 Fc y métodos de uso |
UA118028C2 (uk) | 2013-04-03 | 2018-11-12 | Рош Глікарт Аг | Біспецифічне антитіло, специфічне щодо fap і dr5, антитіло, специфічне щодо dr5, і спосіб їх застосування |
EP2992010B1 (en) | 2013-04-29 | 2021-03-24 | F.Hoffmann-La Roche Ag | Fc-receptor binding modified asymmetric antibodies and methods of use |
EP2992011B1 (en) | 2013-04-29 | 2017-12-13 | F. Hoffmann-La Roche AG | Fcrn-binding abolished anti-igf-1r antibodies and their use in the treatment of vascular eye diseases |
UA118029C2 (uk) | 2013-04-29 | 2018-11-12 | Ф. Хоффманн-Ля Рош Аг | Модифіковане антитіло, що зв'язується з людським fcrn, й способи його застосування |
PL3594240T3 (pl) | 2013-05-20 | 2024-04-02 | F. Hoffmann-La Roche Ag | Przeciwciała przeciwko receptorowi transferyny i sposoby ich zastosowania |
DK3004162T3 (da) | 2013-05-31 | 2020-05-18 | Genentech Inc | Anti-væg-teichoin-antistoffer og konjugater |
CN105358574B (zh) | 2013-05-31 | 2020-10-16 | 基因泰克公司 | 抗壁磷壁酸抗体和缀合物 |
US10086054B2 (en) | 2013-06-26 | 2018-10-02 | Academia Sinica | RM2 antigens and use thereof |
WO2014210564A1 (en) | 2013-06-27 | 2014-12-31 | Academia Sinica | Glycan conjugates and use thereof |
TW201534726A (zh) | 2013-07-03 | 2015-09-16 | Halozyme Inc | 熱穩定ph20玻尿酸酶變異體及其用途 |
EP3022224A2 (en) | 2013-07-18 | 2016-05-25 | Fabrus, Inc. | Antibodies with ultralong complementarity determining regions |
AU2014290361B2 (en) | 2013-07-18 | 2019-04-18 | Taurus Biosciences, Llc | Humanized antibodies with ultralong complementarity determining regions |
DK3708583T3 (da) | 2013-08-01 | 2022-05-16 | Five Prime Therapeutics Inc | Ikke-fucosylerede anti-fgfr2iiib-antistoffer |
MX2016001854A (es) | 2013-08-12 | 2016-09-06 | Genentech Inc | Composiciones y metodo para tratar condiciones asociadas con el complemento. |
JP6486368B2 (ja) | 2013-09-06 | 2019-03-20 | アカデミア シニカAcademia Sinica | 改変されたグリコシル基を含む糖脂質を用いたヒトiNKT細胞の活性化 |
AR097685A1 (es) | 2013-09-17 | 2016-04-06 | Genentech Inc | Métodos de uso de anticuerpos anti-lgr5 |
CN103524621B (zh) * | 2013-09-27 | 2015-04-01 | 北京济福霖生物技术有限公司 | 一种抗人cd20嵌合单克隆抗体 |
WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
EP3620470B1 (en) | 2013-10-11 | 2023-07-26 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Tem8 antibodies and their use |
EP3055329B1 (en) | 2013-10-11 | 2018-06-13 | F. Hoffmann-La Roche AG | Multispecific domain exchanged common variable light chain antibodies |
CA2926084A1 (en) | 2013-10-11 | 2015-04-16 | Genentech, Inc. | Nsp4 inhibitors and methods of use |
CN105744954B (zh) | 2013-10-18 | 2021-03-05 | 豪夫迈·罗氏有限公司 | 抗rspo2和/或抗rspo3抗体及其用途 |
KR20160068802A (ko) | 2013-10-23 | 2016-06-15 | 제넨테크, 인크. | 호산구성 장애를 진단 및 치료하는 방법 |
CN104623637A (zh) | 2013-11-07 | 2015-05-20 | 健能隆医药技术(上海)有限公司 | Il-22二聚体在制备静脉注射药物中的应用 |
LT3071597T (lt) | 2013-11-21 | 2020-10-12 | F. Hoffmann-La Roche Ag | Antikūnai prieš alfa-sunukleiną ir jų naudojimo būdai |
NZ720769A (en) | 2013-12-09 | 2022-10-28 | Allakos Inc | Anti-siglec-8 antibodies and methods of use thereof |
CN110590950A (zh) | 2013-12-13 | 2019-12-20 | 基因泰克公司 | 抗cd33抗体和免疫缀合物 |
EP3083686B2 (en) | 2013-12-17 | 2023-03-22 | F. Hoffmann-La Roche AG | Methods of treating cancers using pd-1 axis binding antagonists and taxanes |
RU2016128726A (ru) | 2013-12-17 | 2018-01-23 | Дженентек, Инк. | Способы лечения злокачественных опухолей с использованием антагонистов связывания по оси pd-1 и антитела против cd20 |
EP3083687A2 (en) | 2013-12-17 | 2016-10-26 | F. Hoffmann-La Roche AG | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
WO2015095392A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
JP6608827B2 (ja) | 2013-12-20 | 2019-11-20 | エフ.ホフマン−ラ ロシュ アーゲー | ヒト化抗タウ(pS422)抗体及び使用方法 |
TWI670283B (zh) | 2013-12-23 | 2019-09-01 | 美商建南德克公司 | 抗體及使用方法 |
CN105873615B (zh) | 2014-01-03 | 2020-12-25 | 豪夫迈·罗氏有限公司 | 共价连接的helicar-抗helicar抗体缀合物及其用途 |
WO2015103549A1 (en) | 2014-01-03 | 2015-07-09 | The United States Of America, As Represented By The Secretary Department Of Health And Human Services | Neutralizing antibodies to hiv-1 env and their use |
PL3089996T3 (pl) | 2014-01-03 | 2021-12-13 | F. Hoffmann-La Roche Ag | Dwuswoiste przeciwciała przeciw haptenowi/przeciw receptorowi występującemu w barierze krew-mózg, ich kompleksy i ich zastosowanie jako przenośniki wahadłowe występujące w barierze krew-mózg |
RU2682754C2 (ru) | 2014-01-03 | 2019-03-21 | Ф. Хоффманн-Ля Рош Аг | Конъюгаты полипептидного токсина и антитела, соединенных ковалентной связью |
PL3092251T3 (pl) | 2014-01-06 | 2021-08-02 | F. Hoffmann-La Roche Ag | Jednowartościowe moduły transportera wahadłowego przez barierę krew-mózg |
WO2015107026A1 (en) | 2014-01-15 | 2015-07-23 | F. Hoffmann-La Roche Ag | Fc-region variants with modified fcrn- and maintained protein a-binding properties |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US9982041B2 (en) | 2014-01-16 | 2018-05-29 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
JP2017505305A (ja) | 2014-01-24 | 2017-02-16 | ジェネンテック, インコーポレイテッド | 抗steap1抗体及びイムノコンジュゲートを使用する方法 |
US20160347798A1 (en) | 2014-01-27 | 2016-12-01 | Molecular Templates, Inc. | Mhc class i epitope delivering polypeptides and cell-targeted molecules for direct cell killing and immune stimulation via mhc class i presentation and methods regarding the same |
WO2015191764A1 (en) | 2014-06-11 | 2015-12-17 | Molecular Templates, Inc. | Protease-cleavage resistant, shiga toxin a subunit effector polypeptides and cell-targeted molecules comprising the same |
ES2694857T3 (es) | 2014-02-04 | 2018-12-27 | Genentech, Inc. | Smoothened mutante y métodos de uso de la misma |
AU2015214058B2 (en) | 2014-02-08 | 2020-07-09 | Genentech, Inc. | Methods of treating Alzheimer's Disease |
CA2938731A1 (en) | 2014-02-08 | 2015-08-13 | Genentech, Inc. | Methods of treating alzheimer's disease |
MX2016010433A (es) | 2014-02-12 | 2016-09-22 | Genentech Inc | Anticuerpos anti-jagged1 y metodos de uso. |
UA117608C2 (uk) | 2014-02-21 | 2018-08-27 | Дженентек, Інк. | Спосіб лікування еозинофільного захворювання у пацієнта шляхом застосування біспецифічного анти-il-13/il-17 антитіла |
TWI558399B (zh) | 2014-02-26 | 2016-11-21 | 美國禮來大藥廠 | 癌症之組合療法 |
AU2015222757B2 (en) | 2014-02-28 | 2020-10-08 | Allakos Inc. | Methods and compositions for treating Siglec-8 associated diseases |
TW201622744A (zh) | 2014-03-04 | 2016-07-01 | 美國禮來大藥廠 | 癌症之組合療法 |
US11142584B2 (en) | 2014-03-11 | 2021-10-12 | Molecular Templates, Inc. | CD20-binding proteins comprising Shiga toxin A subunit effector regions for inducing cellular internalization and methods using same |
EP3116999B1 (en) | 2014-03-14 | 2021-09-15 | F. Hoffmann-La Roche AG | Methods and compositions for secretion of heterologous polypeptides |
US20170107294A1 (en) | 2014-03-21 | 2017-04-20 | Nordlandssykehuset Hf | Anti-cd14 antibodies and uses thereof |
WO2015148531A1 (en) | 2014-03-24 | 2015-10-01 | Genentech, Inc. | Cancer treatment with c-met antagonists and correlation of the latter with hgf expression |
EP3129767B1 (en) | 2014-03-27 | 2021-09-01 | Academia Sinica | Reactive labelling compounds and uses thereof |
PL3126394T3 (pl) | 2014-03-31 | 2020-05-18 | F.Hoffmann-La Roche Ag | Przeciwciała anty-OX40 i sposoby stosowania |
AU2015241038A1 (en) | 2014-03-31 | 2016-10-13 | Genentech, Inc. | Combination therapy comprising anti-angiogenesis agents and OX40 binding agonists |
WO2015164615A1 (en) | 2014-04-24 | 2015-10-29 | University Of Oslo | Anti-gluten antibodies and uses thereof |
JP2017522861A (ja) | 2014-05-22 | 2017-08-17 | ジェネンテック, インコーポレイテッド | 抗gpc3抗体及びイムノコンジュゲート |
WO2015179835A2 (en) | 2014-05-23 | 2015-11-26 | Genentech, Inc. | Mit biomarkers and methods using the same |
CN106661099A (zh) | 2014-05-27 | 2017-05-10 | 中央研究院 | 抗her2醣抗体及其用途 |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
KR20240096599A (ko) | 2014-05-27 | 2024-06-26 | 아카데미아 시니카 | 항-cd20 글리코항체 및 이의 용도 |
CA2950423A1 (en) | 2014-05-27 | 2015-12-03 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
ES2880999T3 (es) | 2014-05-27 | 2021-11-26 | Rhizen Pharmaceuticals S A | Sal de tosilato cristalina de un inhibidor selectivo de PI3K delta para uso en formulaciones farmacéuticas |
WO2015184001A1 (en) | 2014-05-28 | 2015-12-03 | Academia Sinica | Anti-tnf-alpha glycoantibodies and uses thereof |
WO2015191715A1 (en) | 2014-06-11 | 2015-12-17 | Genentech, Inc. | Anti-lgr5 antibodies and uses thereof |
WO2015191986A1 (en) | 2014-06-13 | 2015-12-17 | Genentech, Inc. | Methods of treating and preventing cancer drug resistance |
AR100978A1 (es) | 2014-06-26 | 2016-11-16 | Hoffmann La Roche | LANZADERAS CEREBRALES DE ANTICUERPO HUMANIZADO ANTI-Tau(pS422) Y USOS DE LAS MISMAS |
JP6654581B2 (ja) | 2014-06-26 | 2020-02-26 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | 抗brdu抗体および使用方法 |
SG11201700207WA (en) | 2014-07-11 | 2017-02-27 | Genentech Inc | Anti-pd-l1 antibodies and diagnostic uses thereof |
KR20170029490A (ko) | 2014-07-11 | 2017-03-15 | 제넨테크, 인크. | 노치 경로 억제 |
WO2016019969A1 (en) | 2014-08-08 | 2016-02-11 | Ludwig-Maximilians-Universität München | Subcutaneously administered bispecific antibodies for use in the treatment of cancer |
TWI751102B (zh) | 2014-08-28 | 2022-01-01 | 美商奇諾治療有限公司 | 對cd19具專一性之抗體及嵌合抗原受體 |
ES2913865T3 (es) | 2014-08-28 | 2022-06-06 | Bioatla Inc | Receptores de antígeno quimérico condicionalmente activos para células T modificadas |
US20170246272A1 (en) | 2014-09-05 | 2017-08-31 | Opexa Therapeutics, Inc. | Compositions and methods for treating b cell mediated autoimmune disorders |
KR102422375B1 (ko) | 2014-09-08 | 2022-07-18 | 아카데미아 시니카 | 당지질을 사용한 인간 iNKT 세포 활성화 |
TW201625688A (zh) | 2014-09-12 | 2016-07-16 | 建南德克公司 | 經半胱胺酸改造之抗體及接合物 |
MX2017003022A (es) | 2014-09-12 | 2017-05-12 | Genentech Inc | Anticuerpos anti-cll-1 e inmunoconjugados. |
CN114106185A (zh) | 2014-09-12 | 2022-03-01 | 基因泰克公司 | 抗her2抗体和免疫缀合物 |
EP3191518B1 (en) | 2014-09-12 | 2020-01-15 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
US20160137727A1 (en) | 2014-09-15 | 2016-05-19 | Genentech, Inc. | Antibody formulations |
WO2016044396A1 (en) | 2014-09-17 | 2016-03-24 | Genentech, Inc. | Immunoconjugates comprising anti-her2 antibodies and pyrrolobenzodiazepines |
WO2016049214A1 (en) | 2014-09-23 | 2016-03-31 | Genentech, Inc. | METHOD OF USING ANTI-CD79b IMMUNOCONJUGATES |
WO2016061389A2 (en) | 2014-10-16 | 2016-04-21 | Genentech, Inc. | Anti-alpha-synuclein antibodies and methods of use |
EP3223865A4 (en) | 2014-10-31 | 2018-10-03 | Jounce Therapeutics, Inc. | Methods of treating conditions with antibodies that bind b7-h4 |
SG11201703521UA (en) | 2014-11-03 | 2017-05-30 | Genentech Inc | Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment |
EP3215850B1 (en) | 2014-11-03 | 2019-07-03 | F. Hoffmann-La Roche AG | Assays for detecting t cell immune subsets and methods of use thereof |
AU2015342964B2 (en) | 2014-11-05 | 2021-06-24 | Genentech, Inc. | Methods of producing two chain proteins in bacteria |
RU2017119185A (ru) | 2014-11-05 | 2018-12-05 | Дженентек, Инк. | Антитела против fgfr2/3 и способы их применения |
CA2966558C (en) | 2014-11-05 | 2024-03-12 | Genentech, Inc. | Methods of producing two chain proteins in bacteria |
WO2016073157A1 (en) | 2014-11-06 | 2016-05-12 | Genentech, Inc. | Anti-ang2 antibodies and methods of use thereof |
DK3215528T3 (da) | 2014-11-06 | 2019-10-07 | Hoffmann La Roche | Fc-regionvarianter med modificeret FcRn-binding og anvendelsesfremgangsmåder |
EP3842453A1 (en) | 2014-11-06 | 2021-06-30 | F. Hoffmann-La Roche AG | Fc-region variants with modified fcrn- and protein a-binding properties |
US20160152720A1 (en) | 2014-11-06 | 2016-06-02 | Genentech, Inc. | Combination therapy comprising ox40 binding agonists and tigit inhibitors |
EP3217787B1 (en) | 2014-11-10 | 2019-04-17 | F.Hoffmann-La Roche Ag | Animal model for nephropathy and agents for treating the same |
CA2960297A1 (en) | 2014-11-10 | 2016-05-19 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
US10160795B2 (en) | 2014-11-14 | 2018-12-25 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to Ebola virus glycoprotein and their use |
SG11201703605QA (en) | 2014-11-17 | 2017-06-29 | Genentech Inc | Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists |
EP3221364B1 (en) | 2014-11-19 | 2020-12-16 | Genentech, Inc. | Antibodies against bace1 and use thereof for neural disease immunotherapy |
JP6993228B2 (ja) | 2014-11-19 | 2022-03-03 | ジェネンテック, インコーポレイテッド | 抗トランスフェリン受容体/抗bace1多重特異性抗体および使用方法 |
WO2016081643A1 (en) | 2014-11-19 | 2016-05-26 | Genentech, Inc. | Anti-transferrin receptor antibodies and methods of use |
LT3789402T (lt) | 2014-11-20 | 2022-09-26 | F. Hoffmann-La Roche Ag | Kompleksinė terapija, naudojant t ląsteles aktyvinančias bispecifines antigeną surišančias molekules ir pd-1 ašį surišančius antagonistus |
CA2965540A1 (en) | 2014-12-03 | 2016-06-09 | Genentech, Inc. | Anti-staphylococcus aureus antibody rifamycin conjugates and uses thereof |
BR112017011478A2 (pt) | 2014-12-03 | 2018-02-27 | Genentech, Inc. | composto de conjugado anticorpo-antibiótico, conjugado anticorpo-antibiótico, composição farmacêutica, métodos de tratamento de uma infecção bacteriana e para exterminar staph aureus, processo para a preparação do composto, kit e intermediário antibiótico-ligante |
WO2016087416A1 (en) | 2014-12-03 | 2016-06-09 | F. Hoffmann-La Roche Ag | Multispecific antibodies |
MA40938A (fr) | 2014-12-05 | 2017-10-11 | Hoffmann La Roche | Anticorps anti-cd79b et méthodes d'utilisation desdits anticorps |
MX2017007491A (es) | 2014-12-10 | 2018-05-04 | Genentech Inc | Anticuerpos del receptor de la barrera hematoencefálica y métodos para su uso. |
WO2016094881A2 (en) | 2014-12-11 | 2016-06-16 | Abbvie Inc. | Lrp-8 binding proteins |
EA201791366A1 (ru) | 2014-12-19 | 2018-02-28 | Чугаи Сейяку Кабусики Кайся | Антитела к c5 и способы их применения |
KR20230137502A (ko) | 2014-12-19 | 2023-10-04 | 레제네상스 비.브이. | 인간 c6에 결합하는 항체 및 이의 용도 |
KR102650420B1 (ko) | 2014-12-19 | 2024-03-21 | 추가이 세이야쿠 가부시키가이샤 | 항-마이오스타틴 항체, 변이체 Fc 영역을 함유하는 폴리펩타이드, 및 사용 방법 |
US20160200815A1 (en) | 2015-01-05 | 2016-07-14 | Jounce Therapeutics, Inc. | Antibodies that inhibit tim-3:lilrb2 interactions and uses thereof |
EP3245231B1 (en) | 2015-01-16 | 2020-08-12 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for ror1 |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
WO2016117346A1 (en) | 2015-01-22 | 2016-07-28 | Chugai Seiyaku Kabushiki Kaisha | A combination of two or more anti-c5 antibodies and methods of use |
AU2015378564A1 (en) | 2015-01-24 | 2017-07-13 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
KR102329836B1 (ko) * | 2015-01-26 | 2021-11-19 | 셀렉티스 | 암 면역치료를 위한 항-CLL1 특이적 단일-체인 키메라 항원 수용체들(scCARS) |
JP2018512597A (ja) | 2015-02-04 | 2018-05-17 | ジェネンテック, インコーポレイテッド | 突然変異体スムースンド及びその使用方法 |
AU2016215205B2 (en) | 2015-02-05 | 2021-10-21 | Molecular Templates, Inc. | Multivalent CD20-binding molecules comprising shiga toxin a subunit effector regions and enriched compositions thereof |
US9969800B2 (en) | 2015-02-05 | 2018-05-15 | Chugai Seiyaku Kabushiki Kaisha | IL-8 antibodies |
WO2016138160A1 (en) | 2015-02-24 | 2016-09-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use |
CN107430117A (zh) | 2015-03-16 | 2017-12-01 | 豪夫迈·罗氏有限公司 | 检测和定量IL‑13的方法和在诊断和治疗Th2相关疾病中的用途 |
WO2016146833A1 (en) | 2015-03-19 | 2016-09-22 | F. Hoffmann-La Roche Ag | Biomarkers for nad(+)-diphthamide adp ribosyltransferase resistance |
EP3683233A1 (en) | 2015-03-20 | 2020-07-22 | The U.S.A. as represented by the Secretary, Department of Health and Human Services | Neutralizing antibodies to gp120 and their use |
CN114907481A (zh) | 2015-03-23 | 2022-08-16 | 震动疗法股份有限公司 | Icos的抗体 |
TWI719969B (zh) | 2015-03-23 | 2021-03-01 | 德商拜耳製藥股份有限公司 | 抗-ceacam6抗體及其用途 |
EP3590961A1 (en) | 2015-03-25 | 2020-01-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Bispecific multivalent fusion proteins |
SG10201913158PA (en) | 2015-04-03 | 2020-02-27 | Eureka Therapeutics Inc | Constructs targeting afp peptide/mhc complexes and uses thereof |
AU2016246695A1 (en) | 2015-04-07 | 2017-10-26 | Genentech, Inc. | Antigen binding complex having agonistic activity and methods of use |
EP3283508B1 (en) | 2015-04-17 | 2021-03-17 | Alpine Immune Sciences, Inc. | Immunomodulatory proteins with tunable affinities |
SI3286315T1 (sl) | 2015-04-24 | 2021-09-30 | F. Hoffmann-La Roche Ag | Postopek identifikacije bakterij, ki obsegajo vezavne polipeptide |
CN107709363A (zh) | 2015-05-01 | 2018-02-16 | 基因泰克公司 | 掩蔽抗cd3抗体和使用方法 |
WO2016179194A1 (en) | 2015-05-04 | 2016-11-10 | Jounce Therapeutics, Inc. | Lilra3 and method of using the same |
WO2016183104A1 (en) | 2015-05-11 | 2016-11-17 | Genentech, Inc. | Compositions and methods of treating lupus nephritis |
IL295002A (en) | 2015-05-12 | 2022-09-01 | Genentech Inc | Therapeutic and diagnostic methods for cancer containing a pd–l1 binding antagonist |
AU2016263808B2 (en) | 2015-05-21 | 2019-01-03 | Harpoon Therapeutics, Inc. | Trispecific binding proteins and methods of use |
PL3303632T5 (pl) | 2015-05-29 | 2023-07-03 | F. Hoffmann-La Roche Ag | Terapeutyczne i diagnostyczne sposoby stosowane w nowotworze |
CN107771182A (zh) | 2015-05-29 | 2018-03-06 | 豪夫迈·罗氏有限公司 | 人源化抗埃博拉病毒糖蛋白抗体和使用方法 |
AR105618A1 (es) | 2015-05-29 | 2017-10-25 | Genentech Inc | Metilación del promotor del ligando al receptor de muerte programada (pd-l1) en cáncer |
EP3660035A1 (en) | 2015-05-30 | 2020-06-03 | Molecular Templates, Inc. | De-immunized, shiga toxin a subunit scaffolds and cell-targeting molecules comprising the same |
WO2016196679A1 (en) | 2015-06-02 | 2016-12-08 | Genentech, Inc. | Compositions and methods for using anti-il-34 antibodies to treat neurological diseases |
WO2016196975A1 (en) | 2015-06-03 | 2016-12-08 | The United States Of America, As Represented By The Secretary Department Of Health & Human Services | Neutralizing antibodies to hiv-1 env and their use |
TWI790642B (zh) | 2015-06-05 | 2023-01-21 | 美商建南德克公司 | 抗-tau抗體及使用方法 |
CN107750164A (zh) | 2015-06-08 | 2018-03-02 | 豪夫迈·罗氏有限公司 | 使用抗ox40抗体和pd‑1轴结合拮抗剂治疗癌症的方法 |
CN107810011A (zh) | 2015-06-08 | 2018-03-16 | 豪夫迈·罗氏有限公司 | 使用抗ox40抗体治疗癌症的方法 |
CN108064246A (zh) | 2015-06-15 | 2018-05-22 | 基因泰克公司 | 抗体和免疫结合物 |
TW201710286A (zh) | 2015-06-15 | 2017-03-16 | 艾伯維有限公司 | 抗vegf、pdgf及/或其受體之結合蛋白 |
EP3310811B1 (en) | 2015-06-16 | 2021-06-16 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
TW201718647A (zh) | 2015-06-16 | 2017-06-01 | 建南德克公司 | 抗-cll-1抗體及使用方法 |
AU2016280102B2 (en) | 2015-06-16 | 2022-06-16 | Genentech, Inc. | Humanized and affinity matured antibodies to FcRH5 and methods of use |
JP6896650B2 (ja) | 2015-06-17 | 2021-06-30 | ジェネンテック, インコーポレイテッド | Pd−1軸結合アンタゴニスト及びタキサンを使用した局所進行性または転移性乳癌の治療方法 |
CA2986592A1 (en) | 2015-06-17 | 2016-12-22 | Genentech, Inc. | Anti-her2 antibodies and methods of use |
EP3310385A4 (en) | 2015-06-17 | 2018-12-19 | Allakos Inc. | Methods and compositions for treating fibrotic diseases |
EP3744732A1 (en) | 2015-06-24 | 2020-12-02 | F. Hoffmann-La Roche AG | Humanized anti-tau(ps422) antibodies and methods of use |
CA2985718A1 (en) | 2015-06-24 | 2016-12-29 | F. Hoffmann-La Roche Ag | Anti-transferrin receptor antibodies with tailored affinity |
EP3108897A1 (en) | 2015-06-24 | 2016-12-28 | F. Hoffmann-La Roche AG | Antibodies against human csf-1r for use in inducing lymphocytosis in lymphomas or leukemias |
CA2989936A1 (en) | 2015-06-29 | 2017-01-05 | Genentech, Inc. | Type ii anti-cd20 antibody for use in organ transplantation |
EP3313878B1 (en) | 2015-06-29 | 2021-09-15 | Ventana Medical Systems, Inc. | Materials and methods for performing histochemical assays for human pro-epiregulin and amphiregulin |
CN105384825B (zh) | 2015-08-11 | 2018-06-01 | 南京传奇生物科技有限公司 | 一种基于单域抗体的双特异性嵌合抗原受体及其应用 |
CN108026180B (zh) | 2015-08-28 | 2022-06-07 | 豪夫迈·罗氏有限公司 | 抗羟腐胺赖氨酸抗体及其用途 |
CN108135968A (zh) | 2015-08-28 | 2018-06-08 | 阿穆尼克斯运营公司 | 嵌合多肽组装体及其制备和使用方法 |
TWI814162B (zh) | 2015-09-18 | 2023-09-01 | 日商中外製藥股份有限公司 | Il-8結合抗體及其用途 |
EP3353206A1 (en) | 2015-09-22 | 2018-08-01 | Spring Bioscience Corporation | Anti-ox40 antibodies and diagnostic uses thereof |
MY191756A (en) * | 2015-09-23 | 2022-07-14 | Genentech Inc | Optimized variants of anti-vegf antibodies |
MX2018003533A (es) | 2015-09-24 | 2019-04-25 | Abvitro Llc | Composiciones de anticuerpo de virus de inmunodeficiencia humana (vih) y metodos de uso. |
CN113956358A (zh) | 2015-09-25 | 2022-01-21 | 豪夫迈·罗氏有限公司 | 抗tigit抗体和使用方法 |
AR106188A1 (es) | 2015-10-01 | 2017-12-20 | Hoffmann La Roche | Anticuerpos anti-cd19 humano humanizados y métodos de utilización |
PE20231655A1 (es) | 2015-10-02 | 2023-10-17 | Hoffmann La Roche | Anticuerpos biespecificos contra el cd20 humano y el receptor de transferrina humano y metodos de uso |
AR106189A1 (es) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | ANTICUERPOS BIESPECÍFICOS CONTRA EL A-b HUMANO Y EL RECEPTOR DE TRANSFERRINA HUMANO Y MÉTODOS DE USO |
CN108602887B (zh) | 2015-10-02 | 2022-06-21 | 豪夫迈·罗氏有限公司 | 对共刺激性tnf受体特异性的双特异性抗体 |
SI3356404T1 (sl) | 2015-10-02 | 2021-11-30 | F. Hoffmann-La Roche Ag | Protitelesa proti PD1 in postopki uporabe |
MA43345A (fr) | 2015-10-02 | 2018-08-08 | Hoffmann La Roche | Conjugués anticorps-médicaments de pyrrolobenzodiazépine et méthodes d'utilisation |
AU2016329126B2 (en) | 2015-10-02 | 2023-04-13 | F. Hoffmann-La Roche Ag | Bispecific antibodies specific for PD1 and TIM3 |
EP3150636A1 (en) | 2015-10-02 | 2017-04-05 | F. Hoffmann-La Roche AG | Tetravalent multispecific antibodies |
KR20180075537A (ko) | 2015-10-06 | 2018-07-04 | 제넨테크, 인크. | 다발성 경화증을 치료하기 위한 방법 |
JP7074665B2 (ja) | 2015-10-07 | 2022-05-24 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 共刺激tnf受容体に対する四価の二重特異性抗体発明の分野 |
WO2017062748A1 (en) | 2015-10-07 | 2017-04-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Il-7r-alpha specific antibodies for treating acute lymphoblastic leukemia |
MA43354A (fr) | 2015-10-16 | 2018-08-22 | Genentech Inc | Conjugués médicamenteux à pont disulfure encombré |
MA45326A (fr) | 2015-10-20 | 2018-08-29 | Genentech Inc | Conjugués calichéamicine-anticorps-médicament et procédés d'utilisation |
US10604577B2 (en) | 2015-10-22 | 2020-03-31 | Allakos Inc. | Methods and compositions for treating systemic mastocytosis |
KR20180066236A (ko) | 2015-10-22 | 2018-06-18 | 조운스 테라퓨틱스, 인크. | Icos 발현을 계측하기 위한 유전자 특질 |
EP4015533A1 (en) | 2015-10-29 | 2022-06-22 | F. Hoffmann-La Roche AG | Anti-variant fc-region antibodies and methods of use |
EP3184547A1 (en) | 2015-10-29 | 2017-06-28 | F. Hoffmann-La Roche AG | Anti-tpbg antibodies and methods of use |
WO2017075212A1 (en) | 2015-10-30 | 2017-05-04 | Genentech, Inc. | Anti-htra1 antibodies and methods of use thereof |
WO2017075173A2 (en) | 2015-10-30 | 2017-05-04 | Genentech, Inc. | Anti-factor d antibodies and conjugates |
WO2017079479A1 (en) | 2015-11-03 | 2017-05-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human | Neutralizing antibodies to hiv-1 gp41 and their use |
JP6998869B2 (ja) | 2015-11-08 | 2022-02-04 | ジェネンテック, インコーポレイテッド | 多重特異性抗体のスクリーニング方法 |
CN108368174B (zh) | 2015-11-23 | 2023-04-14 | 戊瑞治疗有限公司 | 用于癌症治疗的单独fgfr2抑制剂或与免疫刺激剂的组合 |
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 |
PE20240365A1 (es) | 2015-12-18 | 2024-03-04 | Chugai Pharmaceutical Co Ltd | Anticuerpos anti-c5 y metodos de uso |
CA3007419A1 (en) | 2015-12-30 | 2017-07-06 | Genentech, Inc. | Formulations with reduced degradation of polysorbate |
PL3400246T3 (pl) | 2016-01-08 | 2021-03-08 | F. Hoffmann-La Roche Ag | Sposoby leczenia nowotworów z dodatnim markerem cea z wykorzystaniem antagonistów wiążących oś pd-1 oraz przeciwciał dwuswoistych anty-cea/anty-cd3 |
CN108602883A (zh) | 2016-01-20 | 2018-09-28 | 基因泰克公司 | 用于阿尔茨海默氏病的高剂量治疗 |
CA3019952A1 (en) | 2016-02-04 | 2017-08-10 | Curis, Inc. | Mutant smoothened and methods of using the same |
JP6821693B2 (ja) | 2016-02-29 | 2021-01-27 | ジェネンテック, インコーポレイテッド | がんのための治療方法及び診断方法 |
CN108699155B (zh) | 2016-03-01 | 2023-03-21 | 豪夫迈·罗氏有限公司 | 具有改变的细胞死亡诱导的奥滨尤妥珠单抗变体 |
JP2019515876A (ja) | 2016-03-08 | 2019-06-13 | アカデミア シニカAcademia Sinica | N−グリカンおよびそのアレイのモジュール合成のための方法 |
AU2017235097B2 (en) | 2016-03-15 | 2023-08-31 | Chugai Seiyaku Kabushiki Kaisha | Methods of treating cancers using PD-1 axis binding antagonists and anti-GPC3 antibodies |
CN108700598A (zh) | 2016-03-25 | 2018-10-23 | 豪夫迈·罗氏有限公司 | 多路总抗体和抗体缀合的药物量化测定法 |
AU2017242031B2 (en) | 2016-03-29 | 2023-07-27 | Geltor, Inc. | Expression of proteins in gram-negative bacteria wherein the ratio of periplasmic volume to cytoplasmic volume is between 0.5:1 and 10:1 |
KR101796277B1 (ko) * | 2016-04-12 | 2017-11-13 | 앱클론(주) | 안정성이 개선된 her2에 특이적으로 결합하는 항체 |
WO2017180864A1 (en) | 2016-04-14 | 2017-10-19 | Genentech, Inc. | Anti-rspo3 antibodies and methods of use |
JP7527758B2 (ja) | 2016-04-15 | 2024-08-05 | アルパイン イミューン サイエンシズ インコーポレイテッド | Cd80バリアント免疫調節タンパク質およびその使用 |
MX2018012493A (es) | 2016-04-15 | 2019-06-06 | Genentech Inc | Métodos para controlar y tratar el cáncer. |
KR102459684B1 (ko) | 2016-04-15 | 2022-10-26 | 바이오아트라, 인코퍼레이티드 | 항 Axl항체 및 이의 면역접합체와 이것들의 용도 |
KR102536850B1 (ko) | 2016-04-15 | 2023-05-26 | 알파인 이뮨 사이언시즈, 인코포레이티드 | Icos 리간드 변이체 면역조절 단백질 및 그의 용도 |
CA3019921A1 (en) | 2016-04-15 | 2017-10-19 | Genentech, Inc. | Methods for monitoring and treating cancer |
EP3442562B1 (en) | 2016-04-15 | 2022-09-21 | Evive Biotechnology (Shanghai) Ltd | An il-22 dimer for use in treating necrotizing enterocolitis |
WO2017192589A1 (en) | 2016-05-02 | 2017-11-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to influenza ha and their use and identification |
EP3889175A1 (en) | 2016-05-02 | 2021-10-06 | F. Hoffmann-La Roche AG | The contorsbody - a single chain target binder |
CN109071640B (zh) | 2016-05-11 | 2022-10-18 | 豪夫迈·罗氏有限公司 | 经修饰抗生腱蛋白抗体及使用方法 |
HRP20221298T1 (hr) | 2016-05-13 | 2022-12-23 | Bioatla, Inc. | Anti-ror2 protutijela, fragmenti protutijela, njihovi imunokonjugati i njihove uporabe |
CN109152843A (zh) | 2016-05-20 | 2019-01-04 | 豪夫迈·罗氏有限公司 | Protac抗体缀合物及其使用方法 |
US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
EP3465221B1 (en) | 2016-05-27 | 2020-07-22 | H. Hoffnabb-La Roche Ag | Bioanalytical method for the characterization of site-specific antibody-drug conjugates |
WO2017205843A1 (en) | 2016-05-27 | 2017-11-30 | Tg Therapeutics, Inc. | Combination of anti-cd20 antibody, p13 kinase-delta selective inhibitor, and btk inhibitor to treat b-cell proliferative disorders |
TW201902512A (zh) | 2016-06-02 | 2019-01-16 | 瑞士商赫孚孟拉羅股份公司 | 治療方法 |
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 |
US10639378B2 (en) | 2016-06-06 | 2020-05-05 | Genentech, Inc. | Silvestrol antibody-drug conjugates and methods of use |
WO2017223405A1 (en) | 2016-06-24 | 2017-12-28 | Genentech, Inc. | Anti-polyubiquitin multispecific antibodies |
EP3478717B1 (en) | 2016-07-04 | 2022-01-05 | F. Hoffmann-La Roche AG | Novel antibody format |
WO2018014260A1 (en) | 2016-07-20 | 2018-01-25 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
US11834490B2 (en) | 2016-07-28 | 2023-12-05 | Alpine Immune Sciences, Inc. | CD112 variant immunomodulatory proteins and uses thereof |
CA3032120A1 (en) | 2016-07-28 | 2018-02-01 | Alpine Immune Sciences, Inc. | Cd155 variant immunomodulatory proteins and uses thereof |
US11471488B2 (en) | 2016-07-28 | 2022-10-18 | Alpine Immune Sciences, Inc. | CD155 variant immunomodulatory proteins and uses thereof |
CN109562282A (zh) | 2016-07-29 | 2019-04-02 | 伊莱利利公司 | 用于治疗癌症的使用merestinib和抗-pd-l1或抗-pd-1抑制剂的组合疗法 |
MX2019001184A (es) | 2016-07-29 | 2019-09-26 | Juno Therapeutics Inc | Anticuerpos anti-idiotípicos y métodos relacionados. |
CN117986372A (zh) | 2016-07-29 | 2024-05-07 | 中外制药株式会社 | 显示增加的备选fviii辅因子功能活性的双特异性抗体 |
WO2018027204A1 (en) | 2016-08-05 | 2018-02-08 | Genentech, Inc. | Multivalent and multiepitopic anitibodies having agonistic activity and methods of use |
EP3494991A4 (en) | 2016-08-05 | 2020-07-29 | Chugai Seiyaku Kabushiki Kaisha | COMPOSITION FOR PREVENTING OR TREATING DISEASES RELATING TO IL-8 |
WO2018029124A1 (en) | 2016-08-08 | 2018-02-15 | F. Hoffmann-La Roche Ag | Therapeutic and diagnostic methods for cancer |
CN109689111B (zh) | 2016-08-11 | 2024-04-05 | 基因泰克公司 | 吡咯并苯并二氮杂䓬前药及其抗体缀合物 |
CA3034057A1 (en) | 2016-08-22 | 2018-03-01 | CHO Pharma Inc. | Antibodies, binding fragments, and methods of use |
CA3035081A1 (en) | 2016-09-02 | 2018-03-08 | Dana-Farber Cancer Institute, Inc. | Composition and methods of treating b cell disorders |
US11168148B2 (en) | 2016-09-07 | 2021-11-09 | The Regents Of The University Of California | Antibodies to oxidation-specific epitopes |
EP3509634A1 (en) | 2016-09-09 | 2019-07-17 | TG Therapeutics Inc. | Combination of an anti-cd20 antibody, pi3 kinase-delta inhibitor, and anti-pd-1 or anti-pd-l1 antibody for treating hematological cancers |
SG10201607778XA (en) | 2016-09-16 | 2018-04-27 | Chugai Pharmaceutical Co Ltd | Anti-Dengue Virus Antibodies, Polypeptides Containing Variant Fc Regions, And Methods Of Use |
EP3515932B1 (en) | 2016-09-19 | 2023-11-22 | F. Hoffmann-La Roche AG | Complement factor based affinity chromatography |
RU2752785C2 (ru) | 2016-09-23 | 2021-08-04 | Дженентек, Инк. | Применение антагонистов il-13 для лечения атопического дерматита |
CA3037086A1 (en) | 2016-10-03 | 2018-04-12 | Juno Therapeutics, Inc. | Hpv-specific binding molecules |
EP3522933B1 (en) | 2016-10-05 | 2021-12-15 | F. Hoffmann-La Roche AG | Methods for preparing antibody drug conjugates |
KR20190072528A (ko) | 2016-10-06 | 2019-06-25 | 제넨테크, 인크. | 암에 대한 치료 및 진단 방법 |
WO2018068201A1 (en) | 2016-10-11 | 2018-04-19 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against ctla-4 |
CN110267678A (zh) | 2016-10-29 | 2019-09-20 | 霍夫曼-拉罗奇有限公司 | 抗mic抗体和使用方法 |
ES2898025T3 (es) | 2016-11-02 | 2022-03-03 | Jounce Therapeutics Inc | Anticuerpos contra PD-1 y sus usos |
WO2018085801A1 (en) * | 2016-11-07 | 2018-05-11 | Weiner David B | Dna antibody constructs for use against lyme disease |
US11466094B2 (en) | 2016-11-15 | 2022-10-11 | Genentech, Inc. | Dosing for treatment with anti-CD20/anti-CD3 bispecific antibodies |
WO2018093669A1 (en) | 2016-11-16 | 2018-05-24 | Eli Lilly And Company | Combination therapy for cancer with exon 14 skipping mutation(s) or exon 14 skipping phenotype |
TW201829463A (zh) | 2016-11-18 | 2018-08-16 | 瑞士商赫孚孟拉羅股份公司 | 抗hla-g抗體及其用途 |
JOP20190100A1 (ar) | 2016-11-19 | 2019-05-01 | Potenza Therapeutics Inc | بروتينات ربط مولد ضد مضاد لـ gitr وطرق استخدامها |
EP3468991A1 (en) | 2016-11-21 | 2019-04-17 | cureab GmbH | Anti-gp73 antibodies and immunoconjugates |
TW202328181A (zh) | 2016-12-07 | 2023-07-16 | 美商建南德克公司 | 抗-tau抗體及使用方法 |
CN110494443A (zh) | 2016-12-07 | 2019-11-22 | 分子模板公司 | 用于位点特异性缀合的志贺毒素a亚基效应子多肽、志贺毒素效应子支架和细胞靶向分子 |
CA3045294A1 (en) | 2016-12-07 | 2018-06-14 | Genentech, Inc. | Anti-tau antibodies and methods of use |
BR112019011199A2 (pt) | 2016-12-12 | 2019-10-08 | Genentech Inc | método para tratar um indivíduo que tem um câncer de próstata e kits |
AU2017384126A1 (en) | 2016-12-20 | 2019-05-02 | F. Hoffmann-La Roche Ag | Combination therapy of anti-CD20/anti-CD3 bispecific antibodies and 4-1BB (CD137) agonists |
JOP20190134A1 (ar) | 2016-12-23 | 2019-06-02 | Potenza Therapeutics Inc | بروتينات رابطة لمولد ضد مضادة لنيوروبيلين وطرق استخدامها |
CR20190309A (es) | 2017-01-03 | 2019-08-21 | Hoffmann La Roche | Moleculas de unión de3 antígeno biespecíficas que comprenden el clon 20h4.9 anti-4-1bb |
TW201825515A (zh) | 2017-01-04 | 2018-07-16 | 美商伊繆諾金公司 | Met抗體以及其免疫結合物及用途 |
EP3568468A4 (en) | 2017-01-12 | 2020-12-30 | Eureka Therapeutics, Inc. | RECOMBINATION PRODUCTS TARGETING PEPTIDE HISTONE H3 / MHC COMPLEXES AND THEIR USES |
US20200024312A1 (en) | 2017-01-25 | 2020-01-23 | Molecular Templates, Inc. | Cell-targeting molecules comprising de-immunized, shiga toxin a subunit effectors and cd8+ t-cell epitopes |
KR101949891B1 (ko) | 2017-01-31 | 2019-02-19 | 추가이 세이야쿠 가부시키가이샤 | C5-관련 질환의 치료 또는 예방용 의약 조성물 및 c5-관련 질환을 치료 또는 예방하기 위한 방법 |
WO2018148660A1 (en) | 2017-02-10 | 2018-08-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use |
US10738131B2 (en) | 2017-02-10 | 2020-08-11 | Genentech, Inc. | Anti-tryptase antibodies, compositions thereof, and uses thereof |
WO2018160841A1 (en) | 2017-03-01 | 2018-09-07 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
EP3596114A2 (en) | 2017-03-16 | 2020-01-22 | Alpine Immune Sciences, Inc. | Cd80 variant immunomodulatory proteins and uses thereof |
EP4306537A3 (en) | 2017-03-16 | 2024-03-06 | Alpine Immune Sciences, Inc. | Pd-l1 variant immunomodulatory proteins and uses thereof |
US11732022B2 (en) | 2017-03-16 | 2023-08-22 | Alpine Immune Sciences, Inc. | PD-L2 variant immunomodulatory proteins and uses thereof |
AR111249A1 (es) | 2017-03-22 | 2019-06-19 | Genentech Inc | Composiciones de anticuerpo optimizadas para el tratamiento de trastornos oculares |
PE20200152A1 (es) | 2017-03-27 | 2020-01-17 | Hoffmann La Roche | Receptores de union a antigeno mejorados |
MA48996A (fr) | 2017-03-28 | 2020-02-05 | Genentech Inc | Méthodes de traitement de maladies neurodégénératives |
JP7205995B2 (ja) | 2017-03-29 | 2023-01-17 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 共刺激性tnf受容体に対する二重特異性抗原結合分子 |
JP7196094B2 (ja) | 2017-03-29 | 2022-12-26 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 共刺激tnf受容体のための二重特異性抗原結合分子 |
JOP20190203A1 (ar) | 2017-03-30 | 2019-09-03 | Potenza Therapeutics Inc | بروتينات رابطة لمولد ضد مضادة لـ tigit وطرق استخدامها |
SG11201909218RA (en) | 2017-04-03 | 2019-11-28 | Hoffmann La Roche | Antibodies binding to steap-1 |
CN110402255B (zh) | 2017-04-04 | 2022-12-02 | 豪夫迈·罗氏有限公司 | 新颖的能够特异性结合cd40和fap的双特异性抗原结合分子 |
KR102408873B1 (ko) | 2017-04-05 | 2022-06-15 | 에프. 호프만-라 로슈 아게 | Pd1 및 lag3에 특이적으로 결합하는 이중특이적 항체 |
DK3606954T3 (en) | 2017-04-05 | 2022-09-26 | Hoffmann La Roche | Anti-LAG3-antistoffer |
AU2018251993A1 (en) | 2017-04-14 | 2019-10-24 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
MA49131A (fr) | 2017-04-21 | 2020-03-25 | Hoffmann La Roche | Utilisation d'antagonistes de klk5 pour le traitement d'une maladie |
SG11201909728XA (en) | 2017-04-26 | 2019-11-28 | Eureka Therapeutics Inc | Constructs specifically recognizing glypican 3 and uses thereof |
TWI791519B (zh) | 2017-04-27 | 2023-02-11 | 美商提薩羅有限公司 | 針對淋巴細胞活化基因-3(lag-3)之抗體藥劑及其用途 |
KR20200016232A (ko) | 2017-05-05 | 2020-02-14 | 알라코스 인크. | 알레르기성 안구 질환을 치료하기 위한 방법 및 조성물 |
JP7090347B2 (ja) | 2017-05-12 | 2022-06-24 | ハープーン セラピューティクス,インク. | メソテリン結合タンパク質 |
CN118416216A (zh) | 2017-05-16 | 2024-08-02 | 戊瑞治疗有限公司 | 癌症治疗中抗fgfr2抗体与化学治疗剂的组合 |
CN110831969B (zh) | 2017-06-20 | 2024-06-21 | 安进公司 | 使用抑胃肽受体(gipr)结合蛋白与glp-1激动剂的组合治疗或改善代谢障碍的方法 |
JP2020527351A (ja) | 2017-07-21 | 2020-09-10 | ジェネンテック, インコーポレイテッド | がんの治療法及び診断法 |
EP3658584A1 (en) | 2017-07-26 | 2020-06-03 | H. Hoffnabb-La Roche Ag | Combination therapy with a bet inhibitor, a bcl-2 inhibitor and an anti-cd20 antibody |
PL3658589T3 (pl) | 2017-07-26 | 2024-03-18 | Forty Seven, Inc. | Przeciwciała anty-sirp-alfa i powiązane sposoby |
WO2019036855A1 (en) | 2017-08-21 | 2019-02-28 | Adagene Inc. | ANTI-CD137 MOLECULES AND THEIR USE |
EP3684413A1 (en) | 2017-09-20 | 2020-07-29 | Chugai Seiyaku Kabushiki Kaisha | Dosage regimen for combination therapy using pd-1 axis binding antagonists and gpc3 targeting agent |
US11180541B2 (en) | 2017-09-28 | 2021-11-23 | Geltor, Inc. | Recombinant collagen and elastin molecules and uses thereof |
SG11201810270SA (en) | 2017-09-29 | 2019-04-29 | Chugai Pharmaceutical Co Ltd | Multispecific antigen-binding molecules having blood coagulation factor viii (fviii) cofactor function-substituting activity and pharmaceutical formulations containing such a molecule as an active ing |
CA3080546A1 (en) | 2017-10-03 | 2019-04-11 | Juno Therapeutics, Inc. | Hpv-specific binding molecules |
KR20230020022A (ko) | 2017-10-10 | 2023-02-09 | 알파인 이뮨 사이언시즈, 인코포레이티드 | Ctla-4 변이체 면역조절 단백질 및 이의 용도 |
AU2018347521A1 (en) | 2017-10-12 | 2020-05-07 | Immunowake Inc. | VEGFR-antibody light chain fusion protein |
EA202090739A1 (ru) | 2017-10-13 | 2020-09-07 | Харпун Терапьютикс, Инк. | Белки, связывающие антиген созревания в-клеток |
WO2019077496A1 (en) | 2017-10-17 | 2019-04-25 | Rhizen Pharmaceuticals Sa | CRAC CANAL MODULATORS FOR THE TREATMENT OF ESOPHAGE CANCER |
WO2019079520A2 (en) | 2017-10-18 | 2019-04-25 | Alpine Immune Sciences, Inc. | ICOS VARIANT LIGAND IMMUNOMODULATORY IMMUNOMODULATORY PROTEINS, COMPOSITIONS AND METHODS THEREOF |
CN111246885B (zh) | 2017-10-20 | 2024-06-11 | 豪夫迈·罗氏有限公司 | 从单特异性抗体生成多特异性抗体的方法 |
WO2019082124A1 (en) | 2017-10-26 | 2019-05-02 | Rhizen Pharmaceuticals Sa | COMPOSITION AND METHOD FOR THE TREATMENT OF LARGE B-CELL DIFFUSED LYMPHOMA |
KR20200079256A (ko) | 2017-10-30 | 2020-07-02 | 리젠 파마슈티컬스 소시에떼 아노님 | 혈액암 및 고형암을 치료하기 위한 칼슘 방출-활성화된 칼슘 채널 조절제 |
MX2020004100A (es) | 2017-10-30 | 2020-07-24 | Hoffmann La Roche | Metodo para generacion in vivo de anticuerpos multiespecificos a partir de anticuerpos monoespecificos. |
SG11202003501XA (en) | 2017-11-01 | 2020-05-28 | Juno Therapeutics Inc | Antibodies and chimeric antigen receptors specific for b-cell maturation antigen |
MX2020004567A (es) | 2017-11-06 | 2020-08-13 | Genentech Inc | Metodos diagnosticos y terapeuticos para el cancer. |
WO2019108639A1 (en) | 2017-12-01 | 2019-06-06 | Pfizer Inc. | Anti-cxcr5 antibodies and compositions and uses thereof |
EP3720557A1 (en) | 2017-12-06 | 2020-10-14 | Rhizen Pharmaceuticals S.A. | Composition and method for treating peripheral t-cell lymphoma and cutaneous t-cell lymphoma |
MX2020006125A (es) | 2017-12-14 | 2020-08-24 | Hoffmann La Roche | Uso de un anticuerpo biespecifico de cea cd3 y un antagonista de la union al eje de pd-1 en un regimen de dosificacion para tratar el cancer. |
US12006356B2 (en) | 2017-12-15 | 2024-06-11 | Juno Therapeutics, Inc. | Anti-CCT5 binding molecules and chimeric antigen receptors comprising the same |
KR102575787B1 (ko) | 2017-12-21 | 2023-09-08 | 에프. 호프만-라 로슈 아게 | Hla-a2/wt1에 결합하는 항체 |
MX2020006668A (es) | 2017-12-22 | 2020-10-07 | Jounce Therapeutics Inc | Anticuerpos para lilrb2. |
EP3728321A1 (en) | 2017-12-22 | 2020-10-28 | F. Hoffmann-La Roche AG | Use of pilra binding agents for treatment of a disease |
TW201930358A (zh) | 2017-12-28 | 2019-08-01 | 大陸商南京傳奇生物科技有限公司 | 針對tigit之單域抗體及其變異體 |
US20220135687A1 (en) | 2017-12-28 | 2022-05-05 | Nanjing Legend Biotech Co., Ltd. | Antibodies and variants thereof against pd-l1 |
EP3731865A1 (en) | 2017-12-29 | 2020-11-04 | F. Hoffmann-La Roche AG | Method for improving vegf-receptor blocking selectivity of an anti-vegf antibody |
EP3724223A1 (en) | 2018-01-02 | 2020-10-21 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Neutralizing antibodies to ebola virus glycoprotein and their use |
CA3087149A1 (en) | 2018-01-03 | 2019-07-11 | Alpine Immune Sciences, Inc. | Multi-domain immunomodulatory proteins and methods of use thereof |
EP3735271A4 (en) | 2018-01-04 | 2022-06-15 | Iconic Therapeutics, Inc. | ANTI-TISSUE FACTOR ANTIBODIES, ANTIBODY DRUG CONJUGATES AND RELATED METHODS |
US11466077B2 (en) | 2018-01-05 | 2022-10-11 | Ac Immune Sa | Misfolded TDP-43 binding molecules |
KR20200120641A (ko) | 2018-01-15 | 2020-10-21 | 난징 레전드 바이오테크 씨오., 엘티디. | Pd-1에 대한 단일-도메인 항체 및 이의 변이체 |
CA3088649A1 (en) | 2018-01-16 | 2019-07-25 | Lakepharma, Inc. | Bispecific antibody that binds cd3 and another target |
KR20200115546A (ko) | 2018-01-26 | 2020-10-07 | 제넨테크, 인크. | IL-22 Fc 융합 단백질 및 사용 방법 |
LT3743088T (lt) | 2018-01-26 | 2022-12-27 | F. Hoffmann-La Roche Ag | Il-22 fc kompozicijos ir jų naudojimo būdai |
TWI732176B (zh) | 2018-02-01 | 2021-07-01 | 大陸商信達生物製藥(蘇州)有限公司 | 全人源的抗b細胞成熟抗原(bcma)單鏈抗體及其應用 |
WO2019148445A1 (en) | 2018-02-02 | 2019-08-08 | Adagene Inc. | Precision/context-dependent activatable antibodies, and methods of making and using the same |
KR20200118065A (ko) | 2018-02-08 | 2020-10-14 | 제넨테크, 인크. | 이중특이적 항원-결합 분자 및 이의 사용 방법 |
KR20220098056A (ko) | 2018-02-09 | 2022-07-08 | 제넨테크, 인크. | 비만 세포 매개 염증성 질환에 대한 치료 및 진단 방법 |
TWI829667B (zh) | 2018-02-09 | 2024-01-21 | 瑞士商赫孚孟拉羅股份公司 | 結合gprc5d之抗體 |
JP7350756B2 (ja) | 2018-02-14 | 2023-09-26 | アバ セラピューティクス アーゲー | 抗ヒトpd-l2抗体 |
WO2019165122A1 (en) | 2018-02-21 | 2019-08-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to hiv-1 env and their use |
AU2019226085A1 (en) | 2018-02-21 | 2020-09-17 | Genentech, Inc. | Dosing for treatment with IL-22 Fc fusion proteins |
WO2019165434A1 (en) | 2018-02-26 | 2019-08-29 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
CA3092002A1 (en) | 2018-03-13 | 2019-09-19 | F. Hoffmann-La Roche Ag | Therapeutic combination of 4-1 bb agonists with anti-cd20 antibodies |
US20200040103A1 (en) | 2018-03-14 | 2020-02-06 | Genentech, Inc. | Anti-klk5 antibodies and methods of use |
US11485782B2 (en) | 2018-03-14 | 2022-11-01 | Beijing Xuanyi Pharmasciences Co., Ltd. | Anti-claudin 18.2 antibodies |
TWI827585B (zh) | 2018-03-15 | 2024-01-01 | 日商中外製藥股份有限公司 | 對茲卡病毒具有交叉反應性的抗登革病毒抗體及其使用方法 |
SG11202009542PA (en) | 2018-03-29 | 2020-10-29 | Genentech Inc | Modulating lactogenic activity in mammalian cells |
TW202003567A (zh) | 2018-03-30 | 2020-01-16 | 大陸商南京傳奇生物科技有限公司 | 針對lag-3之單一結構域抗體及其用途 |
TW202011029A (zh) | 2018-04-04 | 2020-03-16 | 美商建南德克公司 | 偵測及定量fgf21之方法 |
TWI840351B (zh) | 2018-04-05 | 2024-05-01 | 美商奇諾治療有限公司 | T細胞受體及表現其之工程化細胞 |
MX2019009726A (es) | 2018-04-17 | 2020-02-05 | Molecular Templates Inc | Moleculas con direccion hacia her2 que comprenden andamiajes de la sub-unidad a de la toxina shiga desinmunizados. |
AR115052A1 (es) | 2018-04-18 | 2020-11-25 | Hoffmann La Roche | Anticuerpos multiespecíficos y utilización de los mismos |
AR114789A1 (es) | 2018-04-18 | 2020-10-14 | Hoffmann La Roche | Anticuerpos anti-hla-g y uso de los mismos |
CN110464842B (zh) | 2018-05-11 | 2022-10-14 | 信达生物制药(苏州)有限公司 | 包含抗pcsk9抗体的制剂及其用途 |
SG11202011349PA (en) | 2018-05-14 | 2020-12-30 | Werewolf Therapeutics Inc | Activatable interleukin-2 polypeptides and methods of use thereof |
EP3794022A1 (en) | 2018-05-14 | 2021-03-24 | Werewolf Therapeutics, Inc. | Activatable cytokine polypeptides and methods of use thereof |
KR20210056288A (ko) | 2018-06-01 | 2021-05-18 | 타유 후아시아 바이오테크 메디컬 그룹 컴퍼니 리미티드 | 질환 또는 병태를 치료하기 위한 조성물 및 그의 용도 |
EP3805400A4 (en) | 2018-06-04 | 2022-06-29 | Chugai Seiyaku Kabushiki Kaisha | Antigen-binding molecule showing changed half-life in cytoplasm |
US12065476B2 (en) | 2018-06-15 | 2024-08-20 | Alpine Immune Sciences, Inc. | PD-1 variant immunomodulatory proteins and uses thereof |
SG11202012342WA (en) | 2018-06-18 | 2021-01-28 | Eureka Therapeutics Inc | Constructs targeting prostate-specific membrane antigen (psma) and uses thereof |
US20200030443A1 (en) | 2018-06-23 | 2020-01-30 | Genentech, Inc. | Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor |
EP3818082A1 (en) | 2018-07-04 | 2021-05-12 | F. Hoffmann-La Roche AG | Novel bispecific agonistic 4-1bb antigen binding molecules |
WO2020014306A1 (en) | 2018-07-10 | 2020-01-16 | Immunogen, Inc. | Met antibodies and immunoconjugates and uses thereof |
CN112839644A (zh) | 2018-07-18 | 2021-05-25 | 豪夫迈·罗氏有限公司 | 用pd-1轴结合拮抗剂、抗代谢物和铂剂治疗肺癌的方法 |
MX2021000745A (es) | 2018-07-20 | 2021-03-26 | Surface Oncology Inc | Composiciones anti-cd112r y metodos. |
CN112512563A (zh) | 2018-08-01 | 2021-03-16 | 中外制药株式会社 | 用于治疗或预防c5相关疾病的药物组合物和治疗或预防c5相关疾病的方法 |
JP7504027B2 (ja) | 2018-08-03 | 2024-06-21 | 中外製薬株式会社 | 互いに連結された2つの抗原結合ドメインを含む抗原結合分子 |
CA3051549A1 (en) | 2018-08-09 | 2020-02-09 | Regeneron Pharmaceuticals, Inc. | Methods for assessing binding affinity of an antibody variant to the neonatal fc receptor |
WO2020032230A1 (ja) | 2018-08-10 | 2020-02-13 | 中外製薬株式会社 | 抗cd137抗原結合分子およびその使用 |
TW202021618A (zh) | 2018-08-17 | 2020-06-16 | 美商23與我有限公司 | 抗il1rap抗體及其使用方法 |
GB201814281D0 (en) | 2018-09-03 | 2018-10-17 | Femtogenix Ltd | Cytotoxic agents |
AU2019342099A1 (en) | 2018-09-19 | 2021-04-08 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2020061376A2 (en) | 2018-09-19 | 2020-03-26 | Alpine Immune Sciences, Inc. | Methods and uses of variant cd80 fusion proteins and related constructs |
EP4249917A3 (en) | 2018-09-21 | 2023-11-08 | F. Hoffmann-La Roche AG | Diagnostic methods for triple-negative breast cancer |
CA3114038A1 (en) | 2018-09-25 | 2020-04-02 | Harpoon Therapeutics, Inc. | Dll3 binding proteins and methods of use |
SG11202102777PA (en) | 2018-09-27 | 2021-04-29 | Xilio Development Inc | Masked cytokine polypeptides |
AU2019355252A1 (en) | 2018-10-01 | 2021-04-01 | F. Hoffmann-La Roche Ag | Bispecific antigen binding molecules comprising anti-FAP clone 212 |
EP3861025A1 (en) | 2018-10-01 | 2021-08-11 | F. Hoffmann-La Roche AG | Bispecific antigen binding molecules with trivalent binding to cd40 |
CN112804989A (zh) | 2018-10-05 | 2021-05-14 | 戊瑞治疗有限公司 | 抗fgfr2抗体制剂 |
EP3868784A4 (en) | 2018-10-15 | 2022-07-27 | Industry-Academic Cooperation Foundation, Yonsei University | ANTIBODIES WITH INCREASED PRODUCTIVITY AND METHODS FOR THEIR PRODUCTION |
WO2020081493A1 (en) | 2018-10-16 | 2020-04-23 | Molecular Templates, Inc. | Pd-l1 binding proteins |
CA3116324A1 (en) | 2018-10-18 | 2020-04-23 | Genentech, Inc. | Diagnostic and therapeutic methods for sarcomatoid kidney cancer |
US20210395390A1 (en) | 2018-10-31 | 2021-12-23 | Bayer Aktiengesellschaft | Reversal agents for neutralizing the therapeutic activity of anti-fxia antibodies |
RU2724469C2 (ru) | 2018-10-31 | 2020-06-23 | Закрытое Акционерное Общество "Биокад" | Моноклональное антитело, которое специфически связывается с cd20 |
EP3877407A1 (en) | 2018-11-05 | 2021-09-15 | F. Hoffmann-La Roche AG | Methods of producing two chain proteins in prokaryotic host cells |
AU2019380320A1 (en) | 2018-11-16 | 2021-06-03 | Eureka Therapeutics, Inc. | Antibodies to Mucin-16 and methods of use thereof |
CA3101670C (en) | 2018-11-27 | 2024-02-06 | Innovent Biologics (Suzhou) Co., Ltd. | Anti-il-23p19 antibody and use thereof |
CA3120868A1 (en) | 2018-11-30 | 2020-06-04 | Alpine Immune Sciences, Inc. | Cd86 variant immunomodulatory proteins and uses thereof |
AU2019394940A1 (en) | 2018-12-05 | 2021-06-24 | Genentech, Inc. | Diagnostic methods and compositions for cancer immunotherapy |
BR112021010908A2 (pt) | 2018-12-06 | 2021-08-31 | Genentech, Inc. | Método para tratamento de linfoma difuso de grandes células b, kit e imunoconjugado |
JP2022513198A (ja) | 2018-12-10 | 2022-02-07 | ジェネンテック, インコーポレイテッド | Fc含有タンパク質への部位特異的コンジュゲーションのための光架橋性ペプチド |
US20220089694A1 (en) | 2018-12-20 | 2022-03-24 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Ebola virus glycoprotein-specific monoclonal antibodies and uses thereof |
AR117327A1 (es) | 2018-12-20 | 2021-07-28 | 23Andme Inc | Anticuerpos anti-cd96 y métodos de uso de estos |
TW202035442A (zh) | 2018-12-20 | 2020-10-01 | 美商建南德克公司 | 經修飾之抗體Fc及其使用方法 |
SG11202102859TA (en) | 2018-12-21 | 2021-04-29 | Hoffmann La Roche | Antibodies binding to cd3 |
SG11202106100VA (en) | 2018-12-21 | 2021-07-29 | 23Andme Inc | Anti-il-36 antibodies and methods of use thereof |
CA3123503A1 (en) | 2018-12-21 | 2020-06-25 | F. Hoffmann-La Roche Ag | Antibody that binds to vegf and il-1beta and methods of use |
KR20210107025A (ko) | 2018-12-21 | 2021-08-31 | 제넨테크, 인크. | 세포사멸에 내성인 세포주를 사용한 폴리펩티드 생산 방법 |
US20220064301A1 (en) | 2018-12-26 | 2022-03-03 | Xilio Development, Inc. | Anti-ctla4 antibodies and methods of use thereof |
CN113272327A (zh) | 2018-12-30 | 2021-08-17 | 豪夫迈·罗氏有限公司 | 抗兔cd19抗体及其使用方法 |
MX2021008434A (es) | 2019-01-14 | 2021-09-23 | Genentech Inc | Metodos para tratar el cancer con un antagonista de union al eje de pd-1 y una vacuna de arn. |
CN113330030A (zh) | 2019-01-17 | 2021-08-31 | 拜耳公司 | 确定受试者是否适于用可溶性鸟苷酸环化酶(sGC)的激动剂治疗的方法 |
MX2021008621A (es) | 2019-01-22 | 2021-08-19 | Genentech Inc | Anticuerpos de inmunoglobulina a y metodos de produccion y uso. |
WO2020154410A1 (en) | 2019-01-23 | 2020-07-30 | Genentech, Inc. | Methods of producing multimeric proteins in eukaryotic host cells |
JPWO2020153467A1 (ja) | 2019-01-24 | 2021-12-02 | 中外製薬株式会社 | 新規がん抗原及びそれらの抗原に対する抗体 |
US20220096651A1 (en) | 2019-01-29 | 2022-03-31 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1) |
GB201901197D0 (en) | 2019-01-29 | 2019-03-20 | Femtogenix Ltd | G-A Crosslinking cytotoxic agents |
AU2020228383A1 (en) | 2019-02-27 | 2021-09-23 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-CD20 or anti-CD38 antibodies |
JP7402247B2 (ja) | 2019-03-08 | 2023-12-20 | ジェネンテック, インコーポレイテッド | 細胞外小胞の膜結合タンパク質を検出及び定量化するための方法 |
AU2020236015A1 (en) | 2019-03-14 | 2021-09-09 | Genentech, Inc. | Treatment of cancer with HER2XCD3 bispecific antibodies in combination with anti-HER2 MAB |
CN113660953A (zh) | 2019-04-01 | 2021-11-16 | 豪夫迈·罗氏有限公司 | 用于稳定含蛋白质制剂的组合物和方法 |
WO2020210440A1 (en) | 2019-04-12 | 2020-10-15 | Geltor, Inc. | Recombinant elastin and production thereof |
AU2020257238A1 (en) | 2019-04-17 | 2021-12-02 | Alpine Immune Sciences, Inc. | Methods and uses of variant ICOS Ligand (ICOSL) fusion proteins |
JP2022529344A (ja) | 2019-04-18 | 2022-06-21 | エイシー イミューン ソシエテ アノニム | 治療及び診断のための新規分子 |
AU2020258480A1 (en) | 2019-04-19 | 2021-10-21 | Genentech, Inc. | Anti-mertk antibodies and their methods of use |
US20220143094A1 (en) | 2019-04-19 | 2022-05-12 | Chugai Seiyaku Kabushiki Kaisha | Chimeric receptor that recognizes engineered site in antibody |
US20220227853A1 (en) | 2019-05-03 | 2022-07-21 | The United States Of America,As Represented By The Secretary,Department Of Health And Human Services | Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use |
TW202108616A (zh) | 2019-05-03 | 2021-03-01 | 美商建南德克公司 | 用抗pd-l1抗體治療癌症之方法 |
MX2021013825A (es) | 2019-05-14 | 2022-01-18 | Genentech Inc | Procedimientos de uso de inmunoconjugados anti-cd79b para tratar el linfoma folicular. |
SG11202112541RA (en) | 2019-05-14 | 2021-12-30 | Werewolf Therapeutics Inc | Separation moieties and methods and use thereof |
US20230085439A1 (en) | 2019-05-21 | 2023-03-16 | University Of Georgia Research Foundation, Inc. | Antibodies that bind human metapneumovirus fusion protein and their use |
SG11202112453TA (en) | 2019-05-23 | 2021-12-30 | Ac Immune Sa | Anti-tdp-43 binding molecules and uses thereof |
CR20220008A (es) | 2019-06-10 | 2022-02-11 | Chugai Pharmaceutical Co Ltd | Molécula de unión al antígeno anti-células t para usarse en combinación con un inhibidor de citocinas |
AU2020299382A1 (en) | 2019-07-02 | 2022-01-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies that bind EGFRvIII and their use |
JPWO2021010326A1 (zh) | 2019-07-12 | 2021-01-21 | ||
AR119382A1 (es) | 2019-07-12 | 2021-12-15 | Hoffmann La Roche | Anticuerpos de pre-direccionamiento y métodos de uso |
AR119393A1 (es) | 2019-07-15 | 2021-12-15 | Hoffmann La Roche | Anticuerpos que se unen a nkg2d |
EP4004045A1 (en) | 2019-07-31 | 2022-06-01 | F. Hoffmann-La Roche AG | Antibodies binding to gprc5d |
KR102618269B1 (ko) | 2019-07-31 | 2023-12-27 | 에프. 호프만-라 로슈 아게 | 항-c5 항체 크로발리맙의 사용에 의한 c5-관련 질병의 치료 또는 예방을 위한 투여량 및 투여 섭생 |
WO2021019036A1 (en) | 2019-07-31 | 2021-02-04 | F. Hoffmann-La Roche Ag | Dosage and administration regimen for the treatment or prevention of c5-related diseases by the use of the anti-c5 antibody crovalimab |
KR20220028035A (ko) | 2019-07-31 | 2022-03-08 | 에프. 호프만-라 로슈 아게 | Gprc5d에 결합하는 항체 |
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 |
JP7181438B2 (ja) | 2019-08-06 | 2022-11-30 | アプリノイア セラピューティクス リミテッド | 病理学的タウ種に結合する抗体及びその使用 |
CA3146616A1 (en) | 2019-09-12 | 2021-03-18 | Matthew Dominic CASCINO | Compositions and methods of treating lupus nephritis |
WO2021047599A1 (en) * | 2019-09-13 | 2021-03-18 | Beijing Xuanyi Pharmasciences Co., Ltd. | Humanized anti-claudin 18.2 (cldn18.2) antibodies |
CA3150999A1 (en) | 2019-09-18 | 2021-03-25 | James Thomas Koerber | Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use |
CN114423454A (zh) | 2019-09-20 | 2022-04-29 | 豪夫迈·罗氏有限公司 | 抗类胰蛋白酶抗体的给药 |
JP2022550067A (ja) | 2019-09-27 | 2022-11-30 | ヤンセン バイオテツク,インコーポレーテツド | 抗ceacam抗体及びその使用 |
PE20221110A1 (es) | 2019-09-27 | 2022-07-11 | Genentech Inc | Administracion de dosis para tratamiento con anticuerpos antagonistas anti-tigit y anti-pd-l1 |
CA3153880A1 (en) | 2019-10-18 | 2020-06-09 | Juana Elva HERNANDEZ MONTALVO | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
EP4048251A1 (en) | 2019-10-21 | 2022-08-31 | Rhizen Pharmaceuticals AG | Compositions comprising a dhodh inhibitor for the treatment of acute myeloid leukemia |
WO2021092171A1 (en) | 2019-11-06 | 2021-05-14 | Genentech, Inc. | Diagnostic and therapeutic methods for treatment of hematologic cancers |
EP4058471A1 (en) | 2019-11-14 | 2022-09-21 | Werewolf Therapeutics, Inc. | Activatable cytokine polypeptides and methods of use thereof |
JP2023504699A (ja) | 2019-12-04 | 2023-02-06 | エイシー イミューン ソシエテ アノニム | 治療および診断のための新規な分子 |
WO2021113776A1 (en) | 2019-12-06 | 2021-06-10 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to bcma-targeted binding domains and related compositions and methods |
WO2021113780A1 (en) | 2019-12-06 | 2021-06-10 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to gprc5d-targeted binding domains and related compositions and methods |
KR20220113790A (ko) | 2019-12-13 | 2022-08-16 | 제넨테크, 인크. | 항-ly6g6d 항체 및 사용 방법 |
WO2021122875A1 (en) | 2019-12-18 | 2021-06-24 | F. Hoffmann-La Roche Ag | Antibodies binding to hla-a2/mage-a4 |
CN113045655A (zh) | 2019-12-27 | 2021-06-29 | 高诚生物医药(香港)有限公司 | 抗ox40抗体及其用途 |
KR102645629B1 (ko) | 2019-12-27 | 2024-03-07 | 추가이 세이야쿠 가부시키가이샤 | 항ctla-4 항체 및 그의 사용 |
JP2023509323A (ja) | 2020-01-06 | 2023-03-08 | ヴァクシネックス, インコーポレイテッド | 抗ccr8抗体及びその使用 |
CN110818795B (zh) | 2020-01-10 | 2020-04-24 | 上海复宏汉霖生物技术股份有限公司 | 抗tigit抗体和使用方法 |
WO2021194481A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
WO2022050954A1 (en) | 2020-09-04 | 2022-03-10 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
AU2021212197A1 (en) | 2020-01-31 | 2022-08-04 | BioNTech SE | Methods of inducing neoepitope-specific T cells with a PD-1 axis binding antagonist and an RNA vaccine |
CA3165319A1 (en) | 2020-01-31 | 2021-08-05 | Vincent K. Tuohy | Anti-mullerian hormone receptor 2 antibodies and methods of use |
TW202144395A (zh) | 2020-02-12 | 2021-12-01 | 日商中外製藥股份有限公司 | 用於癌症之治療的抗cd137抗原結合分子 |
CN115087488A (zh) | 2020-02-14 | 2022-09-20 | 震动疗法股份有限公司 | 与ccr8结合的抗体和融合蛋白及其用途 |
WO2021168292A1 (en) | 2020-02-20 | 2021-08-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Epstein-barr virus monoclonal antibodies and uses thereof |
EP4110826A4 (en) | 2020-02-28 | 2024-08-14 | Shanghai Henlius Biotech Inc | ANTI-CD137 CONSTRUCTS, MULTISPECIFIC ANTIBODIES AND THEIR USES |
CA3169939A1 (en) | 2020-02-28 | 2021-09-02 | Jie Xue | Anti-cd137 construct and use thereof |
BR112022016720A2 (pt) | 2020-03-06 | 2022-11-16 | Ona Therapeutics S L | Anticorpos anti-cd36 e seu uso para tratamento de câncer |
CR20220461A (es) | 2020-03-13 | 2022-10-21 | Genentech Inc | Anticuerpos anti-interleucina-33 y usos de estos |
EP4121163A1 (en) | 2020-03-19 | 2023-01-25 | Genentech, Inc. | Isoform-selective anti-tgf-beta antibodies and methods of use |
WO2021194913A1 (en) | 2020-03-24 | 2021-09-30 | Genentech, Inc. | Tie2-binding agents and methods of use |
KR20220159426A (ko) | 2020-03-26 | 2022-12-02 | 제넨테크, 인크. | 감소된 숙주 세포 단백질을 보유하는 변형된 포유동물 세포 |
EP4126940A1 (en) | 2020-03-30 | 2023-02-08 | F. Hoffmann-La Roche AG | Antibody that binds to vegf and pdgf-b and methods of use |
AR121706A1 (es) | 2020-04-01 | 2022-06-29 | Hoffmann La Roche | Moléculas de unión a antígeno biespecíficas dirigidas a ox40 y fap |
WO2021202959A1 (en) | 2020-04-03 | 2021-10-07 | Genentech, Inc. | Therapeutic and diagnostic methods for cancer |
WO2021207662A1 (en) | 2020-04-10 | 2021-10-14 | Genentech, Inc. | Use of il-22fc for the treatment or prevention of pneumonia, acute respiratory distress syndrome, or cytokine release syndrome |
WO2021217051A1 (en) | 2020-04-24 | 2021-10-28 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
US20230265204A1 (en) | 2020-04-24 | 2023-08-24 | Hoffmann-La Roche Inc. | Enzyme and pathway modulation with sulfhydryl compounds and their derivatives |
US20230167198A1 (en) | 2020-04-27 | 2023-06-01 | The Regents Of The University Of California | Isoform-independent antibodies to lipoprotein(a) |
WO2021222167A1 (en) | 2020-04-28 | 2021-11-04 | Genentech, Inc. | Methods and compositions for non-small cell lung cancer immunotherapy |
CN116963782A (zh) | 2020-05-03 | 2023-10-27 | 联宁(苏州)生物制药有限公司 | 包含抗trop-2抗体的抗体药物偶联物 |
PE20230494A1 (es) | 2020-05-08 | 2023-03-23 | Alpine Immune Sciences Inc | Proteinas inmunomoduladoras inhibidoras de april y baff y metodos de uso de las mismas |
WO2021238886A1 (en) | 2020-05-27 | 2021-12-02 | Staidson (Beijing) Biopharmaceuticals Co., Ltd. | Antibodies specifically recognizing nerve growth factor and uses thereof |
BR112022024339A2 (pt) | 2020-05-29 | 2022-12-27 | 23Andme Inc | Anticorpos anti cd200r1 e métodos de uso dos mesmos |
WO2021247769A1 (en) | 2020-06-02 | 2021-12-09 | Dynamicure Biotechnology Llc | Anti-cd93 constructs and uses thereof |
CN116529260A (zh) | 2020-06-02 | 2023-08-01 | 当康生物技术有限责任公司 | 抗cd93构建体及其用途 |
CN115697489A (zh) | 2020-06-08 | 2023-02-03 | 豪夫迈·罗氏有限公司 | 抗hbv抗体及其使用方法 |
JP2023529206A (ja) | 2020-06-12 | 2023-07-07 | ジェネンテック, インコーポレイテッド | がん免疫療法のための方法及び組成物 |
KR20230025691A (ko) | 2020-06-16 | 2023-02-22 | 제넨테크, 인크. | 삼중 음성 유방암을 치료하기 위한 방법과 조성물 |
KR20230024368A (ko) | 2020-06-18 | 2023-02-20 | 제넨테크, 인크. | 항-tigit 항체 및 pd-1 축 결합 길항제를 사용한 치료 |
EP4168447A1 (en) | 2020-06-19 | 2023-04-26 | F. Hoffmann-La Roche AG | Antibodies binding to cd3 and cd19 |
CR20220639A (es) | 2020-06-19 | 2023-02-17 | Hoffmann La Roche | Anticuerpos que se unen a cd3 y folr1 |
WO2021255146A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 and cea |
WO2021255142A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 |
TW202214286A (zh) | 2020-06-19 | 2022-04-16 | 日商中外製藥股份有限公司 | 用於與血管新生抑制劑組合使用之抗t細胞抗原結合分子 |
WO2021259880A1 (en) | 2020-06-22 | 2021-12-30 | Almirall, S.A. | Anti-il-36 antibodies and methods of use thereof |
WO2021259199A1 (zh) | 2020-06-22 | 2021-12-30 | 信达生物制药(苏州)有限公司 | 抗cd73抗体及其用途 |
KR20230026491A (ko) | 2020-06-24 | 2023-02-24 | 제넨테크, 인크. | 아폽토시스 내성 세포주 |
EP4178611A1 (en) | 2020-07-07 | 2023-05-17 | BioNTech SE | Therapeutic rna for hpv-positive cancer |
EP4178985A1 (en) | 2020-07-10 | 2023-05-17 | F. Hoffmann-La Roche AG | Antibodies which bind to cancer cells and target radionuclides to said cells |
MX2023000617A (es) | 2020-07-17 | 2023-02-13 | Genentech Inc | Anticuerpos anti-notch2 y metodos de uso. |
GB2597532A (en) | 2020-07-28 | 2022-02-02 | Femtogenix Ltd | Cytotoxic compounds |
CN116783215A (zh) | 2020-07-29 | 2023-09-19 | 当康生物技术有限责任公司 | 抗cd93构建体及其用途 |
EP4189121A1 (en) | 2020-08-03 | 2023-06-07 | Genentech, Inc. | Diagnostic and therapeutic methods for lymphoma |
WO2022029660A1 (en) | 2020-08-05 | 2022-02-10 | Juno Therapeutics, Inc. | Anti-idiotypic antibodies to ror1-targeted binding domains and related compositions and methods |
AR123158A1 (es) | 2020-08-07 | 2022-11-02 | Genentech Inc | Proteínas de fusión del ligando para flt3 y métodos de uso |
TW202221026A (zh) | 2020-08-14 | 2022-06-01 | 瑞士商Ac 免疫有限公司 | 人源化抗tdp-43結合分子及其用途 |
KR20230048422A (ko) | 2020-08-14 | 2023-04-11 | 에프. 호프만-라 로슈 아게 | 오크렐리주맙으로 다발성 경화증을 치료하는 방법 |
EP4204448A2 (en) | 2020-08-27 | 2023-07-05 | cureab GmbH | Anti-golph2 antibodies for macrophage and dendritic cell differentiation |
EP4204447A1 (en) | 2020-08-28 | 2023-07-05 | Sana Biotechnology, Inc. | Modified anti-viral binding agents |
WO2022047222A2 (en) | 2020-08-28 | 2022-03-03 | Genentech, Inc. | Crispr/cas9 multiplex knockout of host cell proteins |
WO2022049165A1 (en) | 2020-09-04 | 2022-03-10 | F. Hoffmann-La Roche Ag | Antibody that binds to vegf-a and ang2 and methods of use |
WO2022053715A1 (en) | 2020-09-14 | 2022-03-17 | Ichnos Sciences SA | Antibodies that bind to il1rap and uses thereof |
MX2023002984A (es) | 2020-09-15 | 2023-04-10 | Bayer Ag | Nuevos anticuerpos anti-a2ap y usos de los mismos. |
MX2023003685A (es) | 2020-09-30 | 2023-06-02 | Dren Bio Inc | Anticuerpos anti-cd94 y metodos de uso de los mismos. |
KR20230082632A (ko) | 2020-10-05 | 2023-06-08 | 제넨테크, 인크. | 항-fcrh5/항-cd3 이중특이성 항체를 사용한 치료를 위한 투약 |
US12037399B2 (en) | 2020-10-07 | 2024-07-16 | Dren Bio, Inc. | Anti-Dectin-1 antibodies and methods of use thereof |
WO2022079297A1 (en) | 2020-10-16 | 2022-04-21 | Ac Immune Sa | Antibodies binding to alpha-synuclein for therapy and diagnosis |
WO2022084210A1 (en) | 2020-10-20 | 2022-04-28 | F. Hoffmann-La Roche Ag | Combination therapy of pd-1 axis binding antagonists and lrrk2 inhitibors |
AR123855A1 (es) | 2020-10-20 | 2023-01-18 | Genentech Inc | Anticuerpos anti-mertk conjugados con peg y métodos de uso |
EP4232475A1 (en) | 2020-10-20 | 2023-08-30 | Kantonsspital St. Gallen | Antibodies or antigen-binding fragments specifically binding to gremlin-1 and uses thereof |
WO2022093981A1 (en) | 2020-10-28 | 2022-05-05 | Genentech, Inc. | Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists |
KR20230100732A (ko) | 2020-11-04 | 2023-07-05 | 제넨테크, 인크. | 항-cd20/항-cd3 이중특이성 항체의 피하 투여 |
WO2022098648A2 (en) | 2020-11-04 | 2022-05-12 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies and anti-cd79b antibody drug conjugates |
JP7402381B2 (ja) | 2020-11-04 | 2023-12-20 | ジェネンテック, インコーポレイテッド | 抗cd20/抗cd3二重特異性抗体による処置のための投与 |
WO2022104150A1 (en) | 2020-11-12 | 2022-05-19 | Tg Therapeutics, Inc. | Triple combination to treat b-cell malignancies |
WO2022122652A1 (en) | 2020-12-07 | 2022-06-16 | UCB Biopharma SRL | Antibodies against interleukin-22 |
AU2021395729A1 (en) | 2020-12-07 | 2023-07-13 | UCB Biopharma SRL | Multi-specific antibodies and antibody combinations |
TW202237638A (zh) | 2020-12-09 | 2022-10-01 | 日商武田藥品工業股份有限公司 | 烏苷酸環化酶c(gcc)抗原結合劑之組成物及其使用方法 |
TW202237639A (zh) | 2020-12-09 | 2022-10-01 | 日商武田藥品工業股份有限公司 | 鳥苷酸環化酶c(gcc)抗原結合劑之組成物及其使用方法 |
KR20230120665A (ko) | 2020-12-17 | 2023-08-17 | 에프. 호프만-라 로슈 아게 | 항-hla-g 항체 및 이의 용도 |
WO2022132904A1 (en) | 2020-12-17 | 2022-06-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies targeting sars-cov-2 |
WO2022135666A1 (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 |
TW202245808A (zh) | 2020-12-21 | 2022-12-01 | 德商拜恩迪克公司 | 用於治療癌症之治療性rna |
KR20230124959A (ko) | 2020-12-23 | 2023-08-28 | 이노벤트 바이오로직스 (쑤저우) 컴퍼니, 리미티드 | 항-b7-h3 항체 및 이의 용도 |
WO2022140797A1 (en) | 2020-12-23 | 2022-06-30 | Immunowake Inc. | Immunocytokines and uses thereof |
CA3207090A1 (en) | 2021-01-06 | 2022-07-14 | F. Hoffmann-La Roche Ag | Combination therapy employing a pd1-lag3 bispecific antibody and a cd20 t cell bispecific antibody |
AU2022207615A1 (en) | 2021-01-12 | 2023-07-13 | F. Hoffmann-La Roche Ag | Split antibodies which bind to cancer cells and target radionuclides to said cells |
JP2024503654A (ja) | 2021-01-13 | 2024-01-26 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 併用療法 |
EP4284422A1 (en) | 2021-01-28 | 2023-12-06 | Vaccinvent GmbH | Method and means for modulating b-cell mediated immune responses |
WO2022162203A1 (en) | 2021-01-28 | 2022-08-04 | Vaccinvent Gmbh | Method and means for modulating b-cell mediated immune responses |
CN117120084A (zh) | 2021-01-28 | 2023-11-24 | 维肯芬特有限责任公司 | 用于调节b细胞介导的免疫应答的方法和手段 |
MX2023009100A (es) | 2021-02-03 | 2023-09-25 | Mozart Therapeutics Inc | Agentes aglutinantes y métodos para usar los mismos. |
WO2022169872A1 (en) | 2021-02-03 | 2022-08-11 | Genentech, Inc. | Multispecific binding protein degrader platform and methods of use |
WO2022173670A1 (en) | 2021-02-09 | 2022-08-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibodies targeting the spike protein of coronaviruses |
CN117396502A (zh) | 2021-02-09 | 2024-01-12 | 佐治亚大学研究基金会有限公司 | 针对肺炎球菌抗原的人类单克隆抗体 |
CA3208365A1 (en) | 2021-02-15 | 2022-08-18 | Chantal KUHN | Cell therapy compositions and methods for modulating tgf-b signaling |
CN117157317A (zh) | 2021-02-26 | 2023-12-01 | 拜耳公司 | 用于治疗异常子宫出血的IL-11或IL-11Ra的抑制剂 |
TW202317612A (zh) | 2021-03-01 | 2023-05-01 | 美商艾希利歐發展股份有限公司 | 用於治療癌症的ctla4及pd1/pdl1抗體之組合 |
WO2022187272A1 (en) | 2021-03-01 | 2022-09-09 | Xilio Development, Inc. | Combination of masked ctla4 and pd1/pdl1 antibodies for treating cancer |
JP2024509169A (ja) | 2021-03-03 | 2024-02-29 | ソレント・セラピューティクス・インコーポレイテッド | 抗bcma抗体を含む抗体-薬物コンジュゲート |
CN117715933A (zh) | 2021-03-05 | 2024-03-15 | 当康生物技术有限责任公司 | 抗vista的构建体及其用途 |
EP4294927A2 (en) | 2021-03-10 | 2023-12-27 | Immunowake Inc. | Immunomodulatory molecules and uses thereof |
JP2024512377A (ja) | 2021-03-12 | 2024-03-19 | ジェネンテック, インコーポレイテッド | 抗klk7抗体、抗klk5抗体、多重特異性抗klk5/klk7抗体、及び使用方法 |
BR112023018621A2 (pt) | 2021-03-15 | 2023-10-24 | Hoffmann La Roche | Métodos para tratar nefrite lúpica, esgotar células b periféricas, kits para tratar nefrite lúpica e anticorpos anti-cd20 tipo ii |
WO2022197877A1 (en) | 2021-03-19 | 2022-09-22 | Genentech, Inc. | Methods and compositions for time delayed bio-orthogonal release of cytotoxic agents |
JP2024511424A (ja) | 2021-03-25 | 2024-03-13 | ダイナミキュア バイオテクノロジー エルエルシー | 抗igfbp7構築物およびその使用 |
PE20240357A1 (es) | 2021-03-30 | 2024-02-27 | Bayer Ag | Anticuerpos anti-sema3a y usos de los mismos |
TW202304524A (zh) | 2021-04-10 | 2023-02-01 | 美商普方生物製藥美國公司 | Folr1結合劑、其結合物及使用方法 |
AR125344A1 (es) | 2021-04-15 | 2023-07-05 | Chugai Pharmaceutical Co Ltd | Anticuerpo anti-c1s |
KR20230173164A (ko) | 2021-04-19 | 2023-12-26 | 제넨테크, 인크. | 변형된 포유류 세포 |
TW202308699A (zh) | 2021-04-23 | 2023-03-01 | 美商普方生物製藥美國公司 | Cd70結合劑、其結合物及其使用方法 |
JP2024514281A (ja) | 2021-04-23 | 2024-04-01 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Nk細胞係合剤関連の有害作用の防止または軽減 |
CN117321078A (zh) | 2021-04-30 | 2023-12-29 | 豪夫迈·罗氏有限公司 | 针对用抗cd20/抗cd3双特异性抗体和抗cd79b抗体药物缀合物进行组合治疗的给药 |
EP4329800A1 (en) | 2021-04-30 | 2024-03-06 | F. Hoffmann-La Roche AG | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibody |
BR112023022844A2 (pt) | 2021-05-03 | 2024-01-23 | UCB Biopharma SRL | Anticorpos |
KR20240004367A (ko) | 2021-05-07 | 2024-01-11 | 비엘라 바이오, 인크. | 중증근무력증 치료를 위한 항-cd19 항체의 사용 |
US20240279310A1 (en) | 2021-05-07 | 2024-08-22 | Alpine Immune Sciences, Inc. | Methods of dosing and treatment with a taci-fc fusion immunomodulatory protein |
MX2023013264A (es) | 2021-05-12 | 2023-11-30 | Genentech Inc | Metodos para usar inmunoconjugados anti-cd79b para tratar linfoma difuso de linfocitos b grandes. |
CN117396510A (zh) | 2021-05-14 | 2024-01-12 | 基因泰克公司 | Trem2的激动剂 |
US20240239902A1 (en) * | 2021-05-18 | 2024-07-18 | Christian-Albrechts-Universität Zu Kiel | Co-stimulatory multispecific antibodies |
WO2022243261A1 (en) | 2021-05-19 | 2022-11-24 | F. Hoffmann-La Roche Ag | Agonistic cd40 antigen binding molecules targeting cea |
JP2024521107A (ja) | 2021-05-21 | 2024-05-28 | ジェネンテック, インコーポレイテッド | 目的の組換え産物を産生するための修飾細胞 |
TW202306994A (zh) | 2021-06-04 | 2023-02-16 | 日商中外製藥股份有限公司 | 抗ddr2抗體及其用途 |
AU2022289684A1 (en) | 2021-06-09 | 2023-10-05 | F. Hoffmann-La Roche Ag | Combination of a particular braf inhibitor (paradox breaker) and a pd-1 axis binding antagonist for use in the treatment of cancer |
CN114990128A (zh) * | 2021-06-16 | 2022-09-02 | 百奥赛图(北京)医药科技股份有限公司 | Cd20基因人源化非人动物的构建方法及应用 |
US20240279334A1 (en) | 2021-06-17 | 2024-08-22 | Amberstone Biosciences, Inc. | Anti-cd3 constructs and uses thereof |
BR112023023480A2 (pt) | 2021-06-25 | 2024-01-30 | Chugai Pharmaceutical Co Ltd | Uso de anticorpo anti-ctla-4 |
CN117616123A (zh) | 2021-06-25 | 2024-02-27 | 中外制药株式会社 | 抗ctla-4抗体 |
KR20240028452A (ko) | 2021-07-02 | 2024-03-05 | 제넨테크, 인크. | 암을 치료하기 위한 방법 및 조성물 |
TW202320857A (zh) | 2021-07-06 | 2023-06-01 | 美商普方生物製藥美國公司 | 連接子、藥物連接子及其結合物及其使用方法 |
TW202317633A (zh) | 2021-07-08 | 2023-05-01 | 美商舒泰神(加州)生物科技有限公司 | 特異性識別tnfr2的抗體及其用途 |
WO2023288182A1 (en) | 2021-07-12 | 2023-01-19 | Genentech, Inc. | Structures for reducing antibody-lipase binding |
AU2022312698A1 (en) | 2021-07-13 | 2024-01-25 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
JP2024525769A (ja) | 2021-07-14 | 2024-07-12 | 舒泰神(北京)生物製薬股フン有限公司 | Cd40を特異的に認識する抗体およびその使用 |
EP4370553A1 (en) | 2021-07-14 | 2024-05-22 | Genentech, Inc. | Anti-c-c motif chemokine receptor 8 (ccr8) antibodies and methods of use |
AU2022315528A1 (en) | 2021-07-22 | 2023-10-19 | F. Hoffmann-La Roche Ag | Heterodimeric fc domain antibodies |
EP4373576A1 (en) | 2021-07-22 | 2024-05-29 | Genentech, Inc. | Brain targeting compositions and methods of use thereof |
EP4377351A1 (en) | 2021-07-28 | 2024-06-05 | F. Hoffmann-La Roche AG | Methods and compositions for treating cancer |
CN118488964A (zh) | 2021-07-30 | 2024-08-13 | Ona疗法有限公司 | 抗cd36抗体及其治疗癌症的用途 |
CA3231174A1 (en) | 2021-08-02 | 2023-02-09 | Innovent Biologics (Suzhou) Co., Ltd. | Anti-cd79bxcd3 bispecific antibody and use thereof |
EP4380980A1 (en) | 2021-08-03 | 2024-06-12 | F. Hoffmann-La Roche AG | Bispecific antibodies and methods of use |
KR20240046524A (ko) | 2021-08-07 | 2024-04-09 | 제넨테크, 인크. | 미만성 거대 b-세포 림프종을 치료하기 위해 항-cd79b 면역접합체를 사용하는 방법 |
EP4384553A1 (en) | 2021-08-13 | 2024-06-19 | Genentech, Inc. | Dosing for anti-tryptase antibodies |
CN117858905A (zh) | 2021-08-19 | 2024-04-09 | 豪夫迈·罗氏有限公司 | 多价抗变体fc区抗体及使用方法 |
GB202111905D0 (en) | 2021-08-19 | 2021-10-06 | UCB Biopharma SRL | Antibodies |
CN118284623A (zh) | 2021-08-23 | 2024-07-02 | 伊莫尼塔斯治疗公司 | 抗cd161抗体及其用途 |
KR20240049296A (ko) | 2021-08-27 | 2024-04-16 | 제넨테크, 인크. | 타우 병증을 치료하는 방법 |
TW202325727A (zh) | 2021-08-30 | 2023-07-01 | 美商建南德克公司 | 抗聚泛素多特異性抗體 |
CA3232223A1 (en) | 2021-09-17 | 2023-03-23 | Ying Fu | Synthetic humanized llama nanobody library and use thereof to identify sars-cov-2 neutralizing antibodies |
TW202321308A (zh) | 2021-09-30 | 2023-06-01 | 美商建南德克公司 | 使用抗tigit抗體、抗cd38抗體及pd—1軸結合拮抗劑治療血液癌症的方法 |
WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
WO2023058705A1 (ja) | 2021-10-08 | 2023-04-13 | 中外製薬株式会社 | 抗hla-dq2.5抗体の製剤 |
TW202333802A (zh) | 2021-10-11 | 2023-09-01 | 德商拜恩迪克公司 | 用於肺癌之治療性rna(二) |
WO2023076876A1 (en) | 2021-10-26 | 2023-05-04 | Mozart Therapeutics, Inc. | Modulation of immune responses to viral vectors |
WO2023081818A1 (en) | 2021-11-05 | 2023-05-11 | American Diagnostics & Therapy, Llc (Adxrx) | Monoclonal antibodies against carcinoembryonic antigens, and their uses |
EP4430072A1 (en) | 2021-11-10 | 2024-09-18 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
MX2024005876A (es) | 2021-11-16 | 2024-05-29 | Ac Immune Sa | Moleculas novedosas para terapias y diagnostico. |
CA3236006A1 (en) | 2021-11-16 | 2023-05-25 | Genentech, Inc. | Methods and compositions for treating systemic lupus erythematosus (sle) with mosunetuzumab |
WO2023094569A1 (en) | 2021-11-26 | 2023-06-01 | F. Hoffmann-La Roche Ag | Combination therapy of anti-tyrp1/anti-cd3 bispecific antibodies and tyrp1-specific antibodies |
WO2023103788A1 (zh) | 2021-12-06 | 2023-06-15 | 北京三诺佳邑生物技术有限责任公司 | 特异性结合肺炎克雷伯菌o2抗原和o1抗原的双特异性抗体以及组合物 |
AR127887A1 (es) | 2021-12-10 | 2024-03-06 | Hoffmann La Roche | Anticuerpos que se unen a cd3 y plap |
MX2024006925A (es) | 2021-12-15 | 2024-06-20 | Genentech Inc | Polipeptidos de il-18 estabilizados y usos de estos. |
WO2023109900A1 (en) | 2021-12-17 | 2023-06-22 | Shanghai Henlius Biotech, Inc. | Anti-ox40 antibodies, multispecific antibodies and methods of use |
CN118574849A (zh) | 2021-12-17 | 2024-08-30 | 上海复宏汉霖生物技术股份有限公司 | 抗ox40抗体和使用方法 |
AU2022423749A1 (en) | 2021-12-20 | 2024-06-13 | F. Hoffmann-La Roche Ag | Agonistic ltbr antibodies and bispecific antibodies comprising them |
AR128222A1 (es) | 2022-01-07 | 2024-04-10 | Johnson & Johnson Entpr Innovation Inc | MATERIALES Y MÉTODOS DE PROTEÍNAS DE UNIÓN A IL-1b |
WO2023141445A1 (en) | 2022-01-19 | 2023-07-27 | Genentech, Inc. | Anti-notch2 antibodies and conjugates and methods of use |
AU2023217695A1 (en) * | 2022-02-08 | 2024-08-15 | Amgen Inc. | Codon-optimized nucleic acids encoding ocrelizumab |
WO2023154824A1 (en) | 2022-02-10 | 2023-08-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies that broadly target coronaviruses |
AU2023221539A1 (en) | 2022-02-16 | 2024-08-22 | Ac Immune Sa | Humanized anti-tdp-43 binding molecules and uses thereof |
TW202342520A (zh) | 2022-02-18 | 2023-11-01 | 美商樂天醫藥生技股份有限公司 | 抗計畫性死亡配體1(pd—l1)抗體分子、編碼多核苷酸及使用方法 |
WO2023172883A1 (en) | 2022-03-07 | 2023-09-14 | Alpine Immune Sciences, Inc. | Immunomodulatory proteins of variant cd80 polypeptides, cell therapies thereof and related methods and uses |
WO2023173026A1 (en) | 2022-03-10 | 2023-09-14 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates and uses thereof |
WO2023178357A1 (en) | 2022-03-18 | 2023-09-21 | Evolveimmune Therapeutics, Inc. | Bispecific antibody fusion molecules and methods of use thereof |
TW202346365A (zh) | 2022-03-23 | 2023-12-01 | 瑞士商赫孚孟拉羅股份公司 | 抗cd20/抗cd3雙特異性抗體及化學療法之組合治療 |
WO2023179740A1 (en) | 2022-03-25 | 2023-09-28 | Shanghai Henlius Biotech , Inc. | Anti-msln antibodies and methods of use |
WO2023192827A1 (en) | 2022-03-26 | 2023-10-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Bispecific antibodies to hiv-1 env and their use |
WO2023192881A1 (en) | 2022-03-28 | 2023-10-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to hiv-1 env and their use |
WO2023186756A1 (en) | 2022-03-28 | 2023-10-05 | F. Hoffmann-La Roche Ag | Interferon gamma variants and antigen binding molecules comprising these |
WO2023191816A1 (en) | 2022-04-01 | 2023-10-05 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2023194565A1 (en) | 2022-04-08 | 2023-10-12 | Ac Immune Sa | Anti-tdp-43 binding molecules |
TW202404637A (zh) | 2022-04-13 | 2024-02-01 | 瑞士商赫孚孟拉羅股份公司 | 抗cd20/抗cd3雙特異性抗體之醫藥組成物及使用方法 |
US20230406930A1 (en) | 2022-04-13 | 2023-12-21 | Genentech, Inc. | Pharmaceutical compositions of therapeutic proteins and methods of use |
WO2023203177A1 (en) | 2022-04-20 | 2023-10-26 | Kantonsspital St. Gallen | Antibodies or antigen-binding fragments pan-specifically binding to gremlin-1 and gremlin-2 and uses thereof |
WO2023215737A1 (en) | 2022-05-03 | 2023-11-09 | Genentech, Inc. | Anti-ly6e antibodies, immunoconjugates, and uses thereof |
WO2023219613A1 (en) | 2022-05-11 | 2023-11-16 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
AR129268A1 (es) | 2022-05-11 | 2024-08-07 | Hoffmann La Roche | Anticuerpo que se une a vegf-a e il6 y métodos de uso |
WO2023235699A1 (en) | 2022-05-31 | 2023-12-07 | Jounce Therapeutics, Inc. | Antibodies to lilrb4 and uses thereof |
US11814439B1 (en) | 2022-06-01 | 2023-11-14 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
US11965032B1 (en) | 2022-06-01 | 2024-04-23 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
US11807689B1 (en) | 2022-06-01 | 2023-11-07 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
US11884740B1 (en) | 2022-06-01 | 2024-01-30 | Tg Therapeutics, Inc. | Anti-CD20 antibody compositions |
WO2023240058A2 (en) | 2022-06-07 | 2023-12-14 | Genentech, Inc. | Prognostic and therapeutic methods for cancer |
WO2023239803A1 (en) | 2022-06-08 | 2023-12-14 | Angiex, Inc. | Anti-tm4sf1 antibody-drug conjugates comprising cleavable linkers and methods of using same |
WO2023237706A2 (en) | 2022-06-08 | 2023-12-14 | Institute For Research In Biomedicine (Irb) | Cross-specific antibodies, uses and methods for discovery thereof |
WO2024015897A1 (en) | 2022-07-13 | 2024-01-18 | Genentech, Inc. | Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies |
WO2024020407A1 (en) | 2022-07-19 | 2024-01-25 | Staidson Biopharma Inc. | Antibodies specifically recognizing b- and t-lymphocyte attenuator (btla) and uses thereof |
TW202413433A (zh) | 2022-07-19 | 2024-04-01 | 美商建南德克公司 | 用抗fcrh5/抗cd3雙特異性抗體進行治療之給藥 |
TW202417504A (zh) | 2022-07-22 | 2024-05-01 | 美商建南德克公司 | 抗steap1抗原結合分子及其用途 |
WO2024030829A1 (en) | 2022-08-01 | 2024-02-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies that bind to the underside of influenza viral neuraminidase |
WO2024030956A2 (en) | 2022-08-03 | 2024-02-08 | Mozart Therapeutics, Inc. | Cd39-specific binding agents and methods of using the same |
WO2024028731A1 (en) | 2022-08-05 | 2024-02-08 | Janssen Biotech, Inc. | Transferrin receptor binding proteins for treating brain tumors |
WO2024028732A1 (en) | 2022-08-05 | 2024-02-08 | Janssen Biotech, Inc. | Cd98 binding constructs for treating brain tumors |
TW202417034A (zh) | 2022-08-19 | 2024-05-01 | 大陸商億一生物醫藥開發(上海)有限公司 | 包含g—csf之調配物及其用途 |
WO2024044779A2 (en) | 2022-08-26 | 2024-02-29 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for delta-like ligand 3 (dll3) |
WO2024049949A1 (en) | 2022-09-01 | 2024-03-07 | Genentech, Inc. | Therapeutic and diagnostic methods for bladder cancer |
WO2024054822A1 (en) | 2022-09-07 | 2024-03-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Engineered sars-cov-2 antibodies with increased neutralization breadth |
WO2024054929A1 (en) | 2022-09-07 | 2024-03-14 | Dynamicure Biotechnology Llc | Anti-vista constructs and uses thereof |
WO2024064826A1 (en) | 2022-09-22 | 2024-03-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use |
WO2024077018A2 (en) | 2022-10-04 | 2024-04-11 | Alpine Immune Sciences, Inc. | Methods and uses of taci-fc fusion immunomodulatory protein |
TW202421664A (zh) | 2022-10-07 | 2024-06-01 | 美商建南德克公司 | 用抗c—c模體趨化因子受體8(ccr8)抗體治療癌症之方法 |
WO2024091991A1 (en) | 2022-10-25 | 2024-05-02 | Genentech, Inc. | Therapeutic and diagnostic methods for multiple myeloma |
WO2024094741A1 (en) | 2022-11-03 | 2024-05-10 | F. Hoffmann-La Roche Ag | Combination therapy with anti-cd19/anti-cd28 bispecific antibody |
WO2024097741A1 (en) | 2022-11-04 | 2024-05-10 | Gilead Sciences, Inc. | Anticancer therapies using anti-ccr8 antibody, chemo and immunotherapy combinations |
WO2024102734A1 (en) | 2022-11-08 | 2024-05-16 | Genentech, Inc. | Compositions and methods of treating childhood onset idiopathic nephrotic syndrome |
WO2024100200A1 (en) | 2022-11-09 | 2024-05-16 | Cis Pharma Ag | Anti-l1-cam antibodies and their uses for diagnostic and therapeutic applications |
WO2024100170A1 (en) | 2022-11-11 | 2024-05-16 | F. Hoffmann-La Roche Ag | Antibodies binding to hla-a*02/foxp3 |
US20240226313A1 (en) | 2022-11-17 | 2024-07-11 | Sanofi | Ceacam5 antibody-drug conjugates and methods of use thereof |
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 |
WO2024137381A1 (en) | 2022-12-19 | 2024-06-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies for treating sars-cov-2 infection |
WO2024145398A1 (en) | 2022-12-27 | 2024-07-04 | Yale University | Antibody drug conjugates |
WO2024155807A1 (en) | 2023-01-18 | 2024-07-25 | Genentech, Inc. | Multispecific antibodies and uses thereof |
WO2024158824A1 (en) | 2023-01-23 | 2024-08-02 | Yale University | Antibody oligonucleotide conjugates |
WO2024156672A1 (en) | 2023-01-25 | 2024-08-02 | F. Hoffmann-La Roche Ag | Antibodies binding to csf1r and cd3 |
WO2024163009A1 (en) | 2023-01-31 | 2024-08-08 | Genentech, Inc. | Methods and compositions for treating urothelial bladder cancer |
WO2024163494A1 (en) | 2023-01-31 | 2024-08-08 | F. Hoffmann-La Roche Ag | Methods and compositions for treating non-small cell lung cancer and triple-negative breast cancer |
WO2024173607A2 (en) | 2023-02-14 | 2024-08-22 | Evolveimmune Therapeutics, Inc. | Combination of bispecific antibodies and chimeric antigen receptor t cells for treatment |
WO2024170756A1 (en) | 2023-02-17 | 2024-08-22 | Ablynx N.V. | Polypeptides binding to the neonatal fc receptor |
WO2024184494A1 (en) | 2023-03-08 | 2024-09-12 | Ac Immune Sa | Anti-tdp-43 binding molecules and uses thereof |
Family Cites Families (105)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2002128A (en) * | 1934-02-19 | 1935-05-21 | Ray A Reidenbaugh | Display rack |
IL47062A (en) | 1975-04-10 | 1979-07-25 | Yeda Res & Dev | Process for diminishing antigenicity of tissues to be usedas transplants by treatment with glutaraldehyde |
US4665077A (en) | 1979-03-19 | 1987-05-12 | The Upjohn Company | Method for treating rejection of organ or skin grafts with 6-aryl pyrimidine compounds |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
DD266710A3 (de) | 1983-06-06 | 1989-04-12 | Ve Forschungszentrum Biotechnologie | Verfahren zur biotechnischen Herstellung van alkalischer Phosphatase |
US4879231A (en) | 1984-10-30 | 1989-11-07 | Phillips Petroleum Company | Transformation of yeasts of the genus pichia |
US5576195A (en) * | 1985-11-01 | 1996-11-19 | Xoma Corporation | Vectors with pectate lyase signal sequence |
US5618920A (en) * | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
GB8610600D0 (en) | 1986-04-30 | 1986-06-04 | Novo Industri As | Transformation of trichoderma |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
US6893625B1 (en) * | 1986-10-27 | 2005-05-17 | Royalty Pharma Finance Trust | Chimeric antibody with specificity to human B cell surface antigen |
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 |
HUT53672A (en) | 1988-02-25 | 1990-11-28 | Gen Hospital Corp | Quick immunoselective cloning process |
US5506126A (en) * | 1988-02-25 | 1996-04-09 | The General Hospital Corporation | Rapid immunoselection cloning method |
IL85746A (en) | 1988-03-15 | 1994-05-30 | Yeda Res & Dev | Preparations comprising t-lymphocyte cells treated with 8-methoxypsoralen or cell membranes separated therefrom for preventing or treating autoimmune diseases |
US4861579A (en) | 1988-03-17 | 1989-08-29 | American Cyanamid Company | Suppression of B-lymphocytes in mammals by administration of anti-B-lymphocyte antibodies |
FI891226A (fi) | 1988-04-28 | 1989-10-29 | Univ Leland Stanford Junior | Reseptordeterminanter i anti-t-celler foer behandling av autoimmunsjukdom. |
IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
US5530101A (en) * | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
WO1990008187A1 (en) | 1989-01-19 | 1990-07-26 | Dana Farber Cancer Institute | Soluble two domain cd2 protein |
CA2046909A1 (en) | 1989-03-21 | 1990-09-22 | Mark D. Howell | Vaccination and methods against diseases resulting from pathogenic responses by specific t cell populations |
EP0402226A1 (en) | 1989-06-06 | 1990-12-12 | Institut National De La Recherche Agronomique | Transformation vectors for yeast yarrowia |
IL95125A (en) | 1989-07-19 | 1995-07-31 | Vandenbark Arthur Allen | T cell peptides receive a method for their selection and preparation, and pharmaceutical preparations containing them |
US5859205A (en) * | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
AU675916B2 (en) * | 1991-06-14 | 1997-02-27 | Genentech Inc. | Method for making humanized antibodies |
US7018809B1 (en) | 1991-09-19 | 2006-03-28 | Genentech, Inc. | Expression of functional antibody fragments |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
US7744877B2 (en) | 1992-11-13 | 2010-06-29 | Biogen Idec Inc. | Expression and use of anti-CD20 Antibodies |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
NZ258392A (en) * | 1992-11-13 | 1997-09-22 | Idec Pharma Corp | Chimeric and radiolabelled antibodies to the b lymphocyte cellsurface antigen bp35 (cd-20) and their use in the treatment of b cell lymphona |
US5417972A (en) | 1993-08-02 | 1995-05-23 | The Board Of Trustees Of The Leland Stanford Junior University | Method of killing B-cells in a complement independent and an ADCC independent manner using antibodies which specifically bind CDIM |
US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
US5789199A (en) | 1994-11-03 | 1998-08-04 | Genentech, Inc. | Process for bacterial production of polypeptides |
US5840523A (en) | 1995-03-01 | 1998-11-24 | Genetech, Inc. | Methods and compositions for secretion of heterologous polypeptides |
US6267958B1 (en) * | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US20010056066A1 (en) * | 1996-07-26 | 2001-12-27 | Smithkline Beecham Corporation | Method of treating immune cell mediated systemic diseases |
US6306393B1 (en) | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
AU740284B2 (en) | 1997-06-13 | 2001-11-01 | Genentech Inc. | Stabilized antibody formulation |
US6171586B1 (en) * | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
CA2293829C (en) | 1997-06-24 | 2011-06-14 | Genentech, Inc. | Methods and compositions for galactosylated glycoproteins |
US6368596B1 (en) * | 1997-07-08 | 2002-04-09 | Board Of Regents, The University Of Texas System | Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells |
EP1028751B1 (en) | 1997-10-31 | 2008-12-31 | Genentech, Inc. | Methods and compositions comprising glycoprotein glycoforms |
US6528624B1 (en) * | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
US6242195B1 (en) * | 1998-04-02 | 2001-06-05 | Genentech, Inc. | Methods for determining binding of an analyte to a receptor |
US6194551B1 (en) * | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
JP2002510481A (ja) | 1998-04-02 | 2002-04-09 | ジェネンテック・インコーポレーテッド | 抗体変異体及びその断片 |
CN1320044A (zh) * | 1998-08-11 | 2001-10-31 | Idec药物公司 | 包括施用抗-cd20抗体的b-细胞淋巴瘤联合疗法 |
US6224866B1 (en) | 1998-10-07 | 2001-05-01 | Biocrystal Ltd. | Immunotherapy of B cell involvement in progression of solid, nonlymphoid tumors |
MY155913A (en) | 1998-11-09 | 2015-12-15 | Biogen Inc | Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transpants |
ES2543819T3 (es) | 1998-11-09 | 2015-08-24 | Biogen Inc. | Tratamiento de neoplasias hematológicas asociadas con células tumorales circulantes utilizando anticuerpo quimérico dirigido contra CD20 |
PL209786B1 (pl) | 1999-01-15 | 2011-10-31 | Genentech Inc | Przeciwciało zawierające wariant regionu Fc ludzkiej IgG1, przeciwciało wiążące czynnik wzrostu śródbłonka naczyń oraz immunoadhezyna |
US6737056B1 (en) * | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
US6897044B1 (en) | 1999-01-28 | 2005-05-24 | Biogen Idec, Inc. | Production of tetravalent antibodies |
US6383276B1 (en) * | 1999-03-12 | 2002-05-07 | Fuji Photo Film Co., Ltd. | Azomethine compound and oily magenta ink |
EP1642596A3 (en) * | 1999-05-07 | 2006-04-12 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to B cell surface markers |
DE60042785D1 (de) | 1999-06-09 | 2009-10-01 | Immunomedics Inc | Immuntherapie von autoimmunerkrankungen durch die verwendung von b-zell spezifischen antikörpern |
ITMI991299A1 (it) * | 1999-06-11 | 2000-12-11 | Consiglio Nazionale Ricerche | Uso di anticorpi contro antigeni di superficie per il trattamento della malattia trapianto contro ospite |
DE19930748C2 (de) * | 1999-07-02 | 2001-05-17 | Infineon Technologies Ag | Verfahren zur Herstellung von EEPROM- und DRAM-Grabenspeicherzellbereichen auf einem Chip |
PL201086B1 (pl) | 1999-07-12 | 2009-03-31 | Genentech Inc | Zastosowanie przeciwciał wiążących się z antygenem CD20 |
AU784971B2 (en) | 1999-08-11 | 2006-08-10 | Biogen Inc. | Treatment of patients having non-Hodgkins lymphoma with bone marrow involvement with anti-CD20 antibodies |
US6451284B1 (en) | 1999-08-11 | 2002-09-17 | Idec Pharmaceuticals Corporation | Clinical parameters for determining hematologic toxicity prior to radioimmunotheraphy |
US8557244B1 (en) | 1999-08-11 | 2013-10-15 | Biogen Idec Inc. | Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody |
AU6929100A (en) * | 1999-08-23 | 2001-03-19 | Biocrystal Limited | Methods and compositions for immunotherapy of b cell involvement in promotion ofa disease condition comprising multiple sclerosis |
AU2001264612C1 (en) | 1999-11-08 | 2007-11-22 | Biogen Idec Inc. | Treatment of B cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
IL149500A0 (en) * | 1999-11-08 | 2002-11-10 | Idec Pharma Corp | Treatment of b cell malignancies using anti-cd40l antibodies in combination with anti-cd20 antibodies and/or chemotherapeutics and radiotherapy |
US20020006404A1 (en) * | 1999-11-08 | 2002-01-17 | Idec Pharmaceuticals Corporation | Treatment of cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
US20030185796A1 (en) * | 2000-03-24 | 2003-10-02 | Chiron Corporation | Methods of therapy for non-hodgkin's lymphoma |
JP2003528155A (ja) | 2000-03-24 | 2003-09-24 | カイロン コーポレイション | Cd20に対する抗体とインターロイキン−2との組み合わせを用いる非ホジキンリンパ腫の治療方法 |
WO2001074388A1 (en) * | 2000-03-31 | 2001-10-11 | Idec Pharmaceuticals Corporation | Combined use of anti-cytokine antibodies or antagonists and anti-cd20 for the treatment of b cell lymphoma |
KR20020093029A (ko) * | 2000-04-11 | 2002-12-12 | 제넨테크, 인크. | 다가 항체 및 그의 용도 |
AU5914201A (en) | 2000-04-25 | 2001-11-07 | Idec Pharma Corp | Intrathecal administration of rituximab for treatment of central nervous system lymphomas |
EP1299128A2 (en) | 2000-06-20 | 2003-04-09 | Idec Pharmaceuticals Corporation | Cold anti-cd20 antibody/radiolabeled anti-cd22 antibody combination |
PT1296714E (pt) * | 2000-06-22 | 2009-10-15 | Coley Pharm Gmbh | Combinação de cpg e anticorpos dirigidos contra cd19, cd20, cd22 ou cd40 para o tratamento ou prevenção do cancro |
KR20040023565A (ko) * | 2000-09-18 | 2004-03-18 | 아이덱 파마슈티칼즈 코포레이션 | B 세포 고갈/면역조절 항체 조합을 이용한 자가면역질환의 치료를 위한 조합 요법 |
US20020128448A1 (en) * | 2000-10-20 | 2002-09-12 | Idec Pharmaceuticals Corporation | Variant IgG3 Rituxan and therapeutic use thereof |
CA2433353C (en) * | 2000-12-28 | 2017-03-21 | Altus Biologics, Inc. | Crystals of whole antibodies and fragments thereof and methods for making and using them |
MXPA03006771A (es) | 2001-01-29 | 2004-05-05 | Idec Pharma Corp | Anticuerpos modificados y metodos de uso. |
AU2002327164A1 (en) | 2001-01-29 | 2002-12-09 | Idec Pharmaceuticals Corporation | Engineered tetravalent antibodies and methods of use |
US20030103971A1 (en) | 2001-11-09 | 2003-06-05 | Kandasamy Hariharan | Immunoregulatory antibodies and uses thereof |
WO2002079255A1 (en) | 2001-04-02 | 2002-10-10 | Idec Pharmaceuticals Corporation | RECOMBINANT ANTIBODIES COEXPRESSED WITH GnTIII |
EP2359849A1 (en) * | 2001-04-02 | 2011-08-24 | Genentech, Inc. | Combination therapy |
WO2003061694A1 (en) | 2001-05-10 | 2003-07-31 | Seattle Genetics, Inc. | Immunosuppression of the humoral immune response by anti-cd20 antibodies |
EP1404366A4 (en) | 2001-06-14 | 2006-06-07 | Intermune Inc | COMBINED THERAPY USING INTERFERON GAMMA AND SPECIFIC B-CELL ANTIBODIES |
US7321026B2 (en) | 2001-06-27 | 2008-01-22 | Skytech Technology Limited | Framework-patched immunoglobulins |
ATE443259T1 (de) * | 2001-09-20 | 2009-10-15 | Univ Texas | Bestimmung der zirkulierenden therapeutischen antikörper, antigene sowie antigen-antikörper- komplexe mit elisa-tests |
MXPA04003798A (es) * | 2001-10-25 | 2004-07-30 | Genentech Inc | Composiciones de glicoproteina. |
US7127096B2 (en) * | 2001-11-20 | 2006-10-24 | Accuimage Diagnostics Corp. | Method and software for improving coronary calcium scoring consistency |
WO2003049694A2 (en) | 2001-12-07 | 2003-06-19 | Chiron Corporation | Methods of therapy for non-hodgkin's lymphoma |
US20040093621A1 (en) * | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
CN101914158A (zh) * | 2002-02-14 | 2010-12-15 | 免疫医疗公司 | 抗cd 20抗体及其融合蛋白和使用方法 |
US20040002587A1 (en) * | 2002-02-20 | 2004-01-01 | Watkins Jeffry D. | Fc region variants |
US20030180292A1 (en) * | 2002-03-14 | 2003-09-25 | Idec Pharmaceuticals | Treatment of B cell malignancies using anti-CD40L antibodies in combination with anti-CD20 antibodies and/or chemotherapeutics and radiotherapy |
US20030219818A1 (en) * | 2002-05-10 | 2003-11-27 | Bohen Sean P. | Methods and compositions for determining neoplastic disease responsiveness to antibody therapy |
US20050180972A1 (en) | 2002-07-31 | 2005-08-18 | Wahl Alan F. | Anti-CD20 antibody-drug conjugates for the treatment of cancer and immune disorders |
CN101928344B (zh) | 2002-10-17 | 2014-08-13 | 根马布股份公司 | 抗cd20的人单克隆抗体 |
BRPI0316779B1 (pt) * | 2002-12-16 | 2020-04-28 | Genentech Inc | anticorpo humanizado que liga cd20 humano, composição, artigo manufaturado, método de indução da apoptose, método de tratamento de câncer cd20 positivo, métodos de tratamento de doenças autoimunes, ácidos nucléicos isolados, vetores de expressão, células hospedeiras, método para a produção de um anticorpo 2h7 humanizado, polipeptídeo isolado, formulação líquida, método de tratamento de artrite reumatóide (ra) e anticorpos de ligação de cd20 humanizados |
JP2006522811A (ja) * | 2003-04-09 | 2006-10-05 | ジェネンテック・インコーポレーテッド | TNFαインヒビターに対して不十分な反応を示す患者の自己免疫疾患治療法 |
AR044388A1 (es) | 2003-05-20 | 2005-09-07 | Applied Molecular Evolution | Moleculas de union a cd20 |
EP3130349A1 (en) * | 2004-06-04 | 2017-02-15 | Genentech, Inc. | Method for treating multiple sclerosis |
WO2006127517A2 (en) * | 2005-05-20 | 2006-11-30 | Genentech, Inc. | Pretreatment of a biological sample from an autoimmune disease subject |
US8144978B2 (en) * | 2007-08-01 | 2012-03-27 | Tandent Vision Science, Inc. | System and method for identifying complex tokens in an image |
KR101041914B1 (ko) * | 2008-06-26 | 2011-06-15 | 부산대학교 산학협력단 | 셀레늄에 의해 탈분화된 세포, 이의 제조방법 및 이의 용도 |
TW201014605A (en) | 2008-09-16 | 2010-04-16 | Genentech Inc | Methods for treating progressive multiple sclerosis |
-
2003
- 2003-12-16 BR BRPI0316779-8A patent/BRPI0316779B1/pt active IP Right Grant
- 2003-12-16 RU RU2005122448/13A patent/RU2326127C2/ru active IP Right Revival
- 2003-12-16 CN CN201410056459.3A patent/CN103833854B/zh not_active Expired - Lifetime
- 2003-12-16 TW TW092135563A patent/TWI335821B/zh not_active IP Right Cessation
- 2003-12-16 HU HUE10179942A patent/HUE035898T2/en unknown
- 2003-12-16 KR KR1020077009450A patent/KR20070055625A/ko not_active Application Discontinuation
- 2003-12-16 PT PT03813759T patent/PT1572744E/pt unknown
- 2003-12-16 HU HU0500954A patent/HU227217B1/hu unknown
- 2003-12-16 UA UAA200507058A patent/UA89350C2/uk unknown
- 2003-12-16 EP EP08005671A patent/EP1944320A1/en not_active Withdrawn
- 2003-12-16 WO PCT/US2003/040426 patent/WO2004056312A2/en active Application Filing
- 2003-12-16 SI SI200332542T patent/SI2289936T1/sl unknown
- 2003-12-16 SI SI200331856T patent/SI1572744T1/sl unknown
- 2003-12-16 ES ES03813759T patent/ES2347241T3/es not_active Expired - Lifetime
- 2003-12-16 AR ARP030104652A patent/AR042485A1/es active IP Right Grant
- 2003-12-16 EP EP10179942.7A patent/EP2289936B1/en not_active Expired - Lifetime
- 2003-12-16 RS YUP-2005/0467A patent/RS51318B/sr unknown
- 2003-12-16 EP EP10179949A patent/EP2301966A1/en not_active Withdrawn
- 2003-12-16 AT AT03813759T patent/ATE470675T1/de active
- 2003-12-16 AU AU2003301079A patent/AU2003301079C1/en active Active
- 2003-12-16 PL PL377328A patent/PL212899B1/pl unknown
- 2003-12-16 DK DK03813759.2T patent/DK1572744T3/da active
- 2003-12-16 CA CA2507898A patent/CA2507898C/en not_active Expired - Lifetime
- 2003-12-16 EP EP17167520.0A patent/EP3263596A1/en not_active Withdrawn
- 2003-12-16 ES ES10179942.7T patent/ES2633311T3/es not_active Expired - Lifetime
- 2003-12-16 MX MXPA05006511A patent/MXPA05006511A/es active IP Right Grant
- 2003-12-16 BR BRPI0316779A patent/BRPI0316779B8/pt active IP Right Grant
- 2003-12-16 EP EP03813759A patent/EP1572744B1/en not_active Expired - Lifetime
- 2003-12-16 TW TW098128310A patent/TW201000132A/zh unknown
- 2003-12-16 NZ NZ566907A patent/NZ566907A/en not_active IP Right Cessation
- 2003-12-16 DK DK10179942.7T patent/DK2289936T3/en active
- 2003-12-16 DE DE60332957T patent/DE60332957D1/de not_active Expired - Lifetime
- 2003-12-16 SG SG2013036975A patent/SG2013036975A/en unknown
- 2003-12-16 RS RSP-2010/0366A patent/RS20100366A/en unknown
- 2003-12-16 JP JP2005502639A patent/JP4351674B2/ja not_active Expired - Lifetime
-
2005
- 2005-05-24 IL IL168754A patent/IL168754A/en active Protection Beyond IP Right Term
- 2005-06-07 US US11/147,780 patent/US7799900B2/en active Active
- 2005-06-14 CR CR7875A patent/CR7875A/es unknown
- 2005-06-15 KR KR10-2005-7011004A patent/KR100910433B1/ko active IP Right Grant
- 2005-07-11 MA MA28378A patent/MA27704A1/fr unknown
- 2005-07-14 HR HRP20050649AA patent/HRP20050649B1/hr not_active IP Right Cessation
- 2005-07-15 NO NO20053435A patent/NO338402B1/no not_active IP Right Cessation
- 2005-07-26 US US11/190,364 patent/US20060024300A1/en not_active Abandoned
- 2005-09-16 HK HK05108180.8A patent/HK1074208A1/xx not_active IP Right Cessation
-
2008
- 2008-10-22 US US12/256,349 patent/US8562992B2/en active Active
- 2008-11-07 CL CL2008003323A patent/CL2008003323A1/es unknown
- 2008-11-21 JP JP2008297806A patent/JP2009159950A/ja not_active Withdrawn
-
2009
- 2009-07-17 AR ARP090102739A patent/AR072523A2/es unknown
-
2010
- 2010-04-13 CR CR11367A patent/CR11367A/es unknown
- 2010-08-31 CY CY20101100794T patent/CY1110759T1/el unknown
-
2011
- 2011-07-14 IL IL214083A patent/IL214083A0/en unknown
- 2011-10-18 JP JP2011228813A patent/JP5885457B2/ja not_active Expired - Lifetime
-
2013
- 2013-09-17 US US14/029,717 patent/US20140154242A1/en not_active Abandoned
- 2013-10-17 AR ARP130103770A patent/AR093046A2/es unknown
-
2016
- 2016-07-22 US US15/217,838 patent/US20170158773A1/en not_active Abandoned
-
2018
- 2018-02-26 US US15/905,406 patent/US20190071511A1/en not_active Abandoned
- 2018-03-15 CY CY2018009C patent/CY2018009I2/el unknown
- 2018-05-31 BE BE2018C021C patent/BE2018C021I2/nl unknown
- 2018-06-04 FR FR18C1023C patent/FR18C1023I2/fr active Active
- 2018-06-27 HU HUS1800030C patent/HUS1800030I1/hu unknown
- 2018-07-03 HK HK18108517.7A patent/HK1248731A1/zh unknown
-
2021
- 2021-04-20 US US17/235,805 patent/US20220002430A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI335821B (en) | Immunoglobulin variants and uses thereof | |
CN100460421C (zh) | 免疫球蛋白变体及其用途 | |
JP2008529499A (ja) | 抗体変異体とその使用 | |
US20130183288A1 (en) | Non-fucosylated antibodies | |
AU2011226858B2 (en) | Immunoglobulin variants and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
GD4A | Issue of patent certificate for granted invention patent | ||
MK4A | Expiration of patent term of an invention patent |